WO2001032142A1 - Cyclosporin formulation - Google Patents
Cyclosporin formulation Download PDFInfo
- Publication number
- WO2001032142A1 WO2001032142A1 PCT/GB2000/004143 GB0004143W WO0132142A1 WO 2001032142 A1 WO2001032142 A1 WO 2001032142A1 GB 0004143 W GB0004143 W GB 0004143W WO 0132142 A1 WO0132142 A1 WO 0132142A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- component
- preconcentrate
- composition
- composition according
- solid
- Prior art date
Links
Classifications
-
- 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
- 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
- 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
- A61K9/143—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 inorganic 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
- A61K9/141—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
- A61K9/145—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 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
- A61K9/141—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
Definitions
- This invention relates to improved pharmaceutical compositions for the administration of water-insoluble pharmaceutically active substances especially, but not exclusively, cyclosporin.
- EP-A-0760237 there is described a pre-concentrate microemulsion composition
- a pre-concentrate microemulsion composition comprising a water- insoluble pharmaceutically active material; a C 8 - C 2 o fatty acid mono-, di- or tri- glyceride from a vegetable oil or any mixture of two or more thereof; and a phospholipid and another surfactant.
- a stable oil-in-water microemulsion can be formed by mixing the preconcentrate composition with a hydrophihc phase.
- the microemulsion compositions of EP 0760237 are made by directly dissolving the active material in the oil phase and then dispersing the oil phase in the hydrophihc phase. This has certain advantages.
- a pharmaceutical composition in the form of a preconcentrate mixed either with a liquid hydrophihc phase to form a stable oil-in-water microemulsion or with a solid carrier to form a stable, solid blend of carrier and preconcentrate which composition is substantially free from ethanol and comprises: a) a water-insoluble pharmaceutically active material; b) one or more propylene glycol esters of a fatty acid; c) surfactant; and either d) a hydrophihc phase, wherein component (a) has been wholly directly dissolved in component (b) and component (b) is dispersed as tiny particles in component (d); or e) a solid carrier.
- a process for making a composition according to the invention comprises dissolving component (a) in component (b) optionally with component (c), and then mixing the resulting solution either with component (d) or with component (e), and component (c) if not included earlier.
- the method of the invention thus comprises first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c) but being free from hydrophihc phase, and then mixing the preconcentrate with the hydrophihc phase, to form a stable oil-in water microemulsion, the composition being free from ethanol.
- the method of the invention comprises first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c), and then mixing the preconcentrate with the solid carrier, to form a solid, table composition of preconcentrate and carrier, the composition being free from ethanol.
- the present invention therefore encompasses two different formulations of the basic preconcentrate mixture. Both of these formulations possess the advantage of increased bioavailability of the active material.
- the invention provides a stable oil-in-water microemulsion composition wherein components (a) to (c) above have first been formed into a preconcentrate by wholly directly dissolving component (a) in component (b) optionally in the presence of component (c) (i.e. component (c) may be added later), and then mixing the preconcentrate with a hydrophihc phase.
- the microemulsion composition is generally liquid at room temperature and can, therefore, be advantageously provided in, for example, a soft gelatine capsule or as an oral solution such as an aqueous drink, for instance.
- the invention provides a stable, solid formulation comprising a blend of the basic preconcentrate mixture with a solid carrier.
- the preconcentrate mixture having increased bioavailability of the active material can, for example, be formulated into a free-flowing powder which, in turn can, for instance, be put into a hard gelatin capsule or compressed into a table.
- component (a) is a water insoluble pharmaceutically active material.
- the invention is particularly useful with the cyclosporins, e.g. cyclosporin A. dihydrocyclosporin C, cyclosporin D and dihydrocyclosporin D. It is also useful with other water-insoluble substances such as, for example, water-insoluble peptides, or water-insoluble antimicrobial or antineoplastic substances. Examples include desmopresin, calcitonin, insulin, lenprolide, erythropoetin, a cephalosporin, vincristine, vinblastine, taxol, etoposide or mixtures thereof.
- component (a) is in solution in component (b).
- Component (b) can be a propylene glycol ester of a fatty acid or a mixture of any two or more such esters.
- the fatty acids may optionally be derived from a vegetable oil and are preferably C 8 - C 20 residues.
- Particular preferred compounds are propylene glycol monocaprylate (Caprgol 90) and propylene glycol monolaurate (Lauroglycol 90).
