LU87409A1 - NOVEL CRYSTALLINE FORM OF CICLOSPORIN, ITS PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING IT - Google Patents

Description

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The present invention relates to a new crystalline form of Ciclosporin, its preparation and the pharmaceutical compositions containing it.

Ciclosporin, or cyclosporine A, is a known fungal metabolite of great therapeutic utility. Ciclosporin is a cyclic poly-N-methylated undecapeptide of formula r-MeBmt-aAbu-Sar-MeLeu-Val-MeLeu-Ala- (D) Ala-MeLeu-MeLeu-MeVal- 1 234567 8 9 10 11 in which -MeBmt - means an N-methyl- (4R) - 4-but-2E-en-l-yl-4-methyl- (L) threonyl residue.

Ciclosporin and its preparation methods are described, for example, in US Pat. No. 4,117,118. The main field of clinical investigation for Ciclosporin has been as an immunosuppressive agent, in particular in relation to its use in recipients of organ transplants, for example heart, lung, heart-lung, liver, kidney, pancreas, bone marrow, skin and cornea transplants, and in particular transplants 'allogenic organs. In this sector, Ciclosporin has had major successes and acquired an excellent reputation; it is widely used in hospitals and is now * commercially available under the brand name SANDIMMUN R

or SANDIMMUNE R, for example in the form of a concentrate for infusion, an oral solution and a solution encapsulated in a soft capsule, the latter two variants being described, for example in US Patent No. 4,388,307.

At the same time, intensive research has been carried out into the possibilities of applying Ciclosporin to various autoimmune diseases and to inflammatory conditions, in particular to inflammatory states having an etiology comprising an autoimmune component, such as arthritis. (e.g. rheumatoid arthritis, active chronic arthritis and deforming arthritis) and rheumatic diseases, and reports of the results of these tests performed in vitro, on test animals and in clinics are widely reported in the literature . As autoimmune diseases for which Ciclosporin has been proposed or used, mention may be made of autoimmune hematological disorders (including, for example, haemolytic anemia, aplastic anemia, purely erythrocytic anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson disease, idiopathic sprue, autoimmune intestinal inflammation ( including for example ulcerative colitis and Crohn's disease), pemphi-gus, endocrine opthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, primary liver cirrhosis, primary juvenile diabetes (diabetes mellitus) type I), Behcet's disease, uveitis (anterior and posterior), vernal conjunctivitis, dry keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomeru lonephritis (with or without nephrotic syndrome, for example including idiopathic nephrotic syndrome or low-change nephropathy).

As another area of research, mention may be made of the possibilities of using cyclosporine as an anti-parasitic agent, in particular as an anti-protozoan agent, in particular for the possible use in the treatment of malaria, t 0 3 coccidioidomycosis and schistosomiasis, as well as suppressing the resistance of tumors to chemotherapeutic agents, for example to cytostatics, and for promoting hair growth, for example for the treatment of alopecia.

In the solid state, Ciclosporin exists in amorphous form and in crystalline form. The known crystalline forms of Cyclosporine are the tetragonal and orthorhombic form.

The tetragonal form (P4].), Hereinafter designated "Cy-A / XI" for practical reasons, is described as well as its preparation methods, for example in Austrian patent application No. 353 961. Cy-A / XI has a reticular distance a »b» 13.8 p | | A c = * 41.2 A, volume per asymmetric unit 1974 A3, a melting point of approximately 140-150 ° C and comprises approximately 2 molecules of H2O per molecule of Ciclosporin.

A first orthorhombic form (P212121) can be obtained by recrystallization from di-isopropyl ether as described by R. Wenger in "Sandorama" 1984 / III "Total synthesis - change in molecular structure - biological effect: Ciclosporin as example". This particular form is a solvate of Ciclosporin and di-isopropyl ether (approximately 1: 2), with a reticular distance of a 12.5 A, b - 22.9 A, c * 28.4 A, volume per unit asymmetrical = 2027 A 3 and a melting point of approximately 150 ° C. The orthorhombic crystals of Ciclosporin solvate can be obtained by recrystallization of supersaturated solutions of Ciclosporin in an appropriate solvent medium, for extended periods of time. Thus the orthorhombic form of the solvate of Ciclosporin and of diisopropyl ether prepared by Wenger is obtained by addition of a concentrated solution of Ciclosporin in methylene chloride (in * 4 4 in which Ciclosporin is easily soluble) to di-isopropyl ether (in which Ciclosporin is relatively less soluble) and evaporation of methylene chloride. The crystallization from the remaining di-isopropyl ether is then carried out for approximately 7 days at room temperature. For practical reasons, the orthorhombic crystalline form of this Ciclosporin solvate will hereinafter be designated "Cy-A / x-li".

Another orthorhombic form (P212121) has now been identified, characterized by the total or substantial absence of any solvent, that is to say substantially consisting of free Ciclosporin or essentially consisting of free Ciclosporin.

The dimensions of the crystal lattice of the solvent-free or unsolvated orthorhombic form of Ciclosporin are a »12.7Â, b» 15.7Â, c = 36.3 Â, volume per asymmetric unit 1804 A3. The melting point is between approximately 180 and approximately 190 ° C, up to 195 ° C, depending for example on the degree of purity and the origin as indicated in Examples 1 and 2 below, in which the methods specific methods for obtaining this form are described. For practical reasons, Ciclosporin in unsolvated orthorhombic crystalline form (or solvent-free) will be referred to below as "Cy-A / X-III". Other characteristic data (X-ray diffraction of the powder) for Cy-A / X-III are provided in Table III and Figure IV below, as well as the corresponding data for Cy-A / XI and Cy-A / x it.

Despite the considerable success and reputation of Ciclosporin and despite its great contribution to medical science, particularly in the organ transplant sector, its practical use is not yet ideal and problem free. One of the difficulties resides in the provision of galenical forms allowing a convenient and entirely satisfactory administration or better suited to the treatment of specific diseases or conditions for which Ciclosporin has already been "recognized as a potential drug of choice.

These difficulties are partly attributable to the particular physical characteristics of Ciclosporin, for example to its solubility or compatibility (experimented until now) relatively limited with the available and pharmaceutically applicable vehicles. Such difficulties are linked to the very nature of certain diseases for which Ciclosporin represents a potential first therapy as well as to the appearance of undesirable side effects that Ciclosporin can cause after oral administration. For example, the efficacy of Ciclosporin has been demonstrated in the treatment of psoriasis after oral administration. Psoriasis is a very common disease causing severe suffering to patients and for which there is currently no effective and generally accepted treatment. People with psoriasis obviously constitute a population in need of effective treatment, ÿ While there is every reason to believe that Ciclosporin could meet this need, it seems unlikely that oral administration of Ciclosporin is justified as a standard means of treatment of psoriasis. Such considerations apply to the treatment, for example, of eye diseases such as posterior uveitis and dry keratoconjunctivitis.

Various systems have been proposed for the administration of cyclosporine, including dosage forms for topical or dermal application or for ophthalmic application, i.e., topical application to the eye, for example for possible use in the treatment of psoriasis or other dermatological diseases, for example atopic dermatosis and alopecia, or for the treatment of uveitis. Such systems have so far not given remarkable results or have not proved entirely satisfactory.

Various attempts to treat psoriasis patients have been mentioned, for example, by applying known oral solution directly to the site of the psoriatic lesion, but this has been unsatisfactory or unsatisfactory from the top and n was also not very successful in patients with atopic dermatosis. Likewise, while topical application to the eye has been shown to be effective as a means of prevention, such as rejection of a corneal transplant or to treat disease in the anterior segment of the eye, however, a formulation for topical application has not yet been described which allows easy, safe or effective treatment of diseases which affect the deeper sites of the eye, for example for the general treatment of uveitis, including posterior uveitis.

Similar difficulties have been encountered in the development of other Ciclosporin delivery systems, for example in injectable form, for example suitable for intra-articular injection in the local treatment of arthritis, for example as indicated above, or for an injection through the lesion, for example in the treatment of severe psoriatic lesions, or tm 7 with regard to new oral administration systems, for example having a modified bioavailability or modified release characteristics of the substance.

Up to now, attempts to formulate Ciclosporin have consisted in using the compound in solution or, to a lesser extent, in amorphous form or in the form of Cy-A / XI, the latter being, for example, the crystalline form identified for example for marketing authorization. Despite considerable efforts to find new or improved forms, the oral solution and the infusion concentrate already mentioned have, however, remained the only widely used delivery systems.

According to the invention, the Applicant has now surprisingly found that the orthorhombic crystalline forms of Ciclosporin, for example Cy-A / X-II and, in particular, Cy-A / X-IIl, have advantages for the preparation of various dosage forms of Ciclosporin.

