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WO2004056363A2 - A physically and chemically stable nicotine-containing particulate material - Google Patents

A physically and chemically stable nicotine-containing particulate material Download PDF

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Publication number
WO2004056363A2
WO2004056363A2 PCT/EP2003/014802 EP0314802W WO2004056363A2 WO 2004056363 A2 WO2004056363 A2 WO 2004056363A2 EP 0314802 W EP0314802 W EP 0314802W WO 2004056363 A2 WO2004056363 A2 WO 2004056363A2
Authority
WO
WIPO (PCT)
Prior art keywords
nicotine
particulate material
pharmaceutical composition
composition according
pharmaceutically acceptable
Prior art date
Application number
PCT/EP2003/014802
Other languages
French (fr)
Other versions
WO2004056363A3 (en
Inventor
Henri Hansson
Original Assignee
Niconovum Ab
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
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=32683718&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2004056363(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CA2511185A priority Critical patent/CA2511185C/en
Priority to DK03789400T priority patent/DK1578422T3/en
Priority to DE60313216T priority patent/DE60313216T2/en
Priority to NZ540817A priority patent/NZ540817A/en
Priority to SI200330825T priority patent/SI1578422T1/en
Priority to EP18203402.5A priority patent/EP3473251B1/en
Priority to CN2003801090255A priority patent/CN1738621B/en
Application filed by Niconovum Ab filed Critical Niconovum Ab
Priority to EP03789400A priority patent/EP1578422B1/en
Priority to JP2004561429A priority patent/JP4708795B2/en
Priority to NO20191286A priority patent/NO346973B1/en
Priority to EP07007325.9A priority patent/EP1803443B1/en
Priority to EP07007326.7A priority patent/EP1803444B1/en
Priority to AU2003293987A priority patent/AU2003293987B2/en
Publication of WO2004056363A2 publication Critical patent/WO2004056363A2/en
Publication of WO2004056363A3 publication Critical patent/WO2004056363A3/en
Priority to NO20053309A priority patent/NO344367B1/en
Priority to CY20071100738T priority patent/CY1106477T1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse

Definitions

  • the present invention relates to a nicotine-containing particulate material comprising a microcrystalline cellulose into which nicotine or a pharmaceutically acceptable salt, complex or solvent thereof has been incorporated.
  • the invention also relates to pharmaceutical compositions and for method for treating or preventing tobacco dependence, Parkinsons disease, ulcerative colitis, Alzheimers disease, schizophrenia and/or ADHD.
  • the treatment with nicotine-containing products today produces either too small quantities of nicotine in plasma and/ or plasma profiles with a too flat and/or slow peak.
  • the desired plasma profile is one that has a faster uptake of nicotine than other marketed treatment products.
  • nicotine in its base form is preferred. Nicotine in its base form is readily absorbed through the oral mucosa but is highly volatile and subject to oxidative degradation. The available nicotine salts are more stable compounds but are not as readily absorbed as the free base. In order to deal with the volatility and stability problems of the free base different techniques are possible.
  • nicotine is absorbed in different water insoluble materials, e.g. paper, cellulose acetate, polyethylene or polypropylene.
  • the sorbed nicotine is to be released slowly in an oral environment.
  • the object of the present invention is to provide a physically and chemically stable nicotine-containing particulate material that can be designed to release nicotine relatively fast from the material in order to enable a rapid absorption after administration.
  • the inventors have surprisingly found that sorption of nicotine (e.g. in the form of a solution containing nicotine as a base) on a microcrystalline cellulose (MCC) results in physical and chemical stable dry particulate material with a very fast and complete release in vitro.
  • the dissolution profiles of nicotine base from such a particulate material may typically be that about 90 % of loaded nicotine released after 1 minute in 1 litre phosphate buffer, pH 7.4 maintained at 37° C in a dissolution apparatus according to USP, paddle.
  • the invention relates to a nicotine-containing particulate material for release of nicotine, the material comprising a combination of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof and a microcrystalline cellulose, the particulate material - when tested in an in vitro dissolution test - releasing at least 90% w/w such as, e.g.
  • the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof within at the most about 30 min such as, e.g., at the most about 25 min, at the most about 20 min, at the most about 15 min, at the most about 10 min, at the most about 7.5 min, at the most about 5 min, at the most about 4 min, at the most about 3 min or at the most about 2 min.
  • the invention relates to a particulate material for fast release of nicotine, the material - when tested in an in vitro dissolution test - releasing at least 90% w/w such as, e.g. at least 95 % w/w of the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof within at the most about 20 min such as, e.g, at the most about 15 min, at the most about 10 min, at the most about 7.5 min, at the most about 5 min, at the most about 4 min, at the most about 3 min, at the most about 2 min or at the most about 1 min.
  • the most about 20 min such as, e.g, at the most about 15 min, at the most about 10 min, at the most about 7.5 min, at the most about 5 min, at the most about 4 min, at the most about 3 min, at the most about 2 min or at the most about 1 min.
  • Tobacco smoking can result in a dependence disorder.
  • the WHO has in its International Classification of Disorders a diagnosis Tobacco Dependence. Others like the American Psychiatric Association labels the addiction Nicotine Dependence.
  • Nicotine is the world's second most used drug, after caffeine from coffee and tea. Even though tobacco smoking is decreasing in many developed countries today it is hard to see how the societies could get rid of the world's second most used drug. Societies are not even successful in protecting themselves against illegal drugs that have more profound psychotoxic effects. It is therefore most likely that when tobacco smoking will become more or less socially and legally outlawed there will be a need for discovering other forms of taking nicotine. Nicotine containing medications are currently the dominating treatments for tobacco dependence. There is also evidence of broader use of these medications like for smoking reduction and long term maintenance / substitution. However the products are not very acceptable to many smokers. Among other things they are too far from the cigarette in some major characteristics.
  • nicotine gum is marketed in two strengths, 2 and 4 mg, which is the actual content of nicotine.
  • biological available dose from these gums are only about 1 and 2 mg, respectively. This is because it is difficult to completely empty the gum and some of the nicotine that is extracted from the gum cannot be absorbed into the circulatory system due to swallowing into the gastrointestinal tract where most of the nicotine is metabolised before entering the circulation.
  • speed by which the nicotine is absorbed is much slower than from the cigarette. This is an important factor since when individuals want to change their state of mind with psychoactive drugs the effects are strongly dependent on the speed by which the drug enters the brain.
  • Nicotine patches delivers from 15 - 21 mg nicotine (different brands have different doses). Most of the nicotine that is delivered through the skin is absorbed. For a smoker consuming 15 - 20 cigarettes a day one can assume a nicotine intake per day of 15 - 25 mg. If the smoking takes place during roughly a 16 hours waking period that means one to one and a half mg per hour. The nicotine patch gives close to one mg per hour. However one has to keep in mind that some smokers take in much more nicotine and that the pharmacokinetic profile of nicotine from a patch is relatively stable and does not allow for any discrete variations. With smoking there are peaks in nicotine concentration corresponding with each cigarette that may also be necessary for the experience of certain of the nicotine's effects.
  • the dose and speed of absorption for producing a subjective effect may vary from individual to individual but it seems to be a rule that an increase in concentration of 5-10 ng/ml over 10 minutes is a requirement.
  • the increase in concentration is time related so probably an increase of 3-5 ng/ml over 5 minutes is as good.
  • This requirement to get a psychoactive effect is probably one of the most important characteristics in developing products that will be well accepted by consumers so they can rid themselves of the very high risk associated with cigarette smoking.
  • a particulate material according to the present invention is chemically and physically stable.
  • stable means that the material and/or the nicotine or the pharmaceutically acceptable salt, complex or solvate contained therein is chemically and/or physically stable for at least about 22 weeks such as, e.g., at least 14 weeks when stored open at a temperature of 40 °C and a relative humidity of 50%. It is especially of importance that nicotine or a pharmaceutically acceptable salt, complex or solvate thereof does not migrate out of the material as such a migration will lead to a marked loss in the content of nicotine in the material.
  • nicotine as a base is a volatile substance and, therefore, it is normally difficult to maintain a relatively constant concentration of the nicotine base in a composition comprising a mere admixture of nicotine and a pharmaceutically acceptable excipient.
  • a particulate material according to the present invention is also physically stable. Thus, within a time period of 22 weeks or more no visible changes had been observed and the dissolution profile did not change.
  • microcrystalline cellulose is of utmost importance for the success of a particulate material according to the present invention.
  • Suitable microcrystalline celluloses are highly crystalline particulate cellulose containing crystallite aggregates obtained by removing amorphous (fibrous cellulose) regions of a purified cellulose source material by hydrolytic degradation, typically with a strong mineral acid such as hydrogen chloride.
  • the acid hydrolysis process produces a microcrystalline cellulose of predominantly coarse particulate aggregate, typically having a mean size range of about 15 to 250 ⁇ m.
  • microcrystalline cellulose has a suitable porosity and/or bulk density, especially it has a very large surface area due to the porous structure of MCC. It is believed that nicotine after being contacted with MCC mainly is located in the porous structure of MCC, i.e. nicotine is sorbed to MCC most likely by adsorption. Accordingly, in an embodiment of the present invention at least part of the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof is adsorbed to the microcrystalline cellulose in the particulate material.
  • MCM qualities suitable for the purpose of the present invention include but are not limited to any of commercial pharmaceutically accepted qualities of e.g. Avicel® such as, e.g., the grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, Vivacel® such as, e.g., grades 101 , 102, 12 or 20, Emcocel® such as, e.g., the grades 50M or 90M.
  • Avicel® such as, e.g., the grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, Vivacel® such as, e.g., grades 101 , 102, 12 or 20, Emcocel® such as, e.g., the grades 50M or 90M.
  • crystalline celluloses are also contemplated to be suitable for use according to the invention. Without being bound to any theory, it is contemplated that due to its size and amphiphilic character, nicotine is entrapped and/or weekly bonded inside the void volume of the cellulose cells by means of hydrogen bonding or by Van deer Waals attraction.
  • the nicotine is dissolved in a hydrophilic solvent, i.e. water or alcohol or mixtures thereof, and, according to the above-mentioned theory it is contemplated that by means of capillary forces the nicotine is introduced into the voids of the crystalline cellulose. After the removal of the solvent nicotine is retained inside said voids until a suitable solvent again enters the voids and releases the nicotine into said solvent.
  • a hydrophilic solvent i.e. water or alcohol or mixtures thereof
  • nicotine encompasses nicotine or a nicotine derivative in any form such as, e.g., physical form like amorphous, crystalline, polymorphous etc. or chemical form like isomers and enantiomers etc as well as any pharmaceutically acceptable salt, complex or solvate thereof.
  • Nicotine may be selected from nicotine base, nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride such as nicotine zinc chloride monohydrate and nicotine salicylate.
  • the concentration of nicotine or the pharmaceutically acceptable salt, complex or solvate thereof in the particulate material is at the most about 20% w/w such as, e.g., at the most about 15% w/w, at the most about 12.5% w/w, at the most about 10% w/w, at the most about 9.5% w/w, at the most about 9% w/w, at the most about 8.5% w/w or at the most about 8% w/w, and the concentration being calculated as the nicotine base.
  • a particulate material according to the present invention has a concentration of nicotine or the pharmaceutically acceptable salt, complex or solvate thereof in the particulate material is at the most about 7.5% w/w such as, e.g., at the most about 7% w/w, at the most about 6.5 % w/w, at the most about 6% w/w, at the most about 5.5% w/w, at the most about 5% w/w, at the most about 4.5% w/w, at the most about 4% w/w, at the most about 3% w/w, at the most about 2% w/w or at the most about 1 % w/w, and the concentration being calculated as the nicotine base.
  • the present inventors have found that in order to obtain a relatively fast release the nicotine should typically be used in its base form. Moreover, the inventors have documented that if nicotine base is sorbed on MCC in concentrations of 0.1 - 8 % (w/w) then a rapid absorption of nicotine in vivo takes place. Moreover, pH at the absorption site may influence the absorption rate and the inventors have found that at a pH > 7 suitable results have been obtained with respect to a rapid absorption. It seems as the absorption is decreased when the pH is lowered.
  • embodiments of the present invention relate especially to particulate material that releases nicotine or a pharmaceutically acceptable salt, complex or solvate thereof in a manner that results in a maximum concentration after 10-30 min after administration.
  • a particulate material according to the present invention is a material, which - when administered to at least one healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml or more of nicotine within at the most about 30 min such as, e.g. within at the most about 25 min, within at the most about 20 min, within at the most about 15 min or within at the most about 10 after administration.
  • a particulate material according to the present invention is a material, which - when administered to at least one healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or o more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml nicotine within at the most about 15 min such as, e.g. within at the most about 10 min, within at the most about 7.5 min, within at the most about 5 min, within at the most about 4 min or within at the most about 3 min after administration.
  • the release of nicotine from a particulate material or from a composition containing the material may be varied.
  • the scope of the present invention is also the following embodiments:
  • a particulate material which - when administered to at least one healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof -
  • i) results in a plasma concentration of at least about 6 ng/ml nicotine within at the most about 10 min such as, e.g. within at the most about 9 min, at the most about 8 min, at the most about 7 min, at the most about 6 min, at the most about 5 min, at the most about 4 min or at the most about 3 min after administration (e.g. could apply for a relatively fast release composition),
  • ii) results in a plasma concentration of at least about 8 ng/ml nicotine such as, e.g., at least about 10 ng/ml, at least about 12.5 ng/ml, at least about 15 ng/ml or at least about 16 ng/ml within at the most 10 min after administration,
  • iiii) results in a plasma concentration of at least about 10 ng/ml nicotine within at the most about 30 min such as, e.g. within at the most about 25 min, within at the most about 20 min, within at the most about 15 min or within at the most about 10 after administration (e.g. could apply for a more extended release composition),
  • iv) results in a plasma concentration of at least about 10 ng/ml nicotine within at the most about 15 min such as, e.g. within at the most about 10 min, within at the most about 7.5 min, within at the most about 5 min, within at the most about 4 min or within at the most about 3 min after administration (e.g. could apply for a medium-fast release composition),
  • v) results in a plasma concentration of at least about 4 ng/ml nicotine such as, e.g., at least about 5 ng/ml, or at least about 6 ng/ml after administration, and/or vi) results in a plasma concentration of at least about 7.5 ng/ml or at least about 10 ng/ml after administration.
  • a particulate material according to the invention when administered to a healty subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine - results in a plasma concentration of at least about 4 ng nicotine such as, e.g., at least about 5 ng, at least about 7.5 ng or at least about 10 ng within at the most 10 min after administration, or for the material that is designed to release nicotine in a faster manner - results in a plasma concentration of at least about 8 ng nicotine such as, e.g., at least about 10 ng, at least about 12.5 ng, at least about 15 ng or at least about 16 ng within at the most 10 min after administration.
  • the different release may be obtained in different ways.
  • coating of the particulate material may be employed in order to obtain a coated particulate material from which the nicotine is released in a slower or delayed manner in order to achieve a prolonged action.
  • a combination of uncoated and coated particulate material may be employed in order to adjust the release profile to a desired release pattern (e.g. not a very fast and not a very slow release) etc.
  • the particulate material can be incorporated into compositions such as, e.g., pharmaceutical compositions and dependent on the specific formulation and formulation technology applied different release patterns can be obtained.
  • the present invention provides a particulate material that can be formulated to provide fast, medium and slow release of a nicotine, and combinations of such releases.
  • a particulate material or a composition of the invention may be coated so as to delay the release of nicotine or the pharmaceutically acceptable salt, complex or solvate thereof from that part of the material.
  • Suitable coating materials are e.g. film forming polymers such as, e.g., carbomer, carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, polymethacrylates, polyvinyl alcohol, povidone, shellac, a fatty substance e.g.
  • hard fat hydrogenated cottonseed oil, hydrogenated vegetable oil , a polyethylene glycol, a polyethylene oxide, a wax, a zein, a sugar or derivatives of sugar e.g. glucose, maltodextrin, polydextrose, sucrose, lactose, alginic acid, carrageenan, sugar alcohols or derivatives of sugar alcohols e.g. mannitol, maltitol, isomalt, xylitol, sorbitol etc.
  • a particulate material containing a nicotine salt and MCC obtained e.g. by using a nicotine salt solution on MCC
  • the dissolution profile has been found to be somewhat slower in vitro.
  • the dissolution profiles of nicotine tartrate from a nicotine/MCC particulate material is typically 90 % of loaded nicotine released after 5 - 10 minutes in 1 litre phosphate buffer, pH 7.4 maintained at 37° C in a dissolution apparatus according to USP, paddle.
  • the absorption rate is controlled primarily by the release rate from the carrier and pH (amount uncharged nicotine) at the absorptive site.
  • pH amount uncharged nicotine
  • one or more buffer substances may be incorporated into the particulate material or composition of the present invention.
  • the buffer substance may at least partially be sorbed by the MCC. Suitable buffer substances for use in the present context are e.g.
  • alkaline or alkaline earth metal salts such as, e.g., sodium hydroxide, potassium hydroxide, magnesium hydroxyde, carbonates including monocarbonate, bicarbonate and sesquicarbonate such as, e.g, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, magnesium carbonate, calcium carbonate etc., glycinate, phosphate including monohydrogenphosphate, dihydrogenphosphate and trihydrogenphosphate, glycerophosphate, gluconate, borate, ammonium, and mixtures thereof salts of organic or inorganic acids such as, e.g., acetates, citrates, tartrates etc.,
  • the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof for use in a particulate material or composition according to the invention is selected from nicotine base, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride and nicotine salicylate.
  • a particulate material or compositon according to the invention may comprise nicotine and one or more pharmaceutically acceptable salts, complexes or solvates thereof.
  • a particulate material or a composition according to the invention comprises nicotine and at least one of nicotine tartrate or nicotine bitartrate.
  • the invention relates to a composition such as, e.g. a pharmaceutical composition
  • a composition such as, e.g. a pharmaceutical composition
  • a particulate material according to the invention optionally together with one or more pharmaceutically acceptable excipients.
  • the details and particulars described above with respect to the particulate material applies, whenever relevant, also for a composition of the invention.
  • the nicotine-containing compositions may be administered to the subject including a human any convenient administration route such as, e.g., oral including the buccal route, nasal, ocular, pulmonary, topical or transdermal route in a dose that is effective for the individual purposes.
  • oral including the buccal route, nasal, ocular, pulmonary, topical or transdermal route in a dose that is effective for the individual purposes.
  • a person skilled in the art will know how to chose a suitable administration route.
  • the effective dosage of nicotine may vary depending on the particular nicotine (salt, base etc.) employed, the mode of administration, the condition being treated, the age and condition of the animal to be treated and the severity of the condition being treated. A person skilled in the art can easily ascertain suitable dosages.
  • concentration of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof in the composition is from about 0.5 to about 6 mg calculated as nicotine base.
  • a pharmaceutical composition according to the invention may be in the form of a solid, semi-solid or fluid dosage form such as, e.g., powders, granules, granulates, dispersions or it may be in the form of a oral suspension, soluble tablet, oral gel, oral powder, granules, cachet, capsule, tablet, controlled release tablet, oral lyophilisate, orodispersible tablet, chewable tablet, oral gum, oromucosal suspension, oromucosal spray, sublingual spray, oromucosal gel, oromucosal paste, medicated chewing gum, gingival gel, gingival paste, gingival patch, oromucosal capsule, sublingual tablet, muco-adhesive buccal tablet, buccal tablet, buccal patch, buccal wafer, lozenge, gel, cutaneous paste, ointment, cutaneous spray, transdermal patch, cutaneous stick, impregnated dressing.
  • compositions may be prepared by any of the method well known to a person skilled in pharmaceutical formulation.
  • the particulate material is normally combined with a pharmaceutical excipient, i.e. a therapeutically inert substance or carrier.
  • the carrier may take a wide variety of forms depending on the desired dosage form and administration route.
  • the pharmaceutically or cosmetically acceptable excipients may be e.g. fillers, binders, disintegrants, diluents, glidants, solvents, emulsifying agents, suspending agents, stabilizers, enhancers, flavours, colors, pH adjusting agents, retarding agents, wetting agents, surface active agents, preservatives etc. Details can be found in pharmaceutical handbooks such as, e.g., Remington's Pharmaceutical Science or Handbook of Pharmaceutical Excipients.
  • a pharmaceutical composition according to the invention may comprise an additive selected from the group consisting of pH-adjusting agents, stabilizing agents, preservatives, aroma-adjusting agents, flavor-adjusting agents, coloring agents, release-adjusting agents, complexing agents including EDTA. Furthermore, it may contain a buffer substance such as one mentioned herein before.
  • one or more bulk sweeteners may be incorporated in the compositon.
  • Suitable bulk sweeteners are selected from the group consisting of mono- , di-, tri- and polysaccharides, and natural and synthetic non-saccharide-based sweeteners.
  • the bulk sweetener is isomalt, xylitol or sorbitol, or combinations thereof.
  • a pharmaceutical composition according to the invention may comprise a further therapeutically and/or prophylactically active substance.
  • a pharmaceutical composition of the invention may also have a further amount of a nicotine incorporated in the composition.
  • a nicotine may be nicotine cation exchange resin complexes wherein the cation exchanger is selected from the group consisting of methacrylic type containing carboxylic functional groups or polystyrene type either with sulfonic functional groups or phosphonic functional groups.
  • the particulate material comprised in the composition comprises nicotine base and the futher amount of a nicotine that is incorporated into the composition is selected from the group consisting of nicotine tartrate and nicotine bitartrate.
  • a pharmaceutical composition according to the invention may also be coated in order to adjust or control the release of nicotine.
  • the coating materials mentioned herein before also applies to the composition.
  • a taste-masking coating may be employed.
  • the invention relates to the use of a particulate material according to the invention for the preparation of a pharmaceutical composition having a relatively fast onset of nicotine after administration.
  • the pharmaceutical composition may also be designed to release the nicotine in a more controlled or delayed manner.
  • many different release patterns can be obtained dependent on e.g. use of a combination of coated and uncoated particulate material, use of a combination of two or more diffemt nicotines (e.g. free base and salt), use of specific formulation technologies to achieve e.g. a controlled release composition etc. and combinations of these different ways.
  • specific embodiments of the invention defined with respect to the release of nicotine of, alternative, with respect to the plasma concentration obtained after administration to a subject.
  • the invention relates to a pharmaceutical composition, wherein
  • At least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min after oral administration (e.g. fast, medium fast release),
  • At least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min determined in an in vitro dissolution test according to Ph.Eur (e.g. fast, medium fast release),
  • w/w such as, e.g., at the most about 55% w/w, at the most about 50% w/w, at the most about 45%, at the most about 40%, at the most about 35% w/w or at the most about 30% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min after oral administration (e.g.
  • medium slow, slow release iv) at at the most about 60% w/w such as, e.g., at the most about 55% w/w, at the most about 50% w/w, at the most about 45%, at the most about 40%, at the most about 35% w/w or at the most about 30% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min determined in an in vitro dissolution test according to Ph.Eur (e.g. medium slow, slow release),
  • the invention relates to a pharmaceutical composition, which - when administered to at least one healthy subject in an amount corresponding to 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof
  • i) results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml or more of nicotine within at the most about 30 min such as, e.g. within at the most about 25 min, within at the most about 20 min, within at the most about 15 min or within at the most about 10 after administration (e.g. relatively fast to medium fast release and fast to medium fast onset of action),
  • ii) results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml nicotine within at the most about 15 min such as, e.g. within at the most about 10 min, within at the most about 7.5 min, within at the most about 5 min, within at the most about 4 min or within at the most about 3 min after administration (e.g. relatively fast to medium fast release and fast to medium fast onset of action),
  • iii) results in a plasma concentration of at least about 6 ng/ml nicotine within at the most about 10 min such as, e.g. within at the most about 9 min, at the most about 8 min, at the most about 7 min, at the most about 6 min, at the most about 5 min, at the most about 4 min or at the most about 3 min after administration (e.g. fast release, fast onset of action),
  • iv) results in a plasma concentration of at least about 8 ng/ml nicotine such as, e.g., at least about 10 ng/ml, at least about 12.5 ng/ml, at least about 15 ng/ml or at least about 16 ng/ml within at the most 10 min after administration (e.g. relatively fast release and fast onset of action).
  • v) results in a plasma concentration of at least about 4 ng/ml nicotine such as, e.g., at least about 5 ng/ml, or at least about 6 ng/ml after administration, and/or
  • the release of nicotine can be adjusted to a desired situation.
  • the composition may be designed to release nicotine relatively fast to obtain an enhanced onset of action or it may be designed to release nicotine in an extended manner to obtain a prolonged effect.
  • it may be designed to release at least a part of the nicotine contained in the composition in a fast manner to obtain an enhanced onset of action and the remaining part of the nicotine in an extended manner to obtain a prolonged action.
  • the plasma concentration of nicotine after oral administration shows a mono-, bi- or multiphasic curve.
  • a composition is in the form of a chewing gum.
  • the gum bases may be of any conventional nature known in the art such as, e.g., a gum base of natural or synthetic origin available from a commercial source.
  • Natural gum bases include e.g. chicle, jelutong gum, lechi de caspi gum, soh gum, siak gum, katiau gum, sorwa gum, balata gum, pendare gum, malaya gum and peach gum, natural cauchouc and natural resins such as dammar and mastix.
  • Synthetic gum bases include elastomers (polymers, masticating substances). Normally, additives like plasticizers, fillers (e.g. texturizers), softeners (e.g. fats or waxes), sweeteners, mouth-feel improving agents and/or emulsifiers are added.
  • plasticizers e.g. texturizers
  • softeners e.g. fats or waxes
  • sweeteners e.g. fats or waxes
  • mouth-feel improving agents and/or emulsifiers are added.
  • the invention relates to a method for treating a nicotine-related disorder of a subject, the method comprising administering a sufficient amount of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof in a particulate material or in a pharmaceutical composition according to the invention to the subject in need thereof.
  • the nicotine-related disorder mentioned above may be tobacco dependence, Parkinsons disease, ulcerative colitis, Alzheimers disease, schizophrenia, ADHD (Attention Deficit Hyperactivity Disorder), Tourette's syndrome, ulcerous colitis and post-smoking-cessation weight control.
  • Fig. 1 shows the plasma concentration versus time profile of nicotine from commercially available products
  • Fig. 2 shows the plasma concentration versus time profile of nicotine from compositions according to the invention compared with commercially available products.
  • Nicotine base is dissolved in ethanol to a concentration of 0.1 - 8 % (w/w) calculated on the dried adduct, and added on MCC in a high shear mixer equipped with vacuum drying or equivalent equipment. After a mixing/distribution step the powder is dried and the nicotine concentration determined by HPLC. The in vitro release is determined using a standard dissolution apparatus described in USP (paddle) and HPLC. Salts of nicotine e.g. nicotine tartrate, is dissolved in a water/ethanol mixture and processed as described above.
  • the drying process is of importance since a too effective drying; high vacuum and/or temperature will negatively influence the stability and content of the added nicotine.
  • the dried nicotine/MCC particulate material is stable for up to 14 weeks stored openly at 40°C and 50 % relative humidity (RH) and for over 14 weeks stored openly at 20°C and 55 % RH.
  • Stability has been determined for nicotine/MCC particulate materials with a nicotine concentration of 1 % (w/w).
  • the dried powder has been stored openly in a thin layer at 20 °C/55% RH and 40 °C/50% RH.
  • Table 1 Stability of nicotine/MCC particulate materials, 1% nicotine (w/w) stored openly, i.e. distributed in thin layer in a petri dish, at 20 °C/55% RH and 40 °C/50% RH
  • the load ratio has been determined for nicotine/MCC particulate materials with a starting nicotine concentration of approx. 12% (w/w).
  • the dried powder has been stored openly in a thin layer at 20 °C 55% RH and 40 °C/50% RH.
  • the release in vitro can be varied depending on origin of nicotine, i.e. base and salt form.
  • the release is rapid for all tested combinations and generally more so when the base is used.
  • With the use of coating on the dried nicotine/MCC particulate material more prolonged release profiles could be achieved.
  • a slight retardation in the release profile was achieved with the use of approx. 50 % (w/w) polyethylene glycole (PEG) 8000.
  • a more retarded release profile was achieved by the use of approx. 50 % (w/w) hydrogenated cottonseed oil (Akofine E).
  • the dried adduct was coated with 50 % (w/w) PEG 8000.
  • the dried adduct was coated with 50% (w/w) hydrogenated cottonseed oil (Akofine E). 3
  • the dried adduct was coated with 60% (w/w) hard fat (mixture of Witepsol E-76 and E-85 in a 1 :1 ratio).
  • the production process is a conventional process utilising standard equipment for pharmaceutical manufacturing. Nicotine is incorporated in MCC. Nicotine base is pre- added to the granulation liquid, ethanol, 99.5 % and added to MCC in a vacuum high shear mixer i.e. Zanchetta Rotolab, or equivalent. The wet mass is dried under vacuum in the mixer. Drying on trays could be an alternative.
  • the gum powder is passed through a 1 mm sieve to ensure that no lumps remain from the transportation.
  • the gum powder and the nicotine-incorporated MCC is mixed with all other excipients except magnesium stearate in an ordinary mixer, double cone mixer or equivalent.
  • magnesium stearate is admixed.
  • DC chewing gums of 1.25 g are compressed in an ordinary rotary tablet press equipped with diameter 17 mm concave punches.
  • the compressed gum cores can be coated in an ordinary rotating coating pan with the coating solution described above to an target end weight of 1 600 mg.
  • the final polishing is done with carnauba wax.