- Caprgol 90 propylene glycol monocaprylate
- Liauroglycol 90 propylene glycol monolaurate
- oleoyl macrogol-6 glycerides (Labrafil M 1944 CS), linoleoyl macrogol-6 glycerides (Labrafil M 2125 CS), and caprylocaproyl macrogol-8 glycerides (Labrasol) are particularly preferred compounds for use with the oils employed in the present invention.
- Component (c) is a surfactant to provide the preconcentrate mixture and, where employed, the fully formed microemulsion with stability.
- surfactants which can be used, but we prefer to use polyoxyl 40 hydrogenated castor oil, polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate or polyoxyethylene sorbitan monostearate.
- the surfactant can be mixed with a phospholipid, such as lecithin.
- a weight ratio of component (a) to surfactant of about 1 :1 to about 1 :50, but ratios outside this range can also be employed if desired.
- a phospholipid is included in the composition, we prefer to use a weight ratio of component (a) to phospholipid of about 1 :05 to about 1 :5.0, but, again, other ratios can be used.
- component (d) is a hydrophihc phase.
- the preferred material is propylene glycol or diethylene glycol monoethyl ether (transcutol) but other substances can be used. Ethanol cannot be present. Water can of course also be present but it is not preferred.
- propylene glycol component (a) remains wholly dissolved in the oil phase (component (b)).
- Microemulsions are transparent due to the very small particle size of the dispersed phase, typically less than 200 nm. Such small droplets produce only weak scattering of visible light when compared with that from the coarse droplets (1 -10 nm) of normal emulsions.
- An essential difference between microemulsions and emulsions is that microemulsions form spontaneously and, unlike emulsions, required little mechanical work in their formulation.
- General reviews on microemulsions are provided by Attwood D. et al J. Colloid Interface Sci 46:249 and Kahlweit M. et al J. Colloid Interface Sci 118:436.
- microemulsions can be formed by diluting with aqueous liquid (e.g. water, fruit juice, milk etc.) to form an oil-in-water microemulsion, e.g. for oral administration.
- aqueous liquid e.g. water, fruit juice, milk etc.
- the role played by bile salts in the initial step of fragmentation of fat globules, essential for fat digestion, is circumvented.
- the rate determining factor for the absorption of drug in the vehicle is not the enzymatic metabolism of triglycerides but rests primarily in the breakdown of the fat globules into micro particles since the enzymes (lipases) act mainly at the surface of the fat globules.
- the weight percent of hydrophilic phase is generally up to about 75%, most usually from 15 to 50%, and preferably from 35 to 50%.
- component (e) is employed instead of component (d).
- Preferred solid carriers include colloidal silicon dioxide and polyvinyl pyrrolidone (cross Povidone) but other suitable inert solid substances can also be used, as will be clear to those skilled in the art.
- the solid carrier will be in the form of a dry powder.
- the preconcentrate mixture (comprising active material, oil and surfactant) is simply blended with the solid material such that the oily preconcentrate is absorbed by the material.
- the blended mixture is provided in the form of a free-flowing powder.
- Such a powder can then be easily coated, for example, into a hard gelatin capsule or, alternatively, compressed into tablets, for instance.
- the technique of absorbing an oily phase (in this case an oily preconcentrate) on to a solid phase such as colloidal silicon dioxide followed by formulation into a final dosage form is a technique well known by those skilled in the art of formulation, so further details are considered unnecessary.
- Both the microemulsion and solid compositions can consist only of the components described, or they can contain other substances.
- an antioxidant e.g. D- to copherol can be used.
- Propyl gallate may be used as an alternative.
- compositions comprising a blend of preconcentrate and solid carrier are:
- Glyceryl Monolinoleate (Maisine 33-1) 17.25 Propylene glycol monocaprylate
- the blended preparations were made as follows:
- Microemulsions of the invention were made of the compositions indicated, by dissolving the cyclosporin A in the oils and then forming the oil-in- water emulsions. The procedure was:
- the oral solution which is filled into bottles can be administered using a syringe or more preferably with the aid of a metered dose pump with a dropper actuator.
- compositions described in Examples 4 to 8 were subjected to stability examinations under accelerated conditions of temperature and humidity.