It has been found in particular that such crystal forms can be used to prepare dosage forms containing Ciclosporin in a stable form of fine particles and / or having improved stability or release properties. This opens the way to the preparation of new and improved systems for the release of Ciclosporin, having, for example, characteristics of prolonged or delayed release of Ciclosporin, and / or adapted or suitable for the treatment of diseases or conditions resistant to treatment with Ciclosporin or for which conventional treatment with Ciclosporin is less appropriate. It has been found more specifically that by using such crystal forms t 8 lines, for example in the form of fine particles as indicated above, it is possible to obtain pharmaceutical forms suitable for topical or dermal application or for topical application on the eye, in the treatment of diseases or conditions affecting the skin or the eye, as indicated above, in particular in the treatment of psoriasis, atopic dermatitis, contact dermatitis, occular symptoms of Behcet's disease, uveitis and dry keratoconjunctivitis. The use of such crystalline forms also allows the preparation of injectable forms of Ciclosporin having extended or delayed release characteristics and therefore of particular utility, for example for the treatment of diseases or conditions for which the required frequency d administration could interfere with its usefulness, for example for the treatment of arthritis or similar diseases of the joints by intra-articular injection or for the treatment of psoriasis or similar diseases of the skin by injection into the lesion.

In this regard, it has been found that the orthorhombic crystalline forms, in particular Cy-A / X-III, are better suited than the other available forms, in particular amorphous cyclosporine or Cy-A / XI, for example in terms physicochemical properties, especially in terms of stability and release characteristics, that is to say the release of Ciclosporin from the crystal lattice, and in terms of possibilities of manipulations necessary to prepare galenic forms. Cy-A / X-III is new and is the preferred orthorhombic crystalline form for galenical and / or therapeutic use according to the invention. In a first aspect, the invention therefore relates to:? * 9 With Cy-A / X-III, that is to say Ciclosporin in orthorhombic crystalline form unsolvated, in particular: A1 Cy-A / xm having a reticular distance or other physical characteristics such as defined above, and / or A2 Cy-A / Xm having the X-ray diffraction characteristics of the powder as defined in Table III or Figure IV.

The present invention also relates to: B a process for the preparation of Cy-A / X-III, process according to which the Ciclosporin is crystallized in a medium giving rise to Cy-A / X-III and the Cy-A / is recovered X-III thus obtained.

Suitable media giving rise to Cy-A / X-III for use in the process described above, are in particular solvent media for Ciclosporin consisting of high molecular weight solvents, for example having a molecular weight> 200 Particularly suitable media include high molecular weight ethers, particularly polymer ethers, for example polyoxyalkylene ethers, for example polyethylene glycols and polypropylene glycols. As examples of suitable polymer ethers, mention may be made of polyethylene glycols and polypropylene glycols, for example having a molecular weight> 200; polyethylene glycol esters of glycerol, for example polyethylene glycol glycerol ricin-oleates and polyethylene glycol glycerol oxystearates, for example those available under the brands "Cremophor EL" and "Cremophor RH" (see Fiedler, "Lexikon der Hilfstoffe" 2nd edition, vol. 1 ^, p. 257 and 258); polyoxyethylenic esters of sorbitan, for example those sold under the brand name "Tween" (see t 10

Fiedler, 2, p. 972-975); polyoxyethylenic esters, for example polyoxethylenic esters of stearic acid, for example those sold under the brand "Myrj" (see Fiedler, 2, p, 636); and the trans-esterification products of triglycerides of natural oils with polyoxyalkylenic polyols, comprising the trans-esterification products of corn oil, of core oil, of sweet almond oil, peanut oil, olive oil, palm oil and mixtures thereof, with polyethylene glycols, in particular polyethylene glycols having a molecular weight of between 200 and 800, for example those sold under the brand "Labrafil" (see Fiedler, p. 539). Especially suitable media include polyethylene glycols having a molecular weight between about 200 and about 600, particularly between about 300 and about 400.

It will be noted that the medium giving rise to Cy-A / Xm may comprise one or more components in addition to those indicated above, for example low molecular weight alcohols and / or water, serving to modify the characteristics of crystallization and / or solvent. A medium giving rise to Cy-A / Xm and which is particularly suitable, is that comprising approximately 0.5 part by volume of ethanol, approximately 8.0 parts by volume of polyethylene glycol (300) and approximately 1.0 part by volume of H20.

The process of the invention firstly comprises “11 the dissolution at a high temperature of cyclosporine, for example in amorphous or tetragonal form, in the medium chosen giving rise to Cy-A / X-III. The dissolution temperature depends of course on the particular medium chosen, but is generally located at> 40 ° C., more particularly at> 50 ° C. In the case of a medium based on polyethylene glycol, the dissolution temperature is generally> 70 ° C., for example between approximately 75 ° C. and 130 ° C. The solution obtained suitably contains> 5% by weight of Ciclosporin, preferably> 10%, for example up to about 40-60%, preferably up to a maximum of 20% by weight relative to the total weight of the solution. The crystallization of cyclosporine is then carried out by cooling, suitably for an extended period of time, for example between 10 and 35 minutes or more, depending on the desired size of the crystals.

If necessary, nucleation processes can be carried out, for example by treatment with ultrasound or by the addition of germs. When using ethanol / polyethylene glycol / H2O media giving rise to crystals, for example as described above, it has been found, for example, that nucleation can be easily carried out at temperatures between about 60 and 90 ° C, for example between 65 and 85 ° C by application of ultrasonic vibrations at around 20,000 cpc (cycles per second). As indicated in Example 2 below, thus continuing the treatment with ultrasound for the duration of the crystallization, it is possible to obtain very fine micro-crystals of relatively constant size.

The growth rate of the crystals and the size of the crystals obtained depends, of course, on the particular medium chosen and on the conditions under which the crystallization is carried out, for example whether the treatment is carried out with ultrasound or not and at what frequency. For use according to the invention, for example for the preparation of dosage forms as described below, Cy-A / X-III is preferably used in the form of fine particles, for example having an average size of less than 200 μΐ \, for example between 0.5 and 200 // M. When the crystals obtained initially have a relatively large size, preparations of particles with the desired dimensions can naturally be obtained according to the usual methods allowing a reduction in the size of the particles, for example by grinding, spraying, micronization or other methods intended to reduce the particle size. While the preparations obtained in this way may be quite suitable for certain applications, for example for the preparation of topical compositions intended to be applied to the skin, the use of grinding processes or equivalent processes is not preferred in most of the cases. The reasons for this are that products from such processes tend to have a relatively large particle size distribution and a relatively coarse or abrasive structure due to the breaking of the crystals. In addition, these methods tend to destroy the physical characteristics of the natural surface of the crystals and it is difficult and expensive to operate while maintaining the requisite conditions of sterility, for example when preparing dosage forms for intravenous administration. articular. It is for these reasons that it is usually preferred to carry out the process of the invention in such a way as to obtain crystals, for example micro-crystals, having a size situated in the desired final particle size range. . Thus, for use in the preparation, for example, of compositions intended for administration by the intra-articular or parenteral route, use will preferably be made of preparations of Cy-A / x-ili particles in non-fragmented microcrystalline form (i.e. - say microcrystals of Cy-A / X-III in the native or unfragmented state, which have not been subjected for example to grinding, to micronization or to any other method of reduction of the size of the particles) .

To obtain Cy-A / X-III micro-crystals which can be used directly without the need to fragment them as described above, the process of the invention is carried out with stirring, for example at 200- 300 rpm, passing for example to 700 rpm during crystallization and, especially, by application of ultrasonic vibrations, for example between 10,000 and 30,000 cycles per second, advantageously about 20,000 cycles per second.

By varying the medium giving rise to Cy-A / X-III and by adjusting the cooling rate and the degree of agitation during crystallization according to techniques known to specialists and described below in the examples, it is possible to prepare Cy-A / X-1XI micro-crystals having a varied average size, for example as described above or as indicated below for use in connection with the individual types of dosage forms according to the invention.

As indicated above, the crystallization according to the process of the invention is carried out in an appropriate manner under sterile conditions. The purification of the Cy-A / X-III obtained can be carried out according to the usual methods, for example by rinsing with polyethylene glycol (300) and water for example in a 3-4: 1 parts ratio. by weight, and / or washing with hot water, as described in the examples. Cy-A / X-III thus obtained is appropriately recovered free or substantially free of Ciclosporin in any other form, preferably in a pure or substantially pure form. The rinsing step described above makes it possible to avoid the formation of amorphous cyclosporine.

The invention also relates to a Ciclosporin prepared according to any one of the methods described above as well as A3 Cy-A / X-III according to any one of the preceding points A to A2, free or substantially free of Ciclosporin under another form, for example free or substantially free of Ciclosporin in amorphous form, Cy-A / XI or Cy-A / X-11; A4 CY-A / X-III according to any one of the preceding points A to A3, in pure or substantially pure form; A5 CY-A / X-III according to any one of the preceding points A to A4, in the form of fine particles, having for example the characteristics of particle size as described above or below, for example in relation with dosage forms containing Cy-A / X-III; A6 the CY-A / X-III according to any one of the preceding points A to A5, predominantly constituted or entirely or almost entirely composed of unfragmented crystals, for example Cy-A / X-III according to A5 in which the particles are predominantly made up or made up entirely or almost entirely of unfragmented micro-crystals; and A7 the CY-A / X-III according to any one of the points A to A6 above in the sterile or substantially sterile state, for example in a state suitable for pharmaceutical use, for example for parenteral administration, for example an intra-articular injection.