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Abstract

A nicotine-containing particulate material for release of nicotine, the material comprising a combination of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof and a microcrystalline cellulose, The particulate material is stable upon storage and releases nicotine relatively fast. The particulate material can be used in the manufacture of nicotine-containing pharmaceutical composition, wherein the release of nicotine can be designed to be relatively fast so as to obtain a fast onset of action.

Description

A PHYSICALLY AND CHEMICALLY STABLE NICOTINE-CONTAINING PARTICULATE MATERIAL
Field of the invention
The present invention relates to a nicotine-containing particulate material comprising a microcrystalline cellulose into which nicotine or a pharmaceutically acceptable salt, complex or solvent thereof has been incorporated. The invention also relates to pharmaceutical compositions and for method for treating or preventing tobacco dependence, Parkinsons disease, ulcerative colitis, Alzheimers disease, schizophrenia and/or ADHD.
Background of the invention
The treatment with nicotine-containing products today produces either too small quantities of nicotine in plasma and/ or plasma profiles with a too flat and/or slow peak. The desired plasma profile is one that has a faster uptake of nicotine than other marketed treatment products. To solve this problem nicotine in its base form is preferred. Nicotine in its base form is readily absorbed through the oral mucosa but is highly volatile and subject to oxidative degradation. The available nicotine salts are more stable compounds but are not as readily absorbed as the free base. In order to deal with the volatility and stability problems of the free base different techniques are possible.
In US 5,939,100 nicotine in its base form is incorporated in degradable starch microspheres. The use of degradable starch microspheres with incorporated nicotine gives a 3-dimensional matrix releasing the nicotine in a rather sustained fashion depending on both binding properties, nicotine - starch matrix and the biological degradation profile of the microspheres.
In WO 91/09599 an inclusion complex is produced between nicotine and β-cyclodextrin. The release of nicotine from the produced complex was filled in a porous bag of synthetic material (type tea bag) and the plasma profile was measured with a peak nicotine concentration (8 ng/ml) after approx. 45 min. in humans. The release is highly dependent on the affinity of nicotine to β-cyclodextrin and considered rather slow.
In US 4,967,773 synthetic silica is used together with nicotine. The rational for this is to ensure the stability in a lozenge where nicotine together with silica could be mixed with lactose. The manipulation is done due to the formulation of a product where incompatible constituents (nicotine and lactose) are desired.
In US 4,907,605 nicotine is absorbed in different water insoluble materials, e.g. paper, cellulose acetate, polyethylene or polypropylene. The sorbed nicotine is to be released slowly in an oral environment.
In US 6,264,981 solid solutions of different active principals with a dissolution agent are presented. Nicotine is mentioned as an active principal together with a list of other substances.
None of the above-mentioned documents has addressed the need for a truly rapid release and absorption of nicotine through the oral mucosa in combination with high physical and chemical stability. The need for a solid carrier is evident but the combination of sorbing nicotine in a solid matrix is not just a stability concern but equally, if not more important, are the release properties from the carrier.
Description of the invention
The object of the present invention is to provide a physically and chemically stable nicotine-containing particulate material that can be designed to release nicotine relatively fast from the material in order to enable a rapid absorption after administration.
The inventors have surprisingly found that sorption of nicotine (e.g. in the form of a solution containing nicotine as a base) on a microcrystalline cellulose (MCC) results in physical and chemical stable dry particulate material with a very fast and complete release in vitro. The dissolution profiles of nicotine base from such a particulate material may typically be that about 90 % of loaded nicotine released after 1 minute in 1 litre phosphate buffer, pH 7.4 maintained at 37° C in a dissolution apparatus according to USP, paddle.
Thus, in one aspect the invention relates to a nicotine-containing particulate material for release of nicotine, the material comprising a combination of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof and a microcrystalline cellulose, the particulate material - when tested in an in vitro dissolution test - releasing at least 90% w/w such as, e.g. at least 95 % w/w of the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof within at the most about 30 min such as, e.g., at the most about 25 min, at the most about 20 min, at the most about 15 min, at the most about 10 min, at the most about 7.5 min, at the most about 5 min, at the most about 4 min, at the most about 3 min or at the most about 2 min.
More specifically, the invention relates to a particulate material for fast release of nicotine, the material - when tested in an in vitro dissolution test - releasing at least 90% w/w such as, e.g. at least 95 % w/w of the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof within at the most about 20 min such as, e.g, at the most about 15 min, at the most about 10 min, at the most about 7.5 min, at the most about 5 min, at the most about 4 min, at the most about 3 min, at the most about 2 min or at the most about 1 min.
The problem that goes parallel with tobacco smoking is its enormous implications on health. Today it is estimated that smoking related diseases cause some 3 - 4 million deaths annually. This grim consequence of tobacco smoking has lead many medical associations and health authorities to take very strong actions against the use of tobacco. More recently the World Health Organisation (WHO) has made the control of tobacco to a priority on par with the control of malaria.
Tobacco smoking can result in a dependence disorder. The WHO has in its International Classification of Disorders a diagnosis Tobacco Dependence. Others like the American Psychiatric Association labels the addiction Nicotine Dependence.
Nicotine is the world's second most used drug, after caffeine from coffee and tea. Even though tobacco smoking is decreasing in many developed countries today it is hard to see how the societies could get rid of the world's second most used drug. Societies are not even successful in protecting themselves against illegal drugs that have more profound psychotoxic effects. It is therefore most likely that when tobacco smoking will become more or less socially and legally outlawed there will be a need for discovering other forms of taking nicotine. Nicotine containing medications are currently the dominating treatments for tobacco dependence. There is also evidence of broader use of these medications like for smoking reduction and long term maintenance / substitution. However the products are not very acceptable to many smokers. Among other things they are too far from the cigarette in some major characteristics.
When smoke from a cigarette is inhaled, the nicotine reaches its targets in the brain in about 10 seconds. Most cigarettes normally contain 10 - 15 mg of nicotine. Most of that nicotine is not used by the smoker since a lot of the smoke is not inhaled and moreover a good amount of these 10 - 15 mg are left in the but. When the cigarette smokes itself and is forgotten in an ashtray then less nicotine is absorbed than when a smoker hungrily smokes a cigarette e.g. after a long meeting. On average something between 0.5 - 2 mg / cigarette is absorbed. The absorption is almost 100 % of what is coming into the lower airways and the speed is very high.
The most widely used smoking cessation product, nicotine gum is marketed in two strengths, 2 and 4 mg, which is the actual content of nicotine. However the biological available dose from these gums are only about 1 and 2 mg, respectively. This is because it is difficult to completely empty the gum and some of the nicotine that is extracted from the gum cannot be absorbed into the circulatory system due to swallowing into the gastrointestinal tract where most of the nicotine is metabolised before entering the circulation. Moreover the speed by which the nicotine is absorbed is much slower than from the cigarette. This is an important factor since when individuals want to change their state of mind with psychoactive drugs the effects are strongly dependent on the speed by which the drug enters the brain.
Nicotine patches delivers from 15 - 21 mg nicotine (different brands have different doses). Most of the nicotine that is delivered through the skin is absorbed. For a smoker consuming 15 - 20 cigarettes a day one can assume a nicotine intake per day of 15 - 25 mg. If the smoking takes place during roughly a 16 hours waking period that means one to one and a half mg per hour. The nicotine patch gives close to one mg per hour. However one has to keep in mind that some smokers take in much more nicotine and that the pharmacokinetic profile of nicotine from a patch is relatively stable and does not allow for any discrete variations. With smoking there are peaks in nicotine concentration corresponding with each cigarette that may also be necessary for the experience of certain of the nicotine's effects. There are other products on the market today like Inhalers, a Sublingual tablet, a Lozenge and a Nasal spray. They all relatively well fall within the category of nicotine absorption that one can see from 2 and 4 mg gum, see fig 1 for a comparison with a cigarette. Many smokers, particularly those that ideally would like to continue with their smoking want nicotine stimulation that they easily can get from a cigarette but not at all from a nicotine patch. It is difficult but not entirely impossible to get nicotine stimulation from the other more acute delivery systems.
The dose and speed of absorption for producing a subjective effect (nicotine stimulation) may vary from individual to individual but it seems to be a rule that an increase in concentration of 5-10 ng/ml over 10 minutes is a requirement. The increase in concentration is time related so probably an increase of 3-5 ng/ml over 5 minutes is as good. This requirement to get a psychoactive effect is probably one of the most important characteristics in developing products that will be well accepted by consumers so they can rid themselves of the very high risk associated with cigarette smoking.
As mentioned above, a particulate material according to the present invention is chemically and physically stable. In the present context the term "stable" means that the material and/or the nicotine or the pharmaceutically acceptable salt, complex or solvate contained therein is chemically and/or physically stable for at least about 22 weeks such as, e.g., at least 14 weeks when stored open at a temperature of 40 °C and a relative humidity of 50%. It is especially of importance that nicotine or a pharmaceutically acceptable salt, complex or solvate thereof does not migrate out of the material as such a migration will lead to a marked loss in the content of nicotine in the material. Furthermore, as mentioned above, nicotine as a base is a volatile substance and, therefore, it is normally difficult to maintain a relatively constant concentration of the nicotine base in a composition comprising a mere admixture of nicotine and a pharmaceutically acceptable excipient. A particulate material according to the present invention is also physically stable. Thus, within a time period of 22 weeks or more no visible changes had been observed and the dissolution profile did not change.
It is contemplated that the microcrystalline cellulose is of utmost importance for the success of a particulate material according to the present invention.
However, other pharmaceutically acceptable excipients having the same behavior towards nicotine may of course also be of importance for the invention. Suitable microcrystalline celluloses are highly crystalline particulate cellulose containing crystallite aggregates obtained by removing amorphous (fibrous cellulose) regions of a purified cellulose source material by hydrolytic degradation, typically with a strong mineral acid such as hydrogen chloride. The acid hydrolysis process produces a microcrystalline cellulose of predominantly coarse particulate aggregate, typically having a mean size range of about 15 to 250 μm.
The microcrystalline cellulose (MCC) has a suitable porosity and/or bulk density, especially it has a very large surface area due to the porous structure of MCC. It is believed that nicotine after being contacted with MCC mainly is located in the porous structure of MCC, i.e. nicotine is sorbed to MCC most likely by adsorption. Accordingly, in an embodiment of the present invention at least part of the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof is adsorbed to the microcrystalline cellulose in the particulate material.
MCM qualities suitable for the purpose of the present invention include but are not limited to any of commercial pharmaceutically accepted qualities of e.g. Avicel® such as, e.g., the grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, Vivacel® such as, e.g., grades 101 , 102, 12 or 20, Emcocel® such as, e.g., the grades 50M or 90M.
Other crystalline celluloses are also contemplated to be suitable for use according to the invention. Without being bound to any theory, it is contemplated that due to its size and amphiphilic character, nicotine is entrapped and/or weekly bonded inside the void volume of the cellulose cells by means of hydrogen bonding or by Van deer Waals attraction.
To obtain a particulate material according to the present invention, the nicotine is dissolved in a hydrophilic solvent, i.e. water or alcohol or mixtures thereof, and, according to the above-mentioned theory it is contemplated that by means of capillary forces the nicotine is introduced into the voids of the crystalline cellulose. After the removal of the solvent nicotine is retained inside said voids until a suitable solvent again enters the voids and releases the nicotine into said solvent.
In the present context the term "nicotine" encompasses nicotine or a nicotine derivative in any form such as, e.g., physical form like amorphous, crystalline, polymorphous etc. or chemical form like isomers and enantiomers etc as well as any pharmaceutically acceptable salt, complex or solvate thereof. Nicotine may be selected from nicotine base, nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride such as nicotine zinc chloride monohydrate and nicotine salicylate.
In a particulate material according to the present invention the concentration of nicotine or the pharmaceutically acceptable salt, complex or solvate thereof in the particulate material is at the most about 20% w/w such as, e.g., at the most about 15% w/w, at the most about 12.5% w/w, at the most about 10% w/w, at the most about 9.5% w/w, at the most about 9% w/w, at the most about 8.5% w/w or at the most about 8% w/w, and the concentration being calculated as the nicotine base. In a specific embodiment, a particulate material according to the present invention has a concentration of nicotine or the pharmaceutically acceptable salt, complex or solvate thereof in the particulate material is at the most about 7.5% w/w such as, e.g., at the most about 7% w/w, at the most about 6.5 % w/w, at the most about 6% w/w, at the most about 5.5% w/w, at the most about 5% w/w, at the most about 4.5% w/w, at the most about 4% w/w, at the most about 3% w/w, at the most about 2% w/w or at the most about 1 % w/w, and the concentration being calculated as the nicotine base.
To this end, the present inventors have found that in order to obtain a relatively fast release the nicotine should typically be used in its base form. Moreover, the inventors have documented that if nicotine base is sorbed on MCC in concentrations of 0.1 - 8 % (w/w) then a rapid absorption of nicotine in vivo takes place. Moreover, pH at the absorption site may influence the absorption rate and the inventors have found that at a pH > 7 suitable results have been obtained with respect to a rapid absorption. It seems as the absorption is decreased when the pH is lowered. However, such a decreased absorption rate may also be of therapeutic relevance and embodiments of the present invention relate especially to particulate material that releases nicotine or a pharmaceutically acceptable salt, complex or solvate thereof in a manner that results in a maximum concentration after 10-30 min after administration.
In order to obtain a suitable effect, a particulate material according to the present invention is a material, which - when administered to at least one healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml or more of nicotine within at the most about 30 min such as, e.g. within at the most about 25 min, within at the most about 20 min, within at the most about 15 min or within at the most about 10 after administration.
In certain cases a very fast onset of action is desired and the nicotine contained in a particulate material or a composition according to the invention must be released relatively fast. In such specific embodiments a particulate material according to the present invention is a material, which - when administered to at least one healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or o more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml nicotine within at the most about 15 min such as, e.g. within at the most about 10 min, within at the most about 7.5 min, within at the most about 5 min, within at the most about 4 min or within at the most about 3 min after administration.
Dependent on the desired effect, the release of nicotine from a particulate material or from a composition containing the material may be varied. Thus, within the scope of the present invention is also the following embodiments:
A particulate material, which - when administered to at least one healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof -
i) results in a plasma concentration of at least about 6 ng/ml nicotine within at the most about 10 min such as, e.g. within at the most about 9 min, at the most about 8 min, at the most about 7 min, at the most about 6 min, at the most about 5 min, at the most about 4 min or at the most about 3 min after administration (e.g. could apply for a relatively fast release composition),
ii) results in a plasma concentration of at least about 8 ng/ml nicotine such as, e.g., at least about 10 ng/ml, at least about 12.5 ng/ml, at least about 15 ng/ml or at least about 16 ng/ml within at the most 10 min after administration,
iiii) results in a plasma concentration of at least about 10 ng/ml nicotine within at the most about 30 min such as, e.g. within at the most about 25 min, within at the most about 20 min, within at the most about 15 min or within at the most about 10 after administration (e.g. could apply for a more extended release composition),
iv) results in a plasma concentration of at least about 10 ng/ml nicotine within at the most about 15 min such as, e.g. within at the most about 10 min, within at the most about 7.5 min, within at the most about 5 min, within at the most about 4 min or within at the most about 3 min after administration (e.g. could apply for a medium-fast release composition),
v) results in a plasma concentration of at least about 4 ng/ml nicotine such as, e.g., at least about 5 ng/ml, or at least about 6 ng/ml after administration, and/or vi) results in a plasma concentration of at least about 7.5 ng/ml or at least about 10 ng/ml after administration.
Alternatively or complementary, a particulate material according to the invention - when administered to a healty subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine - results in a plasma concentration of at least about 4 ng nicotine such as, e.g., at least about 5 ng, at least about 7.5 ng or at least about 10 ng within at the most 10 min after administration, or for the material that is designed to release nicotine in a faster manner - results in a plasma concentration of at least about 8 ng nicotine such as, e.g., at least about 10 ng, at least about 12.5 ng, at least about 15 ng or at least about 16 ng within at the most 10 min after administration.
The different release may be obtained in different ways. Thus, e.g. coating of the particulate material may be employed in order to obtain a coated particulate material from which the nicotine is released in a slower or delayed manner in order to achieve a prolonged action. A combination of uncoated and coated particulate material may be employed in order to adjust the release profile to a desired release pattern (e.g. not a very fast and not a very slow release) etc. Furthermore, the particulate material can be incorporated into compositions such as, e.g., pharmaceutical compositions and dependent on the specific formulation and formulation technology applied different release patterns can be obtained. In other words, the present invention provides a particulate material that can be formulated to provide fast, medium and slow release of a nicotine, and combinations of such releases.
