NL8803125A - NEW CICLOSPORIN CRYSTAL FORM, PROCESS FOR ITS PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THIS CRYSTAL FORM AND ITS USE. - Google Patents

Description

- 1 - »<ί £

Novel cyclosporine crystal form, process for its preparation, pharmaceutical preparations containing this crystal form and its use.

The present invention relates to new pharmaceutical preparations containing Ciclosporin as an active ingredient.

Ciclosporin or cyclosporin A is a known fungal meta-5 bolite with valuable pharmaceutical utility. Ciclosporin is a cyclic poly-N-methylated endecapeptide of formula ~ MeBmt-aAbu-Sar-MeLeu-Val-MeLeu-Ala- (D) Ala-MeLeu-MeLeu-MeVal -J 2 3 4 567 89 10 11 J0 —-- -, in which -MeBmt- represents an N-methyl- (4R) -4-but-2E-en-1-yl-4-methyl- (L) -threonyl radical.

Ciclosporin, as well as methods for its preparation, are described, for example, in U.S. Patent No. 4,117,118. The main field of clinical studies for ciclosporin has been as an immunosuppressive agent, particularly in connection with its use in the treatment of recipients of transplanted organs, for example, heart, lungs, combined heart-lung, liver, kidney, pancreas, bone marrow, 20 skin and cornea transplants and, in particular, allogeneic organ transplants. In this area hiccicsporin haft. has achieved remarkable success and reputation and is now widely used in hospitals and is commercially available under

R R

the registered trademark SANDIMMUN or SANDIMMUNE, for example in the form of a concentrated infusion preparation, of an oral solution and of a gelatin encapsulated solution, the latter two variants being described, for example, in US Pat. No. 4,388,307,

At the same time, there was an intensive study of the applicability of Ciclosporin in various autoimmune diseases and in inflammatory conditions, in particular inflammations with an etiology including an autoimmune component, such as arthritis (eg rheumatoid arthritis, arthritis chronica progediente 8803125?

I

- 2 - and arthritis deformans1 and rheumatic diseases, and reports and results of in vitro experiments on animal models and in clinical studies are available in literature. Specific autoimmune diseases for which Ciclosporin therapy has been proposed or used are For example; autoimmune haematological disorders, (including, for example, haemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythema tosses, polychondritis, sclerodoma, Wegener granulajnatosis, dermatomyositis, chronic myopic hepatitis Steven Johnson syndrome, idiopathic thrush, autoimmune intestinal inflammation (including, for example, ulcerative colitis (and Crohn's disease), pemphigus, endocrine ophthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, primary liver cirrhosis, primary juvenile diabetes (diabetes mellitus J5 type) I), Behcet's disease, uveitis (anterior and posteriori, vernal conjunctivitis, keratoconjunctivitis sicca, interstitial pulmonary fibrosis, psoriatic and glomeruloneffitis (with and without nephrotic syndrome, for example including idiopathic nephrotic syndrome or nephropathy with minimal change).

Further fields of research include the potential utility as an anti-parasitic agent, in particular anti-protozoal agent, with potential proposed uses including treatment of malaria, coccidiomycosis and schistosomiasis, as well as use in reversing tumor resistance to chemotherapeutic, eg cytostatic , therapy and .... ...

promoting hair growth, for example for the treatment of alopeceia,

Xh solid state Ciclosporin occurs in both amorphous and crystalline form. In the crystalline state, both a tetragonal and an orthorhombic modification are known.

The tetragonal modification (^4 ^ 1, also referred to herein as "Cy-A / XI" for convenience's sake), along with processes for its preparation, are described, for example, in Austrian Patent Specification No. 353,963, Cy-A / Xi has a lattice a = h = 13.8 A c = 41.2A, ** 3 volume per asymmetric unit of «1974 Δ, a melting point at about 140-125 ° C and contains about 2 moles of water per Ciclosporin molecule.

A first orthorhombic modification (P2 ^. 2 ^ 2 ^) can be obtained by recrystallization from diisopropyl ether, such as 8803 12 5 i "i - 3 - is described in an article entitled" Total synthesis - change in molecular structure - biological effect : Ciclosporin as example "by R. Wenger, in" Sandorama "3984/111. This special modification concerns a Ciclosporin diisopropyl ether (about 1: 2) solvate, with a crystal lattice of a * 12.5 A, b = 22.9 A, c = 28.4 A, volume per ° 3 asymmetric unit = 2027 A and melting point about 150 ° C. Rhororombi8chf Ciclosporin solvate crystals can be obtained by recrystallization of supersaturated Ciclosporin solutions in a suitable solvent medium for prolonged periods of time The orthorhombic Ciclosporin diisopropyl ether solvate preparation prepared according to Wenger is thus obtained by adding a concentrated solution of Ciclosporin in methylene chloride (in which Ciclosporin tam is freely soluble) to diisopropyl ether (in which Ciclosporin is relatively less soluble) and evaporation of the methylene chloride. Crystallization from the remaining di-isopropyl ether is then allowed to proceed at ambient temperature for about 7 days. Orthorhombic crystal forms concerning such Cyclosporin solvates are also generally referred to herein as "CY-A / X-II" for convenience.

Another orthorhombic (P2j2 ^ 2 ^) modification has now been identified, which is characterized by the absence or almost absence of any solvent component, that is, it consists almost entirely or substantially of free Ciclosporin.

The dimensions of the crystal lattice for the solvent-free or non-solvate, orthorhombic Ciclosporin modification * O β · are a = 12.7 A, b ** 35.7 A, c * 36.3 A, vol. per asymmetric «3 unit · = 1804 A. The melting point is of the order of from about 180 to about 190 ° C to about 195 ° C, depending, for example, on the degree of purity source, as can be seen from the following Examples J and 2, in which specific methods of obtaining this modification are Described, Ciclosporin in an unsolvated (or no solvent containing) orthorhombic crystal form is also referred to herein as "CY-A / X-III" for convenience. Further characteristic (X-ray diffraction) values for CY-A / X-III are included in Table III and Fig. IV below, along with corresponding data for CY-A / X-I and CY-A / X-II,

Despite the very great success and fame that 8803125.

Λ - 4 - Λ

Ciclosporin, and of its great contribution to medical science, especially in the field of organ transplants, which it had already obtained, its application was not yet ideal in practice and was not without difficulty. A particular area in which difficulties have been encountered has been the provision of galenic forms that allow appropriate or completely satisfactory administration, whether best suited for the treatment of specific diseases or conditions for which Ciclosporin already had a potentially selected drug Turn out to be JO.

These difficulties are due in part to the particular physical properties of Ciclosporin, for example its relatively limited solubility or (hitherto found) compatibility with suitable pharmaceutically applicable carrier media, J5. These difficulties are exacerbated by the special nature of certain which make Ciclosporin. the potential is first-line therapy, as well as diseases from the occurrence of undesirable side effects, that Ciclosporin may induce when this compound is administered orally. For example, Ciclosporin was found to be effective in the 2Q treatment of psoriasis after oral administration. Psoriasis is a widespread disease that causes considerable distress in patients and for which no generally acceptable, effective therapy has been found to date. Sufferers from psoriasis clearly form a patient population that can use help. Although available data may indicate that

Ciclosporin could provide this assistance, it is unlikely that oral Ciclosporin therapy could be an appropriate means of treating psoriasis. Corresponding considerations apply to the treatment of, for example, eye diseases, such as posterior uveitis and keratoconjunctivitis sicca,

They have proposed many systems for the administration of Ciclosporin, including galenic forms intended for topical or dermal application or for ophthalmic administration, ie topical application to the eye, for example for possible use to treat psoriasis or other dermatological diseases and conditions, for example, atopic dermatosis and alopecia, or to treat uveitis. However, such systems have not hitherto led to any notable beneficial effect or have been found to be not fully satisfactory.

Several described attempts to treat psoriasis patients by administering the known oral solution directly to the surface portion of the psoriasis lesion have had minimal success or no success at all and success in patients suffering from atopic dermatosis is extremely Limited. While topical application to the eye has been shown to be widely effective as a means of preventing, for example, corneal transplant rejection, or to treat diseases in the anterior part of the eye, neither has a preparation for topical application hitherto been described. allows for quick, safe or effective treatment of diseases or conditions as they act on deeper parts of the eye, for example for the J5 general Treatment of uveitis including posterior uveitis.

Similar difficulties have arisen in connection with the development of other drug systems that deliver Ciclosporin, for example injectable forms, which are suitable, for example, for injection into the joints for the local treatment of arthritic conditions, for example as described above, or for injections in lesions, for example, to treat severe psoriatic conditions or alternative oral delivery systems, with, for example, a modified bioavailability or drug release properties, So far attempts to formulate Ciclosporin have used the compound in solution, or, less usually, in amorphous or Cy-A / XI form, the latter form being, for example, the crystal form identified for, for example, drug registries. Despite the extensive efforts that 3Q has made to find new or improved alternatives,

The oral solution and concentrated infusion preparation previously mentioned remained the only widely used delivery systems for Ciclosporin,

According to the present invention, it has now surprisingly been found that orthorhomic crystal forms of Ciclosporin, heiroor Cy-A / X-II in particular, Cy-A / X-III, have particular advantages and are advantageous for preparing Ciclosporin galenic preparations. different and diverse nature,

In particular, it was found that such crystal modification 8803125.