The invention further relates to: C a pharmaceutical composition comprising a) as active substance Ciclosporin in the form of orthorhombic crystals and b) a pharmaceutically acceptable diluent or vehicle.

Ciclosporin can be present in the compositions of the invention in any form of orthorhombic crystals, for example in the form of Cy-A / X-II or Cy-A / X-III. However, the use of Cy-A / X-il is generally less preferred due to its physicochemical properties which are less suitable for use in terms of tolerance and suitability for use in the preparation of dosage forms. effective with Ciclosporin.

More preferably, Ciclosporin is present in the compositions of the invention in the form of Cy-A / x-III, for example according to any one of the points A to A7 indicated above.

Although Ciclosporin is present in the compositions of the invention in solid (crystalline) form, the compositions themselves can have any suitable constitution. The compositions according to the invention therefore comprise solid forms such as capsules, tablets, dragees, powders and granules, semi-solid forms such as ointments, gels, creams and pastes, as well as liquid forms such as those comprising Ciclosporin ” 16 in the form of fine particles (for example in micronized form or of micro-particles), put in suspension or dispersed in a diluent or a liquid pharmaceutical vehicle, in which the crystalline form chosen can be preserved.

The compositions of the invention comprise systems consisting of a single phase or compartment containing Ciclosporin, for example simple creams, gels and ointments, etc., or single capsules or ampoules with one compartment, for example hard or soft gelatin capsules or ampoules for injection, as well as systems comprising several phases or compartments. Thus, the invention is said to be understood to include, for example, compositions comprising a phase or compartment containing Ciclosporin and one or more phases or compartments not containing Ciclosporin, for example coating, vehicle, delay, or placebo, or phases or compartments comprising other active substances or other adjuvants. The invention therefore therefore includes, for example: coated tablets consisting of a core containing Ciclosporin in the form of orthorhombic crystals surrounded for example by coating phases not containing Ciclosporin; double tablets in which Ciclosporin in orthorhombic form is found either in the nucleus or in the envelope; mixed granules comprising a first phase of granules comprising Ciclosporin in the form of orthorhombic crystals and a second phase of granules free of Ciclosporin; and slit capsules having two or more compartments, separated for example by an internal wall, one containing Ciclosporin in the form of orthorhombic crystals and the other not. Other alternatives are obvious to

T

17 specialists. In the compositions of the invention, cyclosporine is predominantly present or, preferably, entirely or almost entirely in the form of orthorhombic crystals, for example in the form of Cy-A / x-III.

The compositions of the invention advantageously comprise at least one phase or compartment containing Ciclosporin in the form of orthorhombic crystals, for example Cy-A / X-III, in which Ciclosporin is distributed uniformly. Such systems include, for example, homogeneous creams, ointments, gels and the like, as well as liquid systems in which the crystalline cyclosporine which they contain is or can be readily distributed homogeneously, for example by manual agitation.

The compositions according to the invention can include the forms suitable for topical application, for example for dermal or topical application to the eye; for parenteral administration, for example by infusion or injection, including by subcutaneous or intramuscular injection and, in particular, for injection into the lesion or intra-articular; as well as forms for enteral administration, for example suppositories, ova and the like, and forms for oral administration. Enteral forms, for example oral forms are however less preferred.

Ciclosporin in orthorhombic crystalline form, for example Cy-A / X-III, is present in the compositions of the invention preferably in the form of fine particles, for example in micronized form, of microparticles or in non-microcrystalline form fragmented as described above. The appropriate particle size of course depends on the particular nature of the composition, the use for which it is intended, its mode of application and the desired effects. In general, however, the average particle size is advantageously between 0.5 and 200 μΜ. The orders of magnitude for the oral, topical or injectable forms are also indicated below.

Topical forms: suitable for example for a dermal or topical application on the eye, for example for the treatment of psoriasis or atopic dermatosis or of diseases or conditions of the eye requiring immunosuppressive treatment, for example l uveitis, conjunctivitis, including dry keratoconjunctivitis or vernal keratoconjunctivitis, or corneal transplants.

Gels, creams, ointments and the like intended for topical or dermal application may be prepared according to any of the techniques known and usually used in the art, for example by combining cyclosporine in crystalline orthorhombic form with a base material flowable, for example an aqueous gel, for example a gel based on cellulose ether, and addition of surfactants, suitable thickeners, etc., comprising, for example, aerosil.

Ciclosporin is preferably present in the form of fine particles, for example having an average particle size of between 0.5 and 200 μΜ. The average particle size is preferably less than 60-80 μΜ, more preferably less than 40 μΜ, especially less than 30 μΜ and very particularly less than 20 μΜ. Advantageously, the particles have a particle size distribution as narrow as possible. Preferably, all the particles are essentially less than 60-80 μΜ.

The compositions of the invention intended for topical ophthalmic use, that is to say for application to the eye, can for example comprise sufficiently thick suspensions or dispersions presented for example in the form of viscous preparations for ophthalmic drops or creams or gels for application to the eye. In the case of compositions intended for application to the eye, the average size of the crystalline Ciclosporin particles is advantageously less than 25 μΜ. More preferably, all the particles present are less than 25 μΜ. The average particle size for such eye drops is advantageously between 0.1 or, preferably, between approximately 0.5 and approximately 20 μΜ or, preferably, approximately 10 μΜ.

The content of hydrophilic / lipophilic component of the system serving as a vehicle for use in the forms intended for dermal application or for use in preparations intended for application to the eye may vary, for example, depending on the surface particular to which the composition is applied, for example according to the characteristics of the particular skin area to be treated.

The compositions intended for topical application, in particular dermal application, advantageously comprise a carrier medium in which the active substance (Ciclosporin) is only sparingly soluble. Advantageously, the solubility of Ciclosporin (for example Cy-A / X-III) in such compositions is less than 10%, preferably less than 1.0% by weight. The solubility is more preferably less than 0.1%, most preferably less than 0.001% by weight.

Suitable carrier media include hydrophilic, water-miscible vehicles, as well as hydrophobic vehicles.

Hydrophilic, water-miscible vehicles advantageously have relatively low volatility. Examples of suitable vehicles belonging to this class include liquid polyalkylene glycols, propylene glycol, glycerol and ethylene glycol. As suitable polyalkylene glycols, mention may be made in particular of liquid polyethylene glycols, for example having an average molecular weight of up to 600, preferably between 250 and 450, especially around 300.

The compositions according to the invention, intended for example for topical application, therefore comprise: C1 a) Ciclosporin in orthorhombic crystalline form, preferably in unsolvated orthorhombic crystalline form, for example Cy-A / Xm, for example as defined in any one of the points A to A7 above; b) a hydrophilic vehicle, miscible in water, for example as described above, and optionally c) water for pharmaceutical use.

The amount of component (a) present is advantageously between approximately 0.1 and approximately 30.0%, especially between approximately 0.5 or 1.0 and 20%, for example approximately 1.0, 2.0, 5.0 or 10% by weight relative to the total weight of the composition. The components (b) and (c) are advantageously present in a ratio of between 1: 0 and 1:20 parts by weight. The components (b) 21 and (c) are more preferably present in a ratio of between 1: 0.5 and 1: 5, for example between 1: 1 and 1: 3, especially between 1: 1.5 and 1: 2.5 parts by weight.

Such compositions advantageously also comprise: d) a surfactant.