In accordance with the above, a particulate material or a composition of the invention may be coated so as to delay the release of nicotine or the pharmaceutically acceptable salt, complex or solvate thereof from that part of the material. Suitable coating materials are e.g. film forming polymers such as, e.g., carbomer, carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, polymethacrylates, polyvinyl alcohol, povidone, shellac, a fatty substance e.g. hard fat, hydrogenated cottonseed oil, hydrogenated vegetable oil , a polyethylene glycol, a polyethylene oxide, a wax, a zein, a sugar or derivatives of sugar e.g. glucose, maltodextrin, polydextrose, sucrose, lactose, alginic acid, carrageenan, sugar alcohols or derivatives of sugar alcohols e.g. mannitol, maltitol, isomalt, xylitol, sorbitol etc. With respect to a particulate material containing a nicotine salt and MCC (obtained e.g. by using a nicotine salt solution on MCC), the dissolution profile has been found to be somewhat slower in vitro. Thus, the dissolution profiles of nicotine tartrate from a nicotine/MCC particulate material is typically 90 % of loaded nicotine released after 5 - 10 minutes in 1 litre phosphate buffer, pH 7.4 maintained at 37° C in a dissolution apparatus according to USP, paddle.
The absorption rate is controlled primarily by the release rate from the carrier and pH (amount uncharged nicotine) at the absorptive site. In order to adjust pH at the absorption site, one or more buffer substances may be incorporated into the particulate material or composition of the present invention. The buffer substance may at least partially be sorbed by the MCC. Suitable buffer substances for use in the present context are e.g. alkaline or alkaline earth metal salts such as, e.g., sodium hydroxide, potassium hydroxide, magnesium hydroxyde, carbonates including monocarbonate, bicarbonate and sesquicarbonate such as, e.g, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, magnesium carbonate, calcium carbonate etc., glycinate, phosphate including monohydrogenphosphate, dihydrogenphosphate and trihydrogenphosphate, glycerophosphate, gluconate, borate, ammonium, and mixtures thereof salts of organic or inorganic acids such as, e.g., acetates, citrates, tartrates etc.,
In one embodiment, the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof for use in a particulate material or composition according to the invention is selected from nicotine base, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride and nicotine salicylate.
To achieve slower release different salts of nicotine is used. Also combinations of the nicotine in its base form and salts can be used to achieve the desired release.
Accordingly, a particulate material or compositon according to the invention may comprise nicotine and one or more pharmaceutically acceptable salts, complexes or solvates thereof. In a specific embodiment a particulate material or a composition according to the invention comprises nicotine and at least one of nicotine tartrate or nicotine bitartrate.
In another aspect, the invention relates to a composition such as, e.g. a pharmaceutical composition comprising a particulate material according to the invention, optionally together with one or more pharmaceutically acceptable excipients. The details and particulars described above with respect to the particulate material applies, whenever relevant, also for a composition of the invention.
The nicotine-containing compositions may be administered to the subject including a human any convenient administration route such as, e.g., oral including the buccal route, nasal, ocular, pulmonary, topical or transdermal route in a dose that is effective for the individual purposes. A person skilled in the art will know how to chose a suitable administration route.
The effective dosage of nicotine may vary depending on the particular nicotine (salt, base etc.) employed, the mode of administration, the condition being treated, the age and condition of the animal to be treated and the severity of the condition being treated. A person skilled in the art can easily ascertain suitable dosages. Normally, in a pharmaceutical composition according to the invention the concentration of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof in the composition is from about 0.5 to about 6 mg calculated as nicotine base.
A pharmaceutical composition according to the invention may be in the form of a solid, semi-solid or fluid dosage form such as, e.g., powders, granules, granulates, dispersions or it may be in the form of a oral suspension, soluble tablet, oral gel, oral powder, granules, cachet, capsule, tablet, controlled release tablet, oral lyophilisate, orodispersible tablet, chewable tablet, oral gum, oromucosal suspension, oromucosal spray, sublingual spray, oromucosal gel, oromucosal paste, medicated chewing gum, gingival gel, gingival paste, gingival patch, oromucosal capsule, sublingual tablet, muco-adhesive buccal tablet, buccal tablet, buccal patch, buccal wafer, lozenge, gel, cutaneous paste, ointment, cutaneous spray, transdermal patch, cutaneous stick, impregnated dressing.
The pharmaceutical compositions may be prepared by any of the method well known to a person skilled in pharmaceutical formulation.
In pharmaceutical compositions, the particulate material is normally combined with a pharmaceutical excipient, i.e. a therapeutically inert substance or carrier.
The carrier may take a wide variety of forms depending on the desired dosage form and administration route. The pharmaceutically or cosmetically acceptable excipients may be e.g. fillers, binders, disintegrants, diluents, glidants, solvents, emulsifying agents, suspending agents, stabilizers, enhancers, flavours, colors, pH adjusting agents, retarding agents, wetting agents, surface active agents, preservatives etc. Details can be found in pharmaceutical handbooks such as, e.g., Remington's Pharmaceutical Science or Handbook of Pharmaceutical Excipients.
To be more specific, a pharmaceutical composition according to the invention may comprise an additive selected from the group consisting of pH-adjusting agents, stabilizing agents, preservatives, aroma-adjusting agents, flavor-adjusting agents, coloring agents, release-adjusting agents, complexing agents including EDTA. Furthermore, it may contain a buffer substance such as one mentioned herein before.
In those cases where the composition is designed for oral administration including administration to the mouth cavity (e.g. in the form of solid or semi-solid composition such as, e.g., in the form of a chewing gum or lozenge including pastils, toffees, hard boilies and other candy-like compositions) one or more bulk sweeteners may be incorporated in the compositon. Suitable bulk sweeteners are selected from the group consisting of mono- , di-, tri- and polysaccharides, and natural and synthetic non-saccharide-based sweeteners. In specific embodiments, the bulk sweetener is isomalt, xylitol or sorbitol, or combinations thereof.
In other embodiments, a pharmaceutical composition according to the invention may comprise a further therapeutically and/or prophylactically active substance.
A pharmaceutical composition of the invention may also have a further amount of a nicotine incorporated in the composition. Besides the nicotine compounds mentioned above, it may be nicotine cation exchange resin complexes wherein the cation exchanger is selected from the group consisting of methacrylic type containing carboxylic functional groups or polystyrene type either with sulfonic functional groups or phosphonic functional groups.
In a specific embodiment, the particulate material comprised in the composition comprises nicotine base and the futher amount of a nicotine that is incorporated into the composition is selected from the group consisting of nicotine tartrate and nicotine bitartrate. A pharmaceutical composition according to the invention may also be coated in order to adjust or control the release of nicotine. The coating materials mentioned herein before also applies to the composition. Furthermore, a taste-masking coating may be employed.
In another aspect, the invention relates to the use of a particulate material according to the invention for the preparation of a pharmaceutical composition having a relatively fast onset of nicotine after administration. As mentioned above, the pharmaceutical composition may also be designed to release the nicotine in a more controlled or delayed manner. As described above concerning the particulate material according to the invention, many different release patterns can be obtained dependent on e.g. use of a combination of coated and uncoated particulate material, use of a combination of two or more diffemt nicotines (e.g. free base and salt), use of specific formulation technologies to achieve e.g. a controlled release composition etc. and combinations of these different ways. In the following is described specific embodiments of the invention defined with respect to the release of nicotine of, alternative, with respect to the plasma concentration obtained after administration to a subject.
Thus, in various embodiments the invention relates to a pharmaceutical composition, wherein
i) at least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min after oral administration (e.g. fast, medium fast release),
ii) at least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min determined in an in vitro dissolution test according to Ph.Eur (e.g. fast, medium fast release),
iii) at the most about 60% w/w such as, e.g., at the most about 55% w/w, at the most about 50% w/w, at the most about 45%, at the most about 40%, at the most about 35% w/w or at the most about 30% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min after oral administration (e.g. medium slow, slow release), iv) at at the most about 60% w/w such as, e.g., at the most about 55% w/w, at the most about 50% w/w, at the most about 45%, at the most about 40%, at the most about 35% w/w or at the most about 30% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min determined in an in vitro dissolution test according to Ph.Eur (e.g. medium slow, slow release),
With respect to the effect obtained after administration of a composition according to the invention a suitable plasma concentration of nicotine must be obtained within a suitable period of time. Accordingly, the invention relates to a pharmaceutical composition, which - when administered to at least one healthy subject in an amount corresponding to 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof
i) results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml or more of nicotine within at the most about 30 min such as, e.g. within at the most about 25 min, within at the most about 20 min, within at the most about 15 min or within at the most about 10 after administration (e.g. relatively fast to medium fast release and fast to medium fast onset of action),
ii) results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml nicotine within at the most about 15 min such as, e.g. within at the most about 10 min, within at the most about 7.5 min, within at the most about 5 min, within at the most about 4 min or within at the most about 3 min after administration (e.g. relatively fast to medium fast release and fast to medium fast onset of action),,
iii) results in a plasma concentration of at least about 6 ng/ml nicotine within at the most about 10 min such as, e.g. within at the most about 9 min, at the most about 8 min, at the most about 7 min, at the most about 6 min, at the most about 5 min, at the most about 4 min or at the most about 3 min after administration (e.g. fast release, fast onset of action),
iv) results in a plasma concentration of at least about 8 ng/ml nicotine such as, e.g., at least about 10 ng/ml, at least about 12.5 ng/ml, at least about 15 ng/ml or at least about 16 ng/ml within at the most 10 min after administration (e.g. relatively fast release and fast onset of action). v) results in a plasma concentration of at least about 4 ng/ml nicotine such as, e.g., at least about 5 ng/ml, or at least about 6 ng/ml after administration, and/or
vi) results in a plasma concentration of at least about 7.5 ng/ml or at least about 10 ng/ml after administration.
As it appears from the above, the release of nicotine can be adjusted to a desired situation. Thus, the composition may be designed to release nicotine relatively fast to obtain an enhanced onset of action or it may be designed to release nicotine in an extended manner to obtain a prolonged effect. Furthermore it may be designed to release at least a part of the nicotine contained in the composition in a fast manner to obtain an enhanced onset of action and the remaining part of the nicotine in an extended manner to obtain a prolonged action. In the latter case, the plasma concentration of nicotine after oral administration shows a mono-, bi- or multiphasic curve.
In a specific embodiment, a composition is in the form of a chewing gum.
Manufacturing of chewing gum as well as suitable excipients and additve for use in chewing gums are well-known to a person skilled in the art (see e.g. WO 03/084338 including references cited therein; these references are hereby included by reference). Accordingly, the gum bases may be of any conventional nature known in the art such as, e.g., a gum base of natural or synthetic origin available from a commercial source. Natural gum bases include e.g. chicle, jelutong gum, lechi de caspi gum, soh gum, siak gum, katiau gum, sorwa gum, balata gum, pendare gum, malaya gum and peach gum, natural cauchouc and natural resins such as dammar and mastix. Synthetic gum bases include elastomers (polymers, masticating substances). Normally, additives like plasticizers, fillers (e.g. texturizers), softeners (e.g. fats or waxes), sweeteners, mouth-feel improving agents and/or emulsifiers are added.
In a still further aspect, the invention relates to a method for treating a nicotine-related disorder of a subject, the method comprising administering a sufficient amount of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof in a particulate material or in a pharmaceutical composition according to the invention to the subject in need thereof.
More specifically, the nicotine-related disorder mentioned above may be tobacco dependence, Parkinsons disease, ulcerative colitis, Alzheimers disease, schizophrenia, ADHD (Attention Deficit Hyperactivity Disorder), Tourette's syndrome, ulcerous colitis and post-smoking-cessation weight control.
The details and description relating to the particulate material aspect apply mutatis mutandis to the other aspects of the invention.
The invention is further illustrated in the following non-limiting examples and in the figures, wherein
Fig. 1 shows the plasma concentration versus time profile of nicotine from commercially available products
Fig. 2 shows the plasma concentration versus time profile of nicotine from compositions according to the invention compared with commercially available products.
EXAMPLES
Loading nicotine on MCC
Nicotine base is dissolved in ethanol to a concentration of 0.1 - 8 % (w/w) calculated on the dried adduct, and added on MCC in a high shear mixer equipped with vacuum drying or equivalent equipment. After a mixing/distribution step the powder is dried and the nicotine concentration determined by HPLC. The in vitro release is determined using a standard dissolution apparatus described in USP (paddle) and HPLC. Salts of nicotine e.g. nicotine tartrate, is dissolved in a water/ethanol mixture and processed as described above.
The drying process is of importance since a too effective drying; high vacuum and/or temperature will negatively influence the stability and content of the added nicotine. The dried nicotine/MCC particulate material is stable for up to 14 weeks stored openly at 40°C and 50 % relative humidity (RH) and for over 14 weeks stored openly at 20°C and 55 % RH.
Stability
Stability has been determined for nicotine/MCC particulate materials with a nicotine concentration of 1 % (w/w). The dried powder has been stored openly in a thin layer at 20 °C/55% RH and 40 °C/50% RH. Table 1. Stability of nicotine/MCC particulate materials, 1% nicotine (w/w) stored openly, i.e. distributed in thin layer in a petri dish, at 20 °C/55% RH and 40 °C/50% RH
Figure imgf000018_0001
No discoloration of the product and no increase in non-nicotine peaks in the chromatograms where observed, indicating a stable product over the period investigated.
Load ratio
The load ratio has been determined for nicotine/MCC particulate materials with a starting nicotine concentration of approx. 12% (w/w). The dried powder has been stored openly in a thin layer at 20 °C 55% RH and 40 °C/50% RH.
Table 2. Load ratio of nicotine base/MCC particulate materials, initially loaded with approx. 12% nicotine (w/w) stored openly, i.e. distributed in thin layer in a petri dish, at 40 °C/50% RH
Figure imgf000018_0002
The results shows that a load ratio of approx. 8% (w/w) of nicotine base can be used with maintained good stability properties on the different MCC qualities. Above 8% (w/w) the MCC (in the employed qualities) seems to be over-saturated with nicotine. The first steep loss of nicotine is most probably due to a over-saturation of the pores' content of nicotine; the excess nicotine will most likely evaporate quickly from the particulate material.
In vitro release
The release in vitro can be varied depending on origin of nicotine, i.e. base and salt form. The release is rapid for all tested combinations and generally more so when the base is used. With the use of coating on the dried nicotine/MCC particulate material more prolonged release profiles could be achieved. A slight retardation in the release profile was achieved with the use of approx. 50 % (w/w) polyethylene glycole (PEG) 8000. A more retarded release profile was achieved by the use of approx. 50 % (w/w) hydrogenated cottonseed oil (Akofine E).
Table 3. In vitro release of nicotine/MCC particulate materials in 37 °C phosphate buffer, pH 7.4 in USP dissolution apparatus. Steady state concentration is used for calculations.
Figure imgf000019_0001
The dried adduct was coated with 50 % (w/w) PEG 8000. The dried adduct was coated with 50% (w/w) hydrogenated cottonseed oil (Akofine E). 3 The dried adduct was coated with 60% (w/w) hard fat (mixture of Witepsol E-76 and E-85 in a 1 :1 ratio).
In vivo plasma nicotine Nicotine/MCC particulate material, 4 - 5% (w/w) was incorporated in a chewing gum composition to final concentrations of 2 and 4 mg nicotine/gum. The gums were produced using direct compression and analysed for initial nicotine content. The gums were chewed by the same test person and blood samples were retrieved prior chewing and after 5, 10, 15 and 20 minutes. The blood samples were analysed for nicotine and cotinine. The human in vivo plasma profiles demonstrate that the desired profiles could be achieved with good margin with the use of the nicotine/MCC particulate material in one formulation type, chewing gum. Other products like tablets, lozenges, gels, suspensions, sprays, patches etc may also be used with proper formulation strategies. In Figure 2 is shown the results of the in vivo study.
The production process is a conventional process utilising standard equipment for pharmaceutical manufacturing. Nicotine is incorporated in MCC. Nicotine base is pre- added to the granulation liquid, ethanol, 99.5 % and added to MCC in a vacuum high shear mixer i.e. Zanchetta Rotolab, or equivalent. The wet mass is dried under vacuum in the mixer. Drying on trays could be an alternative.
The gum powder is passed through a 1 mm sieve to ensure that no lumps remain from the transportation. The gum powder and the nicotine-incorporated MCC is mixed with all other excipients except magnesium stearate in an ordinary mixer, double cone mixer or equivalent. In a second mixing step magnesium stearate is admixed. Thereafter DC chewing gums of 1.25 g are compressed in an ordinary rotary tablet press equipped with diameter 17 mm concave punches.
Composition of 2 mg chewing gum tablet core
Ingredient Quantity Function (mg/unit)
Nicotine base* 2.00 Active ingredient
Gum Powder 1000 Gum base
Isomalt, DC 100 134 Filling agent, sweetener
Microcrystalline cellulose, type PH-102 61.0 Nicotine carrier
Talc 37.5 Antiadherent
Magnesium stearate 12.5 Lubricant
Silica, colloidal anhydrous, Aerosil 200 2.00 Glidant
Acesulfame potassium 0.625 Sweetener
Ethanol 99.5 % (w/w)* — Granulation liquid
Target Weight 1 250 Composition of the coating solution
Ingredient Amount Function
(%)
Isomalt, GS 65.00 Coating sugar
Purified water 29.80 Solvent
Gum arabicum, 50 % 4.10 Binder
Titan dioxide 1.00 Coloring agent
Aspartame 0.05 Sweetener
Acesulfame potassium 0.05 Sweetener
Target Amount 100
The compressed gum cores can be coated in an ordinary rotating coating pan with the coating solution described above to an target end weight of 1 600 mg. The final polishing is done with carnauba wax.
Composition of 4 mg chewing gum tablet core
Ingredient Quantity Function (mg/unit)
Nicotine base* 4.00 Active ingredient
Gum Powder 1000 Gum base
Isomalt, DC 100 125 Filling agent, sweetener
Microcrystalline cellulose, type PH-102 70.0 Nicotine carrier
Talc 37.5 Antiadherent
Magnesium stearate 12.5 Lubricant
Silica, colloidal anhydrous, Aerosil 200 2.00 Glidant
Acesulfame potassium 0.625 Sweetener
Ethanol 99.5 % (w/w)* — Granulation liquid Target Weight 1 250

