SK847488A3 - Process for producing of cyclosporine a - Google Patents

Description

Process for the preparation of cyclosporin A

Technical field

The present invention relates to a process for the production of cyclosporin A in orthorhombic (P2 ₁ 2 ₁ 2 ₁ ) crystalline form having a crystal lattice in which dimension a is 12.5 A, dimension b is 22.9 A, dimension c is 28.4 A and volume per asymmetric unit is equal to 2027 Å ³ .

The compound referred to herein as cyclosporin is also known as ciclosporin.

BACKGROUND OF THE INVENTION

Cyclosporin A is a known fungal metabolite which has a wide pharmaceutical application. It is a cyclic poly-N-methylated endecapeptide of the formula -MeBmt-aAbu-Sar-MeLeu-Val-MeLeu-Ala- (D) Ala-MeLeu-MeLeu-MeVal-1234 567 8 9 10 11 wherein:

-MeBmt- means N-methyl- (4R) -4-but-2E-en-1-yl-4-methyl- (L) threonyl radical

Cyclosporin A and methods for its production have already been described, for example, in U.S. Pat. No. 4,117,118. The primary area of clinical research for this compound has been in suppressing the immunological response of an organism, particularly when it has been necessary to pre-treat recipients of transplanted organs such as heart, lung, both the heart and the lungs, liver, gadgets, pancreas, bone marrow, skin and cornea, especially in the case of allogeneic organ transplantation. Significant successes have been achieved in this field, so that cyclosporin A (Ciclosporin) is now clinically widely used and is commonly marketed under the trademark Sandimmun ^R or Sandimmune ^R , for example in the form of a concentrate for infusion, as a solution for oral administration or in the form of a solution embedded in gelatin capsules, the last two formulations have been described in U.S. Patent No. 4,388,307.

At the same time, efforts have been made to identify other uses of the compound in other autoimmune diseases and in inflammatory conditions, particularly those in which the autoimmune component plays a role, such as joint inflammations such as rheumatoid arthritis, arthritis chronica progressiva and arthritis deformans, other rheumatoid diseases, in these cases a number of reports have been reported on the results obtained both in vitro in animals and in clinical trials. Specific autoimmune diseases in which ciclosporin A treatment is appropriate include, for example, autoimmunological haematological disorders such as haemolytic anemia, aplastic anemia and idioathic thrombocytopenia, systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatisis, dermatomyneisis, dermatomynaisis, dermatomy Jonson's syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases including, for example, ulcerative colitis and Crohn's disease, pemphigus, endocrine optalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, primary diabetes mellitus, juvenile diabetes mellitus, primary diabetes mellitus anterior and posterior, spring conjunctivitis, keratoconjuctivitis sicca, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome or nephropathy with minimal changes).

Other areas of research included the potential for administration of the substance against parasites, especially against protozoa, the research mainly concerned the use in malaria, coccidiomycosis and schistosomiasis, as well as attempts to reverse the resistance of tumors to chemotherapeutic agents such as cytostatics. hair growth, for example in the treatment of alopecia.

In the solid state, cyclosporin A exists as an amorphous or crystalline form. As for the crystalline form, it may be a tetragonal or orthorhombic modification.

The tetragonal modification of Cy-A / XI is described together in the Austrian patent (P4 ₁ ), which is also referred to as a method for its production, for example, 3553 961. This modification has a lattice of a = b = 13.8 Å, c = 41.2 Å , the volume per asymmetric unit is 1974 Å ³ , the melting point is about 140-150 ° C, this modification contains approximately two molecules of water in one molecule of cyclosporin A.

The first orthorhombic modification (P2 ₁ 2 ₁ 2 ₁ ) can be obtained by recrystallization from diisopropyl ether as described in Ciclosporin as an example by R.Wenger in Sandorama 1984 / III. This particular modification includes a solvate with diisopropyl ether in a ratio of about 1: 2, with a crystal lattice a = 12.5 Å, b = 22.9 Å, c = 28.4 Å, the volume of the asymmetric unit is equal to 2027 Å ^3, a melting point of about 150 "C. The ortorombic crystals of the solvate may be obtained by recrystallization from supersaturated solutions in an appropriate medium for a further period of time. The ortorombic modifications of the cyclosporin A solvate with diisopropyl ether prepared by Wenger were obtained by adding a concentrated solution of cyclosporin A in methylene chloride, in which the substance is readily soluble, to a diisopropyl ether in which the compound is relatively poorly soluble, followed by evaporation of methylene chloride. Crystallization from the remaining diisopropyl ether can then take place for about 7 days at room temperature. Ortorombic crystalline forms containing these sulfates are commonly referred to as CY-A / X-II.

Other orthorhombic modifications (P2 ₁ 2 ₁ 2 ₁ ) have now been identified which are characterized in that the constituent of any solvent is substantially absent, i.e., these modifications consist essentially of or only free cyclosporin A.

Dimensions of the crystal lattice of the orthorhombic type of modification, that is without solvent and have the form of a solvate, are a = 12.7 Å, b = 15.7 Å, c = 36.3 Å, the volume of the asymmetric unit 1804 and the ^third The melting point is about 180 DEG-190 DEG to 195 DEG C., for example, it also depends on the degree of purity and the source from which the crystals were obtained, as will be described in Examples 1 and 2 below, which describe specific procedures for obtaining this modification. Solvent-free cyclosporin A in unsolvated form of orthorhombic crystals is also referred to as CY-A / X-III. Additional characteristics, such as X-ray diffraction for CY-A / X-III, are further shown in Table III and FIG. IV together with the corresponding data for CY-A / XI and CY-A / X-II above.

In spite of the substantial progress that has been made with the use of cyclosporin. And despite its great medical use, especially in organ transplantation, the use of this substance is not yet a problem. Problems arise in particular in the manufacture of galenic forms that would allow convenient and fully satisfactory administration in the case of certain specific diseases or conditions in which cyclosporin A has been shown to be an effective drug.

The problems encountered are due in part to the physical properties of the substance, for example the relatively limited solubility or compatibility with commonly used pharmaceutical carriers or environments. These difficulties are also associated with the nature of certain disease states in which cyclosporin A is the first and main therapeutic agent to experience undesirable side effects when administered orally. For example, in the treatment of psoriasis, it would be most advantageous to administer the active ingredient orally. Psoriasis is a widespread disease that adversely affects the mental state of the patient, and at present there is no generally recognized effective treatment. It would therefore be desirable to suggest a similar treatment. Obviously, cyclosporin A could meet these requirements, but it is not yet possible to ensure effective oral administration in this case. Similar ratios exist, for example, in the treatment of certain eye diseases such as uveitis posterior and keratoconjuctivitis sicca.

To date, various systems have been proposed for the administration of ciclosporin A, including galenic forms for topical, dermal or ocular administration, particularly for use in ophthalmology, in the treatment of psoriasis or other dermacological diseases and conditions such as atopic dermatitis and alopecia and uveitis treatment. However, the use of these systems has not yet achieved the desired improvement or has not been fully satisfactory.

Reports of attempts to treat psoriasis by administering known oral solutions directly to psoriatic affections indicate that no or minimal success has been achieved, and in cases of atopic dermatitis, the use has been severely limited. A similar situation can also be described for ophthalmic use, where the use of this substance has been considered desirable in preventing, for example, corneal transplant rejection or treating certain anterior eye segment diseases, but no means for such topical use has been reported yet. easy, safe and effective treatment of said diseases or conditions as they extend deeper into the eye, for example uveitis including uveitis posterior.

Comparable problems have also been encountered in the development of other delivery systems for the active ingredient, for example in the case of intra-articular injections for topical treatment of arthritic diseases, for example as described above or where the active ingredient should be administered directly to the disease foci such as this is the case for various oral administration systems, for example those intended to achieve a modified bioavailability or modified release of the active ingredient.

Attempts to process cyclosporin A into a dosage form have hitherto been carried out using the compound in solution, less frequently using the amorphous form of CY-A / X-I, crystalline forms being identified predominantly for the purpose of, for example, drug registration. In spite of the great effort that has been made to find new or improved alternatives, so far only reports on widely used systems have been reported for oral solutions and infusion concentrates.

It has now unexpectedly been found that the use of an orthorhombic crystalline form, such as CY-A / X-II and in particular CY-A / X-III, provides a particular advantage in the preparation of galenical dosage forms of various types containing cyclosporin A.

