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US20160199306A1 - Tamper-resistant tablet providing immediate drug release - Google Patents

Tamper-resistant tablet providing immediate drug release Download PDF

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Publication number
US20160199306A1
US20160199306A1 US15/073,920 US201615073920A US2016199306A1 US 20160199306 A1 US20160199306 A1 US 20160199306A1 US 201615073920 A US201615073920 A US 201615073920A US 2016199306 A1 US2016199306 A1 US 2016199306A1
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US
United States
Prior art keywords
particulates
tablet
active compound
pharmacologically active
matrix material
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/073,920
Inventor
Sebastian Schwier
Marcel Haupts
Udo Rüttgers
Lutz BARNSCHEID
Jana Pätz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44951601&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20160199306(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Priority to US15/073,920 priority Critical patent/US20160199306A1/en
Publication of US20160199306A1 publication Critical patent/US20160199306A1/en
Assigned to Grünenthal GmbH reassignment Grünenthal GmbH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAUPTS, MARCEL, RÜTTGERS, Udo, BARNSCHEID, LUTZ, SCHWIER, SEBASTIAN, DENKER, JANA
Priority to US16/117,712 priority patent/US20180369149A1/en
Priority to US16/416,532 priority patent/US10695297B2/en
Abandoned legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/26Psychostimulants, e.g. nicotine, cocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36Opioid-abuse