Claims

1. A nicotine-containing particulate material for release of nicotine, the material comprising a combination of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof and a microcrystalline cellulose, the particulate material - when tested in an in vitro dissolution test - releasing at least 90% w/w such as, e.g. at least 95 % w/w of the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof within at the most about 30 min such as, e.g., at the most about 25 min, at the most about 20 min, at the most about 15 min, at the most about 10 min, at the most about 7.5 min, at the most about 5 min, at the most about 4 min, at the most about 3 min or at the most about 2 min.
2. A particulate material according to claim 1 for fast release of nicotine, the material - when tested in an in vitro dissolution test - releasing at least 90% w/w such as, e.g. at least 95 % w/w of the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof within at the most about 20 min such as, e.g., at the most about 15 min, at the most about 10 min, at the most about 7.5 min, at the most about 5 min, at the most about 4 min, at the most about 3 min, at the most about 2 min or at the most about 1 min.
3. A particulate material according to claim 1 or 2, wherein the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof is chemically and/or physically stable for at least 22 weeks such as, e.g., at least 14 weeks, when stored open at a temperature of 40 °C and a relative humidity of 50%.
4. A particulate material according to any of claims 1-3, wherein the concentration of nicotine or the pharmaceutically acceptable salt, complex or solvate thereof in the particulate material is at the most about 20% w/w such as, e.g., at the most about 15% w/w, at the most about 12.5% w/w, at the most about 10% w/w, at the most about 9.5% w/w, at the most about 9% w/w, at the most about 8.5% w/w or at the most about 8% w/w, and the concentration being calculated as the nicotine base.
5. A particulate material according to any of the preceding claims, wherein the concentration of nicotine or the pharmaceutically acceptable salt, complex or solvate thereof in the particulate material is at the most about 7.5% w/w such as, e.g., at the most about 7% w/w, at the most about 6.5 % w/w, at the most about 6% w/w, at the most about 5.5% w/w, at the most about 5% w/w, at the most about 4.5% w/w, at the most about 4% w/w, or at the most about 3% w/w, and the concentration being calculated as the nicotine base.
6. A particulate material according to any of the preceding claims, wherein at least part of the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof is adsorbed to the microcrystalline cellulose.
7. A particulate material according to any of the preceding claims, which - when administered to at least one healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml or more of nicotine within at the most about 30 min such as, e.g. within at the most about 25 min, within at the most about 20 min, within at the most about 15 min or within at the most about 10 after administration.
8. A particulate material according to any of the preceding claims, which - when administered to at least one healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml nicotine within at the most about 15 min such as, e.g. within at the most about 10 min, within at the most about 7.5 min, within at the most about 5 min, within at the most about 4 min or within at the most about 3 min after administration.
9. A particulate material according to any of the preceding claims, which - when administered to at least one healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 6 ng/ml nicotine within at the most about 10 min such as, e.g. within at the most about 9 min, at the most about 8 min, at the most about 7 min, at the most about 6 min, at the most about 5 min, at the most about 4 min or at the most about 3 min after administration.
10. A particulate material according to any of claims 1-7, which - when administered to a healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 4 ng/ml nicotine such as, e.g., at least about 5 ng/ml, or at least about 6 ng/ml after administration.
11. A particulate material according to any of claims 1-7, which - when administered to a healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 7.5 ng/ml or at least about 10 ng/ml after administration.
12. A particulate material according to any of the preceding claims, which - when administered to a healthy subject in the form of a chewing gum containing a particulate material containing 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 8 ng/ml nicotine such as, e.g., at least about 10 ng/ml, at least about 12.5 ng/ml, at least about 15 ng/ml or at least about 16 ng/ml within at the most 10 min after administration.
13. A particulate material according to any of the preceding claim, wherein at least part of the material is coated so as to delay the release of nicotine or the pharmaceutically acceptable salt, complex or solvate thereof from that part of the material.
14. A particulate material according to claim 13, wherein the material is coated with a film forming polymer e.g. carbomer, carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, polymethacrylates, polyvinyl alcohol, povidone, shellac, a fatty substance e.g. hard fat, hydrogenated cottonseed oil, hydrogenated vegetable oil , a polyethylene glycol, a polyethylene oxide, a wax, a zein, a sugar or derivatives of sugar e.g. glucose, maltodextrin, polydextrose, sucrose, lactose, alginic acid, carrageenan, sugar alcohols or derivatives of sugar alcohols e.g. mannitol, maltitol, isomalt, xylitol, sorbitol etc.
15. A particulate material according to any of the preceding claims, wherein the microcrystalline cellulose is any of commercial pharmaceutically accepted qualities of e.g. Avicel, Vivacel, Emcocel.
16. A particulate material according to any of the preceding claims, wherein the nicotine or the pharmaceutically acceptable salt, complex or solvate thereof is selected from nicotine base, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride and nicotine salicylate.
17. A particulate material according to any of the preceding claims comprising nicotine and one or more pharmaceutically acceptable salts, complexes or solvates thereof.
18. A particulate material according to any of the preceding claims comprising nicotine and at least one of nicotine tartrate or nicotine bitartrate.
19. A particulate material according to any of the preceding claims, wherein nicotine is present as racemate or in the form of any of its enantiomers or mixtures thereof.
20. A particulate material according to any of the preceding claims further comprising a buffer substance.
21. A particulate material according to claim 20, wherein the buffer substance is at least partially sorbed by the MCC
22. A particulate material according to claim 20 or 21 , wherein the buffer substance is selected from the group consisting of a carbonate including monocarbonate, bicarbonate and sesquicarbonate, glycinate, phosphate including monohydrogenphosphate, dihydrogenphosphate and trihydrogenphosphate, glycerophosphate, acetate, gluconate, citrate, borate, ammonium, and mixtures thereof
23. A pharmaceutical composition comprising a particulate material according to any of claims 1-22.
24. A pharmaceutical composition according to claim 23, wherein at least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min after oral administration.
25. A pharmaceutical composition according to claim 23 or 24, wherein at least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min determined in an in vitro dissolution test according to Ph.Eur.
26. A pharmaceutical composition according to any of claims 23-25 further comprising one or more pharmaceutically acceptable excipient.
27. A pharmaceutical composition according to any of claims 23-26, wherein the concentration of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof in the composition is from about 0.5 to about 6 mg calculated as nicotine base.
28. A pharmaceutical composition according to any of claims 23-27 in the form of a solid, semi-solid or fluid dosage form.
29. A pharmaceutical composition according to any of claims 23-28 in the form of a oral suspension, soluble tablet, oral gel, oral powder, granules, sachet, capsule, tablet, controlled release tablet, oral lyophilisate, orodispersible tablet, chewable tablet, oral gum, oromucosal suspension, oromucosal spray, sublingual spray, oromucosal gel, oromucosal paste, medicated chewing gum, gingival gel, gingival paste, gingival patch, oromucosal capsule, sublingual tablet, muco-adhesive buccal tablet, buccal tablet, buccal patch, buccal wafer, lozenge, gel, cutaneous paste, ointment, cutaneous spray, transdermal patch, cutaneous stick, impregnated dressing,
30. A pharmaceutical composition according to any of claims 23-29 further comprising an additive selected from the group consisting of pH-adjusting agents, stabilizing agents, preservatives, aroma-adjusting agents, flavor-adjusting agents, coloring agents, release- adjusting agents, complexing agents including EDTA.
31. A pharmaceutical composition according to any of claims 23-30 comprising a buffer substance.
32. A pharmaceutical composition according to claim 31 , wherein the buffer substance is selected from the group consisting of a carbonate including monocarbonate, bicarbonate and sesquicarbonate, glycinate, phosphate including monohydrogenphosphate, dihydrogenphosphate and trihydrogenphosphate, glycerophosphate, acetate, gluconate, citrate, borate, ammonium, and mixtures thereof
33. A pharmaceutical composition according to any of claims 23-32 comprising one or more bulk sweeteners selected from the group consisting of mono-, di-, tri- and polysaccharides, and natural and synthetic non-saccharide-based sweeteners.
34. A pharmaceutical composition according to claim 33, wherein the bulk sweetener is isomalt, xylitol or sorbitol, or combinations thereof.
35. A pharmaceutical composition according to any of claims 23-34 in solid or semi-solid form designed for oral application.
36. A pharmaceutical composition according to claim 35 in the form of chewing gum or lozenge including pastil, toffee, hard boilies and other candy-like compositions.
37. A pharmaceutical composition according to any of claims 23-36 comprising a further active substance.
38. A pharmaceutical composition according to any of claims 23-37, wherein a further amount of a nicotine is incorporated in the composition.
39. A pharmaceutical composition according to claim 38, wherein the nicotine is selected from the group consisting of pharmaceutically acceptable salts, solvates and complexes of nicotine including nicotine cation exchange resin complexes wherein the cation exchanger is selected from the group consisting of methacrylic type containing carboxylic functional groups or polystyrene type either with sulfonic functional groups or phosphonic functional groups.
40. A pharmaceutical composition according to claim 38, wherein the particulate material comprised in the composition comprises nicotine base and the futher amount of a nicotine that is incorporated into the composition is selected from the group consisting of nicotine tartrate and nicotine bitartrate.
41. A pharmaceutical composition according to any of claim 23-40, wherein the composition is coated with a film forming polymer e.g. carbomer, carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, polymethacrylates, polyvinyl alcohol, povidone, shellac, a fatty substance e.g. hard fat, hydrogenated cottonseed oil, hydrogenated vegetable oil , a polyethylene glycol, a polyethylene oxide, a wax, a zein, a sugar or derivatives of sugar e.g. glucose, maltodextrin, polydextrose, sucrose, lactose, alginic acid, carrageenan, sugar alcohols or derivatives of sugar alcohols e.g. mannitol, maltitol, isomalt, xylitol, sorbitol etc.
42. A pharmaceutical composition according to any of claims 23-41 , which - when administered to at least one healthy subject in an amount corresponding to 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof
- results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml or more of nicotine within at the most about 30 min such as, e.g. within at the most about 25 min, within at the most about 20 min, within at the most about 15 min or within at the most about 10 after administration.
43. A pharmaceutical composition according to any of claims 23-42, which - when administered to at least one healthy subject in an amount corresponding to 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof
- results in a plasma concentration of at least about 5 ng/ml such as, e.g., about 6 ng/ml or more, about 7 ng/ml or more, about 8 ng/ml or more, about 9 ng/ml or more or about 10 ng/ml nicotine within at the most about 15 min such as, e.g. within at the most about 10 min, within at the most about 7.5 min, within at the most about 5 min, within at the most about 4 min or within at the most about 3 min after administration.
44. A pharmaceutical composition according to any of claims 23-43, which - when administered to at least one healthy subject in an amount corresponding to 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 6 ng/ml nicotine within at the most about 10 min such as, e.g. within at the most about 9 min, at the most about 8 min, at the most about 7 min, at the most about 6 min, at the most about 5 min, at the most about 4 min or at the most about 3 min after administration.
45. A pharmaceutical composition according to any of claims 23-41 , which - when administered to a healthy subject i in an amount corresponding to 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 4 ng/ml nicotine such as, e.g., at least about 5 ng/ml, or at least about 6 ng/ml after administration.
46. A pharmaceutical composition according to any of claims 23-41 , which - when administered to a healthy subject in an amount corresponding to 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 7.5 ng/ml or at least about 10 ng/ml after administration.
47. A pharmaceutical composition according to any of claims 23-46, which - when administered to a healthy subject in an amount corresponding to 4 mg nicotine or an equivalent amount of a pharmaceutically acceptable salt, complex or solvate thereof - results in a plasma concentration of at least about 8 ng/ml nicotine such as, e.g., at least about 10 ng/ml, at least about 12.5 ng/ml, at least about 15 ng/ml or at least about 16 ng/ml within at the most 10 min after administration.
48. A pharmaceutical composition according to any of claims 23-47 in the form of a chewing gum.
49. A pharmaceutical composition according to any of claims 23-48 containing a mixture of coated and uncoated particulate material according to any of claims 1-23.
50. A pharmaceutical composition according to any of claims 23-49 designed to fast release of nicotine to obtain an enhanced onset of action.
51. A pharmaceutical composition according to any of claims 23-49 designed to extended release of nicotine.
52. A pharmaceutical composition according to any of claims 23-51 designed to release at least a part of the nicotine contained in the composition in a fast manner to obtain an enhanced onset of action and the remaining part of the nicotine in an extended manner to obtain a prolonged action.
53. A pharmaceutical composition according to claim 52, wherein the plasma concentration of nicotine after oral administration shows a mono-, bi- or multiphasic curve.
54. A pharmaceutical composition according to claim 52, wherein in vitro dissolution profile of nicotine a mono-, bi- or multiphasic curve, and the dissolution test is carried out in accordance with Ph.Eur.
55. A pharmaceutical composition according to any of claims 23, 26-54, wherein at the most about 60% w/w such as, e.g., at the most about 55% w/w, at the most about 50% w/w, at the most about 45%, at the most about 40%, at the most about 35% w/w or at the most about 30% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min after oral administration.
) 56. A pharmaceutical composition according to any of claims 23, 26-54, wherein at at the most about 60% w/w such as, e.g., at the most about 55% w/w, at the most about 50% w/w, at the most about 45%, at the most about 40%, at the most about 35% w/w or at the most about 30% w/w nicotine is released within at the most about 45 min such as, e.g., at the most about 30 min determined in an in vitro dissolution test according to Ph.Eur.
57. Use of a particulate material according to any of claims 1-23 for the preparation of a pharmaceutical composition having a fast onset of nicotine after administration.
58. Use of a particulate material according to any of claims 1-23 for the preparation of a pharmaceutical composition having an extended release of nicotine after administration.
59. A method for treating a nicotine-related disorder of a subject, the method comprising administering a sufficient amount of nicotine or a pharmaceutically acceptable salt, complex or solvate thereof in a particulate material according to any of claims 1-23 or in a pharmaceutical composition according to any of claims 24-57 to the subject in need thereof.
60. A method according to claim 59 the treatment of tobacco dependence, Parkinsons disease, ulcerative colitis, Alzheimers disease, schizophrenia, ADHD, Tourette's syndrome, ulcerous colitis and post-smoking-cessation weight control.
PCT/EP2003/014802 2002-12-20 2003-12-19 A physically and chemically stable nicotine-containing particulate material WO2004056363A2 (en)

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EP03789400A EP1578422B1 (en) 2002-12-20 2003-12-19 A physically and chemically stable nicotine and micorcrystalline cellulose containing particulate material
JP2004561429A JP4708795B2 (en) 2002-12-20 2003-12-19 Physically and chemically stable nicotine-containing particulate matter
DK03789400T DK1578422T3 (en) 2002-12-20 2003-12-19 Physically and chemically stable nicotine-containing particulate matter
NO20191286A NO346973B1 (en) 2002-12-20 2003-12-19 A physically and chemically stable nicotine-containing particulate material
SI200330825T SI1578422T1 (en) 2002-12-20 2003-12-19 A physically and chemically stable nicotine and micorcrystalline cellulose containing particulate material
EP18203402.5A EP3473251B1 (en) 2002-12-20 2003-12-19 A nicotine-cellulose combination
CN2003801090255A CN1738621B (en) 2002-12-20 2003-12-19 Physically and chemically stable nicotine-containing particulate material
CA2511185A CA2511185C (en) 2002-12-20 2003-12-19 A physically and chemically stable nicotine-containing particulate material
AU2003293987A AU2003293987B2 (en) 2002-12-20 2003-12-19 A physically and chemically stable nicotine-containing particulate material
DE60313216T DE60313216T2 (en) 2002-12-20 2003-12-19 CHEMICALLY AND PHYSICALLY STABLE PARTICLE MATERIAL CONTAINING NICOTIN AND MICROCRYSTALLINE CELLULOSE
NZ540817A NZ540817A (en) 2002-12-20 2003-12-19 A physically and chemically stable nicotine-containing particulate material
EP07007325.9A EP1803443B1 (en) 2002-12-20 2003-12-19 A nicotine-containing particulate material with a crystalline cellulose
EP07007326.7A EP1803444B1 (en) 2002-12-20 2003-12-19 A method for the preparation of a nicotine-containing particulate material with a crystalline cellulose (in particular MCC)
NO20053309A NO344367B1 (en) 2002-12-20 2005-07-06 A physically and chemically stable nicotine-containing particulate matter
CY20071100738T CY1106477T1 (en) 2002-12-20 2007-06-04 PHYSICALLY AND CHEMICALLY STABLE NICOTINE PARTICLE MATERIAL