In particular, it has been found that said crystalline modifications can be used for the preparation of galenic dosage forms which contain cyclosporin A in a stable, fine particulate form and / or have increased stability or particular release properties. This finding opens the way for the production of new and improved delivery systems of the active ingredient, for example, sustained or delayed release and / or properties which are suitable for the treatment of diseases or conditions which have hitherto not been treated in this way or for which treatment with conventional cyclosporin A preparations is less appropriate. In particular, it has been shown that the use of the crystalline modifications mentioned above provides galenic forms suitable for topical or dermal use or topical administration in ophthalmology for the treatment of skin or eye diseases, for example those mentioned above, in particular psoriasis, atopic dermatitis, contact dermatitis, eye symptoms of Behchet's disease, uveitis and keratoconjunctivitis sicca. The use of crystalline modifications also allows the preparation of delayed or prolonged-release injectable forms, which are particularly useful, for example, in the treatment of diseases or conditions in which frequent administration would reduce the usefulness of the dosage form, for example in the treatment of joint inflammations or other joint diseases in need. inject the drug directly into the joint or in the treatment of psoriasis and similar skin diseases in which the active substance is injected directly into the damaged areas of the skin.

For all these uses, it has been shown that the orthorhombic crystalline forms, especially the CY-A / X-III form, are much more suitable than the other available forms, especially the amorphous form or the CY-A / XI form, for example in particular physicochemical properties, especially the stability, speed and course of release from the crystalline lattice and the possibility of processing into galenic dosage forms. CY-A / X-III is a new and preferred orthorhombic crystalline form for therapeutic purposes.

The process according to the invention can thus be obtained

A CY-A / X-III, i. cyclosporin A in unsolvated orthrombic crystalline form, in particular

A ¹ CY-A / X-III with crystalline lattice and other physical properties listed above and / or

A ² CY-A / X-III with X-ray diffraction properties corresponding to those given in Table III or drawing IV.

The invention also relates to

B of a process for the production of CY-A / X-III comprising crystallizing cyclosporin A from a medium containing CY-A / X-III, followed by isolation of said form.

SUMMARY OF THE INVENTION

The present invention provides a process for producing cyclosporin A in orthrombic (P2 ₁ 2 ₁ 2 ₁ ) crystalline form having a crystal lattice in which the dimension a is 12.5 A, the dimension b is 22.9 A, the dimension c is 28.4 A and the volume per asymmetric % of the unit is 2027 Å ³ , characterized in that cyclosporin A is dissolved in a solvent medium consisting of a polymeric ether having a molecular weight of at least 200, at a temperature of at least 40 ° C to a solution containing from 5 to 60 wt. cyclolsporin A, based on the total weight of the solution; and cyclosporin A crystallizes from this solvent to form the orthorhombic crystalline form as defined above.

In a preferred embodiment of the invention, the dissolution medium comprises polyethylene glycol or polypropylene glycol. In a particularly preferred embodiment, the dissolution medium comprises glycerol polyethylene glycol ester, a polyoxyethylene sorbitan ester, a polyoxyethylene ester or a transesterification product of natural triglycerides from oils and polyalkylene polyols.

The following is a more detailed description of the invention in a broader context.

An environment suitable for use in carrying out the process of the invention, in particular an environment suitable for dissolving cyclosporin A, is in particular a medium containing solvents having a higher molecular weight greater than 200. A particularly suitable medium is a medium containing high molecular ethers, especially polymer ethers, e.g. polyalkylethers such as polyethylene glycols and polypropylene glycols. Examples of polymeric ethers that may be used are polyethylene glycol and polypropylene glycol, for example having a molecular weight of more than 200. Glycerol and polyethylene glycol esters, for example glycerol polyethylene glycolricinoleate and glycolpolyethylene glycol oxystearates, such as are marketed under the trade name Cremop, for example. These substances have been described in Fiedler: Lexikon der Hilfstoffe, 2nd edition, Vol. 257 and 258, polyoxyethylene sorbitan esters available, for example, under the trade name Tween (Fiedler, ibid., Vol. 2, pp. 972-975), polyoxyethylene esters such as polyoxyethylene with stearic acid, sold under the trade name, for example. Myrj (Fiedler, Vol.2, p.636) and trans-esterification products of natural triglycerides from oils and polyalkylene polyols, including the transesterification products of corn oil, kernel oil, almond oil, peanut oil, olive oil, palm oil or a mixture of these oils with polyethylene glycol , especially with polyethylene glycols having a molecular weight of 200 to 800, which are supplied, for example, under the trade name Labrafil (Fiedler, p.539). Especially suitable are media which contain polyethylene glycols having a molecular weight of 200 to 600, preferably 300 to 400.

The medium containing the form CY-A / X-III may contain one or more components in addition to the above components, for example, low molecular weight alcohols and / or water may also be used as an environment which modifies the relationship between solvents and the active ingredient. substance and aids crystallization. A particularly suitable medium for use as a vehicle for the CY-A / X-III form is one comprising 0.5 parts by volume of ethanol, 8.0 parts by volume of polyethylene glycol (300) and 1.0 parts by volume of water.

The process according to the invention consists in first dissolving cyclosporin A, for example in amorphous or tetragonal form, in a selected environment at a higher temperature. The dissolution temperature will depend on the environment, but will usually be higher. above 40, especially above 50 ° C. In the case of a polyethylene glycol environment, the dissolution temperature will generally be above 70 ° C, for example in the range of 75 to 130 ° C. The solution obtained will contain more than 5%, preferably more than 10%, for example 40 to 60%, preferably 20% by weight, of cyclosporin A, based on the weight of the total solution. Thereafter, crystallization of cyclosporin A is initiated with cooling, usually over a relatively longer period, for example 10 to 35 minutes or more, depending on the desired crystal growth.

If desired, crystallization can be initiated, for example, by sonication or by using seeding material. When the medium used consists of ethanol, polyethylene glycol and water as described above, it has been found that crystal formation can be easily initiated in a temperature range of 60 to 90 ° C, for example 65 to 85 ° C by ultrasonication at approximately 20,000 cycles / sec. As will be shown in Example 2 below, it is possible to obtain microcrystals with a very small and relatively very stable size by continuous sonication during crystallization.

The rate of growth of the crystals and their dimensions will, of course, depend upon the environment selected and the conditions under which crystallization takes place, for example, whether or not ultrasound is used and at what frequency. When used for the preparation of galenical forms as described below, the resulting form of CY-A / X-III is preferably used in the form of very fine particles, for example with a mean diameter less than 200 μιη, for example 0.5 to 200 μιη. If the crystals initially obtained have a larger diameter, it is possible to obtain a material having the desired particle size by conventional techniques, for example, grinding, crushing, dusting, micronizing or other fragmentation to the desired size. The smaller particle formulations thus obtained may be suitable for some purposes, for example, in topical dosage forms for use on the skin, but in many cases grinding, crushing or similar processing is not suitable. A disadvantage is that the resulting material has a relatively wide range of particle size distributions and the particles are relatively sharp as a result of crushing the crystals. In addition, the crushing usually alters the physical properties of the natural surface of the crystals and, moreover, it is expensive to maintain sterile conditions, for example, in the manufacture of galenic dosage forms intended for intra-articular administration. For the above reasons, it is generally preferred to carry out the process of the invention so as to obtain crystals, for example microcrystals, which already have the desired final particle dimensions. For example, for the use of a composition for intra-articular or parenteral administration, it is preferred to use the form of CY-A / X-III in an uncrushed crystalline state, i. micro-crystals which have not been crushed, ground, micronized and otherwise treated to reduce particulate matter.

In order to obtain microcrystals of the form CY-A / X-III which can be used directly in the crushed state as described above, the process according to the invention is preferably carried out with stirring, for example in the range 200-300 to e.g. 700 revolutions per minute. crystallization, and in particular under sonication, for example in the range of 10,000 to 30,000 cycles / sec, typically 20,000 cycles / sec.

By varying the medium for forming the CY-A / X-III form and adjusting the cooling rate and stirring rate during recrystallization in a known manner and as described in the examples below, it is possible to obtain a microcrystalline form of CY-A / X-III with different mean diameters % of the particles, for example, in the above range or as discussed below in connection with the various dosage forms.

