WO1996036316A1 - Formulations auto-emulsifiantes de medicaments lipophiles - Google Patents

Formulations auto-emulsifiantes de medicaments lipophiles Download PDF

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Publication number
WO1996036316A1
WO1996036316A1 PCT/US1996/007155 US9607155W WO9636316A1 WO 1996036316 A1 WO1996036316 A1 WO 1996036316A1 US 9607155 W US9607155 W US 9607155W WO 9636316 A1 WO9636316 A1 WO 9636316A1
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WO
WIPO (PCT)
Prior art keywords
self
tpgs
concentrate according
emulsifying
weight
Prior art date
Application number
PCT/US1996/007155
Other languages
English (en)
Inventor
John M. Lipari
Lisa L. Mcchesney-Harris
Glenn A. Meyer
John J. Wieland
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 JP8535087A priority Critical patent/JPH11505257A/ja
Priority to EP96915876A priority patent/EP0825849A1/fr
Publication of WO1996036316A1 publication Critical patent/WO1996036316A1/fr
Priority to MXPA/A/1997/008934A priority patent/MXPA97008934A/xx

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Classifications

    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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

Definitions

  • This invention relates to pharmaceutical compositions of medicinal compounds, and in particular to spontaneously self -emulsifying pre-concentrates of lipophilic compounds the uses of which include (but are not limited to) the preparation of liquid oral formulations, soft elastic or other capsule formulations for oral delivery, topical formulations for local delivery, suppository formulations, and eye- and ear-drop formulations.
  • Lipophilic compounds 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 irregular bioavailability when given orally or via other routes requiring transmembrane absorption.
  • 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 the United States patent issued to Cavanak on June 14, 1983 (Patent No. 4,388,307), a commercial example of which is the oral cyclosporin-containing product S ANDIMMUNE.
  • This product comprises the emulsifier LABRAFIL (transesterified triglyceride), olive oil and alcohol in a ratio of approximately 36:52: 12, the drug cyclosporin A being present at a concentration of 100 mg/ml.
  • LABRAFIL transesterified triglyceride
  • such glyceride carriers may assist in alleviating problems of physical instability (e.g., precipitation of 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.
  • self-emulsification permits such formulations to be administered as "pre- concentrates" (that is, in concentrated form, as for example in a gelatin or soft elastic capsule) with the expectation that a fine emulsion will be formed in the digestive tract Moreover, it has been suggested that self -emulsifying formulations, when given orally, may offer improvements in both the rate and extent of absorption of the medicinal compound and also the consistency of the resulting plasma concentration profiles. (See S. A. Charman et al., Pharmaceutical Research 9(l):87-93 (1992), and N. H.
  • Previously-disclosed self-emulsifying systems include those in which a lipophilic drug is combined with mixtures of (i) medium-chain triglyceride oils and nonionic surfactants,
  • vegetable oils and nonionic emulsifiers 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.
  • compositions which contain little or no alcohol, which can tolerate a wide range of temperatures and other conditions, and which therefore can be administered orally in pre-concentrate form via gelatin or other capsules or by parenteral means in instances where alcohols may be unduly irritating or incompatible with other formulating vehicles.
  • TPGS d-alpha-tocopheryl polyethylene glycol 1000 succinate
  • TPGS has been employed as an emulsifier for lipophilic compounds, a solubilizer of hydrophilic compounds in fats and oils, and as an enhancer of oral bioavailability (when coadministered with, for example, vitamin D or cyclosporin); however, such earlier uses gave no indication that TPGS -containing formulations could be either (i) self-emulsifying or (ii) capable of forming stable emulsions of small particle size. Hence, the present finding that TPGS imparts these properties to formulations of highly lipophilic drugs is an unexpected one. Moreover, such formulations have the additional advantage that TPGS is readily tolerated, or even beneficial, when given orally or topically.
  • spontaneously self-emulsifying pharmaceutical pre-concentrate compositions comprising (a) a lipophilic medicinal compound, (b) d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), and (c) a lipophilic phase.
  • Preferred pre-concentrates are those in which the TPGS is present in an amount of between about 0.1% and about 50% by weight; more preferred are those in which the TPGS is present in an amount of between about 0.5% and about 15% by weight; and most preferred are those in which the TPGS is present in an amount of between about 1 % and about 5% by weight
