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WO1998040051A1 - Systemes lipophiles binaires permettant l'administration de composes lipophiles - Google Patents

Systemes lipophiles binaires permettant l'administration de composes lipophiles Download PDF

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Publication number
WO1998040051A1
WO1998040051A1 PCT/US1998/004899 US9804899W WO9840051A1 WO 1998040051 A1 WO1998040051 A1 WO 1998040051A1 US 9804899 W US9804899 W US 9804899W WO 9840051 A1 WO9840051 A1 WO 9840051A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
weight
binary
binary composition
cyclosporine
Prior art date
Application number
PCT/US1998/004899
Other languages
English (en)
Inventor
Laman A. Al-Razzak
Panayiotis Pericleous Constantinides
Rong Gao
Dilip Kaul
John M. Lipari
Terrence B. Mazer
Lisa L. Mcchesney-Harris
Original Assignee
Abbott Laboratories
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
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to EP98909159A priority Critical patent/EP0973502A1/fr
Priority to CA002283780A priority patent/CA2283780A1/fr
Priority to JP53981798A priority patent/JP2001515491A/ja
Publication of WO1998040051A1 publication Critical patent/WO1998040051A1/fr

Links

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to pharmaceutical compositions containing lipophilic medicinal compounds, suitable for oral as well as topical, local and other routes of administration.
  • the invention relates to binary formulations of cyclosporines which comprise a lipophilic phase and one or more surfactants, but which lack a hydrophilic phase.
  • compositions which are highly lipophilic present considerable formulation challenges. Because of their low solubility in aqueous media, including the contents of the mammalian digestive tract, they often suffer from poor or variable bioavailability when given orally or via other routes that require transmembrane absorption. Examples of such medicinal compounds include the immunosuppressants cyclosporine and
  • FK506 tacrolimus
  • protease inhibitors such as ritonavir
  • central nervous system drugs such as tiagabine
  • anti-inflammatory agents such as zileuton and other 5-lipoxygenase inhibitors.
  • One method of formulating lipophilic compounds is to combine them with glyceride carriers which form emulsions upon mixing with water. Emulsions are described, for example, in U.S. Patent No. 4,388,307 issued to Cavanak, a commercial example of which is the cyclosporine-containing product SANDIMMUNE® oral solution.
  • This product comprises the emulsifier LABRAFTL® (a polyoxyethylated kernel oil), olive oil and alcohol, with the compound cyclosporin A present at a concentration of 100 mg/ml.
  • LABRAFTL® a polyoxyethylated kernel oil
  • olive oil and alcohol with the compound cyclosporin A present at a concentration of 100 mg/ml.
  • Cavanak suggests that such glyceride carriers may assist in alleviating problems of physical instability such as precipitation of the drug from solution, and may also enable higher plasma concentrations.
  • a preferred vehicle for lipophilic compounds is the so-called "self-emulsifying drug delivery system" which, when exposed to an aqueous medium, forms a fine oil-in-water emulsion with little or no agitation.
  • the property of self- emulsification permits such formulations to be administered in concentrated form, as for example in a hard gelatin or soft elastic capsule, with the expectation that a fine emulsion will be formed in the digestive tract.
  • self-emulsifying formulations when given orally, may offer improvements in both the rate and extent of absorption of the medicinal compound and can result in reduced variability in plasma concentration profiles. (See, S. A.
  • Previously-disclosed self-emulsifying systems include those in which a lipophilic drug is combined with mixtures of (i) medium-chain triglycerides and nonionic surfactants, (ii) vegetable oils and partial glycerides such as polyglycolyzed glycerides or medium-chain mono- and diglycerides, or (iii) vegetable oils and nonionic surfactants such as polysorbate 80 or PEG-25 glyceryl trioleate.
