WO1998033512A1 - Oil-free pharmaceutical compositions containing cyclosporin a - Google Patents

Oil-free pharmaceutical compositions containing cyclosporin a Download PDF

Info

Publication number
WO1998033512A1
WO1998033512A1 PCT/EP1998/000453 EP9800453W WO9833512A1 WO 1998033512 A1 WO1998033512 A1 WO 1998033512A1 EP 9800453 W EP9800453 W EP 9800453W WO 9833512 A1 WO9833512 A1 WO 9833512A1
Authority
WO
WIPO (PCT)
Prior art keywords
hard gelatine
gelatine capsule
present
cyclosporin
polyethylene glycol
Prior art date
Application number
PCT/EP1998/000453
Other languages
French (fr)
Inventor
Armin Meinzer
Barbara Haeberlin
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft Mbh
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=26310891&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1998033512(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from GBGB9701881.6A external-priority patent/GB9701881D0/en
Priority claimed from GBGB9702594.4A external-priority patent/GB9702594D0/en
Priority to HU0500385A priority Critical patent/HUP0500385A3/en
Priority to DK98904156T priority patent/DK0988046T3/en
Priority to CA002278675A priority patent/CA2278675A1/en
Priority to AT98904156T priority patent/ATE275963T1/en
Priority to PL372850A priority patent/PL191919B1/en
Priority to GB9917521A priority patent/GB2335854B/en
Priority to US09/284,391 priority patent/US6475519B1/en
Priority to IL13079798A priority patent/IL130797A0/en
Priority to SK1020-99A priority patent/SK285019B6/en
Priority to BR9807528-4A priority patent/BR9807528A/en
Priority to DE69826272T priority patent/DE69826272T2/en
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft Mbh filed Critical Novartis Ag
Priority to JP10532524A priority patent/JP2000516256A/en
Priority to AU62141/98A priority patent/AU737053B2/en
Priority to KR10-2003-7005807A priority patent/KR20040004416A/en
Priority to DE19882037T priority patent/DE19882037T1/en
Priority to PL98334850A priority patent/PL190420B1/en
Priority to HU0001013A priority patent/HUP0001013A3/en
Priority to NZ336900A priority patent/NZ336900A/en
Priority to EP98904156A priority patent/EP0988046B1/en
Priority to DE29824679U priority patent/DE29824679U1/en
Priority to SI9830695T priority patent/SI0988046T1/en
Publication of WO1998033512A1 publication Critical patent/WO1998033512A1/en
Priority to IL130797A priority patent/IL130797A/en
Priority to HK00106122A priority patent/HK1027745A1/en