  • Lipophilic phase components which are suitable for use in the above pre- concentrates include (a) fatty acid esters of glycerol, (b) fatty acid esters of propylene glycol, and (c) vegetable oil.
  • the weight ratio between such lipophilic phase components and TPGS is between about 1:1 and about 999:1; more preferably, the weight ratio between the lipophilic phase and TPGS is between about 9: 1 and about 99: 1.
  • Particular lipophilic phase component which may be used in the pre-concentrates of the present invention include, but are not limited to, propylene glycol laurate (PGL), caprylic/capric triglyceride (such as NEOBEE M-5 oil, a widely-used commercial product), propylene glycol dicaprylate/dicaprate, corn oil, sesame oil and cottonseed oil, either alone or in combination.
  • PGL propylene glycol laurate
  • caprylic/capric triglyceride such as NEOBEE M-5 oil, a widely-used commercial product
  • propylene glycol dicaprylate/dicaprate such as NEOBEE M-5 oil, a widely-used commercial product
  • corn oil sesame oil and cottonseed oil
  • the lipophilic phase comprises propylene glycol laurate and caprylic/capric triglyceride together
  • a weight ratio between the lipophilic phase and TPGS of between about 20: 1 and about 85: 1
  • particulary preferred embodiments of such pre-concentrates include those which, when the weight ratio between the PGL and caprylic/capric triglyceride is about 2:1, have a weight ratio between the lipophilic phase and TPGS of about 25: 1 or of about 80: 1.
  • the lipophilic phase comprises propylene glycol dicaprylate/dicaprate
  • a weight ratio between the lipophilic phase and TPGS of between about 1:1 and about 99:1 is preferred.
  • the pre-concentrates of the present invention may optionally comprise ethanol as well.
  • the ethanol is preferably used in an amount of between about 1% and about 9% by weight, with an amount of about 5% by weight being especially preferred.
  • a preferred medicinal compound for use therein is cyclosporin.
  • Preferred cyclosporin-containing compositions are those in which the drug is present in an amount of between about 0.5% and 25% by weight; more preferred are those in which the drug is present in an amount of between about 10% and about 15%, with a cyclosporin concentration of about 10% being especially preferred.
  • compositions comprising one of the above self -emulsifying pre-concentrates of the invention in combination with a sufficient amount of water to produce a stable emulsion.
  • Stable emulsions in which the emulsion particle size is relatively independent of the proportions of internal (lipophilic) and external (aqueous) phases, may be obtained with lipophilic-to-aqueous phase ratios of up to 1:10 or even higher.
  • cyclosporin refers to one or more of the cyclosporins and especially to cyclosporin A, as described in the United States patent issued to Harri et al.
  • emulsion refers to a dispersion of fine droplets of a lipophilic phase in an aqueous phase, which droplets are stabilized at their lipophilic phase/aqueous phase interface by TPGS.
  • pre-concentrate refers to pharmaceutical compositions or formulations of sufficiently high concentration such that they may be administered directly
  • self-emulsifying refers to pre-concentrates which spontaneously or with only minimal agitation form a stable emulsion or dispersion upon being added to an aqueous medium.
  • stable as used herein in connection with emulsions refers to emulsions which exhibit no phase separation when kept, without agitation, at room temperature for one hour or longer.
  • compositions of the present invention may be administered orally, parenterally (as by intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection or infusion) or topically (as by ointments, drops or transdermal patches), as known in the pharmaceutical arts.
  • Oral formulations include gelatin capsules into which the pre-concentrates of the invention have been filled directly, as well as emulsions of the invention which are formed by combination of such a pre-concentrate with a suitable aqueous medium such as water.
  • the oral formulations may also include adjuvants such as viscosity inducers (for example, microcrystalline cellulose or beeswax); wetting, sweetening, flavoring and/or perfuming agents; and such other inert and pharmaceutically acceptable excipients as may be desired.
  • Solvents may also be included to facilitate dissolution of the drug in the lipophilic phase and/or to prevent congealing of the pre-concentrate; such solvents include, but are not limited to, ethanol, propylene glycol and dimethyl isosorbide and their pharmaceutically acceptable alternatives.