  • formulations have been characterized as self-emulsifying, including the above-mentioned SANDIMMUNE® cyclosporine formulation; however, these additionally contain a substantial amount of a solubilizing agent or solvent such as ethanol, rendering them unsuitable for certain uses such as filling into gelatin capsules, from which the solvent can readily escape.
  • a solubilizing agent or solvent such as ethanol
  • binary system As used herein, the terms “binary system”, “binary composition” and “binary system of excipients” include those formulations and compositions which contain, in addition to the active ingredient or ingredients, a combination of at least one lipophilic solvent and at least one surfactant in the absence of any hydrophilic solvents or excipients (such as water). For example, freeze-dried formulations that contain even a minimal amount of water are not considered to be binary compositions as that term is used herein.
  • a binary system of the invention is combined with a lipophilic active ingredient, such as a cyclosporine compound.
  • a lipophilic active ingredient such as a cyclosporine compound.
  • cyclosporine refers to one or more of the cyclosporines, and especially to cyclosporin A, as described in United States Patent No. 4,117,118 issued to Harri et al. and incorporated herein by reference.
  • binary compositions of the present invention may be selected which are bioequivalent to compositions that use the ternary excipient systems of the prior art; that is, when such binary and ternary compositions containing equal amounts of active ingredient are administered separately to comparable test subjects, about the same amount of active ingredient will be delivered to the subjects' bloodstreams by the inventive composition as by the ternary composition.
  • the amount of drug delivered may be measured by any of the methods known in the art, as for example the maximum plasma concentration (C max ), the time from dosing until the maximum plasma concentration is reached (T max ), and the integral or time-course of plasma concentration over time (area under the curve, or AUC).
  • the binary systems of the invention comprise a lipophilic phase and one or more surfactants.
  • lipophilic component or “lipophilic solvent” refers to a pharmaceutically acceptable solvent, carrier, excipient, or diluent that has an affinity for fats or lipids.
  • lipophilic phase refers to the portion of the composition that is lipophilic, which phase can be a single component or a mixture of components.
  • surfactant as used herein describes that portion of a composition of the invention which comprises one or more surfactants.
  • the surfactants may be any of the known pharmaceutically acceptable surfactants, including nonionic, anionic and cationic surfactants. A single surfactant or a mixture of surfactants may be used.
  • the lipophilic phase may comprise one or more of any of the known pharmaceutically acceptable lipophilic solvents or excipients that are capable of dissolving a cyclosporine compound.
  • Suitable classes of lipophilic solvents include, for example, fatty acid esters of glycerol; fatty acid esters of propylene glycol; vegetable oils; mineral oils; and acetylated mono- and diglycerides.
  • Preferred solvents include fatty acid esters of propylene glycol as well as C12 and longer fatty acid esters of glycerol .
  • Particular lipophilic phase components useful in the compositions of the invention include, but are not limited to, propylene glycol mono- and/or dicaprylate/caprates; propylene glycol mono- and/or dilaurate (for example, LAUROGLYCOL®, available from Gattefosse Corporation, Westwood, New Jersey); vegetable oil; corn oil; sesame oil; safflower oil; peanut oil; olive oil; cottonseed oil; glyceryl monostearate; glyceryl caprylate/caprate (for example, CAPMUL® MCM, available from Abitec Corporation, Columbus, Ohio); glyceryl mono-, di- and/or trioleate (for example, CAPMUL® GMO, available from Abitec Corporation), or PECEOL®, available from Gattefosse); caprylic/capric triglyceride (for example, NEOBEE® M-5, available from Stepan Corporation); and fractionated coconut oils, such as the MIGLYOL® 810, 812 and 818 products,