Suitable components (d) include inter alia d1 the trans-esterification products of triglycerides of natural vegetable oils with polyoxyalkylene polyols. Such trans-esterification products are known to specialists and can be obtained, for example, according to the general methods described in US Pat. No. 3,288,824. They include the trans-esterification products of various natural vegetable oils (for example non- hydrogenated), for example corn oil, kernel oil, sweet almond oil, peanut oil, olive oil and palm oil and mixtures thereof, with polyethylene glycols, in particular with polyethylene glycols having an average molecular weight of between 200 and 800. The preferred products are those obtained by transesterification of 2 molar parts of a triglyceride of natural vegetable oil with 1 molar part of polyethylene glycol (for example with an average molecular weight of between 200 and 800). Various forms of transesterification products of this class are known and marketed under the brand name Labrafil [see Fiedler, "Lexikon der Hilfstoffe", 2 · 1 "· revised and supplemented edition (1981), vol. 2, page 539], The 22 products specially useful as components of the compositions of the invention are: Labrafil M 1944 CS, a product for trans-esterification of core oil with polyethylene glycol, having an acid number of approximately 2, a saponification index of 145-175 and an iodine index of 60-90, and Labrafil M 2130 CS, a transesterification product of a Ci2-Ci8 glyceride with polyethylene glycol "having a melting point between about 35 and 40 ° C, an acid number <2, a saponification number of about 185-200 and an iodine number <3.

d2 The reaction products of a natural or hydrogenated castor oil with ethylene oxide. Such products can be obtained according to known methods, for example by reaction of a natural or hydrogenated castor oil with ethylene oxide, for example in a molar ratio of between approximately 1:35 and approximately 1:60, with possible elimination of the polyethylene glycol from the product, for example according to the methods described in the German patent applications 1 182 388 and 1 518 819. The various surfactants sold under the brand Cremophor are particularly suitable. Especially suitable products are Cremophor RH 40 having a saponification index of about 50-60, an acid index <1, an iodine index <1, a water content (Fischer) <2%, a value nD60 of about 1.453-1.4578 and an HLB value of about 14-16; Cremophor RH 60 having a saponification index of around 40-50, an acid index <1, an iodine index <1, a water content (Fischer) of 4.5-5.5%, an nD25 value of about 1.453-1.57 and an HLB value of about 15-17; and Cremophore EL having a molecular weight of about 1630, a saponification number of about 65-70, an acid number of about 2, an iodine number of about 28-32 and an nD25 d value 'about 1,471. The various surfactants sold under the brand Nikkol, for example Nikkol HCO-60, are also suitable. Said product Nikkol HCO-60 is a reaction product of hydrogenated castor oil with ethylene oxide having the following characteristics: acid number 0.3; saponification index of 47.4; hydroxy value of 42.5; pH (5%) of 4.6; color APHA 40; melting point 36.0 ° C; freezing point of 32.4 ° C; H2O content (%, KF) of 0.03.

d3 Fatty acid esters with poly-oxyethylenic ethers of sorbitan or polysorba-tes, for example those known and marketed under the brands Tween and Armotan (see Fiedler, 2, p. 745-746 and 972-975) comprising Tween products 20 [polyoxyethylene (20) -sorbitane monolaurate], 40 [polyoxyethylene (20) -sorbitane monopalmitate], 60 [polyoxyethylene (20) -sorbitane monostearate], 65 [polyoxyethylene (20) -sorbitane tristearate] , 80 [polyoxyethylene (20) -sorbitane monooleate], 85 [polyoxyethylene (20) - 24 sorbitan trioleate], 21 [polyoxyethylene (4) -sorbitane monolaurate], 61 [polyoxyethylene (4) -sorbitane monostearate], and 81 [polyoxyethylene (5) -sorbitane monooleate].

d4 Esters of polyoxyethylenic ether fatty acids, for example esters of stearic acid with polyoxyethylene ethers such as those known and marketed under the brand Myrj (see Fiedler, 2, p. 636) as well as esters fatty acids of polyoxyethylenic ethers known and marketed under the trade mark Cetiol HE (see Fiedler, 1, p. 228) and polyoxyethylenic ethers of fatty alcohols, for example stearyl, oleyl or polyoxyethylene ketyl ethers, for example those known and marketed under the brand Brij (see Fiedler, 1, 184-186), for example Brij 78 and 96, and Cetomacrogel 1000 (see Fiedler, 1, 229).

d5 polyoxyethylene-polyoxypropylene co-polymers, such as those known and marketed under the brands Pluronic and Emkalyx (see Fiedler, 2, p. 720-722).

d6 Esters of fatty acids with sorbitan, for example those known and marketed under the brand Span, comprising for example the monolauryl, monopalmityl, monostearyl, tristearyl, monoolyl and trioleyl esters of sorbitan (see Fiedler, 2, p. 850-851).

d7 Partial glycerides, for example products comprising mono- and / or di-glyceride components, for example surfactants based on mixtures of mono- / di- / tri-glycerides / glycerol, as well as for example, glycerol monostearates and glycerol monooleates. As examples of such products, mention may be made of those known and marketed under the brands Imwitor (see Fiedler, 1, 491), for example Imwitor 191 and Imwitor 780 and Softigen (see Fiedler, 2, 833), for example Softigen 701.

d8 Ionic surfactants or emulsifying agents such as sodium lauryl sulfate and sodium ketostearyl sulfate.

When the components (d) are present, they preferably represent a maximum amount of 30%, more preferably up to 15% by weight, relative to the total weight of the composition. The components (d) especially represent an amount of between approximately 0.5 and approximately 10%, for example approximately 1.0% by weight, relative to the total weight of the composition.

Such compositions also include: e) A thickener.

Suitable components (e) include, for example, the following: e1 Polymethacrylic resins, for example those known and sold under the trademark Eudispert (see Fiedler, 1, 371-372). e2 Cellulose derivatives, including for example ethyl-, propyl-, methyl-, hydroxypropylmethyl- and carboxymethyl-cellulose.

e3 Polyvinyl resins, including for example polyvinyl alcohols and polyvinylpyrrolidones, as well as other polymeric materials including gelatin, alginates, pectins, tragacanth, gum arabic, xanthan gum and polyacrylic acids such as those known and marketed under the Carbopol brand (see Fiedler, 1, 206-207).

e4 Materials such as silica gel, bentonite, magnesium-aluminum silicate.

When the components (e) are present, they preferably represent a maximum amount of 20%, more preferably up to 10% by weight, relative to the total weight of the composition. The components (e) advantageously represent an amount of between approximately 0.5 and approximately 15%, especially between approximately 1.0 and 3.0% by weight, relative to the total weight of the composition.

Advantageously, such compositions also comprise an antimicrobial agent such as methylparaben, propylparaben, benzalconium chloride or benzyl alcohol, for example in an amount between 0.05 and 0.5% or, in the case benzyl alcohol, up to 2.0%, for example about 0.1% or, in the case of benzyl alcohol, about 1.0% by weight relative to the total weight of the composition.

As other vehicle media, mention may be made of hydrophobic materials, for example those meeting the solubility criteria with regard to the active substance specified above. Other preferred compositions according to the invention, for example for topical application, therefore comprise C2 a) Ciclosporin in arthorhombic crystalline form, preferably in unsolvated orthorhombic crystalline form, for example 27

Cy-A / X-III as defined under A to A7 above, and f) a hydrophobic vehicle, as indicated above.

The amount of component (a) present is advantageously as described above concerning the compositions defined under C1. As suitable components (f), there may be mentioned for example petroleum derivatives, comprising mineral oils, fats and jellies, such as, for example, petrolatum (mineral fat), liquid petrolatum (white mineral oil or liquid paraffin), or any of the products known and marketed under the brand Vaseline [see Fiedler 2, 986], as well as non-ionic derivatives based on lanolin such as those marketed under the brand Amerchol, for example Amerchol CAB [Fiedler, 1, 119-120].

As other suitable components (f), mention may be made, for example, of natural or saturated vegetable or oils and fats, for example fractionated coconut oils such as those sold under the brand Miglyol, for example Miglyol 812 (see Fiedler, 2, 616). , peanut oils and saturated peanut oils, as well as higher or branched fatty alcohols and fatty esters such as stearic alcohol, cetyl palmitate and 2-octyldodecanol which is known and marketed under the brand Eutanol G (see Fiedler, 1, 375).

Such compositions can also comprise one or more of the components (d) and (e) described above, as well as one or more of the antimicrobial agents described above.

Such compositions may also additionally comprise one or more components (d), advantageously in a maximum amount not exceeding 28 30%, preferably not exceeding 20%, in particular an amount comprised between approximately 1 and approximately 15% by weight relative to the total weight of the composition.

The hydrophobic compositions according to c2 and comprising an emulsifier (d) can also be prepared in the form of creams or emulsions by the addition of water. The creams or emulsions obtained can be either of the oil in water type or of the water in oil type. The amount of water present in such compositions can thus vary for example from 5 to 80%, preferably from 20 to 70% relative to the total weight of the composition.

The amounts of components (e) and of antimicrobial agent, when incorporated, will be of the same order or identical to those indicated for the compositions of the invention according to C1.

The amount of form used for topical application, of course depends on the concentration of the composition, the conditions to be treated and the desired effects as well as, in the case of a dermal application, the area to be covered. In the case of compositions intended for dermal application, for example for the treatment of psoriasis or atopic dermatosis, the amounts applied are generally sufficient to allow a dose of Ciclosporin of between approximately 0.1 and approximately 5 mg / cm 2, per example of approximately 0.5 mg / cm2, applied twice a day to the desired area. In the case of ophthalmic preparations, the application is advantageously carried out using preparations containing from about 0.1 to about 10%, for example 1.0 or 2% of Ciclosporin by weight, applied to each eye in the form of drops. up to 3 times a day.

Injectable forms, for example for a subcutaneous, intramuscular injection or any other parenteral form, comprising in particular the injection by intra-articular route, for example for the treatment of arthritis such as rheumatoid arthritis, or for injection into the lesion, for example for the treatment of psoriasis.