-6-.

Cations can be used to prepare galenic formulations containing cyclosporin in stable fine particle form and / or greater stability or better release properties. to have. This discovery opened the way to the production of new and improved drug delivery systems containing Ciclosporin, for example, sustained or delayed release of Ciclosporin and / or adapted or suitable for the treatment of previously insensitive diseases or conditions. for a Ciclosporin therapy or for which the usual Ciclosporin therapy was inherently less suitable.

In particular, it has been found that the use of such crystal modifications, for example in the aforementioned fine particulate form, can yield galenic forms suitable for topical or dermal use or topical eye applications, to treat diseases or conditions which affect the skin or the eye, heyoorheeld as mentioned above, in particular for the treatment of psoriasis, atopic dermatitis, contact dermatitis, occular symptoms of Behchet's disease, uveitis and keratoconjunctivitis 2Q sicca. The use of such crystal modifications also allows for the preparation of injectable forms of Ciclosporin with a longer or delayed release and these crystal forms are thus of particular use, for example, for treating diseases or conditions for which the required frequency of administration would otherwise be useful. for example to treat arthritis or similar diseases of the joints by injection into the joints or to treat psoriasis or similar skin diseases by injection into the injuries.

For such purposes, orthorhombic 3Q crystal forms, in particular CY-A / X-11, have been found to be inherently much better suited than the other available forms, in particular amorphous Ciclosporin or CY'-A / X-I, for example, in physicochemical terms. properties, in particular stability, release properties, for example the release of Ciclosporin from the crystal roaster and the suitability for the necessary treatments for the preparation of galenic preparations, CY ^ A, / X ** HX is a novel and aanheyolen orthorhombic crystal form for follow galenic and / or therapeutic application? the invention. Accordingly, a first embodiment of the present invention provides: 8803125.

-ΊΑ CY-A / X-III, ie cyclosporine in an ortho-rhombic crystal form cKie which is not a solvate, in particular: AJ CY-A / X-III with a crystal lattice or other physical properties that are almost the same as before 5 and / or 2 A CY-A / X-III with X-ray diffraction properties substantially the same as those listed in Table III or in Figure IV.

The present invention also provides: JO B A process for the preparation of CY-A / X-III, which process crystallizes Ciclosporin from a CY-A / X-III:: '. medium and recovery of the CY-A / X-III thus obtained.

Suitable CY-A / X-III-forming media for use in the process described in J5 above are especially solvent media for cyclosporin containing solvent components having a high molecular weight, for example, with molar weight> 200. Media which contain high molecular weight ethers are particularly suitable. beats, especially polymer ethers, such as polyalkyl-2Q ethers, for example, polyethylene and polypropylene glycols.

Examples of polymer ethers that have been found to be suitable are polyethylene and polypropylene glycols, for example, with a molecular weight. of> 200, glycerol polyethylene glycol ethers, for example, glycerol polyethylene glycol ricinoleates and glycerol polyethylene glycol oxystearates, as obtained, for example, under the trademarks "Cremophor EL" and "Cremophor RH" (see Fiedler, "Lezikon der Hilfstoffe" 2nd part, Vol. 1 , pp. 257-258), polyozyethylene sorbitan esters, for example, available under the trademark "Tween" (see Fiedler, 2, pp. 972-9751, polyoxyethylene-3Q esters, for example, polyoxyethylene stearic acid esters, for example, available under the trademark "Myrj "(see Fiedler, 2, p. 6361 and transesterification products. Natural oil triglycerides and polyalkylene polyols, including the transesterification products of the corn oil, kernel seed, almond oil, ground nut oil, olive oil, palm oil and mixtures thereof with polyethylene glycols, in particular polyethylene glycols glycols having a molecular weight between 2QQ and 8QQ, for example, available under the registered trademark "Lahrafil" (see Fi edler, p. 5391, Particularly suitable are media containing polyethylene glycols with molecular weight, from about 200Q to about 6GQ, especially from about 300 to about 8803-125-4-8> 400.

As will be appreciated, the CY-A / X-III generating medium may contain, in addition to the aforementioned one or a number of components, for example, low mole alcohols, wt. and / or water, as an agent for modifying the solvent crystallization properties. A particularly suitable CY-A / X-III-forming medium was found to be a medium containing about 0.5 parts by volume of ethanol, about 8.0 parts by volume of polyethylene glycol (300], and about 3.0 parts by volume of water, The method according to the invention first of all includes dissolving cyclosporin, for example in amorphous or tetragonal form, in the chosen CY-A / X-III forming medium at an elevated temperature, the dissolution temperature will of course vary depending on the selected special medium but will generally be> 40 ° C, in particular> 5 ° C. In the case of media based on polyethylene glycol, the dissolution temperature will generally be> 7 ° C, for example about 75-330 ° C. Suitably, the solution obtained will be> 5%, preferably> 30%, for example up to about 4CL-6Q%, preferably up to a maximum of 20% by weight, 20 Ciclosporin, based on the total weight of the solution. It is then possible to crystallize Ciclosporin: under cooling, sc hiccups for a relatively long period of time, for example of the order of 30-35 min or more, depending on the desired crystal growth.

If desired, methods of nucleation can be used, for example, by using sound waves or grafting. If ethanol-polyethylene glycol-water crystallizing media are used, for example as described above, it has been found, for example, that nucleation can be easily initiated at temperatures of about 60-90 ° C, for example about 65-85 ° C, by using of sonic vibration at about 20,000 cpc As will be explained in Example 2 below, continuing the treatment with sound waves in this manner during the crystallization process yields 35 microcrystals of a very small and relatively constant particle size.

The rate of crystal growth and the size of the crystals obtained will, of course, depend on the particular medium chosen and the conditions under which the crystallization is carried out, 8803,125.

t - 9 - for example whether or not treatment with sound waves is applied and if so with what frequency. For use according to the present invention, for example for the preparation of galenic preparations, as described above, CY-A / X-III will preferably be used in a fine particle form, for example with an average particle size of <20öpM, for example of 0.5 up to 200μΜ. Although the crystals initially obtained are of relatively large size, particulate preparations of the desired size can, of course, be obtained by conventional crushing methods, for example, by grinding, crushing, pulverizing, micronizing or otherwise breaking down to a smaller size. size. Although particulate preparations obtained in this way may be perfectly suitable for some purposes, for example, for the preparation of preparations for topical application to the skin, the use of crushing or grinding methods or corresponding techniques is in many cases not recommended, The reason being is that the products obtained by these methods tend to exhibit a relatively large particle size distribution and have a relatively coarse or worn structure due to crystal breakage. In addition, the comminution may result in the physical properties and the natural crystal surface being nullified and in any case it is difficult or expensive to perform while meeting the required sterility conditions, for example, to prepare galenic preparations for administration through the joints. For these reasons, it is usually recommended to practice the process of the invention in such a manner that crystals, for example, microcrystals with cross-links within the desired final particle size range, are obtained.

Thus, for use in the preparation of, for example, preparations for administration through the joints or according to another patrental administration, the use of CY-A / X-III particle preparations in an unmixed, microcrystalline state (ie 55 CY-A / X-III microcrystals in a native or undamaged state, for example, which have not been subjected to crushing, grinding, micronizing or other crushing methods, are recommended.

To obtain CY-A / X-III microcrystals that are directly in a non-crushed state in the manner described above 8003125.

4-10, the process according to the invention will be suitably agitated, for example by stirring, for example at 200-300 rpm, increasing to, for example, 700 rpm. during the crystallization and in particular by the use of ultrasonic vibration, for example in the range of 100,000 cycles per second, suitably of the order of about 20,000 cycles per second.

By varying the CY-A / X-III forming medium and adjusting the cooling rate and degree of movement during the recrystallization JQ process according to the prior art :; Known methods, as will be explained below, CY-A / X-III microcrystals of varying mean particle size can be obtained, for example, those listed above or described below for use in connection with individual types of galenic formulation according to the invention.

As mentioned above, the crystallization according to the process of the invention will suitably be stirred under sterile conditions. Purification of the obtained CY-A / X-lIt can be done in the usual manner, for example by rinsing with polyethylene glycol (3001: water, for example in a ratio of 3 - 4: J ppw / washing with warm water, as in the examples) The obtained CY-A / X will suitably be recovered without or almost without Ciclosporin in any other form, preferably in a pure or almost pure form. The rinsing step described above promotes the prevention of the formation of amorphous Ciclosporin,

According to the foregoing, the present invention additionally provides: Ciclosporin formed by one of the methods described above, as well as; 3 2 3-3 A CY-A / X-III 'according to A - A above, without or almost without Ciclosporin in another form, for example without or almost without Ciclosporin in amorphous form, CY-A / XI or of CY-A / X-II, 4 3 A CY-A / X-HI according to A - A above in pure or almost pure form,

- c ζ A

A CY-A / X-III according to A - A above, in fine particle form, for example with a particle size as described above * or will be described hereinafter, for example in connection with galenic forms containing CY-A / X-III .6 5 A CY-A / X-III according to A - A above, mainly, entirely 8803125.

