PT89279B - METHOD FOR PREPARING A NEW CRYSTALLINE FORM OF CYCLOSPORINS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

INVENTORY DESCRIPTION MEMORY for

PROCESS FOR THE PREPARATION OF A NEW CRYSTALLINE PORK OF CYCLOSPORINS AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM

SANDOZ, S.A., Switzerland, industrial, headquartered in Basel, Switzerland.

RESUME

The invention relates to the process for the preparation of a new crystalline form of unsolvated cyclosporins crystallized in the orthorhombic system, characterized by the dissolution of cyclosporin in a dissolving medium that causes the formation of unsolvated orthorhombic crystals, promoting its crystallization and recover the unsolvated crystalline orthorhombic cyclosporine thus obtained.

The orthorhombic cyclosporins thus obtained specially, cyclosporin A, are used as an active ingredient for the preparation of pharmaceutical compositions, in particular,

in forms for topical application, for example, dermal or ophthalmic, and for application and injectable forms, for example, for intralesional or intraarticular injections.

The present invention relates to a process for the preparation of new pharmaceutical compositions comprising, as an ingredient, Ciclosporin.

Cyclosporine, or cyclosporine A, is a known fungal metabolite of valuable pharmaceutical utility. Cyclosporine is! a cyclic poly-N-methylated endecapeptide with the formula pMeBmt-d ^ Ab u-Sar-Me Leu-Val-Mel eu-Ala- (D) Ala-Mel eu-Mel and u-MeValII 234567 8 9 10 11 where -Mebmt- represents an N-met il- (4R) “4-but-2E-eq-1-yl-4-m et il- (L) tr eonyl radical ·

Ciclosporin as well as methods for their preparation esji as described, for example, U.S. Patent ^Nos ··

117 118. The main field of clinical research for Ciclosporin has been as an immunosuppressive substance, particularly in relation to its use in the treatment of recipients of organ transplants (grafts) for example, trans

I

plantations of heart, lungs, combined heart-lung, liver, kidney, pancreas, bone marrow, skin and corneal transplants and, in particular, in the treatment of allotigenic organ transplants.

In this field, Ciclosporin has made it possible to achieve important successes having achieved an excellent reputation so that today it is widely used in medicine and can be obtained commercially under the trademark SANDIMOli OR SAKDIllTULTE ^x , for example, in the form of a concentrate for infusion, a drinkable solution and a solution encapsulated in a gelatin capsule, the latter two variants being described and claimed, for example, in United States Patent no. 4 3θ8 307.

At the same time, intensive investigations were carried out regarding the possibility of applying Ciclosporin to various autoimmune diseases and inflammatory conditions, in particular inflammatory conditions with an etiology comprising an autoimmune component, such as arthritis (for example, rheumatoid arthritis, chronic progressive arthritis and deforming arthritis) and rheumatic diseases, with information on the results obtained in these trials, carried out in vitro, in animal experiments and in clinical trials, amjplamento published in the literature. Specific autoimmune diseases for which Oiclosporin has been proposed or used include autoimmune haematological disorders (comprising, for example, hemolytic anemia, aplastic anemia, purely erythrocyte anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, VZegener granulomatosis, dermatoniositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven - Johnson syndrome, "idiopathic" squeeze, autoimmune intestinal inflammation ( comprising, for example, ulcerative cyclitis and Crohn's disease, pemphigus, ophthalmopathy

endocrine aunt, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, primary juvenile diabetes (type I diabetes mellitus), behchet's disease, uveitis (anterior and posterior), conjunctivitis vernal, sicc keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, for example comprising idiopathic nephrotic syndrome or nephropathy, with minor changes).

As further research fields, the possibilities of using Cyclosporine as an antiparasitic agent, in particular as an anti-protozoic agent, in particular for the eventual use in the treatment of malaria, coccidiomycosis, and kistosomiasis, ”as well as to reverse the resistance of tumors to chemotherapeutic agents, for example to cytostatics, and to favor hair growth, for example for the treatment of alopecia.