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
    • 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
    • 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
    • A61K9/48—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • 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 novel pharmaceutical compositions comprising cyclosporin A, also known as ciclosporine, as active agent (hereinafter referred to as cyclosporin).
  • cyclosporin A also known as ciclosporine
  • active agent hereinafter referred to as cyclosporin
  • compositions of the present invention are compositions containing cyclosporin which meet the requirements for approval in the US or elsewhere, yet can be produced in a form administrable as a hard gelatine capsule.
  • Such capsules are well known in the art and may be made and filled in conventional manner.
  • an oral pharmaceutical composition comprising cyclosporin A in a mixture with (i) a surfactant of HLB value at least 10, and optionally (ii) a viscosity increasing agent and/or (iii) a hydrophilic phase, the hydrophilic phase being a polyethylene glycol and/or a lower alkanol provided that any lower alkanol present is present in less than 12%, preferably less than 10 or 8% of the total weight of the composition, the composition being adapted for filling into, and serving as a centre-fill for, a hard gelatine capsule, and being substantially free of any additional oil.
  • the present compositions are based on the use of very few components, e.g.
  • a surfactant including associated side products normally arising from its preparation
  • a viscosity increasing agent thickener
  • an additional hydrophilic phase added to that present in the surfactant chosen from polyethylene glycol and/or a lower alkanol which said lower alkanol is present in an amount of less than 12%, e.g. 8% by weight of the composition.
  • Cyclosporin compositions which have been proposed before suffer from the disadvantage that they are not stable in hard gelatine capsules, e.g. over 2 to 3 years and have bioavailability or variability similar to SANDIMMUNE OR NEORAL.
  • the present compositions have excellent stability. The capsules do not become brittle.
  • the composition contains few other excipients.
  • This has the advantage of reducing bulk.
  • preferably less than 5%, preferably less than 2% or 1% of lipophilic moieties (oils) apart from those present in the surfactant, or hydrophilic moieties, e.g. alkanols such as ethanol or propylene glycol are present.
  • compositions may contain polyethylene glycol.
  • This may be a part of the surfactant for example if this is produced by polyethoxylation or added separately. This may be present from e.g. 1 to 40% of the formulation.
  • the polyethylene glycol is liquid at 37°C e.g. having a M.W. 200 to 600 daltons.
  • the cyclosporin may be present in the usual dosage form for a cyclosporin formulation e.g. 25 mg; 50 mg; 100 mg per weight dosage form.
  • the dosage form is e.g. a hard gelatine capsule as known in the art.
  • compositions of the invention permit the preparation of solid, semi-solid and liquid compositions containing a cyclosporin in sufficiently high concentration to permit convenient oral administration, while at the same time achieving improved efficacy, e.g. in terms of bioavailability characteristics.
  • compositions in accordance with the present invention enable effective cyclosporin dosaging with concomitant enhancement of resorption/bioavailability levels, as well as reduced variability in resorption/bioavailability levels achieved both for individual patients receiving cyclosporin therapy as well as between individuals.
  • cyclosporin dosage forms are obtainable providing reduced variability in achieved cyclosporin blood/blood serum levels between dosages for individual patients as well as between individuals/ individual patient groups.
  • the invention thus enables reduction of cyclosporin dosage levels required to achieve effective therapy.
  • it permits closer standardisation as well as optimisation of on-going daily dosage requirements for individual subjects receiving cyclosporin therapy as well as for groups of patients undergoing equivalent therapy.
  • monitoring requirements may be reduced, thus substantially reducing the cost of therapy.
  • the present invention also offers a means permitting reduction in the occurrence of undesirable side-effects, in particular nephrotoxic reaction, in patients undergoing cyclosporin therapy.
  • compositions are of a small volume, yet stable, thereby increasing patient compliance.
  • the surfactant is preferably approved by the FDA, e.g. a GRAS surfactant, e.g.
  • Polyethyloxylated castor oil e.g. reaction products of natural or hydrogenated vegetable oils and ethylene glycol, i.e. polyoxyethylene glycolated natural or hydrogenated vegetable oils, for example polyoxyethylene glycolated natural or hydrogenated castor oils.
  • Such products may be obtained in known manner, e.g. by reaction of a natural or hydrogenated castor oil or fractions thereof with ethylene oxide, e.g. in a molar ratio of from about 1:35 to about 1:60, with optional removal of free polyethyleneglycol components from the product, e.g. in accordance with the methods disclosed in German Auslegeschriften 1,182,388 and 1,518,819.
  • Especially suitable are the various tensides available under the trade name Cremophor.
  • Nikkol e.g. Nikkol HCO-60.
  • the said product Nikkol HC0-60 is a reaction product of hydrogenated castor oil and ethylene oxide exhibiting the following characteristics: Acid no.
  • Such products contain a "hydrophilic portion" of ca. 70 to 90% of fatty acid esters of glycerol polyethylene glycol, as well as fatty acid esters of polyethylene glycols and a hydrophilic portion of polyethylene glycol and glycerol ethoxylates.
  • the surfactant is a polyethoxylated hydrogenated castor oil Cremophor RH.
  • Polyoxyethylene-sorbitan-fatty acid esters e.g. produced by co- polymerising ethylene oxide with fatty acid esters of a sorbitol and its anhydrides of e.g. mono- and tri- lauryl, palmityl, stearyl and oleyl esters e.g. of the type known and commercially available under the trade name Tween (c.f. Fiedler, loc. cit. pp. 1300-1304) including the products Tween 20 [polyoxyethy lene(20)sorbitanmonolaurate] , 40 [polyoxyethylene(20)sorbitanmonopalmitate] ,
  • compositions of the invention are the above products Tween 40 and Tween 80;
  • Polyethoxylated glyceryl fatty acid mono esters e.g. of lauryl, stearic, oleyl, or isostearic acid, e.g. those obtainable under the name Tagat O or L.
  • Polyoxyethylene mono esters of a saturated Cioto C 22 e.g. Cjg substituted e.g. hydroxy fatty acid; e.g. 12 hydroxy stearic PEG acid, e.g. of PEG about e.g. 600-900 e.g. 660 daltons MW, e.g. SOLUTOL H515 from BASF, Ludwigshafen, Germany.
  • An especially preferred product of this class for use in the compositions of the invention is the product Pluronic F68 (poloxamer 188).
  • Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and so forth (c.f. Fiedler, loc. cit., pp. 1013 et seq.).
  • propylene glycol caprylic-capric acid diester as known and commercially available under the trade name Miglyol 840 (c.f. Fiedler, loc. cit., p. 809).
  • ionic surfactants examples include:
  • lecithins in particular lecithins (c.f. Fiedler, loc. cit., pp. 731-733).
  • Lecithins suitable for use in the compositions of the invention include, in particular, soya bean lecithins.
  • Bile salts e.g. alkali metal salts, for example sodium taurocholate.
  • lipophilic surfactants for use as surfactant component are, e.g.:
  • Trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols are known from the art and may be obtained e.g. in accordance with the general procedures described in US Patent No. 3,288,824. They include trans-esterification products of various natural (e.g. non-hydrogenated) vegetable oils for example, maize oil, kernel oil, almond oil, ground nut oil, olive oil and palm oil and mixtures thereof with polyethylene glycols, in particular polyethylene glycols having an average molecular weight of from 200 to 800.
  • trans-esterification product of the class defined are known and commercially available under the trade name Labrafil [see Fiedler, loc. cit., 707].
  • Mono-, di- and mono/di-glycerides, especially esterification products of caprylic or capric acid with glycerol are e.g. those comprising or consisting mainly or essentially of caprylic/capric acid mono- and di-glycerides such as are commercially available under the trade name Imwitor (c.f. loc. cit., pp. 645).
  • a particularly suitable product of this class for use in the compositions of the invention is the product Imwitor 742, which is the esterification product of a mixture of ca. 60 p.p.w. caprylic acid and ca. 40 p.p.w. capric acid with glycerol.
  • Sorbitan fatty acid esters e.g. of the type known and commercially available under the trade name Span, for example including sorbitan-monolauryl, -monopalmityl, -monostearyl, -tristearyl, -monooleyl and -trioleyl esters - (c.f. Fiedler, loc. cit., pp. 1139-1140);
  • Pentaerythritol fatty acid esters and polyalkylene glycol ethers for example pentaerythrite- -dioleate, -distearate, -monolaurate, -polyglycol ether and
  • Monoglycerides e.g. glycerol monooleate, glycerol monopalmitate and glycerol monostearate, for example as known and commercially available under the trade names Myvatex, Myvaplex and Myverol (c.f. Fiedler, loc. cit., pp. 836), and acetylated, e.g. mono-and di-acetylated monoglycerides, for example as known and commercially available under the trade name Myvacet (c.f. Fiedler, loc. cit., pp. 835);
  • Sterols and derivatives thereof for example cholesterols and derivatives thereof, in particular phytosterols, e.g. products comprising sitosterol, campesterol or stigmasterol, and ethylene oxide adducts thereof, for example soya sterols and derivatives thereof, such as known under the trade name Generol (c.f. Fiedler loc. cit., p.p. 554 and 555) in particular the products Generol 122, 122 E5, 122 E10, and 122 E25.
  • Generol c.f. Fiedler loc. cit., p.p. 554 and 555
  • surfactants may be complex mixtures containing side products or unreacted starting products involved in the preparation thereof made by e.g. polyoxyethylation may contain another side product, e.g. polyethylene glycol.
  • compositions of the invention may also comprise a thickening agent (also referred to as a viscosity increasing agent).
  • a thickening agent also referred to as a viscosity increasing agent.
  • suitable thickening agents may be of those known and employed in the art, including e.g. pharmaceutically acceptable polymeric materials and inorganic thickening agents which enable the compositions to be filled easily and resists leakage, e.g. thixotropic agents. These should also have the property of dissolving quickly (e.g. within 5 minutes) in the stomach juices or water or at pH
  • TPGS Water soluble tocopheryl polyethylene glycol succinic acid esters
  • Water soluble celluloses and cellulose derivatives including; alkyl celluloses, e.g. methyl-, ethyl- and propyl-celluloses; hydroxyalkyl-celluloses, e.g. hydroxypropyl-celluloses and hydroxypropylalkyl-celluloses such as hydroxypropyl-methyl-celluloses; acylated celluloses, e.g. cellulose-acetates, cellulose-acetatephthallates, cellulose-acetatesuccinates and hydroxypropylmethyl-cellulose phthallates; and salts thereof such as sodium-carboxymethyl- -celluloses.
  • alkyl celluloses e.g. methyl-, ethyl- and propyl-celluloses
  • hydroxyalkyl-celluloses e.g. hydroxypropyl-celluloses and hydroxypropylalkyl-celluloses
  • acylated celluloses e.g. cellulose-acetates, cellulose-acetatephthallates
  • Water soluble polyvinylpyrrolidones including for example poly-N-vinylpyrrolidones and vinylpyrrolidone co-polymers such as vinylpyrrolidone- vinylacetate co-polymers, especially of low molecular weight.
  • Examples of such compounds suitable for use in accordance with the present invention are those known and commercially available, e.g. under the trade name Kollidon (or, in the USA, Povidone) (c.f. Fiedler, loc. cit., pp. 694-696), in particular the products Kollidon 30 and 90;
  • inorganic thickening agents such as atapulgite, bentonite and silicates including hydrophilic silicon dioxide products, e.g. alkylated (for example methylated) silica gels, in particular colloidal silicon dioxide products as known and commercially available under the trade name Aerosil [c.f. Handbook of Pharmaceutical Excipients, loc. cit., p.p. 253-256] in particular the products Aerosil 130, 200, 300, 380, 0, OX 50, TT 600, MOX 80, MOX 170, LK 84 and the methylated Aerosil R 972.
  • hydrophilic silicon dioxide products e.g. alkylated (for example methylated) silica gels, in particular colloidal silicon dioxide products as known and commercially available under the trade name Aerosil [c.f. Handbook of Pharmaceutical Excipients, loc. cit., p.p. 253-256] in particular the products Aerosil 130, 200, 300, 380, 0, OX 50, TT 600, MOX
  • compositions may also include one or more further ingredients e.g. in an amount of from 0.1 to 5%, in particular anti-oxidants [e.g. ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols, e.g. -tocopherol (vitamin E)], flavouring agents and so forth.
  • anti-oxidants e.g. ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols, e.g. -tocopherol (vitamin E)
  • BHA butyl hydroxy anisole
  • BHT butyl hydroxy toluene
  • tocopherols e.g. -tocopherol (vitamin E)
  • the cyclosporin will generally be present in an amount of from 5 to 30%, suitably from about 10 to about 25% by weight based on the total weight of the composition absent the hard gelatine capsule.
  • Any polyethylene glycol amount when present will generally be present in an amount of from about 15% to about 30%, by weight based on the total weight of the composition absent the hard gelatine capsule;
  • any further excipient apart from the surfactant and as thickening agent is preferably present from an amount from 0.1% to 5%, by weight based on the total weight of the composition absent the hard gelatine capsule.
  • compositions above may additionally include a thickening agent, though, as previously indicated, this will generally be less preferred.
  • the amount of thickening agent present may vary e.g. depending on the required consistency of the end product, e.g. whether it is to be in a thickened flowable form, for example for filling into a capsule. The amount will of course also depend on the nature of the thickening agent chosen.
  • the thickeners components (4) when present will be present in an amount of up to about 25% by weight based on the total weight of the composition, more suitably in an amount of up to about 15 or 20% by weight, e.g. in an amount of from 0.5 or 5 up to 15 or 20% by weight based on the total weight of the composition.
  • compositions may also include further additives or ingredients, e.g. as hereinbefore described.
  • they may comprise antioxidants, e.g. in an amount of up to about 0.5 or 1% by weight based on the total weight of the composition, and sweetening or flavouring agents, e.g. in an amount of up to about 2.5 or 5% by weight based on the total weight of the composition.
  • the volume may be kept low and the composition may be filled into a capsule size, 1, 2 or 3.
  • compositions have been found to exhibit especially advantageous properties when administered orally, e.g. in terms of both the consistency and high level of bioavailability achieved as defined in standard tests in humans or e.g. beagle dogs.
  • tenside materials e.g. bile salts
  • they are fully dispersible in aqueous systems comprising such natural tensides and are thus capable of providing microemulsion systems in situ which are stable and do not exhibit precipitation or other disruption of fine particulate structure.
  • compositions accordingly represent an especially preferred embodiment of the invention.
  • the bioavailability characteristics may be observed in standard clinical trials or in dogs using standard radioimmunoassays for cyclosporins.
  • Preferred capsules have a short Tmax.
  • the compositions form, on dilution with water, micellar solutions, in which one may be able to detect droplets of, e.g. from 10 to 150 nm in diameter.
  • the compositions above will preferably be compounded in orally administerable hard gelatine capsule shells to be unit dosage forms.
  • each unit dosage will suitably contain between about 5 or 10 and about 200mg cyclosporin, more suitably between about 15 or 25 and about 150mg, e.g. 25, 50 or lOOmg cyclosporin.
  • unit dosage forms in accordance with the invention suitable for administration lx, 2x or 3x up to 5x daily (e.g. depending on the particular purpose of therapy, the phase of therapy etc..) will appropriately comprise e.g. about 25 mg, about 50 mg or about 100 mg cyclosporin per unit dosage.
  • Example 1 As for Example 1 but containing additionally 10 mg of TPGS.
  • composition shows a bioavailability profile in humans and dogs similar to that of NEORAL, e.g. in terms of AUC, Tmax and Cmax.
  • the hard gelatine capsules are stable for at least 2 years and maintain an excellent condition.

Abstract

The present invention provides a hard gelatine capsule containing a pharmaceutical composition comprising cyclosporin A in a mixture with a surfactant of HLB value at least 10, substantially free of any oil and when a hydrophilic phase is present, the hydrophilic phase being a polyethylene glycol and/or a lower alkanol provided that any lower alkanol present is present in less than 12 % of the total weight of the composition absent the hard gelatine capsule.