ί - η - or almost entirely containing a non-crushed crystalline material, for example CY-A / X-IIÏ according to A above, wherein the particles are predominantly, wholly or almost wholly, non-crushed microcrystals, and 5 CY-A / X III according to A - A ^ above, in a sterile or almost sterile state, for example a state suitable for pharmaceutical application, which is particularly suitable for parenteral administration, for example by parenteral injection, for example by injection into a joint, 10 the present invention also provides: C A pharmaceutical composition which contains a) Ciclosporin in orthorhombic crystal form as active ingredient, together with optionally b] a pharmaceutically acceptable diluent or J5 carrier therefor,

Ciclosporin can be present in the compositions of the invention in any suitable orthorhombic crystal form, for example, as CY-A / X-II or CY-A / X-II. However, the use of CY-A / X-II will generally be less recommended, in view of its physicochemical properties, which are less suitable, in terms of both tolerance and utility, for the preparation or manufacture of effective Ciclosporin based pharmaceuticals. It is most recommendable if Ciclosporin is present in the compositions of the invention as CY-A / X-III, for example, according to A-A above.

Although Ciclosporin is present in solid (crystalline} form in the compositions of the invention, the compositions themselves may have any suitable constitution, so the compositions of the invention include solid forms such as capsules, tablets, dragons, powders, and granular products. semi-solid forms, such as ointments, gels, creams and pastes, as well as liquid forms, for example the defined cyclosporin component in a fine particulate form (for example, micronized or in a microparticulate form, suspended or dispersed in a liquid, pharmaceutical diluent or carrier, in which the chosen crystal form can be retained.

Preparations according to the invention include both systems containing a single Ciclosporin-containing phase or Bd 03ΤΤ $ ^ '^ for simple creams, gels, ointments, etc - J2 - as mentioned above, or simple one-compartment Capsules or ampoules, for example hard or soft gelatin "capsules or ampoules for injection purposes, as systems with a number of phases or compartments. Thus, the invention includes, for example, 5 preparations comprising a Ciclosporin-containing phase or compartment together with one or a number of non-Ciclosporin-containing phases or compartments, for example, coating, carrier, retard, or placebo phases or phases or compartments containing other drug materials or adjuvant materials, Thus, for example, the invention includes coated tablets having a

Ciclosporin in an orthorhombic crystal form beyat surrounded by, for example, other coating shafts which do not contain Ciclosporin or corresponding coating phases, mantle tablets containing a core or shell with Ciclosporin in orthorhombic form and provided with a non-cyclosporin-containing shell or core, mixed granular tablets, which have a first granular phase containing cyclosporin in orthorhombic form and a second, non-cyclosporin heathing granular phase, and split capsules with two or more compartments, for example, which are divided 2Q with an inner wall, one of which comprises cyclosporin in orthorhombic form and the other, not, other alternatives and variants will be apparent to those skilled in the art.

Preferably, the Ciclosporin in the compositions according to the invention will predominantly, preferably wholly or almost wholly, be present in the orthorhombic crystal form, for instance as CT-A / X-Iir,

The compositions of the invention suitably contain at least one phase or compartment containing cyclosporin in orthorhombic crystal form, for example CY-A / X-III, in which this crystal form is or can be uniformly divided. Such systems include, for example, homogeneous creams, ointments, gels, etc., as well as liquid systems in which the crystalline Ciclosporin present is or is easy. can be divided, for example, by hand shaking. Among compositions of the invention, there may be forms suitable for topical application, for example, administration to the skin or topically to the eye, for parenteral administration, for example, by infusion or injection, including sub-cutaneous or intramuscular injection, and, in particular, by injecting 8803 125.i - 13 - into injuries or joints, as well as forms for enteral administration, for example suppositories, pessaries, etc. and oral dosage forms. However, enteral forms, for example oral dosage forms, are generally less recommended.

5 It is recommended that orthorhombic crystalline

Ciclosporin, for example CY-A / X-III, in the compositions of the invention will be present in a fine particulate form, for example, in a micronized, microparticulate or non-comminuted microcrystalline form, as described above. The appropriate particle size will, of course, vary depending on the special nature of the composition, its intended use and the mode of administration and the desired effect. In general, however, the average particle size will suitably be of the order of 0.5-200 µM. Special ranges, for example, in connection with the preparation of oral, topical or injectable forms will be discussed below.

Topically applicable forms, for example, for dermal or topical ophthalmic administration, for example, for the treatment of psoriasis or atopic dermatosis or of diseases or conditions of the eyes requiring immunosuppressive therapy, for example uveitis, conjunctivitis, including keratoconjunctivitu sicca or vernal keratoconjunctivitis or cornea transplants, gels, creams, ointments, etc., for topical or dermal administration, can be prepared by any of the known methods well known in the art, for example, by processing cyclosporine in orthorhombic crystal form with a suitable liquid base material, for example, aqueous gel, for example, an aqueous cellulose ether-based gel, with the addition of suitable surfactants, thickeners, etc., including, for example, aerosil.

The Ciclosporin component is preferably present in a fine particle form, for example, with an average particle size of Q, 5-200 µM. Preferably the average particle size is <60-8QuM, more recommendable <40pM, even more recommendable <30μΜ and most recommendable <2QpM. It is favorable if the particles have the most narrow distribution of the particle size. It is recommended that almost all particles present 8803125.

4 - 14 - less than 60-80pM.

For example, compositions of the invention for topical ophthalmic use, ie, administration to the eye, may be suitably thickened suspensions or dispersions, which are, for example, in the form of viscous eye drop preparations or creams or gels for administration to the eye. In the case of preparations to be administered to an eye, the average particle size of the crystalline Ciclosporin material present will suitably be <25pM. It is even more recommendable if JO all particles present are less than 25 µM. The average particle size for such eye drop formulations will suitably be from about 0.1, preferably from about 0.5, to about 20 µM, or preferably about JOpM.

The hydrophilic-lipophilic content of the carrier system used in forms for dermal application or for use in compositions for ocular administration may vary, for example, depending on the special surface to which the preparation is to be administered, for example depending on the properties of the particular skin surface to be treated, Preparations for topical, in particular dermal, use will suitably contain a carrier medium in which the active ingredient (Ciclosporin ingredient) is only slightly soluble. Suitably, the solubility of the Ciclosporin component (e.g. CY-A / X-III). in such preparations 25 <10%, preferably <1.0% (wt). It is more recommendable if the solubility is <0.1% wt% and most recommendable if it is <0.0.01 wt%,

Suitable carrier media include hydrophilic water-miscible carriers, as well as hydrophobic carriers. Hydrophilic water-miscible carrier components suitably have relatively low volatility. Examples of suitable carrier constituents belonging to this class are, for example, liquid polyalkylene glycols, propylene glycol, glycerol and ethylene glycol. Suitable polyalkylene glycols are in particular liquid polyethylene glycols, for example, with an average mole weight, up to about 6Q, for example with an average mole weight, from about 250 to 45Q, especially from about 3Q0,

Representative compositions of the invention, for example for topical administration, therefore include: 40 C-a-Ciclosporin in orthorhombic, preferably non-8803125.

- 15 - solvated orthorhombic crystal form, for example Cy-A / X-III, as defined under one of the designations A - above, b} a hydrophilic, water-miscible carrier, for example 5 as described above, and, if desired, c) pharmaceutical grade water.

The amount of component present (al will suitably on the order of about 0.1 to about 30.0%, in particular from about 0.5 or 1.0 to 20%, for example about 1.0, 2.0, 20 5.0 or 10, Q%, based on the total weight of the preparation. The ingredients (bl and (cl) will suitably be present in the ratio of 1: 0 to J: 2Q ppw, It is even more convenient if the constituents (bl and (cl in a ratio of 1: Q, 5 to 1: 5, e.g. from J; 1 to 1: 3, most suitably between 1: 1.5, 25 to 1: 2.5 ppw, are present .

Such preparations will suitably additionally contain: dl A surfactant,

Suitable ingredients (d] include d1. Transvertals of natural vegetable oil triglycerides and polyalkylene polyols. Such transesterification products are known in the art and can be obtained, for example, by the general methods described in U.S. Pat. No. 3,288,824. of various natural vegetable oils (eg, not hydrated) 1, for example corn oil, core oil, almond oil, ground nut oil, olive oil and palm oil and mixtures thereof with polyethylene glycols, in particular polyethylene glycols with an average mol, wt. of 200 - 800, Recommendation deserve products obtained by trans-esterifying 2 moles parts of a natural vegetable oil triglyceride with 1 moles part polyethylene glycol (for example, with an average mole wt., From 2Q0 - 80QJ, Many forms of the trans-esterification products of the gedef Initiated class are known and commercially available under the trademark Labrafil / see 35 Fiedler, "Lexikon der Hilfs-toffe", 2nd revised and expanded edition (J98Ji, Vol, 2, p. 539 ^ 7 9), particularly useful as constituents of the compositions According to the invention the products are: Labrafil M 1944 CS, a transesterification product of core kernel oil and polyethylene glycol with an acid number of about 2, an insurance number 8803125 - 16 - of 145 - 175 and a Jew number of 60 - 90, Labrafil M 2130 CS, a transesterification product of a glyceride with 12-18 carbon atoms and polyethylene glycol with a melting point of about 35 - 40 ° C, an acid number of <2, a saponification number of 5 about 185 - 200 and a Jew number of <3.

d2 Reaction products of the natural or hydrogenated recinus oil and ethylene oxide. Such products can be obtained in a known manner, for example by reaction of IQ a natural or hydrogenated castor oil with ethylene oxide, for example in a molar ratio of about 1:35 to about 1:60, if desired removing the polyethylene glycol component from the product, for example according to the methods described in German Auslegeschriften 1,182,388 and 1,518,819.] Especially suitable are the various surfactants, available under the trademark Cremophor, Particularly suitable are the products Cremophor RH 40 with a saponification number of about 50 - 60, an acid number <1, an iodine number <1.60 and a water content (Fischerl <2%, an nQ of approximately 1.453-1.4578 20 and an HLB of approximately 14 - 16, Cremophor RH60 with a saponification number of about 40 - 50, an acid number <1, an iodine number <1.25, a water content (Fischer) 4.5.- 5.5%, an n ^ of about 1.453-1.57 and an HLB of about 15 - 17, and Crem storage EL with a molecular weight.

