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WO1997000080A1 - Preparation pharmaceutique contenant de la cyclosporine a - Google Patents

Preparation pharmaceutique contenant de la cyclosporine a Download PDF

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Publication number
WO1997000080A1
WO1997000080A1 PCT/EP1996/002559 EP9602559W WO9700080A1 WO 1997000080 A1 WO1997000080 A1 WO 1997000080A1 EP 9602559 W EP9602559 W EP 9602559W WO 9700080 A1 WO9700080 A1 WO 9700080A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclosporin
pharmaceutical preparation
content
preparation according
vitamin
Prior art date
Application number
PCT/EP1996/002559
Other languages
German (de)
English (en)
Inventor
Karin Klokkers
Wilfried Fischer
Original Assignee
Hexal Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hexal Ag filed Critical Hexal Ag
Priority to EP96922803A priority Critical patent/EP0833655A1/fr
Priority to CA002224792A priority patent/CA2224792C/fr
Priority to AU63556/96A priority patent/AU705155B2/en
Publication of WO1997000080A1 publication Critical patent/WO1997000080A1/fr
Priority to US09/204,782 priority patent/US6696413B2/en

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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the invention relates to pharmaceutical preparations which contain an effective amount of cyclosporin A in combination with emulsifying vitamin E derivatives and a further emulsifier.
  • Cyclosporin A is a cyclic, water-insoluble, non-polar undecapeptide.
  • the compound is a highly effective immunosuppressant obtained from fungal cultures (Cane et al., Transplant TROC. 13, 349-358 (1981); Ferguson et al., Surgery 92, 175-182 (1982)).
  • the drug is used to prevent rejection of transplanted allogeneic organs (Bennett & Norman, Arzn. Rev. Med. 37, 215-224 (1986); Van Basen, Surg. Clin. North At the. 66, 435-449 (1986)). Its immunosuppressive effect is based on a selective inhibition of cell function, the survival of z. B.
  • Cyclosporin A is a lipophilic molecule with a molecular weight of 1202 daltons. Due to the poor water solubility and the high lipophilicity of cyclosporin A, its pharmaceutical compositions with conventional solid or liquid pharmaceutical carriers often have disadvantages. Thus, the cyclosporins from such compositions are not satisfactorily absorbed (Cavanak & Sucker, Formulation of Dosage Forms, Prog. Allergy 38, 65-72 (1986)), or the compositions are not well tolerated, or they are in the Storage not sufficiently stable, for example against the crystallization of the cyclosporin. Often the dissolved concentration is low in relation to the dose of up to 1 g daily, e.g. B.
  • cyclosporin A is limited by the main side effect in chronic use, which is the nephrotoxicity of the active substance itself (Van Buren, Surg. Clin. North Am. 66, 435-449 (1986)) . Kidney toxicity also occurs in about 80% of kidney transplant patients (Kahan, Dial. Transplant. 12, 620-30 (1983)), specifically because of this substance-inherent side effect which is used to protect the transplant from rejection.
  • cyclosporin treatments in various autoimmune diseases include, in addition to nephrotoxicity, hypertension, hyperkalemia, hyperuricoemia, hepatotoxicity, anemia, hypertrichiosis, gingival hyperplasia, gastrointestinal side effects, tremor and paresthesia (Von Graffenerosporine in, Autoimmune Diseases, editor Schindler, Springer Verlag, Berlin, pages 59-73 (1985)).
  • nephrotoxicity The acute nephrotoxicity induced by cyclosporin is dose-dependent and correlates with the cyclosporin blood levels.
  • Acute cyclosporin ephrotoxicity is morphologically associated with tubular lesions which are characterized by inclusion bodies, isometric vacuolization and microcalcification (Mihatsch et al., Transplant. Proc. 15, 2821 (1983)). This leads to a decrease in the glomerular filtration rate, as can be seen from the rapid increase in serum creatinine in cyclosporin-treated patients.
  • Thromboxan is a prostanoid and therefore a metabolite of arachidonic acid from the cyclooxygenase cycle.
  • the other prostanoids are prostaglandins and prostacyclins.
  • Prostanoids are very effective mediators that arise during immunologically generated inflammatory processes. They can fundamentally change renal hemodynamics (Morley; in: Lymphokines, Pic Editor, Academic Press, New York, 4, 377-391 (1981)).
  • EP-A-0 305 400 describes the relationships between impaired prostanoid synthesis and nephrotoxicity. Thereafter, the administration of cyclosporin is accompanied by an increased synthesis of thromboxane B2, a mediator of inflammation. Accordingly, cyclosporin should also promote the formation of prostaglandins of the E series, also inflammation mediators. The rejection of human kidney transplants has been associated with a rapid increase in renally eliminated thromboxane B2.