Description

OIL-FREE PHARMACEUTICAL COMPOSITIONS CONTAINING CYCLOSPORIN A
The present invention relates to novel pharmaceutical compositions comprising cyclosporin A, also known as ciclosporine, as active agent (hereinafter referred to as cyclosporin).
Hitherto few pharmaceutical compositions containing cyclosporin have been accepted for commercial use for humans. Thus in the USA only SANDIMMUNE and NEORAL (cyclosporin for microemulsion) have been approved.
These formulations are available in the form of a drink solution or a soft gelatine capsule. Such soft gelatine capsules require special manufacturing techniques.
The compositions of the present invention are compositions containing cyclosporin which meet the requirements for approval in the US or elsewhere, yet can be produced in a form administrable as a hard gelatine capsule. Such capsules are well known in the art and may be made and filled in conventional manner.
In one aspect to present invention provides an oral pharmaceutical composition comprising cyclosporin A in a mixture with (i) a surfactant of HLB value at least 10, and optionally (ii) a viscosity increasing agent and/or (iii) a hydrophilic phase, the hydrophilic phase being a polyethylene glycol and/or a lower alkanol provided that any lower alkanol present is present in less than 12%, preferably less than 10 or 8% of the total weight of the composition, the composition being adapted for filling into, and serving as a centre-fill for, a hard gelatine capsule, and being substantially free of any additional oil. The present compositions are based on the use of very few components, e.g. a surfactant (including associated side products normally arising from its preparation), optionally a viscosity increasing agent (thickener) and if desired an additional hydrophilic phase (additional to that present in the surfactant) chosen from polyethylene glycol and/or a lower alkanol which said lower alkanol is present in an amount of less than 12%, e.g. 8% by weight of the composition.
Cyclosporin compositions which have been proposed before suffer from the disadvantage that they are not stable in hard gelatine capsules, e.g. over 2 to 3 years and have bioavailability or variability similar to SANDIMMUNE OR NEORAL. The present compositions have excellent stability. The capsules do not become brittle.
Preferably the composition contains few other excipients. This has the advantage of reducing bulk. Thus preferably less than 5%, preferably less than 2% or 1% of lipophilic moieties (oils) apart from those present in the surfactant, or hydrophilic moieties, e.g. alkanols such as ethanol or propylene glycol are present.
The compositions may contain polyethylene glycol. This may be a part of the surfactant for example if this is produced by polyethoxylation or added separately. This may be present from e.g. 1 to 40% of the formulation. Preferably the polyethylene glycol is liquid at 37°C e.g. having a M.W. 200 to 600 daltons.
The cyclosporin may be present in the usual dosage form for a cyclosporin formulation e.g. 25 mg; 50 mg; 100 mg per weight dosage form. The dosage form is e.g. a hard gelatine capsule as known in the art.
By the present invention there are provided novel cyclosporin galenic formulations, which meet or substantially reduce difficulties in cyclosporin, therapy hitherto encountered in the art. In particular it has been found that the compositions of the invention permit the preparation of solid, semi-solid and liquid compositions containing a cyclosporin in sufficiently high concentration to permit convenient oral administration, while at the same time achieving improved efficacy, e.g. in terms of bioavailability characteristics.
More particularly it has been found that compositions in accordance with the present invention enable effective cyclosporin dosaging with concomitant enhancement of resorption/bioavailability levels, as well as reduced variability in resorption/bioavailability levels achieved both for individual patients receiving cyclosporin therapy as well as between individuals. By application of the teachings of the present invention cyclosporin dosage forms are obtainable providing reduced variability in achieved cyclosporin blood/blood serum levels between dosages for individual patients as well as between individuals/ individual patient groups. The invention thus enables reduction of cyclosporin dosage levels required to achieve effective therapy. In addition it permits closer standardisation as well as optimisation of on-going daily dosage requirements for individual subjects receiving cyclosporin therapy as well as for groups of patients undergoing equivalent therapy.
By closer standardisation of individual patient dosaging rate and blood/blood-serum level response, as well as dosaging and response parameters for patient groups, monitoring requirements may be reduced, thus substantially reducing the cost of therapy.
By reduction of required cyclosporin dosaging standardisation of achieved bio-availability characteristics, the present invention also offers a means permitting reduction in the occurrence of undesirable side-effects, in particular nephrotoxic reaction, in patients undergoing cyclosporin therapy.
The present compositions are of a small volume, yet stable, thereby increasing patient compliance.
The surfactant is preferably approved by the FDA, e.g. a GRAS surfactant, e.g.
1.1 Polyethyloxylated castor oil, e.g. reaction products of natural or hydrogenated vegetable oils and ethylene glycol, i.e. polyoxyethylene glycolated natural or hydrogenated vegetable oils, for example polyoxyethylene glycolated natural or hydrogenated castor oils. Such products may be obtained in known manner, e.g. by reaction of a natural or hydrogenated castor oil or fractions thereof with ethylene oxide, e.g. in a molar ratio of from about 1:35 to about 1:60, with optional removal of free polyethyleneglycol components from the product, e.g. in accordance with the methods disclosed in German Auslegeschriften 1,182,388 and 1,518,819. Especially suitable are the various tensides available under the trade name Cremophor. Particularly suitable are the products Cremophor RH 40 having a saponification no. ca. 50-60, an acid no. = <1, an iodine no. = <1, a water content (Fischer) = <2%, an n[) 0 = ca# 1,453 - 1,457 and an HLB = ca. 14 - 16; Cremophor RH 60 having a saponification no. = ca. 40 - 50, an acid No. =
<1, an iodine no. = <1, a water content (Fischer) = ca. 4.5-5.5%, an nrj> -> = ca.
1.453 - 1,457 and an HLB = ca. 15 - 17; and Cremophor EL having a molecular weight (by steam osmometry) = ca. 1630, a saponification no. = ca. 65-70, an acid no. = ca. 2, an iodine no. = ca. 28 - 32 and an nj}^ = ca. 1.471 (c.f. Fiedler loc. cit. pp. 326-327). Also suitable for use in this category are the various tensides available under the trade name Nikkol, e.g. Nikkol HCO-60. The said product Nikkol HC0-60 is a reaction product of hydrogenated castor oil and ethylene oxide exhibiting the following characteristics: Acid no. = ca. 0.3; Saponification no. = ca. 47.4; Hydroxy value = ca. 42.5; pH (5%) = ca. 4.6; Color APHA = ca. 40; m.p. = ca. 36.0 C; Freezing point = ca. 32.4 C; H2O content (%, KF) = ca. 0.03;
Such products contain a "hydrophilic portion" of ca. 70 to 90% of fatty acid esters of glycerol polyethylene glycol, as well as fatty acid esters of polyethylene glycols and a hydrophilic portion of polyethylene glycol and glycerol ethoxylates.
See for example Karl Mϋller, Tenside, Year 3, Issue 2, p. 37 - 45.
Preferably the surfactant is a polyethoxylated hydrogenated castor oil Cremophor RH.
1.2 Polyoxyethylene-sorbitan-fatty acid esters (polysorbates) e.g. produced by co- polymerising ethylene oxide with fatty acid esters of a sorbitol and its anhydrides of e.g. mono- and tri- lauryl, palmityl, stearyl and oleyl esters e.g. of the type known and commercially available under the trade name Tween (c.f. Fiedler, loc. cit. pp. 1300-1304) including the products Tween 20 [polyoxyethy lene(20)sorbitanmonolaurate] , 40 [polyoxyethylene(20)sorbitanmonopalmitate] ,
60 [polyoxyethy lene(20)sorbitanmonostearate] ,
80 [polyoxyethylene(20)sorbitanmonooleate], 65 [polyoxyethylene(20)sorbitantristearate] , 85 [polyoxyethylene(20)sorbitantrioleate],
21 [polyoxyethy lene(4)sorbitanmonolaurate] ,
61 [polyoxyethy lene(4)sorbitanmonostearate], and
81 [polyoxyethylene(5)sorbitanmonooleate].
Especially preferred products of this class for use in the compositions of the invention are the above products Tween 40 and Tween 80;
1.3 Polyoxyethylene fatty acid esters, e.g. produced by reacting fatty acids with ethylene oxide, e.g. polyoxyl 40 stearate, for example polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj (c.f. Fiedler, loc. cit., p. 834) as well as polyoxyethylene fatty acid esters known and commercially available under the trade name Cetiol HE. (c.f. Fiedler, loc. cit., p. 284); an especially preferred product of this class for use in the compositions of the invention is the product Myrj 52 having a O^= ca. 1.1., m.p.
= ca. 40-44 C, an HLB = ca. 16.9., an acid no. = ca. 0-1 and a saponification no. = ca. 25-35;
1.4 Polyethoxylated glyceryl fatty acid mono esters, e.g. of lauryl, stearic, oleyl, or isostearic acid, e.g. those obtainable under the name Tagat O or L.
1.5 Polyoxyethylene mono esters of a saturated Cioto C22, e.g. Cjg substituted e.g. hydroxy fatty acid; e.g. 12 hydroxy stearic PEG acid, e.g. of PEG about e.g. 600-900 e.g. 660 daltons MW, e.g. SOLUTOL H515 from BASF, Ludwigshafen, Germany. 1.6 Polyoxyethylene-polyoxypropylene co-polymers, poloxamers, e.g. of the type known and commercially available under the trade names Pluronic and Emkalyx (c.f. Fiedler, loc. cit., pp. 956-958). An especially preferred product of this class for use in the compositions of the invention is the product Pluronic F68 (poloxamer 188).
1.7 Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and so forth (c.f. Fiedler, loc. cit., pp. 1013 et seq.). Especially preferred is propylene glycol caprylic-capric acid diester as known and commercially available under the trade name Miglyol 840 (c.f. Fiedler, loc. cit., p. 809). Miglyol 840 has a fatty acid content = Cg max. ca. 3%,
Cg ca. 65-80%, CJQ ca. 15-30%, Cβ max. 3%. Acid no. = max. 0.1, iodine no. = ca. 320-340, iodine no. = max. 1.
Examples of ionic surfactants include:
2.1 Dioctylsuccinate, dioctylsodiumsulfosuccinate, di-[2-ethylhexyl]-succinate or sodium lauryl sulfate.
2.2 Phospholipids, in particular lecithins (c.f. Fiedler, loc. cit., pp. 731-733). Lecithins suitable for use in the compositions of the invention include, in particular, soya bean lecithins.
2.3 Bile salts, e.g. alkali metal salts, for example sodium taurocholate.
Examples of further lipophilic surfactants for use as surfactant component are, e.g.:
2.1 Trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols. Such trans-esterification products are known from the art and may be obtained e.g. in accordance with the general procedures described in US Patent No. 3,288,824. They include trans-esterification products of various natural (e.g. non-hydrogenated) vegetable oils for example, maize oil, kernel oil, almond oil, ground nut oil, olive oil and palm oil and mixtures thereof with polyethylene glycols, in particular polyethylene glycols having an average molecular weight of from 200 to 800. Preferred are products obtained by trans-esterification of 2 molar parts of a natural vegetable oil triglyceride with one molar part of polyethylene glycol (e.g. having an average molecular weight of from 200 to 800). Various forms of trans-esterification product of the class defined are known and commercially available under the trade name Labrafil [see Fiedler, loc. cit., 707]. Especially useful as components of the compositions of the invention are the products: Labrafil M 1944 CS, a trans-esterification product of kernel oil and polyethylene glycol having an acid no. = ca. 2, a saponification no. ca. 145 - 175 and an iodine no. = ca. 60 - 90; and Labrafil M 2130 CS, a trans-esterification product of a Cβ- to Cjg- glyceride and polyethylene glycol having a melting point = ca. 35 - 40 C, an acid no. = <2, a saponification no. = ca. 185 - 200 and an iodine no. = <3;
2.2 Mono-, di- and mono/di-glycerides, especially esterification products of caprylic or capric acid with glycerol. Preferred products of this class are e.g. those comprising or consisting mainly or essentially of caprylic/capric acid mono- and di-glycerides such as are commercially available under the trade name Imwitor (c.f. loc. cit., pp. 645). A particularly suitable product of this class for use in the compositions of the invention is the product Imwitor 742, which is the esterification product of a mixture of ca. 60 p.p.w. caprylic acid and ca. 40 p.p.w. capric acid with glycerol. Imwitor 742 is typically a yellowish crystalline mass, liquid at ca. 26 C; acid no. = max. 2; iodine no. = max. 1; saponification no. = ca. 235 - 275: % monoglycerides = ca. 40-50%; free glycerol = max. 2%; m.p. = ca. 24 - 26 C; unsaponifiables = 0.3% max.; peroxide no. = max. 1;
2.3 Sorbitan fatty acid esters e.g. of the type known and commercially available under the trade name Span, for example including sorbitan-monolauryl, -monopalmityl, -monostearyl, -tristearyl, -monooleyl and -trioleyl esters - (c.f. Fiedler, loc. cit., pp. 1139-1140);
2.4 Pentaerythritol fatty acid esters and polyalkylene glycol ethers, for example pentaerythrite- -dioleate, -distearate, -monolaurate, -polyglycol ether and
-monostearate as well as pentaerythrite-fatty acid esters (c.f. Fiedler, loc. cit. pp. 923-924);
2.5 Monoglycerides, e.g. glycerol monooleate, glycerol monopalmitate and glycerol monostearate, for example as known and commercially available under the trade names Myvatex, Myvaplex and Myverol (c.f. Fiedler, loc. cit., pp. 836), and acetylated, e.g. mono-and di-acetylated monoglycerides, for example as known and commercially available under the trade name Myvacet (c.f. Fiedler, loc. cit., pp. 835);
2.6 Glycerol triacetate or (l,2,3)-triacetin (c.f. Fiedler, loc. cit., pp. 952); and
2.7 Sterols and derivatives thereof, for example cholesterols and derivatives thereof, in particular phytosterols, e.g. products comprising sitosterol, campesterol or stigmasterol, and ethylene oxide adducts thereof, for example soya sterols and derivatives thereof, such as known under the trade name Generol (c.f. Fiedler loc. cit., p.p. 554 and 555) in particular the products Generol 122, 122 E5, 122 E10, and 122 E25.
It is to be appreciated that surfactants may be complex mixtures containing side products or unreacted starting products involved in the preparation thereof made by e.g. polyoxyethylation may contain another side product, e.g. polyethylene glycol.
The compositions of the invention may also comprise a thickening agent (also referred to as a viscosity increasing agent). Suitable thickening agents may be of those known and employed in the art, including e.g. pharmaceutically acceptable polymeric materials and inorganic thickening agents which enable the compositions to be filled easily and resists leakage, e.g. thixotropic agents. These should also have the property of dissolving quickly (e.g. within 5 minutes) in the stomach juices or water or at pH
1 to 2, for example, of the following types:
3.1 Water soluble tocopheryl polyethylene glycol succinic acid esters (TPGS), e.g. with a polymerisation number ca 1000, e.g. available from Eastman Fine Chemicals Kingsport, Texas, USA.
3.2 Water soluble celluloses and cellulose derivatives including; alkyl celluloses, e.g. methyl-, ethyl- and propyl-celluloses; hydroxyalkyl-celluloses, e.g. hydroxypropyl-celluloses and hydroxypropylalkyl-celluloses such as hydroxypropyl-methyl-celluloses; acylated celluloses, e.g. cellulose-acetates, cellulose-acetatephthallates, cellulose-acetatesuccinates and hydroxypropylmethyl-cellulose phthallates; and salts thereof such as sodium-carboxymethyl- -celluloses. Examples of such products suitable for use in accordance with the present invention are those known and commercially available, e.g. under the trade names Klucel and Methocel (c.f. Fiedler, loc. cit., pp. 688 and 790),
3.3 Water soluble polyvinylpyrrolidones, including for example poly-N-vinylpyrrolidones and vinylpyrrolidone co-polymers such as vinylpyrrolidone- vinylacetate co-polymers, especially of low molecular weight.
Examples of such compounds suitable for use in accordance with the present invention are those known and commercially available, e.g. under the trade name Kollidon (or, in the USA, Povidone) (c.f. Fiedler, loc. cit., pp. 694-696), in particular the products Kollidon 30 and 90;
3.4 Low amounts of inorganic thickening agents such as atapulgite, bentonite and silicates including hydrophilic silicon dioxide products, e.g. alkylated (for example methylated) silica gels, in particular colloidal silicon dioxide products as known and commercially available under the trade name Aerosil [c.f. Handbook of Pharmaceutical Excipients, loc. cit., p.p. 253-256] in particular the products Aerosil 130, 200, 300, 380, 0, OX 50, TT 600, MOX 80, MOX 170, LK 84 and the methylated Aerosil R 972.
The compositions may also include one or more further ingredients e.g. in an amount of from 0.1 to 5%, in particular anti-oxidants [e.g. ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols, e.g. -tocopherol (vitamin E)], flavouring agents and so forth. Use of an anti-oxidant, in particular a tocopherol, is particularly advantageous.
The relative proportion of ingredients in the compositions of the invention will, of course, vary considerably depending on the particular type of composition concerned. Determination of workable proportions in any particular instance will generally be within the capability of the man skilled on the art. All indicated proportions and relative weight ranges described below are accordingly to be understood as being indicative of preferred or individually inventive teachings only and not as not limiting the invention in its broadest aspect.
a) The cyclosporin will generally be present in an amount of from 5 to 30%, suitably from about 10 to about 25% by weight based on the total weight of the composition absent the hard gelatine capsule.
b) Any polyethylene glycol amount when present will generally be present in an amount of from about 15% to about 30%, by weight based on the total weight of the composition absent the hard gelatine capsule;
c) Any further excipient apart from the surfactant and as thickening agent is preferably present from an amount from 0.1% to 5%, by weight based on the total weight of the composition absent the hard gelatine capsule.
The compositions above may additionally include a thickening agent, though, as previously indicated, this will generally be less preferred. The amount of thickening agent present may vary e.g. depending on the required consistency of the end product, e.g. whether it is to be in a thickened flowable form, for example for filling into a capsule. The amount will of course also depend on the nature of the thickening agent chosen. In general the thickeners components (4), when present will be present in an amount of up to about 25% by weight based on the total weight of the composition, more suitably in an amount of up to about 15 or 20% by weight, e.g. in an amount of from 0.5 or 5 up to 15 or 20% by weight based on the total weight of the composition.
The compositions may also include further additives or ingredients, e.g. as hereinbefore described. In particular they may comprise antioxidants, e.g. in an amount of up to about 0.5 or 1% by weight based on the total weight of the composition, and sweetening or flavouring agents, e.g. in an amount of up to about 2.5 or 5% by weight based on the total weight of the composition.
Preferably no other excipients are present. Thus the volume may be kept low and the composition may be filled into a capsule size, 1, 2 or 3.
The compositions have been found to exhibit especially advantageous properties when administered orally, e.g. in terms of both the consistency and high level of bioavailability achieved as defined in standard tests in humans or e.g. beagle dogs. In particular, and in contrast with other galenic systems, e.g. as known from the art, it has been found that such compositions are compatible with tenside materials, e.g. bile salts, present in the gastro-intestinal tract. That is, they are fully dispersible in aqueous systems comprising such natural tensides and are thus capable of providing microemulsion systems in situ which are stable and do not exhibit precipitation or other disruption of fine particulate structure. Function of such systems on oral administration remains independent of and/or unimpaired by the relative presence or absence of bile salts at any particular time or for any given individual. Such compositions accordingly represent an especially preferred embodiment of the invention. The bioavailability characteristics may be observed in standard clinical trials or in dogs using standard radioimmunoassays for cyclosporins. Preferred capsules have a short Tmax. Preferably the compositions form, on dilution with water, micellar solutions, in which one may be able to detect droplets of, e.g. from 10 to 150 nm in diameter. The compositions above will preferably be compounded in orally administerable hard gelatine capsule shells to be unit dosage forms. Where the compositions are in unit dosage form, each unit dosage will suitably contain between about 5 or 10 and about 200mg cyclosporin, more suitably between about 15 or 25 and about 150mg, e.g. 25, 50 or lOOmg cyclosporin. Thus unit dosage forms in accordance with the invention, suitable for administration lx, 2x or 3x up to 5x daily (e.g. depending on the particular purpose of therapy, the phase of therapy etc..) will appropriately comprise e.g. about 25 mg, about 50 mg or about 100 mg cyclosporin per unit dosage.
Further details of the excipients are given in Fiedler.
The following non-limitative Examples illustrate the invention.
Example 1:
Hard gelatine capsules
Cyclosporin A 100 mg Surfactant (Cremophor 300 mg
RH or Tween)
Example 2:
As for Example 1 but containing additionally 10 mg of TPGS.
Each composition shows a bioavailability profile in humans and dogs similar to that of NEORAL, e.g. in terms of AUC, Tmax and Cmax.
The hard gelatine capsules are stable for at least 2 years and maintain an excellent condition.
Example 3:
Hard gelatine capsules
Cyclosporin A 50 mg
Surfactant (Cremophor 300 mg RH or Tween) 1,2-Propylene glycol or Ethanol 8% by weight of the total composition Example 4:
Hard gelatine capsules
Cyclosporin A 50 mg
Surfactant (Cremophor 300 mg
RH or Tween)
PEG 300 3 300%% bbyy weight of the total composition