(by steam osmometry) of about 1630, a saponification number of about 65-70, an acid number of about 2, an iodine value of about 28-32, and an n ^ of 1.471. Also suitable for use in this category are the various surfactants available under the trademark Nikkol, e.g. Nikkol HC0-60. The product Nikkol HC0-60 in question is a 3Q reaction product of hydrogenated castor oil and ethylene oxide with the following properties: acid number 0.3, saponification number 47.4, hydroxyl number 42.5, pH (5%) 4.6, color APHA = 40, melting point 36.0 ° C, freezing point: 32.4 ° C, water content (% KP) = 0.03.

3 d Polyoxyethylene sorbitan yet acid esters or polysorbates of, for example, the known type commercially available under, for example, the trademarks Tween and Armotan (see Fiedler, 2, pp. 745-746 and 972-975), including Tween.

8803 125.

- 17 - 20 / polyoxyethylene (20) sorbitan monolaurate_7, 40 / polyoxyethylene (20) sorbitan monopalmitrate_7, 60 / polyoxyethylene (20) sorbitan monostearate 7.65 / polyoxyethylene (20) sorbitan tristearate_7, 5 80 / polyoxyethylene (20) sorbitan, monooleate ethyl_7 sorbitan trioleate 7, 21 / polyoxyethylene (4) sorbitan monolaurate 7, 61 / polyoxyethylene (4) sorbitan monostearate 7 and 81 / polyoxyethylene (5) sorbitan monooleate.

4 d Polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters of the known type and commercially available under the trademark Myrj (see Fiedler, 2, p. 636), as well as known polyoxyethylene fatty acid esters commercially available] are under the trademark Cetiol HE ( see Fiedler, 1, p. 228) and polyoxyethylene higher alcobol ethers, eg polyoxyethylene stearyl ether, oleyl ether, or cetyl ether, for example of the type known under the trademark Brij (see Fiedler, 1, 184-186), e.g.

Brij 78 and 96 and Cetomacrogel 1000 (see Fiedler, 229).

20 d Polyoxyethylene-polyoxypropylene copolymers, for example of the known type and commercially available under the trademarks Pluronic and Emkalyx (see Fiedler, £, pp. 720-722.

Sorbitan fatty acid esters, for example of the known type and commercially available under the trademark Span, including, for example, sorbitan monolauryl, monopalmityl, monostearyl, tristearyl, monooleyl and trioleyl esters, see Fiedler, 2, pp. 850-851.

Partial glycerides, for example, products including mono- and / or di-glyceride components, For example, surfactants based on mixed mono / di- / tri-glyceride / free glycerol base, as well as glycerol monostearates and glycerol mono-oleates. Included among such products are those which are known and commercially available under the trademarks Imvitor (see Fiedler, J_, 491), e.g. Imvitor 191 and Imvitor 78Q <and Softigan (see Fiedler, 2, 833) e.g. Softigen 7QJ, 8803 125.

8 - 18 - d Ionic surfactants or emulsifiers, such as sodium lauryl sulfate and sodium cetostearyl sulfate.

If Ingredients (d) are present, it is suitable in an amount of up to a maximum of 30%, in particular a maximum of 15%, based on the total weight of the preparation. It is most suitable if the ingredients (d) are present in an amount of from about 0.5 to about 30%, for example about 1.0%, based on the total weight of the preparation.

Such preparations will suitably also contain:

I.Q

el A thickener,

Suitable ingredients (el include. For example, the polymethyl acrylate resins, for example, of the known type and commercially available under the trademark Eudispert (see Fiedler, 1, 373-3721).

2 nd Cellulose derivatives including, for example, ethyl, propyl, methyl, hydroxypropylmethyl and carhoxymethyl cellulose.

20 3 rd Polyethyl resins, including, for example, polyvinyl alcohols and polyyinylpyrrolidones, as well as other polymer materials, including gelatin, alginates, pectins, tragacanth gum, gum arabic, xanthan gum and polyacrylic acids, such as of the known type, commercially available under the trademark Carbopol (see Fiedler, 3, 206-2071, 4 e Materials, such as silica gel, hentonite and magnesium-aluminum silicate, 30

The compounds (el, if present, are suitably present in a quantity of up to 201, more particularly up to JQ%, based on the total weight of the composition. Most suitable are the ingredients (el, present in a quantity of approximately From 0.5 to about 35%, for example from about 3.0 to about 3.0%, based on the total weight of the composition,

In addition, such preparations may also suitably contain an anti-microhial agent, such as methyl parahen, propyl paraben, henzylalconium chloride or benzyl alcohol, for example, in an amount of 0.05 to 0.5%, or, in the case of benzyl alcohol, up to 2%. 0%, for example about 0.1%, or, in the case of benzyl alcohol, about 1.0%, based on the total weight of the preparation.

Alternative carrier media includes hydrophobic materials, for example, those that meet the solubility criteria of the above-described active ingredient. Consequently, other recommended preparations according to the invention, for example for topical application, contain a) Ciclosporin in an orthorhombic, preferably unsolvated orthorhombic, crystal form, for example Cy-A / X-III, as defined under one of the designations A - ά above, and f) A hydrophobic support, as mentioned above for example ^ 5,

The amount of component (a) present will suitably be an amount as mentioned above in connection with preparations as defined under. Suitable ingredients (fl include, for example, petroleum derivatives, including mineral oils, fats and jellies, such as, for example, petrolatum (mineral fat or petroleum jelly), liquid petrolatum (white mineral oil or liquid paraffin), or any of the known products commercially available are available under the trademark Vaseline (see Fiedler loc, cit. 2, 986J, eyenals nonionic derivatives on a lanolin basis, such as available under the tradename Amerchol, for example Amerchol CAB / Fiedler, J, J19 - J20_7,

Among other suitable ingredients (f). for example, natural or saturated vegetable oils and fats, for example fractionated coconut oils which are commercially available, are 5 ° under the trademark Miclyol, for example Miglyol 812 (see

Fiedler, 2, 616) and groundnut oil and saturated groundnut oils, as well as higher branched chain fatty acids or alcohols and higher esters such as stearic alcohol, cetyl palmitate and 2-octyl dodecanol, of the known type and commercially available under the trademark Eutanol G (see Fiedler, J ^, 375),

Such preparations may also contain one or a number of any of the above-described components (d) and (e), as well as one or a number of anti-microbial agents, for example as described herein, 8903 125 3 - 20 -

In particular, such. preparations in addition one or a number of constituents (dj, suitable in an amount of up to 30%, more in particular not more than 20%, suitable in an amount of about 3 to about 35% by weight, based on the total weight of the preparation.

2

Preparations on hydrophobic bases according to C containing an emulsifier component (dl) can also be obtained by further addition of water in the form of creams or emulsions. The resulting crimes or solutions can be of the oil-in-water JQ as well as water-in-oil type, The amount of water present in such preparations can thus vary, for example, from 5 to 80%, based on the total weight of the preparation, suitably from 20 to 70% by weight,

The amounts of constituents (el / antimicrobial, if J5 included) will be of the same or similar order as those associated with the compositions of the invention according to CJ above,

The amount of hay of each applied topical form will of course vary depending on the concentration of the 2Q preparation, the condition to be treated and the desired effect, as well as, in the case when applied to the skin, the surface to be treated,

In the case of compositions for dermal use, for example, to treat psoriasis or atopic dermatosis, the amounts used will generally be sufficient to provide a Cic.losporin dose of the order of about 0.3 to about 5mg / cm, for example, about Q , 5mg / cm, with the administration of, for example, twice a day in the desired place. In ophthalmic preparations, the administration can conveniently be done using preparations containing about Q., J to about JQ%, e.g., J, 0 or 2, Q wt% Ciclo-3Q sporine, 3 to 3 times daily in droplet form to each eye administered,

Inject herpes, hijoorheeld yoor suh-lcutane, intra-muscular or other parenteral injection, including in particular, • injection into the joints, for example to treat arthritic conditions, such as rheumatoid arthritis, or for injection into the injuries, for example to treat psoriasis.

Dispersions, suspensions, emulsions and corresponding preparations 8803 125.

Suitable for injection purposes may be by any of the known and well-known methods generally used in the art, for example, by dispersing, suspending or otherwise distributing Ciclosporin in fine, particulate, orthorhombic crystal form, in a suitable , liquid carrier medium, with the addition of suitable emulsifiers, surfactants, stabilizers or flocculants, etc., are prepared.

