WO1997000080A1

WO1997000080A1 - Pharmaceutical preparation with cyclosporin a

Info

Publication number: WO1997000080A1
Application number: PCT/EP1996/002559
Authority: WO
Inventors: Karin Klokkers; Wilfried Fischer
Original assignee: Hexal Ag
Priority date: 1995-06-16
Filing date: 1996-06-13
Publication date: 1997-01-03
Also published as: CA2224792A1; CA2224792C; EP0833655A1; AU6355696A; ZA965087B; AU705155B2; DE19521974A1

Abstract

A pharmaceutical preparation contains or consists of cyclosporin A, an emulsifying α-tocopherol derivative, an ethoxylation product of vegetable oils, fatty acids or fats as additional emulsifier and a pharmaceutically usual alcohol.

Description

Pharmaceutical preparation with Cyclosporin A

1. Field of the Invention

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.

2. State of the art

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. Heart transplants allowed without myelocyte suppression (Myers et al, New England Journal of Medicine 311, 699 (1984)). In addition to the use in transplants, recent clinical tests have shown that cyclosporin A is effective in the treatment of a large number of autoimmune diseases. For example, clinical trials were carried out to treat polymyositis, systemic lupus erythematosus, rheumatoid arthritis or even juvenile insulin-dependent diabetes (see the corresponding chapters in: Cyclosporins in Autoimmune Diseases, published by Schindler, Springer Verlag, Berlin 19985).

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. only 3%, which means taking 30 g of solution. A higher solubility is given in DE-B-2 907 460, which describes a solution of cyclosporin in vegetable oil, such as olive oil or corn oil, ethanol and an emulsifier from a nonionic ester of a triglyceride with a polyalkylene glycol. Examples of the compositions specified by this patent are drinking solution, drinking emulsion, injection solution and solution in capsules. The above composition is preferably administered intramuscularly or subcutaneously or, in particular, orally. Cy¬ closporin A, applied with the above dosage forms, is characterized by good bioavailability. After absorption, the substance quickly binds to plasma proteins and has a terminal half-life of 24 hours. It is metabolized to a high percentage in the liver, with biliary excretion being the main route of elimination (Beverige, Cyclosporin A; in: Procedures of International Symposium, Cambridge, Ed. White, pages 35-44 (1982)).

Despite its great value as an immunosuppressant, the clinical use of 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.

Frequent side effects of 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)). Of the side effects cited here, the most common is nephro toxicity. The acute nephrotoxicity induced by cyclosporin is dose-dependent and correlates with the cyclosporin blood levels. It is reversible after dose reduction or after the end of cyclosporin therapy (Chapman et al., Lancet I, 128 (1985)). 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. One reason for this could be the disruption of the microcirculation due to the interaction of cyclosporin with the local prostacyclin synthesis (Neild et al .; in: Cyclosporine, editor Kahan, Gruen & Stratton, Orlando, Florida, page 182 (1984)).

Although the mechanism of renal dysfunction has not yet been fully elucidated, it has been shown that renal synthesis of thromboxane occurs as immune and non-immune mediated models of renal damage progress (Lianos et al., J. Clin. Invest. 72 , 1983, 1439-1448; Okegawa et al., J. Clin. Invest. 71, 81-90 (1983)). 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. In animal experiments, 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).

A further disadvantage of this composition with w3-unsaturated fatty acids (fish oils) is the apparently low active substance concentration which can be achieved in this oil. For example, 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 (Sandimmun ^) contains in 1 ml solution 50 mg cyclosporin A, 32.9% ethanol and 650 mg Cremophor EL, an ethoxylated, hydrogenated castor oil. In addition to the amount of ethanol of 2 g per application, which is a burden on the liver, according to literature reports 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)). Thus, 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)). Furthermore, 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. 78, 343-345 (1985); Magalini et al., Transplantation 42 , 443-444 (1986)). The disadvantage of the commercially available parenteral preparation is therefore the ingredient Cremophor EL. A formulation should therefore be sought that avoids the above side effects and increases drug safety.

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)). Now it is known from Azone that its permeation-promoting properties are due to a disturbance or even destruction of the protective function of the stratum comeum. Propylene glycol dries out the skin. Both substances would therefore hinder the healing of psoriasis rather than promote it. For this reason, a topical preparation with a therapeutically sufficient cyclosporin A content in combination with substances that promote the healing process would be desirable. In addition, the combination should promote the permeation of cyclosporin A through intact skin.

3. Object of the invention

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.

4. Description of the invention

The object on which the invention is based is now achieved by a pharmaceutical preparation which consists of cyclosporin A, an emulsifying α-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 α-tocopherol derivative.

The pharmaceutical preparation can also be characterized by a content of α-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.

According to the invention it was surprisingly found that emulsifying α-tocopherol derivatives, such as D-α-tocopherol polyethylene glycol 1000 succinate, have excellent 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-α-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) . After oral administration, 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 (Bechterew's disease), Vitaminspur 2, pages 137-142 (1987)). After topical application, 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 μg a 5 percent. Vitamin E solution in ethanol per cm ² 10.7% vitamin E found in the home layer and approx. 40.9% in the underlying skin layers (Djerassi et al., Vitamin E: Bio¬ chemical function and its role in cosmetics, drug & Cosmetic Industry 13, No. 1, pages 29-31, 34, 78 (1986)). Applied locally, 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, Erlangen, 1982). In addition, 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.

Furthermore, the formulations can contain thickeners, such as colloidal silica or polyacrylic acid or polyacrylic acid derivatives or cellulose derivatives, and also antioxidants and flavor additives.

5. Examples

Example 1 (soft gelatin capsule)

The 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

Polyethylene glycol 400 200 mg

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.

1 clearly shows that the capsule preparation according to the invention is equivalent to the commercial product with regard to blood levels.

Claims

claims

1. Pharmaceutical preparation consisting of or containing cyclosporin A, an emulsifying α-tocopherol derivative, an ethoxylation product of vegetable oils, fatty acids or fats as a further emulsifier and a pharmaceutically customary alcohol.

2. Pharmaceutical preparation according to claim 1, characterized by D-α-tocopherol polyethylene glycol 1000 succinate as α-tocopherol derivative.

3. Pharmaceutical preparation according to one of the preceding claims, characterized by a content of an α-tocopherol derivative of up to a 9-fold amount based on cyclosporin A.

4. Pharmaceutical preparation according to one of the preceding claims, characterized by a content of cyclosporin A ≥ 10% based on the composition.

5. Pharmaceutical preparation according to one of the preceding claims, characterized by a content of ethanol or isopropanol as the pharmaceutically customary alcohol, in particular in amounts of up to 30% based on the composition.

6. Pharmaceutical preparation according to one of the preceding claims in the form, characterized by a content of ethoxylated castor oil as a further emulsifier.

7. Pharmaceutical preparation according to claim 6, characterized by a content of thickener.