As already mentioned, it is usually necessary to carry out the crystallization by the process according to the invention under sterile conditions. Purification of the form of CY-A / X-III thus obtained can be accomplished in a conventional manner, for example by rinsing with a mixture of polyethylene glycol (300) and water, for example in a 3-4: 1 weight ratio followed by washing with warm water. The CY-A / X-III form thus obtained will generally be free or substantially free of cyclosporin A in any other form, preferably in pure or substantially pure form. At the same time, the formation of amorphous cyclosporin A is prevented by flushing as described above.

According to the process of the invention, it is thus possible to obtain the above-mentioned forms of cyclosporin A and in addition the following forms:

k ^ CY-A / X-III according to A to A ^ above, the material is free or substantially free of any other form, for example, an amorphous form, a form of CY-A / X-I or CY-A / X-II,

A ⁴ CY-A / X-III according to A to A ^{3 above,} in pure or substantially pure form

A ⁵ CY-A / X-III according to A to A ^{4 above,} in the form of fine particles, for example with the above dimensions or as described below, for example, in the manufacture of galenical molds containing CY-A / X-III

A ⁶ CY-A / X-III according to A to A 2 above, consisting predominantly or wholly or substantially totally of non-crushed crystalline material, for example CY-A / X-III according to A, in which the particles consist predominantly, completely or substantially wholly of uncrushed microcrystals and

⁷ and CY-A / X-III of the above-mentioned A to A ⁶ in a sterile or substantially sterile condition, e.g., suitable for pharmaceutical use, especially suitable for parenteral administration, e.g., for injection, e.g., intra-articular administration.

The microcrystals obtained in this way can be processed into:

C a pharmaceutical composition comprising

(a) cycllosprine A in orthorhombic crystalline form as an active ingredient together with ΐ

(b) a pharmaceutically acceptable diluent or carrier.

Cyclosporin A may be present in the pharmaceutical composition in any suitable orthorhombic crystalline form, for example in the form of CY-A / X-III or in the form of CY-A / X-II. However, the use of the CY-A / X-II form is generally less suitable due to the physicochemical properties of the form, which is less suitable for this use, both in terms of processability into pharmaceutical products and in terms of compatibility. The most preferred form is CY-A / X-III, for example, of any of A to A ⁷ as they were above.

Although cyclosporin A is present in a solid (crystalline) form in the pharmaceutical composition, the pharmaceutical composition itself may take any appropriate form. They may therefore be solid forms, for example capsules, tablets, dragees, powders and granules, semi-solid forms such as lubricants, gels, creams and pastes, and liquid forms, for example containing the active ingredient in the form of fine particles, for example micronized particles or microparticles in suspension. dispersions in a liquid pharmaceutical diluent or carrier in which the active ingredient can be maintained in a selected crystalline form.

Pharmaceutical compositions containing cyclosprin A in the above form include systems which contain the active ingredient in a single phase, for example creams, gels, lubricants and the like, or simple capsules or ampoules, for example, of hard or soft gelatin, or ampoules for storing injectable solutions; forms which contain the active ingredient in a plurality of phases. Thus, they are pharmaceutical compositions containing the active ingredient in one phase together with one or more non-containing active ingredients, such as coatings, carriers, delayed release phases or phases containing the other active ingredient or excipients. Thus, for example, they may be coated tablets, the core of which is cyclosporin A in orthorhombic crystalline form, the core being surrounded by, for example, a coating without the active ingredient and the like, or coated tablets which may contain the active ingredient in the core or coating; o granules which comprise a first granulate phase consisting of the active substance in an orthorhombic crystalline form and a second granule phase which does not contain the active substance may also be capsules divided into two or more spaces, for example by internal walls, one of which contains the active ingredient in orthorhombic form and other compartments do not contain the active ingredient. Other modifications will be apparent to those skilled in the art.

Cyclosporin A is present predominantly or preferably exclusively or at least substantially exclusively in the form of orthorhombic crystals, for example in the form of CY-A / X-III, in the compositions containing the active ingredient.

The pharmaceutical compositions usually comprise at least one phase or compartment containing cyclosporin A in an orthorhombic crystalline form, for example in the form of CY-A / X-III, the crystalline form being uniformly dispersed in this phase or in this compartment. Such systems may be, for example, homogeneous creams, lubricants, gels and the like, as well as liquid systems in which cyclosporin is crystalline. And, homogeneously dispersed or can be readily homogeneously dispersed, for example by hand mixing.

Such pharmaceutical compositions include, for example, forms suitable for topical administration, for example to the skin or eye, or parenteral administration, for example in the form of infusions or injections including subcutaneous or intramuscular injections, but particularly intracranial injections and injections directly into a disease plaque. also enteral forms such as lace, pessaries and oral forms. However, these forms are usually less preferred.

Cyclosprine A present in a preferred form of orthorhombic crystals, for example CY-A / X-III, is contained in the pharmaceutical compositions in the form of fine particles, for example in micronized form, in microparticle form or in the form of uncrushed small microcrystals as described higher. The appropriate particle size will depend on their nature, use and route of administration. Usually, however, the mean particle diameter will range from 0.5 to 200 μπι. Special ranges, such as those for oral, topical or injection, will be given below.

Topical formulations, for example for administration to the skin or the eye, for example in the treatment of psoriasis or atopic dermatoses or ocular diseases in which immunological responses such as uveitis, conjuctivitis including keratoconjuctivitis sicca or vernalis or corneal transplants are required.

Gels, creams, lubricants and other topical or skin preparations may be prepared in a known manner and also routinely administered. For example, cyclosporin A in the form of orthorhombic crystals may be admixed with an appropriate base, for example a water-containing gel such as a cellulose ethers gel in water with the addition of wetting agents, thickeners and the like including, for example, aerosols.

Cyclosporin A is usually present in these dosage forms in the form of fine particles, for example, of medium diameter

0.5-200 μπι. A preferred range of mean particle diameter is less than 60 to 80, preferably less than 40, especially less than 30, and most preferably less than 20 µπι. Preferably, the range of mean particle diameter is narrow and the particle diameter distribution is as narrow as possible.

Preferably, all particles have an average diameter of less than 60 to 80 microns.

Formulations for topical administration to the eye may consist, for example, of a suspension or dispersion, thickened in an appropriate manner, for example, in the form of viscous eye drops, cream or gel for a particle diameter.

ocular administration. In this case, the mean of the crystalline active substance should be less than 55 μιη. Thus, in the case of eye drops, the particles may be advantageous

0.5 to about 20, preferably up to

The content of the hydrophilic and lipophilic components of the carrier system for use for administration to the skin or to the eye may vary, for example, depending on the site of administration, especially the area of skin to which the composition is to be applied.

Formulations for topical administration, especially cutaneous administration, usually contain a vehicle in which the active ingredient is poorly soluble. The solubility of the active ingredient, for example in the form of CY-A / X-III, in these compositions is less than 10%, preferably less than 1% by weight. Even more preferably, the solubility is less than 0.1 and most preferably less than 0.001% by weight.

Suitable carriers include hydrophilic, water-miscible carriers as well as carriers of a hydrophobic nature.

The hydrophilic, water-miscible carrier components are preferably relatively low volatile. Examples of suitable components of this type are, for example, liquid polyalkylene glycols, propylene glycol, glycerol and ethylene glycol. Suitable polyalkylene glycols are, for example, liquid polyethylene glycols, for example having an average molecular weight of up to 600, preferably 250 to 450, and in particular 300.

Thus, a composition containing cyclosporin A, for example for topical administration, may contain the following components:

Ί,

C a) Cyclosporin A in an orthorhombic, preferably unsolvated, crystalline form, for example in the form of CY-A / X-IH, for example as defined above in paragraphs

A to A ⁷ ,

b) a hydrophilic, water-miscible carrier, for example one of the above-described carriers; and

(c) water suitable for pharmaceutical use.

and

The amount of component a) may be in the range of 0.1 to 30, preferably 0.5 or 1.0 to 20%, for example 1.0, 2.0, 5.0 or 10.0% by weight, based on the total weight of the composition. Components b) and c) are preferably present in a ratio of 1: 0 to 1:20 parts by weight. These components are preferably present in a ratio of 1: 0.5 to 1.5, for example 1: 1 to 1: 3, in particular 1: 1.5 to 1: 2.5 parts by weight.

Compositions of this type preferably contain yet

d) wetting agent.