Definitions

  • the invention relates to tamper-resistant tablets comprising a matrix material and a plurality of particulates which comprise a pharmacologically active compound and form a discontinuous phase within the matrix material.
  • a large number of pharmacologically active substances have a potential for being abused or misused, i.e. they can be used to produce effects which are not consistent with their intended use.
  • opioids which exhibit an excellent efficacy in controlling severe to extremely severe pain, are frequently abused to induce euphoric states similar to being intoxicated.
  • active substances which have a psychotropic effect are abused accordingly.
  • the corresponding dosage forms such as tablets or capsules are crushed, for example ground by the abuser, the active substance is extracted from the thus obtained powder using a preferably aqueous liquid and after being optionally filtered through cotton wool or cellulose wadding, the resultant solution is administered parenterally, in particular intravenously.
  • This type of dosage results in an even faster diffusion of the active substance compared to the oral abuse, with the result desired by the abuser, namely the kick.
  • This kick or these intoxication-like, euphoric states are also reached if the powdered dosage form is administered nasally, i.e. is sniffed.
  • Another concept to prevent abuse relies on the mechanical properties of the pharmaceutical dosage forms, particularly an increased breaking strength (resistance to crushing).
  • the major advantage of such pharmaceutical dosage forms is that comminuting, particularly pulverization, by conventional means, such as grinding in a mortar or fracturing by means of a hammer, is impossible or at least substantially impeded.
  • the pulverization, necessary for abuse, of the dosage forms by the means usually available to a potential abuser is prevented or at least complicated.
  • Such pharmaceutical dosage forms are useful for avoiding drug abuse of the pharmacologically active compound contained therein, as they may not be powdered by conventional means and thus, cannot be administered in powdered form, e.g. nasally.
  • the mechanical properties, particularly the high breaking strength of these pharmaceutical dosage forms renders them tamper-resistant.
  • tamper-resistant pharmaceutical dosage forms it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099, and WO2009/092601.
  • dosage forms secured against abuse are distinguished by a controlled, preferably retarded release of the active substance which has abuse potential.
  • a rapid release of the active substance is necessary for numerous therapeutic applications, for example pain relief using active substances with abuse potential.
  • WO 2010/140007 discloses dosage forms comprising melt-extruded particulates comprising a drug, wherein said melt-extruded particulates are present as a discontinuous phase in a matrix.
  • the dosage forms provide prolonged release of the drug.
  • WO 2008/107149 discloses multiparticulate dosage forms with impeded abuse containing, one or more active substances having abuse potential, at least one synthetic or natural polymer, and at least one disintegrant, with the individual particles of the tablet having a breaking strength of at least 500 N and a release of the active substance of at least 75% after 45 minutes.
  • the exemplified capsules provide rapid release of the pharmacologically active compound.
  • US 2010/0092553 discloses solid multiparticulate oral pharmaceutical forms whose composition and structure make it possible to avoid misuse.
  • the microparticles have an extremely thick coating layer which assures the modified release of the drug and simultaneously imparts crushing resistance to the coated microparticles so as to avoid misuse.
  • WO 2008/033523 discloses a pharmaceutical composition that may include a granulate which may at least include one active pharmaceutical ingredient susceptible to abuse.
  • the particle contains both an alcohol soluble and alcohol insoluble and at least partially water soluble material. Both materials are granulated in the presence of alcohol and water.
  • the granulate may also include a coating on the granulate exhibiting crush resistance. Material deposition on the granule is performed using an alcohol based solvent.
  • capsules are not satisfactory in every respect, e.g. with respect to disintegration time, patient compliance (e.g. swallowability) and ease of manufacture. Further, capsules frequently contain gelatine thus causing the risk of bovine spongiform encephalopathy (BSE, or TSE). As far as tamper-resistant dosage forms are concerned, capsules are disadvantageous as they can typically be opened easily thereby releasing the ingredients in powdery or particulate form without requiring any mechanical impact. If components of different type are contained in a capsule, e.g. drug-containing particles besides drug-free particles, a potential abuser might be able to visually distinguish the intact, undisrupted components of different type (e.g. according to their color, size or other macroscopic properties) allowing for manual separation.
  • BSE bovine spongiform encephalopathy
  • tamper-resistant dosage forms that possess crush resistance and release the pharmacologically active compound as quick as possible (immediate release), i.e. should show a gradual increase reaching 85% to 100% at about 30 to 45 minutes or earlier.
  • the dosage form should advantageously be of a shape, size and weight that can be taken orally with ease. Of course, the dosage form should also be easy to make in a cost effective manner.
  • the liquid part of the formulation that can be separated from the remainder by means of a syringe should be as less as possible, e.g. should contain not more than 20 wt.-% of the pharmacologically active compound originally contained in the dosage form.
  • the invention relates to a tamper-resistant tablet, preferably for oral administration, comprising
  • the in vitro release profile of tamper-resistant dosage forms can be accelerated by embedding particulates containing the pharmacologically active compound in a matrix material and increasing the relative weight ratio of the matrix material to the particulates.
  • mixtures of matrix material can be mixed with the particulates and subsequently be compacted to tablets which in turn exhibit excellent, i.e. accelerated disintegration times and in vitro release characteristics.
  • oral dosage forms can be designed that provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • FIG. 1 schematically illustrates a preferred embodiment of the tablets according to the invention.
  • FIG. 2 schematically illustrates another preferred embodiment of the tablets according to the invention.
  • FIG. 3 shows in vitro release profiles of different tablets according to the invention having different compositions and particulate sizes.
  • FIG. 4 shows in vitro release profiles of different tablets according to the invention having different compositions.
  • FIG. 5 illustrates the behavior of the particulates contained in the tablets according to the invention when being subjected to a breaking strength test, in particular their deformability.
  • FIG. 6 illustrates the behavior of conventional particulates when being subjected to a breaking strength test.
  • FIG. 7 shows the distance-force-diagram obtained by measuring the mechanical properties of conventional particulates.
  • FIG. 8 shows the distance-force-diagram obtained by measuring the mechanical properties of particulates according to the invention.
  • FIG. 9 shows the distance-force-diagram obtained by measuring the mechanical properties of particulates according to the invention.
  • tablette refers to a pharmaceutical entity that is comprised of a pharmacologically active compound and which is actually administered to, or taken by, a patient. It may be compressed or molded in its manufacture, and it may be of almost any size, shape, weight, and color. Most tablets are intended to be swallowed whole and accordingly, preferred tablets according to the invention are designed for oral administration. However, alternatively tablets may be dissolved in the mouth, chewed, or dissolved in liquid before swallowing, and some may be placed in a body cavity. Thus, the tablet according to the invention may alternatively be adapted for buccal, lingual, rectal or vaginal administration. Implants are also possible.
  • the tablet according to the invention preferably can be regarded as a MUPS formulation (multiple unit pellet system).
  • the tablet according to the invention is monolithic.
  • the tablet according to the invention is not monolithic.
  • monolithic preferably means that the tablet is formed or composed of material without joints or seams or consists of or constitutes a single unit.
  • the tablet according to the invention contains all ingredients in a dense compact unit which in comparison to capsules has a comparatively high density.
  • the tablets according to the invention comprise subunits having different morphology and properties, namely drug-containing particulates and matrix material, wherein the particulates form a discontinuous phase within the matrix material.
  • the particulates typically have mechanical properties that differ from the mechanical properties of the matrix material.
  • the particulates Preferably, have a higher mechanical strength than the matrix material.
  • the particulates within the tablets according to the invention can be visualized by conventional means such as solid state nuclear magnetic resonance spectroscopy, raster electron microscopy, terahertz spectroscopy and the like.
  • An advantage of the tablets according to the invention is that the same particulates may be mixed with matrix material in different amounts to thereby produce tablets of different strengths.
  • the tablet according to the invention has preferably a total weight in the range of 0.01 to 1.5 g, more preferably in the range of 0.05 to 1.2 g, still more preferably in the range of 0.1 g to 1.0 g, yet more preferably in the range of 0.2 g to 0.9 g, and most preferably in the range of 0.3 g to 0.8 g.
  • the total tablet weight is within the range of 500 ⁇ 450 mg, more preferably 500 ⁇ 300 mg, still more preferably 500 ⁇ 200 mg, yet more preferably 500 ⁇ 150 mg, most preferably 500 ⁇ 100 mg, and in particular 500 ⁇ 50 mg.
  • the total tablet weight which is a function of the total size of the tablet, can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • the tablet according to the invention is a round tablet.
  • Tablets of this embodiment preferably have a diameter in the range of about 1 mm to about 30 mm, in particular in the range of about 2 mm to about 25 mm, more in particular about 5 mm to about 23 mm, even more in particular about 7 mm to about 13 mm; and a thickness in the range of about 1.0 mm to about 12 mm, in particular in the range of about 2.0 mm to about 10 mm, even more in particular from 3.0 mm to about 9.0 mm, even further in particular from about 4.0 mm to about 8.0 mm.
  • the tablet according to the invention is an oblong tablet.
  • Tablets of this embodiment preferably have a lengthwise extension (longitudinal extension) of about 1 mm to about 30 mm, in particular in the range of about 2 mm to about 25 mm, more in particular about 5 mm to about 23 mm, even more in particular about 7 mm to about 20 mm; a width in the range of about 1 mm to about 30 mm, in particular in the range of about 2 mm to about 25 mm, more in particular about 5 mm to about 23 mm, even more in particular about 7 mm to about 13 mm; and a thickness in the range of about 1.0 mm to about 12 mm, in particular in the range of about 2.0 mm to about 10 mm, even more in particular from 3.0 mm to about 9.0 mm, even further in particular from about 4.0 mm to about 8.0 mm.
  • the tablets according to the invention can optionally be provided, partially or completely, with a conventional coating.
  • the tablets according to the invention are preferably film coated with conventional film coating compositions. Suitable coating materials are commercially available, e.g. under the trademarks Opadry® and Eudragit®.
  • suitable materials include cellulose esters and cellulose ethers, such as methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), poly(meth)acrylates, such as aminoalkylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers; vinyl polymers, such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinylacetate; and natural film formers.
  • MC methylcellulose
  • HPMC hydroxypropylmethylcellulose
  • HPC hydroxypropylcellulose
  • HEC hydroxyethylcellulose
  • Na-CMC sodium carboxymethylcellulose
  • poly(meth)acrylates such as aminoalkylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers, methacrylic acid methylmeth
  • the coating is water-soluble.
  • the coating is based on polyvinyl alcohol, such as polyvinyl alcohol-part, hydrolyzed, and may additionally contain polyethylene glycol, such as macrogol 3350, and/or pigments.
  • the coating is based on hydroxypropylmethylcellulose, preferably hypromellose type 2910 having a viscosity of 3 to 15 mPas.
  • the coating can be resistant to gastric juices and dissolve as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the tablet according to the invention passes through the stomach undissolved and the active compound is only released in the intestines.
  • the coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5.
  • the coating can also be applied e.g. to improve the aesthetic impression and/or the taste of the tablets and the ease with which they can be swallowed. Coating the tablets according to the invention can also serve other purposes, e.g. improving stability and shelf-life.
  • Suitable coating formulations comprise a film forming polymer such as, for example, polyvinyl alcohol or hydroxypropyl methylcellulose, e.g. hypromellose, a plasticizer such as, for example, a glycol, e.g. propylene glycol or polyethylene glycol, an opacifier, such as, for example, titanium dioxide, and a film smoothener, such as, for example, talc.
  • Suitable coating solvents are water as well as organic solvents.
  • Coated tablets according to the invention are preferably prepared by first making the cores and subsequently coating said cores using conventional techniques, such as coating in a coating pan.
  • the term “tamper-resistant” refers to tablets that are resistant to conversion into a form suitable for misuse or abuse, particular for nasal and/or intravenous administration, by conventional means such as grinding in a mortar or crushing by means of a hammer.
  • the tablets as such may be crushable by conventional means.
  • the particulates contained in the tablets according to the invention exhibit mechanical properties such that they cannot be pulverized by conventional means any further. As the particulates are of macroscopic size and contain the pharmacologically active compound, they cannot be administered nasally thereby rendering the tablets tamper-resistant.
  • the liquid part of the formulation that can be separated from the remainder by means of a syringe is as less as possible, preferably it contains not more than 20 wt.-%, more preferably not more than 15 wt.-%, still more preferably not more than 10 wt.-%, and most preferably not more than 5 wt.-% of the originally contained pharmacologically active compound.
  • this property is tested by (i) dispensing a tablet that is either intact or has been manually comminuted by means of two spoons in 5 ml of purified water, (ii) heating the liquid up to its boiling point, (iii) boiling the liquid in a covered vessel for 5 min without the addition of further purified water, (iv) drawing up the hot liquid into a syringe (needle 21 G equipped with a cigarette filter), (v) determining the amount of the pharmacologically active compound contained in the liquid within the syringe.
  • the particulates tend to adhere to one another thereby forming aggregates and agglomerates, respectively, which are larger in size than the untreated particulates.
  • the subjects to which the tablets according to the invention can be administered are not particularly limited.
  • the subjects are animals, more preferably human beings.
  • the particulates are incorporated into a matrix material.
  • the matrix material preferably forms a continuous phase in which the particulates are embedded as discontinuous phase.
  • the matrix material is a homogenous coherent mass, preferably a homogeneous mixture of solid constituents, in which the particulates are embedded thereby spatially separating the particulates from one another. While it is possible that the surfaces of particulates are in contact or at least in very close proximity with one another, the plurality of particulates preferably cannot be regarded as a single continuous coherent mass within the tablet.
  • the tablet according to the invention comprises the particulates as volume element(s) of a first type in which the pharmacologically active compound and the polyalkylene oxide are contained, preferably homogeneously, and the matrix material as volume element of a second type differing from the material that forms the particulates, preferably containing neither pharmacologically active compound nor polyalkylene oxide, but optionally polyethylene glycol which differs from polyethylene oxide in its molecular weight.
  • a purpose of the matrix material in the tablet according to the invention is to ensure rapid disintegration and subsequent release of the pharmacologically active compound from the disintegrated tablets, i.e. from the particulates.
  • the matrix material preferably does not contain any excipient that might have a retardant effect on disintegration and drug release, respectively.
  • the matrix material preferably does not contain any polymer that is typically employed as matrix material in prolonged release formulations.
  • FIG. 1 schematically illustrates a preferred embodiment of the tablet according to the invention.
  • Tablet ( 1 ) contains a plurality of particulates ( 2 ) that form a discontinuous phase within matrix material ( 3 ) which in turn forms a continuous phase.
  • the tamper-resistant tablet according to the invention comprises the matrix material in an amount of more than one third of the total weight of the tablet.
  • the content of the matrix material in the tablet can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • the content of the matrix material is at least 35 wt.-%, at least 37.5 wt.-% or at least 40 wt.-%; more preferably at least 42.5 wt.-%, at least 45 wt.-%, at least 47.5 wt.-% or at least 50 wt.-%; still more preferably at least 52.5 wt.-%, at least 55 wt.-%, at least 57.5 wt.-% or at least 60 wt.-%; yet more preferably at least 62.5 wt.-%, at least 65 wt.-%, at least 67.5 wt.-% or at least 60 wt.-%; most preferably at least 72.5 wt.-%, at least 75 wt.-%, at least 77.5 wt.-% or at least 70 wt.-%; and in particular at least 82.5 wt.-%, at least 85 wt.-%, at least 87.5 wt
  • the content of the matrix material is at most 90 wt.-%, at most 87.5 wt.-%, at most 85 wt.-%, or at most 82.5 wt.-%; more preferably at most 80 wt.-%, at most 77.5 wt.-%, at most 75 wt.-% or at most 72.5 wt.-%; still more preferably at most 70 wt.-%, at most 67.5 wt.-%, at most 65 wt.-% or at most 62.5 wt.-%; yet more preferably at most 60 wt.-%, at most 57.5 wt.-%, at most 55 wt.-% or at most 52.5 wt.-%; most preferably at most 50 wt.-%, at most 47.5 wt.-%, at most 45 wt.-% or at most 42.5 wt.-%; and in particular at most 40 wt.-%, at most 37.5 w
  • the content of the matrix material is within the range of 40 ⁇ 5 wt.-%, more preferably 40 ⁇ 2.5 wt.-%, based on the total weight of the tablet. In another preferred embodiment, the content of the matrix material is within the range of 45 ⁇ 10 wt.-%, more preferably 45 ⁇ 7.5 wt.-%, still more preferably 45 ⁇ 5 wt.-%, and most preferably 45 ⁇ 2.5 wt.-%, based on the total weight of the tablet.
  • the content of the matrix material is within the range of 50 ⁇ 10 wt.-%, more preferably 50 ⁇ 7.5 wt.-%, still more preferably 50 ⁇ 5 wt.-%, and most preferably 50 ⁇ 2.5 wt.-%, based on the total weight of the tablet. In yet another preferred embodiment, the content of the matrix material is within the range of 55 ⁇ 10 wt.-%, more preferably 55 ⁇ 7.5 wt.-%, still more preferably 55 ⁇ 5 wt.-%, and most preferably 55 ⁇ 2.5 wt.-%, based on the total weight of the tablet.
  • the matrix material is a mixture, preferably a homogeneous mixture of at least two different constituents, more preferably of at least three different constituents.
  • all constituents of the matrix material are homogeneously distributed in the continuous phase that is formed by the matrix material.
  • the mixture of all constituents of the matrix material is blended and employed as a powder, i.e. in non-pre-compacted form, subsequently mixed with the particulates that contain the pharmacologically active compound and the polyalkylene oxide, and then compressed into tablets.
  • Tablets having acceptance values between about 5 and 6 according to Ph. Eur. 2.9.40 “Uniformity of Dosage Units” (UDU) can be obtained when properly adjusting the tablet press. Vibrations should be avoided to a maximal extent (e.g. by decoupling of hopper and tablet press) and clearance of equipment parts should be as small as possible.
  • IMA S250 for example, on a rotary tablet press IMA S250 plus with 26 stations, the following parameters are suitable: round punches 10 mm diameter, radius of curvature 8 mm without debossing; fill curve 13 mm; tablet weight 500 mg; speed: 13700-13800 tablets per hour; pre compression force 4.7 kN; main compression force 6.7 kN and 8.7 kN; fill depth 14.5 mm and 15 mm; height of tablet bar (pre compression): 3.5 mm; height of tablet bar (main compression): 3.3 mm and 3.1 mm; revolution speed of feeder (Filomat): 40 rmp.
  • the matrix material is also provided in particulate form, i.e. in the course of the manufacture of the tablets according to the invention, the constituents of the matrix material are preferably processed into particulates, subsequently mixed with the particulates that contain the pharmacologically active compound and the polyalkylene oxide, and then compressed into the tablets.
  • the average size of the particulates of the matrix material is within the range of ⁇ 60%, more preferably ⁇ 50%, still more preferably ⁇ 40%, yet more preferably ⁇ 30%, most preferably ⁇ 20%, and in particular ⁇ 10% of the average size of the particulates that contain the pharmacologically active compound and the polyalkylene oxide.
  • the tablets according to the invention are manufactured from comparatively large particulates and optionally, also from comparatively large pre-compacted particulates of matrix material.
  • the AV (acceptance value) concerning the content uniformity of the tablets according to the invention is at most 15, more preferably at most 14, still more preferably at most 13, yet more preferably at most 12, even more preferably at most 11, most preferably at most 10 and in particular at most 9.
  • Methods to determine the AV are known to the skilled artisan.
  • the AV is determined in accordance with Eur. Ph.
  • Tablet ( 1 ) contains a plurality of particulates ( 2 ) that form a discontinuous phase within matrix material ( 3 ) which in turn forms a continuous phase and is also provided in particulate form, the individual particulates being in intimate contact with one another at boundaries ( 4 ).
  • the particulates of the matrix material typically have a mechanical strength lower than that of the particulates ( 2 )
  • the particulates of the matrix material are deformed in the course of the manufacture of the tablets by compression.
  • the particulates of the matrix material can be manufactured by conventional methods for the preparation of aggregates and agglomerates from powder mixtures such as granulating and compacting.
  • the mixture of all constituents of the matrix material is blended and pre-compacted thereby yielding a pre-compacted matrix material.
  • pre-compaction proceeds by dry granulation, preferably slugging or roller compaction.
  • the process parameters are typically to be adjusted in order to achieve the desired properties (see below).
  • Typical process parameters are compaction force (preferably adjusted within the range of 2 to 12 kN), roller displacement (preferably adjusted within the range of 2 to 5 mm) and granule sieve (preferably adjusted within the range of 1.0 to 2.0 mm).
  • the desired properties of the pre-compacted material include primarily the particle size and the content of fine particles. The density may also play a role.
  • the particle size is preferably within the range for the size of the particulates (preferably at least 60%>700 ⁇ m for particulates having dimensions of 0.8 ⁇ 0.8 mm).
  • the content of fine particles i.e. particles having a size of less than 600 ⁇ m
  • the mixture of all constituents of the matrix material is dry granulated thereby yielding a granulated matrix material.
  • the mixture of all constituents of the matrix material is wet granulated by means of a non-aqueous solvent e.g. ethanol thereby yielding another granulated matrix material. Aqueous granulation, however, is preferably avoided, as this typically has a detrimental influence on disintegration of the tablet.
  • the mixture of all constituents of the matrix material is melt granulated, e.g. by means of an extruder, a heatable high-shear mixer or a granulator.
  • the matrix material in the tablet according to the invention should ensure rapid disintegration and subsequent release of the pharmacologically active compound from the disintegrated tablets, i.e. from the particulates.
  • the matrix material preferably does not contain any excipient that might have a retardant effect on disintegration and drug release, respectively. Further, the matrix material preferably does not contain any pharmacologically active compound.
  • the matrix material comprises a disintegrant.
  • Suitable disintegrants are known to the skilled person and are preferably selected from the group consisting of crosslinked sodium carboxymethylcellulose (Na-CMC) (e.g. Crosscarmellose, Ac-Di-Sol®), crosslinked casein (e.g. Esma-Sprene), polysaccharide mixtures obtained from soybeans (e.g. Emcosoy®); pretreated maize starch (e.g. Amijel®); sodium alginate; polyvinylpyrrolidone (PVP) (e.g. Kollidone®, Polyplasdone®, Polydone®); crosslinked polyvinylpyrrolidone (PVP Cl) (e.g.
  • Na-CMC crosslinked sodium carboxymethylcellulose
  • PVP polyvinylpyrrolidone
  • PVP Cl crosslinked polyvinylpyrrolidone
  • Polyplasdone® XL starch and pretreated starch such as sodium carboxymethyl starch (e.g. Explotab®, Prejel®, Primotab® ET, Starch® 1500, Ulmatryl®).
  • Crosslinked polymers are particularly preferred disintegrants, especially crosslinked sodium carboxymethylcellulose (Na-CMC) or crosslinked polyvinylpyrrolidone (PVP Cl).
  • the disintegrant is contained in the matrix material but not in the particulates of the tablet according to the invention.
  • the content of the disintegrant in the matrix material is within the range of 5 ⁇ 4 wt.-%, more preferably 5 ⁇ 3 wt.-%, still more preferably 5 ⁇ 2.5 wt.-%, yet more preferably 5 ⁇ 2 wt.-%, most preferably 5 ⁇ 1.5 wt.-%, and in particular 5 ⁇ 1 wt.-%, based on the total weight of matrix material.
  • the content of the disintegrant in the matrix material is within the range of 7.5 ⁇ 4 wt.-%, more preferably 7.5 ⁇ 3 wt.-%, still more preferably 7.5 ⁇ 2.5 wt.-%, yet more preferably 7.5 ⁇ 2 wt.-%, most preferably 7.5 ⁇ 1.5 wt.-%, and in particular 7.5 ⁇ 1 wt.-%, based on the total weight of matrix material.
  • the content of the disintegrant in the matrix material is within the range of 10 ⁇ 4 wt.-%, more preferably 10 ⁇ 3 wt.-%, still more preferably 10 ⁇ 2.5 wt.-%, yet more preferably 10 ⁇ 2 wt.-%, most preferably 10 ⁇ 1.5 wt.-%, and in particular 10 ⁇ 1 wt.-%, based on the total weight of matrix material.
  • the content of the disintegrant in the matrix material is within the range of 12.5 ⁇ 4 wt.-%, more preferably 12.5 ⁇ 3 wt.-%, still more preferably 12.5 ⁇ 2.5 wt.-%, yet more preferably 12.5 ⁇ 2 wt.-%, most preferably 12.5 ⁇ 1.5 wt.-%, and in particular 12.5 ⁇ 1 wt.-%, based on the total weight of matrix material.
  • the content of the disintegrant in the tablet is within the range of 2 ⁇ 1.8 wt.-%, more preferably 2 ⁇ 1.5 wt.-%, still more preferably 2 ⁇ 1.3 wt.-%, yet more preferably 2 ⁇ 1.0 wt.-%, most preferably 2 ⁇ 0.8 wt.-%, and in particular 2 ⁇ 0.5 wt.-%, based on the total weight of tablet.
  • the content of the disintegrant in the tablet is within the range of 4 ⁇ 1.8 wt.-%, more preferably 4 ⁇ 1.5 wt.-%, still more preferably 4 ⁇ 1.3 wt.-%, yet more preferably 4 ⁇ 1.0 wt.-%, most preferably 4 ⁇ 0.8 wt.-%, and in particular 4 ⁇ 0.5 wt.-%, based on the total weight of tablet.
  • the content of the disintegrant in the tablet is within the range of 6 ⁇ 1.8 wt.-%, more preferably 6 ⁇ 1.5 wt.-%, still more preferably 6 ⁇ 1.3 wt.-%, yet more preferably 6 ⁇ 1.0 wt.-%, most preferably 6 ⁇ 0.8 wt.-%, and in particular 6 ⁇ 0.5 wt.-%, based on the total weight of tablet.
  • the content of the disintegrant in the tablet is within the range of 8 ⁇ 1.8 wt.-%, more preferably 8 ⁇ 1.5 wt.-%, still more preferably 8 ⁇ 1.3 wt.-%, yet more preferably 8 ⁇ 1.0 wt.-%, most preferably 8 ⁇ 0.8 wt.-%, and in particular 8 ⁇ 0.5 wt.-%, based on the total weight of tablet.
  • the matrix material comprises a disintegrant in combination with one or more water insoluble pharmaceutical excipients, preferably fillers/binders and/or lubricants.
  • the matrix material comprises a filler or a binder.
  • fillers can be regarded as binders and vice versa, for the purpose of the specification “filler/binder” refers to any excipient that is suitable as filler, binder or both.
  • the matrix material preferably comprises a filler/binder.
  • fillers are selected from the group consisting of silicium dioxide (e.g. Aerosil®), microcrystalline cellulose (e.g. Avicel®, Elcema®, Emocel®, ExCel®, Vitacell®); cellulose ether (e.g. Natrosol®, Klucel®, Methocel®, Blanose®, Pharmacoat®, Viscontran®); mannitol; dextrines; dextrose; calciumhydrogen phosphate (e.g. Emcompress®); maltodextrine (e.g. Emdex®); lactose (e.g.
  • silicium dioxide e.g. Aerosil®
  • microcrystalline cellulose e.g. Avicel®, Elcema®, Emocel®, ExCel®, Vitacell®
  • cellulose ether e.g. Natrosol®, Klucel®, Methocel®, Blanose®, Pharmacoat®, Viscontran®
  • mannitol dextrines
  • PVP polyvinylpyrrolidone
  • saccharose e.g. Nu-Tab®, Sugar Tab®
  • magnesium salts e.g. MgCO 3 , MgO, MgSiO 3
  • starches and pretreated starches e.g. Prejel®, Primotab® ET, Starch® 1500.
  • the matrix material comprises a glidant such as silicium dioxide.
  • the content of the filler/binder or mixture of fillers/binders in the matrix material is within the range of 50 ⁇ 25 wt.-%, more preferably 50 ⁇ 20 wt.-%, still more preferably 50 ⁇ 15 wt.-%, yet more preferably 50 ⁇ 10 wt.-%, most preferably 50 ⁇ 7.5 wt.-%, and in particular 50 ⁇ 5 wt.-%, based on the total weight of matrix material.
  • the content of the filler/binder or mixture of fillers/binders in the matrix material is within the range of 65 ⁇ 25 wt.-%, more preferably 65 ⁇ 20 wt.-%, still more preferably 65 ⁇ 15 wt.-%, yet more preferably 65 ⁇ 10 wt.-%, most preferably 65 ⁇ 7.5 wt.-%, and in particular 65 ⁇ 5 wt.-%, based on the total weight of matrix material.
  • the content of the filler/binder or mixture of fillers/binders in the matrix material is within the range of 80 ⁇ 19 wt.-%, more preferably 80 ⁇ 17.5 wt.-%, still more preferably 80 ⁇ 15 wt.-%, yet more preferably 80 ⁇ 10 wt.-%, most preferably 80 ⁇ 7.5 wt.-%, and in particular 80 ⁇ 5 wt.-%, based on the total weight of matrix material.
  • the content of the filler/binder or mixture of fillers/binders in the matrix material is within the range of 90 ⁇ 9 wt.-%, more preferably 90 ⁇ 8 wt.-%, still more preferably 90 ⁇ 7 wt.-%, yet more preferably 90 ⁇ 6 wt.-%, most preferably 90 ⁇ 5 wt.-%, and in particular 90 ⁇ 4 wt.-%, based on the total weight of matrix material.
  • the content of the filler/binder or mixture of fillers/binders in the tablet is within the range of 25 ⁇ 24 wt.-%, more preferably 25 ⁇ 20 wt.-%, still more preferably 25 ⁇ 16 wt.-%, yet more preferably 25 ⁇ 12 wt.-%, most preferably 25 ⁇ 8 wt.-%, and in particular 25 ⁇ 4 wt.-%, based on the total weight of tablet.
  • the content of the filler/binder or mixture of fillers/binders in the tablet is within the range of 30 ⁇ 29 wt.-%, more preferably 30 ⁇ 25 wt.-%, still more preferably 30 ⁇ 20 wt.-%, yet more preferably 30 ⁇ 15 wt.-%, most preferably 30 ⁇ 10 wt.-%, and in particular 30 ⁇ 5 wt.-%, based on the total weight of tablet.
  • the content of the filler/binder or mixture of fillers/binders in the tablet is within the range of 35 ⁇ 34 wt.-%, more preferably 35 ⁇ 28 wt.-%, still more preferably 35 ⁇ 22 wt.-%, yet more preferably 35 ⁇ 16 wt.-%, most preferably 35 ⁇ 10 wt.-%, and in particular 35 ⁇ 4 wt.-%, based on the total weight of tablet.
  • the content of the filler/binder or mixture of fillers/binders in the tablet is within the range of 40 ⁇ 39 wt.-%, more preferably 40 ⁇ 32 wt.-%, still more preferably 40 ⁇ 25 wt.-%, yet more preferably 40 ⁇ 18 wt.-%, most preferably 40 ⁇ 11 wt.-%, and in particular 40 ⁇ 4 wt.-%, based on the total weight of tablet.
  • the filler/binder is contained in the matrix material but not in the particulates of the tablet according to the invention.
  • a portion (e.g. 10% of the total tablet mass) of the matrix is granulated on the particulates (preferably by non-aqueous wet granulation, e.g. with isopropylic alcohol) and the remaining matrix material is added to the thus granulated particulates and blended prior to compression/processing to tablets.
  • the particulates are coated by a portion of the matrix material, whereas the remainder of the matrix material is preferably employed in non-granulated form.
  • the matrix material comprises a diluent or lubricant, preferably selected from the group consisting of calcium stearate; magnesium stearate; glycerol monobehenate (e.g. Compritol®); Myvatex®; Precirol®; Precirol® Ato5; sodium stearylfumarate (e.g. Pruv®); and talcum.
  • a diluent or lubricant preferably selected from the group consisting of calcium stearate; magnesium stearate; glycerol monobehenate (e.g. Compritol®); Myvatex®; Precirol®; Precirol® Ato5; sodium stearylfumarate (e.g. Pruv®); and talcum.
  • Magnesium stearate is particularly preferred.
  • the content of the lubricant in the matrix material is at most 10.0 wt.-%, more preferably at most 7.5 wt.-%, still more preferably at most 5.0 wt.-%, yet more preferably at most 2.0 wt.-%, even more preferably at most 1.0 wt.-%, and most preferably at most 0.5 wt.-%, based on the total weight of the matrix material and based on the total weight of tablet.
  • the matrix material comprises a combination of disintegrant, filler/binder and lubricant.
  • disintegrant 11 ⁇ 10 11 ⁇ 7.5 11 ⁇ 5.0 11 ⁇ 3.5 11 ⁇ 2.5 11 ⁇ 1.5 filler/binder 88 ⁇ 12 88 ⁇ 10 88 ⁇ 8 88 ⁇ 6 88 ⁇ 4 88 ⁇ 2.5 lubricant 0.30 ⁇ 0.28 0.30 ⁇ 0.26 0.30 ⁇ 0.24 0.30 ⁇ 0.22 0.30 ⁇ 0.20 0.30 ⁇ 0.15
  • the disintegrant is preferably crosslinked sodium carboxymethyl cellulose (Na-CMC) or crosslinked polyvinylpyrrolidone (PVP Cl)
  • the filler binder is preferably microcrystalline cellulose or a combination of microcrystalline cellulose with colloidal silicon dioxide
  • the lubricant is preferably magnesium stearate.
  • the matrix material of the tablets according to the invention may additionally contain other excipients that are conventional in the art, e.g. diluents, binders, granulating aids, colourants, flavourants, pore formers, surfactants, glidants, wet-regulating agents and disintegrants.
  • excipients e.g. diluents, binders, granulating aids, colourants, flavourants, pore formers, surfactants, glidants, wet-regulating agents and disintegrants.
  • Preferred pore formers include, but are not limited to glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, water-soluble hydrophilic polymers, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, carbowaxes, carbopol, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly( ⁇ - ⁇ )alkylenediols, inorganic compounds; alkali metal salts; alkaline earth metal salts, or combinations thereof.
  • Preferred surfactants are nonionic, anionic, cationic or amphoteric surfactants.
  • the matrix material contains an ionic surfactant, in particular an anionic surfactant.
  • Suitable anionic surfactants include but are not limited to sulfuric acid esters such as sodium lauryl sulfate (sodium dodecyl sulfate, e.g. Texapon® K12), sodium cetyl sulfate (e.g. Lanette E®), sodium cetylstearyl sulfate, sodium stearyl sulfate, sodium dioctylsulfosuccinate (docusate sodium); and the corresponding potassium or calcium salts thereof.
  • sulfuric acid esters such as sodium lauryl sulfate (sodium dodecyl sulfate, e.g. Texapon® K12), sodium cetyl sulfate (e.g. Lanette E®), sodium cetylstearyl sulfate, sodium stearyl sulfate, sodium dioctylsulfosuccinate (docusate sodium); and the corresponding potassium or calcium salts thereof.
  • the anionic surfactant has the general formula (II-a)
  • n is an integer of from 8 to 30, preferably 10 to 24, more preferably 12 to 18; and M is selected from Li + , Na + , K + , NH 4 + 1 ⁇ 2 Mg 2+ and 1 ⁇ 2 Ca 2+ .
  • anionic surfactants include salts of cholic acid including sodium glycocholate (e.g. Konakion® MM, Cernevit®), sodium taurocholate and the corresponding potassium or ammonium salts.
  • the matrix material contains a non-ionic surfactant.
  • Suitable non-ionic surfactants include but are not limited to
  • the matrix material according to the invention comprises a surfactant or mixture of different surfactants obtainable by
  • the content of the surfactant is at least 0.001 wt.-% or at least 0.005 wt.-%, more preferably at least 0.01 wt.-% or at least 0.05 wt.-%, still more preferably at least 0.1 wt.-%, at least 0.2 wt.-%, or at least 0.3 wt.-%, yet more preferably at least 0.4 wt.-%, at least 0.5 wt.-%, or at least 0.6 wt.-%, and in particular at least 0.7 wt.-%, at least 0.8 wt.-%, at least 0.9 wt.-%, or at least 1.0 wt.-%, based on the total weight of the tablet.
  • the matrix material of the tablet according to the invention consists of one or more disintegrants, one or more filler/binder's and one or more lubricants, but does not contain any other constituents.
  • the matrix material of the tablet according to the invention does not contain one or more gel-forming agents and/or a silicone.
  • gel-forming agent is used to refer to a compound that, upon contact with a solvent (e.g. water), absorbs the solvent and swells, thereby forming a viscous or semi-viscous substance.
  • a solvent e.g. water
  • Preferred gel-forming agents are not cross-linked. This substance may moderate pharmacologically active compound release from the embedded particulates in both aqueous and aqueous alcoholic media.
  • a thick viscous solution or dispersion is typically produced that significantly reduces and/or minimizes the amount of free solvent which can contain an amount of solubilized pharmacologically active compound, and which can be drawn into a syringe.
  • the gel that is formed may also reduce the overall amount of pharmacologically active compound extractable with the solvent by entrapping the pharmacologically active compound within a gel structure.
  • the gel-forming agent may play an important role in conferring tamper-resistance to the tablets according to the invention.
  • Gel-forming agents that preferably are not contained in the matrix material include pharmaceutically acceptable polymers, typically hydrophilic polymers, such as hydrogels.
  • Representative examples of gel-forming agent include polyethylene oxide, polyvinyl alcohol, hydroxypropylmethyl cellulose, carbomers, poly(uronic) acids and mixtures thereof.
  • the polyalkylene oxide that is contained in the particulates of the tablets according to the invention is preferably not also contained in the matrix material.
  • the pharmacologically active compound which is contained in the particulates of the tablet according to the invention is preferably not also contained in the matrix material.
  • the total amount of pharmacologically active compound contained in the tablet according to the invention is present in the particulates which form a discontinuous phase within the matrix material; and the matrix material forming a continuous phase does not contain any pharmacologically active compound.
  • the tablet according to the invention contains a plurality of particulates.
  • the particulates comprise a pharmacologically active compound and a polyalkylene oxide.
  • the pharmacologically active compound is dispersed in the polyalkylene oxide.
  • the term “particulate” refers to a discrete mass of material that is solid, e.g. at 20° C. or at room temperature or ambient temperature.
  • a particulate is solid at 20° C.
  • the particulates are monoliths.
  • the pharmacologically active compound and the polyalkylene oxide are intimately homogeneously distributed in the particulates so that the particulates do not contain any segments where either pharmacologically active compound is present in the absence of polyalkylene oxide or where polyalkylene oxide is present in the absence of pharmacologically active compound.
  • the polyalkylene oxide is preferably homogeneously distributed in the core of the pharmaceutical dosage form (tablet), i.e. the film coating preferably does not contain polyalkylene oxide, but optionally polyalkylene glycol that differs from polyalkylene oxide in its lower molecular weight. Nonetheless, the film coating as such may of course contain one or more polymers, which however, preferably differ from the polyalkylene oxide contained in the core.
  • the particulates are of macroscopic size, typically the average diameter is within the range of from 100 ⁇ m to 1500 ⁇ m, preferably 200 ⁇ m to 1500 ⁇ m, more preferably 300 ⁇ m to 1500 ⁇ m, still more preferably 400 ⁇ m to 1500 ⁇ m, most preferably 500 ⁇ m to 1500 ⁇ m, and in particular 600 ⁇ m to 1500 ⁇ m.
  • the tablets according to the invention comprise particulates as a discontinuous phase, i.e. the particulates form a discontinuous phase in the matrix material which in turn preferably forms a continuous phase.
  • discontinuous means that not each and every particulate is in intimate contact with another particulate but that the particulates are at least partially separated from one another by the matrix material in which the particulates are embedded.
  • the particulates preferably do not form a single coherent mass within the tablets according to the invention.
  • the tablet according to the invention comprises particulates in an amount of less than two thirds of the total weight of the tablet.
  • the content of particulates in the tablet can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • the content of the particulates in the tablets according to the invention is at most 65 wt.-%, more preferably at most 62.5 wt.-%, still more preferably at most 60 wt.-%, yet more preferably at most 57.5 wt.-%, most preferably at most 55 wt.-% and in particular at most 52.5 wt.-%, based on the total weight of the tablets.
  • the content of the particulates in the tablets according to the invention is at least 10 wt.-%, at least 12.5 wt.-%, at least 15 wt.-% or at least 17.5 wt.-%; more preferably at least 20 wt.-%, at least 22.5 wt.-%, at least 25 wt.-% or at least 27.5 wt.-%; most preferably at least 30 wt.-%, at least 32.5 wt.-%, at least 35 wt.-% or at least 37.5 wt.-%; and in particular at least 40 wt.-%, at least 42.5 wt.-%, at least 45 wt.-% or at least 47.5 wt.-%; based on the total weight of the tablet.
  • the content of the particulates in the tablets according to the invention is within the range of 35 ⁇ 30 wt.-%, more preferably 35 ⁇ 25 wt.-%, still more preferably 35 ⁇ 20 wt.-%, yet more preferably 35 ⁇ 15 wt.-%, most preferably 35 ⁇ 10 wt.-%, and in particular 35 ⁇ 5 wt.-%, based on the total weight of the tablet.
  • the content of the particulates in the tablets according to the invention is within the range of 40 ⁇ 30 wt.-%, more preferably 40 ⁇ 25 wt.-%, still more preferably 40 ⁇ 20 wt.-%, yet more preferably 40 ⁇ 15 wt.-%, most preferably 40 ⁇ 10 wt.-%, and in particular 40 ⁇ 5 wt.-%, based on the total weight of the tablet.
  • the content of the particulates in the tablets according to the invention is within the range of 45 ⁇ 30 wt.-%, more preferably 45 ⁇ 25 wt.-%, still more preferably 45 ⁇ 20 wt.-%, yet more preferably 45 ⁇ 15 wt.-%, most preferably 45 ⁇ 10 wt.-%, and in particular 45 ⁇ 5 wt.-%, based on the total weight of the tablet.
  • the content of the particulates in the tablets according to the invention is within the range of 50 ⁇ 30 wt.-%, more preferably 50 ⁇ 25 wt.-%, still more preferably 50 ⁇ 20 wt.-%, yet more preferably 50 ⁇ 15 wt.-%, most preferably 50 ⁇ 10 wt.-%, and in particular 50 ⁇ 5 wt.-%, based on the total weight of the tablet.
  • the content of the particulates in the tablets according to the invention is within the range of 55 ⁇ 30 wt.-%, more preferably 55 ⁇ 25 wt.-%, still more preferably 55 ⁇ 20 wt.-%, yet more preferably 55 ⁇ 15 wt.-%, most preferably 55 ⁇ 10 wt.-%, and in particular 55 ⁇ 5 wt.-%, based on the total weight of the tablet.
  • the content of the particulates in the tablets according to the invention is within the range of 60 ⁇ 30 wt.-%, more preferably 60 ⁇ 25 wt.-%, still more preferably 60 ⁇ 20 wt.-%, yet more preferably 60 ⁇ 15 wt.-%, most preferably 60 ⁇ 10 wt.-%, and in particular 60 ⁇ 5 wt.-%, based on the total weight of the tablet.
  • the shape of the particulates is not particularly limited.
  • preferred particulates present in the tablets according to the invention are generally cylindrical in shape.
  • the diameter of such particulates is therefore the diameter of their circular cross section.
  • the cylindrical shape is caused by the extrusion process according to which the diameter of the circular cross section is a function of the extrusion die and the length of the cylinders is a function of the cutting length according to which the extruded strand of material is cut into pieces of preferably more or less predetermined length.
  • the aspect ratio is regarded as an important measure of the spherical shape.
  • the aspect ratio is defined as the ratio of the maximal diameter (d max ) and its orthogonal Feret-diameter.
  • d max maximal diameter
  • the aspect ratio has values above 1. The smaller the value the more spherical is the particulate. Aspect ratios below 1.1 are typically considered satisfactory, aspect ratios above 1.2, however, are typically considered not suitable for the manufacture of conventional tablets.
  • the aspect ratio of the particulates is at most 1.40, more preferably at most 1.35, still more preferably at most 1.30, yet more preferably at most 1.25, even more preferably at most 1.20, most preferably at most 1.15 and in particular at most 1.10.
  • the aspect ratio of the particulates is at least 1.10, more preferably at least 1.15, still more preferably at least 1.20, yet more preferably at least 1.25, even more preferably at least 1.30, most preferably at least 1.35 and in particular at least 1.40.
  • the particulates in the tablets according to the invention are of macroscopic size, i.e. typically have an average particle size of at least 50 ⁇ m, more preferably at least 100 ⁇ m, still more preferably at least 150 ⁇ m or at least 200 ⁇ m, yet more preferably at least 250 ⁇ m or at least 300 ⁇ m, most preferably at least 400 ⁇ m or at least 500 ⁇ m, and in particular at least 550 ⁇ m or at least 600 ⁇ m.
  • Preferred particulates have an average length and average diameter of about 1000 ⁇ m or less.
  • the “length” of particulates is the dimension of the particulates that is parallel to the direction of extrusion.
  • the “diameter” of particulates is the largest dimension that is perpendicular to the direction of extrusion.
  • Particularly preferred particulates have an average diameter of less than about 1000 ⁇ m, more preferably less than about 800 ⁇ m, still more preferably of less than about 650 ⁇ m.
  • Especially preferred particulates have an average diameter of less than 700 ⁇ m, particularly less than 600 ⁇ m, still more particularly less than 500 ⁇ m, e.g. less than 400 ⁇ m.
  • Particularly preferred particulates have an average diameter in the range 200-1000 ⁇ m, more preferably 400-800 ⁇ m, still more preferably 450-700 ⁇ m, yet more preferably 500-650 ⁇ m, e.g. about 500-600 ⁇ m.
  • Further preferred particulates have an average diameter of between about 300 ⁇ m and about 400 ⁇ m, of between about 400 ⁇ m and 500 ⁇ m, or of between about 500 ⁇ m and 600 ⁇ m, or of between 600 ⁇ m and 700 ⁇ m or of between 700 ⁇ m and 800 ⁇ m.
  • Preferred particulates that are present in the tablets according to the invention have an average length of less than about 1000 ⁇ m, preferably an average length of less than about 800 ⁇ m, still more preferably an average length of less than about 650 ⁇ m, e.g. a length of about 800 ⁇ m, about 700 ⁇ m about 600 ⁇ m, about 500 ⁇ m, about 400 ⁇ m or about 300 ⁇ m.
  • Especially preferred particulates have an average length of less than 700 ⁇ m, particularly less than 650 ⁇ m, still more particularly less than 550 ⁇ m, e.g. less than 450 ⁇ m.
  • Particularly preferred particulates therefore have an average length in the range 200-1000 ⁇ m, more preferably 400-800 ⁇ m, still more preferably 450-700 ⁇ m, yet more preferably 500-650 ⁇ m, e.g. about 500-600 ⁇ m.
  • the minimum average length of the microparticulates is determined by the cutting step and may be, e.g. 500 ⁇ m, 400 ⁇ m, 300 ⁇ m or 200 ⁇ m.
  • the particulates have (i) an average diameter of about 750 ⁇ 300 ⁇ m, more preferably 750 ⁇ 250 ⁇ m, still more preferably 750 ⁇ 200 ⁇ m, yet more preferably 750 ⁇ 150 ⁇ m, most preferably 750 ⁇ 100 ⁇ m, and in particular 750 ⁇ 50 ⁇ m; and/or (ii) an average length of about 750 ⁇ 300 ⁇ m, more preferably 750 ⁇ 250 ⁇ m, still more preferably 750 ⁇ 200 ⁇ m, yet more preferably 750 ⁇ 150 ⁇ m, most preferably 750 ⁇ 100 ⁇ m, and in particular 750 ⁇ 50 ⁇ m.
  • the size of the particulates in the tablet can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • the size of particulates may be determined by any conventional procedure known in the art, e.g. laser light scattering, sieve analysis, light microscopy or image analysis.
  • the plurality of particulates that is contained in the tablet according to the invention has an arithmetic average weight, in the following referred to as “aaw”, wherein at least 70%, more preferably at least 75%, still more preferably at least 80%, yet more preferably at least 85%, most preferably at least 90% and in particular at least 95% of the individual particles contained in said plurality of particulates has an individual weight within the range of aaw ⁇ 30%, more preferably aaw ⁇ 25%, still more preferably aaw ⁇ 20%, yet more preferably aaw ⁇ 15%, most preferably aaw ⁇ 10%, and in particular aaw ⁇ 5%.
  • aaw arithmetic average weight
  • the tablet according to the invention contains a plurality of 100 particulates and aaw of said plurality of particulates is 1.00 mg, at least 75 individual particles (i.e. 75%) have an individual weight within the range of from 0.70 to 1.30 mg (1.00 mg ⁇ 30%).
  • the particulates are not film coated.
  • the particulates are film coated. It has been surprisingly found that when the particulates are film coated, the disintegration time and/or the drug release from the tablets can be further accelerated, which is particularly significant for tablets with immediate drug release.
  • the particulates according to the invention can optionally be provided, partially or completely, with a conventional coating.
  • the particulates according to the invention are preferably film coated with conventional film coating compositions. Suitable coating materials are commercially available, e.g. under the trademarks Opadry® and Eudragit®.
  • Suitable materials include cellulose esters and cellulose ethers, such as methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), ethylcellulose (EC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP); poly(meth)acrylates, such as aminoalkylmethacrylate copolymers, ethylacrylate methylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers; vinyl polymers, such as polyvinylpyrrolidone, polyvinylacetatephthalate, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymers, polyvinylacetate; and natural film formers.
  • MC methylcellulose
  • HPMC hydroxypropylmethylcellulose
  • the coating material may contain excipients such as stabilizers (e.g. surfactants such as macrogol cetostearylether, sodium dodecylsulfate, and the like). Suitable excipients of film coating materials are known to the skilled person.
  • stabilizers e.g. surfactants such as macrogol cetostearylether, sodium dodecylsulfate, and the like.
  • Suitable excipients of film coating materials are known to the skilled person.
  • the coating is water-soluble.
  • the coating is based on polyvinyl alcohol, such as polyvinyl alcohol-part, hydrolyzed, and may additionally contain polyethylene glycol, such as macrogol 3350, and/or pigments.
  • the coating is based on hydroxypropylmethylcellulose, preferably hypromellose type 2910 having a viscosity of 3 to 15 mPas.
  • the coating can principally be resistant to gastric juices and dissolve as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the tablet according to the invention passes through the stomach undissolved and the active compound is only released in the intestines.
  • the coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5.
  • Corresponding materials and methods for the delayed release of active compounds and for the application of coatings which are resistant to gastric juices are known to the person skilled in the art, for example from “Coated Pharmaceutical dosage forms—Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials” by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers.
  • a particularly preferred coating contains polyvinyl alcohol and optionally, further excipients such as xanthan gum and/or talkum.
  • the content of the dried film coating is preferably at most 5 wt.-%, more preferably at most 4 wt.-%, still more preferably at most 3.5 wt.-%, yet more preferably at most 3 wt.-%, most preferably at most 2.5 wt.-%, and in particular at most 2 wt.-%, based on the total weight of the particulates.
  • the weight increase relative to the total weight of the particulates (uncoated starting material) is within the range of from 3.0 to 4.7 wt.-%, more preferably 3.1 to 4.6 wt.-%, still more preferably 3.2 to 4.5 wt.-%, yet more preferably 3.3 to 4.4 wt.-%, most preferably 3.4 to 4.3 wt.-%, and in particular 3.5 to 4.2 wt.-%.
  • the relative weight ratio of matrix material:particulates in the tablet can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • said relative weight ratio is within the range of 1:1.00 ⁇ 0.75, more preferably 1:1.00 ⁇ 0.50, still more preferably 1:1.00 ⁇ 0.40, yet more preferably 1:1.00 ⁇ 0.30, most preferably 1:1.00 ⁇ 0.20, and in particular 1:1.00 ⁇ 0.10.
  • the particulates contain at least a pharmacologically active compound and a polyalkylene oxide. Preferably, however, the particulates contain additional pharmaceutical excipients such as antioxidants and plasticizers.
  • the pharmacologically active compound is not particularly limited.
  • the pharmacologically active compound is an opioid.
  • the particulates and the tablet respectively, contain only a single pharmacologically active compound. In another preferred embodiment, the particulates and the tablet, respectively, contain a combination of two or more pharmacologically active compounds.
  • pharmacologically active compound is an active ingredient with potential for being abused.
  • Active ingredients with potential for being abused are known to the person skilled in the art and comprise e.g. tranquillizers, stimulants, barbiturates, narcotics, opioids or opioid derivatives.
  • the pharmacologically active compound exhibits psychotropic action.
  • the pharmacologically active compound is selected from the group consisting of opiates, opioids, stimulants, tranquilizers, and other narcotics.
  • the pharmacologically active compound is an opioid.
  • opioids are divided into natural opium alkaloids, phenylpiperidine derivatives, diphenylpropylamine derivatives, benzomorphan derivatives, oripavine derivatives, morphinan derivatives and others.
  • opiates, opioids, tranquillizers or other narcotics are substances with a psychotropic action, i.e. have a potential of abuse, and hence are preferably contained in the tablet and the particulates, respectively: alfentanil, allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone, amphetamine, amphetaminil, amobarbital, anileridine, apocodeine, axomadol, barbital, bemidone, benzylmorphine, bezitramide, bromazepam, brotizolam, buprenorphine, butobarbital, butorphanol, camazepam, carfentanil, cathine/D-norpseudoephedrine, chlordiazepoxide, clobazam clofedanol, clonazepam, clonitazene, clorazepate
  • the pharmacologically active compound is selected from the group consisting of DPI-125, M6G (CE-04-410), ADL-5859, CR-665, NRP290 and sebacoyl dinalbuphine ester.
  • the pharmacologically active compound is selected from the group consisting of oxymorphone, hydromorphone and morphine.
  • the pharmacologically active compound is selected from the group consisting of tapentadol, faxeladol and axomadol.
  • the pharmacologically active compound is selected from the group consisting of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole, particularly its hemicitrate; 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]indole, particularly its citrate; and 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoroindole, particularly its hemicitrate.
  • These compounds are known from, e.g., WO 2004/043967, WO 2005/066183.
  • the pharmacologically active compound may be present in form of a physiologically acceptable salt, e.g. physiologically acceptable acid addition salt.
  • Physiologically acceptable acid addition salts comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the active ingredient with appropriate organic and inorganic acids. Active ingredients containing an acidic proton may be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • the term addition salt also comprises the hydrates and solvent addition forms which the active ingredients are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • the content of the pharmacologically active compound in the tablet and in the particulates, respectively can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • the pharmacologically active compound is present in the tablet in a therapeutically effective amount.
  • the amount that constitutes a therapeutically effective amount varies according to the active ingredients being used, the condition being treated, the severity of said condition, the patient being treated, and the frequency of administration.
  • the content of the pharmacologically active compound in the tablet is not limited.
  • the dose of the pharmacologically active compound which is adapted for administration preferably is in the range of 0.1 mg to 500 mg, more preferably in the range of 1.0 mg to 400 mg, even more preferably in the range of 5.0 mg to 300 mg, and most preferably in the range of 10 mg to 250 mg.
  • the total amount of the pharmacologically active compound that is contained in the tablet is within the range of from 0.01 to 200 mg, more preferably 0.1 to 190 mg, still more preferably 1.0 to 180 mg, yet more preferably 1.5 to 160 mg, most preferably 2.0 to 100 mg and in particular 2.5 to 80 mg.
  • the content of the pharmacologically active compound is within the range of from 0.01 to 80 wt.-%, more preferably 0.1 to 50 wt.-%, still more preferably 1 to 25 wt.-%, based on the total weight of the tablet.
  • the content of pharmacologically active compound is within the range of from 5.0 ⁇ 4.5 wt.-%, or 7.5 ⁇ 7.0 wt.-%, or 10 ⁇ 9.0 wt.-%, or 12.5 ⁇ 12.0 wt.-%, or 15 ⁇ 14 wt.-%, or 17.5 ⁇ 17.0 wt.-%, or 20 ⁇ 19 wt.-%, or 22.5 ⁇ 22.0 wt.-%, or 25 ⁇ 24 wt.-%; more preferably 5.0 ⁇ 4.0 wt.-%, or 7.5 ⁇ 6.0 wt.-%, or 10 ⁇ 8.0 wt.-%, or 12.5 ⁇ 12.0 wt.-%, or 15 ⁇ 12 wt.-%, or 17.5 ⁇ 15.0 wt.-%, or 20 ⁇ 19 wt.-%, or 22.5 ⁇ 22.0 wt.-%, or 25 ⁇ 24 wt.-%; still more preferably 5.0 ⁇ 3.5 wt.-%, or
  • the content of pharmacologically active compound is within the range of from 20 ⁇ 6 wt.-%, more preferably 20 ⁇ 5 wt.-%, still more preferably 20 ⁇ 4 wt.-%, most preferably 20 ⁇ 3 wt.-%, and in particular 20 ⁇ 2 wt.-%, based on the total weight of the tablet.
  • the content of pharmacologically active compound is within the range of from 25 ⁇ 6 wt.-%, more preferably 25 ⁇ 5 wt.-%, still more preferably 25 ⁇ 4 wt.-%, most preferably 25 ⁇ 3 wt.-%, and in particular 25 ⁇ 2 wt.-%, based on the total weight of the tablet.
  • the skilled person may readily determine an appropriate amount of pharmacologically active compound to include in a tablet.
  • the total amount of pharmacologically active compound present in the tablet is that sufficient to provide analgesia.
  • the total amount of pharmacologically active compound administered to a patient in a dose will vary depending on numerous factors including the nature of the pharmacologically active compound, the weight of the patient, the severity of the pain, the nature of other therapeutic agents being administered etc.
  • the pharmacologically active compound is contained in the tablet in an amount of 7.5 ⁇ 5 mg, 10 ⁇ 5 mg, 20 ⁇ 5 mg, 30 ⁇ 5 mg, 40 ⁇ 5 mg, 50 ⁇ 5 mg, 60 ⁇ 5 mg, 70 ⁇ 5 mg, 80 ⁇ 5 mg, 90 ⁇ 5 mg, 100 ⁇ 5 mg, 110 ⁇ 5 mg, 120 ⁇ 5 mg, 130 ⁇ 5, 140 ⁇ 5 mg, 150 ⁇ 5 mg, 160 ⁇ 5 mg, 170 ⁇ 5 mg, 180 ⁇ 5 mg, 190 ⁇ 5 mg, 200 ⁇ 5 mg, 210 ⁇ 5 mg, 220 ⁇ 5 mg, 230 ⁇ 5 mg, 240 ⁇ 5 mg, 250 ⁇ 5 mg, 260 ⁇ 5 mg, 270 ⁇ 5 mg, 280 ⁇ 5 mg, 290 ⁇ 5 mg, or 300 ⁇ 5 mg.
  • the pharmacologically active compound is contained in the tablet in an amount of 5 ⁇ 2.5 mg, 7.5 ⁇ 2.5 mg, 10 ⁇ 2.5 mg, 15 ⁇ 2.5 mg, 20 ⁇ 2.5 mg, 25 ⁇ 2.5 mg, 30 ⁇ 2.5 mg, 35 ⁇ 2.5 mg, 40 ⁇ 2.5 mg, 45 ⁇ 2.5 mg, 50 ⁇ 2.5 mg, 55 ⁇ 2.5 mg, 60 ⁇ 2.5 mg, 65 ⁇ 2.5 mg, 70 ⁇ 2.5 mg, 75 ⁇ 2.5 mg, 80 ⁇ 2.5 mg, 85 ⁇ 2.5 mg, 90 ⁇ 2.5 mg, 95 ⁇ 2.5 mg, 100 ⁇ 2.5 mg, 105 ⁇ 2.5 mg, 110 ⁇ 2.5 mg, 115 ⁇ 2.5 mg, 120 ⁇ 2.5 mg, 125 ⁇ 2.5 mg, 130 ⁇ 2.5 mg, 135 ⁇ 2.5 mg, 140 ⁇ 2.5 mg, 145 ⁇ 2.5 mg, 150 ⁇ 2.5 mg, 155 ⁇ 2.5 mg, 160 ⁇ 2.5 mg, 165 ⁇ 2.5 mg, 170 ⁇ 2.5 mg, 175 ⁇ 2.5 mg, 180 ⁇ 2.5 mg, 185 ⁇ 2.5 mg, 190 ⁇ 2.5 mg, 195 ⁇ 2.5 mg, 200 ⁇ 2.5 mg, 205 ⁇ 2.5 mg, 210 ⁇ 2.5 mg, 215 ⁇
  • the pharmacologically active compound is tapentadol, preferably its HCl salt, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently.
  • pharmacologically active compound is preferably contained in the tablet in an amount of from 25 to 100 mg.
  • the pharmacologically active compound is oxymorphone, preferably its HCl salt, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently.
  • the pharmacologically active compound is preferably contained in the tablet in an amount of from 5 to 40 mg.
  • the pharmacologically active compound is oxymorphone, preferably its HCl salt, and the tablet is adapted for administration once daily.
  • the pharmacologically active compound is preferably contained in the tablet in an amount of from 10 to 80 mg.
  • the pharmacologically active compound is oxycodone, preferably its HCl salt, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently.
  • the pharmacologically active compound is preferably contained in the tablet in an amount of from 5 to 80 mg.
  • the pharmacologically active compound is hydromorphone, preferably its HCl, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently.
  • the pharmacologically active compound is preferably contained in the tablet in an amount of from 2 to 52 mg.
  • the pharmacologically active compound is hydromorphone, preferably its HCl, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently.
  • the pharmacologically active compound is preferably contained in the tablet in an amount of from 4 to 104 mg.
  • the particulates present in the tablets according to the invention preferably comprise 3 to 75 wt.-% of pharmacologically active compound, more preferably 5 to 70 wt.-% of pharmacologically active compound, still more preferably 7.5 to 65 wt.-% of pharmacologically active compound, based on the total weight of a particulate.
  • the content of the pharmacologically active compound is at least 25 wt.-%, more preferably at least 30 wt.-%, still more preferably at least 35 wt.-%, yet more preferably at least 40 wt.-%, most preferably at least 45 wt.-%, based on the total weight of a particulate.
  • the content of the pharmacologically active compound is at most 70 wt.-%, more preferably at most 65 wt.-%, still more preferably at most 60 wt.-%, yet more preferably at most 55 wt.-%, most preferably at most 50 wt.-%, based on the total weight of a particulate.
  • the content of the pharmacologically active compound is within the range of 35 ⁇ 30 wt.-%, more preferably 35 ⁇ 25 wt.-%, still more preferably 35 ⁇ 20 wt.-%, yet more preferably 35 ⁇ 15 wt.-%, most preferably 35 ⁇ 10 wt.-%, and in particular 35 ⁇ 5 wt.-%, based on the total weight of a particulate.
  • the content of the pharmacologically active compound is within the range of 45 ⁇ 30 wt.-%, more preferably 45 ⁇ 25 wt.-%, still more preferably 45 ⁇ 20 wt.-%, yet more preferably 45 ⁇ 15 wt.-%, most preferably 45 ⁇ 10 wt.-%, and in particular 45 ⁇ 5 wt.-%, based on the total weight of a particulate.
  • the content of the pharmacologically active compound is within the range of 55 ⁇ 30 wt.-%, more preferably 55 ⁇ 25 wt.-%, still more preferably 55 ⁇ 20 wt.-%, yet more preferably 55 ⁇ 15 wt.-%, most preferably 55 ⁇ 10 wt.-%, and in particular 55 ⁇ 5 wt.-%, based on the total weight of a particulate.
  • the pharmacologically active compound that is included in the preparation of the tablets according to the invention preferably has an average particle size of less than 500 microns, still more preferably less than 300 microns, yet more preferably less than 200 or 100 microns. There is no lower limit on the average particle size and it may be, for example, 50 microns.
  • the particle size of pharmacologically active compounds may be determined by any technique conventional in the art, e.g. laser light scattering, sieve analysis, light microscopy or image analysis. Generally speaking it is preferable that the largest dimension of the pharmacologically active compound particle be less than the size of the particulates (e.g. less than the smallest dimension of the particulates).
  • pharmacokinetic parameters such as t 1/2 , T max , C max , AUC and bioavailability.
  • the pharmacokinetic parameters which may be determined from the blood plasma concentrations of 3-(2-dimethylaminomethylcyclohexyl)phenol, are defined as follows:
  • the pharmacologically active compound is tapentadol or a physiologically acceptable salt thereof, e.g. the hydrochloride.
  • the tablet according to the invention provides a mean absolute bioavailability of tapentadol of at least 22%, more preferably at least 24%, still more preferably at least 26%, yet more preferably at least 28%, most preferably at least 30%, and in particular at least 32%.
  • T max of tapentadol is preferably within the range of 1.25 ⁇ 1.20 h, more preferably 1.25 ⁇ 1.00 h, still more preferably 1.25 ⁇ 0.80 h, yet more preferably 1.25 ⁇ 0.60 h, most preferably 1.25 ⁇ 0.40 h, and in particular 1.25 ⁇ 0.20 h.
  • t 112 of tapentadol is preferably within the range of 4.0 ⁇ 2.8 h, more preferably 4.0 ⁇ 2.4 h, still more preferably 4.0 ⁇ 2.0 h, yet more preferably 4.0 ⁇ 1.6 h, most preferably 4.0 ⁇ 1.2 h, and in particular 4.0 ⁇ 0.8 h.
  • C max of tapentadol is preferably within the range of 90 ⁇ 85 ng/mL, more preferably 90 ⁇ 75 ng/mL, still more preferably 90 ⁇ 65 ng/mL, yet more preferably 90 ⁇ 55 ng/mL, most preferably 90 ⁇ 45 ng/mL, and in particular 90 ⁇ 35 ng/mL; and/or AUC of tapentadol is preferably within the range of 420 ⁇ 400 ng/mL ⁇ h, more preferably 420 ⁇ 350 ng/mL ⁇ h, still more preferably 420 ⁇ 300 ng/mL ⁇ h, yet more preferably 420 ⁇ 250 ng/mL ⁇ h, most preferably 420 ⁇ 200 ng/mL ⁇ h, and in particular 420 ⁇ 150 ng/mL ⁇ h.
  • the pharmacologically active compound is oxymorphone or a physiologically acceptable salt thereof, e.g. the hydrochloride.
  • the tablet according to the invention provides a mean absolute bioavailability of oxymorphone of at least 1%, more preferably at least 2%, still more preferably at least 4%, yet more preferably at least 6%, most preferably at least 8%, and in particular at least 10%.
  • T max of oxymorphone is preferably within the range of 0.5 ⁇ 0.45 h, more preferably 0.5 ⁇ 0.40 h, still more preferably 0.5 ⁇ 0.35 h, yet more preferably 0.5 ⁇ 0.30 h, most preferably 0.5 ⁇ 0.25 h, and in particular 0.5 ⁇ 0.20 h.
  • t 12 of oxymorphone is preferably within the range of 9.5 ⁇ 8.0 h, more preferably 9.5 ⁇ 7.0 h, still more preferably 9.5 ⁇ 6.0 h, yet more preferably 9.5 ⁇ 5.0 h, most preferably 9.5 ⁇ 4.0 h, and in particular 9.5 ⁇ 3.0 h.