  • Parenteral formulations may be prepared from emulsions of the present invention, and may contain standard adjuvants as for buffering or control of tonicity.
  • Topical formulations which are intended for administration to the skin or mucosa (such as the surfaces of the lung and eye), may be prepared from both the pre-concentrates and the emulsions of the invention, and may also contain excipients such as those which modify consistency and rate of absorption.
  • the pre-concentrates and emulsions of the present invention may be administered in a sufficient amount, and for a sufficient period of time, as is necessary to provide the desired therapeutic effect.
  • the specific therapeutically effective dose level for any particular patient which will be determined by the attending physician, will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the medicinal compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well-known in the medical arts.
  • the pre-concentrates of the invention may be prepared using readily-available materials and equipment.
  • the lipophilic phase such as propylene glycol laurate, or PGL and caprylic/capric triglyceride in combination
  • the lipophilic phase is warmed to approximately 40-45 °C, with mixing if necessary, before addition of the appropriate amount of TPGS.
  • the combined materials are mixed until dissolved, and the resulting mixture is cooled to room temperature.
  • the medicinal agent may be added before or after cooling, followed by mixing until the drug is fiilly dissolved. If any PGL or lipophilic phase component has been reserved, it is then added with mixing until uniform.
  • the resulting pre-concentrate which at room temperature may range in consistency from a solution to a soft, waxy, homogenous solid, may then be stored as is, filled into soft gelatin capsules or other capsules, or processed into an aqueous pharmaceutical composition of the present invention by mixing with water or other aqueous liquid.
  • TPGS ability of TPGS to facilitate self-emulsification of a lipophilic phase in water was tested by preparing a number of pre-concentrates of the present invention, mixing each one with water, and observing the resulting physical behavior (such as dispersibility and particle size).
  • the specific pre-concentrates were prepared as follows:
  • Caprylic/capric triglyceride (NEOBEE M-5 brand; 80.0-99.9% by weight) was warmed to approximately 40-45°C, and a corresponding amount of TPGS (20.0-0.1% by weight) was added with mixing until dissolved. The solutions were allowed to cool to room temperature. 100 mg of each pre-concentrate were added to 10 mL of filtered, distilled water, and the resulting mixtures were observed.
  • Caprylic/capric triglyceride (NEOBEE M-5 brand; 75.0-94.9% by weight) was warmed to approximately 40-45°C, and a variable amount of TPGS (20.0-0.1% by weight) was added with mixing until dissolved. The solutions were allowed to cool to room temperature, ethanol (5.0 or 6.3% by weight) was added, and the solutions were mixed until uniform. 100 mg of each pre-concentrate were added to 10 mL of filtered, distilled water, and the resulting mixtures were observed.
  • TPGS d-Alpha-tocopheryl polyethylene glycol 1000 succinate
  • Propylene glycol laurate (65.0-74.0% by weight) was warmed to approximately 40-45°C, and a variable amount of TPGS (10.0-1.0% by weight) was added with mixing until dissolved.
  • the solutions were allowed to cool to room temperature, and cyclosporine A USP (25.0% by weight) was added and mixed until dissolved.
  • 100 mg of each pre- concentrate were added to 10 mL of filtered, distilled water, and the physical stabilities and particle size distributions of the resulting mixtures were observed. In each case, the pre- concentrates readily formed stable emulsions comparable to those described in the previous example.
  • the oral bioavailability of two pre-concentrates of the present invention was evaluated in fasted beagle dogs as follows: To prepare the first pre-concentrate containing 100 mg/mL cyclosporine, approximately 1.5 mL of propylene glycol laurate (PGL) were added to 1.25 mL caprylic/capric triglyceride (CCT). After warming the mixture to 40-45°C, 0.25 g TPGS was added and dissolved with stirring, and the mixture was cooled to ambient temperature.
  • PGL propylene glycol laurate
  • CCT caprylic/capric triglyceride
  • the second pre-concentrate also containing 100 mg/mL cyclosporine, approximately 1500 mL of PGL was poured into a vessel and warmed to 40-45°C. 100 g of TPGS were then added and dissolved with stirring, and the mixture was cooled to ambient temperature. 200 g of cyclosporine A were added and dissolved with stirring, after which additional PGL (approximately 200 mL) was added and mixed until uniform to produce a solution containing 5% TPGS and 10% cyclosporine by weight; the resulting pre-concentrate was designated "Formula 2".