  • the lipophilic phase comprising one or more lipophilic solvents, generally comprises about 10 to 90% by weight of the pharmaceutical composition. The precise proportion will vary depending on the nature of the lipophilic solvent(s) used, the amount of active ingredient present, the dosage type, and other factors known to those of skill in the art. Preferably the lipophilic phase comprises about 20 to 85% by weight, and more preferably about 40 to 60% by weight of the pharmaceutical composition of the invention.
  • the binary systems of the present invention also comprise at least one surfactant in combination with the above lipophilic phase. While not intending to be bound by theory, the surfactant is believed to assist in the formation of a micellar system or a microsuspension upon contact with an aqueous medium such as gastrointestinal fluids in a way that the solubility of the active ingredient is enhanced.
  • the size of the particles present in this micellar or microsuspension system are in the sub-micron (sub-micrometer) range and can vary over time. Any of the known pharmaceutically acceptable surfactants may be used, including nonionic, anionic, cationic, and combinations thereof.
  • nonionic surfactants are preferred; especially preferred are (i) surfactants having a hydrophile/lipophile balance (HLB) of 10 or more or (ii) mixtures of surfactants which, when combined, exhibit a final HLB of 10 or more.
  • HLB hydrophile/lipophile balance
  • surfactants include, but are not limited to, polyoxyethylene derivatives of natural or hydrogenated vegetable oils such as castor oil; polyoxyethylene- sorbitan esters of fatty acids, such as mono-, di- and tri-lauryl, palmityl, stearyl and oleyl; polyoxyethylene fatty acid esters; polyoxyethylene-polyoxypropylene copolymers; alkyl/dialkylsulfate, sulfonate or sulfosuccinate salt; sodium lauryl sulfate; phospholipids such as lecithins; trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols; sorbitan fatty acid esters; pentaerythritol fatty acid esters and polyalkylene glycol ethers; and the like.
  • the surfactants may be used alone or in combination.
  • any pharmaceutically acceptable surfactant may be used in the binary system of the invention, certain surfactants are preferred.
  • polyoxyethylene castor oil derivatives such as polyoxyethylene-glycerol-triricinoleate, also known as polyoxyl 35 castor oil (CREMOPHOR® EL), or polyoxyl 40 hydrogenated castor oil (CREMOPHOR® RH40, both available from BASF Corp.
  • mono-fatty acid esters of polyoxyethylene (20) sorbitan such as polyoxyethylene(20)sorbitan monooleate (TWEEN® 80, available), polyoxyethylene monostearate (TWEEN® 60), polyoxyethylene (20) sorbitan monopalmitate (TWEEN® 40), polyoxyethylene (20) sorbitan monolaurate (TWEEN® 20, all available from ICI Surfactants, Wilmington, Delaware); polyglyceryl esters, such as polyglyceryl oleate; and LABRAFTL® Ml 944 CS polyoxyethylated kernel oil (available from
  • the polyoxyethylene castor oil derivatives are particularly preferred, with CREMOPHOR® EL and CREMOPHOR® RH40 the most preferred.
  • the proportion of this type of surfactant in the compositions of the invention increases above about 10% by weight, and upon dilution of the formulation with water or juice, the particle size of the resulting microemulsion or micellar solution decreases.
  • the particle size of the diluted formulation is generally less than about 120 nm; at a concentration of about 30% by weight the particle size is generally less than about 100 nm; and at a concentration of about 50% by weight the particle size is generally less than about 50 nm.
  • the surfactant component generally comprises about 5 to 90% by weight of the composition.
  • the surfactant comprises about 10 to 60% by weight of the composition, and more preferably about 30 to 50% by weight.
  • the active ingredient for example, a cyclosporine, will normally be present in amounts ranging from about 0.01 to 50% by weight of the composition. In a preferred embodiment of the invention the active ingredient is present in an amount ranging between about 5 and 15% by weight, with about 10% by weight particularly preferred. Of course, those of skill in the art understand that the amount of active ingredient present in the composition will vary with the particular situation, including the mode of administration, the size and condition of the subject, and other factors.