The compositions in the form of dispersions, suspensions, emulsions and the like suitable for injection can be prepared according to any of the known techniques and used usually in the art, for example by dispersing, suspending or distributing Ciclosporin in orthorhombic crystalline form and fine particles in a suitable liquid carrier medium by addition of suitable emulsifiers, surfactants, stabilizers or flocculating agents, etc. Preferably, Ciclosporin in such compositions has an average particle size of less than 100 μη, more preferably less than 50 μη, especially less than 20 μη. The average particle size is advantageously between 0.1 or 0.5 and up to the maximum indicatedx of 20, 50 or 100 μη.

When it is desired that the injectable forms have, for example, a sustained-release effect, for example for an injection by the subcutaneous route or by the intramuscular route, larger particles can be used. When such forms are intended for application in the lesion or, in particular, by intra-articular injection, the use of preparations with finer particles is recommended. For such uses, the average particle size is advantageously for example between about 0.1 or about 0.5 to about 20 μη, for example from approximately 5 to 15 μη.

To stabilize the particles in the injectable forms, for example to avoid an increase in the size of the larger crystalline particles at the expense of the smaller particles, the particle size should preferably be as uniform as possible. Advantageously, the variation between the maximum and minimum dimension of the particles does not exceed approximately 50 μM, preferably approximately 20 μM.

Although the desired particle size can be obtained by appropriate fragmentation methods, for example by micronization, it is generally preferred to use non-fragmented micro-crystals, i.e. crystals which have grown to the desired dimensions ( as described above), in order to minimize variations in particle size, to avoid the presence of fragmented particles and modification of the surface of the crystals, for example to maintain wettability characteristics, and to meet requirements even more easily of sterility.

The injectable compositions according to the invention therefore advantageously comprise: C3 a) Ciclosporin, in orthorhombic crystalline form, preferably in unsolvated orthorhombic crystalline form, for example Cy-A / X-III, for example as defined under A to A7, in particular under A6 and A7, and in the form of fine particles, distributed or capable of being distributed in b) a vehicle for injection.

Suitable vehicles include, in particular, water for pharmaceutical use.

In addition, the compositions as defined under C3 advantageously comprise a surfactant (g) as a dispersing or emulsifying agent ft 31 and / or a flocculating agent, to ensure or maintain the distribution of the particles in the vehicle.

As surfactants (g), there may be mentioned fatty acid esters with polyoxyethylenic ethers of sorbitan or polysorbates, as described for example under (d3) above, for example Tween 80 or Polysorbate 80 ( see Fiedler, 2, p, 746).

As suitable flocculating agents (g), mention may be made of ethylenediaminetetraacetic acid and its salts, for example calcium EDTA and sodium EDTA, as well as other equivalent chelating agents, and peptizing agents such as succinic acid or citric acid.

To maintain the particle size distribution, a stabilizing agent is also incorporated. As suitable stabilizers, there may be mentioned, for example, gelatins or modified gelatins such as the plasma substitutes known and sold under the brands Gelafundin and Haemaccel or gelatins soluble in cold water of highly purified collagen hydrolysates.

The compositions according to C3 can also contain one or more antimicrobial agents, for example as described above, as well as peptizing agents such as succinic acid or citric acid.

The weight ratio of component (a) to component (b) in the compositions defined under C3, is advantageously between 1:10 and 1: 1,000, preferably between 1:50 and 1: 200, for example around 1: 100 parts by weight.

In order not to disturb the stability of the particles too much, the surfactants present as component (g) are preferably used only at low concentrations, for example between 0.1 ft 32 and 2.0%, advantageously approximately 1 % by weight relative to the weight of component (a). When a flocculating agent is present, the ratio of the flocculating agent to the component (a) is advantageously of the order of 1: 3 to 1: 8 parts by weight, for example approximately 1: 5 parts by weight. When a stabilizing agent is present, the ratio of the component (a) to the stabilizing agent is advantageously between 1: 5 and 1:30, more preferably between 1:10 and 1:30, for example about 1:20 parts by weight. When a peptizing agent is present, the ratio of the peptizing agent to component (a) is advantageously between 1: 1 and 1:10, for example approximately 1:15 parts by weight.

The amount of Ciclosporin present in the unit doses intended for injection according to the invention naturally depends, for example, on the conditions to be treated, on the injection area and on the desired effect, for example if an effect is desired. prolonged-release or relatively quick-release to neighboring tissues. The unit doses advantageously contain from about 10 to 500 mg of Ciclosporin, especially from about 20 to 100 mg.

It will be noted that the unit doses according to the invention also include more complex systems, for example double-compartment syringes or cartridge syringes in which the particles of Ciclosporin as well as the other appropriate components, for example the stabilizing agent or the antimicrobial agent are contained in a first compartment and the medium serving as a vehicle is located in a second compartment, the components of the two compartments being mixed, for example by manipulation of the plunger of the syringe. Such syringes with double compartments are known to specialists, and the unit doses comprising them also form part of the invention.

Forms for the oral route, for example for the treatment of autoimmune diseases as specified above, for example for the prevention of transplant rejection.

As indicated above, although the forms for oral administration according to the invention are generally of less interest and are therefore less preferred, such forms also form part of the invention.

The forms for oral administration according to the invention can be prepared using any suitable suitable medium known as a vehicle and used in the art. Liquid or semi-liquid forms intended for oral administration may for example comprise Ciclosporin in orthorhombic crystalline form, for example Cy-A / xm, in combination with diluents or pharmaceutically acceptable vehicles in which the crystalline form is insoluble or essentially insoluble. Such vehicles and diluents include, for example, the trans-esterification products of triglycerides of natural vegetable oils with polyoxyalkylene polyols such as those described above under (d1), for example Labrafils as well as; reaction products of natural or hydrogenated castor oil with ethylene oxide as described above under (d2), in particular liquid Cremophore products, for example Cremophore EL.

Ciclosporin is preferably present in the form of fine particles having for example an average dimension of between 0.5 and 200 μΜ, especially between for example 0.5 and 30 μΜ, preferably less than 20 μΜ, for example between 0, 5 and 34 10 // Μ.

To facilitate administration, the compositions described above are contained in hard or soft gelatin capsules.

The unit doses of the invention for oral administration suitably comprise an amount of Ciclosporin of between about 25 and about 75 mg, or up to 200 mg, for example from about 50 to 100 mg. Such forms are administered for example 1 to 4 times a day so that the patient has plasma levels of Ciclosporin (for example as determined by RIA) identical or equivalent to those obtained by a usual treatment with Ciclosporin, for example using the Ciclosporin oral solution.

The ingredients indicated in the description or defined as components of the pharmaceutical compositions of the invention must be understood as being suitable for a pharmaceutical application, for example in the case of the ingredients of the compositions intended for oral administration, as being pharmaceutically acceptable or , in the case of the ingredients of the compositions intended for topical application, as being acceptable or tolerable from a topical point of view, for example from a dermal or ophthalmic point of view.

Other dosage forms intended for administration according to routes other or equivalent to those described above, are obvious to the specialist.

The following examples illustrate the present invention without in any way limiting its scope. The temperatures are indicated in degrees Celsius.

35 EXAMPLE 1

PREPARATION OF Cy-A / X-III

a) With stirring, 100 g of Ciclosporin in amorphous form are dissolved in 400 g of polyethylene glycol 300 at 50 °. The formation of Cy-A / X-III begins shortly after the end of the dissolution. The solution is left to stand for 24-48 hours at a temperature between about 35 and 40 ° to complete the crystallization and is diluted with 1000 ml of water with vigorous stirring. The precipitate obtained is filtered, washed with water to remove the remaining polyethylene glycol and dried, which gives the Cy-A / X-III in essentially pure form; F = 195 °, particle size ”about 100-200 // M.

Cy-A / x-iil forms can be prepared analogously to that described above, but using the following materials as a solvent in place of polyethylene glycol 300. SOLVENT Pt. F "DE Cy-A / - X-III (° C) b) Polyethylene glycol 300 /

Cremophore RH 40 (1: 1 by volume) --- c) Cremophore EL 190 d) Solutol HS 15 188 e) Gelucire 44/14 180 f) Myrj 52 184 g) Tween 80 186 h) Cremophore RH40 190

In each case, the average particle size is between about 50 and about 200 µM. The determined reticular structure is as defined above. The X-ray diffraction data are as described in Table III and 36 "Figure IV.

EXAMPLE 2

PREPARATION OF Cy-A / X-III

20 g of Ciclosporin in the form of Cy-A / X-I are dissolved in 60 ml of ethanol and the solution is concentrated to 1/6 of its initial volume by distillation ’under reduced pressure at a temperature above 60 °. Then added slowly at a temperature between 50 and 85 ° and with stirring at 300 rpm 160 ml of polyethylene glycol (PM 300) + 20 ml of H20. In the solution, an ultrasonic vibrator / mixer is installed at 20,000 cycles per second. The nucleation is started at 65-75 ° for 3 to 5 minutes. The dispersion obtained is then cooled linearly for 10 to 20 minutes at 40 ° with continuous stirring at 700 rpm and vibration with ultrasound. The pasty and thick mixture obtained is filtered, rinsed with polyethylene glycol (PM 300) / H2O (3: 1 parts by volume), washed with hot water (30 °) and dried at 50 ° under high vacuum, which gives Cy-A / xm in pure form: F = 192 °. Particle size »3-15 μΜ. The determined reticular structure is as indicated above. The X-ray diffraction data are described below in Table III and Figure IV.