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

The tetragonal modification (P ^), also referred to in this memory as Cy-A / X-I ”for practical reasons, is described, as are the processes for its production, for example in Austrian Patent Application N-. 353 961. AC ^ -A / XI has a reticular distance a = b = 13.8A c = 41.2A, volume per asymmetric unit = 1974 at a melting point of approximately 140-150 * C and comprises approximately 2 molecules of HgO per Cyclosporine molecule.

A first orthorhombic modification (P _{oo 9} ) can be obtained by recrystallization from diisopropyl ether, as described by R. VJenger in ”S andor ama IO84 / III in the article entitled Total synthesis-change in molecular structure -bio-

logical effect: Ciclosporina as example ”. This particular modification comprises an Oiclosporin / diisopropyl ether solvate (approximately 1: 2), with a crystalline network of: a = 12.5 A, b = 22.9 A, c = 28.4 A, one volume per asymmetric unit = 2027 A , and a melting point of approximately 150 ° C. The orthorhombic critics of Ciclosporin solvate can be obtained by recrystallizing supersaturated Ciclosporin solutions in an appropriate solvent medium for extended periods of time. Thus, the orthoremic modification of the Giclosporin / ether-diisopropyl solvate prepared by Wenger is obtained by adding a concentrated solution of Cyclosporine in methylene chloride (in which Cyclosporine dissolves more easily) to diisopropyl ether ( where Cyclosporine is relatively less soluble) and evaporation of methylene chloride. Crystallization from the remaining diisopropyl ether is then carried out for a period of approximately 7 days at room temperature. For practical reasons, the orthorhombic crystalline forms of this Cyclosporine solvate will hereinafter be referred to generically as »C _y -A / X-II».

A further orthorhombic modification (Ρ2 ^ 2 · ^ 2 · ^) has recently been identified, characterized by the absence or substantial absence of any dissolving component, that is, the one that is substantially constituted by free Cyclosporine, or that is essentially constituted by free Cyclosporine.

The dimensions of the crystal lattice of. orthorhombic modification of Ciclosporin free from solvent or unsolvated are as follows:

QOO _x a - 12.7 Δ, b = 15.7 A, c = 36.3 A, volume per asymmetric unit = 1804 A. The melting point is between approximately 180 and approximately 190 ° 0, up to approximately

195

0, depending, for example, on the degree of purity and origin,

as indicated in Examples 1 and 2 below, in which specific methods for obtaining this modification are described. For practical reasons, Cyclosporine in unsolvated (or solvent-free) orthorhombe crystalline form will be referred to below as C ^ -Α / Σ-ΙΙΙ. Subsequently, the characterization data (X-ray powder diffraction) for C, -A / X-II ± are shown in Table III and Pig. IV plus aV on, as well as the corresponding data for C-A / X-I and C.-A / X-II.

Despite the considerable success and reputation that Ciclosporina has managed to obtain, and despite its great contribution to medical science, particularly in the organ transplant sector, its own. practical use, remains unsuitable and hassle-free. One of the difficulties is the preparation of galenical forms that allow a convenient or entirely satisfactory administration, that is, more appropriate for the treatment of specific diseases or conditions for which Ciclosporin. has been identified as a potential drug of choice.

These difficulties are partly attributable to the particular physical characteristics of the company. Cyclosporine, for example to its relatively limited solubility or to its compatibility (observed to date) with available and pharmaceutically applicable carrier agents. Such difficulties are linked to the very nature of certain disease states pfí, 2? Cl -3.S which Ciclosporin, represents a potential main therapy, as well as the occurrence of unwanted side effects that Ciclosporin can induce when administered orally. Thus, for example, the effectiveness of Ciclosporin has been proven in the treatment of psoriasis after oral administration. Psoriasis is a widely spread disease that causes considerable suffering to patients and for which, today, there is no effective therapy.

that it is generally accepted. People suffering from psoriasis are obviously a population of patients who need effective treatment. Although according to the available evidence it may be assumed that Cyclosporine may satisfy this need, it seems unlikely that the administration of Cyclosporine. orally is justified, as a classic treatment for psoriasis. ' Similar considerations are applied to the treatment, for example, of ophthalmic diseases, such as posterior uveitis and sicca keratoconjunctivitis.

several systems have been proposed for the administration of Ciclos porina, including galenic forms intended for topical or dermal application or for ophthalmic application, that is, a topical application to the eye, for example, for the possible use in the treatment of psoriasis and other diseases and dermatological states or for. The treatment of uveitis. However, l such systems have so far not given remarkable results, or have not been entirely satisfactory.