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023227A2 (en) * 2003-09-08 2005-03-17 Pfizer Health Ab Nicotine formulations and use thereof
WO2006124366A2 (en) 2005-05-18 2006-11-23 Mcneil-Ppc, Inc. Flavoring of drug-containing chewing gums
EP1803443A2 (en) * 2002-12-20 2007-07-04 NicoNovum AB A method for the preparation of a nicotine-containing particulate material with a crystalline cellulose (in particular MCC)
WO2007104573A2 (en) * 2006-03-16 2007-09-20 Niconovum Ab Improved snuff composition
WO2007104575A2 (en) * 2006-03-16 2007-09-20 Niconovum Ab Stable lozenge compositions providing rapid release of nicotine
JP2008521414A (en) * 2004-11-30 2008-06-26 フェルティン ファルマ アー／エス How to bring quick relief to nicotine chewing gum users
WO2010031552A1 (en) * 2008-09-17 2010-03-25 Niconovum Ab Process for preparing snuff composition
WO2009037319A3 (en) * 2007-09-18 2010-04-29 Niconovum Ab Stable chewing gum compositions comprising maltitol and providing rapid release of nicotine
WO2013059592A1 (en) * 2011-10-21 2013-04-25 Niconovum Usa, Inc. Excipients for nicotine-containing therapeutic compositions
WO2013103318A1 (en) * 2012-01-05 2013-07-11 Mcneil Ab Solid nicotine-comprising dosage form with reduced organoleptic disturbance
US8529875B2 (en) 2004-06-29 2013-09-10 Fertin Pharma A/S Tobacco alkaloid releasing chewing gum
US8642016B2 (en) 2006-07-21 2014-02-04 Jsrnti, Llc Medicinal delivery system, and related methods
WO2015009913A1 (en) 2013-07-19 2015-01-22 Altria Client Services Inc. Methods and systems for incorporating nicotine into oral products
US9402810B2 (en) 2011-03-29 2016-08-02 Nyz Ab Pouch containing nicotine in free salt form
WO2017059858A1 (en) * 2015-10-07 2017-04-13 Fertin Pharma A/S Chewing gum comprising nicotine
US9724341B2 (en) 2013-07-11 2017-08-08 Alexza Pharmaceuticals, Inc. Nicotine salt with meta-salicylic acid
WO2018197454A1 (en) 2017-04-24 2018-11-01 Swedish Match North Europe Ab A flavoured moist oral pouched nicotine product comprising triglyceride
EP3491940A1 (en) * 2017-11-29 2019-06-05 Reemtsma Cigarettenfabriken GmbH Method of manufacturing a filling material for a pouched smokeless snus product and filling material manufactured therefrom
WO2019115778A1 (en) 2017-12-15 2019-06-20 Swedish Match North Europe Ab A flavoured moist oral pouched nicotine product comprising monoglyceride
WO2021063727A1 (en) 2019-10-04 2021-04-08 Schjoelin Evaggelos A pouch product suitable for application in an oral cavity
WO2021111340A1 (en) * 2019-12-02 2021-06-10 Arturo Solis Herrera (s)-3-[1-methylpyrrolidin-2-yl]pyridine, analogues thereof, precursors thereof, or its derivatives, for the use as a pharmaceutical in form of a solid substance and a tablet
WO2021116878A1 (en) * 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral products with improved binding of active ingredients
WO2021116842A1 (en) * 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral products with controlled release
EP4094593A1 (en) 2021-05-28 2022-11-30 Swedish Match North Europe AB A flavoured moist oral pouched nicotine product comprising ethyl cellulose
EP4115746B1 (en) 2019-11-20 2023-08-16 Swedish Match North Europe AB An oral pouched nicotine product including a filling material comprising nicotine particles
US11826462B2 (en) 2019-12-09 2023-11-28 Nicoventures Trading Limited Oral product with sustained flavor release
US11872231B2 (en) 2019-12-09 2024-01-16 Nicoventures Trading Limited Moist oral product comprising an active ingredient
US11969502B2 (en) 2019-12-09 2024-04-30 Nicoventures Trading Limited Oral products
US12064424B2 (en) 2019-12-09 2024-08-20 Nicoventures Trading Limited Moist oral compositions

Families Citing this family (210)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0302947D0 (en) * 2003-01-24 2003-11-07 Magle Ab A composition material for transmucosal delivery
CN100508976C (en) * 2003-07-24 2009-07-08 史密丝克莱恩比彻姆公司 Orally dissolving films
EP1691631A4 (en) 2003-11-07 2012-09-05 Us Smokeless Tobacco Co Tobacco compositions
US8627828B2 (en) 2003-11-07 2014-01-14 U.S. Smokeless Tobacco Company Llc Tobacco compositions
WO2005089728A2 (en) * 2004-03-19 2005-09-29 Pfizer Health Ab Means for transdermal administration of nicotine
US8252321B2 (en) 2004-09-13 2012-08-28 Chrono Therapeutics, Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
CA2580329C (en) 2004-09-13 2015-01-06 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery
AU2006245434B2 (en) * 2005-04-29 2012-02-02 Philip Morris Products S.A. Tobacco pouch product
US9044049B2 (en) 2005-04-29 2015-06-02 Philip Morris Usa Inc. Tobacco pouch product
US9675109B2 (en) 2005-07-19 2017-06-13 J. T. International Sa Method and system for vaporization of a substance
US20160345631A1 (en) 2005-07-19 2016-12-01 James Monsees Portable devices for generating an inhalable vapor
US8685478B2 (en) 2005-11-21 2014-04-01 Philip Morris Usa Inc. Flavor pouch
US7766019B2 (en) * 2006-07-21 2010-08-03 Gp Technologies, Inc. Porous plastic smoking cessation devices
EP3578661A1 (en) * 2006-09-13 2019-12-11 22nd Century Limited, LLC Increasing levels of nicotinic alkaloids
CA2660362C (en) * 2006-09-27 2018-03-20 Niconovum Ab Use of a device or spray apparatus for oral administration of a liquid containing an active substance for improved absorption
JP2008120771A (en) * 2006-11-08 2008-05-29 Bhn Kk Ameliorating agent for constipation
US7767248B2 (en) 2007-02-02 2010-08-03 Overly Iii Harry J Soft chew confectionary with high fiber and sugar content and method for making same
US8616221B2 (en) 2007-02-28 2013-12-31 Philip Morris Usa Inc. Oral pouch product with flavored wrapper
US20080210249A1 (en) * 2007-03-02 2008-09-04 Luzenberg Robert S Systems, devices and methods for delivering one or more additives to smokeless tobacco
ES2594867T3 (en) 2007-03-09 2016-12-23 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US20090032040A1 (en) * 2007-03-30 2009-02-05 Luzenberg Jr Robert S Porous plastic smokeless tobacco substitutes
GB2468424B (en) * 2007-04-02 2011-11-09 Parkinson S Inst Methods and compositions for reduction of side effects of therapeutic treatments
CN101772346B (en) * 2007-04-02 2014-05-07 帕金森氏病研究院 Methods and compositions for reduction of side effects of therapeutic treatments
GB0709162D0 (en) * 2007-05-11 2007-06-20 Jagotec Ag Dosage foam
US9888712B2 (en) 2007-06-08 2018-02-13 Philip Morris Usa Inc. Oral pouch products including a liner and tobacco beads
US8950408B2 (en) 2007-07-16 2015-02-10 Philip Morris Usa Inc. Oral pouch product having soft edge
US8202589B2 (en) * 2007-07-16 2012-06-19 Philip Morris Usa Inc. Oral delivery pouch product with coated seam
WO2009010881A2 (en) * 2007-07-16 2009-01-22 Philip Morris Products S.A. Oral pouch products with immobilized flavorant particles
US8424541B2 (en) 2007-07-16 2013-04-23 Philip Morris Usa Inc. Tobacco-free oral flavor delivery pouch product
US8119173B2 (en) 2007-07-16 2012-02-21 Philip Morris Usa Inc. Method of flavor encapsulation through the use of a drum coater
US8991402B2 (en) 2007-12-18 2015-03-31 Pax Labs, Inc. Aerosol devices and methods for inhaling a substance and uses thereof
EP2085077A1 (en) * 2008-01-30 2009-08-05 Südzucker Aktiengesellschaft Mannheim/Ochsenfurt Coating compositions for controlled relaease formulations
CL2009001025A1 (en) 2008-05-01 2010-09-24 Smithkline Beecham Corp Lozenge composition comprising: a) a standard granule with at least: an alkaline buffering agent, a dissolution modifier and a filler, b) a defined extragranular nicotine active ingredient and at least one alkaline buffering agent; preparation procedure; Useful to eliminate or reduce tobacco use.
PT2177213E (en) * 2008-09-17 2013-02-21 Siegfried Ltd Nicotine-containing granulate
US8377215B2 (en) 2008-12-18 2013-02-19 Philip Morris Usa Inc. Moist botanical pouch processing
US8863755B2 (en) 2009-02-27 2014-10-21 Philip Morris Usa Inc. Controlled flavor release tobacco pouch products and methods of making
US8747562B2 (en) 2009-10-09 2014-06-10 Philip Morris Usa Inc. Tobacco-free pouched product containing flavor beads providing immediate and long lasting flavor release
US20110268809A1 (en) * 2010-04-28 2011-11-03 Paul Andrew Brinkley Nicotine-Containing Pharmaceutical Compositions
US20110274628A1 (en) 2010-05-07 2011-11-10 Borschke August J Nicotine-containing pharmaceutical compositions
UA112974C2 (en) * 2010-09-16 2016-11-25 Джеі. Бі. Кемікалс Енд Фармасьютікалс Лімітид NICOTINE COMPOSITION (OPTIONS)
CA2841785A1 (en) 2011-07-06 2013-01-10 The Parkinson's Institute Compositions and methods for treatment of symptoms in parkinson's disease patients
US9084439B2 (en) 2011-09-22 2015-07-21 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US20130078307A1 (en) 2011-09-22 2013-03-28 Niconovum Usa, Inc. Nicotine-containing pharmaceutical composition
US9629392B2 (en) 2011-09-22 2017-04-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US9474303B2 (en) 2011-09-22 2016-10-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
CN102754908B (en) 2012-01-20 2015-06-10 奥驰亚客户服务公司 Oral tobacco product
CN102754907B (en) 2012-01-20 2015-06-24 奥驰亚客户服务公司 Oral product
CN103039688B (en) 2012-01-20 2016-01-06 奥驰亚客户服务公司 Oral product
US9854831B2 (en) 2012-01-20 2018-01-02 Altria Client Services Llc Oral product
CN103040090B (en) 2012-01-20 2016-03-30 奥驰亚客户服务公司 Remove the oral product of tobacco
AU2013204701B2 (en) 2012-01-20 2016-12-01 Altria Client Services Llc Oral product
US9763928B2 (en) 2012-02-10 2017-09-19 Niconovum Usa, Inc. Multi-layer nicotine-containing pharmaceutical composition
FR2987561B1 (en) * 2012-03-02 2014-04-11 Pf Medicament TRANSDERMIC DEVICE COMPRISING POROUS MICRO PARTICLES
US9044035B2 (en) 2012-04-17 2015-06-02 R.J. Reynolds Tobacco Company Remelted ingestible products
US9339058B2 (en) 2012-04-19 2016-05-17 R. J. Reynolds Tobacco Company Method for producing microcrystalline cellulose from tobacco and related tobacco product
US10517530B2 (en) 2012-08-28 2019-12-31 Juul Labs, Inc. Methods and devices for delivering and monitoring of tobacco, nicotine, or other substances
US20140255452A1 (en) 2013-03-11 2014-09-11 Niconovum Usa, Inc. Method and apparatus for differentiating oral pouch products
US10279934B2 (en) 2013-03-15 2019-05-07 Juul Labs, Inc. Fillable vaporizer cartridge and method of filling
IL297399B2 (en) 2013-05-06 2024-02-01 Juul Labs Inc Nicotine salt formulations for aerosol devices and methods thereof
TW201507726A (en) * 2013-05-10 2015-03-01 Glaxosmithkline Llc Nicotine lozenge formulation
CN111642812A (en) 2013-06-14 2020-09-11 尤尔实验室有限公司 Multiple heating elements with individual vaporizable materials in electronic vaporization devices
US10357054B2 (en) 2013-10-16 2019-07-23 R.J. Reynolds Tobacco Company Smokeless tobacco pastille
CA3144602A1 (en) 2013-12-05 2015-06-11 Juul Labs, Inc. Nicotine liquid formulations for aerosol devices and methods thereof
US9549573B2 (en) 2013-12-23 2017-01-24 Pax Labs, Inc. Vaporization device systems and methods
USD842536S1 (en) 2016-07-28 2019-03-05 Juul Labs, Inc. Vaporizer cartridge
US20160366947A1 (en) 2013-12-23 2016-12-22 James Monsees Vaporizer apparatus
USD825102S1 (en) 2016-07-28 2018-08-07 Juul Labs, Inc. Vaporizer device with cartridge
US10076139B2 (en) 2013-12-23 2018-09-18 Juul Labs, Inc. Vaporizer apparatus
DE202014011292U1 (en) 2013-12-23 2019-02-01 Juul Labs Uk Holdco Limited Systems for an evaporation device
US10159282B2 (en) 2013-12-23 2018-12-25 Juul Labs, Inc. Cartridge for use with a vaporizer device
US10058129B2 (en) 2013-12-23 2018-08-28 Juul Labs, Inc. Vaporization device systems and methods
US9375033B2 (en) 2014-02-14 2016-06-28 R.J. Reynolds Tobacco Company Tobacco-containing gel composition
US11478021B2 (en) 2014-05-16 2022-10-25 Juul Labs, Inc. Systems and methods for aerosolizing a vaporizable material
US20150335070A1 (en) 2014-05-20 2015-11-26 R.J. Reynolds Tobacco Company Electrically-powered aerosol delivery system
US11019840B2 (en) 2014-07-02 2021-06-01 R.J. Reynolds Tobacco Company Oral pouch products
US10959456B2 (en) 2014-09-12 2021-03-30 R.J. Reynolds Tobacco Company Nonwoven pouch comprising heat sealable binder fiber
US20160157515A1 (en) 2014-12-05 2016-06-09 R.J. Reynolds Tobacco Company Smokeless tobacco pouch
WO2016090303A1 (en) 2014-12-05 2016-06-09 Pax Labs, Inc. Calibrated dose control
US9968125B2 (en) 2015-01-09 2018-05-15 Philip Morris Products S.A. Nicotine—diketopiperazine microparticle formulations and methods of making the same
EP3250258A4 (en) 2015-01-28 2018-09-05 Chrono Therapeutics, Inc. Drug delivery methods and systems
US10679516B2 (en) 2015-03-12 2020-06-09 Morningside Venture Investments Limited Craving input and support system
US10154689B2 (en) 2015-06-30 2018-12-18 R.J. Reynolds Tobacco Company Heat generation segment for an aerosol-generation system of a smoking article
US10869497B2 (en) 2015-09-08 2020-12-22 R.J. Reynolds Tobacco Company High-pressure cold pasteurization of tobacco material
US9585835B1 (en) 2015-09-16 2017-03-07 Sansa Corporation (Barbados) Inc. Inhalable nicotine formulations and methods of making and using the same
US11224594B2 (en) 2015-09-16 2022-01-18 Philip Morris Products S.A. Nicotine formulations and methods of making and using the same
US20170071248A1 (en) 2015-09-16 2017-03-16 Sansa Corporation (Barbados) Inc. System and Method for Controlling the Harshness of Nicotine-Based Dry Powder Formulations
US10149844B2 (en) 2015-09-16 2018-12-11 Philip Morris Products S.A. Inhalable nicotine formulations, and methods of making and using thereof
EP4059365B1 (en) 2015-11-24 2023-11-08 R. J. Reynolds Tobacco Company Electrically-powered aerosol delivery system
US10532046B2 (en) 2015-12-03 2020-01-14 Niconovum Usa, Inc. Multi-phase delivery compositions and products incorporating such compositions
US20170165252A1 (en) 2015-12-10 2017-06-15 Niconovum Usa Inc. Protein-enriched therapeutic composition
US11612183B2 (en) 2015-12-10 2023-03-28 R.J. Reynolds Tobacco Company Protein-enriched tobacco composition
EP3419443A4 (en) 2016-02-11 2019-11-20 Juul Labs, Inc. Securely attaching cartridges for vaporizer devices
EP3413960B1 (en) 2016-02-11 2021-03-31 Juul Labs, Inc. Fillable vaporizer cartridge and method of filling
US10405582B2 (en) 2016-03-10 2019-09-10 Pax Labs, Inc. Vaporization device with lip sensing
US10329068B2 (en) 2016-05-23 2019-06-25 R.J. Reynolds Tobacco Company Flavoring mechanism for a tobacco related material
USD849996S1 (en) 2016-06-16 2019-05-28 Pax Labs, Inc. Vaporizer cartridge
USD851830S1 (en) 2016-06-23 2019-06-18 Pax Labs, Inc. Combined vaporizer tamp and pick tool
USD848057S1 (en) 2016-06-23 2019-05-07 Pax Labs, Inc. Lid for a vaporizer
USD836541S1 (en) 2016-06-23 2018-12-25 Pax Labs, Inc. Charging device
US10602775B2 (en) 2016-07-21 2020-03-31 Rai Strategic Holdings, Inc. Aerosol delivery device with a unitary reservoir and liquid transport element comprising a porous monolith and related method
US10617151B2 (en) 2016-07-21 2020-04-14 Rai Strategic Holdings, Inc. Aerosol delivery device with a liquid transport element comprising a porous monolith and related method
US11660403B2 (en) 2016-09-22 2023-05-30 Juul Labs, Inc. Leak-resistant vaporizer device
US10080387B2 (en) 2016-09-23 2018-09-25 Rai Strategic Holdings, Inc. Aerosol delivery device with replaceable wick and heater assembly
WO2018122095A1 (en) 2016-12-30 2018-07-05 Philip Morris Products S.A. Nicotine and cellulose containing sheet
EP3565617A1 (en) 2017-01-06 2019-11-13 Chrono Therapeutics Inc. Transdermal drug delivery devices and methods
GB201705693D0 (en) 2017-04-07 2017-05-24 Sensus Invest Ltd Carrier, apparatus and method
US11297876B2 (en) 2017-05-17 2022-04-12 Rai Strategic Holdings, Inc. Aerosol delivery device
SE541358C2 (en) * 2017-05-30 2019-08-13 Enorama Pharma Ab Nicotine-containing chewing gum compositions
EP3641731A1 (en) * 2017-06-23 2020-04-29 Fertin Pharma A/S Nicotine pouch
USD887632S1 (en) 2017-09-14 2020-06-16 Pax Labs, Inc. Vaporizer cartridge
US10786010B2 (en) * 2017-12-15 2020-09-29 Rai Strategic Holdings, Inc. Aerosol delivery device with multiple aerosol delivery pathways
US10555558B2 (en) 2017-12-29 2020-02-11 Rai Strategic Holdings, Inc. Aerosol delivery device providing flavor control
CN108323791B (en) * 2018-01-03 2021-02-12 云南中烟工业有限责任公司 Nicotine-zinc oxide compound, preparation method thereof and tobacco product containing nicotine-zinc oxide compound
CN108391853A (en) * 2018-03-06 2018-08-14 四川三联新材料有限公司 It is a kind of to smell tobacco powder and preparation method thereof and the application in heating not burning tobacco and cigarette
US20190307082A1 (en) 2018-04-05 2019-10-10 R.J. Reynolds Tobacco Company Oriental tobacco production methods
WO2019232077A1 (en) 2018-05-29 2019-12-05 Chrono Therapeutics Inc. Drug delivery methods and systems
EP3807260B1 (en) 2018-06-15 2024-09-18 R. J. Reynolds Tobacco Company Purification of nicotine
SE542990C2 (en) 2019-03-18 2020-09-22 Swedish Match North Europe Ab A packaging material and an oral pouched nicotine product
US20210068447A1 (en) 2019-09-11 2021-03-11 R. J. Reynolds Tobacco Company Pouched products with enhanced flavor stability
US20210068446A1 (en) 2019-09-11 2021-03-11 R. J. Reynolds Tobacco Company Oral product with cellulosic flavor stabilizer
SE1951054A1 (en) * 2019-09-18 2021-03-19 Enorama Pharma Ab Nicotine pouch
CA3156573A1 (en) 2019-10-31 2021-05-06 Nicoventures Trading Limited Oral product and method of manufacture
US20210169788A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Oral product and method of manufacture
WO2021116916A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral product with multiple flavors having different release profiles
US20210169890A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Oral composition with polymeric component
BR112022010979A2 (en) 2019-12-09 2022-08-16 Nicoventures Trading Ltd PACKAGING PRODUCTS WITH HEAT SEALABLE BINDING
US20210169868A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Oral compositions with reduced water content
WO2021116855A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral compositions and methods of manufacture
US20210169129A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Lipid-containing oral composition
WO2021116823A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral product
US11883527B2 (en) 2019-12-09 2024-01-30 Nicoventures Trading Limited Oral composition and method of manufacture
US20210169138A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Fibrous fleece material
US11889856B2 (en) 2019-12-09 2024-02-06 Nicoventures Trading Limited Oral foam composition
WO2021116884A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Layered fleece for pouched product
US11672862B2 (en) 2019-12-09 2023-06-13 Nicoventures Trading Limited Oral products with reduced irritation
AU2020399278A1 (en) 2019-12-09 2022-06-30 Nicoventures Trading Limited Nanoemulsion for oral use
US20210169783A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Oral products with controlled release
US20210169123A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Pouched products with enhanced flavor stability
US20210169126A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Oral composition with salt inclusion
WO2021116854A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral products with active ingredient combinations
WO2021116824A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral product comprising a cannabinoid
WO2021116881A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral product in a pourous pouch comprising a fleece material
US20210169132A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Oral composition including gels
US20210170031A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Oral composition with nanocrystalline cellulose
WO2021116895A2 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Stimulus-responsive pouch
WO2021116856A2 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral products
JP2023505804A (en) 2019-12-09 2023-02-13 ニコベンチャーズ トレーディング リミテッド Oral products with dissolvable components
EP4072329A1 (en) 2019-12-09 2022-10-19 Nicoventures Trading Limited Process
US20210169784A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Buffered oral compositions
AU2020403651A1 (en) 2019-12-09 2022-07-07 Nicoventures Trading Limited Oral product comprising a cannabinoid
US20210169137A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Pouched products
WO2021116825A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Oral product
WO2021116919A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Fleece for oral product with releasable component
US20210169786A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Oral composition with beet material
US20210169785A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Oral compositions with reduced water activity
WO2021116865A1 (en) 2019-12-09 2021-06-17 Nicoventures Trading Limited Agents for oral composition
US20210169121A1 (en) 2019-12-09 2021-06-10 Nicoventures Trading Limited Liquid oral composition
US11712059B2 (en) 2020-02-24 2023-08-01 Nicoventures Trading Limited Beaded tobacco material and related method of manufacture
SE545479C2 (en) 2020-06-03 2023-09-26 Swedish Match North Europe Ab A packaging material made of wetlaid nonwoven and a pouched product for oral use
WO2021250516A1 (en) 2020-06-08 2021-12-16 Nicoventures Trading Limited Effervescent oral composition comprising an active ingredient
US11771132B2 (en) 2020-08-27 2023-10-03 Rai Strategic Holdings, Inc. Atomization nozzle for aerosol delivery device
GB202013491D0 (en) 2020-08-27 2020-10-14 Nicoventures Holdings Ltd Oral Product
GB202013489D0 (en) 2020-08-27 2020-10-14 Nicoventures Holdings Ltd Consumable
KR20230068413A (en) 2020-09-11 2023-05-17 니코벤처스 트레이딩 리미티드 Alginate-based substrate
US20220104532A1 (en) 2020-10-07 2022-04-07 NIlCOVENTURES TRADING LIMITED Methods of making tobacco-free substrates for aerosol delivery devices
CN112220756B (en) * 2020-10-16 2023-06-13 重庆市义力医药科技有限公司 Nicotine granule composition and preparation method thereof
CN114432309A (en) * 2020-11-06 2022-05-06 中国科学院深圳先进技术研究院 Method for improving activity of nicotinamide phosphoribosyltransferase and composition thereof
WO2022094916A1 (en) * 2020-11-06 2022-05-12 中国科学院深圳先进技术研究院 Method for improving activity of nicotinamide phosphoribosyltransferase, and composition thereof
US20240008522A1 (en) 2020-11-18 2024-01-11 Nicoventures Trading Limited Oral products
US11839602B2 (en) 2020-11-25 2023-12-12 Nicoventures Trading Limited Oral cannabinoid product with lipid component
EP4284972A1 (en) 2021-01-28 2023-12-06 Nicoventures Trading Limited Method for sealing pouches
MX2023010620A (en) 2021-03-09 2023-09-19 Nicoventures Trading Ltd Oral products and methods of manufacture.
WO2022195561A1 (en) 2021-03-19 2022-09-22 Nicoventures Trading Limited Beaded substrates for aerosol delivery devices
BR112023018985A2 (en) 2021-03-19 2023-12-05 Nicoventures Trading Ltd EXTRUDED SUBSTRATES FOR AEROSOL DISTRIBUTION DEVICES
WO2022224197A1 (en) 2021-04-22 2022-10-27 Nicoventures Trading Limited Effervescent oral composition
CA3216265A1 (en) 2021-04-22 2022-10-27 Michael Andrew Zawadzki Orally dissolving films
US20220354155A1 (en) 2021-04-30 2022-11-10 Nicoventures Trading Limited Multi-compartment oral pouched product
WO2022229929A1 (en) 2021-04-30 2022-11-03 Nicoventures Trading Limited Oral products with high-density load
EP4355121A1 (en) 2021-06-16 2024-04-24 Nicoventures Trading Limited Pouched product comprising dissolvable composition
MX2023015531A (en) 2021-06-21 2024-03-05 Nicoventures Trading Ltd Oral product tablet and method of manufacture.
MX2023015529A (en) 2021-06-25 2024-03-05 Nicoventures Trading Ltd Oral products and method of manufacture.
EP4366551A1 (en) 2021-07-09 2024-05-15 Nicoventures Trading Limited Extruded structures
US20240251841A1 (en) 2021-07-22 2024-08-01 Nicoventures Trading Limited Composition comprising a constituent, derivative or extract of cannabis
WO2023002196A1 (en) 2021-07-22 2023-01-26 Nicoventures Trading Limited Constituent, derivative or extract of cannabis in a water soluble matrix
JP2024528844A (en) 2021-07-22 2024-08-01 ニコベンチャーズ トレーディング リミテッド Compositions containing cannabis components, derivatives or extracts
JP2024526810A (en) 2021-07-22 2024-07-19 ニコベンチャーズ トレーディング リミテッド Cannabis components, derivatives or extracts in amorphous form
JP2024528831A (en) 2021-07-22 2024-08-01 ニコベンチャーズ トレーディング リミテッド Compositions containing cannabis components, derivatives or extracts
US20240324652A1 (en) 2021-07-22 2024-10-03 Nicoventures Trading Limited Methods of preparing compositions comprising a constituent, derivative or extract of cannabis
EP4373303A1 (en) 2021-07-22 2024-05-29 Nicoventures Trading Limited Compositions comprising a constituent, derivative or extract of cannabis
EP4373311A1 (en) 2021-07-22 2024-05-29 Nicoventures Trading Limited Nanoemulsion comprising cannabinoid and/or cannabimimetic
MX2024000933A (en) 2021-07-22 2024-02-08 Nicoventures Trading Ltd Compositions comprising constituents, derivatives or extracts of cannabis.
WO2023053060A1 (en) 2021-09-30 2023-04-06 Nicoventures Trading Limited Oral gum composition
MX2024005868A (en) 2021-11-15 2024-07-15 Nicoventures Trading Ltd Oral products with nicotine-polymer complex.
WO2023084499A1 (en) 2021-11-15 2023-05-19 Nicoventures Trading Limited Products with enhanced sensory characteristics
CN114304712A (en) * 2021-12-17 2022-04-12 深圳市元雾科技有限公司 Liquid high-load nicotine buccal product particles and preparation method thereof
CA3241938A1 (en) 2021-12-20 2023-06-29 Bridget CRUMP Substrate material comprising beads for aerosol delivery devices
CN114304711A (en) * 2021-12-20 2022-04-12 深圳市元雾科技有限公司 Nicotine buccal product with stable pH
CN114521669A (en) * 2022-02-25 2022-05-24 深圳市元雾科技有限公司 Nicotine-stabilized buccal tobacco product and preparation method thereof
US20230309603A1 (en) 2022-03-31 2023-10-05 R.J. Reynolds Tobacco Company Agglomerated botanical material for oral products
WO2023194959A1 (en) 2022-04-06 2023-10-12 Nicoventures Trading Limited Pouched products with heat sealable binder
WO2024069542A1 (en) 2022-09-30 2024-04-04 R. J. Reynolds Tobacco Company Method for forming reconstituted tobacco
WO2024069544A1 (en) 2022-09-30 2024-04-04 Nicoventures Trading Limited Reconstituted tobacco substrate for aerosol delivery device
WO2024079722A1 (en) 2022-10-14 2024-04-18 Nicoventures Trading Limited Capsule-containing pouched products
WO2024089588A1 (en) 2022-10-24 2024-05-02 Nicoventures Trading Limited Shaped pouched products
WO2024095164A1 (en) 2022-11-01 2024-05-10 Nicoventures Trading Limited Products with spherical filler
WO2024171117A1 (en) 2023-02-15 2024-08-22 Nicoventures Trading Limited Oral products with high-density load
WO2024180481A1 (en) 2023-02-28 2024-09-06 Nicoventures Trading Limited Caffeine-containing oral product
WO2024201346A1 (en) 2023-03-31 2024-10-03 Nicoventures Trading Limited Functionalized fleece material production
WO2024201301A1 (en) 2023-03-31 2024-10-03 Nicoventures Trading Limited Starchless molding process for oral products
GB202306392D0 (en) 2023-04-28 2023-06-14 Nicoventures Trading Ltd Aerosol generating material