  • C max of oxymorphone is preferably within the range of 4.4 ⁇ 3.5 ng/mL, more preferably 4.4 ⁇ 3.0 ng/mL, still more preferably 4.4 ⁇ 2.5 ng/mL, yet more preferably 4.4 ⁇ 2.0 ng/mL, most preferably 4.4 ⁇ 1.5 ng/mL, and in particular 4.4 ⁇ 1.0 ng/mL; and/or AUC of oxymorphone is preferably within the range of 20.0 ⁇ 15.0 ng/mL ⁇ h, more preferably 20.0 ⁇ 12.5 ng/mL ⁇ h, still more preferably 20.0 ⁇ 10.0 ng/mL ⁇ h, yet more preferably 20.0 ⁇ 7.5 ng/mL ⁇ h, most preferably 20.0 ⁇ 6.0 ng/mL ⁇ h, and in particular 20.0 ⁇ 5.0 ng/mL ⁇ h.
  • the pharmacologically active compound is oxycodone or a physiologically acceptable salt thereof, e.g. the hydrochloride.
  • the tablet according to the invention provides a mean absolute bioavailability of oxycodone of at least 40%, more preferably at least 45%, still more preferably at least 50%, yet more preferably at least 55%, most preferably at least 60%, and in particular at least 70%.
  • T max of oxycodone is preferably within the range of 2.6 ⁇ 2.5 h, more preferably 2.6 ⁇ 2.0 h, still more preferably 2.6 ⁇ 1.8 h, yet more preferably 2.6 ⁇ 0.1.6 h, most preferably 2.6 ⁇ 1.4 h, and in particular 2.6 ⁇ 1.20 h.
  • t 112 of oxycodone is preferably within the range of 3.8 ⁇ 3.5 h, more preferably 3.8 ⁇ 3.0 h, still more preferably 3.8 ⁇ 2.5 h, yet more preferably 3.8 ⁇ 2.0 h, most preferably 3.8 ⁇ 1.5 h, and in particular 3.8 ⁇ 1.0 h.
  • C max of oxycodone is preferably within the range of 40 ⁇ 35 ng/mL, more preferably 40 ⁇ 30 ng/mL, still more preferably 40 ⁇ 25 ng/mL, yet more preferably 40 ⁇ 20 ng/mL, most preferably 40 ⁇ 15 ng/mL, and in particular 40 ⁇ 10 ng/mL; and/or AUC of oxycodone is preferably within the range of 270 ⁇ 250 ng/mL ⁇ h, more preferably 270 ⁇ 200 ng/mL ⁇ h, still more preferably 270 ⁇ 150 ng/mL ⁇ h, yet more preferably 270 ⁇ 100 ng/mL ⁇ h, most preferably 270 ⁇ 75 ng/mL ⁇ h, and in particular 270 ⁇ 50 ng/mL ⁇ h.
  • the pharmacologically active compound is morphine or a physiologically acceptable salt thereof, e.g. the sulfate.
  • the tablet according to the invention provides a mean absolute bioavailability of morphine of at least 15%, more preferably at least 20%, still more preferably at least 25%, yet more preferably at least 30%, most preferably at least 35%, and in particular at least 40%.
  • T max of morphine is preferably within the range of 0.625 ⁇ 0.60 h, more preferably 0.625 ⁇ 0.50 h, still more preferably 0.625 ⁇ 0.40 h, yet more preferably 0.625 ⁇ 0.30 h, most preferably 0.625 ⁇ 0.20 h, and in particular 0.625 ⁇ 0.15 h.
  • C max of morphine is preferably within the range of 25 ⁇ 20 ng/mL, more preferably 25 ⁇ 15 ng/mL, still more preferably 25 ⁇ 10 ng/mL, yet more preferably 25 ⁇ 5 ng/mL; and/or AUC of morphine is preferably within the range of 50 ⁇ 45 ng/mL ⁇ h, more preferably 50 ⁇ 40 ng/mL ⁇ h, still more preferably 50 ⁇ 35 ng/mL ⁇ h, yet more preferably 50 ⁇ 30 ng/mL ⁇ h, most preferably 50 ⁇ 25 ng/mL ⁇ h, and in particular 50 ⁇ 20 ng/mL ⁇ h.
  • the tablets according to the invention may also comprise one or more additional pharmacologically active compounds.
  • the additional pharmacologically active compound may be susceptible to abuse or another pharmaceutical. Additional pharmacologically active compounds may be present within the particulates (“intragranular”) or within the matrix (“extragranular”). Where an additional pharmacologically active compound is present intragranularly, it may be present either in combination with one or more pharmacologically active compounds within the same particulates or in a discrete population of particulates alone and separate from any other pharmacologically active compounds present in the tablet.
  • the tablet according to the invention preferably the particulates, comprise an opioid (agonist) as well as an opioid antagonist.
  • opioid antagonist may be present, e.g. naltrexone or naloxone or their pharmaceutically acceptable salts. Naloxone, including its salts, is particularly preferred.
  • the opioid antagonist may be present within the particulates or within the matrix. Alternatively, opioid antagonist may be provided in separate particulates to the pharmacologically active compounds. The preferred composition of such particulates is the same as that described for pharmacologically active compound-containing particulates.
  • the ratio of opioid agonist to opioid antagonist in the tablets according to the invention is preferably 1:1 to 3:1 by weight, for example, about 2:1 by weight.
  • neither the particulates nor the tablet comprise any opioid antagonist.
  • the particulates according to the invention contain a polyalkylene oxide.
  • the polyalkylene oxide is selected from polymethylene oxide, polyethylene oxide and polypropylene oxide, or copolymers thereof. Polyethylene oxide is preferred.
  • the polyalkylene oxide has a weight average molecular weight (M w ) or viscosity average molecular weight (M ⁇ ) of at least 200,000 or at least 500,000 g/mol, preferably at least 1,000,000 g/mol or at least 2,500,000 g/mol, more preferably in the range of about 1,000,000 g/mol to about 15,000,000 g/mol, and most preferably in the range of about 5,000,000 g/mol to about 10,000,000 g/mol.
  • M w weight average molecular weight
  • M ⁇ viscosity average molecular weight
  • Polyalkylene oxide may comprise a single polyalkylene oxide having a particular average molecular weight, or a mixture (blend) of different polymers, such as two, three, four or five polymers, e.g., polymers of the same chemical nature but different average molecular weight, polymers of different chemical nature but same average molecular weight, or polymers of different chemical nature as well as different molecular weight.
  • a polyalkylene glycol has a molecular weight of up to 20,000 g/mol whereas a polyalkylene oxide has a molecular weight of more than 20,000 g/mol.
  • the weight average over all molecular weights of all polyalkylene oxides that are contained in the tablet is at least 200,000 g/mol.
  • polyalkylene glycols, if any, are preferably not taken into consideration when determining the weight average molecular weight of polyalkylene oxide.
  • polyalkylene oxide is homogeneously distributed in the particulates according to the invention.
  • the pharmacologically active compound and polyalkylene oxide are intimately homogeneously distributed in the particulates so that the particulates do not contain any segments where either pharmacologically active compound is present in the absence of polyalkylene oxide or where polyalkylene oxide is present in the absence of pharmacologically active compound.
  • the polyalkylene oxide is preferably homogeneously distributed in the core of the particulates, i.e. the film coating preferably does not contain polyalkylene oxide. Nonetheless, the film coating as such may of course contain one or more polymers, which however, preferably differ from the polyalkylene oxide contained in the core.
  • the polyalkylene oxide may be combined with one or more different polymers selected from the group consisting of polyalkylene oxide, preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyvinylpyrrolidone, poly(alk)acrylate, poly(hydroxy fatty acids), such as for example poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®), poly(hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene succinate, polylactone, polyglycolide, polyurethane, polyamide, polylactide, polyacetal (for example polysaccharides optionally with modified side chains), polylactide/glycolide, polylactone, polyglycolide, polyorthoester, polyanhydride, block polymers of polyethylene glycol and polybutylene terephthalate (Polyactive®), polyanhydride (Pol
  • the molecular weight dispersity M w /M n of polyalkylene oxide is within the range of 2.5 ⁇ 2.0, more preferably 2.5 ⁇ 1.5, still more preferably 2.5 ⁇ 1.0, yet more preferably 2.5 ⁇ 0.8, most preferably 2.5 ⁇ 0.6, and in particular 2.5 ⁇ 0.4.
  • the polyalkylene oxide preferably has a viscosity at 25° C. of 30 to 17,600 cP, more preferably 55 to 17,600 cP, still more preferably 600 to 17,600 cP and most preferably 4,500 to 17,600 cP, measured in a 5 wt.-% aqueous solution using a model RVF Brookfield viscosimeter (spindle no. 2/rotational speed 2 rpm); of 400 to 4,000 cP, more preferably 400 to 800 cP or 2,000 to 4,000 cP, measured on a 2 wt.-% aqueous solution using the stated viscosimeter (spindle no.
  • Polyethylene oxide that is suitable for use in the tablets according to the invention is commercially available from Dow.
  • Polyox WSR N-12K, Polyox N-60K, Polyox WSR 301 NF or Polyox WSR 303NF may be used in the tablets according to the invention.
  • it can be referred to e.g. the product specification.
  • the content of the polyalkylene oxide is within the range of from 1 to 60 wt.-%, more preferably 3 to 55 wt.-%, still more preferably 5 to 50 wt.-%, yet more preferably 7 to 45 wt.-%, most preferably 10 to 40 wt.-% and in particular 15 to 35 wt.-%, based on the total weight of the tablet.
  • the content of the polyalkylene oxide is at least 2 wt.-%, more preferably at least 5 wt.-%, still more preferably at least 10 wt.-%, yet more preferably at least 15 wt.-% and in particular at least 20 wt.-%, based on the total weight of the tablet.
  • the overall content of polyalkylene oxide is within the range of 10 ⁇ 8 wt.-%, more preferably 10 ⁇ 6 wt.-%, most preferably 10 ⁇ 4 wt.-%, and in particular 10 ⁇ 2 wt.-%, based on the total weight of the tablet.
  • the overall content of polyalkylene oxide is within the range of 15 ⁇ 12 wt.-%, more preferably 15 ⁇ 10 wt.-%, most preferably 15 ⁇ 7 wt.-%, and in particular 15 ⁇ 3 wt.-%, based on the total weight of the tablet.
  • the overall content of polyalkylene oxide is within the range of 20 ⁇ 16 wt.-%, more preferably 20 ⁇ 12 wt.-%, most preferably 20 ⁇ 8 wt.-%, and in particular 20 ⁇ 4 wt.-%, based on the total weight of the tablet. In yet another preferred embodiment, the overall content of polyalkylene oxide is within the range of 25 ⁇ 20 wt.-%, more preferably 25 ⁇ 15 wt.-%, most preferably 25 ⁇ 10 wt.-%, and in particular 25 ⁇ 5 wt.-%, based on the total weight of the tablet.
  • the overall content of polyalkylene oxide is within the range of 30 ⁇ 20 wt.-%, more preferably 30 ⁇ 15 wt.-%, most preferably 30 ⁇ 10 wt.-%, and in particular 30 ⁇ 5 wt.-%, based on the total weight of the tablet. In still a further a preferred embodiment, the overall content of polyalkylene oxide is within the range of 35 ⁇ 20 wt.-%, more preferably 35 ⁇ 15 wt.-%, most preferably 35 ⁇ 10 wt.-%, and in particular 35 ⁇ 5 wt.-%.
  • the overall content of polyalkylene oxide is within the range of 40 ⁇ 20 wt.-%, more preferably 40 ⁇ 15 wt.-%, and most preferably 40 ⁇ 10 wt.-%, and in particular 40 ⁇ 5 wt.-%, based on the total weight of the tablet.
  • the content of the polyalkylene oxide is within the range of from 1 to 99 wt.-%, more preferably 5 to 95 wt.-%, still more preferably 10 to 90 wt.-%, yet more preferably 15 to 85 wt.-%, most preferably 20 to 80 wt.-% and in particular 25 to 75 wt.-%, based on the total weight of the particulates.
  • the content of the polyalkylene oxide is at least 10 wt.-%, more preferably at least 15 wt.-%, still more preferably at least 20 wt.-%, yet more preferably at least 25 wt.-% and in particular at least 30 wt.-%, based on the total weight of the particulates.
  • the overall content of polyalkylene oxide is within the range of 30 ⁇ 20 wt.-%, more preferably 30 ⁇ 15 wt.-%, most preferably 30 ⁇ 10 wt.-%, and in particular 30 ⁇ 5 wt.-%, based on the total weight of the particulates.
  • the overall content of polyalkylene oxide is within the range of 35 ⁇ 20 wt.-%, more preferably 35 ⁇ 15 wt.-%, most preferably 35 ⁇ 10 wt.-%, and in particular 35 ⁇ 5 wt.-%, based on the total weight of the particulates.
  • the overall content of polyalkylene oxide is within the range of 40 ⁇ 20 wt.-%, more preferably 40 ⁇ 15 wt.-%, most preferably 40 ⁇ 10 wt.-%, and in particular 40 ⁇ 5 wt.-%, based on the total weight of the particulates.
  • the overall content of polyalkylene oxide is within the range of 45 ⁇ 20 wt.-%, more preferably 45 ⁇ 15 wt.-%, most preferably 45 ⁇ 10 wt.-%, and in particular 45 ⁇ 5 wt.-%, based on the total weight of the particulates.
  • the overall content of polyalkylene oxide is within the range of 50 ⁇ 20 wt.-%, more preferably 50 ⁇ 15 wt.-%, most preferably 50 ⁇ 10 wt.-%, and in particular 50 ⁇ 5 wt.-%, based on the total weight of the particulates. In still a further a preferred embodiment, the overall content of polyalkylene oxide is within the range of 55 ⁇ 20 wt.-%, more preferably 55 ⁇ 15 wt.-%, most preferably 55 ⁇ 10 wt.-%, and in particular 55 ⁇ 5 wt.-%.
  • the overall content of polyalkylene oxide is within the range of 60 ⁇ 15 wt.-%, more preferably 60 ⁇ 10 wt.-%, most preferably 60 ⁇ 5 wt.-%, and in particular 60 ⁇ 5 wt.-%, based on the total weight of the particulates.
  • the relative weight ratio of the polyalkylene oxide to the pharmacologically active compound is within the range of 1:1.00 ⁇ 0.75, more preferably 1:1.00 ⁇ 0.50, still more preferably 1:1.00 ⁇ 0.40, yet more preferably 1:1.00 ⁇ 0.30, most preferably 1:1.00 ⁇ 0.20, and in particular 1:1.00 ⁇ 0.10.
  • the particulates according to the invention may contain additional pharmaceutical excipients conventionally contained in tablets in conventional amounts, such as antioxidants, preservatives, lubricants, plasticizer, fillers, binders, and the like.
  • the particulates do not contain a disintegrant.
  • the particulates further comprise an antioxidant.
  • Suitable antioxidants include ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and the derivatives thereof, coniferyl benzoate, nordihydroguajaretic acid, gallus acid esters, sodium bisulfite, particularly preferably butylhydroxytoluene or butylhydroxyanisole and ⁇ -tocopherol.
  • the antioxidant is preferably present in quantities of 0.01 wt.-% to 10 wt.-%, more preferably of 0.03 wt.-% to 5 wt.-%, most preferably of 0.05 wt.-% to 2.5 wt.-%, based on the total weight of the particulates.
  • the particulates further comprise an acid, preferably citric acid.
  • the amount of acid is preferably in the range of 0.01 wt.-% to about 20 wt.-%, more preferably in the range of 0.02 wt.-% to about 10 wt.-%, and still more preferably in the range of 0.05 wt.-% to about 5 wt.-%, and most preferably in the range of 0.1 wt.-% to about 1.0 wt.-%, based on the total weight of the particulates.
  • the particulates further comprise another polymer which is preferably selected from cellulose esters and cellulose ethers, in particular hydroxypropyl methylcellulose (HPMC).
  • another polymer which is preferably selected from cellulose esters and cellulose ethers, in particular hydroxypropyl methylcellulose (HPMC).
  • polystyrene resin polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymers, such as the one commercially available under the trade name Soluplus®.
  • the amount of the further polymer, preferably hydroxypropyl methylcellulose preferably ranges from 0.1 wt.-% to about 30 wt.-%, more preferably in the range of 1.0 wt.-% to about 20 wt.-%, most preferably in the range of 2.0 wt.-% to about 15 wt.-%, and in particular in the range of 3.5 wt.-% to about 10.5 wt.-%, based on the total weight of the particulates.
  • the relative weight ratio of the polyalkylene oxide to the further polymer is within the range of 4.5 ⁇ 2:1, more preferably 4.5 ⁇ 1.5:1, still more preferably 4.5 ⁇ 1:1, yet more preferably 4.5 ⁇ 0.5:1, most preferably 4.5 ⁇ 0.2:1, and in particular 4.5 ⁇ 0.1:1.
  • the relative weight ratio of the polyalkylene oxide to the further polymer is within the range of 8 ⁇ 7:1, more preferably 8 ⁇ 6:1, still more preferably 8 ⁇ 5:1, yet more preferably 8 ⁇ 4:1, most preferably 8 ⁇ 3:1, and in particular 8 ⁇ 2:1.
  • the relative weight ratio of the polyalkylene oxide to the further polymer is within the range of 11 ⁇ 8:1, more preferably 11 ⁇ 7:1, still more preferably 11 ⁇ 6:1, yet more preferably 11 ⁇ 5:1, most preferably 11 ⁇ 4:1, and in particular 11 ⁇ 3:1.
  • the particulates according to the invention do not contain any further polymer besides the polyalkylene oxide and optionally, polyethylene glycol.
  • the particulates contain at least one lubricant. In another preferred embodiment, the particulates contain no lubricant. Especially preferred lubricants are selected from
  • the amount of the lubricant ranges from 0.01 wt.-% to about 10 wt.-%, more preferably in the range of 0.05 wt.-% to about 7.5 wt.-%, most preferably in the range of 0.1 wt.-% to about 5 wt.-%, and in particular in the range of 0.1 wt.-% to about 1 wt.-%, based on the total weight of the particulates.
  • the particulates further comprise a plasticizer.
  • the plasticizer improves the processability of the polyalkylene oxide.
  • a preferred plasticizer is polyalkylene glycol, like polyethylene glycol, triacetin, fatty acids, fatty acid esters, waxes and/or microcrystalline waxes.
  • Particularly preferred plasticizers are polyethylene glycols, such as PEG 6000.
  • the content of the plasticizer is within the range of from 0.5 to 30 wt.-%, more preferably 1.0 to 25 wt.-%, still more preferably 2.5 wt.-% to 22.5 wt.-%, yet more preferably 5.0 wt.-% to 20 wt.-%, most preferably 6 to 20 wt.-% and in particular 7 wt.-% to 17.5 wt.-%, based on the total weight of the particulates.
  • the plasticizer is a polyalkylene glycol having a content within the range of 7 ⁇ 6 wt.-%, more preferably 7 ⁇ 5 wt.-%, still more preferably 7 ⁇ 4 wt.-%, yet more preferably 7 ⁇ 3 wt.-%, most preferably 7 ⁇ 2 wt.-%, and in particular 7 ⁇ 1 wt.-%, based on the total weight of the particulates.
  • the plasticizer is a polyalkylene glycol having a content within the range of 10 ⁇ 8 wt.-%, more preferably 10 ⁇ 6 wt.-%, still more preferably 10 ⁇ 5 wt.-%, yet more preferably 10 ⁇ 4 wt.-%, most preferably 10 ⁇ 3 wt.-%, and in particular 10 ⁇ 2 wt.-%, based on the total weight of the particulates.
  • the relative weight ratio of the polyalkylene oxide to the polyalkylene glycol is within the range of 5.4 ⁇ 2:1, more preferably 5.4 ⁇ 1.5:1, still more preferably 5.4 ⁇ 1:1, yet more preferably 5.4 ⁇ 0.5:1, most preferably 5.4 ⁇ 0.2:1, and in particular 5.4 ⁇ 0.1:1. This ratio satisfies the requirements of relative high polyalkylene oxide content and good extrudability.
  • Plasticizers can sometimes act as a lubricant, and lubricants can sometimes act as a plasticizer.
  • the particulates and the matrix material of the tablets according to the invention preferably do not contain any polymers selected from the group consisting of
  • the tablet according to the invention contains no substances which irritate the nasal passages and/or pharynx, i.e. substances which, when administered via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the patient that he/she does not wish to or cannot continue administration, for example burning, or physiologically counteracts taking of the corresponding active compound, for example due to increased nasal secretion or sneezing.
  • substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli.
  • Corresponding substances and the quantities thereof which are conventionally to be used are known to the person skilled in the art. Some of the substances which irritate the nasal passages and/or pharynx are accordingly based on one or more constituents or one or more plant parts of a hot substance drug.
  • Corresponding hot substance drugs are known per se to the person skilled in the art and are described, for example, in “Pharmazeutician Biologie—Drogen and emp warsstoffe” by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure.
  • the tablet according to the invention furthermore preferably contains no antagonists for the pharmacologically active compound, preferably no antagonists against psychotropic substances, in particular no antagonists against opioids.
  • Antagonists suitable for a given pharmacologically active compound are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof.
  • the tablet according to the invention preferably contains no antagonists selected from among the group comprising naloxone, naltrexone, nalmefene, nalide, nalmexone, nalorphine or naluphine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate; and no neuroleptics, for example a compound selected from among the group comprising haloperidol, promethacine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopenthixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone and bromperidol.
  • no antagonists selected from among the group comprising naloxone, naltrexone
  • the tablet according to the invention furthermore preferably contains no emetic.
  • Emetics are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof.
  • the tablet according to the invention preferably contains no emetic based on one or more constituents of ipecacuanha (ipecac) root, for example based on the constituent emetine, as are, for example, described in “Pharmazeutician Biologie—Drogen and Hä Kunststoffsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, New York, 1982.
  • the corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure.
  • the tablet according to the invention preferably also contains no apomorphine as an emetic.
  • the tablet according to the invention preferably also contains no bitter substance.
  • bitter substances and the quantities effective for use may be found in US-2003/0064099 A1, the corresponding disclosure of which should be deemed to be the disclosure of the present application and is hereby introduced as a reference.
  • bitter substances are aromatic oils, such as peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit aroma substances, aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof, and/or denatonium benzoate.
  • the tablet according to the invention accordingly preferably contains neither substances which irritate the nasal passages and/or pharynx, nor antagonists for the pharmacologically active compound, nor emetics, nor bitter substances.
  • the pharmacologically active compound is preferably an opioid, particularly preferably tapentadol or a physiologically acceptable salt thereof;
  • the polyalkylene oxide preferably is a polyethylene oxide having a weight average molecular weight of at least 500,000 g/mol;
  • the plasticizer preferably is a polyethylene glycol; and
  • the antioxidant preferably is ⁇ -tocopherol.
  • the tablet according to the invention may comprise one or more pharmaceutical excipients such as binders, fillers, lubricants and the like.
  • the table additionally comprises a lubricant.
  • a lubricant Magnesium stearate is preferred. Further preferred lubricants are described above and therefore are not repeated hereinafter.
  • the tablet contains an additional lubricant outside the preferably pre-compacted or pre-granulated matrix material, its content is preferably not more than 1 wt.-%, more preferably not more than 0.5 wt.-%, based on the total weight of the tablet.
  • the tablet according to the invention preferably exhibit increased mechanical strength
  • the tablet as such preferably has conventional mechanical properties.
  • the tablet according to the invention can be crushed e.g. by means of a hammer thereby yielding a fractured composition containing the matrix material, the particulates and any other ingredients contained in the tablet.
  • the particulates thereby obtained in more or less isolated form preferably cannot be further crushed and fractured by means of a hammer.
  • the particulates are hot melt-extruded and/or have a breaking strength of at least 300 N.
  • the tablet according to the invention is tamper-resistant.
  • tamper-resistance is achieved based on the mechanical properties of the particulates so that comminution is avoided or at least substantially impeded.
  • the term comminution means the pulverization of the particulates using conventional means usually available to an abuser, for example a pestle and mortar, a hammer, a mallet or other conventional means for pulverizing under the action of force.
  • tamper-resistance preferably means that pulverization of the particulates using conventional means is avoided or at least substantially impeded.
  • the mechanical properties of the particulates according to the invention substantially rely on the presence and spatial distribution of polyalkylene oxide, although their mere presence does typically not suffice in order to achieve said properties.
  • the advantageous mechanical properties of the particulates according to the invention may not automatically be achieved by simply processing pharmacologically active compound, polyalkylene oxide, and optionally further excipients by means of conventional methods for the preparation of tablets.
  • suitable apparatuses must be selected for the preparation and critical processing parameters must be adjusted, particularly pressure/force, temperature and time.
  • the process protocols usually must be adapted in order to meet the required criteria.
  • the particulates exhibiting the desired properties may be obtained only if, during preparation of the particulates,
  • the process protocols must be adapted in order to meet the required criteria. Therefore, the breaking strength and deformability of the particulates is separable from the composition.
  • the particulates contained in the tablet according to the invention preferably have a breaking strength of at least 300 N, at least 400 N, or at least 500 N, preferably at least 600 N, more preferably at least 700 N, still more preferably at least 800 N, yet more preferably at least 1000 N, most preferably at least 1250 N and in particular at least 1500 N.
  • breaking strength test can usually be terminated once the force corresponding to the desired breaking strength has been slightly exceeded, e.g. at forces of e.g. 330 N and 550 N, respectively.
  • the “breaking strength” (resistance to crushing) of a tablet and of a particulate is known to the skilled person. In this regard it can be referred to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann et al., Tablets: Tablets, Vol. 2, Informa Healthcare; 2 edition, 1990; and Encyclopedia of Pharmaceutical Technology, Informa Healthcare; 1 edition.
  • the particulates according to the invention are distinguished from conventional particulates that can be contained in tablets in that, due to their breaking strength, they cannot be pulverized by the application of force with conventional means, such as for example a pestle and mortar, a hammer, a mallet or other usual means for pulverization, in particular devices developed for this purpose (tablet crushers).
  • pulverization means crumbling into small particles. Avoidance of pulverization virtually rules out oral or parenteral, in particular intravenous or nasal abuse.
  • Breaking Strength [in N] 10 ⁇ Diameter Of The Tablet/Particulate [in mm].
  • a round tablet/particulate having a breaking strength of at least 300 N would require a diameter of at least 30 mm).
  • Such a particulate could not be swallowed, let alone a tablet containing a plurality of such particulates.
  • the above empirical formula preferably does not apply to the particulates according to the invention, which are not conventional but rather special.
  • the actual mean chewing force is about 220 N (cf., e.g., P. A. Proeschel et al., J Dent Res, 2002, 81(7), 464-468).
  • the particulates according to the invention can preferably withstand a weight of more than 30 kg without being pulverized.
  • the breaking strength can be measured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08 “Resistance to Crushing of Tablets”.
  • the test is intended to determine, under defined conditions, the resistance to crushing of tablets and particulates, respectively, measured by the force needed to disrupt them by crushing.
  • the apparatus consists of 2 jaws facing each other, one of which moves towards the other.
  • the flat surfaces of the jaws are perpendicular to the direction of movement.
  • the crushing surfaces of the jaws are flat and larger than the zone of contact with the tablet and particulate, respectively.
  • the apparatus is calibrated using a system with a precision of 1 Newton.
  • the tablet and particulate, respectively, is placed between the jaws, taking into account, where applicable, the shape, the break-mark and the inscription; for each measurement the tablet and particulate, respectively, is oriented in the same way with respect to the direction of application of the force (and the direction of extension in which the breaking strength is to be measured).
  • the measurement is carried out on 10 tablets and particulates, respectively, taking care that all fragments have been removed before each determination.
  • the result is expressed as the mean, minimum and maximum values of the forces measured, all expressed in Newton.
  • breaking strength breaking force
  • the breaking strength can alternatively be measured in accordance with the method described therein where it is stated that the breaking strength is the force required to cause a tablet and particulate, respectively, to fail (i.e., break) in a specific plane.
  • the tablets and particulates, respectively are generally placed between two platens, one of which moves to apply sufficient force to the tablet and particulate, respectively, to cause fracture.
  • loading occurs across their diameter (sometimes referred to as diametral loading), and fracture occurs in the plane.
  • the breaking force of tablets and particulates, respectively is commonly called hardness in the pharmaceutical literature; however, the use of this term is misleading.
  • hardness refers to the resistance of a surface to penetration or indentation by a small probe.
  • crushing strength is also frequently used to describe the resistance of tablets and particulate, respectively, to the application of a compressive load. Although this term describes the true nature of the test more accurately than does hardness, it implies that tablets and particulate, respectively, are actually crushed during the test, which is often not the case.
  • the breaking strength can be measured in accordance with WO 2008/107149, which can be regarded as a modification of the method described in the Eur. Ph.
  • a skilled person knows how to properly adjust the test speed, e.g. to 10 mm/min, 20 mm/min, or 40 mm/min, for example.
  • LE-position clamping length 150 mm.
  • LE-speed 500 mm/min
  • clamping length after pre-travel 195 mm
  • pre-travel speed 500 mm/min
  • pre-force speed 10 mm/min sample data: no sample form, measuring length traverse distance 10 mm, no input required prior to testing—testing/end of test
  • test speed position-controlled 10 mm/min, delay speed shift: 1, force shut down threshold 50% F max , no force threshold for break-tests, no max length variation
  • upper force limit 600N—expansion compensation: no correction of measuring length—actions after testing: LE to be set after test, no unload of sample—TRS: data memory: TRS distance interval until break 1 ⁇ m, TRS time interval 0.1 s, TRS force interval 1N—machine; traverse distance controller: upper soft end 3
  • the particulate is regarded as being broken if it is fractured into at least two separate pieces of comparable morphology. Separated matter having a morphology different from that of the deformed particulate, e.g. dust, is not considered as pieces qualifying for the definition of breaking.
  • the particulates according to the invention preferably exhibit mechanical strength over a wide temperature range, in addition to the breaking strength (resistance to crushing) optionally also sufficient hardness, yield strength, fatigue strength, impact resistance, impact elasticity, tensile strength, compressive strength and/or modulus of elasticity, optionally also at low temperatures (e.g. below ⁇ 24° C., below ⁇ 40° C. or possibly even in liquid nitrogen), for it to be virtually impossible to pulverize by spontaneous chewing, grinding in a mortar, pounding, etc.
  • breaking strength resistance to crushing
  • sufficient hardness, yield strength, fatigue strength, impact resistance, impact elasticity, tensile strength, compressive strength and/or modulus of elasticity optionally also at low temperatures (e.g. below ⁇ 24° C., below ⁇ 40° C. or possibly even in liquid nitrogen), for it to be virtually impossible to pulverize by spontaneous chewing, grinding in a mortar, pounding, etc.
  • the comparatively high breaking strength of the particulate according to the invention is maintained even at low or very low temperatures, e.g., when the tablet is initially chilled to increase its brittleness, for example to temperatures below ⁇ 25° C., below ⁇ 40° C. or even in liquid nitrogen.
  • the particulate according to the invention is characterized by a certain degree of breaking strength. This does not mean that the particulate must also exhibit a certain degree of hardness. Hardness and breaking strength are different physical properties. Therefore, the tamper-resistance of the tablet does not necessarily depend on the hardness of the particulates. For instance, due to its breaking strength, impact strength, elasticity modulus and tensile strength, respectively, the particulates can preferably be deformed, e.g. plastically, when exerting an external force, for example using a hammer, but cannot be pulverized, i.e., crumbled into a high number of fragments. In other words, the particulates according to the invention are characterized by a certain degree of breaking strength, but not necessarily also by a certain degree of form stability.
  • a particulate that is deformed when being exposed to a force in a particular direction of extension but that does not break is preferably to be regarded as having the desired breaking strength in said direction of extension.
  • Preferred particulates present in the tablets according to the invention are those having a suitable tensile strength as determined by a test method currently accepted in the art. Further preferred particulates are those having a Youngs Modulus as determined by a test method of the art. Still further preferred particulates are those having an acceptable elongation at break.
  • the particulates according to the invention preferably exhibit a certain degree of deformability.
  • the particulates contained in the tablet according to the invention preferably have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above.
  • FIGS. 5 and 6 This mechanical property, i.e. the deformability of the individual particulates, is illustrated in FIGS. 5 and 6 .
  • FIG. 5 schematically illustrates the measurement and the corresponding force-displacement-diagram.
  • FIG. 5A shows the initial situation at the beginning of the measurement.
  • the sample particulate ( 9 ) is placed between upper jaw ( 8 a ) and lower jaw ( 8 b ) which each are in intimate contact with the surface of the particulate ( 9 ).
  • the initial displacement d 0 between upper jaw ( 8 a ) and lower jaw ( 8 b ) corresponds to the extension of the particulate orthogonal to the surfaces of upper jaw ( 8 a ) and lower jaw ( 8 b ).
  • no force is exerted at all and thus, no graph is displayed in the force-displacement-diagram below.
  • FIG. 5B shows a situation where due to the movement of upper jaw ( 8 a ) towards lower jaw ( 8 b ) a force is exerted on particulate ( 9 ). Because of its deformability, the particulate ( 9 ) is flattened without being fractured.
  • 5C shows a situation where due to the continuous movement of upper jaw ( 8 a ) towards lower jaw ( 8 b ), the force that is exerted on particulate ( 9 ) causes further deformation, although the particulate ( 9 ) does not fracture.
  • FIG. 6 schematically illustrates the measurement and the corresponding force-displacement-diagram of a conventional comparative particulate not having the degree of deformability as the particulates according to the invention.
  • FIG. 6A shows the initial situation at the beginning of the measurement.
  • the comparative sample particulate ( 9 ) is placed between upper jaw ( 8 a ) and lower jaw ( 8 b ) which each are in intimate contact with the surface of the comparative particulate ( 9 ).
  • the initial displacement d 0 between upper jaw ( 8 a ) and lower jaw ( 8 b ) corresponds to the extension of the comparative particulate orthogonal to the surfaces of upper jaw ( 8 a ) and lower jaw ( 8 b ).
  • FIG. 6B shows a situation where due to the movement of upper jaw ( 8 a ) towards lower jaw ( 8 b ) a force is exerted on comparative particulate ( 9 ). Because of some deformability, the comparative particulate ( 9 ) is slightly flattened without being fractured.
  • the force-displacement-diagram indicates that after a reduction of the displacement d 0 of upper jaw ( 8 a ) and lower jaw ( 8 b ) by distance x 1 , i.e.
  • FIG. 6C shows a situation where due to the continuous movement of upper jaw ( 8 a ) towards lower jaw ( 8 b ), the force that is exerted on particulate ( 9 ) causes sudden fracture of the comparative particulate ( 9 ).
  • the particulate ( 9 ) has been broken (fractured) and no steady increase of the force in the force-displacement-diagram is measured.
  • the sudden drop (decrease) of the force can easily be recognized and does not need to be quantified for the measurement.
  • the particulates contained in the tablet according to the invention have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant speed), preferably at least until the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) has been reduced to a value of 90% of the original displacement d 0 (i.e.
  • d 0.9 ⁇ d 0 ), preferably to a displacement d of 80% of the original displacement d 0 , more preferably to a displacement d of 70% of the original displacement d 0 , still more preferably to a displacement d of 60% of the original displacement d 0 , yet more preferably to a displacement d of 50% of the original displacement d 0 , even more preferably to a displacement d of 40% of the original displacement d 0 , most preferably to a displacement d of 30% of the original displacement d 0 , and in particular to a displacement d of 20% of the original displacement d 0 , or to a displacement d of 15% of the original displacement d 0 , to a displacement d of 10% of the original displacement d 0 , or to a displacement d of 5% of the original displacement d 0 .
  • the particulates contained in the tablet according to the invention have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant speed), preferably at least until the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) has been reduced to 0.80 mm or 0.75 mm, preferably 0.70 mm or 0.65 mm, more preferably 0.60 mm or 0.55 mm, still more preferably 0.50 mm or 0.45 mm, yet more preferably 0.40 mm or 0.35 mm, even more preferably 0.30 mm or 0.25 mm, most preferably 0.20 mm or 0.15 mm and in particular 0.10 or 0.05 mm.
  • the particulates contained in the tablet according to the invention have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant speed), at least until the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) has been reduced to 50% of the original displacement d 0 (i.e.
  • the force measured at said displacement is at least 25 N or at least 50 N, preferably at least 75 N or at least 100 N, still more preferably at least 150 N or at least 200 N, yet more preferably at least 250 N or at least 300 N, even more preferably at least 350 N or at least 400 N, most preferably at least 450 N or at least 500 N, and in particular at least 625 N, or at least 750 N, or at least 875 N, or at least 1000 N, or at least 1250 N, or at least 1500 N.
  • the particulates contained in the tablet according to the invention have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant speed), at least until the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) has been reduced by at least 0.1 mm, more preferably at least 0.2 mm, still more preferably at least 0.3 mm, yet more preferably at least 0.4 mm, even more preferably at least 0.5 mm, most preferably at least 0.6 mm, and in particular at least 0.7 mm, whereas the force measured at said displacement is within the range of from 5.0 N to 250 N, more preferably from 7.5 N to 225 N, still more preferably from 10 N to 200 N, yet more preferably from 15 N to 175 N, even more preferably from 20 N to 150 N, most preferably from
  • the particulates contained in the tablet according to the invention have a deformability such that they are deformed without being fractured when subjected to a constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant force), until the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) is reduced so that no further deformation takes place at said constant force, whereas at this equilibrated state the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) is at most 90% of the original displacement d 0 (i.e.
  • d ⁇ 0.9 ⁇ d 0 preferably at most 80% of the original displacement d 0 (i.e. d ⁇ 0.8 ⁇ d 0 ), more preferably at most 70% of the original displacement d 0 (i.e. d ⁇ 0.7 ⁇ d 0 ), still more preferably at most 60% of the original displacement d 0 (i.e. d ⁇ 0.6 ⁇ d 0 ), yet more preferably at most 50% of the original displacement d 0 (i.e. d ⁇ 0.5 ⁇ d 0 ), even more preferably at most 40% of the original displacement d 0 (i.e. d ⁇ 0.4 ⁇ d 0 ), most preferably at most 30% of the original displacement d 0 (i.e.
  • d ⁇ 0.3 ⁇ d 0 and in particular at most 20% of the original displacement d 0 (i.e. d ⁇ 0.2 ⁇ d 0 ), or at most 15% of the original displacement d 0 (i.e. d ⁇ 0.15 ⁇ d 0 ), at most 10% of the original displacement d 0 (i.e. d ⁇ 0.1 ⁇ d 0 ), or at most 5% of the original displacement d 0 (i.e. d ⁇ 0.05 ⁇ d 0 ).
  • the particulates contained in the tablet according to the invention have a deformability such that they are deformed without being fractured when subjected to a constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant force), until the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) is reduced so that no further deformation takes place at said constant force, whereas at this equilibrated state the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) is at most 0.80 mm or at most 0.75 mm, preferably at most 0.70 mm or at most 0.65 mm, more preferably at most 0.60 mm or at most 0.55 mm, still more preferably at most 0.50 mm or at most 0.45 mm, yet more preferably at most 0.40 mm or at most 0.35 mm, even more preferably at most 0.30 mm or at most
  • the particulates contained in the tablet according to the invention have a deformability such that they are deformed without being fractured when subjected to a constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant force), until the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) is reduced so that no further deformation takes place at said constant force, whereas at this equilibrated state the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) is at least 5% of the original displacement d 0 (i.e.
  • d ⁇ 0.05 ⁇ d 0 preferably at least 10% of the original displacement d 0 (i.e. d ⁇ 0.1 ⁇ d 0 ), more preferably at least 15% of the original displacement d 0 (i.e. d ⁇ 0.15 ⁇ d 0 ), still more preferably at least 20% of the original displacement d 0 (i.e. d ⁇ 0.2 ⁇ d 0 ), yet more preferably at least 30% of the original displacement d 0 (i.e. d ⁇ 0.3 ⁇ d 0 ), even more preferably at least 40% of the original displacement d 0 (i.e. d ⁇ 0.4 ⁇ d 0 ), most preferably at least 50% of the original displacement d 0 (i.e.
  • d ⁇ 0.5 ⁇ d 0 and in particular at least 60% of the original displacement d 0 (i.e. d ⁇ 0.6 ⁇ d 0 ), or at least 70% of the original displacement d 0 (i.e. d ⁇ 0.7 ⁇ d 0 ), at least 80% of the original displacement d 0 (i.e. d ⁇ 0.8 ⁇ d 0 ), or at least 90% of the original displacement d 0 (i.e. d ⁇ 0.9 ⁇ d 0 ).
  • the particulates contained in the tablet according to the invention have a deformability such that they are deformed without being fractured when subjected to a constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant force), until the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) is reduced so that no further deformation takes place at said constant force, whereas at this equilibrated state the displacement d of upper jaw ( 8 a ) and lower jaw ( 8 b ) is at least 0.05 mm or at least 0.10 mm, preferably at least 0.15 mm or at least 0.20 mm, more preferably at least 0.25 mm or at least 0.30 mm, still more preferably at least 0.35 mm or at least 0.40 mm, yet more preferably at least 0.45 mm or at least 0.50 mm, even more preferably at least 0.55 mm or at least
  • the tablet according to the invention provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur.
  • immediate release as applied to tablets is understood by persons skilled in the art which has structural implications for the respective tablets.
  • the term is defined, for example, in the current issue of the US Pharmacopoeia (USP), General Chapter 1092, “THE DISSOLUTION PROCEDURE: DEVELOPMENT AND VALIDATION”, heading “STUDY DESIGN”, “Time Points”.
  • USP US Pharmacopoeia
  • TONE DISSOLUTION PROCEDURE DEVELOPMENT AND VALIDATION
  • STUDY DESIGN Time Points
  • time Points For immediate-release dosage forms, the duration of the procedure is typically 30 to 60 minutes; in most cases, a single time point specification is adequate for Pharmacopeia purposes.
  • Industrial and regulatory concepts of product comparability and performance may require additional time points, which may also be required for product registration or approval. A sufficient number of time points should be selected to adequately characterize the ascending and plateau phases of the dissolution curve.
  • the tablet according to the invention has released after 30 minutes at least 70%, more preferably at least 75%, still more preferably at least 80%, yet more preferably at least 82%, most preferably at least 84% and in particular at east 86% of the pharmacologically active compound originally contained in the tablet.
  • the tablet according to the invention has released after 10 minutes at least 70%, more preferably at least 73%, still more preferably at least 76%, yet more preferably at least 78%, most preferably at least 80% and in particular at east 82% of the pharmacologically active compound originally contained in the tablet.
  • the release profile, the drug and the pharmaceutical excipients of the tablet according to the invention are stable upon storage, preferably upon storage at elevated temperature, e.g. 40° C., for 3 months in sealed containers.
  • “stable” means that when comparing the initial release profile with the release profile after storage, at any given time point the release profiles deviate from one another by not more than 20%, more preferably not more than 15%, still more preferably not more than 10%, yet more preferably not more than 7.5%, most preferably not more than 5.0% and in particular not more than 2.5%.
  • stable means that the tablets satisfy the requirements of EMEA concerning shelf-life of pharmaceutical products.
  • the release profile is measured under the following conditions: Paddle apparatus equipped without sinker, 50 rpm, 37 ⁇ 5° C., 900 mL simulated intestinal fluid pH 6.8 (phosphate buffer) or pH 4.5.
  • the rotational speed of the paddle is increased to 75 rpm.
  • the tablet according to the invention is adapted for administration once daily. In another preferred embodiment, the tablet according to the invention is adapted for administration twice daily. In still another preferred embodiment, the tablet according to the invention is adapted for administration thrice daily. In yet another preferred embodiment, the tablet according to the invention is adapted for administration more frequently than thrice daily, for example 4 times daily, 5 times daily, 6 times daily, 7 times daily or 8 times daily.
  • “twice daily” means equal or nearly equal time intervals, i.e., about every 12 hours, or different time intervals, e.g., 8 and 16 hours or 10 and 14 hours, between the individual administrations.
  • thrice daily means equal or nearly equal time intervals, i.e., about every 8 hours, or different time intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours, between the individual administrations.
  • the tablet according to the invention has under in vitro conditions a disintegration time measured in accordance with Ph. Eur. of at most 5 minutes, more preferably at most 4 minutes, still more preferably at most 3 minutes, yet more preferably at most 2.5 minutes, most preferably at most 2 minutes and in particular at most 1.5 minutes.
  • oral dosage forms can be designed that provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • the disintegration time of the tablets according to the invention can be influenced by the relative weight ratio of matrix material:particulates. In general, it was observed that the higher this ratio the faster disintegration. However, this ratio cannot be increased ad ultimo, as further tablet properties need to be taken into account, particularly drug load and total tablet size and weight. As a certain dosage of pharmacologically active compound needs to be administered, the content of particulates should still be sufficiently high and the total tablet weight should not exceed a certain limit, as this would deteriorate patient compliance, e.g. swallowability.
  • the tablettability of the tablets according to the invention can also be influenced by the relative weight ratio of matrix material:particulates. In general, it was observed that the lower this ratio the better the tablettability. This trend parallels the trend of the drug load.
  • disintegration time on the one hand and tablettability/drug load on the other hand can be optimized by finding the best compromise.
  • tamper-resistance and drug release also antagonize each other. While smaller particulates should typically show a faster release of the pharmacologically active compound, tamper-resistance requires some minimal size of the particulates in order to effectively prevent abuse, e.g. i.v. administration. The larger the particulates are the less they are suitable for being abused nasally. The smaller the particulates are the faster gel formation occurs.
  • Preferred embodiments D 1 to D 4 of the tablets according to the invention are summarized in the table here below:
  • the particulates according to the invention are preferably prepared by melt-extrusion, although also other methods of thermoforming may be used in order to manufacture the particulates according to the invention such as press-molding at elevated temperature or heating of particulates that were manufactured by conventional compression in a first step and then heated above the softening temperature of the polyalkylene oxide in the particulates in a second step to form hard tablets.
  • thermoforming means the forming, or molding of a mass after the application of heat.
  • the particulates are thermoformed by hot-melt extrusion.
  • the particulates are prepared by hot melt-extrusion, preferably by means of a twin-screw-extruder.
  • Melt extrusion preferably provides a melt-extruded strand that is preferably cut into monoliths, which are then optionally compressed and formed into particulates.
  • compression is achieved by means of a die and a punch, preferably from a monolithic mass obtained by melt extrusion. If obtained via melt extrusion, the compressing step is preferably carried out with a monolithic mass exhibiting ambient temperature, that is, a temperature in the range from 20 to 25° C.
  • the strands obtained by way of extrusion can either be subjected to the compression step as such or can be cut prior to the compression step.
  • This cutting can be performed by usual techniques, for example using rotating knives or compressed air, at elevated temperature, e.g. when the extruded stand is still warm due to hot-melt extrusion, or at ambient temperature, i.e. after the extruded strand has been allowed to cool down.
  • singulation of the extruded strand into extruded particulates is preferably performed by cutting the extruded strand immediately after it has exited the extrusion die.
  • subsequent singulation of the extruded strand into extruded particulates is preferably performed by optionally transporting the still hot extruded strand by means of conveyor belts, allowing it to cool down and to congeal, and subsequently cutting it into extruded particulates.
  • the shaping can take place as described in EP-A 240 906 by the extrudate being passed between two counter-rotating calender rolls and being shaped directly to particulates. It is of course also possible to subject the extruded strands to the compression step or to the cutting step when still warm, that is more or less immediately after the extrusion step.
  • the extrusion is preferably carried out by means of a twin-screw extruder.
  • the particulates according to the invention may be produced by different processes, the particularly preferred of which are explained in greater detail below.
  • Several suitable processes have already been described in the prior art. In this regard it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, and WO 2006/082099.
  • the process for the production of the particulates according to the invention preferably comprises the following steps:
  • Heat may be supplied directly, e.g. by contact or by means of hot gas such as hot air, or with the assistance of ultrasound; or is indirectly supplied by friction and/or shear.
  • Force may be applied and/or the particulates may be shaped for example by direct tabletting or with the assistance of a suitable extruder, particularly by means of a screw extruder equipped with one or two screws (single-screw-extruder and twin-screw-extruder, respectively) or by means of a planetary gear extruder.
  • the final shape of the particulates may either be provided during the hardening of the mixture by applying heat and force (step (c)) or in a subsequent step (step (e)).
  • the mixture of all components is preferably in the plastified state, i.e. preferably, shaping is performed at a temperature at least above the softening point of the polyalkylene oxide.
  • extrusion at lower temperatures e.g. ambient temperature, is also possible and may be preferred.
  • Shaping can be performed, e.g., by means of a tabletting press comprising die and punches of appropriate shape.
  • a particularly preferred process for the manufacture of the particulates according to the invention involves hot-melt extrusion.
  • the particulates according to the invention are produced by thermoforming with the assistance of an extruder, preferably without there being any observable consequent discoloration of the extrudate.
  • Mixing of the components according to process step a) may also proceed in the extruder.
  • the components may also be mixed in a mixer known to the person skilled in the art.
  • the mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer.
  • The, preferably molten, mixture which has been heated in the extruder at least up to the softening point of polyalkylene oxide is extruded from the extruder through a die with at least one bore.
  • the process according to the invention requires the use of suitable extruders, preferably screw extruders. Screw extruders which are equipped with two screws (twin-screw-extruders) are particularly preferred.
  • extrusion is performed in the absence of water, i.e., no water is added.
  • traces of water e.g., caused by atmospheric humidity may be present.
  • the extruder preferably comprises at least two temperature zones, with heating of the mixture at least up to the softening point of the polyalkylene oxide proceeding in the first zone, which is downstream from a feed zone and optionally mixing zone.
  • the throughput of the mixture is preferably from 1.0 kg to 15 kg/hour. In a preferred embodiment, the throughput is from 0.5 kg/hour to 3.5 kg/hour. In another preferred embodiment, the throughput is from 4 to 15 kg/hour.
  • the die head pressure is within the range of from 25 to 200 bar.
  • the die head pressure can be adjusted inter alia by die geometry, temperature profile, extrusion speed, number of bores in the dies, screw configuration, first feeding steps in the extruder, and the like.
  • the die geometry or the geometry of the bores is freely selectable.
  • the die or the bores may accordingly exhibit a round, oblong or oval cross-section, wherein the round cross-section preferably has a diameter of 0.1 mm to 2 mm.
  • the die or the bores have a round cross-section.
  • the casing of the extruder used according to the invention may be heated or cooled.
  • the corresponding temperature control i.e. heating or cooling, is so arranged that the mixture to be extruded exhibits at least an average temperature (product temperature) corresponding to the softening temperature of the polyalkylene oxide and does not rise above a temperature at which the pharmacologically active compound to be processed may be damaged.
  • the temperature of the mixture to be extruded is adjusted to below 180° C., preferably below 150° C., but at least to the softening temperature of polyalkylene oxide.
  • Typical extrusion temperatures are 120° C. and 150° C.
  • the extruder torque is within the range of from 30 to 95%.
  • Extruder torque can be adjusted inter alia by die geometry, temperature profile, extrusion speed, number of bores in the dies, screw configuration, first feeding steps in the extruder, and the like.
  • the extrudates are preferably singulated. This singulation may preferably be performed by cutting up the extrudates by means of revolving or rotating knives, wires, blades or with the assistance of laser cutters.
  • intermediate or final storage of the optionally singulated extrudate or the final shape of the particulates according to the invention is performed under oxygen-free atmosphere which may be achieved, e.g., by means of oxygen-scavengers.
  • the singulated extrudate may be press-formed into particulates in order to impart the final shape to the particulates.
  • the application of force in the extruder onto the at least plasticized mixture is adjusted by controlling the rotational speed of the conveying device in the extruder and the geometry thereof and by dimensioning the outlet orifice in such a manner that the pressure necessary for extruding the plasticized mixture is built up in the extruder, preferably immediately prior to extrusion.
  • the extrusion parameters which, for each particular composition, are necessary to give rise to a tablet with desired mechanical properties, may be established by simple preliminary testing.
  • extrusion may be performed by means of a twin-screw-extruder type ZSE 18 or ZSE27 (Leistritz, 1991, Germany), screw diameters of 18 or 27 mm. Screws having eccentric or blunt ends may be used.
  • a heatable die with a round bore or with a multitude of bores each having a diameter of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 mm may be used.
  • the extrusion parameters may be adjusted e.g.
  • the throughput can generally be increased by increasing the number of dies at the extruder outlet.
  • extrusion is performed by means of twin-screw-extruders or planetary-gear-extruders, twin-screw extruders (co-rotating or contra-rotating) being particularly preferred.
  • the particulates according to the invention are preferably produced by thermoforming with the assistance of an extruder without any observable consequent discoloration of the extrudates.
  • the process for the preparation of the particulates according to the invention is preferably performed continuously.
  • the process involves the extrusion of a homogeneous mixture of all components.
  • the thus obtained intermediate e.g. the strand obtained by extrusion, exhibits uniform properties.
  • Particularly desirable are uniform density, uniform distribution of the active compound, uniform mechanical properties, uniform porosity, uniform appearance of the surface, etc. Only under these circumstances the uniformity of the pharmacological properties, such as the stability of the release profile, may be ensured and the amount of rejects can be kept low.
  • the particulates according to the invention can be regarded as “extruded pellets”.
  • extruded pellets has structural implications which are understood by persons skilled in the art. A person skilled in the art knows that pelletized dosage forms can be prepared by a number of techniques, including:
  • extruded pellets can be obtained either by hot-melt extrusion or by extrusion-spheronization.
  • Extruded pellets can be distinguished from other types of pellets, as extruded pellets typically have a different shape.
  • the shape of the extruded pellets is typically more cut-rod-like than perfectly globated round.
  • Extruded pellets can be distinguished from other types of pellets because they are structurally different. For example, drug layering on nonpareils yields multilayered pellets having a core, whereas extrusion typically yields a monolithic mass comprising a homogeneous mixture of all ingredients. Similarly, spray drying and spray congealing typically yield spheres, whereas extrusion typically yields cylindrical extrudates which can be subsequently spheronized.
  • extruded pellets and “agglomerated pellets” are significant because they may affect the release of active substances from the pellets and consequently result in different pharmacological profiles. Therefore, a person skilled in the pharmaceutical formulation art would not consider “extruded pellets” to be equivalent to “agglomerated pellets”.
  • the tablets according to the invention may be prepared by any conventional method. Preferably, however, the tablets are prepared by compression.
  • particulates as hereinbefore defined are preferably mixed, e.g. blended and/or granulated (e.g. wet granulated), with matrix material and the resulting mix (e.g. blend or granulate) is then compressed, preferably in moulds, to form tablets.
  • the particulates herein described may be incorporated into a matrix using other processes, such as by melt granulation (e.g. using fatty alcohols and/or water-soluble waxes and/or water-insoluble waxes) or high shear granulation, followed by compression.
  • the compression force is preferably within the range of from 5 to 15 kN.
  • the compression force is preferably within the range of from 5 to 40 kN, in certain embodiments>25 kN, in other embodiments about 13 kN.
  • the tablets according to the invention may optionally comprise a coating, e.g. a cosmetic coating.
  • the coating is preferably applied after formation of the tablet.
  • the coating may be applied prior to or after the curing process.
  • Preferred coatings are Opadry® coatings available from Colorcon.
  • Other preferred coating are Opaglos® coatings, also commercially available from Colorcon.
  • the tablet according to the invention is characterized by excellent storage stability.
  • the content of pharmacologically active compound amounts to at least 98.0%, more preferably at least 98.5%, still more preferably at least 99.0%, yet more preferably at least 99.2%, most preferably at least 99.4% and in particular at least 99.6%, of its original content before storage.
  • Suitable methods for measuring the content of the pharmacologically active compound in the tablet are known to the skilled artisan. In this regard it is referred to the Eur. Ph. or the USP, especially to reversed phase HPLC analysis.
  • the tablet is stored in closed, preferably sealed containers.
  • the particulates and tablets according to the invention may be used in medicine, e.g. as an analgesic.
  • the particulates and tablets are therefore particularly suitable for the treatment or management of pain.
  • the pharmacologically active compound is preferably an analgesic.
  • a further aspect according to the invention relates to the tablet as described above for use in the treatment of pain.
  • a further aspect according to the invention relates to the use of a tablet as described above for avoiding or hindering the abuse of the pharmacologically active compound contained therein.
  • a further aspect according to the invention relates to the use of a tablet as described above for avoiding or hindering the unintentional overdose of the pharmacologically active compound contained therein.
  • the invention also relates to the use of a pharmacologically active compound as described above and/or a polyalkylene oxide as described above for the manufacture of the tablet according to the invention for the prophylaxis and/or the treatment of a disorder, thereby preventing an overdose of the pharmacologically active compound, particularly due to comminution of the tablet by mechanical action.
  • comparatively small particulates e.g. particulates having a diameter and length of 0.5 mm ⁇ 0.5 mm already provide a certain degree of tamper resistance: when administered nasally they cause an unpleasant feeling and furthermore, due to the lack of water on the mucous membrane, do not release the pharmacologically active compound as quick as when being administered orally. Therefore, a kick or rush can unlikely be achieved by nasal administration of such particulates.
  • comparatively small particulates already provide tamper resistance, i.e. avoid drug abuse or at least make drug abuse substantially more difficult.
  • such comparatively small particulates have excellent swelling properties thereby effectively preventing conversion into a liquid formulation for intravenous administration.
  • tamper-resistance can even further be improved by increasing the particulate size, e.g. to a diameter and length of 1.0 mm ⁇ 1.0 mm.
  • Such particulates even provide a more unpleasant feeling when being administered nasally and in the absence of sufficient water, rather slowly release the pharmacologically active compound. Further, they cannot be easily converted into a liquid formulation for intravenous administration either.
  • a predetermined particulate size of 800 ⁇ m ⁇ 800 ⁇ m was considered most appropriate, i.e. it was considered most appropriate to adjust the diameter of the extrusion die as well as cutting length of the extruded stand to 800 ⁇ m taking into consideration that die swelling may occur during the extrusion process, particularly when the strand exits the die, so that the diameter of the extruded strand in fact is expanded, depending upon the composition and the extrusion parameters to a diameter of about 1000 ⁇ m.
  • compositions 1 to 9 were extruded under the following extrusion conditions:
  • Heating zone 1 20° C. 20° C. 20° C. 20 25 Heating zone 2 100° C. 100° C. 100° C. 100 100 Heating zone 3 100° C. 100° C. 100° C. 100 100 Heating zone 4 120° C. 140° C. 120° C. 120 100 Heating zone 5 120° C. 120° C. 120° C. 120 100 Heating zone 6 120° C. 120° C. 120° C. 120 100 Heating zone 7 120° C. 140° C. 120° C. 120 100 Heating zone 8 120° C. 140° C. 120° C. 120 100 Heating zone 10 120° C. 140° C. 120° C. 120 120 120 Heating zone 11 130° C. 150° C. 130° C. 130 120 Screw speed [rpm] 100 100 100 100 100 100 100 100 Throughput 10.00-16.66 16.66-28.04 16.66 16.66 16.66 [g/min] Screw low low low low extreme low configuration shear shear shear shear shear shear shear
  • screw configuration can be adopted and temperatures can be raised (e.g., HZ8 and 10: 130° C., HZ11: 145° C.; or HZ11: 150° C. and extreme shear configuration, throughput 25 g/min).
  • the in vitro release characteristics were monitored in 900 mL 0.1N HCl at 37° C., using a paddle apparatus 50 rpm. The results are depicted in FIG. 3 .
  • Granules having the following composition were prepared for manufacturing of pellet-tablets.
  • Granules for outer the phase i.e. the matrix material, were manufactured by wet granulation.
  • Granules and pellets were blended. Segregation (optically) and disintegration of tablets after compression were evaluated. Tablets were manufactured “manually” (components were separately weighed for each tablet and mixed directly prior to tabletting) using a single station press (Korsch EK0):
  • Galen IQ a Galen IQ
  • Na no segregation in mixture disintegration test no carboxymethylstarch (5%) detectable, detectable disintegration aqueous granulation in Diosna after 3 min.
  • b Galen IQ, Kollidon CL (5%) no segregation in mixture disintegration test aqueous granulation in Diosna detectable slightly dissolved mixture showed substantial surface after 3 min. punch deposit upon compression of 3 tablets already c Avicel with PVP-solution significant segregation in disintegration test: granulated mixture detectable partial disintegration after 3 min.
  • d MCC + lactose(20:80) with PVP- no segregation in mixture disintegration test no solution granulated detectable detectable disintegration after 3 min.
  • compositions were processed by slugging involving the steps of:
  • roller displacement 2 to 3 mm revolution velocity: 2 to 5 rpm compaction force: 3 to 15 kN/cm screen size: 1.0 to 1.25 to 1.5 to 2.0 mm
  • Tablets (500 mg) were prepared from the particulates according to Example 2-5 (250 mg) and the matrix material according to Example 4-3 #12 (250 mg).
  • FIGS. 7, 8 and 9 The corresponding force-displacement-diagrams are shown in FIGS. 7, 8 and 9 , respectively.