A suitable component (d) may be, for example, the following compounds:

d ¹ Transesterification products of natural triglycerides and polyalkylene polyols from vegetable oils. These transesterification products are known in the art and can be obtained, for example, as described in U.S. Patent 3,288,824. These products include the transesterification products of various natural, for example, non-hydrogenated vegetable oils such as corn oil, kernel oil, almond oil. oil, peanut oil, olive oil and palm oil, and mixtures of these products with polyethylene glycols, especially polyethylene glycols having an average molecular weight in the range of 200 to 800. Preferred are products obtained by transesterification of two molar proportions of natural vegetable oil, especially triglycerides of this oil with one molar. The various types of transesterification products of this group are known and commonly available under the trade name Labrafil, have been described in Fiedler, Lexicon der Hilfstoffe, second corrected. and extended edition, 1981, vol.2, p.539. The following products are particularly suitable for use:

Labrafil M 1944 CS, a transesterification product of nuclear oil and polyethylene glycol with an acid number of approximately 2, a saponification number of 145 to 175 and an iodine number of 60 to 90, and

Labrafil M 2130 CS, transesterification product of glyceride of 12 to 18 carbon atoms and polyethylene glycol, melting point 35 to 40 ° C, acid number less than 2, saponification number 185 to 200 and iodine number less than 3.

d ² Reaction product of natural or hydrogenated castor oil and ethylene oxide.

These products can be obtained in a known manner, for example by reacting natural or hydrogenated castor oil with ethylene oxide, for example in a molar ratio of 1:35 to 1:60, optionally removing the polyethylene glycol component from the product, for example as described in DAS No. 1,128,388 and 1,518,819. Particularly suitable are those sold under the trade name Cremophor. Especially suitable are Cremophor RH 40 products having a saponification number of 50 to 60, an acid number of less than 1, an iodine number of less than 1, a water content (Fischer) of less than 2% and a _D ^{60 of} about 1,453-1,47878 and HLB of about 14-16. Cremophor RH 60 having also the saponification number 40 to 50, an acid number of less than 1, an iodine number less than 1, a water content (Fischer) of 4.5 - 5.5% and a n D ²⁵ of about 1.453 to 1:57, and a HLB of about 15-17, and Cremophor EL having a molecular weight (osmometry in the form of vapors) about 1,630, saponification number 65 to 70, acid number about 2, iodine number about 28 to 32, and nD ²⁵ about 1.471. Also suitable for this use are various wetting agents available under the trade name Nikkol, for example Nikkol HCO-60, a reaction product of hydrogenated castor oil and ethylene oxide having the following properties: acid number 0.3, saponification number 47.4, hydroxy group 42.5, pH 5% solution 4.6 color APHA = 40, melting point 36.0 ° C, pour point 32.4 C, water content (%, KF) = 0.03.

d ³ Esters of polyoxyethylene sorbitan with aliphatic acids or polysorbates of, for example, the commonly known type, sold under the trademarks Tween or Armotan as described in Fiedler, 2, pp. 745-756 and 972-975, including the following Tween brand products:

[polyoxyethylene (20) sorbitan monolaurate], [polyoxyethylene (20) sorbitan monopalmitate], [polyoxyethylene (20) sorbitan monostearate], [polyoxyethylene (20) sorbitan tristearate], [polyoxyethylene (20) sorbitan monooleate], [polyoxyethylene sorbitan monooleate], [polyoxyethylene] (4) sorbitan monolaurate], [polyoxyethylene (4) sorbitan monostearate], [polyoxyethylene (5) sorbitan monooleate], d ⁴ Polyoxyethylene esters of aliphatic acids, for example polyoxyethylene stearic acid esters as known and commonly marketed under the tradename Myrj (F) , 2, p. 636), as well as polyoxyethylene esters of aliphatic acids, known and sold under the trade name Cetiol HE (Fiedler 1, p.228) and polyoxyethylene ethers with aliphatic alcohols, for example stearyl ether, oleyl ether or polyoxyethylene cetyl ether, known and supplied under the tradename Brij (Fiedler 1, 184-186), for example Brij and 96 and Cetomacrogel 1000 (Fiedler, 1, 229).

d ⁵ Polyoxyethylene and polyoxypropylene copolymers, for example of the type commonly known and sold under the trade names Pluronic and Emkalyx (Fiedler 2, pp.720-722).

^d6 sorbitan with fatty acids, for example of known type, and supplied under the trade name Span, for example, it is a monolaurate, monopalmityl, monostearyl, tristearyl ester, sorbitan trioleate, and monooleylestery (Fiedler 2, p. 850-851).

d ⁷ Partial glycerides, for example products containing monoglyceride and / or diglyceride components, for example wetting agents based on a mixture of monoglycerides, diglycerides, triglycerides and free glycerol as well as glycerol monostearates and glycerol monooleate. Examples of these may be known and commercially available formulations called Imwitor (Fiedler, 1,491), for example Imwitor 191 and Imwitor 780 and Softigen (Fiedler, 2, 833), for example Softigen 701.

d ⁸ Ion-type wetting and emulsifying agents such as sodium lauryl sulphate or cetostearyl sodium sulphate.

Components d) are in. if present, it is present in an amount of up to 30%, preferably not more than 15% of the total weight of the composition. A preferred range is, for example, 0.5 to 10%, for example 1% by weight. based on the total weight of the composition.

Compositions of this type may further comprise (e) a thickening agent.

Examples of suitable components e) are:

e ¹ polymethyl acrylate resins as commonly known and marketed under the trade name Eudispert (Fiedler, 1, 371-372).

e ^c Cellulose derivatives such as ethylcellulose, propylcellulose, methylcellulose, hydroxycellulose, propylmethylcellulose and carboxymethylcellulose.

e ³ polyvinyl resin, including for example polyvinyl alcohol and polyvinyl pyrrolidone as well as other polymeric materials including gelatin, alginates, pectins, tragacanth gum, acacia gum, xanthan gum and polyacrylic acid, as are well known and are supplied under the trade name Carbopol (Fiedler, and , 206-207).

⁴ much more Materials such as silica, bentonite, and magnesium aluminum silicate.

The components (e), if present, are present in an amount of up to 20%, preferably up to 10%, based on the total weight of the composition. These components are preferably present in an amount of 0.5 to 15%, for example 1.0 to 3.0% by weight, based on the total weight of the composition.

In addition, these compositions may also contain antimicrobials, for example methylparaben, propylparaben, benzalconium chloride or benzyl alcohol, for example in an amount of 0.06 to 0.5% or, in the case of benzyl alcohol, up to 2%, for example 0.1% or about 1.0% by weight of benzyl alcohol. the total weight of the composition.

Other carrier media may be hydrophobic materials, for example, those which meet the solubility requirements of the active ingredient as described above. Thus, other suitable active ingredient formulations, for example for topical administration, may consist of the following ingredients:

C ² (a) Cyclosporin A in orthorhombic, preferably unsolvated, for example, a crystalline form of CY-A / X-III, for example as defined in paragraphs A to A ⁷ above, and

f) a hydrophobic carrier, for example one of the aforementioned carriers.

The amount of component a) will be in a certain relationship, the said composition C ^first Suitable components f) are, for example, petroleum derivatives such as mineral oils, fats and gelling agents, for example petrolatum (mineral fat or gelled petroleum derivative), liquid petrolatum (white mineral oil or liquid paraffin) or any other known product commonly commercially available. Vaseline (Fiedler, 2, 986) as well as nonionic lanolin derivatives as marketed under the tradename Amerchol, for example Amerchol CAB (Fiedler, 1, 119-120).

Other suitable components f) are, for example, natural or saturated vegetable oils and fats, such as fractionated coconut oil commonly sold under the trade name Miglyol, for example Miglyol 812 (Fiedler, 2, 616), peanut oil and saturated peanut oil, esters of aliphatic alcohols with straight or branched chain aliphatic acids such as stearyl alcohol, cetyl palmitate and 2-octyldodecanol, which are commercially available under the name Eutanol G (Fiedler, 1, 375).

These compositions may further comprise one or more components (d) and (e) as well as one or more antimicrobials, for example as described above.

In particular, the compositions may contain one or more components d), usually in an amount of at most 30%, preferably at most 20%, particularly preferably 1 to 15% by weight, based on the total weight of the composition.