Repeated experiments have shown that the size of the crystals depends more on the nucleation temperature and the growth rate of the crystals than on the duration of the process. Thus, by starting nucleation at about 75 ° and continuing crystallization at the same temperature, an average size of the crystalline particles is obtained of about 50 µM.

EXAMPLE 3

PREPARATION OF A GALENIC FORM FOR ORAL ADMINISTRATION

*> 37

3.1 CAPSULES; PREPARATIONS I

A suspension comprising 20% by weight of Cy-A / X-III obtained according to the methods of Example 1 is ground at an elevated temperature in Gelucire 44/14 using a colloid mill, until obtaining an average size of Cy-A / X-III particles between 0.5 e 10 μΜ. 2-dimensional capsules are filled with 250 mg portions of the ground suspension obtained, each capsule containing 50 mg of Ciclosporin (as Cy-A / X-III) as the active substance.

3.2 CAPSULES; PREPARATIONS II

The Cy-A / X-III obtained by the method of Example 1 is ground in a colloidal mill until an average particle size of Cy-A / X-III of between 0.5 and 20 μΜ.

50 mg portions are then thoroughly mixed with 200 g of Cremophore EL and capsules of size 2 are filled, each containing 50 mg of Ciclosporin (in the form of Cy-A / X-III) as active substance. EXAMPLE 4

PREPARATION OF GALENIC FORMS FOR TOPICAL APPLICATION

4.1 GEL; PREPARATION I

The Cy-A / X-III obtained by the method of Example 1 is micronized using an air jet mill. The micronized product having a maximum particle size of 60-70 μΜ and an "average particle size of 2-10 μΜ, is combined and mixed using the usual methods with the ingredients indicated in the table below, which gives an aqueous gel comprising 10% by weight of Ciclosporin (in the form of Cy-A / X-III) and suitable for topical application, for example for the treatment of psoriasis.

38

INGREDIENTS% BY WEIGHT

a) CICLOSPORINE (Cy-A / X-III

micronized) 10.0 b) Polyacrylic acid (Carbopol 934P) 0.5 c) NaOH solution (5%) 3.0 d) Methylparaben 0.07 e) Propylparaben 0.03 f) H2O (for pharmaceutical use) up to at 100.0%

4.2 GEL; PREPARATION II

INGREDIENTS% BY WEIGHT

Composition a Composition B

a) CICLOSPORINE (Cy-A / X-III

micronized) 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 0.07 0.07 g) Propylparaben 0.03 0.03 h) H2O (for use 51.9 60.9 pharmaceutical) 100.0% 100.0%

A) is prepared as described under 4.1 above. C), £) and g) are dissolved in b) by heating and the mixture obtained is cooled to ambient temperature. This solution is then dispersed in h) (water). D) is added and the mixture is homogenized to effect the dispersion. Add a) and homogenize the mixture again. E) is added with stirring to neutralize, and gel tubes for gel intended for topical application, for example for the treatment of psoriasis, are filled with gel.

4.3 OINTMENT

39

INGREDIENTS% BY WEIGHT

Composition A Composition B

a) CICLOSPORINE (Cy-A / X-III

micronized) 1.0 10.0 b) Amerchol CAB 2.0 2.0 c) Liquid paraffin 42.0 37.5 d) White petroleum jelly 55.0 50.5 100.0% 100.0%

A) is prepared as described in 4.1. B), c) and d) are melted together, stirred and a) added at about 30 °, the particles being distributed using a homogenizer. The ointment obtained is cooled and poured into gel tubes, intended for topical application, for example for the treatment of psoriasis.

4.4 CREAM

INGREDIENTS% BY WEIGHT

a) CICLOSPORINE

(Micronized Cy-A / X-III) 1.0 b) Polysorbate 60 5.0 c) Cetylstearyl alcohol 10.0 d) 85% glycerol 10.0 e) White petrolatum 24.0 f) Methylparaben 0.07 g ) Propylparaben 0.03 h) H2O (for pharmaceutical use 49.0) 100.0%

A) is prepared as described in 4.1, it is combined with components b) to h) as described in 4.3 and the mixture is poured into tubes for creams intended for topical application, for example for the treatment of psoriasis.

4.5 OINTMENT

A 40 "suspension consisting of 20% by weight of Cy-A / X-III (obtained as described in Example 1) is ground in the wet state in polyethylene glycol 300 until a medium size is obtained Cy-A / X-III particles between 2 and 10 // M. 10 g of the ground product obtained are mixed according to the usual methods with 50 g of polyethylene glycol 300 and 40 g of polyethylene glycol 1500 in the molten state, which gives a flowable paste comprising 10% by weight of Ciclosporin (in the form Cy-A / X-III) and intended for topical application, for example for the treatment of psoriasis.

4.6 GEL

INGREDIENTS% BY WEIGHT

a) 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) Hydroxypropyl methyl cellulose (Methocel E4M) 2.5 f) H2O (for pharmaceutical use 64.5) 100.0%

A) is prepared as indicated in 4.1. B), c) and d) are mixed and f) is added to the mixture. A) is then suspended in the resulting mixture by homogenization. Then e) is added slowly with stirring until the gel formation is complete. The gel is then poured into tubes or gels intended for topical application, for example for the treatment of psoriasis.

4.7 GEL

41

INGREDIENTS% BY WEIGHT

a) CICLOSPORINE

(Micronized Cy-A / X-III) 5.0 b) Polyethylene glycol 300 30.0 c) Glycerol monostearate 5.0 d) Methylparaben 0.07 e) Propylparaben 0.03 f) Carbopol 934 P 1.0 g) Sodium hydroxide 5% 6.0 h) H2O (for pharmaceutical use 52.9) 100.0%

A) is prepared as indicated in 4.1. Dissolve c), d) and e) in b) while heating. The hot mixture is dispersed in h) by homogenization and cooled to room temperature. Then a) and f) are added and the whole is homogenized. Then g) is added and the gel formation is terminated. The gel obtained is poured into tubes intended for topical application, for example for the treatment of psoriasis.

4.8 CREAMS; PREPARATIONS (WATER IN OIL)

INGREDIENTS% BY WEIGHT

a) CICLOSPORINE (Cy-A / X-III

micronized) 2.0 b) Amerchol CAB 5.0 c) Miglyol 812 10.0 d) Vaseline 53.0 e) H2O (for pharmaceutical use 30.0) 100.0%

A) is prepared as indicated in 4.1 and dispersed with b) in e) while heating and homogenizing. It is melted together c) and d), they are mixed and added to the dispersion obtained above under intense homogenization, and the mixture is cooled to obtain a fatty white cream. It is poured into tubes intended for topical application.

V

42 T * than, for example for the treatment of psoriasis.

4.9 GELS / CREAMS; PREPARATIONS

The procedure is as described in Examples 4.1 to 4.8, but using the crystalline cyclosporine of Example 2 directly as the active substance.

EXAMPLE 5

5.1 INJECTABLE FORM, FOR EXAMPLE FOR A PARENTERAL APPLICATION

A suspension of Cy-A / X-III is prepared under sterile conditions using the usual methods and using the following ingredients: WEIGHT INGREDIENTS (MG) a) CICLOSPORINE (Cy-A / X-III) 20.0 b ) Polysorbate 80 4.0 c) Sodium carboxymethylcellulose 5.0 d) NaCl 9.0 e) Benzyl alcohol 9.0 f) h20 (for injection) qs 1.0ml

The release characteristics of the active substance of the formulation obtained depend on the average particle size of the component a). Thus, when activity over longer periods of time is required, the product Cy-A / X-III having a larger particle size is chosen (for example 100-200 // M, which is obtained directly by proceeding as described in example 1). When an activity over shorter periods of time is required, the product Cy-A / X-III is chosen having a relatively smaller particle size (which is obtained for example by micronization or by grinding the product of l 'example 1, for example to a dimension between 0.5 and 10 μΜ). The suspension obtained is poured into ampoules for injection intended for parenteral administration or for injection into the lesion, for the treatment 43 * of psoriasis, in order to obtain for example a prolonged release effect.

According to a preferred aspect, Cy-A / X-III prepared for example 2, having a particle size of between 5 and 15 μΜ, is used for this example. and prepared under sterile conditions.