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4317837A (en) * 1980-11-25 1982-03-02 Life Savers, Inc. Tobacco-flavored chewing gum
FR2608156A1 (en) * 1986-12-12 1988-06-17 Ethypharm Sa Chewing gum for releasing tobacco
US4907605A (en) * 1985-05-24 1990-03-13 Advanced Tobacco Products, Inc. Oral tabacco substitute
WO1991001656A1 (en) * 1989-07-31 1991-02-21 Svein Knudsen Means for use as an aid to stop smoking or for use in non-smoking areas
US5656255A (en) * 1992-01-03 1997-08-12 Pharmacia & Upjohn Ab Composition to help stop smoking
WO1997042941A2 (en) * 1996-05-13 1997-11-20 Novartis Consumer Health S.A. Buccal delivery system
US6264981B1 (en) * 1999-10-27 2001-07-24 Anesta Corporation Oral transmucosal drug dosage using solid solution

Family Cites Families (269)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US865026A (en) 1906-12-15 1907-09-03 Ellis Foster Co Masticable tobacco preparation.
US940521A (en) * 1909-05-06 1909-11-16 George A Endicott Wire-stretching appliance.
US3901248A (en) 1970-07-22 1975-08-26 Leo Ab Chewable smoking substitute composition
US3877468A (en) * 1970-07-22 1975-04-15 Leo Ab Chewable tobacco substitute composition
US3777029A (en) * 1971-01-28 1973-12-04 Hoffmann La Roche Chewable multivitamin tablets contain-ing aluminum nicotinate
CH542002A (en) 1971-07-27 1973-09-30 Coster Tecnologie Speciali Spa Aerosol container on which a dispensing cap equipped with an oscillating cannula is applied
US3845217A (en) 1972-11-16 1974-10-29 Helsingborg L Ab Buffered smoking substitute compositions
JPS5350515Y2 (en) 1975-02-28 1978-12-04
DE2526702A1 (en) 1975-06-14 1976-12-23 Volkswagenwerk Ag Spray nozzle for protectively coating inner walls of hollow spaces - has slots lying in various planes w.r.t. axis of nozzle tube
GB1528391A (en) 1976-01-05 1978-10-11 Gildemeister V Aerosol compositions
JPS52114010A (en) 1976-03-22 1977-09-24 Ozawa Miyo Medicine for nicotinism
GB2030862A (en) 1978-04-10 1980-04-16 Smith A A composition for treating drug addiction such as smoking nicotine-containing products
FR2467604A1 (en) 1979-10-22 1981-04-30 Mercier Jean Nozzle for outlet tube of aerosol nasal spray - has extra discharge passage directed into face sinuses
DE3332429T1 (en) 1982-02-22 1984-01-26 Belorusskij naučno-issledovatel'skij sanitarno-gigieničeskij institut, 220012 Minsk MEDICINAL PRODUCT WITH ANTINICOTINE EFFECT AND METHOD FOR THE PRODUCTION THEREOF
US4489026A (en) * 1982-09-07 1984-12-18 The Upjohn Company Process for preparing solid unit dosage forms of ultra-low dose drugs
DE3241437A1 (en) 1982-11-10 1984-05-10 Ferdinand Prof. Dr.med. 6901 Wilhelmsfeld Schmidt Composition for stopping smoking and/or for intake of nicotine without side effects by addicted smokers
GB8301659D0 (en) * 1983-01-21 1983-02-23 Leo Ab Smoking substitutes
SU1232260A1 (en) 1983-02-01 1986-05-23 Mamchur Fedor Method of obtaining substance possessing antinicotine activity
GB8317576D0 (en) 1983-06-29 1983-08-03 Shaw A S W Consumer tobacco products
US4593572A (en) * 1983-10-03 1986-06-10 Universal Thread Grinding Company Lubricated drive mechanism
US4655231A (en) * 1984-01-09 1987-04-07 Advanced Tobacco Products, Inc. Snuff and preparation thereof
SU1268141A1 (en) 1984-03-26 1986-11-07 Научно-Производственное Объединение Министерства Пищевой Промышленности Армсср Method of producing antinicotine chewing gum
DE3429389C1 (en) * 1984-08-09 1986-03-13 Brugger, Inge, geb. Ritzau, 8130 Starnberg Inhaler
JPS61251619A (en) * 1985-04-30 1986-11-08 Nitto Electric Ind Co Ltd Nicotin-containing tape preparation
EP0205133A1 (en) 1985-06-14 1986-12-17 Marie Luise Dr. Schicht Plastic chewing mass based on chewing gum
US4696315A (en) 1985-09-19 1987-09-29 Better Life International, Inc. Herbal snuff composition
US4817640A (en) * 1985-09-19 1989-04-04 Better Life International Life, Inc. Herbal chew and snuff compositions
JP2543683B2 (en) 1985-12-13 1996-10-16 武田薬品工業株式会社 Sodium Vitamin Dragee
US5198226A (en) 1986-01-30 1993-03-30 Syntex (U.S.A.) Inc. Long acting nicardipine hydrochloride formulation
GB8614805D0 (en) * 1986-06-18 1986-07-23 British American Tobacco Co Aerosol device
GB8615676D0 (en) 1986-06-26 1986-07-30 Stoppers Co Ltd Nicotine containing lozenge
DE3645036A1 (en) 1986-11-18 1989-01-05 Forschungsgesellschaft Rauchen Nicotine-containing composition
US4835162A (en) * 1987-02-12 1989-05-30 Abood Leo G Agonists and antagonists to nicotine as smoking deterents
US4943435A (en) 1987-10-05 1990-07-24 Pharmetrix Corporation Prolonged activity nicotine patch
US4933188B1 (en) 1987-12-31 1997-07-15 Warner Lambert Co Chewing gum composition with improved physical stability
JPH01243945A (en) 1988-03-25 1989-09-28 Lotte Co Ltd Smoking aversion gum
JPH0272118A (en) 1988-09-08 1990-03-12 Kitsuen Kagaku Kenkyu Zaidan Coronary vasodilator
GB8828468D0 (en) * 1988-12-06 1989-01-05 Stoppers Co Ltd Nicotine containing lozenge
IE62662B1 (en) 1989-01-06 1995-02-22 Elan Corp Plc Use of nicotine in the treatment of conditions susceptible to said treatment
US5154927A (en) 1989-01-19 1992-10-13 Wm. Wrigley Jr. Company Gum composition containing dispersed porous beads containing active chewing gum ingredients and method
DK365389D0 (en) 1989-07-24 1989-07-24 Fertin Lab As ANTIFUNGAL CHEMICAL GUM PREPARATION
ES2097155T3 (en) 1989-10-02 1997-04-01 Cima Labs Inc EFFERVESCENT DOSAGE FORM AND METHOD OF ADMINISTRATION.
US4967733A (en) * 1989-10-16 1990-11-06 Rousseau Yvon J Lifting carriage
US5525351A (en) * 1989-11-07 1996-06-11 Dam; Anders Nicotine containing stimulant unit
DK615689A (en) 1989-11-07 1991-05-08 Anders Dam SMOKING SUPPLEMENT OR SMOKING REPLACEMENT PRODUCT
JP2914690B2 (en) * 1989-12-13 1999-07-05 グレラン製薬株式会社 Formulation containing stable vitamin D
SE8904295D0 (en) * 1989-12-21 1989-12-21 Pharmacia Ab SMOKING SUBSTITUTE
US5512306A (en) * 1992-06-19 1996-04-30 Pharmica Ab Smoking substitute
US5077104A (en) * 1989-12-21 1991-12-31 Alza Corporation Nicotine packaging materials
JPH03209327A (en) * 1990-01-11 1991-09-12 Teikoku Seiyaku Kk Nicotine-containing cataplasm for oral cavity membrane
JPH03209326A (en) * 1990-01-11 1991-09-12 Teikoku Seiyaku Kk Nicotine-containing cataplasm for oral cavity membrane
US4996315A (en) * 1990-01-16 1991-02-26 Texaco Chemical Company Novel synthesis of cyclic compounds
US5167242A (en) * 1990-06-08 1992-12-01 Kabi Pharmacia Aktiebolaq Nicotine-impermeable container and method of fabricating the same
FI913526A (en) 1990-08-23 1992-02-24 Wrigley W M Jun Co TUGGUMMI MED LAOG FUKTHALT.
US5488962A (en) * 1990-10-10 1996-02-06 Perfetti, S.P.A. Chewing gum which is a substitute for tobacco smoke
ATE217014T1 (en) * 1991-02-21 2002-05-15 Genencor Int METHOD FOR CONVERTING CELLULOSE MATERIAL INTO CRYSTALLINE CELLULOSE
US5135753A (en) * 1991-03-12 1992-08-04 Pharmetrix Corporation Method and therapeutic system for smoking cessation
GB9111224D0 (en) 1991-05-24 1991-07-17 Charwell Consumer Prod Smoking substitute preparation
RU2029474C1 (en) 1991-06-28 1995-02-27 Тетюшева Светлана Игоревна Chewing gum
US5326570A (en) * 1991-07-23 1994-07-05 Pharmavene, Inc. Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
DK0557129T3 (en) 1992-02-20 1997-04-14 Wielligh Johannes Louw Kot Von Product to help smokers quit smoking
US5654003A (en) * 1992-03-05 1997-08-05 Fuisz Technologies Ltd. Process and apparatus for making tablets and tablets made therefrom
FR2688400B1 (en) 1992-03-11 1999-06-25 Gilles Gagnot DEVICE FOR WASHING PERIODONTAL POCKETS OF A PATIENT.
CA2095776C (en) 1992-05-12 2007-07-10 Richard C. Fuisz Rapidly dispersable compositions containing polydextrose
FR2698268B1 (en) 1992-11-24 1995-01-20 Oreal Photoprotective composition administered orally.
CN1034551C (en) 1993-01-01 1997-04-16 丘波岭 New use of nicotinic acid and its derivative
DE4301782C1 (en) 1993-01-23 1994-08-25 Lohmann Therapie Syst Lts Use of galanthamine to treat nicotine addiction
US5573774A (en) * 1993-02-02 1996-11-12 Keenan; Robert M. Nicotine metabolites, nicotine dependence and human body weight
GB9310412D0 (en) * 1993-05-20 1993-07-07 Danbiosyst Uk Nasal nicotine system
US5318523A (en) * 1993-07-13 1994-06-07 Lu Jieh Shan Drug-feeder for children
US5549906A (en) * 1993-07-26 1996-08-27 Pharmacia Ab Nicotine lozenge and therapeutic method for smoking cessation
US5362496A (en) * 1993-08-04 1994-11-08 Pharmetrix Corporation Method and therapeutic system for smoking cessation
CN1089834A (en) 1993-10-14 1994-07-27 王子芸 The prescription of chewing gum for giving-up smoking and processing technique
SE9303574D0 (en) 1993-11-01 1993-11-01 Kabi Pharmacia Ab Composition for drug delivery and method of manufacturing thereof
SE502268C2 (en) 1994-01-26 1995-09-25 Aga Ab Method, use and preparation of aerosol for drug distribution containing helium and / or neon
GB2289204B (en) 1994-04-21 1998-01-14 Williamson Research Limited A chewing gum for use as a nicotine substitute and slimming aid
AU2703795A (en) * 1994-06-23 1996-01-19 Procter & Gamble Company, The Treatment of nicotine craving and/or smoking withdrawal symptoms with a transdermal or transmucosal composition containing nicotine and caffeine or xanthine
IT1274034B (en) 1994-07-26 1997-07-14 Applied Pharma Res PHARMACEUTICAL COMPOSITIONS BASED ON RUBBER TO BE CHEWED AND PROCEDURE FOR THEIR PREPARATION
US5507278A (en) * 1994-11-18 1996-04-16 Karell; Manuel L. Tongue-guard for inhaler
US5810018A (en) * 1994-12-29 1998-09-22 Monte; Woodrow C. Method, composition and apparatus for reducing the incidence of cigarette smoking
CN1125636C (en) * 1995-02-08 2003-10-29 山之内欧洲有限公司 Oral dosage-forms containing a'beta'-lactam antibiotic
ES2247598T3 (en) 1995-05-11 2006-03-01 University Of Utah Research Foundation TOBACCO SUBSTITUTE.
JPH11508593A (en) 1995-07-05 1999-07-27 ザ、プロクター、エンド、ギャンブル、カンパニー Heating compound
SE9503154D0 (en) 1995-09-13 1995-09-13 Pharmacia Ab Method for marking objects and objects being marked with such method
US6506425B2 (en) * 1995-09-13 2003-01-14 Pharmacia Ab Packaged markable ingestible compressible object
US5875774A (en) 1996-01-05 1999-03-02 Sunrise Medical Hhg Inc. Nebulizer
US5692493A (en) * 1996-03-08 1997-12-02 Diemolding Corporation Tongue Protector
US5955098A (en) 1996-04-12 1999-09-21 Flemington Pharmaceutical Corp. Buccal non polar spray or capsule
ATE260646T1 (en) 1996-04-16 2004-03-15 Novartis Consumer Health Sa RAPID DISSOLVING ORAL DOSAGE FORM
CA2178021C (en) * 1996-04-19 1999-09-28 Theodore H. Stanley Tobacco substitute
TW506836B (en) * 1996-06-14 2002-10-21 Janssen Pharmaceutica Nv Fast-dissolving galanthamine hydrobromide tablet
BR9710265A (en) 1996-07-12 1999-08-10 Daiichi Seiyaku Co Compression molded materials quickly disintegrated and process for producing them
US5667838A (en) 1996-09-05 1997-09-16 The Procter & Gamble Company Separately milling nut solids and particulate water soluble solids to reduce stickiness and improve flavor intensity of nut spreads
DE19639343C2 (en) 1996-09-25 1998-10-08 Suedzucker Ag Comprimate containing a sweetener mixture
GB2318737B (en) 1996-10-30 2000-06-14 Bespak Plc Improved inhalers
JPH10287561A (en) * 1997-04-11 1998-10-27 Taisho Pharmaceut Co Ltd Solid preparation compounded with ibuprofen and its production
US6024981A (en) 1997-04-16 2000-02-15 Cima Labs Inc. Rapidly dissolving robust dosage form
CN1089834C (en) 1997-06-27 2002-08-28 南京英达机械制造有限公司 Method and apparatus for heating, regenerating and repairing asphalt pavement
SE9703458D0 (en) 1997-09-25 1997-09-25 Pharmacia & Upjohn Ab Nicotine compositions and methods of formulation thereof
US6908631B1 (en) * 1997-12-01 2005-06-21 Nicogen, Inc. Therapeutic and diagnostic methods dependent on CYP2A enzymes
US6265541B1 (en) * 1997-12-31 2001-07-24 University Of Utah Research Foundation Uses of α-conotoxin peptides
DE29800300U1 (en) 1998-01-09 1998-04-23 Wieninger, Dieter, Dr., 94036 Passau Nicotine and its derivatives in combination with an antitussive
DK1069900T3 (en) 1998-04-09 2005-10-31 Pharmacia & Upjohn Co Llc Use of reboxetine for the treatment of neuropsychiatric disorders
US6211194B1 (en) * 1998-04-30 2001-04-03 Duke University Solution containing nicotine
WO1999063969A1 (en) 1998-06-08 1999-12-16 Groenewoud Pieter J Stabilized thyroxine medications
WO1999065550A1 (en) 1998-06-15 1999-12-23 Karl Holm Inhalation device
US6476078B2 (en) * 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
US6358060B2 (en) * 1998-09-03 2002-03-19 Jsr Llc Two-stage transmucosal medicine delivery system for symptom relief
US6344222B1 (en) * 1998-09-03 2002-02-05 Jsr Llc Medicated chewing gum delivery system for nicotine
US20020098264A1 (en) 1998-11-27 2002-07-25 Cherukuri Subraman R. Medicated chewing gum delivery system for nicotine
US5997905A (en) * 1998-09-04 1999-12-07 Mcneil-Ppc Preparation of pharmaceutically active particles
AU6412299A (en) 1998-10-08 2000-04-26 Biovail Technologies Limited Composition and method for medicated chewing gum delivery system
JP2000128776A (en) * 1998-10-19 2000-05-09 Asahi Chem Ind Co Ltd Film-coated granule and its production
DE69939457D1 (en) 1998-11-06 2008-10-16 Fuji Chem Ind Co Ltd TOCOTRIENOLE CONTAINING POWDER AND TABLETS MADE BY FORMPRESSING THESE POWDER
US6232082B1 (en) * 1998-12-01 2001-05-15 Nabi Hapten-carrier conjugates for treating and preventing nicotine addiction
US6551634B2 (en) 1998-12-09 2003-04-22 Hans Boerge Joergensen Method for production of chewing or bubble gum pieces
US7163705B2 (en) 1998-12-15 2007-01-16 Wm. Wrigley Jr. Company Coated chewing gum product and method of making
CA2355777A1 (en) * 1998-12-15 2000-06-22 Wm. Wrigley Jr. Company Controlling release of active agents from a chewing gum coating
US6627234B1 (en) 1998-12-15 2003-09-30 Wm. Wrigley Jr. Company Method of producing active agent coated chewing gum products
US6586023B1 (en) 1998-12-15 2003-07-01 Wm. Wrigley Jr. Company Process for controlling release of active agents from a chewing gum coating and product thereof
JP2002532393A (en) 1998-12-16 2002-10-02 ユニヴァーシティー オブ サウス フロリダ Exo-R-mecamylamine formulations and their use in therapy
US6734215B2 (en) * 1998-12-16 2004-05-11 University Of South Florida Exo-S-mecamylamine formulation and use in treatment
ES2211215T3 (en) 1998-12-24 2004-07-01 Janssen Pharmaceutica N.V. COMPOSITION OF GALANTAMINE CONTROLLED LIBERATION.
US6855820B2 (en) * 1999-01-20 2005-02-15 Smithkline Beecham Corporation Pharmaceutically active morpholinol
SE9900215D0 (en) 1999-01-26 1999-01-26 Pharmacia & Upjohn Ab New use
FR2788982B1 (en) 1999-02-02 2002-08-02 Synthelabo PHARMACEUTICAL COMPOSITIONS CONTAINING NICOTINE AND THEIR APPLICATION IN SMOKING WITHDRAWAL
CA2359640C (en) 1999-02-05 2008-11-18 Cipla Limited Topical sprays
US6982089B2 (en) 1999-02-24 2006-01-03 Tact Ip, Llc Cytokine antagonists for neurological and neuropsychiatric disorders
US7374779B2 (en) * 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
JP2002539236A (en) 1999-03-22 2002-11-19 アーテーペー アバン−ギャルド テクノロジーズ アンド プロダクト マーケティング アンド ライセンシング ソシエテ アノニム Composition for medicated chewing gum, and method for producing the composition and tablets thereof
US6426090B1 (en) 1999-04-06 2002-07-30 Wm. Wrigley Jr. Company Over-coated product including tableted center and medicament
US6322806B1 (en) 1999-04-06 2001-11-27 Wm. Wrigley Jr. Company Over-coated chewing gum formulations including tableted center
US6355265B1 (en) 1999-04-06 2002-03-12 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US6773716B2 (en) 1999-04-06 2004-08-10 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US20010016593A1 (en) * 1999-04-14 2001-08-23 Wilhelmsen Paul C. Element giving rapid release of nicotine for transmucosal administration
FR2792200B3 (en) 1999-04-16 2001-06-08 Unicliffe Ltd SUBSTITUTE OF TOBACCO IN THE FORM OF A TABLET OR A SUCKING TABLET