Compositions with a hydrophobic base type C ² containing emulsifying component d) can also be prepared in the form of creams or emulsions by further addition of water. The creams or emulsions obtained may be either oil-in-water or water-in-oil. The amount of water added in these compositions may vary within the range of 5 to 80% based on the total weight of the composition, preferably 20 to 70% by weight.

The amount of component e) and the antimicrobial agent for the presence of these components the same as in the No. ^1st

Of course, the amount of topical form to be applied to a particular site will depend on the concentration of the active ingredient, the nature of the disease and the effect desired and, if administered to the skin, the size of the affected area. In the case of formulations for cutaneous administration, for example in the treatment of psoriasis or atopic dermatoses, the usual amount will be able to provide a sufficient dose of active ingredient in the range of 0.1 to 5 mg / cm ² , for example 0.5 mg / cm ² , twice daily. In the case of administration to the eye, a composition containing 0.1 to 10%, for example 1.0 to 2.0% by weight, may preferably be used. of the active ingredient, wherein the composition will be used as eye drops one to three times a day.

Injectable forms, for example, for subcutaneous, intramuscular or other parenteral administration, in particular intramuscular administration, for example, for inflammation of the joints, such as rheumatoid arthritis, or for administration to damaged areas, such as psoriasis.

Dispersions, suspensions, emulsions and the like suitable for injection may be prepared in conventional manner. For example, the active ingredient in the form of fine orthorhombic crystals may be dispersed, suspended, or otherwise dispersed in a suitable liquid vehicle with the addition of appropriate emulsifying agents, wetting agents, stabilizers, flocculants and the like. The particle size of the active ingredient in these compositions is preferably less than 100, even more preferably less than 50 and most preferably less than 20 µπι. The average particle diameter should range from 0.1 to 0.5 up to 20, 50 or 100 μπι.

In the case where the injection forms are intended, for example, for subcutaneous or intramuscular administration, for example to achieve a depot effect, particles of larger mean diameter can also be used. When these forms are intended for administration to damaged organs, especially the joints, it is desirable to use finer particles. A mean particle diameter of the active compound of, for example, from 0.1 to 0.5 to 20 μπι, i.e. within the range of 5 to 15 μπι, is suitable for this use.

In order to achieve stability of the active ingredient particles in injectable forms, for example, to prevent an increase in the size of larger crystalline particles at the expense of smaller crystalline particles and to keep the particle size as uniform as possible. Suitable deviations between the maximum and minimum particle size should not exceed 50, preferably 20 μιη.

Although the desired particle size can be ensured by appropriate reduction thereof, e.g. by micronization, it is generally avoided to have crushed particles and changes on the crystalline surface, e.g., to maintain wettability and to achieve sterility requirements, it is preferable to use non-crushed microcrystals. crystals, the natural size of which corresponds to their size requirements, as mentioned above.

Thus, the injectable compositions preferably comprise:

ABOUT

C a) Cyclosporin A in the form of fine particles, preferably in the form of orthorhombic unsolvated crystals, for example in the form of CY-A / X-III, for example as defined in paragraphs A to A, these particles being dispersed or dispersed in

(b) carriers for injection.

A suitable carrier medium is, for example, water for pharmaceutical purposes. s

In addition, the compositions defined in paragraph C ³ may further comprise

g) a wetting agent, a dispersing agent, an emulsifying agent and / or a flocculating agent which helps to maintain suspended particles in the carrier phase.

Suitable wetting agents g) can be, for example, polyoxyethylene sorbitan esters with aliphatic acids or polysorbates as mentioned in d ³ above, for example Tween 80 or Polysorbate 80 (Fiedler, 21 p.746). Suitable flocculant g) is, for example, ethylenediaminetetraacetate and its salts, for example calcium or sodium salt, as well as other equivalent chelating and peptizing agents, for example succinic or citric acid.

In order to maintain the particle size distribution, it is possible to incorporate a stabilizing agent into the composition. Suitable stabilizing agents are, for example, gelatin or modified gelatin, as well as some plasma derivatives which are commercially available under the trade names Gelafundin and Haemaccel, or cold-water-soluble types of gelatin, in particular highly pure collagen hydrolysates.

Compositions of the type may also contain one or more antimicrobial agents as described above as well as the above-mentioned peptidizing agents, for example oxalic or citric acid.

The ratio of components a): b) in the type C compositions is generally in the range 1:10 to 1: 1000, preferably 1:50 to 1: 200, for example 1: 100 wt. parts.

In order not to impair the stability of the particles, it is advantageous to use the wetting agent in component g) only in small concentrations, for example 0.1 to 2.0, preferably 1% by weight. based on the weight of component (a). When a flocculant is used, the ratio of flocculant to component a) should be in the range of 1: 3 to 1: 8, for example 1: 5 wt. work. When a stabilizing agent is used, the ratio of component a) to the stabilizing agent should be 1: 5 to 1:30, preferably 1:10 to 1:30, for example 1:20 wt. work. When a peptidizing agent is used, a suitable ratio of peptidizing agent to component a) is in the range of 1: 1 to 1:10, for example 1:15 by weight.

The amount of cyclosporin in a unit dose for injection will vary depending on the disease at the site of administration and the effect desired, for example whether a depot effect is desired or a relatively rapid release into the surrounding tissue. A single dose will be in the range 10 to 500 mg, preferably 20 to 100 mg.

Obviously, a more complex system may also be used, for example a syringe with two compartments, in which the active ingredient is in particulate form with other ingredients, for example a stabilizer or antimicrobial substance stored in the first compartment and the vehicle is stored in the second compartment, the components of the two compartments are mixed, for example, by actuating the piston. Syringes of this type have long been known and their use is also within the scope of the invention.

Oral forms, e.g., for the treatment of autoimmune diseases and the like, e.g., to prevent transplant rejection.

Although, as mentioned above, oral forms are less preferred, their use is also within the scope of the invention.

Oral forms may be prepared using the appropriate carriers or carriers as is conventional in the art. Liquid or semi-solid dosage forms for oral administration may contain the active ingredient in an orthorhombic crystalline form, for example in the form of CY-A / X-III, together with a pharmaceutically acceptable diluent or carrier in which the crystalline form is insoluble in itself or essentially insoluble. Such carriers or diluents include, for example, the transesterification products of triglycerides from natural vegetable oils with polyalkylene polyols as described in paragraph d ^x, for example, Labrafil-type compositions and reaction products of natural or hydrogenated castor oil and ethylene oxide as described in paragraph d ² , in particular liquid products such as Cremophor, especially Cremophor EL.

The active substance is preferably contained in the form of fine particles, for example having an average diameter of 0.5 to 200, in particular 0.5 to

30, preferably less than 20, for example 0.5 to 10 μπι.

For ease of administration, the compositions are usually filled into soft or hard gelatin capsules.

Oral dosage forms generally contain from 25 to 75 to 200, for example 50 or 100 mg of active ingredient per unit dose. They are administered one to four times a day to achieve sufficient plasma levels in the same manner as conventional prior art formulations.

The ingredients that have been listed as possible ingredients of the pharmaceutical compositions can be taken according to the usual rules, i.e., for oral administration, ingredients suitable for such administration and for topical administration, e.g. on the skin or in the eye, ingredients that are well tolerated in this case.

Obviously, in a similar manner, other galenic forms can be designed and manufactured for the same or other administration.

Example 1

Preparation of CY-A / X-III

(a) 100 g of cyclosporin A in amorphous form are dissolved with stirring in 400 g of polyethylene glycol 300 at 50 ° C. The product begins to develop shortly after complete dissolution. The solution is allowed to stand for 24 to 48 hours at about 35 to 40 ° C to complete crystallization and then diluted with 1000 ml of water with vigorous stirring. The precipitate obtained is collected by filtration, washed with water to remove residual polyethylene glycol and then dried to give substantially pure CY-A / X-III with a melting point of 195'C, the particle size being in the range of 100-200 μπι.

Analogously, CY-A / X-III can also be prepared by using the materials listed in the following table instead of polyethylene glycol 300:

solvent

The melting point obtained

CY-A / X-III (° C)

b) polyethylene glycol 300 / Cremophore RH 40 (1: 1 volume ratio) - c) Cremophore EL 190 d) Solutol HS 15 188 e) Gelucire 44/14 180 f) Myrj 52 184 g) Tween 80 186 h) Cremophore RH 40 190

In each case, the mean particle diameter was in the range of 50 to 200 μιη. The lattice structure determined corresponded to the above description. X-ray diffraction will be further shown in Table III and in Figure IV.