  • EP-A-0 305 400 also describes the use of w3-unsaturated fatty acids in combination with cyclosporin A to inhibit prostaglandin or thromboxane formation.
  • a disadvantage of long-term w3 fatty acid administration is the development of a vitamin E deficiency.
  • Deficiency states are e.g. B. hemolysis and a shortened lifespan of the erythrocytes.
  • vitamin E deficiency leads to degenerative muscle changes, creatinuria, increased hemolysis of the erythrocytes and to the influencing of certain hormones and enzymes as well as the protein and arachidonic acid metabolism (Machlin, Vitamin E; in: Machlin, Handbook of Vitamins: Nutritional , Biochemical and Clinical Aspects, pages 99-145, Marcel Dekker, New York, 1984).
  • EP-A-0 305 400 only describes a concentration with 12.5 mg cyclosporin A per gram of fish oil. With a usual daily dose of more than 300 mg cyclosporin A, this means a total intake of about 24 grams of the preparation and with 1 g cyclosporin A of 80 g preparation. This is an unreasonably high amount of oil for patients, which, for example, encapsulated in soft gelatin capsules would lead to a daily intake of 24 capsules with 300 mg of cyclosporin A. Parenteral application by infusion would be, with an optimistic calculation, 10 percent.
  • oil-containing infusion emulsion means an amount of approximately 240 ml of emulsion with 300 mg of cyclosporin A, a volume which can only be infused over a long period of time. Both aspects absolutely oppose a chronic application, as is necessary for transplant patients.
  • the formulations according to DE-B-2 907 460 are distinguished by a very high solution. like for cyclosporin A, However, they have the disadvantage that they only comprise vegetable oils which do not contain any substances that inhibit prostaglandin or thromboxane synthesis. This means that the preparations do not inhibit the nephro-toxicity of cyclosporin A.
  • the commercially available parenteral solution of cyclosporin A contains in 1 ml solution 50 mg cyclosporin A, 32.9% ethanol and 650 mg Cremophor EL, an ethoxylated, hydrogenated castor oil.
  • Cremophor EL is nephrotoxically similar to cyclosporin A itself (Thiel et al., Clin. Nephrol. 25 (Suppl. 1), 540-542 (1986 ); Finn et al., Renal Failure 11, 3-15 (1989)).
  • Cremophor EL leads in the isolated, perfused rat kidney to a clear renal vasoconstriction with reduced renal blood flow and tubular dysfunction (Besarab et al., Transplantation 44, 195-201 (1987); Luke et al., Transplantation 43, 795-799 (1987)).
  • Cremophor EL causes anaphylactic reactions up to shock (Chapuis et al., Engl. J. Med. 312, 1259 (1985), Leunis ⁇ sen et al., Lancet 1, 637 (1986); Magalini et al., Transplanta Tion 42, 443-444 (1986)). Cremophor EL was regarded as the cause of the anaphylactoid reaction since it leads to histamine liberation (Ennis et al., Agents Action 12, 64-80 (1982)). In some therapy cases with the iv solution, the allergic reaction was observed when first used in humans (Friedmann et al., Am. J. Med.
  • cyclosporin A The beneficial immunosuppressive properties of cyclosporin A are used in the treatment of psoriasis. Due to its high molecular weight and its very high lipophilicity, however, cyclosporin A is unable to penetrate intact skin, especially the stratum comeum. For this reason severe cases of psoriasis treated with oral and parenteral cyclosporin administration.
  • the disadvantage of this application is the systemic side effects on the circulation (hypertension) and kidney function.
  • Topical preparations for the treatment of psoriasis which would reduce the systemic side effects, require absorption promoters, such as.
  • B. Propylene glycol and Azone (Duncan et al., British Journal of Dermatology 123, 631-640 (1990)).
  • the object of the present invention is now to find an advantageous solvent system which dissolves cyclosporin A in sufficient quantity so that it can be taken orally in the daily dosage which is therapeutically customary, and can reduce the nephro-toxic effect and, when applied topically, both promote skin permeation as well as support the healing process in the treatment of psoriasis.
  • a pharmaceutical preparation which consists of cyclosporin A, an emulsifying ⁇ -tocopherol derivative, an ethoxylation product of vegetable oils, fatty acids or fats as a further emulsifier and a pharmaceutically customary alcohol or contains them.
  • This pharmaceutical preparation can be characterized by D-o; -tocopherol polyethylene glycol 1000 succinate (vitamin E-TPGS) as an ⁇ -tocopherol derivative.
  • the pharmaceutical preparation can also be characterized by a content of ⁇ -tocopherol derivative of up to 9 times the amount based on cyclosporin A.
  • the pharmaceutical preparation can also be characterized by a content of cyclosporin A ⁇ 10% based on the composition.