Preferably, the Ciclosporin component in such preparations has an average particle size of <10 PpM, more particularly JO <50 PM, most recommendably <20 PM. The average particle size will suitably be on the order of 0.5 or 0.5 to the indicated 20.50 or JOQpM maxima.

If injectable forms are intended, for example for sub-cutaneous or intramuscular injection, for example to obtain a depot effect, the use of a larger particle size is possible. If such forms are intended for administration in the injury, or, in particular, by injection into the joint, the use of fine particle preparations will be indicated. For such applications, a suitable average particle size is, for example, on the order of about 0.3 or about 0.5 to about 20 µM, for example about 5-15 µM.

To stabilize the particles in the injectable forms, for example, to avoid growth in size of the larger crystalline particles at the expense of the smaller particles, the particles will preferably be as uniform in size as possible. A suitable variation between the maximum and minimum particle size will not exceed about 50pM, in particular about 2QpM,

Although the desired particle size can be obtained by using suitable comminution methods, eg micronization, to minimize particle size variation, avoiding the presence of fragments of particles, avoiding modification of the crystal surface for example, in order to maintain the wetting properties and more easily meet the required sterility requirements, it will generally be recommended to use non-comminuted microcrystals, ie crystals grown to the desired required dimensions, as described above, 8803125.

- 22 -

Injectable preparations according to the invention thus suitably contain 3 C a) Ciclosporin, in a fine, particulate, orthorhombic, preferably non-solvate orthorhombic, crystalline form, eg CY-A / X-III, as defined, for example, under each 7 6 7 of the designations A to A, in particular A and A above, divided or subdivided into, b) an injectable carrier medium.

Suitable carrier media in particular include pharmaceutical grade water jO.

In addition, compositions as defined under 3 C suitably g) will contain a surfactant as a dispersing or emulsifying agent and / or a flocculating agent, to promote or maintain the distribution of the particles in the carrier phase.

Suitable surface-active ingredients (g) include polyoxyethylene sorbitan fatty acid esters or polysorbates, for example as mentioned under (d) above, for example Tween 80 or Polysorbate 80 (see Fiedler, 2, p. 746). 2Q suitable flocculants (g) include ethylenediaminetetraacetic acid.

tough and salts thereof, for example Calcium EDTA and Sodium EDTA, as well as other equivalent chelating agents and peptizing agents such as succinic or citric acid.

In order to maintain the particle size distribution, a stabilizing agent is also suitably included. Suitable stabilizers include, for example, gelatins or modified gelatins, such as the well-known plasma expander commercially available under the trademark Gelafundin and Haemaccel or cold water-soluble gelatins of highly purified 3Q collagen hydrolysation products, 3

The preparations according to C above can also contain one or a number of anti-microhial agents, for example as described above, as well as peptizing agents, such as succinic or citric acid, 3

35 The ratio of the components (al: (hl in the under C

defined preparations is suitably of the order of 1: 1Q to JJOOO, preferably of the order of J: 5Q to J; 200L, for example .3; J 00 p.p.w.

In order not to disturb the stability of the particles too much. Algae component (g) will present surface-active agents present, Preferably only present in low concentrations, for example of the order of 0.3 to 2.0%, suitably about 3.0% by weight, based on the weight of component (a). If a flocculant is present, the ratio of flocculant to constituent (already suitably on the order of 3: 3 to 3: 8 ppw, for example, about 3: 5 ppw. If a stabilizing agent is present, then the ratio of component (a) to stabilizing agent suitably of the order of 3.5 to J, 3Q, especially 3.30 to J: 3Q, J0, for example, about 3:20 pp2. If a peptizing agent is present, the ratio of peptizing agent to component is (all suitable from the order of J; J to JUO, heyoorheeld about J; J5 ppw,

The amount of Ciclosporin present in unit dosage forms J5 for injection purposes according to the invention will, of course, vary depending on, for example, the condition to be treated, the site of the injection and the desired effect, for example, whether a depot effect or a relatively rapid release is in the surrounding tissues. considered. Suitable individual unit dosage forms 2Q will contain about 10 to 500 mg, especially about 20 to 100 mg, of Ciclosporin / dose.

As will be appreciated, the unit dosage forms of the invention also include more complex systems, for example dual chamber syringes or injection cylinders in which the particulate cyclosporin together with other suitable ingredients, for example stabilizer or antimicrobial agent, in a first chamber and the carrier medium a second chamber is provided in which the components of the two chambers are mixed, for example after actuation of the plunger of the syringe. Such double chamber injection systems are known in the art and unit dosage forms containing them are within the scope of the present invention,

Oral dosage forms, for example, to treat autoimmune and other diseases and the aforementioned conditions, for example, to prevent transplant rejection.

Although, as mentioned above, oral dosage 8803 125. ' Forms of the present invention are generally of less importance and are thus less recommended, such forms nevertheless fall within the scope of the invention.

Oral dosage forms of the invention can be obtained using any known suitable carrier or carrier medium used in the prior art. Liquid or semi-solid oral dosage forms may contain, for example, cyclosporin in an orthorhombic crystal form, for example as CY-A / X-III, together with pharmaceutically acceptable diluents or carriers in which the crystal form itself is insoluble or substantially insoluble. Such carriers or diluents are, for example, transesterification products of natural vegetable oil triglycerides and polyalkylene polyols, as described above under (d ^), for example Lahrafils, as well as reaction products of natural J5 or hydrogenated recinus oil and ethylene oxide, as described above under (dJ, in the particularly liquid Cremophore products, for example Cremophore EL,

The Ciclosporin is preferably present in fine particle form, for example, with an average particle size of 0.5 - 200 µM, 2Q in particular of the order of, for example, 0.5 - 30 µM, preferably less than 20 µ, for example of Q, 5 - JQpM,

To facilitate administration, the aforementioned compositions will conveniently be placed in hard or soft gelatin capsules.

The unit dosage forms of the invention for oral administration suitably contain about 25 to about 75 or up to 2QQ, for example about 50 or 30Q mg of Ciclosporin per unit dose. For example, such forms are administered J up to 4 times daily to obtain serum cyclosporin concentrations in individual patients (e.g., determined according to RIAl of the same or similar order as those obtained using a conventional cyclosporin therapy, e.g., using available cyclosporin oral solution. ,

The ingredients listed or defined herein as ingredients of the pharmaceutical compositions of the invention will, of course, be suitable for the desired pharmaceutical application, for example, in the case of ingredients of compositions for oral administration, are pharmaceutically acceptable, or, in the case of ingredients of preparations for topical administration, 8903125.

- be locally, for example, dermal or occular, applicable, acceptable or tolerable.

Other galenic forms for administration by equivalent or other swipes than those described above will be apparent to one skilled in the art.

Example 1

Preparation of Cy-A / X-III

A) 100 g of Ciclosporin in amorphous form were dissolved with stirring at 50 ° C in 400 g of polyethylene glycol 300. The formation of CY-A / X-III started shortly after everything had dissolved. The solution was left at about 35-40 ° C for 24-48 hours to complete the crystallization and then diluted with 1000 ml of water with vigorous stirring. The resulting precipitate was filtered off, washed with water to remove residual polyethylene glycol and dried, yielding CY-A / X-III in a nearly pure form with a melting point of 195 ° C, particle size about 100-200 µM.

CY-A / X-III forms can be obtained analogously to the above-described process, but using the following materials as a solvent instead of polyethylene glycol 300,

Solvent Melting point of the obtained 25 __ CY-A / X-III C ° C) _ b) Polyethylene glycol 300 /

Cremophore RH 40 (3: 3 vol} c) Cremophore EL 390 3Q d) Solutol HS 35 388 e) Gelucire 44/34 380 fi Myrj 52 384 µl Tween 8Q 386 h). Cremophor RH40 390 35

Each time, the average particle size obtained is of the order of about 50 to about 200 µM. The Certain lattice structure is that described above. The X-ray diffraction values are those mentioned below in connection with Table III and Figure IV, 8803125.

- 26 -

Example 2:

Preparation of CY-A- / X-III,

20 g of Ciclosporin as CY-A / X-I were dissolved in 60 ml of ethanol and this solution was concentrated by distillation under reduced pressure at a temperature of>. 60 C to 1/6 of the original volume. Then, slowly, at 50 - 85 ° C and with stirring with 300 rpm ^ 160 ml of polyethylene glycol (MW 300} + 20 ml of water) was added. An ultrasonic vibrator mixer was installed, operating at 20,000 cpc, Nuclei formation was initiated for 3-5 min, at 65-75 ° C. The resulting dispersion was then linearly cooled for 10-20 min, to 40 C, continuously at 700 rpm, and ultrasonication stirred. The resulting thick, paste-like mixture was filtered, rinsed with polyethylene glycol (MW 300) water (3: 1, pp. vol. J, washed with warm water at 30 ° C and under high vacuum at 50 ° C dried, whereby CY-A / X-IIII was obtained in pure form with a melting point of 192 ° C. The particle size was 3 - 15 µM. The determined lattice structure was that defined above 20. The X-ray diffraction values are those are described below in Table III and Figure IV,

Repeated tests show that the crystal size is influenced by the nucleation temperature and the rate of crystal growth over the duration of the process. Thus, by starting nucleation at about 75 ° C and allowing crystallization to proceed at the same temperature, an average particle size of about 50 µM is obtained.

Example 3; 3Q Preparation of a galenic form for oral administration, 3.1 Gelatin-encapsulated preparations I.