Claims

CLAIMS:
A hard gelatine capsule containing a pharmaceutical composition comprising cyclosporin A in a mixture with a surfactant of HLB value at least 10, substantially free of any oil and when a hydrophilic phase is present, the hydrophilic phase being a polyethylene glycol and/or a lower alkanol provided that any lower alkanol present is present in less than 12% of the total weight of the composition absent the hard gelatine capsule.
A hard gelatine capsule as defined in claim 1 wherein the lower alkanol present is present in less than 8% of the total weight of the composition absent the hard gelatine capsule.
3. A hard gelatine capsule as defined in claim 1 or 2 wherein the surfactant is a polyoxyethylene-sorbitan-fatty acid ester.
4. A hard gelatine capsule as defined in any preceding claim further comprising a thickening agent which is capable of dissolving in the stomach juices or water.
5. A hard gelatine capsule as defined in any preceding claim wherein cyclosporin is present in an amount of from 10 to 25% by weight based on the total weight of the composition absent the hard gelatine capsule.
6. A hard gelatine capsule as defined in any preceding claim comprising further excipients apart from the surfactant and as thickening agent in an amount of from 0.1 to 5% by weight based on the total weight of the composition absent the hard gelatine capsule.
7. A hard gelatine capsule as defined in any preceding claim wherein the hydrophilic phase is present.
8. A hard gelatine capsule as defined in claim 7 claim wherein the hydrophilic phase is polyethylene glycol and/or propylene glycol.
9. A hard gelatine capsule as defined in claim 7 wherein the hydrophilic phase is polyethylene glycol and/or ethanol.
10. A hard gelatine capsule as defined in claim 1 containing a hydrophilic phase which comprises polyethylene glycol and/or a lower alkanol as defined in claim 1 and when any polyethylene glycol is present this polyethylene glycol is liquid when heated to 37° and the surfactant is a polyoxyethylene sorbitan fatty acid ester or a polyethyloxylated castor oil or a polyoxyethylene fatty acid ester.
11. A hard gelatine capsule as defined in claim 10 wherein the pharmaceutical composition is semi-solid or liquid with the cyclosporin dissolved therein.
PCT/EP1998/000453 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin a WO1998033512A1 (en)

Priority Applications (23)

Application Number Priority Date Filing Date Title
EP98904156A EP0988046B1 (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin a
DE29824679U DE29824679U1 (en) 1997-01-30 1998-01-28 Pharmaceutical compositions
SI9830695T SI0988046T1 (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin a
AU62141/98A AU737053B2 (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin A
CA002278675A CA2278675A1 (en) 1997-01-30 1998-01-28 Hard gelatine capsules containing pharmaceutical compositions substantially free of any oil
AT98904156T ATE275963T1 (en) 1997-01-30 1998-01-28 OIL-FREE PHARMACEUTICAL COMPOSITION CONTAINING CYCLOSPORIN
PL372850A PL191919B1 (en) 1997-01-30 1998-01-28 Gelatin capsule with solid film including oil-free pharmaceutically compositions
GB9917521A GB2335854B (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin A
US09/284,391 US6475519B1 (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin A
IL13079798A IL130797A0 (en) 1997-01-30 1998-01-28 Hard gelatine capsules containing pharmaceutical compositions substantially free of any oil
SK1020-99A SK285019B6 (en) 1997-01-30 1998-01-28 Hard gelatine capsule
BR9807528-4A BR9807528A (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporine a
DE69826272T DE69826272T2 (en) 1997-01-30 1998-01-28 OIL-FREE PHARMACEUTICAL COMPOSITION CONTAINING CYCLOSPORIN
HU0500385A HUP0500385A3 (en) 1998-01-28 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin a
JP10532524A JP2000516256A (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical composition containing cyclosporin A
DK98904156T DK0988046T3 (en) 1998-01-28 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin A
KR10-2003-7005807A KR20040004416A (en) 1997-01-30 1998-01-28 Oil-Free Pharmaceutical Compositions Containing Cyclosporin A
DE19882037T DE19882037T1 (en) 1997-01-30 1998-01-28 Hard gelatin capsule containing essentially oil-free pharmaceutical compositions
PL98334850A PL190420B1 (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin a
HU0001013A HUP0001013A3 (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin a
NZ336900A NZ336900A (en) 1997-01-30 1998-01-28 Hard gelatine capsules containing pharmaceutical compositions comprising cyclosporin A and being substantially free of any oil
IL130797A IL130797A (en) 1997-01-30 1999-07-05 Hard gelatine capsules containing pharmaceutical compositions substantially free of any oil
HK00106122A HK1027745A1 (en) 1997-01-30 2000-09-26 Oil-free pharmaceutical compositions containing cyclosporina.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9701881.6A GB9701881D0 (en) 1997-01-30 1997-01-30 Organic compounds
GB9701881.6 1997-01-30
GB9702594.4 1997-02-07
GBGB9702594.4A GB9702594D0 (en) 1997-02-07 1997-02-07 Organic compounds

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09/284,391 A-371-Of-International US6475519B1 (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin A
US09/992,584 Continuation US6723339B2 (en) 1997-01-30 2001-11-06 Oil-free pharmaceutical compositions containing cyclosporin A

Publications (1)

Publication Number Publication Date
WO1998033512A1 true WO1998033512A1 (en) 1998-08-06

Family

ID=26310891

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/000453 WO1998033512A1 (en) 1997-01-30 1998-01-28 Oil-free pharmaceutical compositions containing cyclosporin a

Country Status (26)