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Abstract

The invention relates to a tamper-resistant tablet comprising
  • (i) a matrix material in an amount of more than one third of the total weight of the tablet; and
  • (ii) a plurality of particulates in an amount of less than two thirds of the total weight of the tablet; wherein said particulates comprise a pharmacologically active compound and a polyalkylene oxide; and form a discontinuous phase within the matrix material;
    and method of using said tablet to treat pain and other conditions.

Description

    PRIORITY
  • This application is a continuation of U.S. application Ser. No. 13/559,635, filed Jul. 27, 2012, which claims priority of U.S. Provisional Patent Application No. 61/512,939, filed on Jul. 29, 2011, and European Patent Application No. 11 006 253.6, filed on Jul. 29, 2011, the contents of which patent applications are incorporated herein by reference.
  • FIELD OF THE INVENTION
  • The invention relates to tamper-resistant tablets comprising a matrix material and a plurality of particulates which comprise a pharmacologically active compound and form a discontinuous phase within the matrix material.
  • BACKGROUND OF THE INVENTION
  • A large number of pharmacologically active substances have a potential for being abused or misused, i.e. they can be used to produce effects which are not consistent with their intended use. Thus, e.g. opioids which exhibit an excellent efficacy in controlling severe to extremely severe pain, are frequently abused to induce euphoric states similar to being intoxicated. In particular, active substances which have a psychotropic effect are abused accordingly.
  • To enable abuse, the corresponding dosage forms, such as tablets or capsules are crushed, for example ground by the abuser, the active substance is extracted from the thus obtained powder using a preferably aqueous liquid and after being optionally filtered through cotton wool or cellulose wadding, the resultant solution is administered parenterally, in particular intravenously. This type of dosage results in an even faster diffusion of the active substance compared to the oral abuse, with the result desired by the abuser, namely the kick. This kick or these intoxication-like, euphoric states are also reached if the powdered dosage form is administered nasally, i.e. is sniffed.
  • Various concepts for the avoidance of drug abuse have been developed.
  • It has been proposed to incorporate in dosage forms aversive agents and/or antagonists in a manner so that they only produce their aversive and/or antagonizing effects when the dosage forms are tampered with. However, the presence of such aversive agents is principally not desirable and there is a need to provide sufficient tamper-resistance without relying on aversive agents and/or antagonists.
  • Another concept to prevent abuse relies on the mechanical properties of the pharmaceutical dosage forms, particularly an increased breaking strength (resistance to crushing). The major advantage of such pharmaceutical dosage forms is that comminuting, particularly pulverization, by conventional means, such as grinding in a mortar or fracturing by means of a hammer, is impossible or at least substantially impeded. Thus, the pulverization, necessary for abuse, of the dosage forms by the means usually available to a potential abuser is prevented or at least complicated.
  • Such pharmaceutical dosage forms are useful for avoiding drug abuse of the pharmacologically active compound contained therein, as they may not be powdered by conventional means and thus, cannot be administered in powdered form, e.g. nasally. The mechanical properties, particularly the high breaking strength of these pharmaceutical dosage forms renders them tamper-resistant. In the context of such tamper-resistant pharmaceutical dosage forms it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099, and WO2009/092601.
  • These dosage forms secured against abuse are distinguished by a controlled, preferably retarded release of the active substance which has abuse potential. However, a rapid release of the active substance is necessary for numerous therapeutic applications, for example pain relief using active substances with abuse potential.
  • WO 2010/140007 discloses dosage forms comprising melt-extruded particulates comprising a drug, wherein said melt-extruded particulates are present as a discontinuous phase in a matrix. The dosage forms provide prolonged release of the drug.
  • WO 2008/107149 discloses multiparticulate dosage forms with impeded abuse containing, one or more active substances having abuse potential, at least one synthetic or natural polymer, and at least one disintegrant, with the individual particles of the tablet having a breaking strength of at least 500 N and a release of the active substance of at least 75% after 45 minutes. The exemplified capsules provide rapid release of the pharmacologically active compound.
  • US 2010/0092553 discloses solid multiparticulate oral pharmaceutical forms whose composition and structure make it possible to avoid misuse. The microparticles have an extremely thick coating layer which assures the modified release of the drug and simultaneously imparts crushing resistance to the coated microparticles so as to avoid misuse.
  • WO 2008/033523 discloses a pharmaceutical composition that may include a granulate which may at least include one active pharmaceutical ingredient susceptible to abuse. The particle contains both an alcohol soluble and alcohol insoluble and at least partially water soluble material. Both materials are granulated in the presence of alcohol and water. The granulate may also include a coating on the granulate exhibiting crush resistance. Material deposition on the granule is performed using an alcohol based solvent.
  • The properties of capsules, however, are not satisfactory in every respect, e.g. with respect to disintegration time, patient compliance (e.g. swallowability) and ease of manufacture. Further, capsules frequently contain gelatine thus causing the risk of bovine spongiform encephalopathy (BSE, or TSE). As far as tamper-resistant dosage forms are concerned, capsules are disadvantageous as they can typically be opened easily thereby releasing the ingredients in powdery or particulate form without requiring any mechanical impact. If components of different type are contained in a capsule, e.g. drug-containing particles besides drug-free particles, a potential abuser might be able to visually distinguish the intact, undisrupted components of different type (e.g. according to their color, size or other macroscopic properties) allowing for manual separation.
  • The properties of these tamper-resistant dosage forms, however, are not satisfactory in every respect. There is a need for tamper-resistant dosage forms that possess crush resistance and release the pharmacologically active compound as quick as possible (immediate release), i.e. should show a gradual increase reaching 85% to 100% at about 30 to 45 minutes or earlier. The dosage form should advantageously be of a shape, size and weight that can be taken orally with ease. Of course, the dosage form should also be easy to make in a cost effective manner. When trying to tamper the dosage form in order to prepare a formulation suitable for abuse by intravenous administration, the liquid part of the formulation that can be separated from the remainder by means of a syringe should be as less as possible, e.g. should contain not more than 20 wt.-% of the pharmacologically active compound originally contained in the dosage form.
  • It is an object according to the invention to provide tamper-resistant pharmaceutical dosage forms that provide rapid release of the pharmacologically active compound and that have advantages compared to the tamper-resistant pharmaceutical dosage forms of the prior art.
  • This object has been achieved by the patent claims.
  • SUMMARY OF THE INVENTION
  • The invention relates to a tamper-resistant tablet, preferably for oral administration, comprising
    • (i) a matrix material in an amount of more than one third of the total weight of the tablet; and
    • (ii) a plurality of particulates in an amount of less than two thirds of the total weight of the tablet; wherein said particulates comprise a pharmacologically active compound and a polyalkylene oxide; and form a discontinuous phase within the matrix material.
  • It has been surprisingly found that the in vitro release profile of tamper-resistant dosage forms can be accelerated by embedding particulates containing the pharmacologically active compound in a matrix material and increasing the relative weight ratio of the matrix material to the particulates.
  • Further, it has been surprisingly found that mixtures of matrix material, optionally in pre-compacted or pre-granulated form, can be mixed with the particulates and subsequently be compacted to tablets which in turn exhibit excellent, i.e. accelerated disintegration times and in vitro release characteristics.
  • Still further, it has been surprisingly found that oral dosage forms can be designed that provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • The invention will now be described in greater detail with reference to the drawings, wherein:
  • FIG. 1 schematically illustrates a preferred embodiment of the tablets according to the invention.
  • FIG. 2 schematically illustrates another preferred embodiment of the tablets according to the invention.
  • FIG. 3 shows in vitro release profiles of different tablets according to the invention having different compositions and particulate sizes.
  • FIG. 4 shows in vitro release profiles of different tablets according to the invention having different compositions.
  • FIG. 5 illustrates the behavior of the particulates contained in the tablets according to the invention when being subjected to a breaking strength test, in particular their deformability.
  • FIG. 6 illustrates the behavior of conventional particulates when being subjected to a breaking strength test.
  • FIG. 7 shows the distance-force-diagram obtained by measuring the mechanical properties of conventional particulates.
  • FIG. 8 shows the distance-force-diagram obtained by measuring the mechanical properties of particulates according to the invention.
  • FIG. 9 shows the distance-force-diagram obtained by measuring the mechanical properties of particulates according to the invention.
  • DETAILED DESCRIPTION OF THE INVENTION
  • As used herein, the term “tablet” refers to a pharmaceutical entity that is comprised of a pharmacologically active compound and which is actually administered to, or taken by, a patient. It may be compressed or molded in its manufacture, and it may be of almost any size, shape, weight, and color. Most tablets are intended to be swallowed whole and accordingly, preferred tablets according to the invention are designed for oral administration. However, alternatively tablets may be dissolved in the mouth, chewed, or dissolved in liquid before swallowing, and some may be placed in a body cavity. Thus, the tablet according to the invention may alternatively be adapted for buccal, lingual, rectal or vaginal administration. Implants are also possible.
  • The tablet according to the invention preferably can be regarded as a MUPS formulation (multiple unit pellet system). In a preferred embodiment, the tablet according to the invention is monolithic. In another preferred embodiment, the tablet according to the invention is not monolithic. In this regard, monolithic preferably means that the tablet is formed or composed of material without joints or seams or consists of or constitutes a single unit.
  • Preferably, the tablet according to the invention contains all ingredients in a dense compact unit which in comparison to capsules has a comparatively high density.
  • The tablets according to the invention comprise subunits having different morphology and properties, namely drug-containing particulates and matrix material, wherein the particulates form a discontinuous phase within the matrix material. The particulates typically have mechanical properties that differ from the mechanical properties of the matrix material. Preferably, the particulates have a higher mechanical strength than the matrix material. The particulates within the tablets according to the invention can be visualized by conventional means such as solid state nuclear magnetic resonance spectroscopy, raster electron microscopy, terahertz spectroscopy and the like.
  • An advantage of the tablets according to the invention is that the same particulates may be mixed with matrix material in different amounts to thereby produce tablets of different strengths.
  • The tablet according to the invention has preferably a total weight in the range of 0.01 to 1.5 g, more preferably in the range of 0.05 to 1.2 g, still more preferably in the range of 0.1 g to 1.0 g, yet more preferably in the range of 0.2 g to 0.9 g, and most preferably in the range of 0.3 g to 0.8 g. In a preferred embodiment, the total tablet weight is within the range of 500±450 mg, more preferably 500±300 mg, still more preferably 500±200 mg, yet more preferably 500±150 mg, most preferably 500±100 mg, and in particular 500±50 mg.
  • It has been surprisingly found that the total tablet weight, which is a function of the total size of the tablet, can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • In a preferred embodiment, the tablet according to the invention is a round tablet. Tablets of this embodiment preferably have a diameter in the range of about 1 mm to about 30 mm, in particular in the range of about 2 mm to about 25 mm, more in particular about 5 mm to about 23 mm, even more in particular about 7 mm to about 13 mm; and a thickness in the range of about 1.0 mm to about 12 mm, in particular in the range of about 2.0 mm to about 10 mm, even more in particular from 3.0 mm to about 9.0 mm, even further in particular from about 4.0 mm to about 8.0 mm.
  • In another preferred embodiment, the tablet according to the invention is an oblong tablet. Tablets of this embodiment preferably have a lengthwise extension (longitudinal extension) of about 1 mm to about 30 mm, in particular in the range of about 2 mm to about 25 mm, more in particular about 5 mm to about 23 mm, even more in particular about 7 mm to about 20 mm; a width in the range of about 1 mm to about 30 mm, in particular in the range of about 2 mm to about 25 mm, more in particular about 5 mm to about 23 mm, even more in particular about 7 mm to about 13 mm; and a thickness in the range of about 1.0 mm to about 12 mm, in particular in the range of about 2.0 mm to about 10 mm, even more in particular from 3.0 mm to about 9.0 mm, even further in particular from about 4.0 mm to about 8.0 mm.
  • The tablets according to the invention can optionally be provided, partially or completely, with a conventional coating. The tablets according to the invention are preferably film coated with conventional film coating compositions. Suitable coating materials are commercially available, e.g. under the trademarks Opadry® and Eudragit®.
  • Examples of suitable materials include cellulose esters and cellulose ethers, such as methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), poly(meth)acrylates, such as aminoalkylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers; vinyl polymers, such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinylacetate; and natural film formers.
  • In a particularly preferred embodiment, the coating is water-soluble. In a preferred embodiment, the coating is based on polyvinyl alcohol, such as polyvinyl alcohol-part, hydrolyzed, and may additionally contain polyethylene glycol, such as macrogol 3350, and/or pigments. In another preferred embodiment, the coating is based on hydroxypropylmethylcellulose, preferably hypromellose type 2910 having a viscosity of 3 to 15 mPas.
  • The coating can be resistant to gastric juices and dissolve as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the tablet according to the invention passes through the stomach undissolved and the active compound is only released in the intestines. The coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5.
  • The coating can also be applied e.g. to improve the aesthetic impression and/or the taste of the tablets and the ease with which they can be swallowed. Coating the tablets according to the invention can also serve other purposes, e.g. improving stability and shelf-life. Suitable coating formulations comprise a film forming polymer such as, for example, polyvinyl alcohol or hydroxypropyl methylcellulose, e.g. hypromellose, a plasticizer such as, for example, a glycol, e.g. propylene glycol or polyethylene glycol, an opacifier, such as, for example, titanium dioxide, and a film smoothener, such as, for example, talc. Suitable coating solvents are water as well as organic solvents. Examples of organic solvents are alcohols, e.g. ethanol or isopropanol, ketones, e.g. acetone, or halogenated hydrocarbons, e.g. methylene chloride. Coated tablets according to the invention are preferably prepared by first making the cores and subsequently coating said cores using conventional techniques, such as coating in a coating pan.
  • As used herein, the term “tamper-resistant” refers to tablets that are resistant to conversion into a form suitable for misuse or abuse, particular for nasal and/or intravenous administration, by conventional means such as grinding in a mortar or crushing by means of a hammer. In this regard, the tablets as such may be crushable by conventional means. However, the particulates contained in the tablets according to the invention exhibit mechanical properties such that they cannot be pulverized by conventional means any further. As the particulates are of macroscopic size and contain the pharmacologically active compound, they cannot be administered nasally thereby rendering the tablets tamper-resistant. Preferably, when trying to tamper the dosage form in order to prepare a formulation suitable for abuse by intravenous administration, the liquid part of the formulation that can be separated from the remainder by means of a syringe is as less as possible, preferably it contains not more than 20 wt.-%, more preferably not more than 15 wt.-%, still more preferably not more than 10 wt.-%, and most preferably not more than 5 wt.-% of the originally contained pharmacologically active compound. Preferably, this property is tested by (i) dispensing a tablet that is either intact or has been manually comminuted by means of two spoons in 5 ml of purified water, (ii) heating the liquid up to its boiling point, (iii) boiling the liquid in a covered vessel for 5 min without the addition of further purified water, (iv) drawing up the hot liquid into a syringe (needle 21 G equipped with a cigarette filter), (v) determining the amount of the pharmacologically active compound contained in the liquid within the syringe.
  • Further, when trying to disrupt the tablets by means of a hammer or mortar, the particulates tend to adhere to one another thereby forming aggregates and agglomerates, respectively, which are larger in size than the untreated particulates.
  • The subjects to which the tablets according to the invention can be administered are not particularly limited. Preferably, the subjects are animals, more preferably human beings.
  • In the tablets according to the invention, the particulates are incorporated into a matrix material. From a macroscopic perspective, the matrix material preferably forms a continuous phase in which the particulates are embedded as discontinuous phase.
  • Preferably, the matrix material is a homogenous coherent mass, preferably a homogeneous mixture of solid constituents, in which the particulates are embedded thereby spatially separating the particulates from one another. While it is possible that the surfaces of particulates are in contact or at least in very close proximity with one another, the plurality of particulates preferably cannot be regarded as a single continuous coherent mass within the tablet.
  • In other words, the tablet according to the invention comprises the particulates as volume element(s) of a first type in which the pharmacologically active compound and the polyalkylene oxide are contained, preferably homogeneously, and the matrix material as volume element of a second type differing from the material that forms the particulates, preferably containing neither pharmacologically active compound nor polyalkylene oxide, but optionally polyethylene glycol which differs from polyethylene oxide in its molecular weight.
  • A purpose of the matrix material in the tablet according to the invention is to ensure rapid disintegration and subsequent release of the pharmacologically active compound from the disintegrated tablets, i.e. from the particulates. Thus, the matrix material preferably does not contain any excipient that might have a retardant effect on disintegration and drug release, respectively. Thus, the matrix material preferably does not contain any polymer that is typically employed as matrix material in prolonged release formulations.
  • FIG. 1 schematically illustrates a preferred embodiment of the tablet according to the invention. Tablet (1) contains a plurality of particulates (2) that form a discontinuous phase within matrix material (3) which in turn forms a continuous phase.
  • The tamper-resistant tablet according to the invention comprises the matrix material in an amount of more than one third of the total weight of the tablet.
  • It has been surprisingly found that the content of the matrix material in the tablet can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • Preferably, the content of the matrix material is at least 35 wt.-%, at least 37.5 wt.-% or at least 40 wt.-%; more preferably at least 42.5 wt.-%, at least 45 wt.-%, at least 47.5 wt.-% or at least 50 wt.-%; still more preferably at least 52.5 wt.-%, at least 55 wt.-%, at least 57.5 wt.-% or at least 60 wt.-%; yet more preferably at least 62.5 wt.-%, at least 65 wt.-%, at least 67.5 wt.-% or at least 60 wt.-%; most preferably at least 72.5 wt.-%, at least 75 wt.-%, at least 77.5 wt.-% or at least 70 wt.-%; and in particular at least 82.5 wt.-%, at least 85 wt.-%, at least 87.5 wt.-% or at least 90 wt.-%; based on the total weight of the tablet.
  • Preferably, the content of the matrix material is at most 90 wt.-%, at most 87.5 wt.-%, at most 85 wt.-%, or at most 82.5 wt.-%; more preferably at most 80 wt.-%, at most 77.5 wt.-%, at most 75 wt.-% or at most 72.5 wt.-%; still more preferably at most 70 wt.-%, at most 67.5 wt.-%, at most 65 wt.-% or at most 62.5 wt.-%; yet more preferably at most 60 wt.-%, at most 57.5 wt.-%, at most 55 wt.-% or at most 52.5 wt.-%; most preferably at most 50 wt.-%, at most 47.5 wt.-%, at most 45 wt.-% or at most 42.5 wt.-%; and in particular at most 40 wt.-%, at most 37.5 wt.-%, or at most 35 wt.-%; based on the total weight of the tablet.
  • In a preferred embodiment, the content of the matrix material is within the range of 40±5 wt.-%, more preferably 40±2.5 wt.-%, based on the total weight of the tablet. In another preferred embodiment, the content of the matrix material is within the range of 45±10 wt.-%, more preferably 45±7.5 wt.-%, still more preferably 45±5 wt.-%, and most preferably 45±2.5 wt.-%, based on the total weight of the tablet. In still another preferred embodiment, the content of the matrix material is within the range of 50±10 wt.-%, more preferably 50±7.5 wt.-%, still more preferably 50±5 wt.-%, and most preferably 50±2.5 wt.-%, based on the total weight of the tablet. In yet another preferred embodiment, the content of the matrix material is within the range of 55±10 wt.-%, more preferably 55±7.5 wt.-%, still more preferably 55±5 wt.-%, and most preferably 55±2.5 wt.-%, based on the total weight of the tablet.
  • Preferably, the matrix material is a mixture, preferably a homogeneous mixture of at least two different constituents, more preferably of at least three different constituents.
  • In a preferred embodiment, all constituents of the matrix material are homogeneously distributed in the continuous phase that is formed by the matrix material.
  • In a preferred embodiment, the mixture of all constituents of the matrix material is blended and employed as a powder, i.e. in non-pre-compacted form, subsequently mixed with the particulates that contain the pharmacologically active compound and the polyalkylene oxide, and then compressed into tablets. Tablets having acceptance values between about 5 and 6 according to Ph. Eur. 2.9.40 “Uniformity of Dosage Units” (UDU) can be obtained when properly adjusting the tablet press. Vibrations should be avoided to a maximal extent (e.g. by decoupling of hopper and tablet press) and clearance of equipment parts should be as small as possible. For example, on a rotary tablet press IMA S250 plus with 26 stations, the following parameters are suitable: round punches 10 mm diameter, radius of curvature 8 mm without debossing; fill curve 13 mm; tablet weight 500 mg; speed: 13700-13800 tablets per hour; pre compression force 4.7 kN; main compression force 6.7 kN and 8.7 kN; fill depth 14.5 mm and 15 mm; height of tablet bar (pre compression): 3.5 mm; height of tablet bar (main compression): 3.3 mm and 3.1 mm; revolution speed of feeder (Filomat): 40 rmp.
  • In another preferred embodiment, the matrix material is also provided in particulate form, i.e. in the course of the manufacture of the tablets according to the invention, the constituents of the matrix material are preferably processed into particulates, subsequently mixed with the particulates that contain the pharmacologically active compound and the polyalkylene oxide, and then compressed into the tablets.
  • Preferably, the average size of the particulates of the matrix material is within the range of ±60%, more preferably ±50%, still more preferably ±40%, yet more preferably ±30%, most preferably ±20%, and in particular ±10% of the average size of the particulates that contain the pharmacologically active compound and the polyalkylene oxide.
  • It has been surprisingly found that when proceeding this way, segregation phenomena upon blending the particulates can be reduced or even completely suppressed, thereby substantially improving the content uniformity of the tablets according to the invention.
  • This is particularly surprising, as the larger the particulates are which are to be mixed and compressed to tablets, the more difficult it typically is to satisfy content uniformity requirements. Compared to conventional tablets, the tablets according to the invention are manufactured from comparatively large particulates and optionally, also from comparatively large pre-compacted particulates of matrix material. Preferably, the AV (acceptance value) concerning the content uniformity of the tablets according to the invention is at most 15, more preferably at most 14, still more preferably at most 13, yet more preferably at most 12, even more preferably at most 11, most preferably at most 10 and in particular at most 9. Methods to determine the AV are known to the skilled artisan. Preferably, the AV is determined in accordance with Eur. Ph.
  • This preferred embodiment of the tablets according to the invention is schematically illustrated in FIG. 2. Tablet (1) contains a plurality of particulates (2) that form a discontinuous phase within matrix material (3) which in turn forms a continuous phase and is also provided in particulate form, the individual particulates being in intimate contact with one another at boundaries (4). As the particulates of the matrix material typically have a mechanical strength lower than that of the particulates (2), the particulates of the matrix material are deformed in the course of the manufacture of the tablets by compression.
  • The particulates of the matrix material can be manufactured by conventional methods for the preparation of aggregates and agglomerates from powder mixtures such as granulating and compacting.
  • In a preferred embodiment, the mixture of all constituents of the matrix material is blended and pre-compacted thereby yielding a pre-compacted matrix material.
  • Suitable methods for the manufacture of such a pre-compacted matrix material are known to the skilled person. Preferably, pre-compaction proceeds by dry granulation, preferably slugging or roller compaction. When proceeding this way, the process parameters are typically to be adjusted in order to achieve the desired properties (see below). Typical process parameters are compaction force (preferably adjusted within the range of 2 to 12 kN), roller displacement (preferably adjusted within the range of 2 to 5 mm) and granule sieve (preferably adjusted within the range of 1.0 to 2.0 mm). The desired properties of the pre-compacted material include primarily the particle size and the content of fine particles. The density may also play a role. The particle size is preferably within the range for the size of the particulates (preferably at least 60%>700 μm for particulates having dimensions of 0.8×0.8 mm). The content of fine particles (i.e. particles having a size of less than 600 μm) is preferably at most 40%, more preferably at most 30%, most preferably at most 20%. The effect of said process parameters on said desired properties can be easily determined by a skilled person by routine experimentation.
  • In another preferred embodiment, the mixture of all constituents of the matrix material is dry granulated thereby yielding a granulated matrix material. In still another preferred embodiment, the mixture of all constituents of the matrix material is wet granulated by means of a non-aqueous solvent e.g. ethanol thereby yielding another granulated matrix material. Aqueous granulation, however, is preferably avoided, as this typically has a detrimental influence on disintegration of the tablet. In yet another preferred embodiment, the mixture of all constituents of the matrix material is melt granulated, e.g. by means of an extruder, a heatable high-shear mixer or a granulator.
  • As already mentioned above, the matrix material in the tablet according to the invention should ensure rapid disintegration and subsequent release of the pharmacologically active compound from the disintegrated tablets, i.e. from the particulates. Thus, the matrix material preferably does not contain any excipient that might have a retardant effect on disintegration and drug release, respectively. Further, the matrix material preferably does not contain any pharmacologically active compound.
  • Preferably, the matrix material comprises a disintegrant. Suitable disintegrants are known to the skilled person and are preferably selected from the group consisting of crosslinked sodium carboxymethylcellulose (Na-CMC) (e.g. Crosscarmellose, Ac-Di-Sol®), crosslinked casein (e.g. Esma-Sprene), polysaccharide mixtures obtained from soybeans (e.g. Emcosoy®); pretreated maize starch (e.g. Amijel®); sodium alginate; polyvinylpyrrolidone (PVP) (e.g. Kollidone®, Polyplasdone®, Polydone®); crosslinked polyvinylpyrrolidone (PVP Cl) (e.g. Polyplasdone® XL); starch and pretreated starch such as sodium carboxymethyl starch (e.g. Explotab®, Prejel®, Primotab® ET, Starch® 1500, Ulmatryl®). Crosslinked polymers are particularly preferred disintegrants, especially crosslinked sodium carboxymethylcellulose (Na-CMC) or crosslinked polyvinylpyrrolidone (PVP Cl).
  • Preferably, the disintegrant is contained in the matrix material but not in the particulates of the tablet according to the invention.
  • In a preferred embodiment, the content of the disintegrant in the matrix material is within the range of 5±4 wt.-%, more preferably 5±3 wt.-%, still more preferably 5±2.5 wt.-%, yet more preferably 5±2 wt.-%, most preferably 5±1.5 wt.-%, and in particular 5±1 wt.-%, based on the total weight of matrix material. In another preferred embodiment, the content of the disintegrant in the matrix material is within the range of 7.5±4 wt.-%, more preferably 7.5±3 wt.-%, still more preferably 7.5±2.5 wt.-%, yet more preferably 7.5±2 wt.-%, most preferably 7.5±1.5 wt.-%, and in particular 7.5±1 wt.-%, based on the total weight of matrix material. In still another preferred embodiment, the content of the disintegrant in the matrix material is within the range of 10±4 wt.-%, more preferably 10±3 wt.-%, still more preferably 10±2.5 wt.-%, yet more preferably 10±2 wt.-%, most preferably 10±1.5 wt.-%, and in particular 10±1 wt.-%, based on the total weight of matrix material. In another preferred embodiment, the content of the disintegrant in the matrix material is within the range of 12.5±4 wt.-%, more preferably 12.5±3 wt.-%, still more preferably 12.5±2.5 wt.-%, yet more preferably 12.5±2 wt.-%, most preferably 12.5±1.5 wt.-%, and in particular 12.5±1 wt.-%, based on the total weight of matrix material.
  • In a preferred embodiment, the content of the disintegrant in the tablet is within the range of 2±1.8 wt.-%, more preferably 2±1.5 wt.-%, still more preferably 2±1.3 wt.-%, yet more preferably 2±1.0 wt.-%, most preferably 2±0.8 wt.-%, and in particular 2±0.5 wt.-%, based on the total weight of tablet. In another preferred embodiment, the content of the disintegrant in the tablet is within the range of 4±1.8 wt.-%, more preferably 4±1.5 wt.-%, still more preferably 4±1.3 wt.-%, yet more preferably 4±1.0 wt.-%, most preferably 4±0.8 wt.-%, and in particular 4±0.5 wt.-%, based on the total weight of tablet. In still another preferred embodiment, the content of the disintegrant in the tablet is within the range of 6±1.8 wt.-%, more preferably 6±1.5 wt.-%, still more preferably 6±1.3 wt.-%, yet more preferably 6±1.0 wt.-%, most preferably 6±0.8 wt.-%, and in particular 6±0.5 wt.-%, based on the total weight of tablet. In another preferred embodiment, the content of the disintegrant in the tablet is within the range of 8±1.8 wt.-%, more preferably 8±1.5 wt.-%, still more preferably 8±1.3 wt.-%, yet more preferably 8±1.0 wt.-%, most preferably 8±0.8 wt.-%, and in particular 8±0.5 wt.-%, based on the total weight of tablet.
  • Preferably, the matrix material comprises a disintegrant in combination with one or more water insoluble pharmaceutical excipients, preferably fillers/binders and/or lubricants.
  • Preferably, the matrix material comprises a filler or a binder. As many fillers can be regarded as binders and vice versa, for the purpose of the specification “filler/binder” refers to any excipient that is suitable as filler, binder or both. Thus, the matrix material preferably comprises a filler/binder.
  • Preferred fillers (=filler/binders) are selected from the group consisting of silicium dioxide (e.g. Aerosil®), microcrystalline cellulose (e.g. Avicel®, Elcema®, Emocel®, ExCel®, Vitacell®); cellulose ether (e.g. Natrosol®, Klucel®, Methocel®, Blanose®, Pharmacoat®, Viscontran®); mannitol; dextrines; dextrose; calciumhydrogen phosphate (e.g. Emcompress®); maltodextrine (e.g. Emdex®); lactose (e.g. Fast-Flow Lactose®; Ludipress®, Tablettose®, Zeparox®); polyvinylpyrrolidone (PVP) (e.g. Kollidone®, Polyplasdone®, Polydone®); saccharose (e.g. Nu-Tab®, Sugar Tab®); magnesium salts (e.g. MgCO3, MgO, MgSiO3); starches and pretreated starches (e.g. Prejel®, Primotab® ET, Starch® 1500). Preferred binders are selected from the group consisting of alginates; chitosanes; and any of the fillers mentioned above (=fillers/binders).
  • Some fillers/binders may also serve other purposes. It is known, for example, that silicium dioxide exhibits excellent function as a glidant. Thus, preferably, the matrix material comprises a glidant such as silicium dioxide.
  • In a preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the matrix material is within the range of 50±25 wt.-%, more preferably 50±20 wt.-%, still more preferably 50±15 wt.-%, yet more preferably 50±10 wt.-%, most preferably 50±7.5 wt.-%, and in particular 50±5 wt.-%, based on the total weight of matrix material. In another preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the matrix material is within the range of 65±25 wt.-%, more preferably 65±20 wt.-%, still more preferably 65±15 wt.-%, yet more preferably 65±10 wt.-%, most preferably 65±7.5 wt.-%, and in particular 65±5 wt.-%, based on the total weight of matrix material. In still another preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the matrix material is within the range of 80±19 wt.-%, more preferably 80±17.5 wt.-%, still more preferably 80±15 wt.-%, yet more preferably 80±10 wt.-%, most preferably 80±7.5 wt.-%, and in particular 80±5 wt.-%, based on the total weight of matrix material. In another preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the matrix material is within the range of 90±9 wt.-%, more preferably 90±8 wt.-%, still more preferably 90±7 wt.-%, yet more preferably 90±6 wt.-%, most preferably 90±5 wt.-%, and in particular 90±4 wt.-%, based on the total weight of matrix material.
  • In a preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the tablet is within the range of 25±24 wt.-%, more preferably 25±20 wt.-%, still more preferably 25±16 wt.-%, yet more preferably 25±12 wt.-%, most preferably 25±8 wt.-%, and in particular 25±4 wt.-%, based on the total weight of tablet. In another preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the tablet is within the range of 30±29 wt.-%, more preferably 30±25 wt.-%, still more preferably 30±20 wt.-%, yet more preferably 30±15 wt.-%, most preferably 30±10 wt.-%, and in particular 30±5 wt.-%, based on the total weight of tablet. In still another preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the tablet is within the range of 35±34 wt.-%, more preferably 35±28 wt.-%, still more preferably 35±22 wt.-%, yet more preferably 35±16 wt.-%, most preferably 35±10 wt.-%, and in particular 35±4 wt.-%, based on the total weight of tablet. In another preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the tablet is within the range of 40±39 wt.-%, more preferably 40±32 wt.-%, still more preferably 40±25 wt.-%, yet more preferably 40±18 wt.-%, most preferably 40±11 wt.-%, and in particular 40±4 wt.-%, based on the total weight of tablet.
  • Preferably, the filler/binder is contained in the matrix material but not in the particulates of the tablet according to the invention.
  • In a preferred embodiment, a portion (e.g. 10% of the total tablet mass) of the matrix is granulated on the particulates (preferably by non-aqueous wet granulation, e.g. with isopropylic alcohol) and the remaining matrix material is added to the thus granulated particulates and blended prior to compression/processing to tablets. Thus, according to this embodiment, the particulates are coated by a portion of the matrix material, whereas the remainder of the matrix material is preferably employed in non-granulated form.
  • Preferably, the matrix material comprises a diluent or lubricant, preferably selected from the group consisting of calcium stearate; magnesium stearate; glycerol monobehenate (e.g. Compritol®); Myvatex®; Precirol®; Precirol® Ato5; sodium stearylfumarate (e.g. Pruv®); and talcum. Magnesium stearate is particularly preferred. Preferably, the content of the lubricant in the matrix material is at most 10.0 wt.-%, more preferably at most 7.5 wt.-%, still more preferably at most 5.0 wt.-%, yet more preferably at most 2.0 wt.-%, even more preferably at most 1.0 wt.-%, and most preferably at most 0.5 wt.-%, based on the total weight of the matrix material and based on the total weight of tablet.
  • In particularly preferred embodiment, the matrix material comprises a combination of disintegrant, filler/binder and lubricant.
  • Particularly preferred contents of disintegrant, filler/binder and lubricant of the matrix material, relative to the total weight of the matrix material, are summarized as embodiments A1 to A6 in the table here below:
  • wt.-% A1 A2 A3 A4 A5 A6
    disintegrant 11 ± 10  11 ± 7.5  11 ± 5.0  11 ± 3.5  11 ± 2.5 11 ± 1.5
    filler/binder 88 ± 12 88 ± 10 88 ± 8  88 ± 6  88 ± 4  88 ± 2.5
    lubricant 0.30 ± 0.28 0.30 ± 0.26 0.30 ± 0.24 0.30 ± 0.22 0.30 ± 0.20 0.30 ± 0.15 

    wherein the disintegrant is preferably crosslinked sodium carboxymethyl cellulose (Na-CMC) or crosslinked polyvinylpyrrolidone (PVP Cl); the filler binder is preferably microcrystalline cellulose or a combination of microcrystalline cellulose with colloidal silicon dioxide; and the lubricant is preferably magnesium stearate.
  • The matrix material of the tablets according to the invention may additionally contain other excipients that are conventional in the art, e.g. diluents, binders, granulating aids, colourants, flavourants, pore formers, surfactants, glidants, wet-regulating agents and disintegrants. The skilled person will readily be able to determine appropriate quantities of each of these excipients.
  • Preferred pore formers include, but are not limited to glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, water-soluble hydrophilic polymers, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, carbowaxes, carbopol, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly(α-ω)alkylenediols, inorganic compounds; alkali metal salts; alkaline earth metal salts, or combinations thereof.
  • Preferred surfactants are nonionic, anionic, cationic or amphoteric surfactants.
  • In a preferred embodiment, the matrix material contains an ionic surfactant, in particular an anionic surfactant.
  • Suitable anionic surfactants include but are not limited to sulfuric acid esters such as sodium lauryl sulfate (sodium dodecyl sulfate, e.g. Texapon® K12), sodium cetyl sulfate (e.g. Lanette E®), sodium cetylstearyl sulfate, sodium stearyl sulfate, sodium dioctylsulfosuccinate (docusate sodium); and the corresponding potassium or calcium salts thereof.
  • Preferably, the anionic surfactant has the general formula (II-a)

  • CnH2n+1O—SO3 M+  (II-a),
  • wherein n is an integer of from 8 to 30, preferably 10 to 24, more preferably 12 to 18; and M is selected from Li+, Na+, K+, NH4 + ½ Mg2+and ½ Ca2+.
  • Further suitable anionic surfactants include salts of cholic acid including sodium glycocholate (e.g. Konakion® MM, Cernevit®), sodium taurocholate and the corresponding potassium or ammonium salts.
  • In another preferred embodiment, the matrix material contains a non-ionic surfactant. Suitable non-ionic surfactants include but are not limited to
      • fatty alcohols that may be linear or branched, such as cetylalcohol, stearylalcohol, cetylstearyl alcohol, 2-octyldodecane-1-ol and 2-hexyldecane-1-ol;
      • sterols, such as cholesterole;
      • partial fatty acid esters of sorbitan such as sorbitanmonolaurate, sorbitanmonopalmitate, sorbitanmonostearate, sorbitantristearate, sorbitanmonooleate, sorbitansesquioleate and sorbitantrioleate;
      • partial fatty acid esters of polyoxyethylene sorbitan (polyoxyethylene-sorbitan-fatty acid esters), preferably a fatty acid monoester of polyoxyethylene sorbitan, a fatty acid diester of polyoxyethylene sorbitan, or a fatty acid triester of polyoxyethylene sorbitan; e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters, such as the type known under the name “polysorbat” and commercially available under the trade name “Tween” including Tween® 20 [polyoxyethylene(20)sorbitan monolaurate], Tween® 21 [polyoxyethylene(4)sorbitan monolaurate], Tween® 40 [polyoxyethylene(20)sorbitan monopalmitate], Tween® 60 [polyoxyethylene(20)-sorbitan monostearate], Tween® 65 [polyoxyethylene(20)sorbitan tristearate], Tween® 80 [polyoxyethylene(20)sorbitan monooleate], Tween 81 [polyoxyethylene(5)sorbitan monooleate], and Tween® 85 [polyoxyethylene(20)sorbitan trioleate]; preferably a fatty acid monoester of polyoxyethylene-sorbitan according to general formula (II-b)
  • Figure US20160199306A1-20160714-C00001
        • wherein (w+x+y+z) is within the range of from 15 to 100, preferably 16 to 80, more preferably 17 to 60, still more preferably 18 to 40 and most preferably 19 to 21; and alkylene is an optionally unsaturated alkylene group comprising 6 to 30 carbon atoms, more preferably 8 to 24 carbon atoms and most preferably 10 to 16 carbon atoms;
      • polyoxyethyleneglycerole fatty acid esters such as mixtures of mono-, di- and triesters of glycerol and di- and monoesters of macrogols having molecular weights within the range of from 200 to 4000 g/mol, e.g., macrogolglycerolcaprylocaprate, macrogolglycerollaurate, macrogolglycerolococoate, macrogolglycerollinoleate, macrogol-20-glycerolmonostearate, macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate; macrogolglycerolstearate, macrogolglycerolhydroxystearate (e.g. Cremophor® RH 40), and macrogolglycerolrizinoleate (e.g. Cremophor® EL);
      • polyoxyethylene fatty acid esters, the fatty acid preferably having from about 8 to about 18 carbon atoms, e.g. macrogololeate, macrogolstearate, macrogol-15-hydroxystearate, polyoxyethylene esters of 12-hydroxystearic acid, such as the type known and commercially available under the trade name “Solutol HS 15”; preferably according to general formula (II-c)