  • the compositions of the invention may additionally comprise other pharmaceutically acceptable excipients such as fillers, diluents, flavoring agents, coloring agents, antioxidants, preservatives such as antibacterial or antifungal agents, and the like.
  • Such additives may comprise about 0.01 to 10% by weight of the composition.
  • the pharmaceutical compositions of the invention may be administered by any of the methods known in the art. Such methods include but are not limited to oral administration of a suspension formed by mixing the composition of the invention with an aqueous medium such as water, milk or juice; in the form of a soft elastic or hard gelatin capsule into which the composition of the invention has been directly placed; parenteral administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection or infusion; or topical administration, such as by ointments, drops or transdermal patches.
  • Topical formulations intended for administration to the skin or mucosa including the surfaces of the lung and eye, may be prepared directly from the compositions of the invention or from a suspension or microsuspension prepared by combining an appropriate composition of the invention with an aqueous diluent.
  • Such topical formulations may include additional excipients as necessary, for example to modify consistency or the rate of absorption of the active ingredient.
  • compositions of the present invention may be combined in any order with mixing or light agitation to ensure complete solubilization. If necessary, the mixture may be warmed slightly to aid liquification and dissolution. If all components of the formulation are liquid at ambient temperatures (about 25 to 30°C), they may be combined without heating.
  • compositions and formulations of the invention may be administered in a sufficient amount, and for a sufficient time, as required to provide the desired therapeutic effect.
  • the specific therapeuticaUy effective dosage level wUl be dependent on a number of factors including the specific condition being treated, the severity of the disorder, the activity of the particular active ingredient, the specific formulation employed, the time and method of administration, the duration of treatment, and other factors which are weU known in the medical arts.
  • the invention wiU be better understood by reference to the following examples, which are understood to be Ulustrative only and are not intended as a Umitation upon the scope of the invention.
  • compositions were prepared by placing the component or components of the UpophUic phase into a suitable vessel, heating to a temperature of about 40 to 45 °C, and mixing until uniform.
  • the surfactant or surfactants were pre-melted, if necessary, and added, with continuous mixing, whUe maintaining the temperature at about 40 to 45°C.
  • the active ingredient(s) were then added, stirring continuously, with the temperature maintained at about 40 to 45 °C.
  • the product was transferred to appropriate containers and allowed to cool.
  • Examples 1 to 27 were prepared to Ulustrate the binary compositions of the present invention.
  • Example 28 was prepared as a comparative example of a formulation comprising a UpophiUc solvent in the absence of a surfactant.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
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  • Transplantation (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des préparations pharmaceutiques binaires comprenant (i) un composé de cyclosporine, (ii) une phase lipophile et (iii) un tensio-actif. Ces préparations assurent une biodisponibilité du composant actif équivalente à celle assurée par des compositions ternaires mais sans nécessiter de phase hydrophile.
PCT/US1998/004899 1997-03-12 1998-03-12 Systemes lipophiles binaires permettant l'administration de composes lipophiles WO1998040051A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP98909159A EP0973502A1 (fr) 1997-03-12 1998-03-12 Systemes lipophiles binaires permettant l'administration de composes lipophiles
CA002283780A CA2283780A1 (fr) 1997-03-12 1998-03-12 Systemes lipophiles binaires permettant l'administration de composes lipophiles
JP53981798A JP2001515491A (ja) 1997-03-12 1998-03-12 親油性化合物の投与のための親油性二成分系