Country Link
US (3) US6475519B1 (en)
EP (2) EP0988046B1 (en)
JP (2) JP2000516256A (en)
KR (3) KR20000069900A (en)
CN (2) CN1246058A (en)
AT (1) ATE275963T1 (en)
AU (1) AU737053B2 (en)
BR (1) BR9807528A (en)
CA (1) CA2278675A1 (en)
CY (1) CY2548B1 (en)
CZ (1) CZ295207B6 (en)
DE (3) DE29824679U1 (en)
ES (1) ES2229473T3 (en)
GB (2) GB2335854B (en)
HK (1) HK1027745A1 (en)
HU (1) HUP0001013A3 (en)
ID (1) ID26696A (en)
IL (2) IL130797A0 (en)
NZ (1) NZ336900A (en)
PL (1) PL190420B1 (en)
PT (1) PT988046E (en)
RU (1) RU2211047C2 (en)
SG (1) SG115386A1 (en)
SK (1) SK285019B6 (en)
TR (1) TR199901686T2 (en)
WO (1) WO1998033512A1 (en)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998058629A2 (en) * 1997-06-20 1998-12-30 Phares Pharmaceutical Research N.V. Preparation of pharmaceutical compositions
EP0985412A2 (en) * 1998-08-18 2000-03-15 Panacea Biotec Limited Cyclosporin compositions
WO2000048571A1 (en) * 1999-02-16 2000-08-24 Novartis Ag Spontaneously dispersible n-benzoyl staurosporine compositions
WO2000072867A2 (en) * 1999-05-28 2000-12-07 Novartis Ag Substantially oil-free cyclosporin compositions
WO2002089773A2 (en) * 2001-05-09 2002-11-14 Novartis Ag Pharmaceutical compositions comprising cyclosporin
WO2003068266A1 (en) * 2002-02-14 2003-08-21 Solvay Pharmaceuticals B.V. Oral solid solution formulation of a poorly water-soluble active substance
EP2062571A1 (en) * 2007-11-21 2009-05-27 Innopharmax Inc. Self-emulsifying pharmaceutical composition with enhanced bioavailability
US7919113B2 (en) 1999-12-30 2011-04-05 Yissum Research Development Company Of The Hebrew University Of Jerusalem Dispersible concentrate lipospheres for delivery of active agents
JP2011105754A (en) * 1997-03-12 2011-06-02 Abbott Lab Hydrophilic binary systems for administration of cyclosporine
HRP20040320B1 (en) * 2001-09-10 2012-11-30 Tibotec Pharmaceuticals Ltd. Method for the preparation of hexahydro-furo(2,3-b) furan-3-ol
US8865695B2 (en) 2009-01-08 2014-10-21 Lipocine Inc. Steroidal compositions
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US10561615B2 (en) 2010-12-10 2020-02-18 Lipocine Inc. Testosterone undecanoate compositions
US11433083B2 (en) 2010-11-30 2022-09-06 Lipocine Inc. High-strength testosterone undecanoate compositions
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy
US11707467B2 (en) 2014-08-28 2023-07-25 Lipocine Inc. (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5858401A (en) * 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
CA2278675A1 (en) * 1997-01-30 1998-08-06 Novartis Ag Hard gelatine capsules containing pharmaceutical compositions substantially free of any oil
MY139721A (en) * 2002-04-19 2009-10-30 Cpex Pharmaceuticals Inc Pharmaceutical composition
US7101566B2 (en) * 2002-06-28 2006-09-05 Ethicon, Inc. Polymer coated microparticles for sustained release
GB2391471B (en) * 2002-08-02 2005-05-04 Satishchandra Punambhai Patel Pharmaceutical compositions
AU2004222306A1 (en) * 2003-03-17 2004-09-30 Albany Molecular Research, Inc. Novel cyclosporins
PT1660047E (en) 2003-08-13 2014-02-27 Biocon Ltd Micro-particle fatty acid salt solid dosage formulations for therapeutic agents
US20050059583A1 (en) 2003-09-15 2005-03-17 Allergan, Inc. Methods of providing therapeutic effects using cyclosporin components
WO2005053727A2 (en) * 2003-11-29 2005-06-16 Sangstat Medical Corporation Pharmaceutical compositions for bioactive peptide agents
JP2005255677A (en) * 2004-02-12 2005-09-22 Nof Corp Cyclosporine preparation
US7511013B2 (en) * 2004-09-29 2009-03-31 Amr Technology, Inc. Cyclosporin analogues and their pharmaceutical uses
JP2008514701A (en) * 2004-09-29 2008-05-08 エーエムアール テクノロジー インコーポレイテッド Cyclosporine alkyne analogs and their pharmaceutical use
WO2006041631A2 (en) * 2004-10-06 2006-04-20 Amr Technology, Inc. Novel cyclosporin alkynes and their utility as pharmaceutical agents
US7825087B2 (en) 2005-04-12 2010-11-02 Elan Pharma International Limited Nanoparticulate and controlled release compositions comprising cyclosporine
US20060240051A1 (en) * 2005-04-26 2006-10-26 Singleton Andy H Eutectic blends containing a water soluble vitamin derivative
US7297679B2 (en) 2005-07-13 2007-11-20 Allergan, Inc. Cyclosporin compositions
US7202209B2 (en) 2005-07-13 2007-04-10 Allergan, Inc. Cyclosporin compositions
US20070015693A1 (en) * 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US7288520B2 (en) 2005-07-13 2007-10-30 Allergan, Inc. Cyclosporin compositions
US7276476B2 (en) * 2005-07-13 2007-10-02 Allergan, Inc. Cyclosporin compositions
US20070015691A1 (en) 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
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
US7745400B2 (en) * 2005-10-14 2010-06-29 Gregg Feinerman Prevention and treatment of ocular side effects with a cyclosporin
US7696165B2 (en) * 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne analogues for preventing or treating viral-induced disorders
US7696166B2 (en) * 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders
WO2008103712A2 (en) * 2007-02-20 2008-08-28 Bisco, Inc. Polymerizable dental pulp healing, capping, and lining material and method for use
EP2164466A1 (en) * 2007-06-01 2010-03-24 Novo Nordisk A/S Spontaneously dispersible preconcentrates including a peptide drug in a solid or semisolid carrier
PL2910570T3 (en) 2008-03-18 2017-06-30 Novo Nordisk A/S Protease stabilized, acylated insulin analogues
SA109300195B1 (en) 2008-03-28 2013-04-20 Astrazeneca Ab A Novel Anti-Cancer Pharmaceutical Composition
AU2013247047A1 (en) 2012-04-11 2014-10-23 Novo Nordisk A/S Insulin formulations
CN110087674B (en) 2016-12-16 2023-01-03 诺和诺德股份有限公司 Pharmaceutical composition containing insulin

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2230440A (en) * 1989-02-09 1990-10-24 Sandoz Ltd Cyclosporin compositions
EP0589843A1 (en) * 1992-09-25 1994-03-30 Sandoz Ag Pharmaceutical compositions containing cyclosporins
DE4412201A1 (en) * 1993-04-20 1994-11-10 Rentschler Arzneimittel New pharmaceutical preparations for oral administration containing cyclosporin
DE19539860A1 (en) * 1994-11-03 1996-05-09 Dresden Arzneimittel Oral cyclosporin formulations
WO1996036316A1 (en) * 1995-05-19 1996-11-21 Abbott Laboratories Self-emulsifying formulations of lipophilic drugs
WO1997034622A1 (en) * 1996-03-21 1997-09-25 Sangstat Medical Corporation Oral cyclosporin formulations