  • CH3CH2—(OCH2CH3)n—O—CO—(CH2)mCH3  (II-c)
        • wherein n is an integer of from 6 to 500, preferably 7 to 250, more preferably 8 to 100, still more preferably 9 to 75, yet more preferably 10 to 50, even more preferably 11 to 30, most preferably 12 to 25, and in particular 13 to 20; and wherein m is an integer of from 6 to 28; more preferably 6 to 26, still more preferably 8 to 24, yet more preferably 10 to 22, even more preferably 12 to 20, most preferably 14 to 18 and in particular 16;
      • polyoxyethylene fatty alcohol ethers, e.g. macrogolcetylstearylether, macrogollarylether, macrogololeylether, macrogolstearylether;
      • polyoxypropylene-polyoxyethylene block copolymers (poloxamers);
      • fatty acid esters of saccharose; e.g. saccharose distearate, saccharose dioleate, saccharose dipalmitate, saccharose monostearate, saccharose monooleate, saccharose monopalmitate, saccharose monomyristate and saccharose monolaurate;
      • fatty acid esters of polyglycerol, e.g. polyglycerololeate;
      • polyoxyethylene esters of alpha-tocopheryl succinate, e.g. D-alpha-tocopheryl-PEG-1000-succinate (TPGS);
      • polyglycolyzed glycerides, such as the types known and commercially available under the trade names “Gelucire 44/14”, “Gelucire 50/13 and “Labrasol”;
      • reaction products of a natural or hydrogenated castor oil and ethylene oxide such as the various liquid surfactants known and commercially available under the trade name “Cremophor”; and
      • partial fatty acid esters of multifunctional alcohols, such as glycerol fatty acid esters, e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters, for example glycerol monostearate, glycerol monooleate, e.g. glyceryl monooleate 40, known and commercially available under the trade name “Peceol”; glycerole dibehenate, glycerole distearate, glycerole monolinoleate; ethyleneglycol monostearate, ethyleneglycol monopalmitostearate, pentaerythritol monostearate.
  • In a preferred embodiment, the matrix material according to the invention comprises a surfactant or mixture of different surfactants obtainable by
      • (i) esterifying saturated or unsaturated C12-C18-fatty acids, optionally bearing a hydroxyl group, with a polyethylene glycol and optionally, glycerol; wherein the polyethylene glycol preferably comprises 10 to 40 ethylene oxide units (—CH2CH2O—); and/or
      • (ii) etherifying triglycerides of saturated or unsaturated C12-C18-fatty acids bearing a hydroxyl group with ethylene oxide so that a polyethylene glycol moiety is linked to the hydroxyl group of the C12-C18-fatty acids via an ether bond; wherein the polyethylene glycol moiety preferably comprises 30 to 50 ethylene oxide units (—CH2CH2O).
  • In a preferred embodiment, the content of the surfactant is at least 0.001 wt.-% or at least 0.005 wt.-%, more preferably at least 0.01 wt.-% or at least 0.05 wt.-%, still more preferably at least 0.1 wt.-%, at least 0.2 wt.-%, or at least 0.3 wt.-%, yet more preferably at least 0.4 wt.-%, at least 0.5 wt.-%, or at least 0.6 wt.-%, and in particular at least 0.7 wt.-%, at least 0.8 wt.-%, at least 0.9 wt.-%, or at least 1.0 wt.-%, based on the total weight of the tablet.
  • In a preferred embodiment, however, the matrix material of the tablet according to the invention consists of one or more disintegrants, one or more filler/binder's and one or more lubricants, but does not contain any other constituents.
  • In a particularly preferred embodiment, the matrix material of the tablet according to the invention does not contain one or more gel-forming agents and/or a silicone.
  • As used herein the term “gel-forming agent” is used to refer to a compound that, upon contact with a solvent (e.g. water), absorbs the solvent and swells, thereby forming a viscous or semi-viscous substance. Preferred gel-forming agents are not cross-linked. This substance may moderate pharmacologically active compound release from the embedded particulates in both aqueous and aqueous alcoholic media. Upon full hydration, a thick viscous solution or dispersion is typically produced that significantly reduces and/or minimizes the amount of free solvent which can contain an amount of solubilized pharmacologically active compound, and which can be drawn into a syringe. The gel that is formed may also reduce the overall amount of pharmacologically active compound extractable with the solvent by entrapping the pharmacologically active compound within a gel structure. Thus the gel-forming agent may play an important role in conferring tamper-resistance to the tablets according to the invention.
  • Gel-forming agents that preferably are not contained in the matrix material include pharmaceutically acceptable polymers, typically hydrophilic polymers, such as hydrogels. Representative examples of gel-forming agent include polyethylene oxide, polyvinyl alcohol, hydroxypropylmethyl cellulose, carbomers, poly(uronic) acids and mixtures thereof.
  • Thus, the polyalkylene oxide that is contained in the particulates of the tablets according to the invention is preferably not also contained in the matrix material.
  • Preferably, the pharmacologically active compound which is contained in the particulates of the tablet according to the invention is preferably not also contained in the matrix material.
  • Thus, in a preferred embodiment, the total amount of pharmacologically active compound contained in the tablet according to the invention is present in the particulates which form a discontinuous phase within the matrix material; and the matrix material forming a continuous phase does not contain any pharmacologically active compound.
  • The tablet according to the invention contains a plurality of particulates. The particulates comprise a pharmacologically active compound and a polyalkylene oxide. Preferably, the pharmacologically active compound is dispersed in the polyalkylene oxide.
  • For the purpose of the specification, the term “particulate” refers to a discrete mass of material that is solid, e.g. at 20° C. or at room temperature or ambient temperature. Preferably a particulate is solid at 20° C. Preferably, the particulates are monoliths.
  • Preferably, the pharmacologically active compound and the polyalkylene oxide are intimately homogeneously distributed in the particulates so that the particulates do not contain any segments where either pharmacologically active compound is present in the absence of polyalkylene oxide or where polyalkylene oxide is present in the absence of pharmacologically active compound.
  • When the particulates are film coated, the polyalkylene oxide is preferably homogeneously distributed in the core of the pharmaceutical dosage form (tablet), i.e. the film coating preferably does not contain polyalkylene oxide, but optionally polyalkylene glycol that differs from polyalkylene oxide in its lower molecular weight. Nonetheless, the film coating as such may of course contain one or more polymers, which however, preferably differ from the polyalkylene oxide contained in the core.
  • The particulates are of macroscopic size, typically the average diameter is within the range of from 100 μm to 1500 μm, preferably 200 μm to 1500 μm, more preferably 300 μm to 1500 μm, still more preferably 400 μm to 1500 μm, most preferably 500 μm to 1500 μm, and in particular 600 μm to 1500 μm. The tablets according to the invention comprise particulates as a discontinuous phase, i.e. the particulates form a discontinuous phase in the matrix material which in turn preferably forms a continuous phase. In this regard, discontinuous means that not each and every particulate is in intimate contact with another particulate but that the particulates are at least partially separated from one another by the matrix material in which the particulates are embedded. In other words, the particulates preferably do not form a single coherent mass within the tablets according to the invention.
  • The tablet according to the invention comprises particulates in an amount of less than two thirds of the total weight of the tablet.
  • It has been surprisingly found that the content of particulates in the tablet can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • Preferably, the content of the particulates in the tablets according to the invention is at most 65 wt.-%, more preferably at most 62.5 wt.-%, still more preferably at most 60 wt.-%, yet more preferably at most 57.5 wt.-%, most preferably at most 55 wt.-% and in particular at most 52.5 wt.-%, based on the total weight of the tablets.
  • Preferably, the content of the particulates in the tablets according to the invention is at least 10 wt.-%, at least 12.5 wt.-%, at least 15 wt.-% or at least 17.5 wt.-%; more preferably at least 20 wt.-%, at least 22.5 wt.-%, at least 25 wt.-% or at least 27.5 wt.-%; most preferably at least 30 wt.-%, at least 32.5 wt.-%, at least 35 wt.-% or at least 37.5 wt.-%; and in particular at least 40 wt.-%, at least 42.5 wt.-%, at least 45 wt.-% or at least 47.5 wt.-%; based on the total weight of the tablet.
  • In a preferred embodiment, the content of the particulates in the tablets according to the invention is within the range of 35±30 wt.-%, more preferably 35±25 wt.-%, still more preferably 35±20 wt.-%, yet more preferably 35±15 wt.-%, most preferably 35±10 wt.-%, and in particular 35±5 wt.-%, based on the total weight of the tablet. In another preferred embodiment, the content of the particulates in the tablets according to the invention is within the range of 40±30 wt.-%, more preferably 40±25 wt.-%, still more preferably 40±20 wt.-%, yet more preferably 40±15 wt.-%, most preferably 40±10 wt.-%, and in particular 40±5 wt.-%, based on the total weight of the tablet. In still another preferred embodiment, the content of the particulates in the tablets according to the invention is within the range of 45±30 wt.-%, more preferably 45±25 wt.-%, still more preferably 45±20 wt.-%, yet more preferably 45±15 wt.-%, most preferably 45±10 wt.-%, and in particular 45±5 wt.-%, based on the total weight of the tablet. In yet another preferred embodiment, the content of the particulates in the tablets according to the invention is within the range of 50±30 wt.-%, more preferably 50±25 wt.-%, still more preferably 50±20 wt.-%, yet more preferably 50±15 wt.-%, most preferably 50±10 wt.-%, and in particular 50±5 wt.-%, based on the total weight of the tablet. In another preferred embodiment, the content of the particulates in the tablets according to the invention is within the range of 55±30 wt.-%, more preferably 55±25 wt.-%, still more preferably 55±20 wt.-%, yet more preferably 55±15 wt.-%, most preferably 55±10 wt.-%, and in particular 55±5 wt.-%, based on the total weight of the tablet. In still another preferred embodiment, the content of the particulates in the tablets according to the invention is within the range of 60±30 wt.-%, more preferably 60±25 wt.-%, still more preferably 60±20 wt.-%, yet more preferably 60±15 wt.-%, most preferably 60±10 wt.-%, and in particular 60±5 wt.-%, based on the total weight of the tablet.
  • The shape of the particulates is not particularly limited. As the particulates are preferably manufactured by hot-melt extrusion, preferred particulates present in the tablets according to the invention are generally cylindrical in shape. The diameter of such particulates is therefore the diameter of their circular cross section. The cylindrical shape is caused by the extrusion process according to which the diameter of the circular cross section is a function of the extrusion die and the length of the cylinders is a function of the cutting length according to which the extruded strand of material is cut into pieces of preferably more or less predetermined length.
  • The suitability of cylindrical, i.e. a spherical particulates for the manufacture of the tablets according to the invention is unexpected. Typically, the aspect ratio is regarded as an important measure of the spherical shape. The aspect ratio is defined as the ratio of the maximal diameter (dmax) and its orthogonal Feret-diameter. For aspherical particulates, the aspect ratio has values above 1. The smaller the value the more spherical is the particulate. Aspect ratios below 1.1 are typically considered satisfactory, aspect ratios above 1.2, however, are typically considered not suitable for the manufacture of conventional tablets. The inventors have surprisingly found that when manufacturing the tablets according to the invention, even particulates having aspect ratios above 1.2 can be processed without difficulties and that it is not necessary to provide spherical particulates. In a preferred embodiment, the aspect ratio of the particulates is at most 1.40, more preferably at most 1.35, still more preferably at most 1.30, yet more preferably at most 1.25, even more preferably at most 1.20, most preferably at most 1.15 and in particular at most 1.10. In another preferred embodiment, the aspect ratio of the particulates is at least 1.10, more preferably at least 1.15, still more preferably at least 1.20, yet more preferably at least 1.25, even more preferably at least 1.30, most preferably at least 1.35 and in particular at least 1.40.
  • The particulates in the tablets according to the invention are of macroscopic size, i.e. typically have an average particle size of at least 50 μm, more preferably at least 100 μm, still more preferably at least 150 μm or at least 200 μm, yet more preferably at least 250 μm or at least 300 μm, most preferably at least 400 μm or at least 500 μm, and in particular at least 550 μm or at least 600 μm.
  • Preferred particulates have an average length and average diameter of about 1000 μm or less. When the particulates are manufactured by extrusion technology, the “length” of particulates is the dimension of the particulates that is parallel to the direction of extrusion. The “diameter” of particulates is the largest dimension that is perpendicular to the direction of extrusion.
  • Particularly preferred particulates have an average diameter of less than about 1000 μm, more preferably less than about 800 μm, still more preferably of less than about 650 μm. Especially preferred particulates have an average diameter of less than 700 μm, particularly less than 600 μm, still more particularly less than 500 μm, e.g. less than 400 μm. Particularly preferred particulates have an average diameter in the range 200-1000 μm, more preferably 400-800 μm, still more preferably 450-700 μm, yet more preferably 500-650 μm, e.g. about 500-600 μm. Further preferred particulates have an average diameter of between about 300 μm and about 400 μm, of between about 400 μm and 500 μm, or of between about 500 μm and 600 μm, or of between 600 μm and 700 μm or of between 700 μm and 800 μm.
  • Preferred particulates that are present in the tablets according to the invention have an average length of less than about 1000 μm, preferably an average length of less than about 800 μm, still more preferably an average length of less than about 650 μm, e.g. a length of about 800 μm, about 700 μm about 600 μm, about 500 μm, about 400 μm or about 300 μm. Especially preferred particulates have an average length of less than 700 μm, particularly less than 650 μm, still more particularly less than 550 μm, e.g. less than 450 μm. Particularly preferred particulates therefore have an average length in the range 200-1000 μm, more preferably 400-800 μm, still more preferably 450-700 μm, yet more preferably 500-650 μm, e.g. about 500-600 μm. The minimum average length of the microparticulates is determined by the cutting step and may be, e.g. 500 μm, 400 μm, 300 μm or 200 μm.
  • In a preferred embodiment, the particulates have (i) an average diameter of about 750±300 μm, more preferably 750±250 μm, still more preferably 750±200 μm, yet more preferably 750±150 μm, most preferably 750±100 μm, and in particular 750±50 μm; and/or (ii) an average length of about 750±300 μm, more preferably 750±250 μm, still more preferably 750±200 μm, yet more preferably 750±150 μm, most preferably 750±100 μm, and in particular 750±50 μm.
  • It has been surprisingly found that the size of the particulates in the tablet can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • The size of particulates may be determined by any conventional procedure known in the art, e.g. laser light scattering, sieve analysis, light microscopy or image analysis.
  • Preferably, the plurality of particulates that is contained in the tablet according to the invention has an arithmetic average weight, in the following referred to as “aaw”, wherein at least 70%, more preferably at least 75%, still more preferably at least 80%, yet more preferably at least 85%, most preferably at least 90% and in particular at least 95% of the individual particles contained in said plurality of particulates has an individual weight within the range of aaw±30%, more preferably aaw±25%, still more preferably aaw±20%, yet more preferably aaw±15%, most preferably aaw±10%, and in particular aaw±5%. For example, if the tablet according to the invention contains a plurality of 100 particulates and aaw of said plurality of particulates is 1.00 mg, at least 75 individual particles (i.e. 75%) have an individual weight within the range of from 0.70 to 1.30 mg (1.00 mg±30%).
  • In a preferred embodiment, the particulates are not film coated.
  • In another preferred embodiment, the particulates are film coated. It has been surprisingly found that when the particulates are film coated, the disintegration time and/or the drug release from the tablets can be further accelerated, which is particularly significant for tablets with immediate drug release.
  • The particulates according to the invention can optionally be provided, partially or completely, with a conventional coating. The particulates according to the invention are preferably film coated with conventional film coating compositions. Suitable coating materials are commercially available, e.g. under the trademarks Opadry® and Eudragit®.
  • Examples of suitable materials include cellulose esters and cellulose ethers, such as methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), ethylcellulose (EC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP); poly(meth)acrylates, such as aminoalkylmethacrylate copolymers, ethylacrylate methylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers; vinyl polymers, such as polyvinylpyrrolidone, polyvinylacetatephthalate, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymers, polyvinylacetate; and natural film formers.
  • The coating material may contain excipients such as stabilizers (e.g. surfactants such as macrogol cetostearylether, sodium dodecylsulfate, and the like). Suitable excipients of film coating materials are known to the skilled person.
  • In a particularly preferred embodiment, the coating is water-soluble. In a preferred embodiment, the coating is based on polyvinyl alcohol, such as polyvinyl alcohol-part, hydrolyzed, and may additionally contain polyethylene glycol, such as macrogol 3350, and/or pigments. In another preferred embodiment, the coating is based on hydroxypropylmethylcellulose, preferably hypromellose type 2910 having a viscosity of 3 to 15 mPas.
  • Though less preferred, the coating can principally be resistant to gastric juices and dissolve as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the tablet according to the invention passes through the stomach undissolved and the active compound is only released in the intestines. The coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5. Corresponding materials and methods for the delayed release of active compounds and for the application of coatings which are resistant to gastric juices are known to the person skilled in the art, for example from “Coated Pharmaceutical dosage forms—Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials” by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers.
  • A particularly preferred coating contains polyvinyl alcohol and optionally, further excipients such as xanthan gum and/or talkum.
  • When the particulates are film coated, the content of the dried film coating is preferably at most 5 wt.-%, more preferably at most 4 wt.-%, still more preferably at most 3.5 wt.-%, yet more preferably at most 3 wt.-%, most preferably at most 2.5 wt.-%, and in particular at most 2 wt.-%, based on the total weight of the particulates. In a particularly preferred embodiment, the weight increase relative to the total weight of the particulates (uncoated starting material) is within the range of from 3.0 to 4.7 wt.-%, more preferably 3.1 to 4.6 wt.-%, still more preferably 3.2 to 4.5 wt.-%, yet more preferably 3.3 to 4.4 wt.-%, most preferably 3.4 to 4.3 wt.-%, and in particular 3.5 to 4.2 wt.-%.
  • It has been surprisingly found that the relative weight ratio of matrix material:particulates in the tablet can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • Preferably, said relative weight ratio is within the range of 1:1.00±0.75, more preferably 1:1.00±0.50, still more preferably 1:1.00±0.40, yet more preferably 1:1.00±0.30, most preferably 1:1.00±0.20, and in particular 1:1.00±0.10.
  • The particulates contain at least a pharmacologically active compound and a polyalkylene oxide. Preferably, however, the particulates contain additional pharmaceutical excipients such as antioxidants and plasticizers.
  • The pharmacologically active compound is not particularly limited. Preferably, the pharmacologically active compound is an opioid.
  • In a preferred embodiment, the particulates and the tablet, respectively, contain only a single pharmacologically active compound. In another preferred embodiment, the particulates and the tablet, respectively, contain a combination of two or more pharmacologically active compounds.
  • Preferably, pharmacologically active compound is an active ingredient with potential for being abused. Active ingredients with potential for being abused are known to the person skilled in the art and comprise e.g. tranquillizers, stimulants, barbiturates, narcotics, opioids or opioid derivatives.
  • Preferably, the pharmacologically active compound exhibits psychotropic action.
  • Preferably, the pharmacologically active compound is selected from the group consisting of opiates, opioids, stimulants, tranquilizers, and other narcotics.
  • Particularly preferably, the pharmacologically active compound is an opioid. According to the ATC index, opioids are divided into natural opium alkaloids, phenylpiperidine derivatives, diphenylpropylamine derivatives, benzomorphan derivatives, oripavine derivatives, morphinan derivatives and others.
  • The following opiates, opioids, tranquillizers or other narcotics are substances with a psychotropic action, i.e. have a potential of abuse, and hence are preferably contained in the tablet and the particulates, respectively: alfentanil, allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone, amphetamine, amphetaminil, amobarbital, anileridine, apocodeine, axomadol, barbital, bemidone, benzylmorphine, bezitramide, bromazepam, brotizolam, buprenorphine, butobarbital, butorphanol, camazepam, carfentanil, cathine/D-norpseudoephedrine, chlordiazepoxide, clobazam clofedanol, clonazepam, clonitazene, clorazepate, clotiazepam, cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene, etorphine, faxeladol, fencamfamine, fenethylline, fenpipramide, fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam, haloxazolam, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, hydroxymethylmorphinan, ketazolam, ketobemidone, levacetylmethadol (LAAM), levomethadone, levorphanol, levophenacylmorphane, levoxemacin, lisdexamfetamine dimesylate, lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, metapon, meptazinol, metazocine, methylmorphine, metamphetamine, methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil, morphine, myrophine, nabilone, nalbuphene, nalorphine, narceine, nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam, oxycodone, oxymorphone, Papaver somniferum, papaveretum, pemoline, pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine, pholcodeine, phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol, piritramide, prazepam, profadol, proheptazine, promedol, properidine, propoxyphene, remifentanil, secbutabarbital, secobarbital, sufentanil, tapentadol, temazepam, tetrazepam, tilidine (cis and trans), tramadol, triazolam, vinylbital, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol, (1R,2R)-3-(2-dimethylamino-methyl-cyclohexyl)phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, preferably as racemate, 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(6-methoxy-naphthalen-2-yl)propionate, (RR—SS)-2-acetoxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2-hydroxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-4-chloro-2-hydroxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2-hydroxy-4-methyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2-hydroxy-4-methoxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, and corresponding stereoisomeric compounds, in each case the corresponding derivatives thereof, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, e.g. ethers, esters or amides, and in each case the physiologically acceptable compounds thereof, in particular the acid or base addition salts thereof and solvates, e.g. hydrochlorides.
  • In a preferred embodiment, the pharmacologically active compound is selected from the group consisting of DPI-125, M6G (CE-04-410), ADL-5859, CR-665, NRP290 and sebacoyl dinalbuphine ester.
  • In a preferred embodiment, the pharmacologically active compound is selected from the group consisting of oxymorphone, hydromorphone and morphine.
  • In another preferred embodiment, the pharmacologically active compound is selected from the group consisting of tapentadol, faxeladol and axomadol.
  • In still another preferred embodiment, the pharmacologically active compound is selected from the group consisting of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole, particularly its hemicitrate; 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]indole, particularly its citrate; and 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoroindole, particularly its hemicitrate. These compounds are known from, e.g., WO 2004/043967, WO 2005/066183.
  • The pharmacologically active compound may be present in form of a physiologically acceptable salt, e.g. physiologically acceptable acid addition salt.
  • Physiologically acceptable acid addition salts comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the active ingredient with appropriate organic and inorganic acids. Active ingredients containing an acidic proton may be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. The term addition salt also comprises the hydrates and solvent addition forms which the active ingredients are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • It has been surprisingly found that the content of the pharmacologically active compound in the tablet and in the particulates, respectively, can be optimized in order to provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • The pharmacologically active compound is present in the tablet in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies according to the active ingredients being used, the condition being treated, the severity of said condition, the patient being treated, and the frequency of administration.
  • The content of the pharmacologically active compound in the tablet is not limited. The dose of the pharmacologically active compound which is adapted for administration preferably is in the range of 0.1 mg to 500 mg, more preferably in the range of 1.0 mg to 400 mg, even more preferably in the range of 5.0 mg to 300 mg, and most preferably in the range of 10 mg to 250 mg. In a preferred embodiment, the total amount of the pharmacologically active compound that is contained in the tablet is within the range of from 0.01 to 200 mg, more preferably 0.1 to 190 mg, still more preferably 1.0 to 180 mg, yet more preferably 1.5 to 160 mg, most preferably 2.0 to 100 mg and in particular 2.5 to 80 mg.
  • Preferably, the content of the pharmacologically active compound is within the range of from 0.01 to 80 wt.-%, more preferably 0.1 to 50 wt.-%, still more preferably 1 to 25 wt.-%, based on the total weight of the tablet.
  • In a preferred embodiment, the content of pharmacologically active compound is within the range of from 5.0±4.5 wt.-%, or 7.5±7.0 wt.-%, or 10±9.0 wt.-%, or 12.5±12.0 wt.-%, or 15±14 wt.-%, or 17.5±17.0 wt.-%, or 20±19 wt.-%, or 22.5±22.0 wt.-%, or 25±24 wt.-%; more preferably 5.0±4.0 wt.-%, or 7.5±6.0 wt.-%, or 10±8.0 wt.-%, or 12.5±12.0 wt.-%, or 15±12 wt.-%, or 17.5±15.0 wt.-%, or 20±19 wt.-%, or 22.5±22.0 wt.-%, or 25±24 wt.-%; still more preferably 5.0±3.5 wt.-%, or 7.5±5.0 wt.-%, or 10±7.0 wt.-%, or 12.5±10.0 wt.-%, or 15±10 wt.-%, or 17.5±13.0 wt.-%, or 20±17 wt.-%, or 22.5±19.0 wt.-%, or 25±21 wt.-%; yet more preferably 5.0±3.0 wt.-%, or 7.5±4.0 wt.-%, or 10±6.0 wt.-%, or 12.5±8.0 wt.-%, or 15±8.0 wt.-%, or 17.5±11.0 wt.-%, or 20±15 wt.-%, or 22.5±16.0 wt.-%, or 25±18 wt.-%; even more preferably 5.0±2.5 wt.-%, or 7.5±3.0 wt.-%, or 10±5.0 wt.-%, or 12.5±6.0 wt.-%, or 15±6.0 wt.-%, or 17.5±9.0 wt.-%, or 20±13 wt.-%, or 22.5±13.0 wt.-%, or 25±15 wt.-%; most preferably 5.0±2.0 wt.-%, or 7.5±2.0 wt.-%, or 10±4.0 wt.-%, or 12.5±4.0 wt.-%, or 15±4.0 wt.-%, or 17.5±7.0 wt.-%, or 20±11 wt.-%, or 22.5±10.0 wt.-%, or 25±12 wt.-%; and in particular 5.0±1.5 wt.-%, or 7.5±1.0 wt.-%, or 10±3.0 wt.-%, or 12.5±2.0 wt.-%, or 15±2.0 wt.-%, or 17.5±5.0 wt.-%, or 20±9 wt.-%, or 22.5±7.0 wt.-%, or 25±9 wt.-%; in each case based on the total weight of the tablet.
  • In a further preferred embodiment, the content of pharmacologically active compound is within the range of from 20±6 wt.-%, more preferably 20±5 wt.-%, still more preferably 20±4 wt.-%, most preferably 20±3 wt.-%, and in particular 20±2 wt.-%, based on the total weight of the tablet. In another preferred embodiment, the content of pharmacologically active compound is within the range of from 25±6 wt.-%, more preferably 25±5 wt.-%, still more preferably 25±4 wt.-%, most preferably 25±3 wt.-%, and in particular 25±2 wt.-%, based on the total weight of the tablet.
  • The skilled person may readily determine an appropriate amount of pharmacologically active compound to include in a tablet. For instance, in the case of analgesics, the total amount of pharmacologically active compound present in the tablet is that sufficient to provide analgesia. The total amount of pharmacologically active compound administered to a patient in a dose will vary depending on numerous factors including the nature of the pharmacologically active compound, the weight of the patient, the severity of the pain, the nature of other therapeutic agents being administered etc.
  • In a preferred embodiment, the pharmacologically active compound is contained in the tablet in an amount of 7.5±5 mg, 10±5 mg, 20±5 mg, 30±5 mg, 40±5 mg, 50±5 mg, 60±5 mg, 70±5 mg, 80±5 mg, 90±5 mg, 100±5 mg, 110±5 mg, 120±5 mg, 130±5, 140±5 mg, 150±5 mg, 160±5 mg, 170±5 mg, 180±5 mg, 190±5 mg, 200±5 mg, 210±5 mg, 220±5 mg, 230±5 mg, 240±5 mg, 250±5 mg, 260±5 mg, 270±5 mg, 280±5 mg, 290±5 mg, or 300±5 mg. In another preferred embodiment, the pharmacologically active compound is contained in the tablet in an amount of 5±2.5 mg, 7.5±2.5 mg, 10±2.5 mg, 15±2.5 mg, 20±2.5 mg, 25±2.5 mg, 30±2.5 mg, 35±2.5 mg, 40±2.5 mg, 45±2.5 mg, 50±2.5 mg, 55±2.5 mg, 60±2.5 mg, 65±2.5 mg, 70±2.5 mg, 75±2.5 mg, 80±2.5 mg, 85±2.5 mg, 90±2.5 mg, 95±2.5 mg, 100±2.5 mg, 105±2.5 mg, 110±2.5 mg, 115±2.5 mg, 120±2.5 mg, 125±2.5 mg, 130±2.5 mg, 135±2.5 mg, 140±2.5 mg, 145±2.5 mg, 150±2.5 mg, 155±2.5 mg, 160±2.5 mg, 165±2.5 mg, 170±2.5 mg, 175±2.5 mg, 180±2.5 mg, 185±2.5 mg, 190±2.5 mg, 195±2.5 mg, 200±2.5 mg, 205±2.5 mg, 210±2.5 mg, 215±2.5 mg, 220±2.5 mg, 225±2.5 mg, 230±2.5 mg, 235±2.5 mg, 240±2.5 mg, 245±2.5 mg, 250±2.5 mg, 255±2.5 mg, 260±2.5 mg, or 265±2.5 mg.
  • In a particularly preferred embodiment, the pharmacologically active compound is tapentadol, preferably its HCl salt, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently. In this embodiment, pharmacologically active compound is preferably contained in the tablet in an amount of from 25 to 100 mg.
  • In a particularly preferred embodiment, the pharmacologically active compound is oxymorphone, preferably its HCl salt, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently. In this embodiment, the pharmacologically active compound is preferably contained in the tablet in an amount of from 5 to 40 mg. In another particularly preferred embodiment, the pharmacologically active compound is oxymorphone, preferably its HCl salt, and the tablet is adapted for administration once daily. In this embodiment, the pharmacologically active compound is preferably contained in the tablet in an amount of from 10 to 80 mg.
  • In another particularly preferred embodiment, the pharmacologically active compound is oxycodone, preferably its HCl salt, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently. In this embodiment, the pharmacologically active compound is preferably contained in the tablet in an amount of from 5 to 80 mg.
  • In still another particularly preferred embodiment, the pharmacologically active compound is hydromorphone, preferably its HCl, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently. In this embodiment, the pharmacologically active compound is preferably contained in the tablet in an amount of from 2 to 52 mg. In another particularly preferred embodiment, the pharmacologically active compound is hydromorphone, preferably its HCl, and the tablet is adapted for administration once daily, twice daily, thrice daily or more frequently. In this embodiment, the pharmacologically active compound is preferably contained in the tablet in an amount of from 4 to 104 mg.
  • The particulates present in the tablets according to the invention preferably comprise 3 to 75 wt.-% of pharmacologically active compound, more preferably 5 to 70 wt.-% of pharmacologically active compound, still more preferably 7.5 to 65 wt.-% of pharmacologically active compound, based on the total weight of a particulate.
  • Preferably, the content of the pharmacologically active compound is at least 25 wt.-%, more preferably at least 30 wt.-%, still more preferably at least 35 wt.-%, yet more preferably at least 40 wt.-%, most preferably at least 45 wt.-%, based on the total weight of a particulate.
  • Preferably, the content of the pharmacologically active compound is at most 70 wt.-%, more preferably at most 65 wt.-%, still more preferably at most 60 wt.-%, yet more preferably at most 55 wt.-%, most preferably at most 50 wt.-%, based on the total weight of a particulate.
  • In a preferred embodiment, the content of the pharmacologically active compound is within the range of 35±30 wt.-%, more preferably 35±25 wt.-%, still more preferably 35±20 wt.-%, yet more preferably 35±15 wt.-%, most preferably 35±10 wt.-%, and in particular 35±5 wt.-%, based on the total weight of a particulate. In another preferred embodiment, the content of the pharmacologically active compound is within the range of 45±30 wt.-%, more preferably 45±25 wt.-%, still more preferably 45±20 wt.-%, yet more preferably 45±15 wt.-%, most preferably 45±10 wt.-%, and in particular 45±5 wt.-%, based on the total weight of a particulate. In still another preferred embodiment, the content of the pharmacologically active compound is within the range of 55±30 wt.-%, more preferably 55±25 wt.-%, still more preferably 55±20 wt.-%, yet more preferably 55±15 wt.-%, most preferably 55±10 wt.-%, and in particular 55±5 wt.-%, based on the total weight of a particulate.
  • The pharmacologically active compound that is included in the preparation of the tablets according to the invention preferably has an average particle size of less than 500 microns, still more preferably less than 300 microns, yet more preferably less than 200 or 100 microns. There is no lower limit on the average particle size and it may be, for example, 50 microns. The particle size of pharmacologically active compounds may be determined by any technique conventional in the art, e.g. laser light scattering, sieve analysis, light microscopy or image analysis. Generally speaking it is preferable that the largest dimension of the pharmacologically active compound particle be less than the size of the particulates (e.g. less than the smallest dimension of the particulates).
  • A skilled person knows how to determine pharmacokinetic parameters such as t1/2, Tmax, Cmax, AUC and bioavailability. For the purposes of the description, the pharmacokinetic parameters, which may be determined from the blood plasma concentrations of 3-(2-dimethylaminomethylcyclohexyl)phenol, are defined as follows:
  • Cmax maximum measured plasma concentration of the active ingredient
    after single administration (≡ average peak plasma level)
    tmax interval of time from administration of the active ingredient until
    Cmax is reached
    AUC total area of the plasma concentration/time curve including the
    subarea from the final measured value extrapolated to infinity
    t1/2 half-life
  • The above parameters are in each case stated as mean values of the individual values for all investigated patients/test subjects.
  • A person skilled in the art knows how the pharmacokinetic parameters of the active ingredient may be calculated from the measured concentrations of the active ingredient in the blood plasma. In this connection, reference may be made, for example, to Willi Cawello (ed.) Parameters for Compartment-free Pharmacokinetics, Shaker Verlag Aachen (1999).
  • In a preferred embodiment, the pharmacologically active compound is tapentadol or a physiologically acceptable salt thereof, e.g. the hydrochloride. Preferably, the tablet according to the invention provides a mean absolute bioavailability of tapentadol of at least 22%, more preferably at least 24%, still more preferably at least 26%, yet more preferably at least 28%, most preferably at least 30%, and in particular at least 32%. Tmax of tapentadol is preferably within the range of 1.25±1.20 h, more preferably 1.25±1.00 h, still more preferably 1.25±0.80 h, yet more preferably 1.25±0.60 h, most preferably 1.25±0.40 h, and in particular 1.25±0.20 h. t112 of tapentadol is preferably within the range of 4.0±2.8 h, more preferably 4.0±2.4 h, still more preferably 4.0±2.0 h, yet more preferably 4.0±1.6 h, most preferably 4.0±1.2 h, and in particular 4.0±0.8 h. Preferably, when normalized to a dose of 100 mg tapentadol, Cmax of tapentadol is preferably within the range of 90±85 ng/mL, more preferably 90±75 ng/mL, still more preferably 90±65 ng/mL, yet more preferably 90±55 ng/mL, most preferably 90±45 ng/mL, and in particular 90±35 ng/mL; and/or AUC of tapentadol is preferably within the range of 420±400 ng/mL·h, more preferably 420±350 ng/mL·h, still more preferably 420±300 ng/mL·h, yet more preferably 420±250 ng/mL·h, most preferably 420±200 ng/mL·h, and in particular 420±150 ng/mL·h.
  • In another preferred embodiment, the pharmacologically active compound is oxymorphone or a physiologically acceptable salt thereof, e.g. the hydrochloride. Preferably, the tablet according to the invention provides a mean absolute bioavailability of oxymorphone of at least 1%, more preferably at least 2%, still more preferably at least 4%, yet more preferably at least 6%, most preferably at least 8%, and in particular at least 10%. Tmax of oxymorphone is preferably within the range of 0.5±0.45 h, more preferably 0.5±0.40 h, still more preferably 0.5±0.35 h, yet more preferably 0.5±0.30 h, most preferably 0.5±0.25 h, and in particular 0.5±0.20 h. t12 of oxymorphone is preferably within the range of 9.5±8.0 h, more preferably 9.5±7.0 h, still more preferably 9.5±6.0 h, yet more preferably 9.5±5.0 h, most preferably 9.5±4.0 h, and in particular 9.5±3.0 h. Preferably, when normalized to a dose of 20 mg oxymorphone, Cmax of oxymorphone is preferably within the range of 4.4±3.5 ng/mL, more preferably 4.4±3.0 ng/mL, still more preferably 4.4±2.5 ng/mL, yet more preferably 4.4±2.0 ng/mL, most preferably 4.4±1.5 ng/mL, and in particular 4.4±1.0 ng/mL; and/or AUC of oxymorphone is preferably within the range of 20.0±15.0 ng/mL·h, more preferably 20.0±12.5 ng/mL·h, still more preferably 20.0±10.0 ng/mL·h, yet more preferably 20.0±7.5 ng/mL·h, most preferably 20.0±6.0 ng/mL·h, and in particular 20.0±5.0 ng/mL·h.
  • In another preferred embodiment, the pharmacologically active compound is oxycodone or a physiologically acceptable salt thereof, e.g. the hydrochloride. Preferably, the tablet according to the invention provides a mean absolute bioavailability of oxycodone of at least 40%, more preferably at least 45%, still more preferably at least 50%, yet more preferably at least 55%, most preferably at least 60%, and in particular at least 70%. Tmax of oxycodone is preferably within the range of 2.6±2.5 h, more preferably 2.6±2.0 h, still more preferably 2.6±1.8 h, yet more preferably 2.6±0.1.6 h, most preferably 2.6±1.4 h, and in particular 2.6±1.20 h. t112 of oxycodone is preferably within the range of 3.8±3.5 h, more preferably 3.8±3.0 h, still more preferably 3.8±2.5 h, yet more preferably 3.8±2.0 h, most preferably 3.8±1.5 h, and in particular 3.8±1.0 h. Preferably, when normalized to a dose of 30 mg oxycodone, Cmax of oxycodone is preferably within the range of 40±35 ng/mL, more preferably 40±30 ng/mL, still more preferably 40±25 ng/mL, yet more preferably 40±20 ng/mL, most preferably 40±15 ng/mL, and in particular 40±10 ng/mL; and/or AUC of oxycodone is preferably within the range of 270±250 ng/mL·h, more preferably 270±200 ng/mL·h, still more preferably 270±150 ng/mL·h, yet more preferably 270±100 ng/mL·h, most preferably 270±75 ng/mL·h, and in particular 270±50 ng/mL·h.
  • In still another preferred embodiment, the pharmacologically active compound is morphine or a physiologically acceptable salt thereof, e.g. the sulfate. Preferably, the tablet according to the invention provides a mean absolute bioavailability of morphine of at least 15%, more preferably at least 20%, still more preferably at least 25%, yet more preferably at least 30%, most preferably at least 35%, and in particular at least 40%. Tmax of morphine is preferably within the range of 0.625±0.60 h, more preferably 0.625±0.50 h, still more preferably 0.625±0.40 h, yet more preferably 0.625±0.30 h, most preferably 0.625±0.20 h, and in particular 0.625±0.15 h. Preferably, when normalized to a dose of 30 mg morphine sulfate, Cmax of morphine is preferably within the range of 25±20 ng/mL, more preferably 25±15 ng/mL, still more preferably 25±10 ng/mL, yet more preferably 25±5 ng/mL; and/or AUC of morphine is preferably within the range of 50±45 ng/mL·h, more preferably 50±40 ng/mL·h, still more preferably 50±35 ng/mL·h, yet more preferably 50±30 ng/mL·h, most preferably 50±25 ng/mL·h, and in particular 50±20 ng/mL·h.
  • The tablets according to the invention may also comprise one or more additional pharmacologically active compounds. The additional pharmacologically active compound may be susceptible to abuse or another pharmaceutical. Additional pharmacologically active compounds may be present within the particulates (“intragranular”) or within the matrix (“extragranular”). Where an additional pharmacologically active compound is present intragranularly, it may be present either in combination with one or more pharmacologically active compounds within the same particulates or in a discrete population of particulates alone and separate from any other pharmacologically active compounds present in the tablet.
  • In a preferred embodiment, the tablet according to the invention, preferably the particulates, comprise an opioid (agonist) as well as an opioid antagonist.
  • Any conventional opioid antagonist may be present, e.g. naltrexone or naloxone or their pharmaceutically acceptable salts. Naloxone, including its salts, is particularly preferred. The opioid antagonist may be present within the particulates or within the matrix. Alternatively, opioid antagonist may be provided in separate particulates to the pharmacologically active compounds. The preferred composition of such particulates is the same as that described for pharmacologically active compound-containing particulates.
  • The ratio of opioid agonist to opioid antagonist in the tablets according to the invention is preferably 1:1 to 3:1 by weight, for example, about 2:1 by weight.
  • In another preferred embodiment, neither the particulates nor the tablet comprise any opioid antagonist.
  • The particulates according to the invention contain a polyalkylene oxide.
  • Preferably, the polyalkylene oxide is selected from polymethylene oxide, polyethylene oxide and polypropylene oxide, or copolymers thereof. Polyethylene oxide is preferred.
  • In a preferred embodiment, the polyalkylene oxide has a weight average molecular weight (Mw) or viscosity average molecular weight (Mη) of at least 200,000 or at least 500,000 g/mol, preferably at least 1,000,000 g/mol or at least 2,500,000 g/mol, more preferably in the range of about 1,000,000 g/mol to about 15,000,000 g/mol, and most preferably in the range of about 5,000,000 g/mol to about 10,000,000 g/mol. Suitable methods to determine Mw and Mη are known to a person skilled in the art. Mη is preferably determined by rheological measurements, whereas Mw can be determined by gel permeation chromatography (GPC).
  • Polyalkylene oxide may comprise a single polyalkylene oxide having a particular average molecular weight, or a mixture (blend) of different polymers, such as two, three, four or five polymers, e.g., polymers of the same chemical nature but different average molecular weight, polymers of different chemical nature but same average molecular weight, or polymers of different chemical nature as well as different molecular weight.
  • For the purpose of the specification, a polyalkylene glycol has a molecular weight of up to 20,000 g/mol whereas a polyalkylene oxide has a molecular weight of more than 20,000 g/mol. In a preferred embodiment, the weight average over all molecular weights of all polyalkylene oxides that are contained in the tablet is at least 200,000 g/mol. Thus, polyalkylene glycols, if any, are preferably not taken into consideration when determining the weight average molecular weight of polyalkylene oxide.
  • In a preferred embodiment, polyalkylene oxide is homogeneously distributed in the particulates according to the invention. Preferably, the pharmacologically active compound and polyalkylene oxide are intimately homogeneously distributed in the particulates so that the particulates do not contain any segments where either pharmacologically active compound is present in the absence of polyalkylene oxide or where polyalkylene oxide is present in the absence of pharmacologically active compound.
  • When the particulates are film coated, the polyalkylene oxide is preferably homogeneously distributed in the core of the particulates, i.e. the film coating preferably does not contain polyalkylene oxide. Nonetheless, the film coating as such may of course contain one or more polymers, which however, preferably differ from the polyalkylene oxide contained in the core.
  • The polyalkylene oxide may be combined with one or more different polymers selected from the group consisting of polyalkylene oxide, preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyvinylpyrrolidone, poly(alk)acrylate, poly(hydroxy fatty acids), such as for example poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®), poly(hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene succinate, polylactone, polyglycolide, polyurethane, polyamide, polylactide, polyacetal (for example polysaccharides optionally with modified side chains), polylactide/glycolide, polylactone, polyglycolide, polyorthoester, polyanhydride, block polymers of polyethylene glycol and polybutylene terephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymers thereof, block-copolymers thereof (e.g., Poloxamer®), and mixtures of at least two of the stated polymers, or other polymers with the above characteristics.
  • Preferably, the molecular weight dispersity Mw/Mn of polyalkylene oxide is within the range of 2.5±2.0, more preferably 2.5±1.5, still more preferably 2.5±1.0, yet more preferably 2.5±0.8, most preferably 2.5±0.6, and in particular 2.5±0.4.
  • The polyalkylene oxide preferably has a viscosity at 25° C. of 30 to 17,600 cP, more preferably 55 to 17,600 cP, still more preferably 600 to 17,600 cP and most preferably 4,500 to 17,600 cP, measured in a 5 wt.-% aqueous solution using a model RVF Brookfield viscosimeter (spindle no. 2/rotational speed 2 rpm); of 400 to 4,000 cP, more preferably 400 to 800 cP or 2,000 to 4,000 cP, measured on a 2 wt.-% aqueous solution using the stated viscosimeter (spindle no. 1 or 3/rotational speed 10 rpm); or of 1,650 to 10,000 cP, more preferably 1,650 to 5,500 cP, 5,500 to 7,500 cP or 7,500 to 10,000 cP, measured on a 1 wt.-% aqueous solution using the stated viscosimeter (spindle no. 2/rotational speed 2 rpm).
  • Polyethylene oxide that is suitable for use in the tablets according to the invention is commercially available from Dow. For example, Polyox WSR N-12K, Polyox N-60K, Polyox WSR 301 NF or Polyox WSR 303NF may be used in the tablets according to the invention. For details concerning the properties of these products, it can be referred to e.g. the product specification.
  • Preferably, the content of the polyalkylene oxide is within the range of from 1 to 60 wt.-%, more preferably 3 to 55 wt.-%, still more preferably 5 to 50 wt.-%, yet more preferably 7 to 45 wt.-%, most preferably 10 to 40 wt.-% and in particular 15 to 35 wt.-%, based on the total weight of the tablet. In a preferred embodiment, the content of the polyalkylene oxide is at least 2 wt.-%, more preferably at least 5 wt.-%, still more preferably at least 10 wt.-%, yet more preferably at least 15 wt.-% and in particular at least 20 wt.-%, based on the total weight of the tablet.
  • In a preferred embodiment, the overall content of polyalkylene oxide is within the range of 10±8 wt.-%, more preferably 10±6 wt.-%, most preferably 10±4 wt.-%, and in particular 10±2 wt.-%, based on the total weight of the tablet. In another preferred embodiment, the overall content of polyalkylene oxide is within the range of 15±12 wt.-%, more preferably 15±10 wt.-%, most preferably 15±7 wt.-%, and in particular 15±3 wt.-%, based on the total weight of the tablet. In still another preferred embodiment, the overall content of polyalkylene oxide is within the range of 20±16 wt.-%, more preferably 20±12 wt.-%, most preferably 20±8 wt.-%, and in particular 20±4 wt.-%, based on the total weight of the tablet. In yet another preferred embodiment, the overall content of polyalkylene oxide is within the range of 25±20 wt.-%, more preferably 25±15 wt.-%, most preferably 25±10 wt.-%, and in particular 25±5 wt.-%, based on the total weight of the tablet. In a further preferred embodiment, the overall content of polyalkylene oxide is within the range of 30±20 wt.-%, more preferably 30±15 wt.-%, most preferably 30±10 wt.-%, and in particular 30±5 wt.-%, based on the total weight of the tablet. In still a further a preferred embodiment, the overall content of polyalkylene oxide is within the range of 35±20 wt.-%, more preferably 35±15 wt.-%, most preferably 35±10 wt.-%, and in particular 35±5 wt.-%. In a still further a preferred embodiment, the overall content of polyalkylene oxide is within the range of 40±20 wt.-%, more preferably 40±15 wt.-%, and most preferably 40±10 wt.-%, and in particular 40±5 wt.-%, based on the total weight of the tablet.
  • Preferably, the content of the polyalkylene oxide is within the range of from 1 to 99 wt.-%, more preferably 5 to 95 wt.-%, still more preferably 10 to 90 wt.-%, yet more preferably 15 to 85 wt.-%, most preferably 20 to 80 wt.-% and in particular 25 to 75 wt.-%, based on the total weight of the particulates. In a preferred embodiment, the content of the polyalkylene oxide is at least 10 wt.-%, more preferably at least 15 wt.-%, still more preferably at least 20 wt.-%, yet more preferably at least 25 wt.-% and in particular at least 30 wt.-%, based on the total weight of the particulates.
  • In a preferred embodiment, the overall content of polyalkylene oxide is within the range of 30±20 wt.-%, more preferably 30±15 wt.-%, most preferably 30±10 wt.-%, and in particular 30±5 wt.-%, based on the total weight of the particulates. In another preferred embodiment, the overall content of polyalkylene oxide is within the range of 35±20 wt.-%, more preferably 35±15 wt.-%, most preferably 35±10 wt.-%, and in particular 35±5 wt.-%, based on the total weight of the particulates. In still another preferred embodiment, the overall content of polyalkylene oxide is within the range of 40±20 wt.-%, more preferably 40±15 wt.-%, most preferably 40±10 wt.-%, and in particular 40±5 wt.-%, based on the total weight of the particulates. In yet another preferred embodiment, the overall content of polyalkylene oxide is within the range of 45±20 wt.-%, more preferably 45±15 wt.-%, most preferably 45±10 wt.-%, and in particular 45±5 wt.-%, based on the total weight of the particulates. In a further preferred embodiment, the overall content of polyalkylene oxide is within the range of 50±20 wt.-%, more preferably 50±15 wt.-%, most preferably 50±10 wt.-%, and in particular 50±5 wt.-%, based on the total weight of the particulates. In still a further a preferred embodiment, the overall content of polyalkylene oxide is within the range of 55±20 wt.-%, more preferably 55±15 wt.-%, most preferably 55±10 wt.-%, and in particular 55±5 wt.-%. In a still further a preferred embodiment, the overall content of polyalkylene oxide is within the range of 60±15 wt.-%, more preferably 60±10 wt.-%, most preferably 60±5 wt.-%, and in particular 60±5 wt.-%, based on the total weight of the particulates.
  • Preferably, the relative weight ratio of the polyalkylene oxide to the pharmacologically active compound is within the range of 1:1.00±0.75, more preferably 1:1.00±0.50, still more preferably 1:1.00±0.40, yet more preferably 1:1.00±0.30, most preferably 1:1.00±0.20, and in particular 1:1.00±0.10.
  • The particulates according to the invention may contain additional pharmaceutical excipients conventionally contained in tablets in conventional amounts, such as antioxidants, preservatives, lubricants, plasticizer, fillers, binders, and the like.
  • The skilled person will readily be able to determine appropriate further excipients as well as the quantities of each of these excipients. Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate the tablets according to the invention are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).
  • In a preferred embodiment, the particulates do not contain a disintegrant.
  • Preferably, the particulates further comprise an antioxidant. Suitable antioxidants include ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and the derivatives thereof, coniferyl benzoate, nordihydroguajaretic acid, gallus acid esters, sodium bisulfite, particularly preferably butylhydroxytoluene or butylhydroxyanisole and α-tocopherol. The antioxidant is preferably present in quantities of 0.01 wt.-% to 10 wt.-%, more preferably of 0.03 wt.-% to 5 wt.-%, most preferably of 0.05 wt.-% to 2.5 wt.-%, based on the total weight of the particulates.
  • In a preferred embodiment, the particulates further comprise an acid, preferably citric acid. The amount of acid is preferably in the range of 0.01 wt.-% to about 20 wt.-%, more preferably in the range of 0.02 wt.-% to about 10 wt.-%, and still more preferably in the range of 0.05 wt.-% to about 5 wt.-%, and most preferably in the range of 0.1 wt.-% to about 1.0 wt.-%, based on the total weight of the particulates.
  • In a preferred embodiment, the particulates further comprise another polymer which is preferably selected from cellulose esters and cellulose ethers, in particular hydroxypropyl methylcellulose (HPMC).
  • Other preferred polymers are polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymers, such as the one commercially available under the trade name Soluplus®.
  • The amount of the further polymer, preferably hydroxypropyl methylcellulose, preferably ranges from 0.1 wt.-% to about 30 wt.-%, more preferably in the range of 1.0 wt.-% to about 20 wt.-%, most preferably in the range of 2.0 wt.-% to about 15 wt.-%, and in particular in the range of 3.5 wt.-% to about 10.5 wt.-%, based on the total weight of the particulates.
  • In a preferred embodiment, the relative weight ratio of the polyalkylene oxide to the further polymer is within the range of 4.5±2:1, more preferably 4.5±1.5:1, still more preferably 4.5±1:1, yet more preferably 4.5±0.5:1, most preferably 4.5±0.2:1, and in particular 4.5±0.1:1. In another preferred embodiment, the relative weight ratio of the polyalkylene oxide to the further polymer is within the range of 8±7:1, more preferably 8±6:1, still more preferably 8±5:1, yet more preferably 8±4:1, most preferably 8±3:1, and in particular 8±2:1. In still another preferred embodiment, the relative weight ratio of the polyalkylene oxide to the further polymer is within the range of 11±8:1, more preferably 11±7:1, still more preferably 11±6:1, yet more preferably 11±5:1, most preferably 11±4:1, and in particular 11±3:1.
  • In another preferred embodiment, the particulates according to the invention do not contain any further polymer besides the polyalkylene oxide and optionally, polyethylene glycol.
  • In a preferred embodiment, the particulates contain at least one lubricant. In another preferred embodiment, the particulates contain no lubricant. Especially preferred lubricants are selected from
      • magnesium stearate and stearic acid;
      • glycerides of fatty acids, including monoglycerides, diglycerides, triglycerides, and mixtures thereof; preferably of C6 to C22 fatty acids; especially preferred are partial glycerides of the C16 to C22 fatty acids such as glycerol behenat, glycerol palmitostearate and glycerol monostearate;
      • polyoxyethylene glycerol fatty acid esters, such as mixtures of mono-, di- and triesters of glycerol and di- and monoesters of macrogols having molecular weights within the range of from 200 to 4000 g/mol, e.g., macrogolglycerolcaprylocaprate, macrogolglycerollaurate, macrogolglycerolococoate, macrogolglycerollinoleate, macrogol-20-glycerolmonostearate, macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate, macrogolglycerolstearate, macrogolglycerolhydroxystearate, and macrogolglycerolrizinoleate,
      • polyglycolyzed glycerides, such as the one known and commercially available under the trade name “Labrasol”;
      • fatty alcohols that may be linear or branched, such as cetylalcohol, stearylalcohol, cetylstearyl alcohol, 2-octyldodecane-1-ol and 2-hexyldecane-1-ol;
      • polyethylene glycols having a molecular weight between 10.000 and 60.000 g/mol; and
      • natural semi-synthetic or synthetic waxes, preferably waxes with a softening point of at least 50° C., more preferably 60° C., and in particular carnauba wax and bees wax.
  • Preferably, the amount of the lubricant ranges from 0.01 wt.-% to about 10 wt.-%, more preferably in the range of 0.05 wt.-% to about 7.5 wt.-%, most preferably in the range of 0.1 wt.-% to about 5 wt.-%, and in particular in the range of 0.1 wt.-% to about 1 wt.-%, based on the total weight of the particulates.
  • Preferably, the particulates further comprise a plasticizer. The plasticizer improves the processability of the polyalkylene oxide. A preferred plasticizer is polyalkylene glycol, like polyethylene glycol, triacetin, fatty acids, fatty acid esters, waxes and/or microcrystalline waxes. Particularly preferred plasticizers are polyethylene glycols, such as PEG 6000.
  • Preferably, the content of the plasticizer is within the range of from 0.5 to 30 wt.-%, more preferably 1.0 to 25 wt.-%, still more preferably 2.5 wt.-% to 22.5 wt.-%, yet more preferably 5.0 wt.-% to 20 wt.-%, most preferably 6 to 20 wt.-% and in particular 7 wt.-% to 17.5 wt.-%, based on the total weight of the particulates.
  • In a preferred embodiment, the plasticizer is a polyalkylene glycol having a content within the range of 7±6 wt.-%, more preferably 7±5 wt.-%, still more preferably 7±4 wt.-%, yet more preferably 7±3 wt.-%, most preferably 7±2 wt.-%, and in particular 7±1 wt.-%, based on the total weight of the particulates.
  • In another preferred embodiment, the plasticizer is a polyalkylene glycol having a content within the range of 10±8 wt.-%, more preferably 10±6 wt.-%, still more preferably 10±5 wt.-%, yet more preferably 10±4 wt.-%, most preferably 10±3 wt.-%, and in particular 10±2 wt.-%, based on the total weight of the particulates.
  • In a preferred embodiment, the relative weight ratio of the polyalkylene oxide to the polyalkylene glycol is within the range of 5.4±2:1, more preferably 5.4±1.5:1, still more preferably 5.4±1:1, yet more preferably 5.4±0.5:1, most preferably 5.4±0.2:1, and in particular 5.4±0.1:1. This ratio satisfies the requirements of relative high polyalkylene oxide content and good extrudability.
  • Plasticizers can sometimes act as a lubricant, and lubricants can sometimes act as a plasticizer.
  • The particulates and the matrix material of the tablets according to the invention preferably do not contain any polymers selected from the group consisting of
      • acrylates (such as acrylic and methacrylic polymers including acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers; e.g., Eudragit® NE, NM, RS or RL).
      • alkylcelluloses and hydroxy alkyl celluloses (such as methylcellulose, ethylcellulose, hydroxy propyl cellulose and hydroxylpropyl methylcellulose); and
      • gelling agents which hydrate to form gels to control the movement of water, such as high molecular weight grade (high viscosity) hydroxypropylmethyl cellulose (HPMC), pectin, locust bean gum and xanthan gum.
  • In a preferred embodiment, the tablet according to the invention contains no substances which irritate the nasal passages and/or pharynx, i.e. substances which, when administered via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the patient that he/she does not wish to or cannot continue administration, for example burning, or physiologically counteracts taking of the corresponding active compound, for example due to increased nasal secretion or sneezing. Further examples of substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Corresponding substances and the quantities thereof which are conventionally to be used are known to the person skilled in the art. Some of the substances which irritate the nasal passages and/or pharynx are accordingly based on one or more constituents or one or more plant parts of a hot substance drug. Corresponding hot substance drugs are known per se to the person skilled in the art and are described, for example, in “Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure.
  • The tablet according to the invention furthermore preferably contains no antagonists for the pharmacologically active compound, preferably no antagonists against psychotropic substances, in particular no antagonists against opioids. Antagonists suitable for a given pharmacologically active compound are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. The tablet according to the invention preferably contains no antagonists selected from among the group comprising naloxone, naltrexone, nalmefene, nalide, nalmexone, nalorphine or naluphine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate; and no neuroleptics, for example a compound selected from among the group comprising haloperidol, promethacine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopenthixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone and bromperidol.
  • The tablet according to the invention furthermore preferably contains no emetic. Emetics are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. The tablet according to the invention preferably contains no emetic based on one or more constituents of ipecacuanha (ipecac) root, for example based on the constituent emetine, as are, for example, described in “Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, New York, 1982. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure. The tablet according to the invention preferably also contains no apomorphine as an emetic.
  • Finally, the tablet according to the invention preferably also contains no bitter substance. Bitter substances and the quantities effective for use may be found in US-2003/0064099 A1, the corresponding disclosure of which should be deemed to be the disclosure of the present application and is hereby introduced as a reference. Examples of bitter substances are aromatic oils, such as peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit aroma substances, aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof, and/or denatonium benzoate.
  • The tablet according to the invention accordingly preferably contains neither substances which irritate the nasal passages and/or pharynx, nor antagonists for the pharmacologically active compound, nor emetics, nor bitter substances.
  • Particularly preferred contents of pharmacologically active compound, polyalkylene oxide, plasticizer and antioxidant of the particulates, relative to the total weight of the particulates, are summarized as embodiments B1 to B6 in the table here below:
  • wt.-% B1 B2 B3 B4 B5 B6
    active compound 45 ± 30 45 ± 25 45 ± 20 45 ± 15 45 ± 10 45 ± 5 
    polyalkylene oxide 45 ± 30 45 ± 25 45 ± 20 45 ± 15 45 ± 10 45 ± 5 
    plasticizer 8 ± 6 8 ± 5 8 ± 4 8 ± 3 8 ± 2 8 ± 1
    antioxidant 0.10 ± 0.08 0.10 ± 0.06 0.10 ± 0.04 0.10 ± 0.03 0.10 ± 0.02 0.10 ± 0.01