JP4249847B2 (en) * 1999-05-31 2009-04-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Orally disintegrating tablets containing vitamin K
US8256433B2 (en) 1999-07-16 2012-09-04 Aradigm Corporation Systems and methods for effecting cessation of tobacco use
US20080138399A1 (en) 1999-07-16 2008-06-12 Aradigm Corporation Dual release nicotine formulations, and systems and methods for their use
US20080138398A1 (en) 1999-07-16 2008-06-12 Aradigm Corporation Dual release nicotine formulations, and systems and methods for their use
US6799576B2 (en) 1999-07-16 2004-10-05 Aradigm Corporation System for effecting smoking cessation
DE19943491B4 (en) 1999-09-10 2010-04-01 Südzucker AG Mannheim/Ochsenfurt Improved compressed
US6322828B1 (en) 1999-09-13 2001-11-27 Deseret Laboratories, Inc. Process for manufacturing a pharmaceutical chewing gum
EP1231900A1 (en) 1999-11-23 2002-08-21 The Robert Gordon University Bilayered buccal tablets comprising nicotine
GB0004708D0 (en) 2000-02-28 2000-04-19 Britannia Pharmaceuticals Ltd Restricting reinstatement of drug use
DE10013712A1 (en) 2000-03-20 2001-09-27 Nutrinova Gmbh Nicotine salts with improved taste, process for their preparation and their use
US20010036943A1 (en) 2000-04-07 2001-11-01 Coe Jotham W. Pharmaceutical composition for treatment of acute, chronic pain and/or neuropathic pain and migraines
US6607752B2 (en) * 2000-07-27 2003-08-19 Rohm And Haas Company Method for the anhydrous loading of nicotine onto ion exchange resins
NZ524741A (en) * 2000-08-16 2005-01-28 Upjohn Co Heterocyclic amines, phenylazacycloalkanes, cabergoline and aromatic bicyclic amines for the treatment of alcohol, nicotine and drug addiction
DE10044545A1 (en) 2000-09-05 2002-04-04 Roland Bodmeier Retardpartikeldispersion
DE60223659T2 (en) 2001-03-23 2008-10-30 Gumlink A/S One-step process for the production of chewing gum
US6861434B2 (en) * 2001-04-26 2005-03-01 Wyeth Antipsychotic aminomethyl derivatives of 1,3,7,8-tetrahydro-6,9-dioxa-1,3-diaza-cyclopenta[a]-naphthalen-2-one
US6872405B2 (en) 2001-05-10 2005-03-29 Yamanouchi Pharmaceutical Co., Ltd. Quick-disintegrating tablet in buccal cavity and manufacturing method thereof
KR20010078976A (en) 2001-05-28 2001-08-22 전창호 Compound of chewing gum
SE0102197D0 (en) 2001-06-20 2001-06-20 Pharmacia Ab New product and use and manufacture thereof
US6602518B2 (en) 2001-06-28 2003-08-05 Wm. Wrigley Jr. Company Chewable product including active ingredient
US6849624B2 (en) 2001-07-31 2005-02-01 Hoffmann-La Roche Inc. Aromatic and heteroaromatic substituted amides
JP2005510339A (en) 2001-08-08 2005-04-21 ザ プロクター アンド ギャンブル カンパニー Doped highly active adsorbent material
US7208186B2 (en) 2001-09-18 2007-04-24 Spi Pharma, Inc. Chewing gum formulation and method of making the same
HU227543B1 (en) * 2001-09-28 2011-08-29 Richter Gedeon Nyrt N-[4-(2-piperazin- and 2-piperidin-1-yl-ethyl)-cyclohexyl]-sulfon- and sulfamides, process for their preparation, their use and pharmaceutical compositions containing them
ATE276676T1 (en) * 2001-10-22 2004-10-15 Ivo Pera COMPOSITION FOR REDUCING OR CANCELING NICOTINE DEPENDENCE
US20030082109A1 (en) * 2001-10-30 2003-05-01 Leonard Gorenstein Dextrorotary nicotine for smoking cessation
US20040037879A1 (en) * 2001-11-02 2004-02-26 Adusumilli Prasad S. Oral controlled release forms useful for reducing or preventing nicotine cravings
US6599901B1 (en) 2001-11-19 2003-07-29 Hoffman-La Roche Inc. Pyridone substituted benzothiazole derivatives
FR2832311B1 (en) * 2001-11-21 2004-04-16 Besins Int Belgique FILM-FORMING POWDER, COMPOSITIONS COMPRISING SAME, PREPARATION METHODS AND USES THEREOF
NZ532435A (en) * 2001-11-30 2005-04-29 Pfizer Prod Inc Pharmaceutical compositions of 5,7,14-triazatetracyclo [10.3.1.0(2,11).0(4,9)]-hexadeca-2(11)3,5,7,9-pentaene
US20060057207A1 (en) * 2001-11-30 2006-03-16 Pfizer Inc Fast-disintegrating dosage forms of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene
JP2005510568A (en) * 2001-11-30 2005-04-21 ファイザー・プロダクツ・インク Azapolycyclic compounds with aryl groups attached
WO2003053175A2 (en) 2001-12-21 2003-07-03 Galenica Ab Tobacco and/or tobacco substitute composition for use as a snuff in the oral cavity
DE10163667B4 (en) * 2001-12-21 2006-10-26 Hf Arzneimittelforschung Gmbh Use of deoxypeganine for the treatment of clinical depression
FR2834212B1 (en) 2001-12-27 2004-07-09 Besins Int Belgique USE OF IMMEDIATE RELEASE POWDER IN PHARMACEUTICAL AND NUTRACEUTICAL COMPOSITIONS
SE0104388D0 (en) 2001-12-27 2001-12-27 Pharmacia Ab New formulation and use and manufacture thereof
KR100352030B1 (en) * 2002-01-10 2002-09-11 Orion Corp Gum composition for removing nicotine
US20040102440A1 (en) 2002-07-01 2004-05-27 Wong Erik Ho Fong Method of promoting smoking cessation
WO2003061399A1 (en) 2002-01-25 2003-07-31 De Abhijit Chewing gum composition and a process for preparing the same
AU2003213140A1 (en) * 2002-03-01 2003-10-13 The Board Of Regents Of The University Of Nebraska Compositions and compounds for use as molecular adjuvant for a nicotine vaccine
US20030171408A1 (en) 2002-03-11 2003-09-11 Caplan Jay L. Therapeutic method of delivering a medicament to avoid irritating effects on membranes of user
SE0200895D0 (en) 2002-03-22 2002-03-22 Astrazeneca Ab New pharmaceutical composition
US6797707B2 (en) * 2002-03-29 2004-09-28 University Of Florida Antagonists of RF-amide neuropeptides
EP1350434A1 (en) 2002-04-05 2003-10-08 Gum Base Co. S.p.A. Chewing gum in powder form and method of preparation
CN1383814A (en) 2002-05-28 2002-12-11 沈阳东宇工业技术研究院有限公司 Oral quick disintegrating tablet and its prepn process
US6586449B1 (en) * 2002-05-28 2003-07-01 Cambrex Charles City, Inc. Nicotine-containing, controlled release composition and method
SE0201669D0 (en) 2002-06-03 2002-06-03 Pharmacia Ab New formulation and use thereof
ITMI20021392A1 (en) 2002-06-25 2003-12-29 Nicox Sa PHARMACEUTICAL FORMS FOR THE ORAL ADMINISTRATION OF LIQUID DRUGS AT AMBIENT TEMPERATURE EQUIPPED WITH BETTER BIOAVAILABILITY
US20040002520A1 (en) 2002-07-01 2004-01-01 Soderlund Patrick L. Composition and method for cessation of Nicotine cravings
ATE399467T1 (en) 2002-07-02 2008-07-15 Gumlink As COMPRESSED RESIN-MODERATED CHEWING GUM
AU2002320959A1 (en) 2002-07-02 2004-01-23 Gumlink As Compressed chewing gum tablet ii
WO2004004479A1 (en) 2002-07-02 2004-01-15 Gumlink A/S Compressed chewing gum
KR20050075281A (en) 2002-07-04 2005-07-20 쉬바르츠파르마에이지 Utilization of heteroarene carboxamide as dopamine-d3 ligands for the treatment of cns diseases
US20040013752A1 (en) * 2002-07-05 2004-01-22 Wolfson Philip E. Buccal and sublingual mucosally absorbed herbal compositions for relieving nicotine withdrawal symptoms and craving for nicotine and nicotine containing substances
JP5084103B2 (en) * 2002-07-18 2012-11-28 サイトス バイオテクノロジー アーゲー Hapten carrier conjugates and uses thereof
AU2003268026A1 (en) 2002-07-30 2004-02-16 Peter Migaly Combination therapy for depression, prevention of suicide, and varous medical and psychiatric conditions
US8216609B2 (en) 2002-08-05 2012-07-10 Torrent Pharmaceuticals Limited Modified release composition of highly soluble drugs
SE0202465D0 (en) 2002-08-14 2002-08-14 Astrazeneca Ab New compounds
SE0202430D0 (en) 2002-08-14 2002-08-14 Astrazeneca Ab New Compounds
EP1539149B1 (en) 2002-09-10 2012-01-04 Novartis AG Combinations of metabotropic glutamate receptor antagonists and their use in treating addictive disorders
US7345092B2 (en) * 2002-09-12 2008-03-18 Summit Vetpharm, Llc High concentration topical insecticides containing pyrethroids
GB2393392A (en) 2002-09-17 2004-03-31 Abhijit De Betel nut and nicotine chewing gum
CN100471398C (en) 2002-09-24 2009-03-25 古木林科有限公司 Chewing gum comprising at least two different biodegradable polymers
DE60228341D1 (en) 2002-09-24 2008-09-25 Gumlinck As BIODEGRADABLE CHEWING GUM CONTAINING AT LEAST ONE BIODEGRADABLE POLYMER WITH HIGH MOLECULAR WEIGHT
CN1315394C (en) 2002-09-24 2007-05-16 古木林科有限公司 Low moisture chewing gum
CN1668206A (en) 2002-09-24 2005-09-14 古木林科有限公司 Chewing gum having improved release of chewing gum ingredients
BR0317392A (en) * 2002-12-19 2005-12-20 Pharmacia Corp Non-hygroscopic formulation including a hygroscopic drug
EP1575384B1 (en) 2002-12-19 2011-06-15 Swedish Match North Europe AB A non-chewable tobacco composition
DK1803443T3 (en) * 2002-12-20 2019-02-25 Niconovum Ab Nicotine-containing particulate material with a crystalline cellulose
CN1511550A (en) 2002-12-27 2004-07-14 袁冀平 Medicinal preparation for reducing nicotine and use
US7361667B2 (en) 2003-01-09 2008-04-22 P2D, Inc. 4′,4″-substituted 3α-(diphenylmethoxy) tropane analogs for treatment of mental disorders
JP5283334B2 (en) 2003-01-24 2013-09-04 マグル ホールディング エービー Composition material for transmucosal transmission
SE0302947D0 (en) 2003-01-24 2003-11-07 Magle Ab A composition material for transmucosal delivery
US20040151771A1 (en) 2003-02-04 2004-08-05 Gin Jerry B. Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth
WO2004068965A1 (en) 2003-02-04 2004-08-19 Gumlink A/S Compressed chewing gum tablet
MXPA05007346A (en) 2003-02-04 2005-09-30 Gumlink As Compressed chewing gum tablet.
EP1449525A1 (en) 2003-02-20 2004-08-25 Cross Chem Llc chewing gum in the form of multi-layer tablets
DK1599186T3 (en) 2003-02-24 2013-07-08 Pharmaceutical Productions Inc TRANSMUKAL MEDICINE ADMINISTRATION SYSTEM
US20040224963A1 (en) 2003-05-09 2004-11-11 Pfizer Inc Pharmaceutical composition for the prevention and treatment of nicotine addiction in a mammal
EP1633358A1 (en) 2003-05-20 2006-03-15 Pfizer Products Inc. Pharmaceutical compositions of varenicline
WO2005040338A2 (en) 2003-05-21 2005-05-06 The Scripps Research Institute Constrained alkaloid immunogens and antibodies and uses thereof
JP2005025135A (en) * 2003-07-04 2005-01-27 Showa Electric Wire & Cable Co Ltd High reliability optical waveguide type device
JP2006528169A (en) 2003-07-21 2006-12-14 ファイザー・プロダクツ・インク Heteroaryl fused azapolycyclic compounds reduce nicotine addiction
US20050058609A1 (en) * 2003-07-22 2005-03-17 Alireza Nazeri Medicated toothpick
WO2005018348A2 (en) 2003-08-11 2005-03-03 William Whalen Chewing tobacco substitute with nicotine
ES2300807T3 (en) 2003-09-05 2008-06-16 Actelion Pharmaceuticals Ltd. GUANIDINE DERIVATIVES
KR100526760B1 (en) 2003-09-05 2005-11-08 김현석 An oriental herb extracts composition having detoxification effect on the nicotine and dioxin
EP1663168B1 (en) 2003-09-08 2009-02-11 McNeil AB Nicotine formulations and use thereof
AU2003286868A1 (en) 2003-09-15 2005-04-27 Luis Viola Solution for cessation of smoking and method to use
CN1871244A (en) 2003-09-19 2006-11-29 弗·哈夫曼-拉罗切有限公司 Thiazolopyridine derivatives as adenosine receptor ligands
JP4317729B2 (en) 2003-10-01 2009-08-19 ジ・エコ株式会社 Non-smoking socks and their manufacturing method
US20050123502A1 (en) * 2003-10-07 2005-06-09 Chan Shing Y. Nicotine containing oral compositions
DK1678172T3 (en) * 2003-10-15 2010-04-06 Targacept Inc Azabicyclic compounds for pain relief and treatment of central nervous system disorders
US20050100513A1 (en) * 2003-11-10 2005-05-12 Watkins Mary B. Homeopathic method and system for treating nicotine addiction
US7816356B2 (en) * 2003-11-14 2010-10-19 Daniel Yohannes Aryl and heteroaryltetrahydrocyclobutapyrroles as nicotinic acetylcholine receptor ligands
ATE439839T1 (en) 2003-12-02 2009-09-15 Fertin Pharma As NICOTINE DELIVERY PRODUCT AND PRODUCTION METHOD
TW200522944A (en) 2003-12-23 2005-07-16 Lilly Co Eli CB1 modulator compounds
CN1557177A (en) 2004-02-05 2004-12-29 高永安 Vitamine, anti oxidant nutrient, microelement containing chewing gum
US20050222270A1 (en) 2004-02-26 2005-10-06 Olney John W Prolonged administration of NMDA antagonist drug and safener drug to create improved stable neural homeostasis
IL160753A0 (en) 2004-03-04 2004-08-31 Smoking cessation pacifier
US20050226920A1 (en) * 2004-04-13 2005-10-13 Kirk Voelker Method of decreasing nicotine withdrawal symptoms during smoking cessation.
SE0402258D0 (en) 2004-05-07 2004-09-17 Katarina Saend Portion
AU2005244966A1 (en) 2004-05-21 2005-12-01 Alza Corporation Dosage form for delivery of multiple drug forms
DE602005004142T2 (en) * 2004-05-24 2009-01-02 F. Hoffmann-La Roche Ag 4-hydroxy-4-methylpiperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-YLBENZOTHIAZOL-2-yl) -amide
WO2005115471A2 (en) * 2004-05-27 2005-12-08 Neurocure Ltd. Methods and compositions for treatment of nicotine dependence and dementias
WO2006000232A1 (en) 2004-06-29 2006-01-05 Fertin Pharma A/S Tobacco alkaloid releasing chewing gum
US20060062835A1 (en) * 2004-07-19 2006-03-23 Smoke Free In 3, Inc. Multi-disciplinary nicotine craving reduction kit with potentiating homeopathic elements
DE602005019408D1 (en) 2004-07-22 2010-04-01 Hoffmann La Roche benzothiazole
RU2381227C2 (en) 2004-07-22 2010-02-10 Ф. Хоффманн-Ля Рош Аг Substituted benzothiazoles
JP2008510711A (en) * 2004-08-20 2008-04-10 ターガセプト，インコーポレイテッド Use of N-aryl diazaspira cyclic compounds in the treatment of addiction
JP5022901B2 (en) 2004-09-09 2012-09-12 インダストリー−アカデミック コープレーション ファンデーション テグ ハーニ ユニバーシティ Composition comprising purified essential oil extract and lower alcohol soluble extract isolated from Angelica giga for prevention and treatment of nicotine addiction and withdrawal symptoms
GT200500246A (en) 2004-09-09 2006-04-17 COMBINATION OF ORGANIC COMPOUNDS
WO2006041769A2 (en) 2004-10-05 2006-04-20 Merck & Co., Inc. Methods for the treatment of substance abuse and addiction
DE102004048927A1 (en) 2004-10-06 2006-04-20 Lts Lohmann Therapie-Systeme Ag Pharmaceutical combination containing deoxypeganine and Cyp2D6 inhibitors
EP1802276A1 (en) * 2004-10-15 2007-07-04 Pfizer Products Inc. Compositions and methods for intranasal, buccal, sublingual and pulmonary delivery of varenicline
ES2393191T3 (en) 2004-11-30 2012-12-19 Fertin Pharma A/S Method to provide quick relief to a consumer of a nicotine gum
RU2007133503A (en) 2005-02-10 2009-03-20 Орексо Аб (Se) NEW PHARMACEUTICAL COMPOSITIONS SUITABLE FOR TRANSMUZOSAL DOSAGE OF MEDICINES
WO2006115202A1 (en) 2005-04-25 2006-11-02 Fuji Sangyo Co., Ltd. Composition for lessening nicotine toxicity
EP1904182A2 (en) * 2005-05-06 2008-04-02 Boehringer Ingelheim International GmbH Method for the treatment of drug abuse with flibanserin
US8323683B2 (en) 2005-05-18 2012-12-04 Mcneil-Ppc, Inc. Flavoring of drug-containing chewing gums
US7629342B2 (en) 2005-06-17 2009-12-08 Bristol-Myers Squibb Company Azabicyclic heterocycles as cannabinoid receptor modulators
WO2007006117A1 (en) 2005-07-13 2007-01-18 Nicogen Inc. Novel cyp2a6 inhibitors
US20070134169A1 (en) 2005-12-11 2007-06-14 Rabinoff Michael D Methods for smoking cessation or alcohol cessation or other addiction cessation
EP1998754A2 (en) 2006-03-16 2008-12-10 NicoNovum AB Stable lozenge compositions providing rapid release of nicotine
CA2646942C (en) 2006-03-16 2014-07-29 Niconovum Ab Improved snuff composition
US8642016B2 (en) 2006-07-21 2014-02-04 Jsrnti, Llc Medicinal delivery system, and related methods
MX2009005671A (en) 2006-12-01 2009-06-08 Cima Labs Inc Oral transmucosal nicotine dosage form.
US20080286340A1 (en) 2007-05-16 2008-11-20 Sven-Borje Andersson Buffered nicotine containing products
US20080286341A1 (en) 2007-05-16 2008-11-20 Sven-Borje Andersson Buffered coated nicotine containing products
US20080292683A1 (en) 2007-05-24 2008-11-27 Monosolrx, Llc. Film shreds and delivery system incorporating same
US20090081291A1 (en) 2007-09-26 2009-03-26 Gin Jerry B Sustained Release Dosage Forms For Delivery of Agents to an Oral Cavity of a User
US20090098192A1 (en) 2007-10-11 2009-04-16 Fuisz Richard C Extrudable and Extruded Compositions for Delivery of Bioactive Agents, Method of Making Same and Method of Using Same
FR2984713B1 (en) 2011-12-22 2013-12-27 Seb Sa CULINARY ELECTRICAL APPARATUS AND RELATED SECURITY MEANS