Thus, several attempts to treat patients suffering from psoriasis were mentioned, applying them directly to the site of the psoriatic lesion, the known drinkable solution, but such attempts have met with minimal or no success, and the relative success of patients suffering from atopic dermatosis was strictly limited. Similarly, while topical application to the eye has proven to be largely effective as a means of prevention, for example, in the case of rejection of a corneal transplant or in treating the disease in the anterior segment of the eye, it has not been described until now. present, a topical formulation that allows an easy, safe or effective treatment of diseases or conditions that affect the deepest points of the eye, for example, for the general treatment of uveitis, including 0 for posterior uveitis.

‘Similar difficulties were encountered in relation to de7

development of other Oiclosporin administration systems, for example the injectable forms suitable, for example, for intra-articular injection in the local treatment of arthritic diseases, for example as indicated above, or for intra-lesion injection, for example, in the treatment of severe psoriatic lesions, or in relation to new oral administration systems, for example, those that have characteristics of a modified bioavailability or modified characteristics, of release of the active substance.

Until now, attempts to formulate Ciclosporin consisted of using the compound in solution or, less frequently, in amorphous form or in the form of C-A / XI, the latter being, for example, the crystalline form identified by example for active substance registration purposes. Despite the very considerable efforts that have been made in the search for new or improved alternatives, the previously mentioned drinkable solution and concentrate for infusion remain the only widely used administration systems of Ciclosporina.

In accordance with the present invention, it has now surprisingly been discovered that the cyclic orthorhombic forms of cycles by _{ia £} , for example, O _y -A / Z-II and, in particular, 0 _y -A / X-III are of special advantage and benefit in the preparation of several and diverse classes of galenic formulations of CiclospOl? Íilct ·

In particular, it has been found that such crystalline modifications can be used to prepare galenical formulations comprising Cyclosporine in the form of fine, stable particles and / or having improved stability or release characteristics. Thanks to this discovery, the path is open for the production of new and improved delivery systems of the active substance Ciclosporin, for example, systems that have characteristics of prolonged or delayed release of Ciclosporin and / or that are adapted to / or appropriate for the treatment of diseases or conditions hitherto resistant to Ciclosporin therapy, or for which conventional Ciclosporin therapy has been inherently less suitable. It has been found, more especially, that for the use of such crystalline modifications, for example, in the form of fine particles, as mentioned above, the appropriate dosage forms can be obtained for topical or dermal application, or for topical application in the eye for the treatment of diseases or conditions affecting the skin or the eye, for example as indicated above, in particular for the treatment of psoriasis, atopic dermatitis, contact dermatitis, eye symptoms of Eelichetc disease, uveitis, and sicca keratoconjunctivitis. The use of such crystalline modifications thus allows the preparation of injectable forms of Cyclosporine, which have characteristics of controlled or delayed release and, therefore, are of particular use, for example, for the treatment of diseases or conditions for patients. which the necessary frequency of administration could be an obstacle, on the other hand, to its usefulness, for example, for the treatment of arthritis diseases or similar diseases of the joints by intra-articular injection, or for the treatment of psoriasis or diseases analogous to the skin by intra-lesion injection.

For such purposes, it has been found that orthorhombic crystalline forms, in particular the C -ΙΙΙ / Σ-ΙΙΙ form, are inherently better adapted than the other available forms (in particular the amorphous forms of Cyclosporine or C -A / XI), for example in terms of physico-chemical properties, in particular in terms of stability and release characteristics,

9,

that is, the release of Oiclosporin from the crystalline network, and in terms of susceptibility to the necessary processes of the galenic formulation. C-A / X-III is new and is the preferred orthorhombic crystalline form for galenic and / or therapeutic use according to the present invention. According to a first variant, the present invention offers:

THE'

Cy-Α / Σ-ΙΙΙ, that is, Oiclosporin in orthorhombic crystalline form, unsolvated: in particular:

-A / X-III having a crystalline lattice or other physical characteristic substantially as defined above, and / or

C_-A / X-III having the Σ-ray diffraction characteristics in the powder, substantially as and defined in Table III, or as shown in Fig. IV.