- the solutions were stored at RT (25°C ⁇ 2°C). Ref 40°C-80% RH and 45°C, after filling into flint glass vials.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00971598A EP1227793A1 (en) | 1999-11-02 | 2000-10-27 | Cyclosporin formulation |
AU10432/01A AU1043201A (en) | 1999-11-02 | 2000-10-27 | Cyclosporin formulation |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IN1999/000062 WO2001032143A1 (en) | 1999-11-02 | 1999-11-02 | A pharmaceutical composition for the administration of water-insoluble pharmaceutically active substances and a process for preparation thereof |
INPCT/IN99/00062 | 1999-11-02 | ||
GB0012816A GB2362573A (en) | 2000-05-25 | 2000-05-25 | Cyclosporin formulation |
GB0012816.5 | 2000-05-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001032142A1 true WO2001032142A1 (en) | 2001-05-10 |
Family
ID=26244360
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2000/004143 WO2001032142A1 (en) | 1999-11-02 | 2000-10-27 | Cyclosporin formulation |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1227793A1 (en) |
AU (1) | AU1043201A (en) |
WO (1) | WO2001032142A1 (en) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006501208A (en) * | 2002-08-02 | 2006-01-12 | パテル、サティシュチャンドラ・プナンバイ | A pharmaceutical composition containing cyclosporine, propylene glycol ester and nonionic surfactant for oral administration. |
WO2006021709A2 (en) * | 2004-08-05 | 2006-03-02 | Gattefosse Holding | Anhydrous solid particle containing a lipid composition and pharmaceutical composition containing said particles |
WO2006085217A2 (en) * | 2005-02-08 | 2006-08-17 | Pfizer Products Inc. | Solid adsorbates of hydrophobic drugs |
WO2007016073A1 (en) * | 2005-07-27 | 2007-02-08 | Allergan, Inc. | Pharmaceutical emulsion compositions comprising cyclosporin |
EP1767193A3 (en) * | 2000-04-10 | 2009-01-28 | Novartis AG | Pharmaceutical compositions |
JP2010120930A (en) * | 2008-10-22 | 2010-06-03 | Santen Pharmaceut Co Ltd | Pharmaceutical composition improving absorbability through intestinal tract |
US8501174B2 (en) | 2005-10-14 | 2013-08-06 | Allergan, Inc. | Prevention and treatment of ocular side effects with a cyclosporin |
US9248191B2 (en) | 2003-09-15 | 2016-02-02 | Allergan, Inc. | Methods of providing therapeutic effects using cyclosporin components |
US9278070B2 (en) | 2009-05-18 | 2016-03-08 | Sigmoid Pharma Limited | Composition comprising oil drops |
US9320746B2 (en) | 2013-02-21 | 2016-04-26 | Sigmoid Pharma Limited | Method for treating intestinal fibrosis |
US9387179B2 (en) | 2007-04-04 | 2016-07-12 | Sigmoid Pharma Limited | Pharmaceutical cyclosporin compositions |
US9821024B2 (en) | 2010-11-25 | 2017-11-21 | Sigmoid Pharma Limited | Immunomodulatory compositions |
US9839667B2 (en) | 2005-10-14 | 2017-12-12 | Allergan, Inc. | Prevention and treatment of ocular side effects with a cyclosporin |
US9878036B2 (en) | 2009-08-12 | 2018-01-30 | Sigmoid Pharma Limited | Immunomodulatory compositions comprising a polymer matrix and an oil phase |
US10993987B2 (en) | 2014-11-07 | 2021-05-04 | Sublimity Therapeutics Limited | Compositions comprising Cyclosporin |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2222770A (en) * | 1988-09-16 | 1990-03-21 | Sandoz Ltd | Cyclosporin emulsion compositions |
US5543393A (en) * | 1994-02-25 | 1996-08-06 | Chong Kun Dang Corp. | Cyclosporin containing powder composition |
EP0760237A1 (en) * | 1995-08-30 | 1997-03-05 | Cipla Limited | Oil-in-water microemulsions |
WO1998040051A1 (en) * | 1997-03-12 | 1998-09-17 | Abbott Laboratories | Lipophilic binary systems for the administration of lipophilic compounds |
WO1999044584A1 (en) * | 1998-03-06 | 1999-09-10 | Novartis Ag | Emulsion preconcentrates containing cyclosporin or a macrolide |
-
2000
- 2000-10-27 WO PCT/GB2000/004143 patent/WO2001032142A1/en not_active Application Discontinuation
- 2000-10-27 AU AU10432/01A patent/AU1043201A/en not_active Abandoned