5.2 INJECTABLE FORMS, FOR EXAMPLE FOR INTRA-ARTICULAR INJECTION

WEIGHT INGREDIENTS (MG)

Composition A

a) CICLOSPORINE (Cy-A / X-III) 10.0 b) Sodium carboxymethylcellulose 10.0 c) EDTA of Na 2.0 d) H2O (for injection) q.s.p. 1.0 ml

Composition B

a) CICLOSPORINE (Cy-A / X-III) 10.0 b) Polysorbate 80 0.1 c) Citric acid 2.0 d) H2O (for injection) q.s.p. 1.0 ml

The formulation is carried out according to the usual techniques under sterile conditions. Component a) consists of non-fragmented micro-crystals, prepared under sterile conditions and according to the method of Example 2, having a particle size between 3 and 15 μΡΐ. Under sterile conditions, the compositions obtained are poured into ampoules for injection, for example for an injection by intra-articular route, for the treatment of rheumatoid arthritis.

The advantageous properties of the compositions of the invention can be demonstrated during tests carried out on animals or in the clinic. The particular utility of the compositions of the invention intended for a dermal application, for example for the treatment of psoriasis or of dermatosis, can be demonstrated in the following test: DERMATITIS OF ALLERGIC CONTACT IN THE COBAYA (TEST DELAYED HYPERSENSITIVITY)

Guinea pigs (sensitized from Hartley strain, <$, 400-500 g) are sensitized by application in the inner part of the right ear of 50 μΐ of 2% dinitro-fluorobenzene (DNFB) in a mixture of acetone and d olive oil (1: 1). 7 days later, the animals are removed with 20 μΐ of 0.5% DNFB in a mixture of acetone and olive oil (4: 1) applied to marked areas of the left flank and the right flank shaved . The second exposure causes allergic inflammation, with redness and cellular infiltration (thickening) of the skin. Using a spatula, the composition to be tested is applied to the DNFB treated area of the right flank in an amount between 200 and 250 mg. The left flank is treated similarly using a placebo, to serve as a control. The composition to be tested and the placebo are applied 5 times, that is to say at intervals of 20 minutes, 8 hours, 24 hours, 32 hours and 48 hours. The thickness of the skin on the application area is determined before each application and 8 hours after the last application, by pinching the skin to measure the thickness. The degree of redness or inflammation of the skin is also assessed visually on a scale of 0 to 4.

The effectiveness of the preparation to be tried to prevent inflammation is determined by comparison with the results obtained on the sides treated with the placebo.

The results obtained in the above test using the compositions according to Examples 4.1 and 4.5, but comprising 0.1% by weight of Ciclosporin in the form of Cy-A / X-III, compared with those obtained with placebo and with 0.1% by weight of Ciclosporin by topical application of the known oral solution, 45 "are presented in Figures I, II and III in the appendix. [A concentration of 0.1% Cy-A / X-III is used in this test because of its extreme sensitivity. The compositions to be tested are prepared as described in Examples 4.1 and 4.5, but by reducing the content of Ciclosporin to 0.1 g and by compensation by adding 9.9 g of water in the case of Example 4.1 and polyethylene glycol in the case of Example 4.5).

In each figure, the thickness of the skin is indicated in relation to time. FIG. 1 shows the results obtained by the use of 0.1% by weight of Ciclosporin, applied in the form of the commercial oral solution, in comparison with the results obtained with placebo. Regarding the oral solution, there is a slight reduction in the reaction compared to placebo. In Figures II and III, the results obtained with the compositions containing 0.1% by weight of Ciclosporin according to Examples 4.1 and 4.5 are respectively compared with placebo. In both cases, there is a substantial reduction in the thickness of the skin relative to the placebo after the first application and continuing throughout the duration of the treatment.

The usefulness of the compositions of the invention can also be demonstrated by the following clinical trials: CLINICAL TRIAL: TREATMENT OF PSORIASIS BY TOPICAL APPLICATION (DERMAL) The randomized trial is carried out in double blind controlled by placebo. Each patient receives simultaneously the composition to be tested and the placebo (only the vehicle) on two symmetrical lesions.

The active composition and the placebo are applied to the right and left lesions according to randomization.

46

The patients selected are divided into groups of 12 to 24, from 18 to 70 years of age and comprising post-menopausal men and women, sterile following an operation or using oral contraceptives and whose pregnancy test is negative.

The criteria for participation in the trial are as follows: a) written consent and b) a chronic, stable and clinically determined plaque for psoriasis. Each patient must present at least two moderate to severe bilateral symmetrical lesions, each measuring 4 to 25 cm2 and with a gravity> 5 on a scale of 0 to 9. This score ”is a combination of individual scores of 0 (not serious) to 3 (very serious) for each of the following three parameters: erythema, scaling and skin inflammation. Lesions on both sides must be comparable for the same patient (i.e. they must not differ by more than 20% in severity or area).

The following exclusion criteria are applied: a) any medical condition which, according to the specialist, could jeopardize the smooth running of the study.

b) Systemic treatment of psoriasis (PUVA, methotrexate, steroids, retinoids, Ciclosporin) during the last two months.

c) Specific topical treatment - with the exception of neutral substances (for example white petrolatum) or formulations containing salicylic acid (not more than 10%) - on the lesions chosen for the study and carried out during two weeks before the start of the study. These emollients can however be used on lesions not chosen for the study.

d) Patients whose psoriasis appears to improve spontaneously, increase without treatment or worsen after stopping treatment.

e) Known hypersensitivity to one of the ingredients of the product to be tested.

f) Uncooperative patients who are unlikely to follow medical instructions exactly, patients unwilling or unable to perform regular medical checkups.

g) Participation in another clinical trial in the month preceding inclusion in the study.

h) A serious concomitant disease, especially renal failure with a serum creatinine greater than 130 // Mole / l.

i) High blood pressure (diastolic> 95 mm Hg after 5 minutes in a sitting position). Patients with treatment-controlled hypertension are included in the study.

j) Patients who have had or have cancer, including skin cancer.

k) Acute skin lesions of bacterial, viral or fungal origin.

l) Pregnancy, breastfeeding.

m) Alcoholic, drug abusing patients with psychosis, emotional or intellectual problems.

n) Patients requiring continuous concomitant treatment with other immunosuppressive agents, with chemotherapeutic agents, compounds with nephrotoxic potential (for example aminoglucosides) and medicinal products known to have an interaction on the pharmacokinetics of Ciclosporin ( ketoconazole, erythromycin, phenytoin, phenobarbitone, rifampicin, INH, carbamazepine, sodium valproate).

o) Patients with initial laboratory results 15% above laboratory normal.

p) Patients with an abnormality in the clinical examination.

The test compositions used are as described in one of the examples 4.1 to 4.9 described above, for example composition B at 1% from example 4.2 or composition B at 10% from example 4.3.

Each patient receives two 20 g coded tubes with a double label. The label is blue to designate the substance to be applied on the right side and red for the left side. In addition, the side to be treated, left or right, the study code, the name of the doctor, the patient number and the date of treatment start are written on each part of the label. The detachable part of the label is stuck on the patient's file.

The test substance is applied 2 times a day, in the morning and in the evening, the amount applied being a function of the extent of the lesion, which corresponds to a daily dose of Ciclosporin of between 0.2 and 2.0 mg per cm2, for example in a test series about 0.5 mg of Ciclosporin per cm2. Apply the placebo in equivalent quantities. The composition to be tested or the placebo is not applied over an area greater than 25 cm 2 and no more than 1 g of Ciclosporin is applied per week. At each visit, the tubes containing the drug and the placebo are weighed and the daily dose applied topically is determined. Patients can bathe shortly before applying the substance. Disposable gloves are available to apply each of the treatments to avoid cross-contamination. It is necessary to wait 3 hours between the administration 49 and the washing of the treated surfaces. The first application is made under medical supervision and the patient is provided with an instruction sheet. The duration of treatment is 4 weeks. When complete elimination of lesions occurs earlier, treatment is continued until the fourth week. Patients are examined before the start of the trial (week 1), at the start of the trial (week 0) and after 1, 2, 3 and 4 weeks.

The dermatological evaluation (local psoriasis severity index or IGLP) is carried out by the same doctor, not involved in the application of the treatment, using the following numerical scales from 0 to 3:

Erythema Desquamation Skin inflammation 0 - none 0 * none 0 = none 1 minimum: 1 = minimum: 1 = minimum: erythema barely flaking barely detectable elevation; slightly defined pink noticeable very pale 2 "moderate 2 = moderate: 2 = moderate: dull red peeling well visible perceptibility well defined ceptibles giving thick scales 3 = pronounced: 3 = serious: 3 = serious: deep / peeling bright red elevation well defined; large dander well · thick to compact

The total IGLP scale is determined = the value of erythema plus scaling and more thickness = 0 to 9. To participate in the study, at least 2 signs must be moderate to pronounced for the 50 two lesions chosen ( IGLP> 5).

At the start of the study and at each visit, the area of lesions treated is evaluated (dimension at the start: 4 to 25 cm2 for each plaque). The area refers to one or more of the three criteria, erythema, scaling and skin inflammation. Pigmentation inside the lesion is not taken into account for the evaluation.

The plates are photographed before (week -1) and after the treatment (week 4). We take three photos: one showing the two lesions together and one for each lesion.