A slurry containing 20 wt% Cy-A / X-III obtained by the methods of Example 1 in Gelucire 44/14 was ground at an elevated temperature using a colloidal grinder until the mean particle size of Cy ^ A / X- ΧΐΓ 'is on the order of 0.5 - 10 µM. 250 mg aliquots of the obtained ground suspension were introduced into hard gelatin capsules of size 2, 88 03 125. * - 27 - each containing 50 mg of Ciclosporin (as Cy-A / X-III as active ingredient.

3.2 Gelatin encapsulated formulation II, 5

CY-A / X-III obtained according to the methods of Example J was milled in a colloidal grinder until the average particle size of CY-A / X-III was of the order of 0.5-20 µm.

50 mg portions were then intimately mixed with 200 mg of Cremophore EL and placed in hard gelatin capsules of size 2, each containing 50 mg of Ciclosporin (as CY-A / X-III) as the active ingredient.

Example 4: 15 Beer preparation of galenic forms for topical application.

4.1 Gel preparation I

Cy-A / X-III was micronized according to the methods of Example J using an air-driven grinder. The micronized product with a maximum particle size of 60 - 70 µm and an average particle size of 2 - 10 µM was conventionally combined and mixed with the ingredients listed in the following tahel, yielding an aqueous gel containing J0 wt% Ciclosporin (as Cy-A / X-III) has been obtained which is suitable for topical application, for example for the treatment of psoriasis,

Ingredient Wt% 3Q a) CICLOSPORIN ^ micronized

Cy-A / X-IIl) 10.0 b] Polyacrylic acid (Carbopol 934P] 0.5 c) NaOH solution (5%) 3.0 dl Methylparaben 0.0.7 35 tbsp Propylparaben Q, Q3 fl H2O (pharmaceutical grade) up to J00, Q% 88031257 - 28 -

4.2 Gel preparation II

Components Wt,%

Preparation A Preparation B 5 a) CICLOSPORINE (micronized Cy-A / X-111) 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 10 e) Sodium hydroxide 5% 6.0 6.0 f) Methyl paraben 0.07 0.07 g) Propyl paraben 0.03 0.03 h) H2 O (pg) 51.9 60.9 15 100.0% 100.0% a) was prepared in the manner described above for 4.1. C), f) and g) were dissolved under heating in b) and the resulting mixture was cooled to room temperature. This solution was then dispersed in water h). Mene ^ added d) and homogenized the whole to effect dispersion. Then a) was added. and homogenized the mixture again. Finally, e) was added to neutralize, with stirring, and the resulting gel was placed in compressible tubes for topical use, for example to treat psoriasis.

4.3 Self-preparation

Components Wt%

3Q Preparation A Preparation B

aï CICLOSPORINE (micronized

Cy-A / X-III) 1.0 10.0 b) Amerchol CAB 2.0 2.0 35 cl Liquid paraffin 42.0 37.5 dj White petrolatum 55.0 50.5 100.0% 100.0 % 8803125.

- 29 - a) was prepared as for 4.1 above. B), c) and d) were melted together and stirred and added at about 30 ° C a), distributing the particles using a homogenizer.

The resulting ointment was cooled and placed in compressible tubes for topical application, for example to treat psoriasis.

4.4 Cream preparation 10 Components Wt% a} CICLOSPORINE (micronized

Cy-A / X-III} 1.0 b) Polysorbate 60 5.0 J5 c) Cetylstearyl alcohol 30.0 dl Glycerol 85% 10.0 tb White petrolatum 24.0 fl Methylparaben 0.07 g Propylparaben 0.03 20 hl H20 (pg1 45.0 J00.0%

A) was prepared as described above for 4.1, combined with the components b) -hl, analogous to 4.3 above, and this mixture was placed in compressible tubes for topical application, for example for the treatment of psoriasis, 4.5. an ointment,

3Q A suspension containing 2Q wt.% Cy-A / X-III was ground

(obtained according to the procedures of Example 11 in polyethylene glycol 3QQ in the wet state until the average particle size of Cy-A / X-III was on the order of 2 - 10 µM, then 10 g of the crushed product obtained were mixed in a conventional manner with 5Q g of polyethylene glycol 300 and 40 g of molten polyethylene glycol 150.0., thereby obtaining a liquid paste containing 10 wt% Ciclosporin (as Cy-A / X-XII and suitable for topical application, for example, to treat psoriasis, 8903 125.

- 30 - 4.6. Gel preparation

Components Wt% 5 al CICLOSPORINE (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 10 (Methocel E4M) 2.5 f) H 2 O (pg) 64.5 100.0% 15 A) was prepared in the manner described above for 4.1.

B), c) and d) were mixed, f) was added and mixed. Then a) was suspended in the resulting mixture by homogenization. Then e) was added slowly with stirring until the formation of the gel was completed. The gel was then placed in compressible 2Q tubes for topical application, for example to treat psoriasis.

4.7 Gel preparation 25 Components Wt% a) CICLOSPORIN (micronized CT-A / X-IIIl 5.0 b). Polyethylene glycol 3Q0 30.0 c} Glyceryl monos tearate 5.0 30 dl Methylparahen Q, Q7 and Propylparaben 0.03 fl Carhopol 934 P 1.0

g). Sodium hydroxide 5% 6, Q

ill 1 ^ 0 (p, g. L. 52.9 35 300.0%

Preparations were already carried out according to 4.1 above. Cl, d) and el were dissolved in 61 with heating. The warm mixture was dispersed and cooled to room temperature by homogenization. Then 88 03 125 ^ -31-a) and f) were added and the whole mixture was homogenized. Then g) was added and the formation of the gel completed.

The gel obtained was placed in compressible tubes for topical application, for example to treat psoriasis.

5 4.8 Cream preparation (water in oil)

Components Wt,% 10 a) CICLOSPORINE (micronized CY-A / X-IIIl 2.0 b) Amerchol CAB 5.0 cj Miglyol 812 10.0 dl White petrolatum 53.0 tb H20 (pg) 30.0 15 _ 100 .0%

Preparations were made as 4.1 above and dispersed with b} in el, with heating and homogenization. Cl and d} 20 were melted together, mixed and the mixture was added with intensive homogenization to the previously obtained dispersion and then the whole was added off, whereby a fat-like, white cream was obtained,

This was placed in compressible tubes for topical application, for example for the treatment of psoriasis, 4.9 Gel-cream preparations

Examples 4.3 to 4.8 were repeated above, but now the crystalline product of Example 2 was added directly as CICLOSPORINE 30 component.

Example 5; 5J Injectable form, for example for parenteral administration.

A Cy-A / X-III suspension was prepared according to conventional methods under sterile conditions and the following ingredients were used; 8803125.

- 32 -

Component Wt% al CICLOSPORIN (CY-A / X-III) 20.0 b) Polysorbate 80 4.0 5 c) Sodium carboxymethylcellulose 5.0 parts NaCl 9.0 parts Benzyl alcohol 9.0 £} H ^ O (injection quality) up to a final volume of 1.0 ml. The release properties of the active ingredient from the obtained preparation depend on the average particle size of ingredient a). Thus, if an operation for longer periods of time is desired, a Cy-A / X-III product with a large average particle size (eg 100-200 µM such as can be obtained directly by the methods of Example 1) will be selected. If the operation is desired for relatively short periods of time, a Cy-A / X-III product with a relatively small: average particle size (e.g. obtained by micronizing or grinding a product according to example 1, for example up to a particle size of 0, 5-10 µM) are selected. The suspension is administered in injection ampoules for parenteral administration or injection into the lesions in the treatment of psoriasis, for example to obtain a depot effect.

According to a specially recommended recommended embodiment, the process is performed using CY-A / X-III obtained according to Example 2 described above, which has a particle size of 5-15 µM and is prepared under sterile conditions.

5.2 Injection hair forms, for example for injection into the joints,

Injectable forms suitable for administration through the joints were prepared using the following ingredients: Readiness, 8803125.

- 33 -

Ingredient Wt%

Preparation A

5 al CICLOSPORIN (CY-A / X-III) 10.0 b) Sodium carboxymethyl cellulose 10.0 cl Na EDTA 2.0 d) H ^ O (injection quality) to a final volume of 1.0 ml

10 Preparation B

a) CICLOSPORIN (CY-A / X-III) 10.0 b) Polysorbate 80 0.1 c) Citric acid 2.0 d) ^ 0 (injection quality) to a final volume of 1.0

Formulation was carried out under sterile conditions according to standard methods. Component (a) consisted of non-comminuted microcrystals obtained under sterile conditions according to the methods of Example 2 and having a particle size of 3-J5 µM. The resulting preparations were returned to sterile conditions in ampoules for injection purposes, for example, for injection into joints for the treatment of rheumatoid arthritis.

The favorable properties of the preparations according to the invention can be demonstrated both in animal test models and in the hospital. For example, the particular utility of the compositions which the invention intended for dermal administration, for example, to treat psoriasis or dermatosis, can be demonstrated by means of the following research model.

Allergic contact dermatitls in a guinea pig (DTH trial1, 55 guinea pigs (Hartley, 40Q-500 were sensitized by administering 50 µl 2% dinitrofluorobenzene (DNFB) in a mixture of equal parts acetone and olive oil on the inside of the right ear The animals were treated again with 2Q yl of a 0.5% solution of DNFB in a mixture of 8803125 7 days later.