Family Cites Families (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE738604C (en) 1935-07-09 1943-08-23 Rudolf Degkwitz Dr Process for the production of hydrosols with a selectable shape and size of the colloidal particles
CH240789A (en) 1942-01-28 1946-01-31 Reichstein Tadeus Dr Professor Process for the preparation of a new compound of the cyclopentanopolyhydrophenanthrene series.
GB616190A (en) 1945-11-06 1949-01-18 Procter & Gamble Improvements in application of low temperature inter-esterification or alcoholysis to glycerides
FR1274354A (en) 1956-03-10 1961-10-27 Surfactants obtained from triglycerides and polyethylene glycol
GB1171125A (en) 1966-06-08 1969-11-19 Glaxo Lab Ltd Improvements in or relating to Injectable Preparations
US3954967A (en) 1971-08-05 1976-05-04 Vanguard Chemical Company, Inc. Method of producing microcolloidal aqueous emulsions of unsaturated organic insecticidal compounds
US3813345A (en) 1971-08-05 1974-05-28 Vanguard Chem Co Inc Method of producing microcolloidal aqueous emulsions of unsaturated organic compounds
US4073943A (en) 1974-09-11 1978-02-14 Apoteksvarucentralen Vitrum Ab Method of enhancing the administration of pharmalogically active agents
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US4210581A (en) 1975-11-04 1980-07-01 Sandoz Ltd. Organic compounds
CH614931A5 (en) 1975-11-04 1979-12-28 Sandoz Ag
US4146499A (en) 1976-09-18 1979-03-27 Rosano Henri L Method for preparing microemulsions
JPS53107408A (en) 1977-02-28 1978-09-19 Yamanouchi Pharmaceut Co Ltd Micellar preparation for rectal infusion
DE2819094A1 (en) 1977-05-10 1978-11-23 Sandoz Ag CYCLOSPORIN DERIVATIVES, THEIR USE AND MANUFACTURING
SE445174B (en) 1978-03-07 1986-06-09 Sandoz Ag PHARMACEUTICAL COMPOSITION CONTAINING A CYCLOSPORIN AND A HEALING SUBSTANCE
CH641356A5 (en) 1979-02-27 1984-02-29 Sandoz Ag Pharmaceutical compositions containing cyclosporin
US4571926A (en) 1979-06-22 1986-02-25 Pneumatic Scale Corporation Apparatus for forming, filling and depositing filled bags into cartons
JPS6033429B2 (en) 1980-04-28 1985-08-02 小野薬品工業株式会社 Prostaglandin-like compounds
NZ199915A (en) 1981-03-11 1985-07-12 Unilever Plc Treating edible oils to raise melting point thereof
FR2502951B1 (en) 1981-04-06 1985-12-06 Sandoz Sa TOPICAL PHARMACEUTICAL COMPOSITIONS IN THE FORM OF A MICRO-EMULSION
PH19156A (en) 1982-02-01 1986-01-15 Sandoz Ltd Dihydrocyclosporin d in the treatment of multiple sclerosis
JPS58208215A (en) 1982-05-31 1983-12-03 Sato Seiyaku Kk Oil-soluble composition containing fat-soluble vitamin
DE3225706C2 (en) 1982-07-09 1984-04-26 A. Nattermann & Cie GmbH, 5000 Köln Liquid active ingredient formulations in the form of concentrates for microemulsions
DE3235612A1 (en) 1982-09-25 1984-03-29 Bayer Ag, 5090 Leverkusen MICROEMULSIONS
DE3237814A1 (en) 1982-10-12 1984-04-12 Warner-Lambert Co., 07950 Morris Plains, N.J. WATER-FREE EMULSIONS AND USE THEREOF
DE3315805A1 (en) 1983-04-30 1984-11-08 Bayer Ag, 5090 Leverkusen Active substance compositions
JPS6061535A (en) 1983-08-24 1985-04-09 エフ・ホフマン・ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト Pharmaceutical composition
FR2553661B1 (en) 1983-10-19 1985-12-20 Rhone Poulenc Sante NEW PHARMACEUTICALLY ACCEPTABLE MICROEMULSIONS
DE3406497A1 (en) 1984-02-23 1985-09-05 Mueller Bernhard Willi Werner HIGHLY DISPERSAL PHARMACEUTICAL MULTI-COMPONENT SYSTEMS AND METHOD FOR THEIR PRODUCTION
US4794000A (en) 1987-01-08 1988-12-27 Synthetic Blood Corporation Coacervate-based oral delivery system for medically useful compositions
US4963367A (en) 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods
US5639724A (en) 1984-07-24 1997-06-17 Sandoz Ltd. Cyclosporin galenic forms
GB8903804D0 (en) 1989-02-20 1989-04-05 Sandoz Ltd Improvements in or relating to organic compounds
DE3580717D1 (en) 1984-08-02 1991-01-10 Sandoz Ag PHARMACEUTICAL APPLICATION OF (NVA) 2-CYCLOSPORINE.
CH662944A5 (en) 1984-10-18 1987-11-13 Pier Luigi Prof Dr Luisi PROCEDURE FOR THE PREPARATION OF BIOCOMPATIBLE REVERSE MICROCOMPATIBLES AND THEIR USE.
DE3444893A1 (en) 1984-12-08 1986-06-12 Henkel KGaA, 4000 Düsseldorf METHOD FOR PRODUCING FATTY ACID METHYL ESTERS
JPS61280435A (en) 1985-04-04 1986-12-11 Kanji Takada Lymph orienting preparation of cyclosporin
JPS61249918A (en) 1985-04-26 1986-11-07 Yutaka Mizushima Eye drops
JPS6224776A (en) 1985-07-25 1987-02-02 Matsushita Electric Works Ltd Compression system for picture data
IL78929A0 (en) 1985-07-29 1986-09-30 Abbott Lab Microemulsion compositions for parenteral administration
US5023271A (en) 1985-08-13 1991-06-11 California Biotechnology Inc. Pharmaceutical microemulsions
US4797272A (en) 1985-11-15 1989-01-10 Eli Lilly And Company Water-in-oil microemulsions for cosmetic uses
SE8601624D0 (en) 1986-04-11 1986-04-11 Haessle Ab NEW PHARMACEUTICAL PREPARATIONS
SE457693B (en) 1986-07-01 1989-01-23 Drilletten Ab COMPOSITION WITH REGULATED RELEASE WAS A BIOLOGICAL MATERIAL LOST OR DISPERSED IN AN L2 PHASE
CA1318589C (en) 1986-08-14 1993-06-01 Bernard Ecanow Drug delivery system
DE3629386A1 (en) 1986-08-29 1988-03-03 Scherer Gmbh R P GELATINE CAPSULES AND METHOD FOR THEIR PRODUCTION
DE3707711A1 (en) 1987-03-11 1988-09-22 Hoechst Ag OIL-IN-WATER EMULSIONS, METHOD FOR THEIR PRODUCTION AND THEIR USE
CA1301642C (en) 1987-03-30 1992-05-26 Howard Bernard Dawson Chemical formulations
US4798823A (en) 1987-06-03 1989-01-17 Merck & Co., Inc. New cyclosporin analogs with modified "C-9 amino acids"
JP2577049B2 (en) 1987-06-04 1997-01-29 三共株式会社 Cyclosporine preparation
EP0296122B1 (en) 1987-06-17 1993-09-29 Sandoz Ag Cyclosporins and their use as pharmaceuticals
GB2206119B (en) 1987-06-22 1990-10-31 Merck & Co Inc A new cyclosporin derivative with modified "8-amino acid"
US4835002A (en) 1987-07-10 1989-05-30 Wolf Peter A Microemulsions of oil in water and alcohol
HU205010B (en) 1987-09-15 1992-03-30 Sandoz Ag Process for producing pharmaceutical compositions comprising compounds soluble up to 1 per cent and having medical activity
US5756450A (en) 1987-09-15 1998-05-26 Novartis Corporation Water soluble monoesters as solubilisers for pharmacologically active compounds and pharmaceutical excipients and novel cyclosporin galenic forms
IL88076A (en) 1987-10-28 1993-01-14 Nippon Shinyaku Co Ltd Fat emulsions as drug carriers
US4914188A (en) 1987-11-16 1990-04-03 Merck & Co., Inc. Novel 6-position cyclosporin analogs as non-immunosuppressive antagonists of cyclosporin binding to cyclophilin
HU203564B (en) 1987-12-21 1991-08-28 Sandoz Ag Process for producing new orthorombos cyclosporin without solvatation
EP0327280B1 (en) 1988-01-29 1992-03-18 Sankyo Company Limited Cyclosporin compositions
CH679119A5 (en) 1988-05-13 1991-12-31 Sandoz Ag
HU201567B (en) 1988-07-21 1990-11-28 Gyogyszerkutato Intezet Process for production of intravenous medical compositions containing cyclosphorin
KR0148748B1 (en) 1988-09-16 1998-08-17 장 크라메르, 한스 루돌프 하우스 A multiphase cyclosporin composition
US5342625A (en) * 1988-09-16 1994-08-30 Sandoz Ltd. Pharmaceutical compositions comprising cyclosporins
US6007840A (en) 1988-09-16 1999-12-28 Novartis Ag Pharmaceutical compositions comprising cyclosporins
DE68914929T2 (en) 1988-09-29 1994-08-11 Shiseido Co Ltd Emulsified composition.
FR2638089A1 (en) 1988-10-26 1990-04-27 Sandoz Sa NOVEL OPHTHALMIC COMPOSITIONS BASED ON CYCLOSPORINE
JPH0738771B2 (en) 1989-01-17 1995-05-01 花王株式会社 Liquid edible oil composition
AU5157590A (en) 1989-02-06 1990-08-24 Abbott Laboratories Pharmaceutical compositions for oral administration
US4996193A (en) 1989-03-03 1991-02-26 The Regents Of The University Of California Combined topical and systemic method of administration of cyclosporine
DD298351A5 (en) 1989-11-06 1992-02-20 Jenapharm Gmbh,De METHOD FOR PRODUCING A CARRIER-RELATED MEDICAMENT
AU6785490A (en) 1989-12-18 1991-06-20 Kraft General Foods, Inc. Low-saturate edible oils and transesterification methods for production thereof
HU208491B (en) 1990-11-27 1993-11-29 Gyogyszerkutato Intezet Process for producing oral pharmaceutical composition containing cyclosporin
US6262022B1 (en) 1992-06-25 2001-07-17 Novartis Ag Pharmaceutical compositions containing cyclosporin as the active agent
FR2683225B1 (en) 1991-10-31 1993-12-31 Gattefosse Sa PROCESS FOR IMPROVING A GLYCEROLYZED OIL.
US5206219A (en) 1991-11-25 1993-04-27 Applied Analytical Industries, Inc. Oral compositions of proteinaceous medicaments
DK0642332T3 (en) 1992-05-13 1997-06-16 Sandoz Ltd Ophthalmic preparations containing cyclosporin
CZ291237B6 (en) * 1993-04-20 2003-01-15 Novartis Ag Pharmaceutical preparation for oral administration and containing cyclosporin A
ES2308955T5 (en) 1993-09-28 2012-04-03 R.P. Scherer Gmbh Manufacture of soft gelatin capsules
DE4340781C3 (en) 1993-11-30 2000-01-27 Novartis Ag Liquid preparations containing cyclosporin and process for their preparation
EP0697214A1 (en) * 1994-07-19 1996-02-21 Vestar, Inc. Liposomal cyclosporin pharmaceutical formulations
KR0167613B1 (en) 1994-12-28 1999-01-15 한스 루돌프 하우스, 니콜 케르커 Cyclosporin-containing soft capsule compositions
US5827822A (en) 1996-03-25 1998-10-27 Sangstat Medical Corporation Cyclosporin a formulations as nanoparticles
US5834017A (en) 1995-08-25 1998-11-10 Sangstat Medical Corporation Oral cyclopsporin formulations
US5962019A (en) 1995-08-25 1999-10-05 Sangstat Medical Corporation Oral cyclosporin formulations
CA2278675A1 (en) * 1997-01-30 1998-08-06 Novartis Ag Hard gelatine capsules containing pharmaceutical compositions substantially free of any oil
JP4718653B2 (en) * 1997-03-12 2011-07-06 アボツト・ラボラトリーズ Hydrophilic two-component system for administration of cyclosporine
US6008191A (en) 1997-09-08 1999-12-28 Panacea Biotec Limited Pharmaceutical compositions containing cyclosporin
GB9912476D0 (en) * 1999-05-28 1999-07-28 Novartis Ag Organic compounds

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2230440A (en) * 1989-02-09 1990-10-24 Sandoz Ltd Cyclosporin compositions
EP0589843A1 (en) * 1992-09-25 1994-03-30 Sandoz Ag Pharmaceutical compositions containing cyclosporins
DE4412201A1 (en) * 1993-04-20 1994-11-10 Rentschler Arzneimittel New pharmaceutical preparations for oral administration containing cyclosporin
DE19539860A1 (en) * 1994-11-03 1996-05-09 Dresden Arzneimittel Oral cyclosporin formulations
WO1996036316A1 (en) * 1995-05-19 1996-11-21 Abbott Laboratories Self-emulsifying formulations of lipophilic drugs
WO1997034622A1 (en) * 1996-03-21 1997-09-25 Sangstat Medical Corporation Oral cyclosporin formulations