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Abstract

L'invention concerne des compositions pharmaceutiques préconcentrées auto-émulsifiantes contenant: (a) un médicament lipophile, (b) du succinate de d-alpha-tocophéryl polyéthylène glycol 1000 et (c) une phase lipophile, ainsi que des compositions pharmaceutiques comprenant de tels préconcentrés en combinaison avec une quantité suffisante d'eau pour produire une émulsion stable.
PCT/US1996/007155 1995-05-19 1996-05-17 Formulations auto-emulsifiantes de medicaments lipophiles WO1996036316A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP8535087A JPH11505257A (ja) 1995-05-19 1996-05-17 親油性薬物の自己乳化性製剤
EP96915876A EP0825849A1 (fr) 1995-05-19 1996-05-17 Formulations auto-emulsifiantes de medicaments lipophiles
MXPA/A/1997/008934A MXPA97008934A (en) 1995-05-19 1997-11-19 Self-emulsifying formulations of lipofili drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44524295A 1995-05-19 1995-05-19
US08/445,242 1995-05-19

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WO1996036316A1 true WO1996036316A1 (fr) 1996-11-21

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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022358A1 (fr) * 1995-12-15 1997-06-26 Bernard Charles Sherman Preconcentres en microemulsion comprenant des cyclosporines
EP0793966A1 (fr) * 1996-03-05 1997-09-10 Hanmi Pharm. Co. Ltd Composition pharmaceutique topique contenant de la cyclosporine
WO1997035587A1 (fr) * 1996-03-22 1997-10-02 Glaxo Group Limited Compositions contenant un inhibiteur de la protease du vih tel que le vx 478 et un compose hydrosoluble de vitamine e tel que la vitamine e-tpgs
WO1998033512A1 (fr) * 1997-01-30 1998-08-06 Novartis Ag Compositions pharmaceutiques exemptes d'huile, a base de cyclosporine a
US5886030A (en) * 1994-05-06 1999-03-23 Alcon Laboratories, Inc. Use of vitamin E tocopheryl derivatives in ophthalmic compositions
WO1999026607A1 (fr) * 1997-11-21 1999-06-03 Fuisz Technologies Ltd. Systemes d'administration de medicaments mettant en application des structures de cristaux liquides
GB2317562B (en) * 1995-07-20 1999-08-18 Danbiosyst Uk Lipid vehicle drug delivery composition containing vitamin E
WO2000033862A1 (fr) 1998-12-11 2000-06-15 Pharmasolutions, Inc. Compositions auto-emulsifiantes pour medicaments peu solubles dans l'eau
EP1017366A1 (fr) * 1996-09-01 2000-07-12 Pharmos Corporation Coprecipites solides augmentant la biodisponibilite de substances lipophiles
AU724239B2 (en) * 1996-03-22 2000-09-14 Glaxo Group Limited Compositions comprising an HIV protease inhibitor such as VX 478 and a water soluble vitamin E compound such as vitamin E-TPGS
EP1039893A1 (fr) * 1997-12-10 2000-10-04 Severson, Mary L. Compositions pharmaceutiques contenant une huile d'acide gras omega-3
WO2002051414A1 (fr) * 2000-12-22 2002-07-04 Takeda Chemical Industries, Ltd. Compositions médicinales s'administrant par voie orale
US6432445B1 (en) 1999-05-28 2002-08-13 Novartis Ag Pharmaceutical capsules comprising a cyclosporin
US6730679B1 (en) 1996-03-22 2004-05-04 Smithkline Beecham Corporation Pharmaceutical formulations
US6828301B2 (en) 2002-02-07 2004-12-07 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for hepatitis C viral protease inhibitors
EP1498122A1 (fr) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Systèmes semi-solides contenant des dérivés d'azétidine
US7070802B1 (en) 1996-01-22 2006-07-04 Pliva, Inc. Pharmaceutical compositions for lipophilic drugs
CZ297206B6 (cs) * 1997-07-29 2006-10-11 Pharmacia & Upjohn Company Farmaceutická kompozice a samoemulgující formulace pro lipofilní slouceniny
EP1810694A2 (fr) * 2001-02-02 2007-07-25 National Research Council of Canada Compositions hydrosolubles de composés lipophiles bioactifs
JP2007332157A (ja) * 1997-01-07 2007-12-27 Sonus Pharmaceuticals Inc 溶解性に劣る薬物のためのエマルジョンビヒクル
WO2008142090A1 (fr) * 2007-05-23 2008-11-27 Boehringer Ingelheim International Gmbh Formulation auto-émulsionnante de tipranavir s'administrant par voie orale
WO2009117152A1 (fr) 2008-03-20 2009-09-24 Virun, Inc. Émulsions comprenant un dérivé de peg de tocophérol
WO2011005646A2 (fr) 2009-07-07 2011-01-13 Boehringer Ingelheim International Gmbh Composition pharmaceutique pour un inhibiteur de protéase virale de l'hépatite c
US8337931B2 (en) 2008-06-23 2012-12-25 Virun, Inc. Compositions containing non-polar compounds
US20130108674A1 (en) * 2010-06-11 2013-05-02 Medivis S.R.L. Ophthalmic compositions for the administration of liposoluble active ingredients
WO2013120025A1 (fr) 2012-02-10 2013-08-15 Virun, Inc. Compositions de boisson contenant des composés non polaires
US8524696B2 (en) 1999-04-02 2013-09-03 National Research Council Of Canada Water-soluble compositions of bioactive lipophilic compounds
US8722093B2 (en) 2009-02-23 2014-05-13 NanoRx, Inc. Policosanol nanoparticles
US9034383B2 (en) 2010-08-23 2015-05-19 NanoRx, Inc. Policosanol nanoparticles
US9320295B2 (en) 2010-03-23 2016-04-26 Virun, Inc. Compositions containing non-polar compounds
US9351517B2 (en) 2013-03-15 2016-05-31 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and compositions containing same
US9693574B2 (en) 2013-08-08 2017-07-04 Virun, Inc. Compositions containing water-soluble derivatives of vitamin E mixtures and modified food starch
US9788564B2 (en) 2008-03-20 2017-10-17 Virun, Inc. Compositions containing non-polar compounds
US9861611B2 (en) 2014-09-18 2018-01-09 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same
US10016363B2 (en) 2014-09-18 2018-07-10 Virun, Inc. Pre-spray emulsions and powders containing non-polar compounds
US10335385B2 (en) 2010-06-21 2019-07-02 Virun, Inc. Composition containing non-polar compounds
WO2021050697A1 (fr) * 2019-09-11 2021-03-18 Barlean's Organic Oils, Llc Matériaux de remplissage de capsule à enveloppe molle
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FR2861992B1 (fr) * 2003-11-10 2007-07-20 Sanofi Synthelabo Composition pharmaceutique destinee a l'administration orale d'un derive de pyrazole-3-carboxamide.
TW202402319A (zh) * 2022-03-28 2024-01-16 日商中外製藥股份有限公司 含有包含聚氧乙烯構造的油性成分之化合物製劑