The pruritus is determined after an interview with the patient, using the following scale: 0 »none 1» minimum: occasionally feels the need to scratch.

2 = moderate: frequently feels the need to scratch.

3 = pronounced: very often feels the need to scratch, can disturb sleep.

At the end of the study, an overall evaluation of the treatment is carried out according to the following criteria:

Cleaning of the lesion = resolution of 100% significant improvement = reduction of at least 66% of the IGLP, and / or at least 66% of the surface of the plates.

moderate improvement: reduction of 33 to 65% of the IGLP, and / or of 33 to 65% of the surface of the plates.

weak improvement: reduction of less than 32% of the IGLP, and / or less than 32% of the area of the plates.

Worsening: resumption of the disease.

51

Treatment success is defined by elimination or a marked improvement in the disease.

The doctor and the patient also indicate their preference between treatment on the left or right side according to the following criteria:. significantly improved on the left side. left side slightly better. no visible difference. right side slightly better. significantly improved right side.

To check the efficacy at the end of the treatment, compare the results of the patient's iGLP and the areas of lesions using the Wilcoxon test and compare the treatments on the side treated with Ciclosporin and that treated with the placebo depending on the variations in results between the start of treatment and after 4 weeks.

All other comparisons (at other time intervals and for other efficiency parameters), including the associated p-values, are considered as indicators of progress.

In the above trial, the patients showed improvement in the psoriatic lesion, for example with regard to the IGLP results for erythema, flaking and skin inflammation, on the sides which were applied the composition to be tested according to the invention and containing Ciclosporin in comparison with the side receiving the placebo. There was also a subjective improvement as well as an improvement in the pruritus values for the sides treated with Ciclosporin, in comparison with the sides treated with placebo.

Positive results are also obtained 52 in trials following a parallel protocol on patients with atopic dermatitis whose diagnosis was made on the basis of 3 or more of the following criteria:

Pruritus

Typical morphology and distribution: lichenification at fold level or linear in adults; facial and extension lesions in infants and children, Chronic or recurrent dermatitis,

Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis); plus three or more of the following minor criteria: xerosis, ichthyosis / palmar hyperlinearitis / keratosis pilaris, immediate type hypersensitivity (type I) after skin test, elevated serum IgE level, onset of precosis (<5 years), propensity for infections skin (especially Staph. aureus and Herpes simplex) / defect in cell-mediated immunity, propensity for non-specific dermatitis of the hand or foot, nipple eczema, cheilitis, recurrent conjunctivitis, Dennie-Morgan fold lower eyelid, keratoconus, anterior subcapsular cataract, periorbital pigmentation, facial pallor / facial erythema, pityriasis alba, marked neck folds, itching during sweating, intolerance to wool and lipid solvents, worsening of the heart, intolerance with food, aggravation of lesions under the influence of emotional and environmental factors and white dermographism. The test lasts three weeks, with an evaluation on a scale of 0 to 3 for the following parameters: pruritus, erythema, exudation, abrasions and lichenification.

The topical formulations as described above in Examples 4.1 to 4.9, containing from 1 to 10% of Ciclosporin, for example the composition at 5.0% according to Example 4.7, are also effective for the treatment of dermatitis of allergic contact as well as alopecia.

In accordance with the above, the present invention also relates to:

Ciclosporin in unsolvated orthorhombic crystalline form, for example Cy-A / X-III, for example as defined in any one of points A to A7 above, for use as a medicament, for example as an immunosuppressive agent or anti-inflammatory, for example for the prevention of transplant rejection, the treatment of autoimmune or rheumatic diseases, the treatment of diseases or conditions involving an undesirable high immune system response, the treatment of parasitic infections, resistance to chemotherapeutic agents -qu.es, for example to suppress the resistance of tumors to anticancer agents, as well as the treatment of alopecia, in particular for the treatment of diseases and conditions of the skin or of the eye, for example psoriasis , atopic or contact dermatitis, corneal transplant, conjunctivitis and uveitis, by topical application, as well as the treatment of rheumatoid arthritis and other diseases .: or conditions of a cross-links, by intra-articular administration; and Ciclosporin in orthorhombic crystalline form, for example Cy-A / X-III, for example as defined in any of points A to A7 above, for use in the preparation of a medicament for use as defined above.

In the attached figure IV, the diffraction diagram was obtained using a camera f 54

Guinier-DeWolff II, using CuKa radiation λ = 1.542 Ä

TAB-IT TO I

X-ray diagram of d.i ff-ra ^ ti on of Cy-A / X-I

Line N ° d (To) I-ntens'i’té

1. 13.0 VS

2. 11.4 VS

3.10.3 VS

4. 9.7 VS

5. 9.4 VS

6. 8.25 VS

7. 7.1 S

8. 6.1M

9. 5.85 S

10. 5.6 S

11. 5.25 VS

12. 4.81 S

13. 4.58 S

14. 4.25 M

15. 4.0M

16. 3.67 M

17. 3.45 M

»55 u v

TABLE II

; Cy-A / X-II X-ray diffraction pattern

Ligfie N ° d (À) In-terVs-itë

1.17.9 S

2. 11.4 VS

3. 11.0 S

4. 10.6 M

5. 10.2 S

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 S

15. 4.85 S

16. 4.8 M

17. 4.55 M

18. 4.4 M

56

TABLE III

Di a.gramrne ‘of X-ray diffraction of Cy-A / X-III

Line '· fl0 d (À) Intensity

1.12.0 M

2. 10.4 VS

3. 9.6 S

4. 8.7 S

5. 7.9 M

6. 7.7 S

7. 6.7M

8. 6.0M

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. 4.0M

17. 3.59 M

'18. 3.38 M

vs "very strong S =, f cmte M =" oyenne

Claims (20)

1. Ciclosporin in an unsolvated orthorhombic crystalline form. 2. Ciclosporin according to claim 1, characterized in that the reticular distances are a 12.7 Â, b "15.7 Â, c - 36.3 Â, volume per asymmetric unit = 1804 Â. 3. Ciclosporin according to claim 1 or 2, characterized in that it has the following X-ray diffraction characteristics: f-- JLignè '.. No. d (Â) Intensity 1. 12.0 M 2. 10 , 4 VS 3. 9.6 S 4. 8.7 S 5. 7.9 M 6. 7.7 S 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. 4.0 M 17. 3.59 M 18. 3.38 M * * 58 VS »very strong S = strong M = medium 4. Ciclosporin according to any one of claims 1 to 3, free or substantially free from Ciclosporin in another form, or in pure or substantially pure form. 5. Ciclosporin according to any one of claims 1 to 4, in the form of fine particles. 6. Ciclosporin according to claim 5, characterized in that the particles have an average size of less than 200 µm. 7. Ciclosporin according to claim 6, characterized in that the particles have an average size of between 0.5 and 200 μΜ. 8. Ciclosporin according to claim 6 and 7, characterized in that the particles have an average size less than 25 // M. 9. Ciclosporin according to any one of claims 1 to 8, characterized in that it consists predominantly or consists entirely or almost entirely of unfragmented crystals. 10. Ciclosporin according to any one of claims 5 to 8, characterized in that the particles consist predominantly or entirely or almost entirely of unfragmented micro-crystals. 11. Ciclosporin according to any one of claims 1 to 10, characterized in that it is presented in the sterile or substantially sterile state. 12. A process for the preparation of Ciclosporin in crystalline orthorhombic unsolvated crystalline form, characterized in that Ciclosporin is crystallized in a solvent medium giving rise to Ciclosporin in crystalline orthorhombic unsolvated form and the Ciclosporin is recovered under unsolvated orthorhombic crystalline form thus obtained. 13. A pharmaceutical composition, characterized in that it comprises a) Ciclosporin in orthorhombic crystalline form as active substance and b) a pharmaceutically acceptable diluent or vehicle. 14. A pharmaceutical composition according to claim 13, characterized in that the ciclosporin present in said composition is predominantly or entirely or almost entirely in orthorhombic crystalline form. 15. A pharmaceutical composition according to claim 13 or 14, characterized in that it contains at least one compartment or one phase comprising Ciclosporin in orthorhombic crystalline form, said crystalline form being distributed or being able to be distributed in said compartment or said phase , or being distributed or capable of being distributed in a homogeneous or substantially homogeneous manner in said compartment or said phase. 16. A pharmaceutical composition according to any one of claims 13 to 15, characterized in that it comprises ciclosporin as defined in any one of claims 1 to 11. 17. A pharmaceutical composition according to any one of claims 13 to 16, in flowable form allowing topical application or administration by injection or by infusion. 18. A pharmaceutical composition according to any one of claims 13 to 17, characterized in that it comprises from 0.05 to 30% by weight of Ciclosporin relative to the total weight of the composition. 19. A Ciclosporin according to any one of claims 1 to 11, for use as a medicament. 20. A cyclosporine according to claim ÿr 19, for use as an immunosuppressive or anti-inflammatory agent.