- 2000-10-27 EP EP00971598A patent/EP1227793A1/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2222770A (en) * | 1988-09-16 | 1990-03-21 | Sandoz Ltd | Cyclosporin emulsion compositions |
US5543393A (en) * | 1994-02-25 | 1996-08-06 | Chong Kun Dang Corp. | Cyclosporin containing powder composition |
EP0760237A1 (en) * | 1995-08-30 | 1997-03-05 | Cipla Limited | Oil-in-water microemulsions |
WO1998040051A1 (en) * | 1997-03-12 | 1998-09-17 | Abbott Laboratories | Lipophilic binary systems for the administration of lipophilic compounds |
WO1999044584A1 (en) * | 1998-03-06 | 1999-09-10 | Novartis Ag | Emulsion preconcentrates containing cyclosporin or a macrolide |
Cited By (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1767193A3 (en) * | 2000-04-10 | 2009-01-28 | Novartis AG | Pharmaceutical compositions |
JP2006501208A (en) * | 2002-08-02 | 2006-01-12 | パテル、サティシュチャンドラ・プナンバイ | A pharmaceutical composition containing cyclosporine, propylene glycol ester and nonionic surfactant for oral administration. |
US9248191B2 (en) | 2003-09-15 | 2016-02-02 | Allergan, Inc. | Methods of providing therapeutic effects using cyclosporin components |
WO2006021709A2 (en) * | 2004-08-05 | 2006-03-02 | Gattefosse Holding | Anhydrous solid particle containing a lipid composition and pharmaceutical composition containing said particles |
WO2006021709A3 (en) * | 2004-08-05 | 2006-10-12 | Gattefosse Holding | Anhydrous solid particle containing a lipid composition and pharmaceutical composition containing said particles |
WO2006085217A2 (en) * | 2005-02-08 | 2006-08-17 | Pfizer Products Inc. | Solid adsorbates of hydrophobic drugs |
WO2006085217A3 (en) * | 2005-02-08 | 2006-09-28 | Pfizer Prod Inc | Solid adsorbates of hydrophobic drugs |
US8906861B2 (en) | 2005-07-27 | 2014-12-09 | Allergan, Inc. | Pharmaceutical compositions comprising cyclosporins |
WO2007016073A1 (en) * | 2005-07-27 | 2007-02-08 | Allergan, Inc. | Pharmaceutical emulsion compositions comprising cyclosporin |
US7501393B2 (en) | 2005-07-27 | 2009-03-10 | Allergan, Inc. | Pharmaceutical compositions comprising cyclosporins |
US9839667B2 (en) | 2005-10-14 | 2017-12-12 | Allergan, Inc. | Prevention and treatment of ocular side effects with a cyclosporin |
US8501174B2 (en) | 2005-10-14 | 2013-08-06 | Allergan, Inc. | Prevention and treatment of ocular side effects with a cyclosporin |
US10434139B2 (en) | 2007-04-04 | 2019-10-08 | Sublimity Therapeutics Limited | Oral pharmaceutical composition |
US9387179B2 (en) | 2007-04-04 | 2016-07-12 | Sigmoid Pharma Limited | Pharmaceutical cyclosporin compositions |
US9585844B2 (en) | 2007-04-04 | 2017-03-07 | Sigmoid Pharma Limited | Oral pharmaceutical composition |
US9675558B2 (en) | 2007-04-04 | 2017-06-13 | Sigmoid Pharma Limited | Pharmaceutical cyclosporin compositions |
US10434140B2 (en) | 2007-04-04 | 2019-10-08 | Sublimity Therapeutics Limited | Pharmaceutical cyclosporin compositions |
JP2010120930A (en) * | 2008-10-22 | 2010-06-03 | Santen Pharmaceut Co Ltd | Pharmaceutical composition improving absorbability through intestinal tract |
US9999651B2 (en) | 2009-05-18 | 2018-06-19 | Sigmoid Pharma Limited | Composition comprising oil drops |
US9278070B2 (en) | 2009-05-18 | 2016-03-08 | Sigmoid Pharma Limited | Composition comprising oil drops |
US9878036B2 (en) | 2009-08-12 | 2018-01-30 | Sigmoid Pharma Limited | Immunomodulatory compositions comprising a polymer matrix and an oil phase |
US9821024B2 (en) | 2010-11-25 | 2017-11-21 | Sigmoid Pharma Limited | Immunomodulatory compositions |
US9980902B2 (en) | 2013-02-21 | 2018-05-29 | Sigmoid Pharma Limited | Method for treating intestinal fibrosis |
US9320746B2 (en) | 2013-02-21 | 2016-04-26 | Sigmoid Pharma Limited | Method for treating intestinal fibrosis |
US10993987B2 (en) | 2014-11-07 | 2021-05-04 | Sublimity Therapeutics Limited | Compositions comprising Cyclosporin |
Also Published As
Publication number | Publication date |
---|---|
AU1043201A (en) | 2001-05-14 |
EP1227793A1 (en) | 2002-08-07 |
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