  • the pharmaceutical preparation can also be characterized by its ethanol or isopropanol content as the pharmaceutically customary alcohol, in particular in amounts of up to 30%.
  • the pharmaceutical preparation can also be characterized by a content of ethoxylated castor oil as a further emulsifier.
  • the pharmaceutical preparation can also be characterized by a thickener content.
  • emulsifying ⁇ -tocopherol derivatives such as D- ⁇ -tocopherol polyethylene glycol 1000 succinate
  • emulsifying or solvent properties for cyclosporin A and at the same time the synthesis of prostanoids such as prostaglandins and inhibit thromboxanes, which can be used to reduce the nephrotoxicity and to subside inflammatory reactions in the skin and at the same time the absorption of cyclosporin A by the intact Promotes skin.
  • the particular advantage of the solutions according to the invention in addition to achieving high concentrations of dissolved cyclosporin A of at least 10%, is that the D- ⁇ -tocopherol derivatives, as a derivative of natural vitamin E, have intrinsic effects, the toxic effects of cyclosporin A in the usual ones counteract high doses with oral use and on the other hand strengthen the intended immunosuppressive effect in the topical treatment of psoriasis via the absorption-promoting effect.
  • Vitamin E and its derivatives influence arachidonic acid metabolism in the sense of inhibiting prostaglandin, thromboxane and leukotriene biosynthesis and increasing prostacyclin formation. These properties are related to biological anti-inflammatory and thrombotic diseases (Machlin, Vitamin E .; in: Machlin, Handbook of Vitamins: Ntritional, Biochemical and Clinical Aspects, pages 99-145, Marcel Dekker, New York, 1984) .
  • vitamin E can also promote the activity of non-steroidal anti-inflammatory drugs (Bertolini et al., Rivista di Pharmakologia et Therapia 8, pages 27-34 (1982); Klein & Blankenhom, comparison of the clinical efficacy of vitamin E) and diclofenac sodium in ankylosing spondylitis (Bmürew's disease), Vitaminspur 2, pages 137-142 (1987)).
  • vitamin E permeates the stratum comeum very well. Quantitative absorption studies on the skin of experimental animals were carried out. So 16 hours after application of 300 ⁇ g a 5 percent. Vitamin E solution in ethanol per cm 2 10.7% vitamin E found in the home layer and approx.
  • vitamin E acts as a membrane-stabilizing antioxidant and inhibits the release of histamine and hydrolytic enzymes.
  • B from the mast cells and the lysosomes by stabilizing tion of their membranes. It also inhibits the synthesis of certain prostaglandins, deactivates oxygen radicals and detoxifies corresponding secondary products (Si, formation of superoxide radicals and peroxides; in: superoxide dismutase - biochemistry and therapeutic use; publisher Puhl & Ries, Perimed Verlag, Er Weg, 1982).
  • vitamin E increases skin moisture and acts as an occlusion agent. All of these properties described are beneficial in treating psoriasis.
  • Cyclosporin A now dissolves completely unexpectedly in such a high concentration so 10% in preparations according to the invention that the combination as a solution is therapeutically useful both in soft gelatin capsules and in topical formulations.
  • formulations can contain thickeners, such as colloidal silica or polyacrylic acid or polyacrylic acid derivatives or cellulose derivatives, and also antioxidants and flavor additives.
  • thickeners such as colloidal silica or polyacrylic acid or polyacrylic acid derivatives or cellulose derivatives, and also antioxidants and flavor additives.
  • composition of the formulation was as follows:
  • Cyclosporin A 100 mg ethyl alcohol 96% 200 mg vitamin E-TPGS 300 mg polyethoxylated castor oil 200 mg as an ethoxylation product of a fat
  • the mixture was filled into hard gelatin capsules and compared to a commercial product in a cross-over experiment on dogs.
  • duct (Sandimmun Optival R ) tested.
  • Blood level analysis was performed using a fluorescence immunoassay.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La préparation pharmaceutique décrite contient ou est constituée de cyclosporine A, d'un dérivé émulsifiant d'α-tocophérol, d'un produit d'éthoxylation d'huiles végétales, d'acides gras ou de corps gras comme émulsifiant additionnel et d'un alcool usuel en pharmacie.
PCT/EP1996/002559 1995-06-16 1996-06-13 Preparation pharmaceutique contenant de la cyclosporine a WO1997000080A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP96922803A EP0833655A1 (fr) 1995-06-16 1996-06-13 Preparation pharmaceutique contenant de la cyclosporine a
CA002224792A CA2224792C (fr) 1995-06-16 1996-06-13 Preparation pharmaceutique contenant de la cyclosporine a
AU63556/96A AU705155B2 (en) 1995-06-16 1996-06-13 Pharmaceutical preparation containing cyclosporin A
US09/204,782 US6696413B2 (en) 1995-06-16 1998-12-03 Pharmaceutical preparation with cyclosporin A