The present invention also provides:

A process for the preparation of Gy-Α / Σ-ΙΙΙ, characterized by the fact that Oiclosporin crystallizes from a medium that gives rise to C -A / X-III e. then recover the 0 -A / X-III thus obtained.

The appropriate media that give rise to C--A / X-III for use in the aforementioned process are, in particular, the dissolving media for Oiclosporin, comprising dissolving components of higher molecular weight, for example having a molecular weight> 200 . Especially suitable media are those comprising high molecular weight ethers, in particular polymeric ethers, for example, polyalkyl ethers, such as, for example, polyethylene glycols, and polypropylene glycols. Examples of suitable polymeric ethers are, as demonstrated, polyethylene glycols and polypro10

pyylene glycols having, for example, a molecular weight> 200; (glycerol polyethylene glycol esters, eg glycerol polyethylene glycol ricin and glycerol polyethylene glycol oxystearates, for example those available under the trademarks Cremophor EL ”and Cremophor RH” (see Eiedler, lexikon der der Hilfsstoffe 2nd edition, Volume 1, pages 257 and 258), the polyoxyethylene esters of corbitan, for example as obtained under the trademark Tween ”(see Eiedler, 2, page 972-975); polyoxyethylene esters, for example, polyoxyethylene esters of stearic acid, for example, those marketed under the Trade Mark Myrj ”(see Eiedler, 2, p. 636); and products of trans-esterification of triglycerides of natural oils with polyoxyalkylene polyols, comprising the transesterification products of corn oil, (core) oil, sweet almond oil, peanut oil, olive oil, palm oil, and mixtures of same c with polyethylene glycols, in particular, polyethylene glycols with a molecular weight between 200 and 800, for example, those marketed under the trademark Labrafil ”(see Eiedler, Page 539). Especially suitable are media comprising polyethylene glycols having a molecular weight comprised between approximately 200 and approximately 600, in particular between approximately 300 and approximately 400.

Note that the medium that gives rise to 0 -A / X-III may comprise, in addition to the above components, one or more components, for example, low molecular weight alcohols and / or mare, as the medium that it serves to modify the characteristics of crystallization and / or solvent. A medium that gives rise to

Particularly appropriate G.-A / X-III is, as found, 'y one comprising approximately 0.5 part by volume of ethanol, approximately 8.0 part by volume of polyethylene glycol (300) and approximately 1.0 part by volume. volume of B ^ O.

The process of the present invention comprises, first, dissolution, at an elevated temperature, of Oiclosporin, for example in amorphous, or tetragonal form, in the selected medium, giving rise to G -A / X-III. The dissolution temperature will vary depending on the particular medium chosen, but in general it will be> 40 ° 0, in particular> 50 ° G. In the case of media based on polyethylene glycol, the dissolution temperature will, in general, be ^ 70 ° 0, for example, between approximately 75 and 130 ° G. The solution obtained will advantageously comprise> 5 1 ° by weight of Cyclosporine, for example example> 10 for example, up to approximately 40-50 preferably, up to a maximum of 20% by weight of Oiclosporin based on the total weight of the solution. The crystallization of Oiclosporin is then allowed to proceed, under cooling, advantageously for a prolonged period of time, for example between 10 and 35 minutes or more, depending on the desired size of the crystals.

The desired nucleation processes can be initiated, for example, by treatment with ultrasound or by adding germs. When using ethanol-polyethylene glycol / / H? 0 media containing crystals, for example as described above, if, for example, nucleation can easily be carried out at temperatures between approximately 50 and 90 ° C, for example between 55 and 85 ° G, by applying ultrasonic vibrations at approximately -20 000 cpc (cycles per second). As indicated in Example 2 below, thus continuing ultrasonic treatment throughout the course of crystallization, very fine micro-crystals of relatively constant dimensions can be obtained.