    wherein the pharmacologically active compound is preferably an opioid, particularly preferably tapentadol or a physiologically acceptable salt thereof; the polyalkylene oxide preferably is a polyethylene oxide having a weight average molecular weight of at least 500,000 g/mol; the plasticizer preferably is a polyethylene glycol; and the antioxidant preferably is α-tocopherol.
  • Besides the particulates and the preferably pre-compacted or granulated matrix material, the tablet according to the invention may comprise one or more pharmaceutical excipients such as binders, fillers, lubricants and the like.
  • In a preferred embodiment, the table additionally comprises a lubricant. Magnesium stearate is preferred. Further preferred lubricants are described above and therefore are not repeated hereinafter.
  • If the tablet contains an additional lubricant outside the preferably pre-compacted or pre-granulated matrix material, its content is preferably not more than 1 wt.-%, more preferably not more than 0.5 wt.-%, based on the total weight of the tablet.
  • While the particulates that are contained in the tablet according to the invention preferably exhibit increased mechanical strength, the tablet as such preferably has conventional mechanical properties. Typically, the tablet according to the invention can be crushed e.g. by means of a hammer thereby yielding a fractured composition containing the matrix material, the particulates and any other ingredients contained in the tablet. However, the particulates thereby obtained in more or less isolated form preferably cannot be further crushed and fractured by means of a hammer.
  • Preferably, the particulates are hot melt-extruded and/or have a breaking strength of at least 300 N.
  • The tablet according to the invention is tamper-resistant. Preferably, tamper-resistance is achieved based on the mechanical properties of the particulates so that comminution is avoided or at least substantially impeded. According to the invention, the term comminution means the pulverization of the particulates using conventional means usually available to an abuser, for example a pestle and mortar, a hammer, a mallet or other conventional means for pulverizing under the action of force. Thus, tamper-resistance preferably means that pulverization of the particulates using conventional means is avoided or at least substantially impeded.
  • Preferably, the mechanical properties of the particulates according to the invention, particularly their breaking strength and deformability, substantially rely on the presence and spatial distribution of polyalkylene oxide, although their mere presence does typically not suffice in order to achieve said properties. The advantageous mechanical properties of the particulates according to the invention may not automatically be achieved by simply processing pharmacologically active compound, polyalkylene oxide, and optionally further excipients by means of conventional methods for the preparation of tablets. In fact, usually suitable apparatuses must be selected for the preparation and critical processing parameters must be adjusted, particularly pressure/force, temperature and time. Thus, even if conventional apparatuses are used, the process protocols usually must be adapted in order to meet the required criteria.
  • In general, the particulates exhibiting the desired properties may be obtained only if, during preparation of the particulates,
      • suitable components
      • in suitable amounts
      • are exposed to
      • a sufficient pressure
      • at a sufficient temperature
      • for a sufficient period of time.
  • Thus, regardless of the apparatus used, the process protocols must be adapted in order to meet the required criteria. Therefore, the breaking strength and deformability of the particulates is separable from the composition.
  • The particulates contained in the tablet according to the invention preferably have a breaking strength of at least 300 N, at least 400 N, or at least 500 N, preferably at least 600 N, more preferably at least 700 N, still more preferably at least 800 N, yet more preferably at least 1000 N, most preferably at least 1250 N and in particular at least 1500 N.
  • In order to verify whether a particulate exhibits a particular breaking strength of e.g. 300 N or 500 N it is typically not necessary to subject said particulate to forces much higher than 300 N and 500 N, respectively. Thus, the breaking strength test can usually be terminated once the force corresponding to the desired breaking strength has been slightly exceeded, e.g. at forces of e.g. 330 N and 550 N, respectively.
  • The “breaking strength” (resistance to crushing) of a tablet and of a particulate is known to the skilled person. In this regard it can be referred to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann et al., Tablets: Tablets, Vol. 2, Informa Healthcare; 2 edition, 1990; and Encyclopedia of Pharmaceutical Technology, Informa Healthcare; 1 edition.
  • For the purpose of the specification, the breaking strength is preferably defined as the amount of force that is necessary in order to fracture the particulate (=breaking force). Therefore, for the purpose of the specification a particulate does preferably not exhibit the desired breaking strength when it breaks, i.e., is fractured into at least two independent parts that are separated from one another. In another preferred embodiment, however, the particulate is regarded as being broken if the force decreases by 50% (threshold value) of the highest force measured during the measurement (see below).
  • The particulates according to the invention are distinguished from conventional particulates that can be contained in tablets in that, due to their breaking strength, they cannot be pulverized by the application of force with conventional means, such as for example a pestle and mortar, a hammer, a mallet or other usual means for pulverization, in particular devices developed for this purpose (tablet crushers). In this regard “pulverization” means crumbling into small particles. Avoidance of pulverization virtually rules out oral or parenteral, in particular intravenous or nasal abuse.
  • Conventional particulates typically have a breaking strength well below 200 N.
  • The breaking strength of conventional round tablets/particulates may be estimated according to the following empirical formula: Breaking Strength [in N]=10× Diameter Of The Tablet/Particulate [in mm]. Thus, according to said empirical formula, a round tablet/particulate having a breaking strength of at least 300 N would require a diameter of at least 30 mm). Such a particulate, however, could not be swallowed, let alone a tablet containing a plurality of such particulates. The above empirical formula preferably does not apply to the particulates according to the invention, which are not conventional but rather special.
  • Further, the actual mean chewing force is about 220 N (cf., e.g., P. A. Proeschel et al., J Dent Res, 2002, 81(7), 464-468). This means that conventional particulates having a breaking strength well below 200 N may be crushed upon spontaneous chewing, whereas the particulates according to the invention may preferably not.
  • Still further, when applying a gravitational acceleration of about 9.81 m/s2, 300 N correspond to a gravitational force of more than 30 kg, i.e. the particulates according to the invention can preferably withstand a weight of more than 30 kg without being pulverized.
  • Methods for measuring the breaking strength of a tablet are known to the skilled artisan. Suitable devices are commercially available.
  • For example, the breaking strength (resistance to crushing) can be measured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08 “Resistance to Crushing of Tablets”. The test is intended to determine, under defined conditions, the resistance to crushing of tablets and particulates, respectively, measured by the force needed to disrupt them by crushing. The apparatus consists of 2 jaws facing each other, one of which moves towards the other. The flat surfaces of the jaws are perpendicular to the direction of movement. The crushing surfaces of the jaws are flat and larger than the zone of contact with the tablet and particulate, respectively. The apparatus is calibrated using a system with a precision of 1 Newton. The tablet and particulate, respectively, is placed between the jaws, taking into account, where applicable, the shape, the break-mark and the inscription; for each measurement the tablet and particulate, respectively, is oriented in the same way with respect to the direction of application of the force (and the direction of extension in which the breaking strength is to be measured). The measurement is carried out on 10 tablets and particulates, respectively, taking care that all fragments have been removed before each determination. The result is expressed as the mean, minimum and maximum values of the forces measured, all expressed in Newton.
  • A similar description of the breaking strength (breaking force) can be found in the USP. The breaking strength can alternatively be measured in accordance with the method described therein where it is stated that the breaking strength is the force required to cause a tablet and particulate, respectively, to fail (i.e., break) in a specific plane. The tablets and particulates, respectively, are generally placed between two platens, one of which moves to apply sufficient force to the tablet and particulate, respectively, to cause fracture. For conventional, round (circular cross-section) tablets and particulates, respectively, loading occurs across their diameter (sometimes referred to as diametral loading), and fracture occurs in the plane. The breaking force of tablets and particulates, respectively, is commonly called hardness in the pharmaceutical literature; however, the use of this term is misleading. In material science, the term hardness refers to the resistance of a surface to penetration or indentation by a small probe. The term crushing strength is also frequently used to describe the resistance of tablets and particulate, respectively, to the application of a compressive load. Although this term describes the true nature of the test more accurately than does hardness, it implies that tablets and particulate, respectively, are actually crushed during the test, which is often not the case.
  • Alternatively, the breaking strength (resistance to crushing) can be measured in accordance with WO 2008/107149, which can be regarded as a modification of the method described in the Eur. Ph. The apparatus used for the measurement is preferably a “Zwick Z 2.5” materials tester, Fmax=2.5 kN with a maximum draw of 1150 mm, which should be set up with one column and one spindle, a clearance behind of 100 mm and a test speed adjustable between 0.1 and 800 mm/min together with testControl software. A skilled person knows how to properly adjust the test speed, e.g. to 10 mm/min, 20 mm/min, or 40 mm/min, for example. Measurement is performed using a pressure piston with screw-in inserts and a cylinder (diameter 10 mm), a force transducer, Fmax. 1 kN, diameter=8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturers test certificate M according to DIN 55350-18 (Zwick gross force Fmax=1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 for the tester, Order No BTC-LC 0050N. P01 for the force transducer, Order No BO 70000 S06 for the centring device.
  • When using the testControl software (testXpert V10.11), the following exemplified settings and parameters have revealed to be useful: LE-position: clamping length 150 mm. LE-speed: 500 mm/min, clamping length after pre-travel: 195 mm, pre-travel speed: 500 mm/min, no pre-force control—pre-force: pre-force 1N, pre-force speed 10 mm/min—sample data: no sample form, measuring length traverse distance 10 mm, no input required prior to testing—testing/end of test; test speed: position-controlled 10 mm/min, delay speed shift: 1, force shut down threshold 50% Fmax, no force threshold for break-tests, no max length variation, upper force limit: 600N—expansion compensation: no correction of measuring length—actions after testing: LE to be set after test, no unload of sample—TRS: data memory: TRS distance interval until break 1 μm, TRS time interval 0.1 s, TRS force interval 1N—machine; traverse distance controller: upper soft end 358 mm, lower soft end 192 mm—lower test space. Parallel arrangement of the upper plate and the ambos should be ensured—these parts must not touch during or after testing. After testing, a small gap (e.g. 0.1 or 0.2 mm) should still be present between the two brackets in intimated contact with the tested particulate, representing the remaining thickness of the deformed particulate.
  • In a preferred embodiment, the particulate is regarded as being broken if it is fractured into at least two separate pieces of comparable morphology. Separated matter having a morphology different from that of the deformed particulate, e.g. dust, is not considered as pieces qualifying for the definition of breaking.
  • The particulates according to the invention preferably exhibit mechanical strength over a wide temperature range, in addition to the breaking strength (resistance to crushing) optionally also sufficient hardness, yield strength, fatigue strength, impact resistance, impact elasticity, tensile strength, compressive strength and/or modulus of elasticity, optionally also at low temperatures (e.g. below −24° C., below −40° C. or possibly even in liquid nitrogen), for it to be virtually impossible to pulverize by spontaneous chewing, grinding in a mortar, pounding, etc. Thus, preferably, the comparatively high breaking strength of the particulate according to the invention is maintained even at low or very low temperatures, e.g., when the tablet is initially chilled to increase its brittleness, for example to temperatures below −25° C., below −40° C. or even in liquid nitrogen.
  • The particulate according to the invention is characterized by a certain degree of breaking strength. This does not mean that the particulate must also exhibit a certain degree of hardness. Hardness and breaking strength are different physical properties. Therefore, the tamper-resistance of the tablet does not necessarily depend on the hardness of the particulates. For instance, due to its breaking strength, impact strength, elasticity modulus and tensile strength, respectively, the particulates can preferably be deformed, e.g. plastically, when exerting an external force, for example using a hammer, but cannot be pulverized, i.e., crumbled into a high number of fragments. In other words, the particulates according to the invention are characterized by a certain degree of breaking strength, but not necessarily also by a certain degree of form stability.
  • Therefore, in the meaning of the specification, a particulate that is deformed when being exposed to a force in a particular direction of extension but that does not break (plastic deformation or plastic flow) is preferably to be regarded as having the desired breaking strength in said direction of extension.
  • Preferred particulates present in the tablets according to the invention are those having a suitable tensile strength as determined by a test method currently accepted in the art. Further preferred particulates are those having a Youngs Modulus as determined by a test method of the art. Still further preferred particulates are those having an acceptable elongation at break.
  • Irrespective of whether the particulates according to the invention have an increased breaking strength or nor, the particulates according to the invention preferably exhibit a certain degree of deformability. The particulates contained in the tablet according to the invention preferably have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above.
  • This mechanical property, i.e. the deformability of the individual particulates, is illustrated in FIGS. 5 and 6.
  • FIG. 5 schematically illustrates the measurement and the corresponding force-displacement-diagram. In particular, FIG. 5A shows the initial situation at the beginning of the measurement. The sample particulate (9) is placed between upper jaw (8 a) and lower jaw (8 b) which each are in intimate contact with the surface of the particulate (9). The initial displacement d0 between upper jaw (8 a) and lower jaw (8 b) corresponds to the extension of the particulate orthogonal to the surfaces of upper jaw (8 a) and lower jaw (8 b). At this time, no force is exerted at all and thus, no graph is displayed in the force-displacement-diagram below. When the measurement is commenced, the upper jaw is moved in direction of lower jaw (8 b), preferably at a constant speed. FIG. 5B shows a situation where due to the movement of upper jaw (8 a) towards lower jaw (8 b) a force is exerted on particulate (9). Because of its deformability, the particulate (9) is flattened without being fractured. The force-displacement-diagram indicates that after a reduction of the displacement d0 of upper jaw (8 a) and lower jaw (8 b) by distance x1, i.e. at a displacement of d1=d0−x1, a force F1 is measured. FIG. 5C shows a situation where due to the continuous movement of upper jaw (8 a) towards lower jaw (8 b), the force that is exerted on particulate (9) causes further deformation, although the particulate (9) does not fracture. The force-displacement-diagram indicates that after a reduction of the displacement d0 of upper jaw (8 a) and lower jaw (8 b) by distance x2, i.e. at a displacement of d2=d0−x2, a force F2 is measured. Under these circumstances, the particulate (9) has not been broken (fractured) and a substantially steady increase of the force in the force-displacement-diagram is measured.
  • In contrast, FIG. 6 schematically illustrates the measurement and the corresponding force-displacement-diagram of a conventional comparative particulate not having the degree of deformability as the particulates according to the invention. FIG. 6A shows the initial situation at the beginning of the measurement. The comparative sample particulate (9) is placed between upper jaw (8 a) and lower jaw (8 b) which each are in intimate contact with the surface of the comparative particulate (9). The initial displacement d0 between upper jaw (8 a) and lower jaw (8 b) corresponds to the extension of the comparative particulate orthogonal to the surfaces of upper jaw (8 a) and lower jaw (8 b). At this time, no force is exerted at all and thus, no graph is displayed in the force-displacement-diagram below. When the measurement is commenced, the upper jaw is moved in direction of lower jaw (8 b), preferably at a constant speed. FIG. 6B shows a situation where due to the movement of upper jaw (8 a) towards lower jaw (8 b) a force is exerted on comparative particulate (9). Because of some deformability, the comparative particulate (9) is slightly flattened without being fractured. The force-displacement-diagram indicates that after a reduction of the displacement d0 of upper jaw (8 a) and lower jaw (8 b) by distance x1, i.e. at a displacement of d1=d0−x1, a force F1 is measured. FIG. 6C shows a situation where due to the continuous movement of upper jaw (8 a) towards lower jaw (8 b), the force that is exerted on particulate (9) causes sudden fracture of the comparative particulate (9). The force-displacement-diagram indicates that after a reduction of the displacement d0 of upper jaw (8 a) and lower jaw (8 b) by distance x2, i.e. at a displacement of d2=d0−x2, a force F2 is measured that suddenly drops when the particulate fractures. Under these circumstances, the particulate (9) has been broken (fractured) and no steady increase of the force in the force-displacement-diagram is measured. The sudden drop (decrease) of the force can easily be recognized and does not need to be quantified for the measurement. The steady increase in the force-displacement-diagram ends at displacement d2=d0−x2 when the particulate breaks.
  • In a preferred embodiment, the particulates contained in the tablet according to the invention have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant speed), preferably at least until the displacement d of upper jaw (8 a) and lower jaw (8 b) has been reduced to a value of 90% of the original displacement d0 (i.e. d=0.9·d0), preferably to a displacement d of 80% of the original displacement d0, more preferably to a displacement d of 70% of the original displacement d0, still more preferably to a displacement d of 60% of the original displacement d0, yet more preferably to a displacement d of 50% of the original displacement d0, even more preferably to a displacement d of 40% of the original displacement d0, most preferably to a displacement d of 30% of the original displacement d0, and in particular to a displacement d of 20% of the original displacement d0, or to a displacement d of 15% of the original displacement d0, to a displacement d of 10% of the original displacement d0, or to a displacement d of 5% of the original displacement d0.
  • In another preferred embodiment, the particulates contained in the tablet according to the invention have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant speed), preferably at least until the displacement d of upper jaw (8 a) and lower jaw (8 b) has been reduced to 0.80 mm or 0.75 mm, preferably 0.70 mm or 0.65 mm, more preferably 0.60 mm or 0.55 mm, still more preferably 0.50 mm or 0.45 mm, yet more preferably 0.40 mm or 0.35 mm, even more preferably 0.30 mm or 0.25 mm, most preferably 0.20 mm or 0.15 mm and in particular 0.10 or 0.05 mm.
  • In still another preferred embodiment, the particulates contained in the tablet according to the invention have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant speed), at least until the displacement d of upper jaw (8 a) and lower jaw (8 b) has been reduced to 50% of the original displacement d0 (i.e. d=d0/2), whereas the force measured at said displacement (d=d0/2) is at least 25 N or at least 50 N, preferably at least 75 N or at least 100 N, still more preferably at least 150 N or at least 200 N, yet more preferably at least 250 N or at least 300 N, even more preferably at least 350 N or at least 400 N, most preferably at least 450 N or at least 500 N, and in particular at least 625 N, or at least 750 N, or at least 875 N, or at least 1000 N, or at least 1250 N, or at least 1500 N.
  • In another preferred embodiment, the particulates contained in the tablet according to the invention have a deformability such that they show an increase, preferably a substantially steady increase of the force at a corresponding decrease of the displacement in the force-displacement-diagram when being subjected to a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant speed), at least until the displacement d of upper jaw (8 a) and lower jaw (8 b) has been reduced by at least 0.1 mm, more preferably at least 0.2 mm, still more preferably at least 0.3 mm, yet more preferably at least 0.4 mm, even more preferably at least 0.5 mm, most preferably at least 0.6 mm, and in particular at least 0.7 mm, whereas the force measured at said displacement is within the range of from 5.0 N to 250 N, more preferably from 7.5 N to 225 N, still more preferably from 10 N to 200 N, yet more preferably from 15 N to 175 N, even more preferably from 20 N to 150 N, most preferably from 25 N to 125 N, and in particular from 30 N to 100 N.
  • In yet another embodiment, the particulates contained in the tablet according to the invention have a deformability such that they are deformed without being fractured when subjected to a constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant force), until the displacement d of upper jaw (8 a) and lower jaw (8 b) is reduced so that no further deformation takes place at said constant force, whereas at this equilibrated state the displacement d of upper jaw (8 a) and lower jaw (8 b) is at most 90% of the original displacement d0 (i.e. d≦0.9·d0), preferably at most 80% of the original displacement d0 (i.e. d≦0.8·d0), more preferably at most 70% of the original displacement d0 (i.e. d≦0.7·d0), still more preferably at most 60% of the original displacement d0 (i.e. d≦0.6·d0), yet more preferably at most 50% of the original displacement d0 (i.e. d≦0.5·d0), even more preferably at most 40% of the original displacement d0 (i.e. d≦0.4·d0), most preferably at most 30% of the original displacement d0 (i.e. d≦0.3·d0), and in particular at most 20% of the original displacement d0 (i.e. d≦0.2·d0), or at most 15% of the original displacement d0 (i.e. d≦0.15·d0), at most 10% of the original displacement d0 (i.e. d≦0.1·d0), or at most 5% of the original displacement d0 (i.e. d≦0.05·d0).
  • Preferably, the particulates contained in the tablet according to the invention have a deformability such that they are deformed without being fractured when subjected to a constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant force), until the displacement d of upper jaw (8 a) and lower jaw (8 b) is reduced so that no further deformation takes place at said constant force, whereas at this equilibrated state the displacement d of upper jaw (8 a) and lower jaw (8 b) is at most 0.80 mm or at most 0.75 mm, preferably at most 0.70 mm or at most 0.65 mm, more preferably at most 0.60 mm or at most 0.55 mm, still more preferably at most 0.50 mm or at most 0.45 mm, yet more preferably at most 0.40 mm or at most 0.35 mm, even more preferably at most 0.30 mm or at most 0.25 mm, most preferably at most 0.20 mm or at most 0.15 mm and in particular at most 0.10 or at most 0.05 mm.
  • In another embodiment, the particulates contained in the tablet according to the invention have a deformability such that they are deformed without being fractured when subjected to a constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant force), until the displacement d of upper jaw (8 a) and lower jaw (8 b) is reduced so that no further deformation takes place at said constant force, whereas at this equilibrated state the displacement d of upper jaw (8 a) and lower jaw (8 b) is at least 5% of the original displacement d0 (i.e. d≧0.05·d0), preferably at least 10% of the original displacement d0 (i.e. d≧0.1·d0), more preferably at least 15% of the original displacement d0 (i.e. d≧0.15·d0), still more preferably at least 20% of the original displacement d0 (i.e. d≧0.2·d0), yet more preferably at least 30% of the original displacement d0 (i.e. d≧0.3·d0), even more preferably at least 40% of the original displacement d0 (i.e. d≧0.4·d0), most preferably at least 50% of the original displacement d0 (i.e. d≧0.5·d0), and in particular at least 60% of the original displacement d0 (i.e. d≧0.6·d0), or at least 70% of the original displacement d0 (i.e. d≧0.7·d0), at least 80% of the original displacement d0 (i.e. d≧0.8·d0), or at least 90% of the original displacement d0 (i.e. d≧0.9·d0).
  • Preferably, the particulates contained in the tablet according to the invention have a deformability such that they are deformed without being fractured when subjected to a constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test as described above (“Zwick Z 2.5” materials tester, constant force), until the displacement d of upper jaw (8 a) and lower jaw (8 b) is reduced so that no further deformation takes place at said constant force, whereas at this equilibrated state the displacement d of upper jaw (8 a) and lower jaw (8 b) is at least 0.05 mm or at least 0.10 mm, preferably at least 0.15 mm or at least 0.20 mm, more preferably at least 0.25 mm or at least 0.30 mm, still more preferably at least 0.35 mm or at least 0.40 mm, yet more preferably at least 0.45 mm or at least 0.50 mm, even more preferably at least 0.55 mm or at least 0.60 mm, most preferably at least 0.65 mm or at least 0.70 mm and in particular at least 0.75 or at least 0.80 mm.
  • Preferably, the tablet according to the invention provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur.
  • The term “immediate release” as applied to tablets is understood by persons skilled in the art which has structural implications for the respective tablets. The term is defined, for example, in the current issue of the US Pharmacopoeia (USP), General Chapter 1092, “THE DISSOLUTION PROCEDURE: DEVELOPMENT AND VALIDATION”, heading “STUDY DESIGN”, “Time Points”. For immediate-release dosage forms, the duration of the procedure is typically 30 to 60 minutes; in most cases, a single time point specification is adequate for Pharmacopeia purposes. Industrial and regulatory concepts of product comparability and performance may require additional time points, which may also be required for product registration or approval. A sufficient number of time points should be selected to adequately characterize the ascending and plateau phases of the dissolution curve. According to the Biopharmaceutics Classification System referred to in several FDA Guidances, highly soluble, highly permeable drugs formulated with rapidly dissolving products need not be subjected to a profile comparison if they can be shown to release 85% or more of the active drug substance within 15 minutes. For these types of products a one-point test will suffice. However, most products do not fall into this category. Dissolution profiles of immediate-release products typically show a gradual increase reaching 85% to 100% at about 30 to 45 minutes. Thus, dissolution time points in the range of 15, 20, 30, 45, and 60 minutes are usual for most immediate-release products.
  • Preferably, under physiological conditions the tablet according to the invention has released after 30 minutes at least 70%, more preferably at least 75%, still more preferably at least 80%, yet more preferably at least 82%, most preferably at least 84% and in particular at east 86% of the pharmacologically active compound originally contained in the tablet.
  • Preferably, under physiological conditions the tablet according to the invention has released after 10 minutes at least 70%, more preferably at least 73%, still more preferably at least 76%, yet more preferably at least 78%, most preferably at least 80% and in particular at east 82% of the pharmacologically active compound originally contained in the tablet.
  • Further preferred release profiles C1 to C10 are summarized in the table here below [all data in wt.-% of released pharmacologically active compound]:
  • time C1 C2 C3 C4 C5 C6 C7 C8 C9 C10
    10 min ≧30 ≧35 ≧40 ≧45 ≧50 ≧60 ≧70 ≧80 ≧80 ≧80
    20 min ≧50 ≧55 ≧60 ≧65 ≧70 ≧75 ≧80 ≧85 ≧90 ≧95
    30 min ≧55 ≧60 ≧65 ≧70 ≧75 ≧85 ≧90 ≧95 ≧95 ≧95
    40 min ≧60 ≧65 ≧70 ≧80 ≧85 ≧90 ≧95 ≧95 ≧95 ≧95
    50 min ≧65 ≧70 ≧80 ≧85 ≧88 ≧92 ≧95 ≧95 ≧95 ≧95
    60 min ≧75 ≧80 ≧85 ≧90 ≧92 ≧94 ≧95 ≧95 ≧95 ≧95
  • Preferably, the release profile, the drug and the pharmaceutical excipients of the tablet according to the invention are stable upon storage, preferably upon storage at elevated temperature, e.g. 40° C., for 3 months in sealed containers.
  • In connection with the release profile “stable” means that when comparing the initial release profile with the release profile after storage, at any given time point the release profiles deviate from one another by not more than 20%, more preferably not more than 15%, still more preferably not more than 10%, yet more preferably not more than 7.5%, most preferably not more than 5.0% and in particular not more than 2.5%.
  • In connection with the drug and the pharmaceutical excipients “stable” means that the tablets satisfy the requirements of EMEA concerning shelf-life of pharmaceutical products.
  • Suitable in vitro conditions are known to the skilled artisan. In this regard it can be referred to, e.g., the Eur. Ph. Preferably, the release profile is measured under the following conditions: Paddle apparatus equipped without sinker, 50 rpm, 37±5° C., 900 mL simulated intestinal fluid pH 6.8 (phosphate buffer) or pH 4.5. In a preferred embodiment, the rotational speed of the paddle is increased to 75 rpm.
  • In a preferred embodiment, the tablet according to the invention is adapted for administration once daily. In another preferred embodiment, the tablet according to the invention is adapted for administration twice daily. In still another preferred embodiment, the tablet according to the invention is adapted for administration thrice daily. In yet another preferred embodiment, the tablet according to the invention is adapted for administration more frequently than thrice daily, for example 4 times daily, 5 times daily, 6 times daily, 7 times daily or 8 times daily.
  • For the purpose of the specification, “twice daily” means equal or nearly equal time intervals, i.e., about every 12 hours, or different time intervals, e.g., 8 and 16 hours or 10 and 14 hours, between the individual administrations.
  • For the purpose of the specification, “thrice daily” means equal or nearly equal time intervals, i.e., about every 8 hours, or different time intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours, between the individual administrations.
  • Preferably, the tablet according to the invention has under in vitro conditions a disintegration time measured in accordance with Ph. Eur. of at most 5 minutes, more preferably at most 4 minutes, still more preferably at most 3 minutes, yet more preferably at most 2.5 minutes, most preferably at most 2 minutes and in particular at most 1.5 minutes.
  • It has been surprisingly found that oral dosage forms can be designed that provide the best compromise between tamper-resistance, disintegration time and drug release, drug load, processability (especially tablettability) and patient compliance.
  • It has been found that the disintegration time of the tablets according to the invention can be influenced by the relative weight ratio of matrix material:particulates. In general, it was observed that the higher this ratio the faster disintegration. However, this ratio cannot be increased ad ultimo, as further tablet properties need to be taken into account, particularly drug load and total tablet size and weight. As a certain dosage of pharmacologically active compound needs to be administered, the content of particulates should still be sufficiently high and the total tablet weight should not exceed a certain limit, as this would deteriorate patient compliance, e.g. swallowability.
  • The situation is more complicated by trends in opposite direction. In particular, it has been found that the tablettability of the tablets according to the invention can also be influenced by the relative weight ratio of matrix material:particulates. In general, it was observed that the lower this ratio the better the tablettability. This trend parallels the trend of the drug load.
  • Thus, disintegration time on the one hand and tablettability/drug load on the other hand can be optimized by finding the best compromise.
  • Similarly, tamper-resistance and drug release also antagonize each other. While smaller particulates should typically show a faster release of the pharmacologically active compound, tamper-resistance requires some minimal size of the particulates in order to effectively prevent abuse, e.g. i.v. administration. The larger the particulates are the less they are suitable for being abused nasally. The smaller the particulates are the faster gel formation occurs.
  • Thus, drug release on the one hand and tamper-resistance on the other hand can be optimized by finding the best compromise.
  • Preferred embodiments D1 to D4 of the tablets according to the invention are summarized in the table here below:
  • [wt.-%, relative to weight of tablet] D1 D2 D3 D4
    tablet
    total weight [mg] 500 ± 300 500 ± 250 500 ± 200 500 ± 150
    particulates
    total content [wt.-%] 50 ± 15   50 ± 12.5 50 ± 10  50 ± 7.5
    average particle size [μm] 800 ± 400 800 ± 300 800 ± 200 800 ± 100
    content of ph. active compound 23 ± 20 23 ± 15 23 ± 10 23 ± 5 
    content of polyalkylene oxide [wt.-%] 22 ± 12 22 ± 10 22 ± 8  22 ± 6 
    content of plasticizer [wt.-%]   4 ± 3.5 4 ± 3   4 ± 2.5 4 ± 2
    content of further excipients [wt.-%] 0.05 ± 0.05 0.05 ± 0.04 0.05 ± 0.03 0.05 ± 0.02
    matrix material
    total content [wt.-%] 49 ± 15 49 ± 12 49 ± 9  49 ± 6 
    content of filler(s)/binder(s) [wt.-%] 43 ± 10 43 ± 8  43 ± 6  43 ± 4 
    content of disintegrant [wt.-%] 5 ± 4   5 ± 3.5 5 ± 3   5 ± 2.5
    content of lubricant [wt.-%] 0.15 ± 0.15 0.15 ± 0.14 0.15 ± 0.13 0.15 ± 0.12
  • The particulates according to the invention are preferably prepared by melt-extrusion, although also other methods of thermoforming may be used in order to manufacture the particulates according to the invention such as press-molding at elevated temperature or heating of particulates that were manufactured by conventional compression in a first step and then heated above the softening temperature of the polyalkylene oxide in the particulates in a second step to form hard tablets. In this regards, thermoforming means the forming, or molding of a mass after the application of heat. In a preferred embodiment, the particulates are thermoformed by hot-melt extrusion.
  • In a preferred embodiment, the particulates are prepared by hot melt-extrusion, preferably by means of a twin-screw-extruder. Melt extrusion preferably provides a melt-extruded strand that is preferably cut into monoliths, which are then optionally compressed and formed into particulates. Preferably, compression is achieved by means of a die and a punch, preferably from a monolithic mass obtained by melt extrusion. If obtained via melt extrusion, the compressing step is preferably carried out with a monolithic mass exhibiting ambient temperature, that is, a temperature in the range from 20 to 25° C. The strands obtained by way of extrusion can either be subjected to the compression step as such or can be cut prior to the compression step. This cutting can be performed by usual techniques, for example using rotating knives or compressed air, at elevated temperature, e.g. when the extruded stand is still warm due to hot-melt extrusion, or at ambient temperature, i.e. after the extruded strand has been allowed to cool down. When the extruded strand is still warm, singulation of the extruded strand into extruded particulates is preferably performed by cutting the extruded strand immediately after it has exited the extrusion die. However, when the extruded strand is cut in the cooled state, subsequent singulation of the extruded strand into extruded particulates is preferably performed by optionally transporting the still hot extruded strand by means of conveyor belts, allowing it to cool down and to congeal, and subsequently cutting it into extruded particulates. Alternatively, the shaping can take place as described in EP-A 240 906 by the extrudate being passed between two counter-rotating calender rolls and being shaped directly to particulates. It is of course also possible to subject the extruded strands to the compression step or to the cutting step when still warm, that is more or less immediately after the extrusion step. The extrusion is preferably carried out by means of a twin-screw extruder.
  • The particulates according to the invention may be produced by different processes, the particularly preferred of which are explained in greater detail below. Several suitable processes have already been described in the prior art. In this regard it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, and WO 2006/082099.
  • In general, the process for the production of the particulates according to the invention preferably comprises the following steps:
    • (a) mixing all ingredients;
    • (b) optionally pre-forming the mixture obtained from step (a), preferably by applying heat and/or force to the mixture obtained from step (a), the quantity of heat supplied preferably not being sufficient to heat the polyalkylene oxide up to its softening point;
    • (c) hardening the mixture by applying heat and force, it being possible to supply the heat during and/or before the application of force and the quantity of heat supplied being sufficient to heat the polyalkylene oxide at least up to its softening point; and thereafter allowing the material to cool and removing the force
    • (d) optionally singulating the hardened mixture;
    • (e) optionally shaping the particulates; and
    • (f) optionally providing a film coating.
  • Heat may be supplied directly, e.g. by contact or by means of hot gas such as hot air, or with the assistance of ultrasound; or is indirectly supplied by friction and/or shear. Force may be applied and/or the particulates may be shaped for example by direct tabletting or with the assistance of a suitable extruder, particularly by means of a screw extruder equipped with one or two screws (single-screw-extruder and twin-screw-extruder, respectively) or by means of a planetary gear extruder.
  • The final shape of the particulates may either be provided during the hardening of the mixture by applying heat and force (step (c)) or in a subsequent step (step (e)). In both cases, the mixture of all components is preferably in the plastified state, i.e. preferably, shaping is performed at a temperature at least above the softening point of the polyalkylene oxide. However, extrusion at lower temperatures, e.g. ambient temperature, is also possible and may be preferred.
  • Shaping can be performed, e.g., by means of a tabletting press comprising die and punches of appropriate shape.
  • A particularly preferred process for the manufacture of the particulates according to the invention involves hot-melt extrusion. In this process, the particulates according to the invention are produced by thermoforming with the assistance of an extruder, preferably without there being any observable consequent discoloration of the extrudate.
  • This process is characterized in that
      • a) all components are mixed,
      • b) the resultant mixture is heated in the extruder at least up to the softening point of the polyalkylene oxide and extruded through the outlet orifice of the extruder by application of force,
      • c) the still plastic extrudate is singulated and formed into the particulates or
      • d) the cooled and optionally reheated singulated extrudate is formed into the particulates.
  • Mixing of the components according to process step a) may also proceed in the extruder.
  • The components may also be mixed in a mixer known to the person skilled in the art. The mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer.
  • The, preferably molten, mixture which has been heated in the extruder at least up to the softening point of polyalkylene oxide is extruded from the extruder through a die with at least one bore.
  • The process according to the invention requires the use of suitable extruders, preferably screw extruders. Screw extruders which are equipped with two screws (twin-screw-extruders) are particularly preferred.
  • Preferably, extrusion is performed in the absence of water, i.e., no water is added. However, traces of water (e.g., caused by atmospheric humidity) may be present.
  • The extruder preferably comprises at least two temperature zones, with heating of the mixture at least up to the softening point of the polyalkylene oxide proceeding in the first zone, which is downstream from a feed zone and optionally mixing zone. The throughput of the mixture is preferably from 1.0 kg to 15 kg/hour. In a preferred embodiment, the throughput is from 0.5 kg/hour to 3.5 kg/hour. In another preferred embodiment, the throughput is from 4 to 15 kg/hour.
  • In a preferred embodiment, the die head pressure is within the range of from 25 to 200 bar. The die head pressure can be adjusted inter alia by die geometry, temperature profile, extrusion speed, number of bores in the dies, screw configuration, first feeding steps in the extruder, and the like.
  • The die geometry or the geometry of the bores is freely selectable. The die or the bores may accordingly exhibit a round, oblong or oval cross-section, wherein the round cross-section preferably has a diameter of 0.1 mm to 2 mm. Preferably, the die or the bores have a round cross-section. The casing of the extruder used according to the invention may be heated or cooled. The corresponding temperature control, i.e. heating or cooling, is so arranged that the mixture to be extruded exhibits at least an average temperature (product temperature) corresponding to the softening temperature of the polyalkylene oxide and does not rise above a temperature at which the pharmacologically active compound to be processed may be damaged. Preferably, the temperature of the mixture to be extruded is adjusted to below 180° C., preferably below 150° C., but at least to the softening temperature of polyalkylene oxide. Typical extrusion temperatures are 120° C. and 150° C.
  • In a preferred embodiment, the extruder torque is within the range of from 30 to 95%. Extruder torque can be adjusted inter alia by die geometry, temperature profile, extrusion speed, number of bores in the dies, screw configuration, first feeding steps in the extruder, and the like.
  • After extrusion of the molten mixture and optional cooling of the extruded strand or extruded strands, the extrudates are preferably singulated. This singulation may preferably be performed by cutting up the extrudates by means of revolving or rotating knives, wires, blades or with the assistance of laser cutters.
  • Preferably, intermediate or final storage of the optionally singulated extrudate or the final shape of the particulates according to the invention is performed under oxygen-free atmosphere which may be achieved, e.g., by means of oxygen-scavengers.
  • The singulated extrudate may be press-formed into particulates in order to impart the final shape to the particulates.
  • The application of force in the extruder onto the at least plasticized mixture is adjusted by controlling the rotational speed of the conveying device in the extruder and the geometry thereof and by dimensioning the outlet orifice in such a manner that the pressure necessary for extruding the plasticized mixture is built up in the extruder, preferably immediately prior to extrusion. The extrusion parameters which, for each particular composition, are necessary to give rise to a tablet with desired mechanical properties, may be established by simple preliminary testing.
  • For example but not limiting, extrusion may be performed by means of a twin-screw-extruder type ZSE 18 or ZSE27 (Leistritz, Nürnberg, Germany), screw diameters of 18 or 27 mm. Screws having eccentric or blunt ends may be used. A heatable die with a round bore or with a multitude of bores each having a diameter of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 mm may be used. The extrusion parameters may be adjusted e.g. to the following values: rotational speed of the screws: 120 Upm, delivery rate 2 kg/h for a ZSE 18 or 3 kg/h, 8 kg/h, or even 10 kg/h and more for a ZSE27, product temperature: in front of die 125° C. and behind die 135° C., and jacket temperature: 110° C. The throughput can generally be increased by increasing the number of dies at the extruder outlet.
  • Preferably, extrusion is performed by means of twin-screw-extruders or planetary-gear-extruders, twin-screw extruders (co-rotating or contra-rotating) being particularly preferred.
  • The particulates according to the invention are preferably produced by thermoforming with the assistance of an extruder without any observable consequent discoloration of the extrudates.
  • The process for the preparation of the particulates according to the invention is preferably performed continuously. Preferably, the process involves the extrusion of a homogeneous mixture of all components. It is particularly advantageous if the thus obtained intermediate, e.g. the strand obtained by extrusion, exhibits uniform properties. Particularly desirable are uniform density, uniform distribution of the active compound, uniform mechanical properties, uniform porosity, uniform appearance of the surface, etc. Only under these circumstances the uniformity of the pharmacological properties, such as the stability of the release profile, may be ensured and the amount of rejects can be kept low.
  • Preferably, the particulates according to the invention can be regarded as “extruded pellets”. The term “extruded pellets” has structural implications which are understood by persons skilled in the art. A person skilled in the art knows that pelletized dosage forms can be prepared by a number of techniques, including:
      • drug layering on nonpareil sugar or microcrystalline cellulose beads,
      • spray drying,
      • spray congealing,
      • rotogranulation,
      • hot-melt extrusion,
      • spheronization of low melting materials, or
      • extrusion-spheronization of a wet mass.
  • Accordingly, “extruded pellets” can be obtained either by hot-melt extrusion or by extrusion-spheronization.
  • “Extruded pellets” can be distinguished from other types of pellets, as extruded pellets typically have a different shape. The shape of the extruded pellets is typically more cut-rod-like than perfectly globated round.
  • “Extruded pellets” can be distinguished from other types of pellets because they are structurally different. For example, drug layering on nonpareils yields multilayered pellets having a core, whereas extrusion typically yields a monolithic mass comprising a homogeneous mixture of all ingredients. Similarly, spray drying and spray congealing typically yield spheres, whereas extrusion typically yields cylindrical extrudates which can be subsequently spheronized.
  • The structural differences between “extruded pellets” and “agglomerated pellets” are significant because they may affect the release of active substances from the pellets and consequently result in different pharmacological profiles. Therefore, a person skilled in the pharmaceutical formulation art would not consider “extruded pellets” to be equivalent to “agglomerated pellets”.
  • The tablets according to the invention may be prepared by any conventional method. Preferably, however, the tablets are prepared by compression. Thus, particulates as hereinbefore defined are preferably mixed, e.g. blended and/or granulated (e.g. wet granulated), with matrix material and the resulting mix (e.g. blend or granulate) is then compressed, preferably in moulds, to form tablets. It is also envisaged that the particulates herein described may be incorporated into a matrix using other processes, such as by melt granulation (e.g. using fatty alcohols and/or water-soluble waxes and/or water-insoluble waxes) or high shear granulation, followed by compression.
  • When the tablets according to the invention are manufactured by means of an eccentric press, the compression force is preferably within the range of from 5 to 15 kN. When the tablets according to the invention are manufactured by means of a rotating press, the compression force is preferably within the range of from 5 to 40 kN, in certain embodiments>25 kN, in other embodiments about 13 kN.
  • The tablets according to the invention may optionally comprise a coating, e.g. a cosmetic coating. The coating is preferably applied after formation of the tablet. The coating may be applied prior to or after the curing process. Preferred coatings are Opadry® coatings available from Colorcon. Other preferred coating are Opaglos® coatings, also commercially available from Colorcon.
  • The tablet according to the invention is characterized by excellent storage stability. Preferably, after storage for 4 weeks at 40° C. and 75% rel. humidity, the content of pharmacologically active compound amounts to at least 98.0%, more preferably at least 98.5%, still more preferably at least 99.0%, yet more preferably at least 99.2%, most preferably at least 99.4% and in particular at least 99.6%, of its original content before storage. Suitable methods for measuring the content of the pharmacologically active compound in the tablet are known to the skilled artisan. In this regard it is referred to the Eur. Ph. or the USP, especially to reversed phase HPLC analysis. Preferably, the tablet is stored in closed, preferably sealed containers.
  • Further aspects according to the invention—basis for additional claim categories
  • The particulates and tablets according to the invention may be used in medicine, e.g. as an analgesic. The particulates and tablets are therefore particularly suitable for the treatment or management of pain. In such tablets, the pharmacologically active compound is preferably an analgesic.
  • A further aspect according to the invention relates to the tablet as described above for use in the treatment of pain.
  • A further aspect according to the invention relates to the use of a tablet as described above for avoiding or hindering the abuse of the pharmacologically active compound contained therein.
  • A further aspect according to the invention relates to the use of a tablet as described above for avoiding or hindering the unintentional overdose of the pharmacologically active compound contained therein.
  • In this regard, the invention also relates to the use of a pharmacologically active compound as described above and/or a polyalkylene oxide as described above for the manufacture of the tablet according to the invention for the prophylaxis and/or the treatment of a disorder, thereby preventing an overdose of the pharmacologically active compound, particularly due to comminution of the tablet by mechanical action.
  • EXAMPLES
  • The following examples further illustrate the invention but are not to be construed as limiting its scope.
  • Example 1
  • The relevance of the particulate size on tamper resistance was investigated.
  • It was found that comparatively small particulates, e.g. particulates having a diameter and length of 0.5 mm×0.5 mm already provide a certain degree of tamper resistance: when administered nasally they cause an unpleasant feeling and furthermore, due to the lack of water on the mucous membrane, do not release the pharmacologically active compound as quick as when being administered orally. Therefore, a kick or rush can unlikely be achieved by nasal administration of such particulates. Thus, even when being administered nasally, such comparatively small particulates already provide tamper resistance, i.e. avoid drug abuse or at least make drug abuse substantially more difficult. Furthermore, such comparatively small particulates have excellent swelling properties thereby effectively preventing conversion into a liquid formulation for intravenous administration.
  • It was found that tamper-resistance can even further be improved by increasing the particulate size, e.g. to a diameter and length of 1.0 mm×1.0 mm. Such particulates even provide a more unpleasant feeling when being administered nasally and in the absence of sufficient water, rather slowly release the pharmacologically active compound. Further, they cannot be easily converted into a liquid formulation for intravenous administration either.
  • As such a more pronounced retardant effect, however, is detrimental for the desired immediate release upon prescribed oral administration of the tablets, a compromise must be found between tamper resistance on the one hand and immediate drug release upon prescribed oral administration on the other hand, particularly with respect to disintegration time and drug release kinetics. Furthermore, drug load, processability (especially tablettability) and patient compliance are also important requirements to be satisfied with.
  • A predetermined particulate size of 800 μm×800 μm was considered most appropriate, i.e. it was considered most appropriate to adjust the diameter of the extrusion die as well as cutting length of the extruded stand to 800 μm taking into consideration that die swelling may occur during the extrusion process, particularly when the strand exits the die, so that the diameter of the extruded strand in fact is expanded, depending upon the composition and the extrusion parameters to a diameter of about 1000 μm. Thus, when proceedings this way, it was considered most appropriate to manufacture extruded particulates having a diameter of about 1000 μm (after die swelling, diameter of extrusion die 800 μm) and a length of about 800 μm.
  • Example 2
  • Different particulate compositions were investigated and particulates of different sizes were manufactured thereform.
  • The particulate compositions are summarized in the table here below:
  • [wt.-%] 1 2 3 4 5 6 7 8 9
    Tramadol HCl 46.59 46.59 46.59 38.83 45.59
    Tapentadol HCl 46.59 46.59 46.59 33.28
    PEG 6000 5.31 6.32 4.31 8.33 8.31 8.31 8.32 10.00 8.40
    HPMC 100 000 5.00 6.00 4.00 9.33 8.00 12.57 8.00
    PEO 7 Mio 33.00 35.99 45.00 43.49 45.00 45.00 36.99 44.14 36.99
    α-tocopherol 0.10 0.10 0.10 0.01 0.10 0.10 0.1 0.01 0.01
    Lutrol 127 10.00
    PVP CL 5.00
    total weight [mg] 250 mg 250 mg 250 mg 300 mg 250 mg 250 mg 250 mg 350 mg 250 mg
    film coating AMB 3.88
    varnish
  • All materials were weighed, sieved (manual sieve, 1 mm), blended (Bohle LM40 with MC5 or MC10, depending on size of bath) for 15 minutes at 14 rpm, and hot-melt extruded (Leistritz extruder Type ZSE18 with different configuration of screws).
  • The compositions 1 to 9 were extruded under the following extrusion conditions:
  • 1, 4, 7, 9 2 3 5 and 6 8
    Heating zone 1  20° C.  20° C.  20° C. 20 25
    Heating zone 2 100° C. 100° C. 100° C. 100 100
    Heating zone 3 100° C. 100° C. 100° C. 100 100
    Heating zone 4 120° C. 140° C. 120° C. 120 100
    Heating zone 5 120° C. 120° C. 120° C. 120 100
    Heating zone 6 120° C. 120° C. 120° C. 120 100
    Heating zone 7 120° C. 140° C. 120° C. 120 100
    Heating zone 8 120° C. 140° C. 120° C. 120 100
    Heating zone 10 120° C. 140° C. 120° C. 120 120
    Heating zone 11 130° C. 150° C. 130° C. 130 120
    Screw speed [rpm] 100 100 100 100 100
    Throughput 10.00-16.66 16.66-28.04 16.66 16.66 16.66
    [g/min]
    Screw low low low extreme low
    configuration shear shear shear shear shear
  • For larger scales, screw configuration can be adopted and temperatures can be raised (e.g., HZ8 and 10: 130° C., HZ11: 145° C.; or HZ11: 150° C. and extreme shear configuration, throughput 25 g/min).
  • The in vitro release characteristics were monitored in 900 mL 0.1N HCl at 37° C., using a paddle apparatus 50 rpm. The results are depicted in FIG. 3.
  • Example 3
  • The influence of the content of particulates in the tablet was investigated.
  • The following compositions were tested:
  • 300 mg particulates in tablets having a total weight of 600 mg
    250 mg particulates in tablets having a total weight of 600 mg
    200 mg particulates in tablets having a total weight of 600 mg
  • The most promising compromise between tablettability and size revealed to be 250 mg particulates in tablets having a total weight of 500 mg. Tablets having a total weight of 600 mg were considered too large with respect to patient compliance, although the relative weight ratio of particulates to matrix material of about 1:1 appeared advantageous with respect to disintegration time and dissolution time.
  • Example 4-1
  • The influence of the matrix material was investigated—wet granulation.
  • Granules having the following composition were prepared for manufacturing of pellet-tablets. Granules for outer the phase, i.e. the matrix material, were manufactured by wet granulation. Granules and pellets were blended. Segregation (optically) and disintegration of tablets after compression were evaluated. Tablets were manufactured “manually” (components were separately weighed for each tablet and mixed directly prior to tabletting) using a single station press (Korsch EK0):
  • a Galen IQ, Na no segregation in mixture disintegration test: no
    carboxymethylstarch (5%) detectable, detectable disintegration
    aqueous granulation in Diosna after 3 min.
    b Galen IQ, Kollidon CL (5%) no segregation in mixture disintegration test:
    aqueous granulation in Diosna detectable slightly dissolved
    mixture showed substantial surface after 3 min.
    punch deposit upon
    compression of 3 tablets
    already
    c Avicel with PVP-solution significant segregation in disintegration test:
    granulated mixture detectable partial disintegration
    after 3 min.
    d MCC + lactose(20:80) with PVP- no segregation in mixture disintegration test: no
    solution granulated detectable detectable disintegration
    after 3 min.
    d MCC + lactose (50:50) with PVP- slight segregation in mixture disintegration test:
    solution granulated detectable partial disintegration
    after 3 min.
    e Gelcarin + lactose (20% + 80%) + no segregation in mixture disintegration test: no
    water (57% + 43%) detectable detectable disintegration
    after 3 min.
    f sugar ester S-1570 + tricalcium- significant segregation in disintegration test: no
    phosphate + Acivel + Gelcarin mixture detectable detectable disintegration
    after 3 min.
    g incrustation granulate from the granulate could not be no tablets manufactured
    saccharose processed or only with
    difficulties
    blending with particulates is
    not possible -> thus, no
    tablets were manufactured
  • It was not possible to manufacture rapidly disintegrating tablets from the above compositions, probably because the disintegrants lose the disintegrating capacity in the course of the wet granulation process.
  • Example 4-2
  • The influence of the matrix material was investigated—dry granulation—roller compaction.
  • The following compositions were processed by slugging involving the steps of:
      • weighing/dispensing of components
      • sieving/blending
      • manufacture of bi-planar tablets of 20 mm diameter using a single station press (Korsch EK0), 25 kN compression force
      • breaking the tablets into parts (manually) and sieving using a Frewitt Sieving machine (1.5 mm mesh size)
      • employing granules as outer phase/matrix material for pellet-tablets
  • The experimental results are summarized in the following table:
  • compacted material tablet surface
    released Tramadol Mg- PVP Esma- (compression (compression film
    after 30 min excipient Pellets Avicel 101 Lactose stearate CL spreng Primojel NaCMC force 20-25 kN) force 7.5 kN) disintegration coated form
    a 87.4 50.00% 22.25% 22.25% 0.50% 5.00% OK + no Round 12 mm
    (5 kN) biplan (5 kN
    and 10 kN),
    oblong
    7 × 17 mm
    (7.5 kN)
    b 64.1 50.00% 45.00% 5.00% OK 0 + no Round 12 mm
    biplan
    c n.d. 15% 50.00% 29.5% 0.50% 5.00% OK −− no Round 12 mm
    PEG6000 biplan
    d 87.7 50.00% 45.00% 5.00% slightly ++ ++ no Round 12 mm
    unstable biplan
    e 72.2 50.00% 45.00% 5.00% OK 0 + no Round 12 mm
    biplan
    f n.d. 50.00% 45.00% 5.00% OK 0 no Round 12 mm
    biplan
    g n.d. 15% 50.00% 25.00% adheres −− no Round 12 mm
    NaHCO3 punch to biplan
    10% citric acid matrix
    i 71.1 1% xanthan 50.00% 44.00% 5.00% can only be 0 no Round 12 mm
    compacted biplan
    with difficulties
    j-1 77.4 45% Prosolv 50.00% 5.00% OK + ++ no Round 12 mm
    SMCCHD90 biplan
    j-2 81.2 50% Prosolv 50.00% OK 0 ++ no Round 12 mm
    SMCCHD90 biplan
    k 28.4 45% Parteck 50.00% 5.00% OK 0 + no
    l n.d. 50% Zaldiar 50.00% adheres −− no Round 12 mm
    effervescent punch to biplan
    tablet matrix
    m 77.6 50.00% 22.25% 22.25% 0.50% 5.00% OK + no Round 12 mm
    biplan
    m′ 89.9 50.98% 21.81% 21.81% 0.49% 4.90% OK + yes Round 12 mm
    biplan
    n 78.2 50.00% 22.25% 22.25% 0.50% 5.00% OK 0 no Round 12 mm
    biplan
    n′ 92.9 50.98% 21.81% 21.81% 0.49% 4.90% OK 0 yes Round 12 mm
    biplan
    n″ 86.3 50.98% 21.81% 21.81% 0.49% 4.90% OK 0 yes penta-
    gonal
    o 60.0 45% Prosolv 50.00% 5.00% OK 0 no Round 12 mm
    SMCCHD90 biplan
    o′ 90.5 44.12% 50.98% 4.90% OK 0 yes Round 12 mm
    Prosolv biplan
    SMCCHD90
    o″ 75.4 44.12% 50.98% 4.90% OK 0 yes penta-
    Prosolv gonal
    SMCCHD90
    p 74.3 45% Prosolv 50.00% 5.00% OK 0 no Round 12 mm
    SMCCHD90 biplan
    p′ 93.5 44.12% 50.98% 4.90% OK 0 yes Round 12 mm
    Prosolv biplan
    SMCCHD90
    q 54.3 50.00% 42.50% 7.50% OK 0 no Round 12 mm
    biplane
    q′ 60.2 50.98% 41.67% 7.35% OK 0 yes Round 12 mm
    biplane
    r 69.3 50.00% 42.50% 7.50% OK 0 no Round 12 mm
    biplane
    r′ 84.8 50.98% 41.67% 7.35% OK 0 yes Round 12 mm
    biplane
    u 39.9 50% 50.00% no Round 12 mm
    MicroceLac biplane
    u′ 70.3 50% 50.00% yes Round 12 mm
    MicroceLac biplane
    v 78.6 50% 50.00% no Round 12 mm
    EASYtab SP biplane
    v′ 93.5 50% 50.00% + + yes Round 12 mm
    EASYtab SP biplane
    w n.d. 50% 50.00% + ++ no Round 12 mm
    EASYtab SP biplane
    w′ n.d. 50% 50.00% yes Round 12 mm
    EASYtab SP biplan
    ++ good,
    + satisfactory,
    0 acceptable,
    − deficient,
    −− inacceptable
  • The release characteristics of tablets containing the thus compacted matrix material were investigated. The results are depicted in FIG. 4 (900 mL HCl, 50 rpm, paddle apparatus without sinker).
  • Example 4-3
  • Since the slugging method is not state of the art for dry granulation, corresponding tests concerning dry granulation were conducted by means of a roller compactor. This has the advantage that all relevant parameters (roller displacement, compression force, granulator size) can be adjusted such that a granulate having the desired properties is obtained (particle size, hardness, compressibility, density).
  • Parameters (Gerteis MiniFactor):
  • roller displacement: 2 to 3 mm
    revolution velocity: 2 to 5 rpm
    compaction force: 3 to 15 kN/cm
    screen size: 1.0 to 1.25 to 1.5 to 2.0 mm
  • The thus prepared compacts (dry granulates) were blended with particulates and compressed to tablets. Upon blending, lubricant (magnesium stearate and sodium stearylfumarate, respectively) was added as an external excipient neither contained in the compacts nor in the particulates.
  • Batch #1 #2 #3 #4 #5
    Avicel PH 101 95.00% 50.00%
    Esma Spreng  5.00%
    Prosolv SMCC HD 90 95.00% 100.00%
    Na-CMC  5.00%
    Lactose Monohydrate 230 50.00%
    Prosolv Easytab 100.00%
  • The experiments revealed that tablets made from compacts and made from slugging-granulates show a similarly fast release.
  • Confirming Experiments:
  • Batch
    #6 #7 #8 #9 #10 #11 #12
    Avicel PH 101 89.5%  94.5 89% 89.50% 89.70%
    Avicel DG 89.5%
    Esma Spreng 10.00% 5%
    Prosolv SMCC HD 90 87.5%
    Na-CMC   12%
    PVP CL 10%   10%   10%   10%
    Na-stearylfumarate 1%
    Mg stearate 0.5  0.5  0.5% 0.5  0.5%  0.3%
  • Example 4-4
  • Tablets (500 mg) were prepared from the particulates according to Example 2-5 (250 mg) and the matrix material according to Example 4-3 #12 (250 mg).
  • The in vitro release was determined according to Ph. Eur.:
  • time % released (n = 6)
    0 0.0
    5 56.8
    10 83.4
    15 93.3
    20 98.1
    25 99.9
    30 101.1
    35 101.4
    40 101.7
    45 101.9
    50 102.0
    55 102.0
    60 102.0
  • The in vitro release of the tablets was compared to a non-tamper resistant commercial product containing Tapentadol HCl (film coated tablets). After 30 minutes (according to Ph. Eur. 2.9.3), both formulations released the entire amount of the pharmacologically active ingredient (100%).
  • Example 5
  • The mechanical properties of conventional, commercial neutral pellets were investigated under the following conditions:
  • 5-1 (comparative) 5-2 5-3
    pellets neutral (Hans G. tramadol TRF tramadol TRF
    product Werner GmbH & Co.) IR pellets IR pellets
    Tramadol HCl 46.59 wt.-% 4.17 wt.-%
    PEG 6000  8.31 wt.-% 8.33 wt.-%
    vitamin E  0.10 wt.-% 0.20 wt.-%
    PEO 45.00 wt.-% 87.30 wt.-% 
    diameter pellets 0.85 mm-1.00 mm
    test equipment Zwick/Roell
    type BTC-FR2.5TH.D09
    force sensor KAF-TC/2.5 kN
    software applications testXpert V10.11
    measuring equipment plate 2.5 cm × 9.0 cm + ambos 2.0 cm × 4.0 cm
    speed 10 mm/min
    soft end 192 mm 192 mm 192 mm
  • The reduction of the displacement between plate and ambos x in mm (=“compression [c]”) and the corresponding force f in N were measured. The maximum force fmax measured during the measurement and the corresponding reduction of displacement xmax are summarized in the table here below:
  • 5-1 (FIG. 7) 5-2 (FIG. 8) 5-3 (FIG. 9)
    fmax [N] xmax [mm] fmax [N] xmax [mm] fmax [N] xmax [mm]
    mean 5.272 0.01 587.285 0.87 588.255 0.89
    s 2.129 0.03 2.320 0.06 2.897 0.05
    ν 40.37 198.70 0.40 6.73 0.49 5.13
    min 2.260 0.00 585.226 0.82 583.385 0.82
    max 8.432 0.08 592.581 1.00 592.413 0.96
  • It becomes clear from the above data that the comparative particulates of example 5-1 break at very low forces of only about 5 N and can be deformed by less than 0.1 mm. In contrast, the inventive particulates of examples 5-2 and 5-3 do not break at all, and can be deformed (flattened) by more than 0.8 mm.
  • The corresponding force-displacement-diagrams are shown in FIGS. 7, 8 and 9, respectively.