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Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5886030A (en) * 1994-05-06 1999-03-23 Alcon Laboratories, Inc. Use of vitamin E tocopheryl derivatives in ophthalmic compositions
GB2317562B (en) * 1995-07-20 1999-08-18 Danbiosyst Uk Lipid vehicle drug delivery composition containing vitamin E
US5998365A (en) * 1995-12-15 1999-12-07 Bernard C. Sherman Microemulsion preconcentrates comprising cyclosporins
WO1997022358A1 (fr) * 1995-12-15 1997-06-26 Bernard Charles Sherman Preconcentres en microemulsion comprenant des cyclosporines
US7070802B1 (en) 1996-01-22 2006-07-04 Pliva, Inc. Pharmaceutical compositions for lipophilic drugs
EP0793966A1 (fr) * 1996-03-05 1997-09-10 Hanmi Pharm. Co. Ltd Composition pharmaceutique topique contenant de la cyclosporine
WO1997035587A1 (fr) * 1996-03-22 1997-10-02 Glaxo Group Limited Compositions contenant un inhibiteur de la protease du vih tel que le vx 478 et un compose hydrosoluble de vitamine e tel que la vitamine e-tpgs
US6730679B1 (en) 1996-03-22 2004-05-04 Smithkline Beecham Corporation Pharmaceutical formulations
EA001484B1 (ru) * 1996-03-22 2001-04-23 Глаксо Груп Лимитед Композиции, содержащие ингибитор вич протеазы, а именно as vx 478, и водорастворимое соединение витамина e, а именно витамин e-tpgs
AU724239B2 (en) * 1996-03-22 2000-09-14 Glaxo Group Limited Compositions comprising an HIV protease inhibitor such as VX 478 and a water soluble vitamin E compound such as vitamin E-TPGS
EP1017366A4 (fr) * 1996-09-01 2006-03-22 Pharmos Corp Coprecipites solides augmentant la biodisponibilite de substances lipophiles
EP1017366A1 (fr) * 1996-09-01 2000-07-12 Pharmos Corporation Coprecipites solides augmentant la biodisponibilite de substances lipophiles
JP2007332157A (ja) * 1997-01-07 2007-12-27 Sonus Pharmaceuticals Inc 溶解性に劣る薬物のためのエマルジョンビヒクル
GB2355195A (en) * 1997-01-30 2001-04-18 Novartis Ag Oil-free pharmaceutical composition containing Cyclosporin A
GB2335854A (en) * 1997-01-30 1999-10-06 Novartis Ag Oil-free pharmaceutical compositions containing cyclosporin a
GB2335854B (en) * 1997-01-30 2001-04-25 Novartis Ag Oil-free pharmaceutical compositions containing cyclosporin A
GB2355195B (en) * 1997-01-30 2001-09-12 Novartis Ag Oil-free pharmaceutical compositions containing cyclosporin A
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CA2221145A1 (fr) 1996-11-21
EP0825849A1 (fr) 1998-03-04
JPH11505257A (ja) 1999-05-18
MX9708934A (es) 1998-03-31

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