The growth rate of the crystals and the size of the crystals obtained will depend, from the outset, on the particular medium chosen and the conditions under which crystallization is carried out, for example, whether the treatment is carried out under ultrasonic or not and at what frequency. For use according to

with the present invention, for example, for the preparation of galenical formulations as described below, C _T -A / Z-III will preferably be used in the form of fine particles, for example, having a medium size less than 200 æ5 for example, between 0.5 to 200 æM. If crystals of relatively large size are initially obtained, particle preparations having the desired size characteristics can, of course, be obtained according to the usual procedures allowing one. reduction of particle size, for example, by crushing, grinding, spraying; micronization or other processes designed to reduce particle size. While the preparations obtained in this way may be entirely suitable for certain applications, for example, for the preparation of topical compositions intended to be applied to the skin, there are many other cases in which neither the grinding or grinding processes are preferred, nor other equivalent techniques; the reason for this is that the products of such processes tend to exhibit a relatively wide particle size distribution and a relatively coarse or abrasive structure, as a result of the fracture of the crystals. In addition, these grinding processes tend to destroy the physical characteristics of the natural surface of the crystals, being, in each case, difficult or expensive to carry out such processes while maintaining the required sterility conditions, for example, in manufacturing galenic formulations for intra-articular administration. For that reason, it is usually preferred to carry out the process of the invention in such a way. obtaining crystals, for example, microcrystals, with a dimension in the final desired range of particle size. So, for, use us. preparation, for example, of compositions intended for administration by intra-articular route, or for another parenteral application, preferably preparations of particles of 0 -A / X-III in «7

non-fragmented microcrystalline form (that is to say C ^ -A / Z-III microcrystals in the natural or non-fragred state, which have not been subjected to, for example, crushing or grinding, nor micronisation, or other processes of particle size reduction.

To obtain the Cj-A / Z-III microcrystals that can be used directly in the non-fragmented state, as described above, the process of the invention will be conveniently carried out under agitation, for example, by stirring throughout the crystallization process, for example at 200-300 revolutions per minute and increasing, for example, to 700 revolutions per minute and, in particular, by applying ultrasonic vibrations, for example, between 10 000-30 000 cycles per second, advantageously from approximately 20,000 cycles per second.

By varying the medium that gives rise to C -Α / Σ-ΙΙΙ and adjusted to the speed «/ cooling city and the degree of agitation during the recrystallization processes according to the techniques known in the art and described later in the Examples, they can be prepared ss 0 -Α / Σ-micr microcrystals which have a varied average size, for example as indicated above, or as described below for use in connection with the individual types of galenical formulations according to the invention.

As indicated above, crystallization according to the process of the invention will be carried out under sterile conditions. The purification of the obtained C -Α / Σ-ΙΙΙ can be carried out according to usual methods, for example, by rinsing with polyethylene glycol (300) and water, for example in a proportion of 3-4: 1 parts by weight and by washing with hot water, as described in the Examples below. The 0 ^ ² Α / Σ-ΙΙΙ thus obtained will be advantageously recovered in an exempt state and

or substantially free of any other form of Cyclosporine, preferably in pure or substantially pure form. The rinsing phase mentioned above prevents the formation of amorphous Cyclosporine.

According to what has been said above, the present invention additionally offers a Cyclosporine prepared according to any of the processes described above, as well as:

to C -A / A-1II, in accordance with any of points A to 2

To the previous ones, exempt or substantially exempt from

Ciclosporin in any other form, for example, free or substantially free of Ciclosporin in amorphous form, C - / X-I or C -Α / Σ-ΙΙ;

y y

A ⁴ to C -A / Z-III, according to any of the points A to A above, in pure or substantially pure form;

to 0 -A / A-III, according to any of the points A to A above, in the form of fine particles having, for example, the particle size characteristics as described above or described below, for example, in relation to the galenic forms containing C -Α / Σ-ΙΙΙ;

a C -A / A-III, according to any of the previous points A to A y _f , constituted predominantly or entirely constituted or almost entirely constituted by a non-fragmented crystalline matter, for example C -A / X-III, of according to the aforementioned A ^, y _t in which the component particles are predominantly or entirely or almost entirely made up of non-fragmented microcrystals; and

A to C _T -A / X-III, according to any of the points A to 1 above, in a sterile or substantially sterile state, for example, in a state suitable for pharmaceutical use, in particular suitable for parenteral administration, for example, for administration by parenteral injection, for example, an intra-articular injection.