Example 2

Preparation of CY-A / X-III g of cyclosporin A in the form of CY-A / X-I is dissolved in 60 ml of ethanol and condensed to 1/6 of the original volume by distillation under reduced pressure at a temperature above 60 ° C. 160 ml of polyethylene glycol 300 and 20 ml of water are then slowly added at 50-85 ° C with stirring at 300 rpm. Thereafter, the mixture is treated with an ultrasonic vibrator at 20,000 cycles per second. Crystals begin to form at a temperature of 65-75 ° C within 3-5 minutes. The resulting dispersion is then gradually cooled to 40 ° C over 10 to 20 minutes with continuous sonication and stirring at 700 rpm. The thick pasty mixture obtained is filtered, washed with a mixture of polyethylene glycol2800 and water in a volume ratio of 3: 1, then washed with water at 30 ° C, after which it is dried under high vacuum at 50 ° C to obtain pure CY-A / X-III, mp 192 ° C. The particle size is in the range of 3 to 15 µm, the crystal lattice corresponds to the above description, the X-ray diffraction is given in Table III and in Fig. IV.

Repeated experiments have shown that the dimensions of the crystals are influenced by the temperature and growth rate of the crystals rather than by the total processing time. For example, if crystals begin to form at 70 ° C and crystallization continues at the same temperature, a crystalline material having a particle size of about 50 µm was obtained.

Example 3

Preparation of galenic forms for oral administration

Formulations I for filling into gelatin capsules

A suspension containing 20 wt. The CY-A / X-III obtained by the method of Example 1 in Gelucire 44/14 is milled at elevated temperature in a colloid mill until the median particle diameter of the active ingredient is in the range of 0.5 to 10 µm. The 250 mg aliquots of this suspension are then filled into hard gelatin size 2 capsules, each containing 50 mg of the active ingredient in the form of CY-A / X-III.

3.2 Formulation II for filling into gelatin capsules

The CY-A / X-III obtained by the method of Example 1 is ground in a colloid mill until the average particle diameter of the active ingredient is in the range of 0.5 to 20 µm. The 50 mg aliquots are then thoroughly mixed with 200 g of Cremophore EL and filled into hard gelatin size 2 capsules, each containing 50 mg of the active ingredient in the form of CY-A / X-III.

Example 4

Preparation of galenic forms for topical administration

4.1 Composition I in the form of a gel

The CY-A / X-III obtained by the method of Example 1 is micronized in an air jet mill. Micronized product with max a small particle size of 60 to 70 μιη and an average particle size of 2 to 10 μιη are mixed in a conventional manner with the other ingredients listed in the following table to form an aqueous gel containing 10% of the active ingredient in the form of CY-A / X-III and suitable for topical administration, for example for the treatment of psoriasis.

component % wt. (a) Cyclosporin (micronized CY-A / X-III) 10.0 b) polyacrylic acid Carbopol 934P 0.5 (c) 5% sodium hydroxide solution 3.0 d) methylparaben 00:07 (e) propylparaben 00:03 (f) water for pharmaceutical purposes to 100

4.2. Composition II in gel form

% Wt.

composition A composition B

(a) Cyclosporin

(micronized CY-A / X-III) 10.0 1.0 (b) polyethylene glycol 300 30.0 30.0 (c) Labrafil M 2130 CS 1.0 1.0 (d) Carbopol 934 P 1.0 1.0 e) 5% sodium hydroxide 6.0 6.0

(f) methylparaben

00:07

(g) propylparaben

00:03

(h) water for pharmaceutical purposes

51.9

00:07

00:03

60.90

100.0%

100.0%

The active substance is prepared as in 4.1. Components c), f) and g) are dissolved in component b) with heating and the resulting mixture is cooled to room temperature, after which the solution obtained is dispersed in water. The active ingredient is then added and the mixture is again homogenized. Component (e) is then added to neutralize the mixture with stirring, and the resulting gel is filled into tubes for topical administration, for example, for psoriasis treatment.

4.3 Lubricant

% Wt.

means A means (a) Cyclosporin (micronized CY-A / X-III) 1.0 10.0 (b) Amerchol CAB 2.0 2.0 (c) liquid paraffin 42.0 37.5 (d) white petrolatum 55 · 0 50.5 100.0% 100.0%

The active substance is prepared as in 4.1. The components (b), (c) and (d) are melted and mixed together and then the active ingredient is added at a temperature of about 30 ° C, after which the resulting mixture is homogenized. The obtained lubricant is cooled and filled into compressible tubes for topical administration, for example for the treatment of psoriasis.

Preparation of the cream

component % wt. (a) Cyclosporin (micronized CY-A / X-III) 1.0 (b) polysorbate 60 5.0 (c) cetyl stearyl alcohol 10.0 d) glycerol 85% 10.0 (e) white petrolatum 24.0 (f) methylparaben 00:07 (g) propylparaben 00:03 (h) water for pharmaceutical purposes 49.0 100.0%

The active substance is prepared as in 4.1, mixed with components b) to h) in an analogous manner to that described in paragraph 4.1.

4.3 and then filled into compressible tubes for topical administration, for example for psoriasis treatment.

4.5 Lubricant preparation

A suspension containing 20 wt. The CY-A / X-III obtained in Example 1 in polyethylene glycol 300 is wet milled until the median particle diameter of the active ingredient is in the range of 2 to 10 μπι. Thereafter, 10 g of the product obtained are mixed in a conventional manner with 50 g of polyethylene glycol 300 and 40 g of molten polyethylene glycol 1500 to form a liquid paste containing 10% of the active ingredient CY-A / X-III, suitable for topical administration, e.g. chips.

4.6 Preparation of the gel

component % wt (a) Cyclosporin (micronized CY-A / X-III) 1.0 (b) Labrafil M 1944 CS 1.0 (c) polyethylene glycol 300 30.0 (d) benzyl alcohol 1.0 e) hydroxypropylmethylcellulose (Methocel E4M) 2.5 (f) water for pharmaceutical purposes 64.50

100.0%

The active ingredient shall be prepared as in 4.1. The components b), c) and d) are mixed, the component f) is added and the mixture is mixed, and the active ingredient is then added to the suspension during homogenization in the resulting mixture. Subsequently, component (e) is added slowly with stirring until the gel formation is complete. The resulting gel is then filled into compressible tubes for topical administration, for example for the treatment of psoriasis.

4.7 Preparation of the gel

component % wt. (a) Cyclosporin (micronized CY-A / X-III) 5.0 (b) polyethylene glycol 300 30.0 c) glyceryl monostearate 5.0 d) methylparabenl 00:07 (e) propylparaben 00:03 (f) Carbopol 934 P 1.0 (g) 5% sodium hydroxide 6.0 (h) water for pharmaceutical purposes 52.9

100.0

component a) sa prepare the same as in paragraph 4.1 . ingredients c) , d) and e) dissolved for heating in component b). warm mixture the then disperses homogenization in component h) and a mixture the Cool to room temperature. added the effective

substance and component f) and the resulting mixture is again homogenized, then component d) is added to form a gel. The gel obtained is filled into compressible tubes for topical administration, for example for the treatment of psoriasis.

4.8 Preparation of cream (water in oil)

component % wt. (a) Cyclosporin (micronized CY-A / X-III) 2.0 (b) Amerchol CAB 5.0 c) Miglyol 812 10.0 (d) white petrolatum 53.0 (e) water for pharmaceutical purposes 30.0

100.0%

The active ingredient is prepared as in 4.1 and then dispersed together with component b) in component e) while heating and homogenizing. The components c) and d) are melted together, mixed and the mixture is added under intense homogenization to the above dispersion and the resulting mixture is cooled to form a white cream which is filled into compressible tubes for topical administration, for example for psoriasis treatment.

4.9 Preparation of gel cream

The procedures of Examples 4.1 to 4.8 were repeated except that the crystalline product obtained by the method of Example 2 was used as the active ingredient.