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4317837A (en) * 1980-11-25 1982-03-02 Life Savers, Inc. Tobacco-flavored chewing gum
US4907605A (en) * 1985-05-24 1990-03-13 Advanced Tobacco Products, Inc. Oral tabacco substitute
FR2608156A1 (en) * 1986-12-12 1988-06-17 Ethypharm Sa Chewing gum for releasing tobacco
WO1991001656A1 (en) * 1989-07-31 1991-02-21 Svein Knudsen Means for use as an aid to stop smoking or for use in non-smoking areas
US5656255A (en) * 1992-01-03 1997-08-12 Pharmacia & Upjohn Ab Composition to help stop smoking
WO1997042941A2 (en) * 1996-05-13 1997-11-20 Novartis Consumer Health S.A. Buccal delivery system
US6264981B1 (en) * 1999-10-27 2001-07-24 Anesta Corporation Oral transmucosal drug dosage using solid solution

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch, Week 198651 Derwent Publications Ltd., London, GB; Class A96, AN 1986-335982 XP002247927 & JP 61 251619 A (NITTO ELECTRIC IND CO) 8 November 1986 (1986-11-08) *
DATABASE WPI Section Ch, Week 199143 Derwent Publications Ltd., London, GB; Class A96, AN 1991-314169 XP002247929 & JP 03 209326 A (TEIKOKU SEIYAKU KK) 12 September 1991 (1991-09-12) *
DATABASE WPI Section Ch, Week 199143 Derwent Publications Ltd., London, GB; Class A96, AN 1991-314170 XP002247928 & JP 03 209327 A (TEIKOKU SEIYAKU KK) 12 September 1991 (1991-09-12) *

Cited By (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1803443A3 (en) * 2002-12-20 2007-07-18 NicoNovum AB A method for the preparation of a nicotine-containing particulate material with a crystalline cellulose (in particular MCC)
EP3473251A1 (en) * 2002-12-20 2019-04-24 NicoNovum AB A nicotine-cellulose combination
US9629832B2 (en) 2002-12-20 2017-04-25 Niconovum Usa, Inc. Physically and chemically stable nicotine-containing particulate material
EP1803444A3 (en) * 2002-12-20 2007-07-18 NicoNovum AB A method for the preparation of a nicotine-containing particulate material with a crystalline cellulose (in particular MCC)
EP1803443A2 (en) * 2002-12-20 2007-07-04 NicoNovum AB A method for the preparation of a nicotine-containing particulate material with a crystalline cellulose (in particular MCC)
WO2005023227A2 (en) * 2003-09-08 2005-03-17 Pfizer Health Ab Nicotine formulations and use thereof
WO2005023227A3 (en) * 2003-09-08 2005-06-16 Pfizer Health Ab Nicotine formulations and use thereof
US8828361B2 (en) 2004-06-29 2014-09-09 Fertin Pharma A/S Tobacco alkaloid releasing chewing gum
US8529875B2 (en) 2004-06-29 2013-09-10 Fertin Pharma A/S Tobacco alkaloid releasing chewing gum
JP4750127B2 (en) * 2004-11-30 2011-08-17 フェルティン ファルマ アー／エス How to bring quick relief to nicotine chewing gum users
US8858919B2 (en) 2004-11-30 2014-10-14 Fertin Pharma A/S Method of providing fast relief to a user of a nicotine chewing gum
JP2008521414A (en) * 2004-11-30 2008-06-26 フェルティン ファルマ アー／エス How to bring quick relief to nicotine chewing gum users
US8524196B2 (en) 2004-11-30 2013-09-03 Fertin Pharma A/S Method of providing fast relief to a user of a nicotine chewing gum
WO2006124366A3 (en) * 2005-05-18 2007-01-25 Warner Lambert Co Flavoring of drug-containing chewing gums
WO2006124366A2 (en) 2005-05-18 2006-11-23 Mcneil-Ppc, Inc. Flavoring of drug-containing chewing gums
US8658200B2 (en) 2005-05-18 2014-02-25 Mcneil-Ppc, Inc. Flavoring of drug-containing chewing gums
US8323683B2 (en) 2005-05-18 2012-12-04 Mcneil-Ppc, Inc. Flavoring of drug-containing chewing gums
WO2007104575A2 (en) * 2006-03-16 2007-09-20 Niconovum Ab Stable lozenge compositions providing rapid release of nicotine
WO2007104573A3 (en) * 2006-03-16 2008-01-03 Niconovum Ab Improved snuff composition
US10219999B2 (en) 2006-03-16 2019-03-05 Niconovum Usa, Inc. Snuff composition
WO2007104573A2 (en) * 2006-03-16 2007-09-20 Niconovum Ab Improved snuff composition
WO2007104574A2 (en) * 2006-03-16 2007-09-20 Niconovum Ab Chewing gum compositions providing rapid release of nicotine
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WO2007104575A3 (en) * 2006-03-16 2008-01-10 Niconovum Ab Stable lozenge compositions providing rapid release of nicotine
WO2007104574A3 (en) * 2006-03-16 2008-01-10 Niconovum Ab Chewing gum compositions providing rapid release of nicotine
US8642016B2 (en) 2006-07-21 2014-02-04 Jsrnti, Llc Medicinal delivery system, and related methods
US10799449B2 (en) 2006-07-21 2020-10-13 Jsrnti, Llc Medicinal delivery system and related methods
WO2009037319A3 (en) * 2007-09-18 2010-04-29 Niconovum Ab Stable chewing gum compositions comprising maltitol and providing rapid release of nicotine
US8833378B2 (en) 2008-09-17 2014-09-16 Niconovum Ab Process for preparing snuff composition
WO2010031552A1 (en) * 2008-09-17 2010-03-25 Niconovum Ab Process for preparing snuff composition
US9402810B2 (en) 2011-03-29 2016-08-02 Nyz Ab Pouch containing nicotine in free salt form
EP2768479B1 (en) 2011-10-21 2020-07-15 Modoral Brands Inc. Excipients for nicotine-containing therapeutic compositions
EP3744313A1 (en) * 2011-10-21 2020-12-02 Modoral Brands Inc. Excipients for nicotine-containing therapeutic compositions
WO2013059592A1 (en) * 2011-10-21 2013-04-25 Niconovum Usa, Inc. Excipients for nicotine-containing therapeutic compositions
US9907748B2 (en) 2011-10-21 2018-03-06 Niconovum Usa, Inc. Excipients for nicotine-containing therapeutic compositions
AU2013206983B2 (en) * 2012-01-05 2017-10-05 Mcneil Ab Solid nicotine-comprising dosage form with reduced organoleptic disturbance
CN104053433A (en) * 2012-01-05 2014-09-17 麦克内尔股份公司 Solid nicotine-comprising dosage form with reduced organoleptic disturbance
RU2623018C2 (en) * 2012-01-05 2017-06-21 Макней Аб Solid nicotine-containing dosage form with reduced unpleasant organoleptic impact
WO2013103318A1 (en) * 2012-01-05 2013-07-11 Mcneil Ab Solid nicotine-comprising dosage form with reduced organoleptic disturbance
US11458130B2 (en) 2013-07-11 2022-10-04 Alexza Pharmaceuticals, Inc. Nicotine salt with meta-salicylic acid and applications therein
US10166224B2 (en) 2013-07-11 2019-01-01 Alexza Pharmaceuticals, Inc. Nicotine salt with meta-salicylic acid and applications therein
US9724341B2 (en) 2013-07-11 2017-08-08 Alexza Pharmaceuticals, Inc. Nicotine salt with meta-salicylic acid
EP3021691B1 (en) 2013-07-19 2019-09-04 Altria Client Services LLC Methods and systems for incorporating nicotine into oral products
WO2015009913A1 (en) 2013-07-19 2015-01-22 Altria Client Services Inc. Methods and systems for incorporating nicotine into oral products
US11944115B2 (en) 2013-07-19 2024-04-02 Altria Client Services Llc Methods and systems for incorporating nicotine into oral products
US11076631B2 (en) 2013-07-19 2021-08-03 Altria Client Services Llc Methods and systems for incorporating nicotine into oral products
US10485247B2 (en) 2015-10-07 2019-11-26 Fertin Pharma A/S Chewing gum comprising nicotine
WO2017059858A1 (en) * 2015-10-07 2017-04-13 Fertin Pharma A/S Chewing gum comprising nicotine
US11717017B2 (en) 2017-04-24 2023-08-08 Swedish Match North Europe Ab Flavoured moist oral pouched nicotine product comprising triglyceride
WO2018197454A1 (en) 2017-04-24 2018-11-01 Swedish Match North Europe Ab A flavoured moist oral pouched nicotine product comprising triglyceride
WO2019105960A1 (en) * 2017-11-29 2019-06-06 Reemtsma Cigarettenfabriken Gmbh Method of manufacturing a filling material for a pouched smokeless snus product and filling material manufactured therefrom
EP3491940A1 (en) * 2017-11-29 2019-06-05 Reemtsma Cigarettenfabriken GmbH Method of manufacturing a filling material for a pouched smokeless snus product and filling material manufactured therefrom
US12041961B2 (en) 2017-11-29 2024-07-23 Reemtsma Cigarettenfabriken GmbM Method of manufacturing a filling material for a pouched smokeless snus product and filling material manufactured therefrom
WO2019115778A1 (en) 2017-12-15 2019-06-20 Swedish Match North Europe Ab A flavoured moist oral pouched nicotine product comprising monoglyceride
US11844368B2 (en) 2017-12-15 2023-12-19 Swedish Match North Europe Ab Flavoured moist oral pouched nicotine product comprising monoglyceride
US11801219B2 (en) 2019-10-04 2023-10-31 Schjoelin Evaggelos Pouch product suitable for application in an oral cavity
WO2021063727A1 (en) 2019-10-04 2021-04-08 Schjoelin Evaggelos A pouch product suitable for application in an oral cavity
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