The present invention further offers:

C A pharmaceutical composition comprising:

a) As an active substance, an Oiclosporin in orthorhombic crystalline form, in association with

b) a pharmaceutically acceptable diluent or carrier.

Oiclosporin. it can be present in the compositions of the invention in any suitable orthorhombic crystalline form, for example even C ^-A / X-II or C-A / X-III. The use of 0 -A / X-II will, however, in general be less preferred due to its physico-chemical properties, which are less suitable for use in terms of tolerability and usability for the preparation of effective pharmaceutical products. based on Oiclosporin. Most preferably, Ciclosporin will be present in the compositions of the invention in the form of

C _T -A / X-III, for example, according to any of the points AJ η to A previously indicated.

Although Oiclosporin is present in the compositions of the invention in solid (crystalline) form, the compositions themselves may be of any suitable constitution. The compositions according to the invention therefore include both solid forms, such as capsules, lozenges, dragees, powders and granules, as well as semi-solid forms, such as ointments, gels, creams, and pastes and also forms liquids, which comprise, for example, the Cyclosporine component defined as fine particles (for example in micronized or micro-particulate form) suspended or dispersed in a diluent or carrier, pharmaceutical, liquid, in which the crystalline form chosen may be preserved.

The compositions according to the invention include both systems, that is, systems consisting of a single phase or a single compartment containing Cyclosporine, for example, creams, gels, simple ointments, etc., as indicated above, or simple capsules or ampoules of a compartment, for example, hard or soft gelatine capsules or ampoules for injection, as well as systems comprising several phases or compartments. Therefore, the invention is to be understood as encompassing, for example, compositions comprising a phase or a compartment containing Ciclosporin together with one or more phases or a compartment which does not contain porous cycles, for example, the coating phases , carrier, delayed or placebo substances, or phases or compartments comprising other active substances or other adjuvant materials. The invention therefore comprises, for example: coated tablets consisting of a nucleus containing Cyclosporine in the form of orthorhombic crystals, wherein said nucleus is coated, for example, by other coating phases or the like that do not contain Cyclosporine; double tablets (mantle tablets) in which Cyclosporine in orthorhombic form is found either in the nucleus or in the coating; mixed granulates comprising a first granulate phase comprising Ciclosporin in the form of orthorhombic crystals and a second granulate phase free of Ciclosporin; and divided capsules having two or more compartments, for example,

capsules divided by an internal wall, containing Ulm of the co-parts of Ciclosporin in the form of orthorhombic crystals and the other containing no Ciclosporin. Other alternatives and variants are evident to experts.

In the compositions of the invention, Cyclosporine will preferably be present predominantly or, preferably, entirely or almost entirely in the form of orthorhombic crystals, for example in the form of C -Α / Σ-ΙΙΙ.

The compositions of the invention advantageously comprise at least one phase or a compartment containing Cyclosporine in the form of orthorhombic crystals, for example C-A / X-III in which said crystalline form is uniformly distributed or is distributable. Such systems include, for example, creams, ointments, homogeneous and similar gels and also liquid systems in which the crystalline cyclosporine contained therein can be or can be homogeneously distributed easily, for example, by hand agitation. .

The compositions according to the invention can include forms suitable for, topical application, for example, for a dermal or topical application on the eye; for parenteral administration, for example, by infusion or injection, including by subcutaneous or intramuscular injection and, in particular, for an intra-lesion or intra-articular injection; and also the forms destined for an enteral administration, for example - of suppositories, of ^!, pe · sarios and the like and the forms for, an oral administration, however, the forms for the enteral administration;., for example, oral dosage forms will generally be the least preferred forms

Cyclosporine, in orthorhombic crystalline form, for example, C, -A / n-III, is present in the compositions of the invention, preferably in the form of fine particles, for example

in a micronised, micro-particle or non-fragmented micro-crystalline form, as described above, an appropriate particle size will depend, of course, on the particular nature of the composition, the use for which it is intended, and the mode of application and the desired effects. In general, however, the average particle size will advantageously be between 0.5 and 200 µl. Particular orders, for example, regarding the preparation of oral, topical or injectable forms are, moreover, indicated below.