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011105754A (en) * 1997-03-12 2011-06-02 Abbott Lab Hydrophilic binary systems for administration of cyclosporine
US6599527B1 (en) 1997-06-20 2003-07-29 Phares Pharmaceutical Research N.V. Preparation of pharmaceutical compositions
WO1998058629A3 (en) * 1997-06-20 1999-03-18 Phares Pharm Res Nv Preparation of pharmaceutical compositions
AU731397B2 (en) * 1997-06-20 2001-03-29 Phares Pharmaceutical Research N.V. Preparation of pharmaceutical compositions
WO1998058629A2 (en) * 1997-06-20 1998-12-30 Phares Pharmaceutical Research N.V. Preparation of pharmaceutical compositions
EP0985412A2 (en) * 1998-08-18 2000-03-15 Panacea Biotec Limited Cyclosporin compositions
EP0985412A3 (en) * 1998-08-18 2001-05-02 Panacea Biotec Limited Cyclosporin compositions
WO2000048571A1 (en) * 1999-02-16 2000-08-24 Novartis Ag Spontaneously dispersible n-benzoyl staurosporine compositions
US8575147B2 (en) 1999-02-16 2013-11-05 Novartis Ag Spontaneously dispersible N-benzoyl staurosporine compositions
US8722664B2 (en) 1999-02-16 2014-05-13 Novartis Ag Spontaneously dispersible N-benzoyl staurosporine compositions
GB2367004B (en) * 1999-05-28 2004-04-14 Novartis Ag A cyclosporin containing composition in the form of a capsule
GB2367004A (en) * 1999-05-28 2002-03-27 Novartis Ag Pharmaceutical compositions
AU765935B2 (en) * 1999-05-28 2003-10-02 Novartis Ag Substantially oil-free cyclosporin compositions
US6767555B2 (en) 1999-05-28 2004-07-27 Novartis Ag Pharmaceutical compositions
WO2000072867A3 (en) * 1999-05-28 2001-04-05 Novartis Ag Substantially oil-free cyclosporin compositions
WO2000072867A2 (en) * 1999-05-28 2000-12-07 Novartis Ag Substantially oil-free cyclosporin compositions
US7919113B2 (en) 1999-12-30 2011-04-05 Yissum Research Development Company Of The Hebrew University Of Jerusalem Dispersible concentrate lipospheres for delivery of active agents
WO2002089773A3 (en) * 2001-05-09 2003-02-06 Novartis Ag Pharmaceutical compositions comprising cyclosporin
WO2002089773A2 (en) * 2001-05-09 2002-11-14 Novartis Ag Pharmaceutical compositions comprising cyclosporin
HRP20040320B1 (en) * 2001-09-10 2012-11-30 Tibotec Pharmaceuticals Ltd. Method for the preparation of hexahydro-furo(2,3-b) furan-3-ol
WO2003068266A1 (en) * 2002-02-14 2003-08-21 Solvay Pharmaceuticals B.V. Oral solid solution formulation of a poorly water-soluble active substance
KR101014545B1 (en) * 2002-02-14 2011-02-16 애보트 헬스케어 프로덕츠 비.브이. Oral solid solution formulation of a poorly water-soluble active substance
AU2003208713B2 (en) * 2002-02-14 2007-10-18 Solvay Pharmaceuticals B.V. Oral solid solution formulation of a poorly water-soluble active substance
AU2003208713B9 (en) * 2002-02-14 2003-09-04 Solvay Pharmaceuticals B.V. Oral solid solution formulation of a poorly water-soluble active substance
EP2062571A1 (en) * 2007-11-21 2009-05-27 Innopharmax Inc. Self-emulsifying pharmaceutical composition with enhanced bioavailability
US8865695B2 (en) 2009-01-08 2014-10-21 Lipocine Inc. Steroidal compositions
US11304960B2 (en) 2009-01-08 2022-04-19 Chandrashekar Giliyar Steroidal compositions
US11052096B2 (en) 2009-01-08 2021-07-06 Lipocine Inc. Steroidal compositions
US10226473B2 (en) 2010-11-30 2019-03-12 Lipocine Inc. High-strength testosterone undecanoate compositions
US10881671B2 (en) 2010-11-30 2021-01-05 Lipocine Inc. High-strength testosterone undecanoate compositions
US11433083B2 (en) 2010-11-30 2022-09-06 Lipocine Inc. High-strength testosterone undecanoate compositions
US9757390B2 (en) 2010-11-30 2017-09-12 Lipocine Inc. High-strength testosterone undecanoate compositions
US11364249B2 (en) 2010-11-30 2022-06-21 Lipocine Inc. High-strength testosterone undecanoate compositions
US9943527B2 (en) 2010-11-30 2018-04-17 Lipocine Inc. High-strength testosterone undecanoate compositions
US9949985B2 (en) 2010-11-30 2018-04-24 Lipocine Inc. High-strength testosterone undecanoate compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US11364250B2 (en) 2010-11-30 2022-06-21 Lipocine Inc. High-strength testosterone undecanoate compositions
US10716794B2 (en) 2010-11-30 2020-07-21 Lipocine Inc. High-strength testosterone undecanoate compositions
US10799513B2 (en) 2010-11-30 2020-10-13 Lipocine Inc. High-strength testosterone undecanoate compositions
US9480690B2 (en) 2010-11-30 2016-11-01 Lipocine Inc. High-strength testosterone undecanoate compositions
US10973833B2 (en) 2010-11-30 2021-04-13 Lipocine Inc. High-strength testosterone undecanoate compositions
US9205057B2 (en) 2010-11-30 2015-12-08 Lipocine Inc. High-strength testosterone undecanoate compositions
US11311555B2 (en) 2010-11-30 2022-04-26 Lipocine Inc. High-strength testosterone undecanoate compositions
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
US10561615B2 (en) 2010-12-10 2020-02-18 Lipocine Inc. Testosterone undecanoate compositions
US11298365B2 (en) 2014-08-28 2022-04-12 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US9757389B2 (en) 2014-08-28 2017-09-12 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US11707467B2 (en) 2014-08-28 2023-07-25 Lipocine Inc. (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use
US11872235B1 (en) 2014-08-28 2024-01-16 Lipocine Inc. Bioavailable solid state (17-β)-Hydroxy-4-Androsten-3-one esters
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy

Also Published As

Publication number Publication date
US20040161458A1 (en) 2004-08-19
CN1679917A (en) 2005-10-12
GB2335854A (en) 1999-10-06
NZ336900A (en) 2001-06-29
HUP0001013A3 (en) 2004-10-28
ID26696A (en) 2001-02-01
GB2355195B (en) 2001-09-12
EP0988046A1 (en) 2000-03-29
PL334850A1 (en) 2000-03-27
GB9917521D0 (en) 1999-09-29
EP0988046B1 (en) 2004-09-15
SG115386A1 (en) 2005-10-28
AU737053B2 (en) 2001-08-09
SK102099A3 (en) 2000-01-18
SK285019B6 (en) 2006-04-06
CZ295207B6 (en) 2005-06-15
GB0024188D0 (en) 2000-11-15
GB2355195A (en) 2001-04-18
KR20050084502A (en) 2005-08-26
US6475519B1 (en) 2002-11-05
ATE275963T1 (en) 2004-10-15
CA2278675A1 (en) 1998-08-06
RU2211047C2 (en) 2003-08-27
CN1246058A (en) 2000-03-01
GB2335854B (en) 2001-04-25
CZ266399A3 (en) 1999-10-13
IL130797A0 (en) 2001-01-28
TR199901686T2 (en) 1999-09-21
DE29824679U1 (en) 2002-03-28
HUP0001013A2 (en) 2000-10-28
KR20000069900A (en) 2000-11-25
BR9807528A (en) 2000-03-14
PL190420B1 (en) 2005-12-30
DE69826272D1 (en) 2004-10-21
PT988046E (en) 2004-12-31
ES2229473T3 (en) 2005-04-16
JP2005225897A (en) 2005-08-25
AU6214198A (en) 1998-08-25
JP2000516256A (en) 2000-12-05
US20020119190A1 (en) 2002-08-29
KR20040004416A (en) 2004-01-13
IL130797A (en) 2006-08-01
US6723339B2 (en) 2004-04-20
EP1331002A2 (en) 2003-07-30
HK1027745A1 (en) 2001-01-23
EP1331002A3 (en) 2004-01-14
DE19882037T1 (en) 1999-12-16
CY2548B1 (en) 2008-07-02
DE69826272T2 (en) 2005-11-17
GB2355195A8 (en) 2002-03-28

Similar Documents

Publication Publication Date Title
US6723339B2 (en) Oil-free pharmaceutical compositions containing cyclosporin A
US8722664B2 (en) Spontaneously dispersible N-benzoyl staurosporine compositions
US7235248B2 (en) Pharmaceutical compositions comprising cyclosporins
US6767555B2 (en) Pharmaceutical compositions
CZ301382B6 (en) Hydrophilic binary systems for administering cyclosporin
AU762247B2 (en) Oil-free pharmaceutical compositions containing cyclosporin A
AU2007201773A1 (en) Oil-free pharmaceutical compositions containing cyclosporin A
MXPA99006916A (en) Oil-free pharmaceutical compositions containing cyclosporin a

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 130797

Country of ref document: IL

Ref document number: 98802163.3

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 09284391

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1998904156

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 62141/98

Country of ref document: AU

Ref document number: 1199900532

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 1019997006094

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 1999/01686

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 336900

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: PA/a/1999/006916

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: PV1999-2663

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 102099

Country of ref document: SK

ENP Entry into the national phase

Ref document number: 2278675

Country of ref document: CA

Ref document number: 2278675

Country of ref document: CA

Kind code of ref document: A

Ref document number: 1998 532524

Country of ref document: JP

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: PV1999-2663

Country of ref document: CZ

RET De translation (de og part 6b)

Ref document number: 19882037

Country of ref document: DE

Date of ref document: 19991216

WWE Wipo information: entry into national phase

Ref document number: 19882037

Country of ref document: DE

WWP Wipo information: published in national office

Ref document number: 1998904156

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1019997006094

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 62141/98

Country of ref document: AU

WWR Wipo information: refused in national office

Ref document number: 1019997006094

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 1998904156

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: PV2005-54

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 50262005

Country of ref document: SK

WWG Wipo information: grant in national office

Ref document number: PV1999-2663

Country of ref document: CZ

REG Reference to national code

Ref country code: DE

Ref legal event code: 8607

WWR Wipo information: refused in national office

Ref document number: PV2005-54

Country of ref document: CZ

REG Reference to national code

Ref country code: DE

Ref legal event code: 8607