- 34 - Acetone and Olive Oil (4: 1) applied to marked surfaces of the shaved left and right flanks. This second challenge induced all kinds of inflammation leading to reddening and cell infiltration (thickening) of the skin. The preparation to be tested, in an amount of 200-250 mg, was applied to the DNFB-treated surface of the right flank with a spatula. The left flank was similarly treated with a placebo as a control. Application of the preparation / placebo to be tested was carried out 5x at 20 min intervals, 8 hours, 24 hours, 32 hours and 48 hours after challenge. The thickness of the skin at the application site was determined before each application and again 8 hours after the last application, by drawing the skin up to a fold and measuring its thickness. The degree of reddening or inflammation was also visually Determined on a scale of 0-4. The effectiveness of the test composition for inhibiting the inflammatory response was determined by comparison with the results obtained on the placebo-treated flanks.

The results obtained in the above-described Study Model 2Q using preparations according to Examples 4.1 and 4.5 above, but containing 0.1% by weight of Ciclosporin as CY-A / X-III, compared with a placebo and with topically administered 0 1% Ciclosporin were obtained in a conventional oral solution form, are shown in Figures I, II and III pertaining to the present application. 0.1% CY-A / X- was used. III concentration in this research model with a view to its extreme sensitivity. The preparations to be tested were prepared entirely analogous to Examples 4.1 and 4.5, except for the reduction of the cyclosporin component to 0.1 g and 3Q compensation by addition of% 9. g water in the case of example 4.1 and polyethylene glycol components in the case of example 4.5).

In each figure, the measured skin thickness is plotted over time. In Figure 1, the results are using 0.1 wt% Ciclosporin in the wafer form of a conventional commercially available oral, drinkable, dissolved form compared to placebo. A slight but insignificant reduction in response to placebo was experienced for the oral solution. In Figs. II and III, the results using 8803125 / -35 - of 0.1 wt% Ciclosporin containing preparations according to Examples 4.1 and 4.5, respectively, were compared with the placebo. In both cases, a significant reduction in thickening of the skin compared to the placebo obtained after the first administration and subsequent treatment was compared to the placebo after the first application and continued until the experiment was ended.

The utility of the compositions of the present invention can also be demonstrated by clinical studies, which have been performed, for example, as follows:

Clinical trial: Treatment of psoriasis by topical (dermalel treatment.

The study was conducted in a randomized, J5 using a placebo, compared, double-blind fashion. Each patient simultaneously received the active preparation and the placebo (carrier only) on two symmetrical lesions. The use of the active and placebo preparations was randomized on the left and right injuries.

2Q Selected patients were enrolled in groups of 12 to 24 patients, aged 18 to 70 years, including men and women who were postmenopausal, surgically sterile, or using oral contraceptives with a negative pregnancy test.

The criteria for adoption include: a) a written consent and b) clinically defined, stable chronic plaque psoriasis. At least two moderately to severely, bilaterally symmetrical, 2 lesions, each with an area of 4 to 25 cm and a severity rating of> 5; on a scale of 0-9 were present, 30 This rating is a summary of individual ratings from 0 (least severe] to 3 (most severe) for each of the 3 parameters; erythema, painting and skin thickness, The lesions on both sides should be be similar in the same patient (ie * have a difference of more than 20% in the severity of the assessment or surface),

The following exclusion criteria were applied; aI Any medical condition that, according to the investigator, could prejudice the study,. b) Systemic psoriasis therapy, 88 03 12 5 - 36 - (PUVA, methotrexate, steroids, retinoids, cyclosporine) within the last two months.

cl Specific topical treatment, except for indifferent products (eg white vasaline) or preparations containing salicylic acid 5 (not more than 10%) for injuries selected for the study, within the last 2 weeks before the start of the study. However, these emollients may be applied to injuries not selected for the study, d) Patients whose posriasis appears to be spontaneously improving, emerging rapidly without treatment, or recurring after cessation of therapy, e known hypersensitivity for each of the constituents of the drug to be investigated, patients who are unwilling to cooperate and who are unlikely to follow medical prescriptions and patients who are unwilling or unable to attend visits regularly.

gl Treatment with a medicine to be investigated within one month before the registration of the study.

2Q hl A serious associated disease, especially renal dysfunction with serum creatinine above 33Q pMol /., I) Hypertension (diastolic ED> 95mm Hg after 5 min, sitting) Patients with drug-controlled hypertension were treated included in the study, ji Malignancy or a history of malignancy, including skin cancer, kl Acute hacterial, viral, or fungi-associated skin lesions, 3Q II Pregnancy, lactation, ml Patients with a history of alcoholism, drug abuse, psychosis, or emotional or intellectual problems .

n_l Patients in need of continuous, concomitant therapy with other immunosuppressive chemotherapeutic agents, compounds with a nephrotoxic potential (eg aminoglycosidesl and drugs known to affect the pharmacokinetics of Ciclosporin (ketoconazole, erythromycin, phenytoin, phenobarbitone, rifamp) INH, carbamazepine, sodium valproate, 8803125.

- 37 - ol Patients with abnormal laboratory baseline values> 15% outside the normal limits of the research laboratory.

p) Patients with clinically significant physical examination results.

The preparations involved in the study are those according to one of Examples 4.1 to 4.9 described above, for example the JZ-like preparation B of example 4.2 or the 10% -like preparation B of example 4.3.

Each patient received a pair of 20 g coded JO tubes with a 2-panel label. The label is blue for the material to be delivered on the right side and red for the left side. In addition, the side to be treated, left or right, study code, investigator name, patient number, and date of first treatment is written on each panel of label 15. The panel to be deducted from the label is attached to the survey form.

Treatment with the preparation to be examined was carried out twice a day, morning and evening, the amount used depending on the size of the injury, to obtain a daily Ciclosporin dose of 0.2 to 2.0 mg 2.

Ciclosporin / cm, for example in a series of experiments about 2 0.5 mg Ciclosporin / cm. The placebo was used in a similar amount. Neither the preparation to be tested nor the placebo were applied to a surface of the body> 25 cm and no more than 1 g of Ciclosporin was administered per week.

At each clinical visit, the drug-placebo tubes were weighed and the topical daily dose determined. Patients were allowed to bathe shortly before applying the medication.

Disposable gloves were put on and changed when applying each test composition and placebo to avoid cross contamination. At least 3 hours were allowed to pass between application and washing of the treated surfaces. Initial administration was monitored and a patient instruction form was provided.

The duration of the treatment was 4 weeks. If a complete healing of the lesions occurred earlier, treatment was continued until week 4. Patients were examined prior to the start of the L study (week-I), at the start of the trial (week 0], and after 1, 2 , 3 and 4 weeks.

8803125.

- 38 -

The dermatological assessment (local psoriasis index or LPSI) was performed by the same investigator who was not involved in the medication, using the following numerical scale of 0-3.5

Erythema Flaking Skin thickness 0 - none 0 = none 0 = none 10 1 = Minimal 3 = Minimal 1 = Minimal difficult to difficult to hardly show true erythema; defining to perceive elevation very light pink flakes 15 2 = Moderate 2 = Moderate 2 = Moderate dark red that can be well defined and clearly distinguishable sub-flakes that can be observed begin to accumulate elevation 20 3 = Severe 3 = Severe 3 = Severe deep / clear well defined large elevation of red flakes that accumulate compactly 25 The total LPSI range = value of the erythema plus the flaking plus the thickness of 0-9 was assessed. To be included in the study, at least 2 aspects must be moderate to severe for both injuries chosen (LPSI> 5).

At the beginning and at each clinical visit, the area of the treated lesions was assessed (Initial size: 4 to 25 cm for each plaque). The examination of the surface relates to the presence of one or some of the three criteria erythema, flaking and thickening, Pigmentation in the injured surface is not included in the Surface contemplation, 35 The plaques are shown by photos for ( week -1) and recorded after the procedure (week 41. Three photos were taken, one of both injuries combined and one for each injury.

Pruritus was assessed by an interview of the patients, using the following scale:

ÖS03125 J

- 39 - 0 = none 1 * minimal: sometimes tendency to scratch 2 moderate: urge to scratch often 3 = severe: urge to scratch very often, possible sleep disturbances.

At the end of the study, a global assessment of the response to therapy according to the following criteria was made: - healing ~ 1QQ% disappearance.

30 - marked improvement = at least 66% reduction in LPSI and / or at least 66% reduction in plaque area.

- moderate improvement: between 65 and 35% reduction in LPSI and / or between 65% and 33% reduction in surface with plaque - poor: less than 32% reduction in LPSI and / or less than J5 32% reduction in surface with plaque, - Even worse: worsening of the disease.

Therapeutic success is defined as any injury that has been "cleared" or healed or that has shown a marked improvement.

The physician and patient also indicate their preference for the medication on the left or right side according to the following criteria:. the left side is clearly better, 25. the left side is slightly better,. no difference can be observed,. the right side is slightly better and. the right side is clearly better.

In order to investigate the efficacy at the end of treatment, the LPSI values of the patients and the surfaces of the lesions were compared using the WILCOXON-Sign Rank test for paired treatments between Ciclosporin-treated and placebo-treated sites. compared the change from baseline assessment to after 4 weeks of treatment, 35 All further comparisons (at other time points and for the other efficacy parameters), including the p-values attached, were taken as a description of the grade of the study.