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82039297A 1997-03-12 1997-03-12
US08/820,392 1997-03-12

Publications (1)

Publication Number Publication Date
WO1998040051A1 true WO1998040051A1 (fr) 1998-09-17

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EP (1) EP0973502A1 (fr)
JP (1) JP2001515491A (fr)
CA (1) CA2283780A1 (fr)
WO (1) WO1998040051A1 (fr)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000033862A1 (fr) 1998-12-11 2000-06-15 Pharmasolutions, Inc. Compositions auto-emulsifiantes pour medicaments peu solubles dans l'eau
WO2001012229A1 (fr) * 1999-08-17 2001-02-22 Ivax-Cr A.S. Compositions pharmaceutiques pour administration orale et topique
WO2001032143A1 (fr) * 1999-11-02 2001-05-10 Cipla Ltd. Composition pharmaceutique pour administer des substances actives sur le plan pharmaceutique insolubles dans l'eau et procede de preparation afferent
WO2001032142A1 (fr) * 1999-11-02 2001-05-10 Cipla Limited Formulation de cyclosporine
EP1158959A1 (fr) 1999-02-26 2001-12-05 Lipocine, Inc. Compositions et procedes pour l'administration amelioree d'agents therapeutiques hydrophobes
WO2001097832A1 (fr) * 2000-06-21 2001-12-27 Audit Institute For Medical Services And Quality Assurance Gmbh Preparations pharmaceutiques contenant des cylosporines et des huiles neutres
US6432445B1 (en) 1999-05-28 2002-08-13 Novartis Ag Pharmaceutical capsules comprising a cyclosporin
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
WO2004006890A1 (fr) * 2002-07-15 2004-01-22 Alcon, Inc. Compositions d'implants pharmaceutiques lipophiles non-polymeres pour utilisation intra-oculaire
WO2004012716A1 (fr) * 2002-08-02 2004-02-12 Smyth, Gyles, Darren Formulation pharmaceutique comprenant de la cyclosporine, un ester du propylene glycol et un tensioactif non ionique
EP1435233A1 (fr) * 2002-12-20 2004-07-07 Polichem S.A. Compositions pharmacéutiques comprenant des cyclosporines
AU2003254754B2 (en) * 1999-08-17 2006-01-12 Ivax Pharmaceuticals, S.R.O. Pharmaceutical compositions for oral and topical administration
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
WO2008041553A1 (fr) 2006-09-26 2008-04-10 Astellas Pharma Inc. Préparation à libération entretenue de tacrolimus
WO2008084698A1 (fr) 2006-12-28 2008-07-17 Astellas Pharma Inc. Composition pharmaceutique à libération entretenue de tacrolimus
WO2011055269A1 (fr) * 2009-11-09 2011-05-12 Pfizer Inc. Véhicule d'administration
US8591920B2 (en) * 2003-10-03 2013-11-26 Emerson Resources, Inc. Stable lipophilic emulsions for acrylic coating and method of making
WO2016071515A1 (fr) * 2014-11-07 2016-05-12 Sigmoid Pharma Limited Compositions comprenant de la cyclosporine
US9636300B2 (en) 2013-03-15 2017-05-02 Johnson & Johnson Consumer Inc. Racecadotril lipid compositions
US9675558B2 (en) 2007-04-04 2017-06-13 Sigmoid Pharma Limited Pharmaceutical cyclosporin compositions
US9821024B2 (en) 2010-11-25 2017-11-21 Sigmoid Pharma Limited Immunomodulatory compositions
US9999651B2 (en) 2009-05-18 2018-06-19 Sigmoid Pharma Limited Composition comprising oil drops
US10039712B2 (en) 2012-06-28 2018-08-07 Johnson & Johnson Consumer Inc. Racecadotril lipid compositions
US10434138B2 (en) 2013-11-08 2019-10-08 Sublimity Therapeutics Limited Formulations
US10894009B2 (en) * 2014-01-16 2021-01-19 Maruho Co., Ltd. Topical agent for transdermal administration

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2255786A1 (fr) * 2009-05-25 2010-12-01 HRA Pharma LLC Composition automicroémulsionnante de mitotane
WO2017047299A1 (fr) * 2015-09-15 2017-03-23 富士フイルム株式会社 Composition liquide pour injection
EP4431115A1 (fr) * 2022-03-28 2024-09-18 Chugai Seiyaku Kabushiki Kaisha Préparation pharmaceutique de composé contenant un constituant huileux comprenant une structure polyoxyéthylène

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2228198A (en) * 1989-02-20 1990-08-22 Sandoz Ltd Orally administrable cyclosporin solutions
WO1996033697A1 (fr) * 1995-04-24 1996-10-31 Yissum Research Development Company Of The Hebrew University Of Jerusalem Formulation auto-emulsionnable formant une emulsion huile dans l'eau
EP0760237A1 (fr) * 1995-08-30 1997-03-05 Cipla Limited Microémulsions huile-dans-l'eau

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2228198A (en) * 1989-02-20 1990-08-22 Sandoz Ltd Orally administrable cyclosporin solutions
WO1996033697A1 (fr) * 1995-04-24 1996-10-31 Yissum Research Development Company Of The Hebrew University Of Jerusalem Formulation auto-emulsionnable formant une emulsion huile dans l'eau
EP0760237A1 (fr) * 1995-08-30 1997-03-05 Cipla Limited Microémulsions huile-dans-l'eau