Example 5

Injectable forms, for example, for parenteral administration

The CY-A / X-III suspension is prepared under sterile conditions in a conventional manner using the following ingredients:

component amount (mg) (a) Ciclosporin (CY-A / X-III) 20.0 (b) polysorbate 80 4.0 c) sodium carboxymethylcellulose 5.0 (d) sodium chloride 9.0 (e) benzyl alcohol 9.0 (f) water for injection to 1.0 ml

The release of the active ingredient from the composition obtained depends on the mean particle diameter of component a). That is, if a longer-term effect is desired, a CY-A / X-III product with a large mean particle diameter of, for example, 100 to 200 μιη can be selected as directly obtainable by the method of Example 1. In the case of If a shorter effect is desired, it is possible to use an active substance with a relatively smaller mean particle diameter, for example after micronizing or grinding the product of Example 1 to a particle size in the range, for example, 0.5 to 10 μιη. The suspension obtained is then filled into injection ampoules and is intended for parenteral administration or administration directly into damaged tissue, for example in the treatment of psoriasis, for example a depot effect can also be achieved.

In a particularly preferred embodiment, the active ingredient in the form of CY-A / X-III, prepared according to the method of Example 2, having a particle size of 5 to 15 μπι, is used for the preparation of the injectable solution.

5.2 Injectable forms, for example, for intramuscular administration

Injectable forms suitable for intravenous administration may be prepared using the following ingredients:

Ingredient amount (mg)

Composition A

(a) Ciclosporin (CY-A / X-III) b) sodium carboxymethylcellulose (c) EDTA sodium salt (d) water for injection 10.0 10.0 2.0 to 1.0 ml Composition B (a) Ciclosporin (CY-A / X-III) 10.0 (b) polysorbate 80 0.1 (c) citric acid 2.0 (d) water for injection to 1.0 ml

The compositions are manufactured in conventional manner under sterile conditions. The active substance consists of non-crushed microcrystals which were obtained under sterile conditions according to the method of Example 2 and whose size ranges from 3 to 15 μη. The formulations are filled under sterile conditions into ampoules for injection, for example, intra-articular administration in rheumatoid arthritis.

The advantageous properties of the compositions obtained by the process of the invention can be demonstrated in animal and clinical trials. The usefulness of these compositions for administration to the skin, for example in the treatment of psoriasis or various dermatoses, can be demonstrated in the following experiments.

Allergic contact dermatitis in guinea pig (DTH test)

Hartley male guinea pigs weighing 400 to 500 g are sensitized by applying a 50 μΐ 2% solution of dinitrofluorobenzene (DNFB) in a 1: 1 by volume mixture of acetone and olive oil on the inside of the right ear. After seven days, the animal is re-injected with a 20 μΐ 0.5% solution of dinitrofluorobenzene (DNFB) in a 4: 1 v / v mixture of acetone and olive oil on the indicated shaved left and right flank area. This second administration causes allergic inflammation, manifested by redness and infiltration (swelling) of the skin. Thereafter, 200 to 250 mg of the test substance is applied to the said areas, usually on the right side. On the left side a placebo is applied as a control. Both sides are applied five times at 20 minutes, 8 hours, 24 hours, 32 hours and 48 hours after the irritant is administered. Skin swelling is checked before each administration, this value is checked again 8 hours after the last administration by pulling the skin into the lash and measuring the thickness of the lash. The degree of redness is assessed visually according to a scale of 0 to 4. The efficacy of said compositions against inflammation is determined by comparison with the other flank treated only with the base.

The results obtained in the above experiments using the compositions of Examples 4.1 and 4.5, but containing 0.1 wt. of the active substance in the form of CY-A / X-III as compared to placebo and topically administered 0.1% cyclosporin solution are shown in FIG. I, II and III. The 0.1% CY-A / X-III concentration is used in this experiment due to the high sensitivity of the animal. The compositions are prepared in analogy to Examples 4.1 and 4.5 except that the amount of active ingredient in these compositions is reduced to 0.1 g and an additional 9.9 g of water in Example 4.1 and polyethylene glycol ingredients in Example 4.5 are added instead of the active ingredient.

Each drawing shows the time in hours on the abscissa axis and the skin thickness in mm on the second axis. Figure 1 shows the results using 0.1 wt. cyclosporin A for conventional use as a commercially available oral solution as compared to placebo. For the oral solution, a small but statistically insignificant reduction in the reaction can be demonstrated. In FIG. II and III show the results using 0.1 wt. cyclosporin in the compositions of Examples 4.1 and 4.5 as compared to placebo. In both cases, there was a significant reduction in skin swelling at the first administration and continuously throughout the treatment compared to placebo until the end of the trial.

The usefulness of the above pharmaceutical compositions can also be demonstrated in clinical trials, for example as follows:

Clinical trial: treatment of lipstick by topical administration

The experiment was performed in a double-blind, randomized, placebo-treated trial. Each of the patients receives an active ingredient and a placebo consisting of only the vehicle in two symmetrically damaged areas. These locations are selected so that one is on the right and the other on the left.

Patients aged 18 to 70 years are grouped into a 12 to 24-member group, men or women postmenopausal, surgically sterilized or using oral contraceptives, with a negative pregnancy test.

All patients must meet two conditions:

(a) they must sign the agreement; and

(b) they must have a clinically defined, chronic, chronic psoriasis with skin manifestations.

The patient must have at least two slightly or severely damaged symmetric spots on both sides of the body with an area of 4 to 25 cm ² with a damage rating of more than 5 using a scale of 0 to 9. This rating is composed of individual ratings 0 (least severe) to 3 ( most severe) for the following parameters: redness, increased lesions and skin thickness.

The damage on both sides of the body must be comparable for the same patient, ie the severity of the two lesions must not differ by more than 20%.

Patients were excluded from the experiments according to the following criteria:

(a) any treatment which could in any way affect the course of the experiment;

b) systemic treatment of psoriasis in the last two months (PUVA, methotrexate, steroids, retionides, cyclosporin),

(c) specific topical treatment with the exception of indifferent substances such as white petrolatum or salycilic acid in an amount of not more than 10% during the two weeks prior to the experiment, but this treatment may be carried out in damaged areas where no trial is performed;

d) diseases in which psoriasis itself better without treatment or better after previous treatment without further intervention,

(e) known hypersensitivity to any of the ingredients of the pharmaceutical compositions administered;

(f) non-cooperating illnesses who are unlikely to receive treatment properly or who do not want or cannot regularly check

g) treatment with another test substance within one month prior to the experiment,

(h) severe current disease, mainly impaired renal function with serum creatidine in excess of 130 μιηοΐ / liter;

i) elevated blood pressure with a diasteric value of 95 mm Hg after 5 minutes of sitting, patients with properly treated higher pressure may participate in the experiment,

(j) a history of cancer, including skin cancer;

(k) acute bacterial, viral or fungal skin diseases

(l) in pregnancy and lactation

(m) history of alcoholics, addicts, psychotics and people with emotional or intellectual problems;

n) patients in need of concomitant treatment with other immunological depressants, chemotherapeutic agents, nephrotoxicity compounds such as aminoglycosides or substances that interact with cyclosporin such as ketoconazole, erythromycin, phenytoin, phenobarbitone, rifambicinepine, rifambicinepine, rifambicinepine, rifambicinepine, rifambicinepine, rifambicinepine .

o) patients with abnormal basal metabolism differing by more than 15% from normal value;

p) patients with deviations in routine examination.

Any of the compositions of Examples 4.1 to 4.9 may be used, for example 1% composition B of Example 4.2 or 10% composition B of Example 4.3.

Each patient receives a pair of tubes containing 20 g of material and a double label. The sticker is blue for the right side and red for the left side. Further, the label includes an indication of the side on which the material is to be applied, i. left or right, the experiment code, the name of the person who leads the experiment, the patient's number, and the start date of the experiment. The label that can be removed from the tube is then affixed to the progress report.

The tube material is applied twice a day, morning and evening, the amount depends on the size of the damaged site, the daily dose should be 0.2 to 2.0 mg cyclosporin A / cm ² , ie in one series of experiments, approximately 0.5 mg / cm ² . Placebo is applied in equal amounts. None of the substances are applied to a surface greater than 25 cm ² and no more than 1 g of active substance is applied per week. At each inspection, the tubes are weighed and the daily dose applied is determined. Patients can bathe shortly before application. Application is to be carried out on disposable gloves to avoid transferring the active substance to the placebo and vice versa. At least 3 hours should elapse before applying the ointment and washing. The first application is carried out under supervision and the patient receives written instructions. The treatment lasts four weeks. However, in the event of complete disappearance of the affection before this time expires, treatment is continued until the fourth week. Patients are checked before the start of the experiment (-1 week), at the start of the experiment (week 0), and after one, two, three and four weeks thereafter.