Claims (18)

1. A tamper-resistant tablet comprising
(i) a matrix material in an amount of more than one third of the total weight of the tablet; and
(ii) a plurality of particulates in an amount of less than two thirds of the total weight of the tablet; wherein said particulates comprise a pharmacologically active compound and a polyalkylene oxide; and form a discontinuous phase within the matrix material.
2. The tablet according to claim 1, which provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur.
3. The tablet according to claim 2, which has under in vitro conditions a disintegration time measured in accordance with Ph. Eur. of at most 3 minutes.
4. The tablet according to claim 1, wherein the content of the matrix material is at least 40 wt.-%, based on the total weight of the tablet.
5. The tablet according to claim 1, wherein the pharmacologically active compound is an opioid.
6. The tablet according to claim 1, wherein the particulates have an average diameter of about 1000±250 μm and/or an average length of about 750±250 μm.
7. The tablet according to claim 1, wherein the pharmacologically active compound is dispersed in the polyalkylene oxide.
8. The tablet according to claim 1, wherein the content of the polyalkylene oxide is at least 25 wt.-%, based on the total weight of a particulate.
9. The tablet according to claim 1, wherein the content of the pharmacologically active compound is at least 25 wt.-%, based on the total weight of a particulate.
10. The tablet according to claim 1, wherein the particulates are hot melt-extruded.
11. The tablet according to claim 1, wherein the particulates are film coated.
12. The tablet according to claim 1, wherein the matrix material is also present in particulate form.
13. The tablet according to claim 1, wherein the matrix material is dry granulated or compacted.
14. The tablet according to claim 1, wherein the matrix material comprises binder, filler, disintegrant and/or lubricant.
15. The tablet according to claim 14, wherein the disintegrant is crosslinked.
16. A method of treating a condition in a patient in need thereof by administering to a patient in need of such treating a tablet comprising an effective amount therefor of a pharmacologically active compound, wherein the tablet is a tablet according to claim 1.
17. The method according to claim 16, wherein the condition is pain.
18. The method according to claim 17, wherein the pharmacologically active compound is an opioid.
US15/073,920 2011-07-29 2016-03-18 Tamper-resistant tablet providing immediate drug release Abandoned US20160199306A1 (en)

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US16/117,712 US20180369149A1 (en) 2011-07-29 2018-08-30 Tamper-resistant tablet providing immediate drug release
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US13/559,635 US20130028972A1 (en) 2011-07-29 2012-07-27 Tamper-resistant tablet providing immediate drug release
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Families Citing this family (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7708741B1 (en) 2001-08-28 2010-05-04 Marctec, Llc Method of preparing bones for knee replacement surgery
WO2003024430A1 (en) 2001-09-21 2003-03-27 Egalet A/S Morphine polymer release system
US20040234602A1 (en) 2001-09-21 2004-11-25 Gina Fischer Polymer release system
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
ATE495732T1 (en) 2003-03-26 2011-02-15 Egalet As CONTROLLED RELEASE MORPHINE SYSTEM
DE102005005446A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Break-resistant dosage forms with sustained release
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
DE10361596A1 (en) 2003-12-24 2005-09-29 Grünenthal GmbH Process for producing an anti-abuse dosage form
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Anti-abuse dosage form
DE102004032049A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Anti-abuse, oral dosage form
DE102005005449A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Process for producing an anti-abuse dosage form
AU2008258596B2 (en) 2007-06-04 2013-02-14 Egalet Ltd Controlled release pharmaceutical compositions for prolonged effect
MX2010008138A (en) 2008-01-25 2010-08-10 Gruenenthal Gmbh Pharmaceutical dosage form.
AU2010211220B2 (en) 2009-02-06 2013-08-01 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
AU2010265213B2 (en) 2009-06-24 2012-08-23 Egalet Ltd. Controlled release formulations
RU2567723C2 (en) 2009-07-22 2015-11-10 Грюненталь Гмбх Oxidation stable and breaking resistance dosage form
ES2534908T3 (en) 2009-07-22 2015-04-30 Grünenthal GmbH Hot melt extruded controlled release dosage form
BR112013005234A2 (en) 2010-09-02 2016-05-03 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer.
BR112013005194A2 (en) 2010-09-02 2016-05-03 Gruenenthal Gmbh tamper-resistant dosage form comprising inorganic salt
CN103857386A (en) 2011-07-29 2014-06-11 格吕伦塔尔有限公司 Tamper-resistant tablet providing immediate drug release
JP2014524925A (en) 2011-07-29 2014-09-25 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Tamper-resistant tablets that provide immediate drug release
US20130183384A1 (en) * 2011-12-22 2013-07-18 Boehringer Ingelheim International Gmbh Immediate release multi unit pellet system
JP6117249B2 (en) 2012-02-28 2017-04-19 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Tamper resistant dosage forms comprising a pharmacologically active compound and an anionic polymer
LT2838512T (en) 2012-04-18 2018-11-12 GrĆ¼nenthal GmbH Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
EP2877161A1 (en) 2012-07-06 2015-06-03 Egalet Ltd. Abuse deterrent pharmaceutical compositions for controlled release
BR112015026549A2 (en) * 2013-05-29 2017-07-25 Gruenenthal Gmbh tamper-proof dosage form containing one or more particles
EP3003283A1 (en) 2013-05-29 2016-04-13 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
BR112016000194A8 (en) 2013-07-12 2019-12-31 Gruenenthal Gmbh tamper-resistant dosage form containing ethylene vinyl acetate polymer
AU2014306759B2 (en) 2013-08-12 2018-04-26 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
BR112016010482B1 (en) 2013-11-26 2022-11-16 Grünenthal GmbH PREPARATION OF A PHARMACEUTICAL COMPOSITION IN POWDER BY MEANS OF CRYOMING
WO2015095391A1 (en) 2013-12-17 2015-06-25 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
AU2015261060A1 (en) 2014-05-12 2016-11-03 Grunenthal Gmbh Tamper resistant immediate release capsule formulation comprising Tapentadol
AU2015266117A1 (en) 2014-05-26 2016-11-24 Grunenthal Gmbh Multiparticles safeguarded against ethanolic dose-dumping
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
CA2964628A1 (en) 2014-10-20 2016-04-28 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
EA035434B1 (en) * 2015-04-24 2020-06-15 Грюненталь Гмбх Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US20160310437A1 (en) 2015-04-24 2016-10-27 Grünenthal GmbH Tamper-resistant fixed dose combination providing fast release of two drugs from particles
MX2017013643A (en) 2015-04-24 2018-03-08 Gruenenthal Gmbh Tamper-resistant fixed dose combination providing fast release of two drugs from particles and a matrix.
AU2016251853A1 (en) 2015-04-24 2017-11-23 Grünenthal GmbH Tamper-resistant fixed dose combination providing fast release of two drugs from different particles
US11234974B2 (en) 2015-05-28 2022-02-01 Lumosa Therapeutics Co., Ltd. Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester
US10183018B2 (en) 2015-05-28 2019-01-22 Lumosa Therapeutics Co., Ltd. Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester
KR20180025835A (en) 2015-06-30 2018-03-09 다이이찌 산쿄 가부시키가이샤 Pharmaceutical composition provided with abuse-prevention function
EP3346991A1 (en) 2015-09-10 2018-07-18 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US10981832B2 (en) * 2015-09-16 2021-04-20 Sofsera Corporation Sintered calcium phosphate molded body and process for manufacturing the same
JP6323846B2 (en) * 2016-04-07 2018-05-16 塩野義製薬株式会社 Abuse prevention formulation containing opioid
WO2018029327A1 (en) 2016-08-12 2018-02-15 Grünenthal GmbH Tamper resistant formulation of ephedrine and its derivatives
MX2020003928A (en) * 2017-10-13 2020-10-14 Gruenenthal Gmbh Modified release abuse deterrent dosage forms.
TW202002957A (en) 2018-02-09 2020-01-16 德商歌林達有限公司 Tamper resistant formulation of ephedrine and its derivatives comprising a conversion inhibitor
EP3698776A1 (en) 2019-02-19 2020-08-26 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
JPWO2022168285A1 (en) * 2021-02-05 2022-08-11

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070224129A1 (en) * 2005-11-10 2007-09-27 Flamel Technologies, Inc. Anti-misuse microparticulate oral pharmaceutical form
US20090215808A1 (en) * 2007-12-06 2009-08-27 Su Il Yum Oral pharmaceutical dosage forms
US20120321716A1 (en) * 2011-02-17 2012-12-20 Michael Vachon Technology for preventing abuse of solid dosage forms