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6982282B2 (en) 1997-01-07 2006-01-03 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6667048B1 (en) 1997-01-07 2003-12-23 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6660286B1 (en) 1997-01-07 2003-12-09 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6638522B1 (en) 1998-12-11 2003-10-28 Pharmasolutions, Inc. Microemulsion concentrate composition of cyclosporin
EP1135150A4 (fr) * 1998-12-11 2006-05-17 Pharmasolutions Inc Compositions auto-emulsifiantes pour medicaments peu solubles dans l'eau
WO2000033862A1 (fr) 1998-12-11 2000-06-15 Pharmasolutions, Inc. Compositions auto-emulsifiantes pour medicaments peu solubles dans l'eau
EP1135150A1 (fr) * 1998-12-11 2001-09-26 Pharmasolutions, Inc. Compositions auto-emulsifiantes pour medicaments peu solubles dans l'eau
US6436430B1 (en) 1998-12-11 2002-08-20 Pharmasolutions, Inc. Self-emulsifying compositions for drugs poorly soluble in water
JP2002531515A (ja) * 1998-12-11 2002-09-24 ファーマソリューションズ・インコーポレイテッド 水に難溶性の薬剤のための自己乳化組成物
EP1158959A1 (fr) 1999-02-26 2001-12-05 Lipocine, Inc. Compositions et procedes pour l'administration amelioree d'agents therapeutiques hydrophobes
US6432445B1 (en) 1999-05-28 2002-08-13 Novartis Ag Pharmaceutical capsules comprising a cyclosporin
US6767555B2 (en) 1999-05-28 2004-07-27 Novartis Ag Pharmaceutical compositions
EP1334717A2 (fr) * 1999-08-17 2003-08-13 IVAX Pharmaceuticals s.r.o. Compositions pharmaceutiques pour administration orale et topique
EP1334717A3 (fr) * 1999-08-17 2004-01-02 IVAX Pharmaceuticals s.r.o. Compositions pharmaceutiques pour administration orale et topique
WO2001012229A1 (fr) * 1999-08-17 2001-02-22 Ivax-Cr A.S. Compositions pharmaceutiques pour administration orale et topique
AU777740B2 (en) * 1999-08-17 2004-10-28 Ivax Pharmaceuticals, S.R.O. Pharmaceutical compositions for oral and topical administration
AU2003254754B2 (en) * 1999-08-17 2006-01-12 Ivax Pharmaceuticals, S.R.O. Pharmaceutical compositions for oral and topical administration
WO2001032142A1 (fr) * 1999-11-02 2001-05-10 Cipla Limited Formulation de cyclosporine
WO2001032143A1 (fr) * 1999-11-02 2001-05-10 Cipla Ltd. Composition pharmaceutique pour administer des substances actives sur le plan pharmaceutique insolubles dans l'eau et procede de preparation afferent
WO2001097832A1 (fr) * 2000-06-21 2001-12-27 Audit Institute For Medical Services And Quality Assurance Gmbh Preparations pharmaceutiques contenant des cylosporines et des huiles neutres
CN100355455C (zh) * 2002-07-15 2007-12-19 爱尔康公司 用于眼内使用的非聚合亲脂性药物植入组合物
WO2004006890A1 (fr) * 2002-07-15 2004-01-22 Alcon, Inc. Compositions d'implants pharmaceutiques lipophiles non-polymeres pour utilisation intra-oculaire
KR101003518B1 (ko) * 2002-07-15 2010-12-30 알콘, 인코퍼레이티드 안내 사용을 위한 비-폴리머성 친지성 약제학적 임플란트조성물
US8178576B2 (en) 2002-07-15 2012-05-15 Novartis Ag Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use
KR101068255B1 (ko) * 2002-08-02 2011-09-28 새티쉬찬드라 프남바이 파텔 시클로스포린, 프로필렌 글리콜 에스테르 및 비이온계면활성제를 포함하는 약학적 제제
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EP0973502A1 (fr) 2000-01-26
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