βθΦ3125.

- 40 -

In the study described above, patients showed marked improvement in psoriatic lesions, for example LPSi Assessments for erythema, flaking, and skin thickness, at sites where the compound to be investigated containing Ciclosporin was applied, compared to sites containing the received placebo. Likewise, a subjective improvement was recorded, along with an improvement in the registered values for itching at the Ciclosporin-treated sites, compared to those treated with placebo, J0 Positive results were also obtained in parallel design trials on patients diagnosed with contact dermatitis via Have 3 or more of the following criteria '- Prutitus or itching - Typical morphology and distribution: 15 Flexural lichenification or linearity In adults

Facial and extensor involvement in babies and children - Chronic or chronic recurrent dermatitis - Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis), 20 plus 3 or more minor features, including:

Xerosis, ichthyosis / palmar hyperlinearity / keratosis pilaris, immediate (type Ij skin test reactivity, increased serum IgE, early age at onset (^ 5 years), tendency to cutaneous infections (especially Staph, aureus, and Herpes simplex affected, cell 25) , immunity, tendency to nonspecific hand or pediatric nerratitis, nipple eczema, cheilitis, recurrent conjunctivitis, Dennie-Morgan infraorbital folds, keratoconus, anterior subcapsular cataracts, orbital donkey, facial pallor facial erythema, pityriasis alba, pityriasis alba , itching with 30 sweats, wool intolerance and solvents for fats, perifollicular acoustics, food intolerance, behavior influenced by environmental or emotional factors and white demographics i-sefee · 'i-até bleaching, The study period was 3 weeks, with a Review on a scale from 0 to 3 for the following 35 parameters: pruritis, erythema, exudation, excoriation and lichenifica Preparations for topical use, as described above in Examples 4.3-4.9, containing 3-30% Ciclosporin, for example the 5.0% composition according to Example 4.7, 8803125.

- 41 - have also been shown to be effective in allergic contact dermatitis, as well as alopecia.

According to the foregoing, the invention also provides: D. A method of administering Ciciosporin to or applying a Ciciosporin therapy to a patient who obtains or needs such therapy, which method comprises administering an effective amount of Ciciosporin in orthorhombic crystal form, especially in the unsolvated orthorhombic crystal form, for example, as CY-A / X-III, JO, for example, as defined under A'-J above to such a patient.

According to a more specific embodiment, the following is given:

A method of applying an immunosuppressive or anti-inflammatory therapy to a patient in need of such therapy, which method comprises administering an effective amount of Ciciosporin in orthorhombic crystal form, in particular in an unsolvated orthorhombic crystal form, for example as CY-A / X-IIÏ, for example, as defined in one of the aforementioned A - above, to such a patient.

Among the purposes for which the subject methods may be used include the treatment of any disease or condition described above. - In connection with the use of Ciciosporin, for example, prevention of transplant rejection, treatment of autoimmune or rheumatic diseases, treatment of any other disease or condition involving an undesired higher immune system response, treatment of parasitic infections, treatment of chemotherapeutic resistance, e.g. reversal of tumor resistance to anti-neoplastic chemotherapy, such as the act of alopecia. The methods described above can be used in particular for the treatment of diseases or conditions of the skin or eyes, such as, for example, psoriasis, atopic or contact dermatitis, corneal transplants, conjunctivitis and uveitis, by topical administration, as well as for the treatment of rheumatoid arthritis or other diseases or conditions of the joints, by administration through the joints. Furthermore, the present invention provides: E, Ciciosporin in an unsolvated, orthorhombic 8803125.

- 42 - crystal form, for example as CY-A / X-III, for example as defined under one of the aforementioned A - èJ, for use as a pharmaceutical, for example for the treatment of any disease or condition as mentioned above in connection with 5 D or D above, for example, for use as an immunosuppressive or anti-inflammatory agent, and F. Ciclosporin in orthorhombic crystal form, for example, as CY-A / X-XII, for example, defined under any of the aforementioned 7 - A, for use in preparation or manufacture 10 of a pharmaceutical preparation for a use defined under E above.

To promote the identification of Cyclosporine in orthorhombic crystal form, in particular CY-A / X-III, X-ray powder diffraction values for CY-A / X-III and for the two two, also referred to herein, are CY- A / X-IIand CY-Α / ΧΊΙΙ given with the following tables I - III. The enclosed Figure IV shows the X-ray powder diffraction diagram from which the values of Tables I - III were obtained. The diffraction diagram was obtained with a Guinier-DeWolff II camera using o 2Q using CuKa radiation, λ = 1.542 A, 8803125.

- 43 -

Table I

X-ray diagram of CY-A / X-I

Line No. d (A) Intensity

1.13.0 US

2. 11.4 US

3.10.3 US

4. 9.7 US

5. 9.4 US

6. 8.25 US

7.1 7.1 S

8.1 6.1 M

9. 5.85 S

10. 5.6 S

Jl. 5.25 US

12. 4.81 S

13. 4.58 S

4.25 M

15.0 M

16. 3.67 M

17. 3.45 M

8803125.

- 44 -

Table II

X-ray diagram of CY-A / X-II

Line No. d (All Intensity

1.17.9 S

2. 11.4 US

3.11.0 S

4.10.6 M

5. IQ, 2 S

6. 8.9 M

7.7 M

8.1 M

9.2 US

30, 6.3 M

11. 5.95 H

12. 5.7 H

13. 5.95 M

14. 5.1 S

15. 4.85 S

16.8 M

17.55 M

18.4 M

8803125 /

Table III

-45-

X-ray diagram of CT-A / X-III

Line No. d (A) Intensity

1.12.0 M

2. 10.4 US

3. 9.6 S

4.8 S

5. 7.9 M

6.7 7.7 S

7.7 6.7 M

8. 6.0 M

9. 5.83 S

10. 5.3 M

11. 5.2 M

12. 4.92 S

13. 4.88 S

14. 4.58 M

15. 4.48 M

16.4, Q M

17.39 M

18. 3.38 M

VS = very strong S = strong 'M = moderate 8803125.

Claims (19)

3, Ciclosporin in an unsolated orthorhombic crystal form. Ciclosporin according to claim 1 with a crystal lattice * C> V o a = 32.7 A, b = 15.7 A, c = 36.3 A, volume per asymmetric <Λ unit = 1804 A. Ciclosporin according to claim 1 or 2 with the following X-ray diffraction characteristics; Line No, d (Al Intensity 1.12.0 M 2. 10.4 US 3. 9.6 S 4. 8.7 S 5. 7.9 H 6. 7.7 S 7. 6.7 M 8 6.QM 9. 5.83 S 3Q, 5.3 H -11. 5.2 M 32, 4.92 S 33, 4.88 S 34, 4.58 M 15, 4.48 H 36.4 .0 M 37, 3.59 M 38, ...... 3.38 ........... M. VS - very strong S p strong H = 5 moderate Ciclosporin according to any one of claims 3-3, which contains no or virtually no Ciclosporin in another form, or in pure or almost pure form. Ciclosporin according to any one of claims 1 to 4 in fine particle form. Ciclosporin according to claim 6, wherein the particles have an average size <200 µM, Ciclosporin according to claim 6, wherein the particles have an average particle size of 0.5-200 µM. Ciclosporin according to claim 6 or 7, wherein the 10 particles have an average particle size <25 µM. to have, Ciclosporin according to any one of claims 1-8 which mainly consists of, or consists wholly or almost entirely of non-crushed crystalline material, Ciclosporin according to any one of claims 6-8, wherein the particles mainly contain or consist wholly or almost wholly non-comminuted microcrystalline material, 11. Ciclosporin according to any one of claims 1 to 10 in a sterile or almost sterile state, 12. Process for the preparation of cyclosporine in a 2Q unsolvated orthorhombic crystal form, characterized in that crystallized ciclosporin from a non-solvated cyclosporin in orthorhombic crystal-forming solution and the thus obtained unsolvated orthorhombic crystals are recovered from cyclosporin 13, A pharmaceutical composition containing al Ciclosporin in an orthorhombic crystal form as active ingredient, optionally together with B} a pharmaceutically acceptable diluent or carrier therefor. A pharmaceutical composition according to claim 13, characterized in that the Ciclosporin present in this preparation is predominantly, or wholly or almost wholly, in orthorhomic crystal form, Pharmaceutical preparation according to claim 13 or 14, 35, characterized in that it contains at least one compartment or phase containing cyclosporin in orthorhombic crystal form, which crystal form is distributed over this compartment or phase or can be distributed homogeneously over this compartment or these compartments. phase is divided or can be homogeneously distributed. 8803125.- 48 - A pharmaceutical preparation according to any one of claims 13-15, characterized in that it contains cyclosporine according to any one of claims 1-11. Pharmaceutical composition according to any one of claims 5-13-16 in a flowable form permitting topical application or use by injection or infusion. Pharmaceutical preparation according to any one of claims 13 to 17, characterized in that it contains 0.05-30% by weight of Ciclosporin based on the total weight of the preparation. Ciclosporin according to any one of claims 1-11 for use as a pharmaceutical. Ciclosporin according to claim 19 for use as an immunosuppressive or anti-inflammatory agent. 21. Methods and pharmaceutical preparations as described in the description and / or examples. -0-0-0-0- ^ 8803125.