The assessment is made by a worker who does not participate in the experiment using the following 0 to 3 numbering scale (LPSIlocal psoriasis severity index score).

redness elevation skin thickness 0 = none 0 = none 0 = unchanged 1 = at least barely noticeable, slightly pink 1 = elevation at least difficult to detect 1 = minimal, barely discernible increase 2 = moderate redness, well distinguishable 2 = moderate, well defined, beginning peeling 2 = mild but well distinguishable 3 = strong, deep to bright red color 3 = strong flaking of compact sections 3 = thick thickening

The sum of these values can therefore be 0 to 9. To be included in the experiment, at least two characters at both selected sites must be moderate to strong, so the overall score must be greater than 5.

The size of the damaged area shall also be measured when enrolled in the experiment and at each check, for placement the size shall be 4 to 25 cm ² . The three above-mentioned features are then evaluated in this area. Damage pigmentation is not evaluated.

Damaged locations are photographed at week -1 and week 4. Three photos are taken. One of them shows both places at the same time and the other two each one of these places.

Itching is evaluated according to the patient's data according to the following scale:

= none = minimally, occasionally forced to scratch, = mild, often forced to scratch = unbearable, very often forced to scratch, and can disturb night sleep. and

At the end of the experiment, an overall evaluation of responses to treatment is performed according to the following considerations:

- cured = 100% response to treatment

- substantial improvement = at least 66% reduction in LPSI and / or at least 66% reduction in damaged area,

- slight improvement, 65% to 33% reduction in LPSI or 65% to 33% reduction in damaged area,

- slight improvement = less than 32% reduction in LPSI and / or less than 32% reduction in damaged area,

- aggravation = exacerbation of the disease.

Therapeutic success is considered to be a damaged site that is healed or where substantial improvement can be demonstrated.

Both the physician and the sick also give their opinion on the benefits of right or left-hand treatment according to the following point of view:

- the left side is clearly better,

- the left side is a little better,

- there is no detectable difference,

- the right side is a little better,

- the right side is clearly better.

For efficacy at end of treatment, LPSI scores and area of lesions were compared by Wilcoxon paired test for treated and placebo-treated affections after 4 weeks of treatment, to assess the significance of changes after that time.

All other comparisons in other work periods or for other parameters are considered only to describe the development of the experiment.

In the above experiment, it was observed that the individual patients had a significant improvement in psoriasis-damaged sites with respect to LPSI at the sites where the active ingredient-containing compositions were applied. There was also a subjective improvement in itching at the ciclosporin A-treated sites compared to the placebo-treated sites.

Positive results were also obtained in experiments with patients with contact dermatitis, where at least three of the following were evaluated:

- itching

- typical morphology and distribution:

flexural lichenification or linearity in adults, face and extensor involvement in children,

- chronic or relapsing dermatitis,

- a personal or family history of atopic manifestations such as asthma, allergic rhinitis, atopic dermatitis.

Also evaluated are at least three sub-features of the following group: xerosisi, ichtyosis / palmar hyperlinearity / keratosis pilaris, immediate type I reactivity in skin reaction, elevated serum IgE, low age at onset of the disease, i. less than five years, tendency to skin infections, especially Staph. aureus and Herpes simplex, cell-mediated immunity, specific dermatitis in the hands and feet, nipple eczema, cheilitis, recurrent conjunctivitis, infra-orbital anomalies Dennie-morgan, keratoconus, cataracta subcapsularis anteria its redness, pityriasis alba, eyelashes on the front of the neck, frequent sweating, formation of sweats, intolerance of solvents, mainly fat, intolerance of various kinds of food, easy influencing mainly by environmental and emotional factors, white dermographism, mainly delayed. The duration of the experiment is three weeks, and the following parameters are evaluated with a scale of 0 to 3: swelling, redness, swelling, peeling and lichenification.

Topical formulations as described in Examples 4.1 to 4.9 containing 1 to 10% active ingredient, for example the formulation of Example 4.7 containing 5.0% active ingredient, are also effective in allergic contact dermatitis and hair loss.

Thus, the active ingredient-containing compositions obtained by the process according to the invention can also be used

D. For the treatment of cyclosporin in patients in need of such treatment, treatment is effected by administering an effective amount of the active ingredient in the form of orthorhombic crystals, especially in unsolvated form, for example CY-A / X-III as defined in paragraphs A to And mainly

D ¹ for the treatment, at which the suppression of the immune system and the anti-inflammatory therapy in patients of such treatment requires the treatment is performed by administering an effective amount of cyclosporin A in a orthorhombic crystal form which is in the form of a solvate, for example a in the form of CY-A / X-III as defined in paragraphs A to ^A7 .

The purposes for which the agent can be administered are, for example, the prevention of transplant rejection, the treatment of autoimmunological and rheumatic diseases, the treatment of any other diseases or conditions in which the immune system responds too high, e.g. treatment of alopecia. These are mainly skin or eye diseases such as psoriasis, atopic or contact dermatitis, corneal transplants, conjunctivitis and uveitis, in this case topical administration, in the case of rheumatoid arthritis or other joint diseases, intra-articular administration is also contemplated.

Therefore,

E Cyclosporin A as unsolvated forms orthorhombic kryštá44 fish, such as CY-A / X-III, as defined in paragraphs A to A ^7, for pharmaceutical use, for example in the treatment of various diseases, in particular for controlling the immune response and inflammation, and

F Cyclosporin A in the form of orthorhombic crystals, such as CY-A / X-III, as defined in paragraphs A to ^A7 .

I

In order to facilitate identification of cyclosporin A in said form, in particular CY-A / X-III, X-ray diffraction data for CY-A / X-III a; also for both forms CY-A / X-I and CY-A / X-II in the following Tables I to III. In FIG. IV is a diagram of diffraction. This diagram was obtained using a camera (Guinier.DeWolff II) and using CuKα radiation, lambda = 1.542 Å.

Table I

X-ray diffraction for CY-A / X-I line no.

d ()) intensity

1 13 VS 2 11.4 VS 3. 10.3 VS 4 9.7 VS 5 9.4 VS 6 8.25 VS 7 7.1 WITH 8 6.1 M 9 5.85 WITH 10 5.6 WITH 11 5.25 VS 12 4.81 with 13 4:58 with 14 4.25 M 15 4.0 M 16 3.67 M 17 3:45 M

Table II

X-ray diffraction for CY-A / X-II

line no. will give) intensity 1 1 17.9 WITH 2 11.4 VS 3 11.0 WITH 4 10.6 M 5 10.2 WITH 6 8.9 M 7 8.7 M 8 8.1 M 9 , 7.2 VS 10 6.3 M 11 5.95 M 12 5.7 M 13 5:35 M 14 5.1 WITH 15 4.85 WITH 16 4.8 M 17 4:55 M 18 4.4 M

e

Table III

X-ray diffraction for CY-A / X-II line no.

d (Ä) intensity

1 12.0 M 2 10.4 VS 3 9.6 WITH 4 8.7 WITH 5 7.9 M 6 7.7 WITH 7 6.7 M 8 6.0 M 9 5.83 WITH 10 5.3 M 11 5.2 M 12 4.92 WITH 13 4.88 WITH 14 4:58 M 15 4:48 M 16 4.0 M 17 3:59 M 18 3:38 M

alpha

Claims (3)

1. A method for the production of cyclosporin A in the orthorhombic (P2 ^ 2 ₁ 2 ₁₎ with a crystallinity talickej crystal lattice, in which the size is equal to 12.5, and A, dimension b is equal to 22.9 Å, the dimension c is equal to 28.4 Å and the volume of the The asymmetric unit is equal to 2027 Å ^3, characterized in that cyclosporin A is dissolved in a solvent medium consisting of a polymeric ether having a molecular weight of at least 200, at a temperature of at least 40 ° C to a solution containing from 5 to 60% by weight. cyclosporine A based on the total weight of the solution and cyclosporin A is crystallized from this solvent to form the orthorhombic crystalline form as defined above. Method according to claim. Characterized in that the dissolution medium comprises polyethylene glycol or polypropylene glycol. 3. The process of claim 1 wherein the dissolution medium comprises glycerol polyethylene glycol ester, a polyoxyethylene sorbitan ester, a polyoxyethylene ester, or a product of transesterification of natural triglycerides from oils and polyalkylene polyols.