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19521974.0 1995-06-16
DE19521974A DE19521974A1 (de) 1995-06-16 1995-06-16 Pharmazeutische Zubereitung mit Cyclosporin A

Publications (1)

Publication Number Publication Date
WO1997000080A1 true WO1997000080A1 (fr) 1997-01-03

Family

ID=7764554

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/002559 WO1997000080A1 (fr) 1995-06-16 1996-06-13 Preparation pharmaceutique contenant de la cyclosporine a

Country Status (6)

Country Link
EP (1) EP0833655A1 (fr)
AU (1) AU705155B2 (fr)
CA (1) CA2224792C (fr)
DE (1) DE19521974A1 (fr)
WO (1) WO1997000080A1 (fr)
ZA (1) ZA965087B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6284268B1 (en) 1997-12-10 2001-09-04 Cyclosporine Therapeutics Limited Pharmaceutical compositions containing an omega-3 fatty acid oil
US6979456B1 (en) 1998-04-01 2005-12-27 Jagotec Ag Anticancer compositions

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030220234A1 (en) 1998-11-02 2003-11-27 Selvaraj Naicker Deuterated cyclosporine analogs and their use as immunodulating agents
DE19859910C2 (de) * 1998-12-23 2001-03-22 Ratiopharm Gmbh Orales Arzneimittel
DK1436321T3 (da) 2001-10-19 2006-11-13 Isotechnika Inc Syntese af cyclosporinanaloger
CA2461730C (fr) 2001-10-19 2012-05-15 Isotechnika Inc. Nouveaux preconcentres en microemulsion d'analogues de cyclosporine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011039A1 (fr) * 1993-10-22 1995-04-27 Hexal Pharma Gmbh COMPOSITION PHARMACEUTIQUE CONTENANT DE LA CYCLOSPORINE A ET DE L'α-TOCOPHEROL
US5430021A (en) * 1994-03-18 1995-07-04 Pharmavene, Inc. Hydrophobic drug delivery systems
EP0712631A2 (fr) * 1994-11-21 1996-05-22 Biogal Gyogyszergyar Rt. Emulsions multiples contenant de la cyclosporine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2551005B1 (fr) * 1983-08-25 1987-06-12 Galland Jean Claude Dispositif d'exploration de l'angle mort de la retrovision optique pour vehicule automobile ou similaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011039A1 (fr) * 1993-10-22 1995-04-27 Hexal Pharma Gmbh COMPOSITION PHARMACEUTIQUE CONTENANT DE LA CYCLOSPORINE A ET DE L'α-TOCOPHEROL
US5430021A (en) * 1994-03-18 1995-07-04 Pharmavene, Inc. Hydrophobic drug delivery systems
EP0712631A2 (fr) * 1994-11-21 1996-05-22 Biogal Gyogyszergyar Rt. Emulsions multiples contenant de la cyclosporine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6284268B1 (en) 1997-12-10 2001-09-04 Cyclosporine Therapeutics Limited Pharmaceutical compositions containing an omega-3 fatty acid oil
US6979456B1 (en) 1998-04-01 2005-12-27 Jagotec Ag Anticancer compositions

Also Published As

Publication number Publication date
CA2224792A1 (fr) 1997-01-03
ZA965087B (en) 1997-01-22
DE19521974A1 (de) 1996-12-19
CA2224792C (fr) 2003-01-07
EP0833655A1 (fr) 1998-04-08
AU705155B2 (en) 1999-05-13
AU6355696A (en) 1997-01-15

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