Family Cites Families (571)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA722109A (en) 1965-11-23 W. Mock Henry Extrusion of ethylene oxide polymers
US2524855A (en) 1950-10-10 Process for the manufacture of
US2806033A (en) 1955-08-03 1957-09-10 Lewenstein Morphine derivative
US2987445A (en) 1958-10-10 1961-06-06 Rohm & Haas Drug composition
US3370035A (en) 1961-06-23 1968-02-20 Takeda Chemical Industries Ltd Stabilization of polyalkylene oxide
US3332950A (en) 1963-03-23 1967-07-25 Endo Lab 14-hydroxydihydronormorphinone derivatives
GB1147210A (en) 1965-06-30 1969-04-02 Eastman Kodak Co Improvements in or relating to vitamins
US3652589A (en) 1967-07-27 1972-03-28 Gruenenthal Chemie 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US3806603A (en) 1969-10-13 1974-04-23 W Gaunt Pharmaceutical carriers of plasticized dried milled particles of hydrated cooked rice endosperm
CH503520A (en) 1969-12-15 1971-02-28 Inventa Ag Process for grinding granular materials, in particular plastic granulates, at low temperatures
DE2210071A1 (en) 1971-03-09 1972-09-14 PPG Industries Inc., Pittsburgh, Pa. (V.StA.) Process for applying and curing a wide variety of coatings
US3865108A (en) 1971-05-17 1975-02-11 Ortho Pharma Corp Expandable drug delivery device
US3966747A (en) 1972-10-26 1976-06-29 Bristol-Myers Company 9-Hydroxy-6,7-benzomorphans
US4014965A (en) 1972-11-24 1977-03-29 The Dow Chemical Company Process for scrapless forming of plastic articles
US3980766A (en) 1973-08-13 1976-09-14 West Laboratories, Inc. Orally administered drug composition for therapy in the treatment of narcotic drug addiction
US3941865A (en) 1973-12-10 1976-03-02 Union Carbide Corporation Extrusion of ethylene oxide resins
US4002173A (en) 1974-07-23 1977-01-11 International Paper Company Diester crosslinked polyglucan hydrogels and reticulated sponges thereof
DE2530563C2 (en) 1975-07-09 1986-07-24 Bayer Ag, 5090 Leverkusen Analgesic drugs with reduced potential for abuse
JPS603286B2 (en) 1977-03-03 1985-01-26 日本化薬株式会社 Constant-dissolution formulation
US4207893A (en) 1977-08-29 1980-06-17 Alza Corporation Device using hydrophilic polymer for delivering drug to biological environment
US4175119A (en) 1978-01-11 1979-11-20 Porter Garry L Composition and method to prevent accidental and intentional overdosage with psychoactive drugs
DE2822324C3 (en) 1978-05-22 1981-02-26 Basf Ag, 6700 Ludwigshafen Manufacture of vitamin E dry powder
US4211681A (en) 1978-08-16 1980-07-08 Union Carbide Corporation Poly(ethylene oxide) compositions
US4200704A (en) 1978-09-28 1980-04-29 Union Carbide Corporation Controlled degradation of poly(ethylene oxide)
NO793297L (en) 1978-10-19 1980-04-22 Mallinckrodt Inc PROCEDURE FOR THE MANUFACTURE OF OXYMORPHONE
US4258027A (en) 1979-03-26 1981-03-24 Mead Johnson & Company Multi-fractionable tablet structure
US4215104A (en) 1979-03-26 1980-07-29 Mead Johnson & Company Multi-fractionable tablet structure
CA1146866A (en) 1979-07-05 1983-05-24 Yamanouchi Pharmaceutical Co. Ltd. Process for the production of sustained release pharmaceutical composition of solid medical material
CH648754A5 (en) 1979-08-16 1985-04-15 Ciba Geigy Ag Pharmaceutical slow release tablet
US4353887A (en) 1979-08-16 1982-10-12 Ciba-Geigy Corporation Divisible tablet having controlled and delayed release of the active substance
US4457933A (en) 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
JPS56169622A (en) 1980-06-03 1981-12-26 Kissei Pharmaceut Co Ltd Method of making solid preparation from oily substance
DE3024416C2 (en) 1980-06-28 1982-04-15 Gödecke AG, 1000 Berlin Process for the production of medicaments with sustained release of active substances
US4473640A (en) 1982-06-03 1984-09-25 Combie Joan D Detection of morphine and its analogues using enzymatic hydrolysis
US4462941A (en) 1982-06-10 1984-07-31 The Regents Of The University Of California Dynorphin amide analogs
US4427778A (en) 1982-06-29 1984-01-24 Biochem Technology, Inc. Enzymatic preparation of particulate cellulose for tablet making
US4485211A (en) 1982-09-15 1984-11-27 The B. F. Goodrich Company Poly(glycidyl ether)block copolymers and process for their preparation
US4427681A (en) 1982-09-16 1984-01-24 Richardson-Vicks, Inc. Thixotropic compositions easily convertible to pourable liquids
US4529583A (en) 1983-03-07 1985-07-16 Clear Lake Development Group Composition and method of immobilizing emetics and method of treating human beings with emetics
US4603143A (en) 1983-05-02 1986-07-29 Basf Corporation Free-flowing, high density, fat soluble vitamin powders with improved stability
US4783337A (en) 1983-05-11 1988-11-08 Alza Corporation Osmotic system comprising plurality of members for dispensing drug
US5082668A (en) 1983-05-11 1992-01-21 Alza Corporation Controlled-release system with constant pushing source
US4612008A (en) 1983-05-11 1986-09-16 Alza Corporation Osmotic device with dual thermodynamic activity
US4765989A (en) 1983-05-11 1988-08-23 Alza Corporation Osmotic device for administering certain drugs
US4599342A (en) 1984-01-16 1986-07-08 The Procter & Gamble Company Pharmaceutical products providing enhanced analgesia
US4629621A (en) 1984-07-23 1986-12-16 Zetachron, Inc. Erodible matrix for sustained release bioactive composition
AU592065B2 (en) 1984-10-09 1990-01-04 Dow Chemical Company, The Sustained release dosage form based on highly plasticized cellulose ether gels
GB8507779D0 (en) 1985-03-26 1985-05-01 Fujisawa Pharmaceutical Co Drug carrier
ZA864681B (en) 1985-06-24 1987-02-25 Ici Australia Ltd Ingestible capsules
DE3689195T2 (en) 1985-06-28 1994-05-05 Carrington Lab Inc Process for the production of aloe products, products and compositions therefor.
US4992279A (en) 1985-07-03 1991-02-12 Kraft General Foods, Inc. Sweetness inhibitor
US4851521A (en) 1985-07-08 1989-07-25 Fidia, S.P.A. Esters of hyaluronic acid
EP0226061B1 (en) 1985-12-17 1994-02-16 United States Surgical Corporation High molecular weight bioresorbable polymers and implantation devices thereof
US5229164A (en) 1985-12-19 1993-07-20 Capsoid Pharma Gmbh Process for producing individually dosed administration forms
US4711894A (en) 1986-01-16 1987-12-08 Henkel Corporation Stabilized tocopherol in dry, particulate, free-flowing form
US4940556A (en) 1986-01-30 1990-07-10 Syntex (U.S.A.) Inc. Method of preparing long acting formulation
US5198226A (en) 1986-01-30 1993-03-30 Syntex (U.S.A.) Inc. Long acting nicardipine hydrochloride formulation
US4764378A (en) 1986-02-10 1988-08-16 Zetachron, Inc. Buccal drug dosage form
JPS62232433A (en) 1986-03-31 1987-10-12 ユニオン、カ−バイド、コ−ポレ−シヨン Catalyst to polymerization of alkylene oxide and polymerization
DE3612211A1 (en) 1986-04-11 1987-10-15 Basf Ag CONTINUOUS TABLET METHOD
US4667013A (en) 1986-05-02 1987-05-19 Union Carbide Corporation Process for alkylene oxide polymerization
US4713243A (en) 1986-06-16 1987-12-15 Johnson & Johnson Products, Inc. Bioadhesive extruded film for intra-oral drug delivery and process
USRE33093E (en) 1986-06-16 1989-10-17 Johnson & Johnson Consumer Products, Inc. Bioadhesive extruded film for intra-oral drug delivery and process
USRE34990E (en) 1986-08-07 1995-07-04 Ciba-Geigy Corporation Oral therapeutic system having systemic action
CA1335748C (en) 1986-09-25 1995-05-30 Jeffrey Lawrence Finnan Crosslinked gelatins
US5227157A (en) 1986-10-14 1993-07-13 Board Of Regents, The University Of Texas System Delivery of therapeutic agents
ES2032802T5 (en) 1986-11-10 2004-01-16 Biopure Corporation SUCEDANEO OF EXTRAPUR SEMISINTETIC BLOOD.
US4892889A (en) 1986-11-18 1990-01-09 Basf Corporation Process for making a spray-dried, directly-compressible vitamin powder comprising unhydrolyzed gelatin
JPH0831303B2 (en) 1986-12-01 1996-03-27 オムロン株式会社 Chip type fuse
ES2039287T3 (en) 1987-01-14 1993-09-16 Ciba-Geigy Ag PROCEDURE FOR OBTAINING A PERORAL THERAPEUTIC SYSTEM FOR HARDLY SOLUBLE ACTIVE PRODUCTS.
US4892778A (en) 1987-05-27 1990-01-09 Alza Corporation Juxtaposed laminated arrangement
US5051261A (en) 1987-11-24 1991-09-24 Fmc Corporation Method for preparing a solid sustained release form of a functionally active composition
KR900700071A (en) 1987-12-17 1990-08-11 로버어트 에이 아미테이지 Tri-scored Drug Tablets
DE3812567A1 (en) 1988-04-15 1989-10-26 Basf Ag METHOD FOR PRODUCING PHARMACEUTICAL MIXTURES
US4954346A (en) 1988-06-08 1990-09-04 Ciba-Geigy Corporation Orally administrable nifedipine solution in a solid light resistant dosage form
US4960814A (en) 1988-06-13 1990-10-02 Eastman Kodak Company Water-dispersible polymeric compositions
US5350741A (en) 1988-07-30 1994-09-27 Kanji Takada Enteric formulations of physiologically active peptides and proteins
JPH0249719A (en) 1988-08-11 1990-02-20 Dai Ichi Kogyo Seiyaku Co Ltd Oil soluble-vitamin powder having readily water-dispersible and soluble performance
GB8820327D0 (en) 1988-08-26 1988-09-28 May & Baker Ltd New compositions of matter
DE3830353A1 (en) 1988-09-07 1990-03-15 Basf Ag METHOD FOR THE CONTINUOUS PRODUCTION OF SOLID PHARMACEUTICAL FORMS
US5139790A (en) 1988-10-14 1992-08-18 Zetachron, Inc. Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith
US5004601A (en) 1988-10-14 1991-04-02 Zetachron, Inc. Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith
US4957668A (en) 1988-12-07 1990-09-18 General Motors Corporation Ultrasonic compacting and bonding particles
US5190760A (en) 1989-07-08 1993-03-02 Coopers Animal Health Limited Solid pharmaceutical composition
US5169645A (en) 1989-10-31 1992-12-08 Duquesne University Of The Holy Ghost Directly compressible granules having improved flow properties
US5200197A (en) 1989-11-16 1993-04-06 Alza Corporation Contraceptive pill
GB8926612D0 (en) 1989-11-24 1990-01-17 Erba Farmitalia Pharmaceutical compositions
EP0449775A3 (en) 1990-03-29 1992-09-02 Ciba-Geigy Ag Polyether-polyester block copolymers and their use as dispersing agents
SU1759445A1 (en) 1990-06-15 1992-09-07 Ленинградский Технологический Институт Им.Ленсовета Method of producing encapsulated hydrophobic substances
FR2664851B1 (en) 1990-07-20 1992-10-16 Oreal METHOD OF COMPACTING A POWDER MIXTURE FOR OBTAINING A COMPACT ABSORBENT OR PARTIALLY DELITABLE PRODUCT AND PRODUCT OBTAINED BY THIS PROCESS.
EP0477135A1 (en) 1990-09-07 1992-03-25 Warner-Lambert Company Chewable spheroidal coated microcapsules and methods for preparing same
US5126151A (en) 1991-01-24 1992-06-30 Warner-Lambert Company Encapsulation matrix
US5273758A (en) 1991-03-18 1993-12-28 Sandoz Ltd. Directly compressible polyethylene oxide vehicle for preparing therapeutic dosage forms
US5149538A (en) 1991-06-14 1992-09-22 Warner-Lambert Company Misuse-resistive transdermal opioid dosage form
JP3073054B2 (en) 1991-07-11 2000-08-07 住友精化株式会社 Method for producing alkylene oxide polymer
JP3126384B2 (en) 1991-08-30 2001-01-22 昭和薬品化工株式会社 Dry gel composition
ATE183642T1 (en) 1991-10-04 1999-09-15 Yoshitomi Pharmaceutical DELAYED-RELEASE TABLET
WO1993006723A1 (en) 1991-10-04 1993-04-15 Olin Corporation Fungicide tablet
DE4138513A1 (en) 1991-11-23 1993-05-27 Basf Ag SOLID PHARMACEUTICAL RETARD FORM
US5266331A (en) 1991-11-27 1993-11-30 Euroceltique, S.A. Controlled release oxycodone compositions
DE69212497T2 (en) 1991-12-05 1996-12-12 Mallinckrodt Veterinary, Inc., Mundelein, Ill. GLASS-LIKE CARBOHYDRATE MATRICE FOR THE ADMINISTRATION OF MEDICINES WITH DELAYED DELIVERY OF ACTIVE SUBSTANCES
ATE157864T1 (en) 1991-12-18 1997-09-15 Warner Lambert Co METHOD FOR PRODUCING A SOLID DISPERSION
US5200194A (en) 1991-12-18 1993-04-06 Alza Corporation Oral osmotic device
US5225417A (en) 1992-01-21 1993-07-06 G. D. Searle & Co. Opioid agonist compounds
IL105553A (en) 1992-05-06 1998-01-04 Janssen Pharmaceutica Inc Solid dosage form comprising a porous network of matrix forming material which disperses rapidly in water
ATE136459T1 (en) 1992-05-22 1996-04-15 Goedecke Ag METHOD FOR PRODUCING SUSTAINED-RELEASE MEDICINAL PREPARATIONS
GB9217295D0 (en) 1992-08-14 1992-09-30 Wellcome Found Controlled released tablets
DE4227385A1 (en) 1992-08-19 1994-02-24 Kali Chemie Pharma Gmbh Pancreatin micropellets
DE4229085C2 (en) 1992-09-01 1996-07-11 Boehringer Mannheim Gmbh Elongated, divisible tablet
RO112991B1 (en) 1992-09-18 1998-03-30 Yamanouchi Pharma Co Ltd Sustained release hydrogel-type preparation
US5472943A (en) 1992-09-21 1995-12-05 Albert Einstein College Of Medicine Of Yeshiva University, Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists
FI101039B (en) 1992-10-09 1998-04-15 Eeva Kristoffersson Method for preparing medicated pellets
AU679937B2 (en) 1992-11-18 1997-07-17 Johnson & Johnson Consumer Products, Inc. Extrudable compositions for topical or transdermal drug delivery
BR9307736A (en) 1992-12-23 1999-08-31 Saitec Srl Process for preparing pharmaceutical formulations with active ingredient released under control for oral, topical or parenteral administration
GB2273874A (en) 1992-12-31 1994-07-06 Pertti Olavi Toermaelae Preparation of pharmaceuticals in a polymer matrix
US6071970A (en) 1993-02-08 2000-06-06 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US5914132A (en) 1993-02-26 1999-06-22 The Procter & Gamble Company Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery
DE4309528C2 (en) 1993-03-24 1998-05-20 Doxa Gmbh Casein film or film tube, process for their production and their use
IL109460A (en) 1993-05-10 1998-03-10 Euro Celtique Sa Controlled release formulation comprising tramadol
IL109944A (en) 1993-07-01 1998-12-06 Euro Celtique Sa Sustained release dosage unit forms containing morphine and a method of preparing these sustained release dosage unit forms
DE4329794C2 (en) 1993-09-03 1997-09-18 Gruenenthal Gmbh Tramadol salt-containing drugs with delayed release
EP1442745A1 (en) 1993-10-07 2004-08-04 Euro-Celtique Orally administrable opioid formulations having extended duration of effect
PT654263E (en) 1993-11-23 2002-06-28 Euro Celtique Sa METHOD FOR THE PREPARATION OF A PROLONGED LIBERTYACAO COMPOSITION
KR100354702B1 (en) 1993-11-23 2002-12-28 유로-셀티크 소시에떼 아노뉨 Manufacturing method and sustained release composition of pharmaceutical composition
AU1266895A (en) 1993-12-20 1995-07-10 Procter & Gamble Company, The Process for making laxatives containing dioctyl sulfosuccinate
IL112106A0 (en) 1993-12-22 1995-03-15 Ergo Science Inc Accelerated release composition containing bromocriptine
GB9401894D0 (en) 1994-02-01 1994-03-30 Rhone Poulenc Rorer Ltd New compositions of matter
ES2199981T3 (en) 1994-02-16 2004-03-01 Abbott Laboratories MODE OF PREPARATION OF PHARMACEUTICAL FORMULATIONS OF FINE PARTICLES.
SE9503924D0 (en) 1995-08-18 1995-11-07 Astra Ab Novel opioid peptides
US5458887A (en) 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
DE4413350A1 (en) 1994-04-18 1995-10-19 Basf Ag Retard matrix pellets and process for their production
HUT77530A (en) 1994-05-06 1998-05-28 Pfizer Inc. Controlled-release dosage forms of azithromycin
DE19509807A1 (en) 1995-03-21 1996-09-26 Basf Ag Process for the preparation of active substance preparations in the form of a solid solution of the active substance in a polymer matrix, and active substance preparations produced using this method
AT403988B (en) 1994-05-18 1998-07-27 Lannacher Heilmittel SOLID ORAL RETARDED PREPARATION
US5460826A (en) 1994-06-27 1995-10-24 Alza Corporation Morphine therapy
DE4426245A1 (en) 1994-07-23 1996-02-22 Gruenenthal Gmbh 1-phenyl-3-dimethylamino-propane compounds with pharmacological activity
IT1274879B (en) 1994-08-03 1997-07-25 Saitec Srl APPARATUS AND METHOD FOR PREPARING SOLID PHARMACEUTICAL FORMS WITH CONTROLLED RELEASE OF THE ACTIVE INGREDIENT.
JP3285452B2 (en) 1994-08-11 2002-05-27 サンスター株式会社 Toothpaste composition
AUPM897594A0 (en) 1994-10-25 1994-11-17 Daratech Pty Ltd Controlled release container
US5965161A (en) 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
DE4446470A1 (en) 1994-12-23 1996-06-27 Basf Ag Process for the production of dividable tablets
DE19504832A1 (en) 1995-02-14 1996-08-22 Basf Ag Solid drug preparations
US5945125A (en) 1995-02-28 1999-08-31 Temple University Controlled release tablet
US6117453A (en) 1995-04-14 2000-09-12 Pharma Pass Solid compositions containing polyethylene oxide and an active ingredient
US6348469B1 (en) 1995-04-14 2002-02-19 Pharma Pass Llc Solid compositions containing glipizide and polyethylene oxide
US5900425A (en) 1995-05-02 1999-05-04 Bayer Aktiengesellschaft Pharmaceutical preparations having controlled release of active compound and processes for their preparation
DE19522899C1 (en) 1995-06-23 1996-12-19 Hexal Pharmaforschung Gmbh Process for the continuous sintering of a granulate
US5759583A (en) 1995-08-30 1998-06-02 Syntex (U.S.A.) Inc. Sustained release poly (lactic/glycolic) matrices
US6007843A (en) 1995-09-29 1999-12-28 Lam Pharmaceuticals Corp. Sustained release delivery system
US5811126A (en) 1995-10-02 1998-09-22 Euro-Celtique, S.A. Controlled release matrix for pharmaceuticals
DE19539361A1 (en) 1995-10-23 1997-04-24 Basf Ag Process for the preparation of multilayer, solid pharmaceutical forms for oral or rectal administration
US5908850A (en) 1995-12-04 1999-06-01 Celgene Corporation Method of treating attention deficit disorders with d-threo methylphenidate
US6355656B1 (en) 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
DE19547766A1 (en) 1995-12-20 1997-06-26 Gruenenthal Gmbh 1-phenyl-2-dimethylaminomethyl-cyclohexan-1-ol compounds as active pharmaceutical ingredients
ES2168610T3 (en) 1996-03-12 2002-06-16 Alza Corp COMPOSITION AND GALENIC FORM CONTAINING AN OPIOID ANTAGONIST.
US6461644B1 (en) 1996-03-25 2002-10-08 Richard R. Jackson Anesthetizing plastics, drug delivery plastics, and related medical products, systems and methods
RU2188013C2 (en) 1996-04-05 2002-08-27 Такеда Кемикал Индастриз, Лтд. Combination containing a compound of angiotensin ii-antagonistic activity
US6096339A (en) 1997-04-04 2000-08-01 Alza Corporation Dosage form, process of making and using same
US20020114838A1 (en) 1996-04-05 2002-08-22 Ayer Atul D. Uniform drug delivery therapy
US5817343A (en) 1996-05-14 1998-10-06 Alkermes, Inc. Method for fabricating polymer-based controlled-release devices
AU717817B2 (en) 1996-06-06 2000-04-06 Bifodan A/S Enteric coating, comprising alginic acid, for an oral preparation
WO1997049384A1 (en) 1996-06-26 1997-12-31 Board Of Regents, The University Of Texas System Hot-melt extrudable pharmaceutical formulation
IL123505A (en) 1996-07-08 2004-12-15 Penwest Pharmaceuticals Compan Sustained release matrix for high-dose insoluble drugs
DE19629753A1 (en) 1996-07-23 1998-01-29 Basf Ag Process for the production of solid dosage forms
NL1003684C2 (en) 1996-07-25 1998-01-28 Weterings B V H Device for dispensing a liquid.
DE19630236A1 (en) 1996-07-26 1998-01-29 Wolff Walsrode Ag Biaxially stretched, biodegradable and compostable sausage casing
BE1010353A5 (en) 1996-08-14 1998-06-02 Boss Pharmaceuticals Ag Method for manufacture of pharmaceutical products, device for such a method and pharmaceutical products obtained.
ATE287928T1 (en) 1996-11-05 2005-02-15 Novamont Spa BIODEGRADABLE POLYMER COMPOSITIONS CONTAINING STARCH AND A THERMOPLASTIC POLYMER
US5991799A (en) 1996-12-20 1999-11-23 Liberate Technologies Information retrieval system using an internet multiplexer to focus user selection
DE19705538C1 (en) 1997-02-14 1998-08-27 Goedecke Ag Process for the separation of active substances in solid pharmaceutical preparations
US5948787A (en) 1997-02-28 1999-09-07 Alza Corporation Compositions containing opiate analgesics
DE19710009A1 (en) 1997-03-12 1998-09-24 Knoll Ag Multi-phase preparation forms containing active ingredients
DE19710008A1 (en) 1997-03-12 1998-09-17 Basf Ag Solid, at least two-phase formulations of a sustained-release opioid analgesic
DE19710213A1 (en) 1997-03-12 1998-09-17 Basf Ag Process for the manufacture of solid combination dosage forms
US6139770A (en) 1997-05-16 2000-10-31 Chevron Chemical Company Llc Photoinitiators and oxygen scavenging compositions
DE19721467A1 (en) 1997-05-22 1998-11-26 Basf Ag Process for the preparation of small-scale preparations of biologically active substances
CA2290624C (en) 1997-06-06 2006-12-05 John W. Shell Gastric-retentive oral drug dosage forms for controlled release of highly soluble drugs
US6635280B2 (en) 1997-06-06 2003-10-21 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
JP3739410B2 (en) 1997-07-02 2006-01-25 ユーロ−セルティーク エス.エイ. Stabilized sustained release tramadol formulation
IE970588A1 (en) 1997-08-01 2000-08-23 Elan Corp Plc Controlled release pharmaceutical compositions containing tiagabine
EP1027305A1 (en) 1997-09-10 2000-08-16 AlliedSignal Inc. Injection molding of structural zirconia-based materials by an aqueous process
US6009390A (en) 1997-09-11 1999-12-28 Lucent Technologies Inc. Technique for selective use of Gaussian kernels and mixture component weights of tied-mixture hidden Markov models for speech recognition
CN1150891C (en) 1997-11-28 2004-05-26 克诺尔有限公司 Method for producing solent-free non-crystalline biologically active substances
DE19753534A1 (en) 1997-12-03 1999-06-10 Bayer Ag Biodegradable thermoplastic polyester-amides with good mechanical properties for molding, film and fiber, useful for e.g. compostable refuse bag
AU1339699A (en) 1997-12-03 1999-06-16 Bayer Aktiengesellschaft Polyether ester amides
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
US6228863B1 (en) 1997-12-22 2001-05-08 Euro-Celtique S.A. Method of preventing abuse of opioid dosage forms
DE19800689C1 (en) 1998-01-10 1999-07-15 Deloro Stellite Gmbh Shaped body made of a wear-resistant material
DE19800698A1 (en) 1998-01-10 1999-07-15 Bayer Ag Biodegradable polyester amides with block-like polyester and polyamide segments
US6251430B1 (en) 1998-02-04 2001-06-26 Guohua Zhang Water insoluble polymer based sustained release formulation
BR9907699A (en) 1998-02-06 2002-01-15 Union Carbide Chem Plastic Polymeric compositions of alkylene oxide
US6235825B1 (en) 1998-03-05 2001-05-22 Mitsui Chemicals, Inc. Polylactic acid resin composition and film therefrom
US6245357B1 (en) 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US6090411A (en) 1998-03-09 2000-07-18 Temple University Monolithic tablet for controlled drug release
US6110500A (en) 1998-03-25 2000-08-29 Temple University Coated tablet with long term parabolic and zero-order release kinetics
KR20010042419A (en) 1998-04-02 2001-05-25 조셉 제이. 스위니 Method for etching low k dielectrics
JP4533531B2 (en) 1998-04-03 2010-09-01 ビーエム リサーチ エイ/エス Controlled release composition
US5962488A (en) 1998-04-08 1999-10-05 Roberts Laboratories, Inc. Stable pharmaceutical formulations for treating internal bowel syndrome containing isoxazole derivatives
DE19822979A1 (en) 1998-05-25 1999-12-02 Kalle Nalo Gmbh & Co Kg Film with starch or starch derivatives and polyester urethanes and process for their production
US6333087B1 (en) 1998-08-27 2001-12-25 Chevron Chemical Company Llc Oxygen scavenging packaging
DE19841244A1 (en) 1998-09-09 2000-03-16 Knoll Ag Method and device for making tablets
GT199900148A (en) 1998-09-10 2001-02-28 Denaturing for the sympathomimetic amine salts.
US6268177B1 (en) 1998-09-22 2001-07-31 Smithkline Beecham Corporation Isolated nucleic acid encoding nucleotide pyrophosphorylase
WO2000023073A1 (en) 1998-10-20 2000-04-27 Korea Institute Of Science And Technology Bioflavonoids as plasma high density lipoprotein level increasing agent
US6322819B1 (en) 1998-10-21 2001-11-27 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
US20060240105A1 (en) 1998-11-02 2006-10-26 Elan Corporation, Plc Multiparticulate modified release composition
ES2141688B1 (en) 1998-11-06 2001-02-01 Vita Invest Sa NEW ESTERS DERIVED FROM SUBSTITUTED FENIL-CICLOHEXIL COMPOUNDS.
DE19855440A1 (en) 1998-12-01 2000-06-08 Basf Ag Process for the production of solid dosage forms by melt extrusion
EP1005863A1 (en) 1998-12-04 2000-06-07 Synthelabo Controlled-release dosage forms comprising a short acting hypnotic or a salt thereof
DE19856147A1 (en) 1998-12-04 2000-06-08 Knoll Ag Divisible solid dosage forms and methods for their preparation
US6419960B1 (en) 1998-12-17 2002-07-16 Euro-Celtique S.A. Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US6238697B1 (en) 1998-12-21 2001-05-29 Pharmalogix, Inc. Methods and formulations for making bupropion hydrochloride tablets using direct compression
AU3469100A (en) 1999-01-05 2000-07-24 Copley Pharmaceutical Inc. Sustained release formulation with reduced moisture sensitivity
EP1070504A4 (en) 1999-02-04 2004-03-10 Nichimo Kk Materials for preventing arteriosclerosis, immunopotentiating materials, vertebrates fed with these materials and eggs thereof
US7374779B2 (en) 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US6375963B1 (en) 1999-06-16 2002-04-23 Michael A. Repka Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof
US6384020B1 (en) 1999-07-14 2002-05-07 Shire Laboratories, Inc. Rapid immediate release oral dosage form
US20030118641A1 (en) 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
MXPA02000725A (en) 1999-07-29 2003-07-14 Roxane Lab Inc Opioid sustained released formulation.
US6562375B1 (en) 1999-08-04 2003-05-13 Yamanouchi Pharmaceuticals, Co., Ltd. Stable pharmaceutical composition for oral use
EP1205190B1 (en) 1999-08-04 2006-05-03 Astellas Pharma Inc. Stable medicinal compositions for oral use using ferric oxides
KR100345214B1 (en) 1999-08-17 2002-07-25 이강춘 The nasal transmucosal delivery of peptides conjugated with biocompatible polymers
DE19940944B4 (en) 1999-08-31 2006-10-12 Grünenthal GmbH Retarded, oral, pharmaceutical dosage forms
DE19940740A1 (en) 1999-08-31 2001-03-01 Gruenenthal Gmbh Pharmaceutical salts
HUP0203623A2 (en) 1999-08-31 2003-02-28 Grünenthal GmbH Delayed-action form of administration containing tramadol saccharinate and its use
DE19960494A1 (en) 1999-12-15 2001-06-21 Knoll Ag Device and method for producing solid active substance-containing forms
ES2160534B1 (en) 1999-12-30 2002-04-16 Vita Invest Sa NEW ESTERS DERIVED FROM (RR, SS) -2-HYDROXIBENZOATE 3- (2-DIMETHYLMINOME-1-HYDROXICICLOHEXIL) PHENYL.
US6680070B1 (en) 2000-01-18 2004-01-20 Albemarle Corporation Particulate blends and compacted products formed therefrom, and the preparation thereof
DK1299104T3 (en) 2000-02-08 2009-08-03 Euro Celtique Sa Oral opioid agonist formulations secured against forgery
US20020015730A1 (en) 2000-03-09 2002-02-07 Torsten Hoffmann Pharmaceutical formulations and method for making
DE10015479A1 (en) 2000-03-29 2001-10-11 Basf Ag Solid oral dosage forms with delayed release of active ingredient and high mechanical stability
US8012504B2 (en) 2000-04-28 2011-09-06 Reckitt Benckiser Inc. Sustained release of guaifenesin combination drugs
US6572887B2 (en) 2000-05-01 2003-06-03 National Starch And Chemical Investment Holding Corporation Polysaccharide material for direct compression
US6419954B1 (en) 2000-05-19 2002-07-16 Yamanouchi Pharmaceutical Co., Ltd. Tablets and methods for modified release of hydrophilic and other active agents
BR0111125A (en) 2000-05-23 2004-12-28 Cenes Pharmaceuticals Inc Nrg-2 Nucleic Acid Molecules, Polypeptides, and Diagnostic and Therapeutic Methods
DE10029201A1 (en) 2000-06-19 2001-12-20 Basf Ag Retarded release oral dosage form, obtained by granulating mixture containing active agent and polyvinyl acetate-polyvinyl pyrrolidone mixture below the melting temperature
US6488962B1 (en) 2000-06-20 2002-12-03 Depomed, Inc. Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms
US6607748B1 (en) 2000-06-29 2003-08-19 Vincent Lenaerts Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture
DE10036400A1 (en) 2000-07-26 2002-06-06 Mitsubishi Polyester Film Gmbh White, biaxially oriented polyester film
US6642205B2 (en) 2000-09-25 2003-11-04 Pro-Pharmaceuticals, Inc. Methods and compositions for reducing side effects in chemotherapeutic treatments
EP1322189A1 (en) 2000-09-27 2003-07-02 Danisco A/S Antimicrobial agent
AU2001294902A1 (en) 2000-09-28 2002-04-08 The Dow Chemical Company Polymer composite structures useful for controlled release systems
GB0026137D0 (en) 2000-10-25 2000-12-13 Euro Celtique Sa Transdermal dosage form
US6344215B1 (en) 2000-10-27 2002-02-05 Eurand America, Inc. Methylphenidate modified release formulations
WO2002035991A2 (en) 2000-10-30 2002-05-10 The Board Of Regents, The University Of Texas System Spherical particles produced by a hot-melt extrusion/spheronization process
KR101167465B1 (en) 2000-10-30 2012-07-27 유로-셀티크 소시에떼 아노뉨 Controlled release hydrocodone formulations
DE10109763A1 (en) 2001-02-28 2002-09-05 Gruenenthal Gmbh Pharmaceutical salts
JP2002265592A (en) 2001-03-07 2002-09-18 Sumitomo Seika Chem Co Ltd Process for producing alkylene oxide polymer
WO2002071860A1 (en) 2001-03-13 2002-09-19 L.A. Dreyfus Co. Gum base and gum manufacturing using particulated gum base ingredients
JP3967554B2 (en) 2001-03-15 2007-08-29 株式会社ポッカコーポレーション Flavonoid compound and method for producing the same
US20020132395A1 (en) 2001-03-16 2002-09-19 International Business Machines Corporation Body contact in SOI devices by electrically weakening the oxide under the body
EP1241110A1 (en) 2001-03-16 2002-09-18 Pfizer Products Inc. Dispensing unit for oxygen-sensitive drugs
AU2002248792B2 (en) 2001-04-18 2006-09-21 Nostrum Pharmaceuticals Inc. A novel coating for a sustained release pharmaceutical composition
US20020187192A1 (en) 2001-04-30 2002-12-12 Yatindra Joshi Pharmaceutical composition which reduces or eliminates drug abuse potential
ATE328028T1 (en) 2001-05-01 2006-06-15 Union Carbide Chem Plastic PHARMACEUTICAL COMPOSITION CONTAINING POLYALKYLENE OXIDES WITH REDUCED AMOUNTS OF FORMIC ACID AND FORMIC ACID DERIVATIVES
UA81224C2 (en) 2001-05-02 2007-12-25 Euro Celtic S A Dosage form of oxycodone and use thereof
WO2002090316A1 (en) 2001-05-08 2002-11-14 The Johns Hopkins University Method of inhibiting methamphetamine synthesis
WO2002092060A1 (en) 2001-05-11 2002-11-21 Endo Pharmaceuticals, Inc. Abuse-resistant controlled-release opioid dosage form
WO2002092059A1 (en) 2001-05-11 2002-11-21 Endo Pharmaceuticals, Inc. Abuse-resistant opioid dosage form
US6623754B2 (en) 2001-05-21 2003-09-23 Noveon Ip Holdings Corp. Dosage form of N-acetyl cysteine
AU2002339378A1 (en) 2001-05-22 2002-12-03 Euro-Celtique Compartmentalized dosage form
US20030064122A1 (en) 2001-05-23 2003-04-03 Endo Pharmaceuticals, Inc. Abuse resistant pharmaceutical composition containing capsaicin
WO2003002100A1 (en) 2001-06-26 2003-01-09 Farrell John J Tamper-proof narcotic delivery system
US20030008409A1 (en) 2001-07-03 2003-01-09 Spearman Steven R. Method and apparatus for determining sunlight exposure
AU2002320309B2 (en) 2001-07-06 2007-07-12 Endo Pharmaceuticals, Inc. Oxymorphone controlled release formulations
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US7276250B2 (en) 2001-07-06 2007-10-02 Penwest Pharmaceuticals Company Sustained release formulations of oxymorphone
JP2003020517A (en) 2001-07-10 2003-01-24 Calp Corp Resin composition for compound fiber
DE60230632D1 (en) 2001-07-18 2009-02-12 Euro Celtique Sa PHARMACEUTICAL COMBINATIONS OF OXYCODONE AND NALOXONE
US6883976B2 (en) 2001-07-30 2005-04-26 Seikoh Giken Co., Ltd. Optical fiber ferrule assembly and optical module and optical connector using the same
WO2003015531A2 (en) 2001-08-06 2003-02-27 Thomas Gruber Pharmaceutical formulation containing dye
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
US7842307B2 (en) 2001-08-06 2010-11-30 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent
US7144587B2 (en) 2001-08-06 2006-12-05 Euro-Celtique S.A. Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent
US20030157168A1 (en) 2001-08-06 2003-08-21 Christopher Breder Sequestered antagonist formulations
KR20040060917A (en) 2001-08-06 2004-07-06 유로-셀티크 소시에떼 아노뉨 Compositions and methods to prevent abuse of opioids
US7332182B2 (en) 2001-08-06 2008-02-19 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant
US20030044458A1 (en) 2001-08-06 2003-03-06 Curtis Wright Oral dosage form comprising a therapeutic agent and an adverse-effect agent
HUP0401344A2 (en) 2001-08-06 2004-11-29 Euro-Celtique S.A. Pharmaceutical compositions to prevent abuse of opioids and process for producing them
US7141250B2 (en) 2001-08-06 2006-11-28 Euro-Celtique S.A. Pharmaceutical formulation containing bittering agent
US7157103B2 (en) 2001-08-06 2007-01-02 Euro-Celtique S.A. Pharmaceutical formulation containing irritant
US20030049272A1 (en) 2001-08-30 2003-03-13 Yatindra Joshi Pharmaceutical composition which produces irritation
US20030059467A1 (en) 2001-09-14 2003-03-27 Pawan Seth Pharmaceutical composition comprising doxasozin
US6691698B2 (en) 2001-09-14 2004-02-17 Fmc Technologies Inc. Cooking oven having curved heat exchanger
US20030068276A1 (en) 2001-09-17 2003-04-10 Lyn Hughes Dosage forms
US20030059397A1 (en) 2001-09-17 2003-03-27 Lyn Hughes Dosage forms
US20030092724A1 (en) 2001-09-18 2003-05-15 Huaihung Kao Combination sustained release-immediate release oral dosage forms with an opioid analgesic and a non-opioid analgesic
WO2003024426A1 (en) 2001-09-21 2003-03-27 Egalet A/S Controlled release solid dispersions
WO2003024430A1 (en) 2001-09-21 2003-03-27 Egalet A/S Morphine polymer release system
AU2002342755A1 (en) 2001-09-26 2003-04-14 Klaus-Jurgen Steffens Method and device for producing granulates that comprise at least one pharmaceutical active substance
WO2003026743A2 (en) 2001-09-26 2003-04-03 Penwest Pharmaceuticals Company Opioid formulations having reduced potential for abuse
WO2003026626A2 (en) 2001-09-28 2003-04-03 Mcneil-Ppc, Inc. Modified release dosage forms
US6837696B2 (en) 2001-09-28 2005-01-04 Mcneil-Ppc, Inc. Apparatus for manufacturing dosage forms
EP1434837B1 (en) 2001-10-09 2006-03-29 The Procter & Gamble Company Aqueous compositions for treating a surface
US6592901B2 (en) 2001-10-15 2003-07-15 Hercules Incorporated Highly compressible ethylcellulose for tableting
JP2003125706A (en) 2001-10-23 2003-05-07 Lion Corp Mouth freshening preparation
PE20030527A1 (en) 2001-10-24 2003-07-26 Gruenenthal Chemie DELAYED-RELEASE PHARMACEUTICAL FORMULATION CONTAINING 3- (3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL) PHENOL OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME AND ORAL TABLETS CONTAINING IT
US20030104052A1 (en) 2001-10-25 2003-06-05 Bret Berner Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract
CA2409552A1 (en) 2001-10-25 2003-04-25 Depomed, Inc. Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract
US6723340B2 (en) 2001-10-25 2004-04-20 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US20030152622A1 (en) 2001-10-25 2003-08-14 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral diuretic
TWI312285B (en) 2001-10-25 2009-07-21 Depomed Inc Methods of treatment using a gastric retained gabapentin dosage
US20030091630A1 (en) 2001-10-25 2003-05-15 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data
WO2003037244A2 (en) 2001-10-29 2003-05-08 Therics, Inc. System for manufacturing controlled release dosage forms, such as a zero-order release profile dosage form manufactured by three-dimensional printing
CA2464528A1 (en) 2001-11-02 2003-05-15 Elan Corporation, Plc Pharmaceutical composition
US20040126428A1 (en) 2001-11-02 2004-07-01 Lyn Hughes Pharmaceutical formulation including a resinate and an aversive agent
AU2002366638A1 (en) 2001-12-06 2003-06-23 Scolr Pharma, Inc. Isoflavone composition for oral delivery
FR2833838B1 (en) 2001-12-21 2005-09-16 Ellipse Pharmaceuticals METHOD FOR MANUFACTURING A TABLET INCLUDING A MORPHINIC ANALGESIC AND TABLET OBTAINED
AUPS044502A0 (en) 2002-02-11 2002-03-07 Commonwealth Scientific And Industrial Research Organisation Novel catalysts and processes for their preparation
US20040033253A1 (en) 2002-02-19 2004-02-19 Ihor Shevchuk Acyl opioid antagonists
US20030158265A1 (en) 2002-02-20 2003-08-21 Ramachandran Radhakrishnan Orally administrable pharmaceutical formulation comprising pseudoephedrine hydrochloride and process for preparing the same
US20030190343A1 (en) 2002-03-05 2003-10-09 Pfizer Inc. Palatable pharmaceutical compositions for companion animals
US6572889B1 (en) 2002-03-07 2003-06-03 Noveon Ip Holdings Corp. Controlled release solid dosage carbamazepine formulations
US6753009B2 (en) 2002-03-13 2004-06-22 Mcneil-Ppc, Inc. Soft tablet containing high molecular weight polyethylene oxide
BRPI0309544B8 (en) 2002-04-05 2021-05-25 Euro Celtique Sa storage stable oral pharmaceutical preparation comprising oxycodone and naloxone
DE10217232B4 (en) 2002-04-18 2004-08-19 Ticona Gmbh Process for the production of filled granules from polyethylene of high or ultra-high molecular weight
AU2003234159A1 (en) 2002-04-22 2003-11-03 Purdue Research Foundation Hydrogels having enhanced elasticity and mechanical strength properties
ATE419830T1 (en) 2002-04-29 2009-01-15 Alza Corp METHODS AND PHARMACEUTICAL FORMS FOR THE CONTROLLED RELEASE OF OXYCODONE
US20050106249A1 (en) 2002-04-29 2005-05-19 Stephen Hwang Once-a-day, oral, controlled-release, oxycodone dosage forms
AU2003234395B2 (en) 2002-05-13 2008-01-24 Endo Pharmaceuticals Inc. Abuse-resistant opioid solid dosage form
MXPA04012021A (en) 2002-05-31 2005-08-16 Johnson & Johnson Dosage forms and compositions for osmotic delivery of variable dosages of oxycodone.
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
DE10250083A1 (en) 2002-06-17 2003-12-24 Gruenenthal Gmbh Dosage form protected against abuse
US7399488B2 (en) 2002-07-05 2008-07-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opiods and other drugs
US20040011806A1 (en) 2002-07-17 2004-01-22 Luciano Packaging Technologies, Inc. Tablet filler device with star wheel
MY136318A (en) 2002-07-25 2008-09-30 Pharmacia Corp Sustained-release tablet composition
US20060099250A1 (en) 2002-08-21 2006-05-11 Wei Tian Use of an aqueous solution of citric acid and a water-soluble sugar like lactitol as granulation liquid in the manufacture of tablets
US7388068B2 (en) 2002-08-21 2008-06-17 Clariant Produkte (Deutschland) Gmbh Copolymers made of alkylene oxides and glycidyl ethers and use thereof as polymerizable emulsifiers
US20040052844A1 (en) 2002-09-16 2004-03-18 Fang-Hsiung Hsiao Time-controlled, sustained release, pharmaceutical composition containing water-soluble resins
EP1635830B1 (en) 2002-09-17 2008-11-05 Wyeth Granulate formulation of the rapamycin ester cci-779
US7815924B2 (en) 2002-09-20 2010-10-19 Fmc Corporation Cosmetic composition containing microcrystalline cellulose
AU2003271024A1 (en) 2002-09-21 2004-04-08 Jin Wang Sustained release compound of acetamidophenol and tramadol
EP1551402A4 (en) 2002-09-23 2009-05-27 Verion Inc Abuse-resistant pharmaceutical compositions
JP2004143071A (en) 2002-10-23 2004-05-20 Hosokawa Funtai Gijutsu Kenkyusho:Kk Method for producing medicine-containing composite particle and medicine-containing composite particle
JP2006507277A (en) 2002-10-25 2006-03-02 ラボファーマ インコーポレイテッド 24 hour sustained release tramadol formulation
DE10250084A1 (en) 2002-10-25 2004-05-06 Grünenthal GmbH Dosage form protected against abuse
US20050186139A1 (en) 2002-10-25 2005-08-25 Gruenenthal Gmbh Abuse-proofed dosage form
DE10250087A1 (en) 2002-10-25 2004-05-06 Grünenthal GmbH Dosage form protected against abuse
US20050191244A1 (en) 2002-10-25 2005-09-01 Gruenenthal Gmbh Abuse-resistant pharmaceutical dosage form
DE10250088A1 (en) 2002-10-25 2004-05-06 Grünenthal GmbH Dosage form protected against abuse
DE10252667A1 (en) 2002-11-11 2004-05-27 Grünenthal GmbH New spiro-((cyclohexane)-tetrahydropyrano-(3,4-b)-indole) derivatives, are ORL1 receptor ligands useful e.g. for treating anxiety, depression, epilepsy, senile dementia, withdrawal symptoms or especially pain
US20040091528A1 (en) 2002-11-12 2004-05-13 Yamanouchi Pharma Technologies, Inc. Soluble drug extended release system
US7018658B2 (en) 2002-11-14 2006-03-28 Synthon Bv Pharmaceutical pellets comprising tamsulosin
US20040121003A1 (en) 2002-12-19 2004-06-24 Acusphere, Inc. Methods for making pharmaceutical formulations comprising deagglomerated microparticles
US20040185097A1 (en) 2003-01-31 2004-09-23 Glenmark Pharmaceuticals Ltd. Controlled release modifying complex and pharmaceutical compositions thereof
US7442387B2 (en) 2003-03-06 2008-10-28 Astellas Pharma Inc. Pharmaceutical composition for controlled release of active substances and manufacturing method thereof
ATE454169T1 (en) 2003-03-13 2010-01-15 Controlled Chemicals Inc OXYCODONE CONJUGATES WITH LOWER ABUSE POTENTIAL AND EXTENDED DURATION
ATE495732T1 (en) 2003-03-26 2011-02-15 Egalet As CONTROLLED RELEASE MORPHINE SYSTEM
WO2004084869A1 (en) 2003-03-26 2004-10-07 Egalet A/S Matrix compositions for controlled delivery of drug substances
MXPA05011071A (en) 2003-04-21 2005-12-12 Euro Celtique Sa Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same.
MY135852A (en) 2003-04-21 2008-07-31 Euro Celtique Sa Pharmaceutical products
TWI350186B (en) 2003-04-30 2011-10-11 Purdue Pharma Lp Tamper resistant transdermal dosage form
US8906413B2 (en) 2003-05-12 2014-12-09 Supernus Pharmaceuticals, Inc. Drug formulations having reduced abuse potential
CN1473562A (en) 2003-06-27 2004-02-11 辉 刘 Mouth cavity quick dissolving quick disintegrating freeze-dried tablet and its preparing method
HU227142B1 (en) 2003-07-02 2010-08-30 Egis Gyogyszergyar Nyilvanosan Capsule of improved release containing fluconazole
US20050015730A1 (en) 2003-07-14 2005-01-20 Srimanth Gunturi Systems, methods and computer program products for identifying tab order sequence of graphically represented elements
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
DE102004020220A1 (en) 2004-04-22 2005-11-10 Grünenthal GmbH Process for the preparation of a secured against misuse, solid dosage form
RU2339365C2 (en) 2003-08-06 2008-11-27 Грюненталь Гмбх Drug dosage form, protected from unintended application
DE10361596A1 (en) 2003-12-24 2005-09-29 Grünenthal GmbH Process for producing an anti-abuse dosage form
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
DE102005005446A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Break-resistant dosage forms with sustained release
DE102004032051A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Process for the preparation of a secured against misuse, solid dosage form
DK1842533T3 (en) 2003-08-06 2013-05-27 Gruenenthal Gmbh Method of administration secured against abuse
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Anti-abuse dosage form
US20050063214A1 (en) 2003-09-22 2005-03-24 Daisaburo Takashima Semiconductor integrated circuit device
WO2005032555A2 (en) * 2003-09-25 2005-04-14 Euro-Celtique S.A. Pharmaceutical combinations of hydrocodone and naltrexone
CN1859900A (en) 2003-09-30 2006-11-08 阿尔萨公司 Osmotically driven active agent delivery device providing an ascending release profile
US20060172006A1 (en) 2003-10-10 2006-08-03 Vincent Lenaerts Sustained-release tramadol formulations with 24-hour clinical efficacy
US20060009478A1 (en) 2003-10-15 2006-01-12 Nadav Friedmann Methods for the treatment of back pain
AU2004285547A1 (en) 2003-10-29 2005-05-12 Alza Corporation Once-a-day, oral, controlled-release, oxycodone dosage forms
US7201920B2 (en) 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
JP2007513147A (en) 2003-12-04 2007-05-24 ファイザー・プロダクツ・インク Spray congealing process for producing a multiparticulate crystalline pharmaceutical composition, preferably containing poloxamer and glyceride, using an extruder
DE602004005076T2 (en) 2003-12-09 2007-11-15 Euro-Celtique S.A. CO-EXTRUDED SAFETY DOSAGE FORM WITH AN ACTIVE AGENT AND AN ADVERSE AGENT AND METHOD OF MANUFACTURING THEREOF
WO2005060942A1 (en) 2003-12-19 2005-07-07 Aurobindo Pharma Ltd Extended release pharmaceutical composition of metformin
DE10360792A1 (en) 2003-12-23 2005-07-28 Grünenthal GmbH Spirocyclic cyclohexane derivatives
JP2007517061A (en) 2003-12-29 2007-06-28 アルザ・コーポレーシヨン Novel pharmaceutical composition and dosage form
US20070196396A1 (en) 2004-02-11 2007-08-23 Rubicon Research Private Limited Controlled release pharmaceutical compositions with improved bioavailability
TWI350762B (en) 2004-02-12 2011-10-21 Euro Celtique Sa Particulates
GB0403100D0 (en) 2004-02-12 2004-03-17 Euro Celtique Sa Particulates
GB0403098D0 (en) 2004-02-12 2004-03-17 Euro Celtique Sa Extrusion
DK1718258T3 (en) 2004-02-23 2009-06-29 Euro Celtique Sa Abuse-safe transdermal opioid delivery device
TW201509943A (en) 2004-03-30 2015-03-16 Euro Celtique Sa Oxycodone hydrochloride composition, pharmaceutical dosage form, sustained release oral dosage form and pharmaceutically acceptable package having less than 25 PPM 14-hydroxycodeinone
US20050220877A1 (en) 2004-03-31 2005-10-06 Patel Ashish A Bilayer tablet comprising an antihistamine and a decongestant
KR20060135875A (en) 2004-04-13 2006-12-29 코닌클리케 필립스 일렉트로닉스 엔.브이. Flyback converter
DE102004019916A1 (en) 2004-04-21 2005-11-17 Grünenthal GmbH Anti-abuse drug-containing patch
EP1740156B8 (en) 2004-04-22 2012-07-11 Grünenthal GmbH Method for the production of an abuse-proof, solid form of administration
WO2005105036A1 (en) 2004-04-28 2005-11-10 Natco Pharma Limited Controlled release mucoadhesive matrix formulation containing tolterodine and a process for its preparation
US20050271594A1 (en) 2004-06-04 2005-12-08 Groenewoud Pieter J Abuse resistent pharmaceutical composition
TWI428271B (en) 2004-06-09 2014-03-01 Smithkline Beecham Corp Apparatus and method for pharmaceutical production
DK1612203T3 (en) 2004-06-28 2007-12-03 Gruenenthal Gmbh Crystalline forms of (-) - (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) phenol hydrochloride
ITMI20041317A1 (en) 2004-06-30 2004-09-30 Ibsa Inst Biochimique Sa PHARMACEUTICAL FORMULATIONS FOR THE SAFE ADMINISTRATION OF DRUGS USED IN THE TREATMENT OF DRUG ADDICTION AND PROCEDURE FOR THEIR OBTAINING
DE102004032049A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Anti-abuse, oral dosage form
PL1786403T3 (en) 2004-07-01 2013-10-31 Gruenenthal Gmbh Oral dosage form safeguarded against abuse containing (1r, 2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
WO2006002884A1 (en) 2004-07-01 2006-01-12 Grünenthal GmbH Oral dosage form safeguarded against abuse
AR049839A1 (en) 2004-07-01 2006-09-06 Gruenenthal Gmbh PROCEDURE FOR THE PRODUCTION OF A SOLID PHARMACEUTICAL FORM, PROTECTED AGAINST ABUSE
DE102004032103A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Anti-abuse, oral dosage form
BRPI0513608A (en) 2004-07-27 2008-05-13 Unilever Nv hair care composition, process for preparing a hair care composition and method for hair treatment
GB2418854B (en) 2004-08-31 2009-12-23 Euro Celtique Sa Multiparticulates
US20060068009A1 (en) 2004-09-30 2006-03-30 Scolr Pharma, Inc. Modified release ibuprofen dosage form
US20070077297A1 (en) 2004-09-30 2007-04-05 Scolr Pharma, Inc. Modified release ibuprofen dosage form
US7426948B2 (en) 2004-10-08 2008-09-23 Phibrowood, Llc Milled submicron organic biocides with narrow particle size distribution, and uses thereof
US20060177380A1 (en) 2004-11-24 2006-08-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20080152595A1 (en) 2004-11-24 2008-06-26 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20070231268A1 (en) 2004-11-24 2007-10-04 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
WO2006080327A1 (en) 2005-01-26 2006-08-03 Taiho Pharmaceutical Co., Ltd. ANTICANCER DRUG CONTAINING α,α,α-TRIFLUOROTHYMIDINE AND THYMIDINE PHOSPHORYLASE INHIBITOR
AP2274A (en) 2005-01-28 2011-08-19 Euro Celtiques Sa Alcohol resistant dosage forms.
DE102005005449A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Process for producing an anti-abuse dosage form
FR2889810A1 (en) 2005-05-24 2007-02-23 Flamel Technologies Sa ORAL MEDICINAL FORM, MICROPARTICULAR, ANTI-MEASUREMENT
BRPI0606883A2 (en) 2005-02-10 2009-12-01 Lifecycle Pharma As pharmaceutical composition for oral administration, method for preparing a tablet, and single solid dosage form
US20060194759A1 (en) 2005-02-25 2006-08-31 Eidelson Stewart G Topical compositions and methods for treating pain and inflammation
EP1695700A1 (en) 2005-02-28 2006-08-30 Euro-Celtique S.A. Dosage form containing oxycodone and naloxone
JP5314894B2 (en) 2005-03-04 2013-10-16 ユーロ−セルティーク エス.エイ. Method for reducing alpha and beta unsaturated ketones in opioid compositions
US20060204575A1 (en) 2005-03-11 2006-09-14 Hengsheng Feng Amphetamine formulations
US7732427B2 (en) 2005-03-31 2010-06-08 University Of Delaware Multifunctional and biologically active matrices from multicomponent polymeric solutions
CA2603649C (en) 2005-04-08 2014-10-14 Ozpharma Pty Ltd Buccal delivery system
RU2405539C2 (en) 2005-05-10 2010-12-10 Новартис Аг Method of obtaining compositions by extrusion of resistant to pressing pharmaceutical substances
US20090274759A1 (en) 2005-06-03 2009-11-05 Egalet A/S Solid pharmaceutical composition with a first fraction of a dispersion medium and a second fraction of a matrix, the latter being at least partially first exposed to gastrointestinal fluids
WO2007005716A2 (en) 2005-06-30 2007-01-11 Cinergen, Llc Methods of treatment and compositions for use thereof
BRPI0612802A2 (en) 2005-07-07 2010-11-30 Farnam Co Inc sustained release pharmaceutical compositions for extremely water soluble drugs
DE102005032806A1 (en) 2005-07-12 2007-01-18 Röhm Gmbh Use of a partially neutralized, anionic (meth) acrylate copolymer as a coating for the preparation of a dosage form with a release of active ingredient at reduced pH values
US8858993B2 (en) 2005-07-25 2014-10-14 Metrics, Inc. Coated tablet with zero-order or near zero-order release kinetics
US20090155357A1 (en) 2005-08-01 2009-06-18 Alpharma Inc. Alcohol Resistant Pharmaceutical Formulations
CN101232871A (en) 2005-08-03 2008-07-30 伊士曼化工公司 Tocopheryl polyethylene glycol succinate powder and process for preparing same
US20070048373A1 (en) 2005-08-30 2007-03-01 Cima Labs Inc. Dried milled granulate and methods
PL1950219T3 (en) 2005-10-14 2011-11-30 The Kitasato Inst Novel dihydropseudoerythromycin derivatives
US20070092573A1 (en) 2005-10-24 2007-04-26 Laxminarayan Joshi Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist
PL116330U1 (en) 2005-10-31 2007-04-02 Alza Corp Method for the reduction of alcohol provoked rapid increase in the released dose of the orally administered opioide with prolonged liberation
US8329744B2 (en) 2005-11-02 2012-12-11 Relmada Therapeutics, Inc. Methods of preventing the serotonin syndrome and compositions for use thereof
WO2008134071A1 (en) 2007-04-26 2008-11-06 Theraquest Biosciences, Inc. Multimodal abuse resistant extended release formulations
FR2892937B1 (en) 2005-11-10 2013-04-05 Flamel Tech Sa MICROPARTICULAR ORAL PHARMACEUTICAL FORM ANTI-MEASURING
DE102005058569B4 (en) 2005-12-08 2010-07-15 Lts Lohmann Therapie-Systeme Ag Foam wafer with polyvinyl alcohol-polyethylene glycol graft copolymer
US20090317355A1 (en) 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
KR20080089653A (en) 2006-01-21 2008-10-07 애보트 게엠베하 운트 콤파니 카게 Dosage form and method for the delivery of drugs of abuse
US20090022798A1 (en) 2007-07-20 2009-01-22 Abbott Gmbh & Co. Kg Formulations of nonopioid and confined opioid analgesics
US20100172989A1 (en) 2006-01-21 2010-07-08 Abbott Laboratories Abuse resistant melt extruded formulation having reduced alcohol interaction
EP1813276A1 (en) 2006-01-27 2007-08-01 Euro-Celtique S.A. Tamper resistant dosage forms
FR2897267A1 (en) 2006-02-16 2007-08-17 Flamel Technologies Sa MULTIMICROPARTICULAR PHARMACEUTICAL FORMS FOR PER OS ADMINISTRATION
FR2898056B1 (en) 2006-03-01 2012-01-20 Ethypharm Sa SQUEEZE-RESISTANT TABLETS TO PREVENT UNLAWFUL MISUSE
MX2008010921A (en) 2006-03-02 2008-09-03 Mallinckrodt Inc Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds.
WO2007103286A2 (en) 2006-03-02 2007-09-13 Spherics, Inc. Rate-controlled bioadhesive oral dosage formulations
US20070224637A1 (en) 2006-03-24 2007-09-27 Mcauliffe Joseph C Oxidative protection of lipid layer biosensors
CN101489756B (en) 2006-03-24 2013-08-07 奥克思利尤姆国际控股公司 Process for the preparation of a hot-melt extruded laminate
JP5536446B2 (en) 2006-03-24 2014-07-02 オクシリウム インターナショナル ホールディングス,インコーポレイティド Stabilized composition comprising an alkali labile drug
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
US9023400B2 (en) 2006-05-24 2015-05-05 Flamel Technologies Prolonged-release multimicroparticulate oral pharmaceutical form
WO2007138466A2 (en) 2006-06-01 2007-12-06 Wockhardt Ltd Pharmaceutical compositions comprising meloxicam and tramadol combination
US20070292508A1 (en) 2006-06-05 2007-12-20 Balchem Corporation Orally disintegrating dosage forms
US20080069891A1 (en) * 2006-09-15 2008-03-20 Cima Labs, Inc. Abuse resistant drug formulation
HUE031590T2 (en) 2006-06-19 2017-07-28 Alpharma Pharmaceuticals Llc Pharmaceutical compositions
CN101091721A (en) 2006-06-22 2007-12-26 孙明 Method for preparing new type asshide
EP2043613A1 (en) 2006-07-14 2009-04-08 Fmc Corporation Solid form
JP4029109B1 (en) 2006-07-18 2008-01-09 タマ生化学株式会社 Complex powder of vitamin E and proline and method for producing the same
US20080075770A1 (en) 2006-07-21 2008-03-27 Vaughn Jason M Hydrophilic abuse deterrent delivery system
SA07280459B1 (en) 2006-08-25 2011-07-20 بيورديو فارما إل. بي. Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic
US8445018B2 (en) * 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
KR101400824B1 (en) 2006-09-25 2014-05-29 후지필름 가부시키가이샤 Resist composition, resin for use in the resist composition, compound for use in the synthesis of the resin, and pattern-forming method usign the resist composition
US8187636B2 (en) 2006-09-25 2012-05-29 Atlantic Pharmaceuticals, Inc. Dosage forms for tamper prone therapeutic agents
US20080085304A1 (en) 2006-10-10 2008-04-10 Penwest Pharmaceuticals Co. Robust sustained release formulations
EP2079453A1 (en) 2006-10-10 2009-07-22 Penwest Pharmaceuticals Co. Robust sustained release formulations
GB0624880D0 (en) 2006-12-14 2007-01-24 Johnson Matthey Plc Improved method for making analgesics
DE102006062120A1 (en) 2006-12-22 2008-06-26 Grünenthal GmbH Pharmaceutical composition for acne treatment
AU2007338631A1 (en) 2006-12-22 2008-07-03 Combinatorx, Incorporated Pharmaceutical compositions for treatment of parkinson's disease and related disorders
US20100291205A1 (en) 2007-01-16 2010-11-18 Egalet A/S Pharmaceutical compositions and methods for mitigating risk of alcohol induced dose dumping or drug abuse
US20080181932A1 (en) 2007-01-30 2008-07-31 Drugtech Corporation Compositions for oral delivery of pharmaceuticals
CN100579525C (en) 2007-02-02 2010-01-13 东南大学 Sustained release preparation of licardipine hydrochloride and its preparing process
EP2119190B1 (en) 2007-02-06 2018-09-12 Transpacific IP Group Limited Service continuity management in a network
ATE552861T1 (en) 2007-02-08 2012-04-15 Kempharm Inc POLAR HYDROPHILIC PRODRUGS OF AMPHETAMINE AND OTHER STIMULANTS AND METHODS OF PRODUCTION AND USE
CN101057849A (en) 2007-02-27 2007-10-24 齐齐哈尔医学院 Slow-releasing preparation containing metformin hydrochloride and glipizide and its preparation method
JP5452236B2 (en) 2007-03-02 2014-03-26 ファーナム・カンパニーズ・インコーポレーテッド Sustained release composition using wax-like substance
DE102007011485A1 (en) 2007-03-07 2008-09-11 Grünenthal GmbH Dosage form with more difficult abuse
EP1980245A1 (en) 2007-04-11 2008-10-15 Cephalon France Bilayer lyophilized pharmaceutical compositions and methods of making and using same
US20080260836A1 (en) 2007-04-18 2008-10-23 Thomas James Boyd Films Comprising a Plurality of Polymers
EP2061587A1 (en) 2007-04-26 2009-05-27 Sigmoid Pharma Limited Manufacture of multiple minicapsules
US20110020408A1 (en) 2007-05-17 2011-01-27 Ranbaxy Laboratories Limited multilayered modified release formulation comprising amoxicillin and clavulanate
US8202542B1 (en) 2007-05-31 2012-06-19 Tris Pharma Abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings
AU2008258596B2 (en) 2007-06-04 2013-02-14 Egalet Ltd Controlled release pharmaceutical compositions for prolonged effect
US20100035886A1 (en) 2007-06-21 2010-02-11 Veroscience, Llc Parenteral formulations of dopamine agonists
RU2477995C2 (en) 2007-07-20 2013-03-27 Эбботт Гмбх Унд Ко.Кг Formulations of non-opioid and limited opioid analgesics
WO2009034541A2 (en) 2007-09-11 2009-03-19 Ranbaxy Laboratories Limited Controlled release pharmaceutical dosage forms of trimetazidine
WO2009035474A1 (en) 2007-09-13 2009-03-19 Cima Labs Inc. Abuse resistant drug formulation
US20100303883A1 (en) 2007-10-17 2010-12-02 Axxia Pharmaceuticals, Llc Polymeric drug delivery systems and thermoplastic extrusion processes for producing such systems
EP2063682B1 (en) 2007-11-21 2016-09-14 Telefonaktiebolaget LM Ericsson (publ) Technique for platform-to-platform communication
CN102908339A (en) 2007-11-23 2013-02-06 格吕伦塔尔有限公司 Tapentadol compositions
CA2707282A1 (en) 2007-12-12 2009-06-18 Basf Se Salts of active ingredients with polymeric counterions
BRPI0821732A2 (en) 2007-12-17 2015-06-16 Labopharm Inc Controlled release formulations, solid dosage form, and use of controlled release formulation
MX2010008138A (en) 2008-01-25 2010-08-10 Gruenenthal Gmbh Pharmaceutical dosage form.
KR100970665B1 (en) 2008-02-04 2010-07-15 삼일제약주식회사 Sustained release tablet containing alfuzosin or its salt
US20110008426A1 (en) 2008-03-05 2011-01-13 Rajesh Jain Modified release pharmaceutical compositions comprising mycophenolate and processes thereof
US8372432B2 (en) 2008-03-11 2013-02-12 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
EP2100598A1 (en) 2008-03-13 2009-09-16 Laboratorios Almirall, S.A. Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease
TWI519322B (en) 2008-04-15 2016-02-01 愛戴爾製藥股份有限公司 Compositions comprising weakly basic drugs and controlled-release dosage forms
JP5674641B2 (en) 2008-05-09 2015-02-25 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Method for producing intermediate powder formulation and final solid dosage form under application of spray coagulation process
JP2011526928A (en) 2008-07-03 2011-10-20 ノバルティス アーゲー Melt granulation method
US9192578B2 (en) 2008-08-20 2015-11-24 Board Of Regents, The University Of Texas System Hot-melt extrusion of modified release multi-particulates
FR2936709B1 (en) 2008-10-02 2012-05-11 Ethypharm Sa ALCOHOL-RESISTANT TABLETS.
WO2010044842A1 (en) 2008-10-16 2010-04-22 University Of Tennessee Research Foundation Tamper resistant oral dosage forms containing an embolizing agent
JP5713911B2 (en) 2008-10-27 2015-05-07 アルザ・コーポレーシヨン Extended-release oral acetaminophen / tramadol dosage form
RU2011123377A (en) 2008-11-14 2012-12-20 Портола Фармасьютиклз, Инк. SOLID COMPOSITION FOR CONTROLLED RELEASE OF ACTIVE IONIZABLE AGENTS CHARACTERIZED BY LOW SOLUBILITY IN WATER AT LOW pH VALVES AND METHODS OF ITS APPLICATION
WO2010066034A1 (en) 2008-12-12 2010-06-17 Paladin Labs Inc. Methadone formulation
ES2509497T3 (en) 2008-12-16 2014-10-17 Paladin Labs Inc. Controlled release formulation to prevent misuse
CA2750400A1 (en) 2009-01-26 2010-07-29 Egalet A/S Controlled release formulations with continuous efficacy
EP2393487B1 (en) 2009-02-06 2016-11-02 Egalet Ltd. Pharmaceutical compositions resistant to abuse
ES2624719T3 (en) 2009-03-18 2017-07-17 Evonik Röhm Gmbh Pharmaceutical controlled release composition with resistance against the influence of ethanol using a coating comprising neutral vinyl polymers and excipients
EP2246063A1 (en) 2009-04-29 2010-11-03 Ipsen Pharma S.A.S. Sustained release formulations comprising GnRH analogues
GB0909680D0 (en) 2009-06-05 2009-07-22 Euro Celtique Sa Dosage form
AU2010265213B2 (en) 2009-06-24 2012-08-23 Egalet Ltd. Controlled release formulations
WO2011008298A2 (en) 2009-07-16 2011-01-20 Nectid, Inc. Novel axomadol dosage forms
RU2567723C2 (en) 2009-07-22 2015-11-10 Грюненталь Гмбх Oxidation stable and breaking resistance dosage form
ES2534908T3 (en) 2009-07-22 2015-04-30 Grünenthal GmbH Hot melt extruded controlled release dosage form
WO2011041414A1 (en) 2009-09-30 2011-04-07 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US9044758B2 (en) 2009-11-13 2015-06-02 Moriroku Chemicals Company, Ltd. Method for producing fine powder and the fine powder produced by the same
WO2011068722A1 (en) 2009-12-01 2011-06-09 Noven Pharmaceuticals, Inc. Transdermal testosterone device and delivery
US9579285B2 (en) 2010-02-03 2017-02-28 Gruenenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
GB201003731D0 (en) 2010-03-05 2010-04-21 Univ Strathclyde Immediate/delayed drug delivery
WO2011112709A1 (en) 2010-03-09 2011-09-15 Elan Pharma International Limited Alcohol resistant enteric pharmaceutical compositions
CA2795158C (en) 2010-04-02 2019-10-22 Alltranz Inc. Abuse-deterrent transdermal formulations of opiate agonists and agonist-antagonists
CA2832436C (en) 2010-04-07 2018-08-14 Lupin Limited Controlled release pharmaceutical compositions of tapentadol
GB201006200D0 (en) 2010-04-14 2010-06-02 Ayanda As Composition
PL2560624T3 (en) 2010-04-23 2019-01-31 Kempharm, Inc. Therapeutic formulation for reduced drug side effects
US20130059010A1 (en) 2010-05-14 2013-03-07 Ethypharm Alcohol-resistant oral pharmaceutical form
FR2960775A1 (en) 2010-06-07 2011-12-09 Ethypharm Sa MICROGRANULES RESISTANT TO MISMATCH
KR20130097201A (en) 2010-09-02 2013-09-02 그뤼넨탈 게엠베하 Tamper resistant dosage form comprising an anionic polymer
BR112013005194A2 (en) 2010-09-02 2016-05-03 Gruenenthal Gmbh tamper-resistant dosage form comprising inorganic salt
BR112013005234A2 (en) 2010-09-02 2016-05-03 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer.
EP2635258A1 (en) 2010-11-04 2013-09-11 AbbVie Inc. Drug formulations
US20120231083A1 (en) 2010-11-18 2012-09-13 The Board Of Trustees Of The University Of Illinois Sustained release cannabinoid medicaments
GB201020895D0 (en) 2010-12-09 2011-01-26 Euro Celtique Sa Dosage form
KR101458334B1 (en) 2010-12-23 2014-11-04 퍼듀 퍼머 엘피 Tamper resistant solid oral dosage forms
EP3287123B1 (en) 2011-03-04 2020-04-22 Grünenthal GmbH Aqueous pharmaceutical formulation of tapentadol for oral administration
ES2646363T3 (en) 2011-04-29 2017-12-13 Grünenthal GmbH Tapentadol for the prevention and treatment of depression and anxiety
US8858963B1 (en) 2011-05-17 2014-10-14 Mallinckrodt Llc Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia
CA2837077A1 (en) 2011-06-01 2012-12-06 Fmc Corporation Controlled release solid dose forms
WO2013003845A1 (en) 2011-06-30 2013-01-03 Neos Therapeutics, Lp Abuse resistant drug forms
JP2014524925A (en) 2011-07-29 2014-09-25 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Tamper-resistant tablets that provide immediate drug release
CN103857386A (en) 2011-07-29 2014-06-11 格吕伦塔尔有限公司 Tamper-resistant tablet providing immediate drug release
CA2844827A1 (en) 2011-08-16 2013-02-21 Merck Sharp & Dohme Corp. Use of inorganic matrix and organic polymer combinations for preparing stable amorphous dispersions
FR2979242A1 (en) 2011-08-29 2013-03-01 Sanofi Sa COMPRESSES AGAINST ABUSIVE USE, BASED ON PARACETAMOL AND OXYCODONE
MX2014003973A (en) 2011-10-06 2014-05-07 Gruenenthal Gmbh Tamper-resistant oral pharmaceutical dosage form comprising opioid agonist and opioid antagonist.
JP6085307B2 (en) 2011-11-17 2017-02-22 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Tamper resistant oral pharmaceutical dosage forms comprising pharmacologically active ingredients, opioid antagonists and / or aversive agents, polyalkylene oxides and anionic polymers
ES2603278T3 (en) 2011-12-09 2017-02-24 Purdue Pharma Lp Pharmaceutical dosage forms comprising poly (epsilon-caprolactone) and polyethylene oxide
JP2013155124A (en) 2012-01-30 2013-08-15 Moriroku Chemicals Co Ltd Bulk powder of medicine and method of producing the same
JP6117249B2 (en) 2012-02-28 2017-04-19 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Tamper resistant dosage forms comprising a pharmacologically active compound and an anionic polymer
EP2819657A1 (en) 2012-02-28 2015-01-07 Grünenthal GmbH Tamper-resistant pharmaceutical dosage form comprising nonionic surfactant
UY34651A (en) 2012-03-02 2013-09-30 Rhodes Pharmaceuticals Lp ? DOSAGE FORMS OF IMMEDIATE RELEASE OF HANDLING, PROCESSES TO PREPARE THEM, METHODS AND USES OF THE SAME? ..
LT2838512T (en) 2012-04-18 2018-11-12 GrĆ¼nenthal GmbH Tamper resistant and dose-dumping resistant pharmaceutical dosage form
NO2846835T3 (en) 2012-05-11 2018-02-03
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
WO2014022541A1 (en) 2012-08-01 2014-02-06 Acura Pharmaceuticals, Inc. Stabilization of one-pot methamphetamine synthesis systems
PL2887925T3 (en) 2012-08-27 2017-07-31 Evonik Röhm Gmbh Gastric resistant pharmaceutical or nutraceutical composition with resistance against the influence of ethanol
PL2887926T3 (en) 2012-08-27 2017-01-31 Evonik Röhm Gmbh Pharmaceutical or nutraceutical composition with sustained release characteristic and with resistance against the influence of ethanol
WO2014038593A2 (en) 2012-09-05 2014-03-13 テイカ製薬株式会社 Granulated material for tablet that rapidly disintegrates in mouth
EP2906202A4 (en) 2012-10-15 2016-04-27 Isa Odidi Oral drug delivery formulations
US9517208B2 (en) 2013-03-15 2016-12-13 Purdue Pharma L.P. Abuse-deterrent dosage forms
CA2903200A1 (en) 2013-03-15 2014-09-25 Mallinckrodt Llc Compositions comprising an opioid and an additional active pharmaceutical ingredient for rapid onset and extended duration of analgesia that may be administered without regard to food
US10420729B2 (en) 2013-03-15 2019-09-24 R.P. Scherer Technologies, Llc Abuse resistant capsule
EP3003283A1 (en) 2013-05-29 2016-04-13 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
BR112015026549A2 (en) 2013-05-29 2017-07-25 Gruenenthal Gmbh tamper-proof dosage form containing one or more particles
CA2817728A1 (en) 2013-05-31 2014-11-30 Pharmascience Inc. Abuse deterrent immediate release formulation
BR112016000194A8 (en) 2013-07-12 2019-12-31 Gruenenthal Gmbh tamper-resistant dosage form containing ethylene vinyl acetate polymer
US9770514B2 (en) 2013-09-03 2017-09-26 ExxPharma Therapeutics LLC Tamper-resistant pharmaceutical dosage forms
WO2015048597A1 (en) 2013-09-30 2015-04-02 Daya Drug Discoveries, Inc. Prevention of illicit methamphetamine manufacture from pseudoephedrine using food flavor excipients
US20150118300A1 (en) 2013-10-31 2015-04-30 Cima Labs Inc. Immediate Release Abuse-Deterrent Granulated Dosage Forms
US10744131B2 (en) 2013-12-31 2020-08-18 Kashiv Biosciences, Llc Abuse-resistant drug formulations
US10632113B2 (en) 2014-02-05 2020-04-28 Kashiv Biosciences, Llc Abuse-resistant drug formulations with built-in overdose protection
TWI631135B (en) 2014-02-12 2018-08-01 建南德克公司 Anti-jagged1 antibodies and methods of use
US20160089439A1 (en) 2014-09-28 2016-03-31 Satara Pharmaceuticals, LLC Prevention of Illicit Manufacutre of Methamphetamine from Pseudoephedrine Using Food Flavor Excipients
CA2975959A1 (en) 2015-02-05 2016-08-11 Akash Gupta Apparatus and method for handling goods
EA035434B1 (en) 2015-04-24 2020-06-15 Грюненталь Гмбх Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US20170112766A1 (en) 2015-04-24 2017-04-27 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US20170296476A1 (en) 2016-04-15 2017-10-19 Grünenthal GmbH Modified release abuse deterrent dosage forms

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070224129A1 (en) * 2005-11-10 2007-09-27 Flamel Technologies, Inc. Anti-misuse microparticulate oral pharmaceutical form
US20090215808A1 (en) * 2007-12-06 2009-08-27 Su Il Yum Oral pharmaceutical dosage forms
US20120321716A1 (en) * 2011-02-17 2012-12-20 Michael Vachon Technology for preventing abuse of solid dosage forms

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