IQPIOAS suitable, for example, for a dermal or topical application on the eye, for example, for treatment>

psoriasis or atopic dermatosis or aawiii- wr ^ -awi / tc- * ur wmmí — w —— »- w —— i -f: τ · ·, · ιι · ι jucj ·· - · ι · «^ · Μ« <—— μ —— μμ »μ · ^ · -γγ ·.

of the eye that need an immunosuppressive treatment, for example, uveitis, conjunctivitis, including that of the rat with siocg- or vernal keratoconjunctivitis or corneal transplants preparation of gels, creams, ointments, and ' of analogous forms intended for topical or dermal application, it can be carried out according to any of the known and commonly used techniques in the art, for example, combining ichiclospoir in an orthorhombic crystalline form with an appropriate fluid based material, for example a aqueous gel, for example a gel based on cellulosic ether and adding appropriate surfactants, thickeners etc., comprising for example Aerosil.

The -Cielosporin component is preferably present in the fine particulate naphtha, for example, with an average particle size between 0.5 and 2 µM. The bad dimensionHadsspbr

particles is preferably less than 50-80 µm, more preferably less than 40 µm, in particular less than 30 µM, more preferably less than 20 µM. The particles advantageously have the particle size distribution as narrow as possible. Preferably, all particles present will be essentially less than 60-80

Compositions of the invention intended for topical ophthalmic use, or application to the eye, may comprise, for example, sufficiently thick suspensions or dispersions presented, for example, in the form of viscous preparations for eye drops or of creams or gels for application to the eye, In the case of compositions intended for administration to the eye, the average particle size of crystalline Cyclosporine present will be advantageously less than 25 µm. Most preferably, all particles present will be substantially less than 25 µg / hf. The average particle size for such eye drop preparations is advantageously between approximately 0.1 or, preferably, between approximately 0.5 and approximately 20 yufá or, preferably, approximately 10 µl.

hydrophilic / lipophilic component content of the system that serves as a carrier for use in forms intended for dermal application or for use in preparations intended & ophthalmic application may vary, for example, depending on the particular surface on which the composition is to be applied , for example, depending on the characteristics of the particular skin area to be treated.

Compositions for topical application, in particular for dermal application, advantageously comprise a carrier medium in which the active substance (the Cyclosporine component) is only slightly soluble. Advantageously, the solubility of

Ciclosporin (for example »C -A / ^ IXI) in the

of the compositions is less than 10%, preferably less than 1.0% by weight. Preferably, the solubility is less than 0.1%, more preferably less than 0.001% by weight

Suitable carrier media comprise both hydrophilic, water-miscible carrier agents and hydrophobic carrier agents.

Hydrophilic vehicle components, mixable with water,. advantageously have relatively low volatility.

Examples of suitable vehicle components belonging to this class include liquid polyalkylene glycols, propylene glycol, glycerol, and ethylene glycol. Suitable polyalkyl glycols can be mentioned, in particular, liquid polyethylene glycols, having for example an average molecular weight of up to approximately 600, for example ones with an average molecular weight of approximately 250 to

AP in the special of approximately 300.

Representative compositions according to the invention, intended, for example, for topical application, therefore comprise;

,1.

Cielosporin in orthorhombic crystalline form, preferably in unsolvated orthorhombic crystalline form, for example 0 -A / Z-III, as defined, in any of the above points A to À;

b) a hydrophilic carrier, mixable with water, therefore as described above; and optionally

o) pharmaceutical grade water.

The amount of component (a) present is advantageously between approximately 0.1 and approximately 30.0%,

in particular between approximately 0.5 or 1.0 and 20%, for example approximately 1.0, 2.0, 5.0 or 10.0 7 by weight based on the total weight of the composition. The components (b) and (c) will advantageously be present in a ratio between 1: C and 1: 20 parts by weight. advantageously, components (b) and (c) will be present in a ratio between 1: 0.5 and 1: 5, for example between 1: 1 and 1: 3, more preferably between 1: 1.5 and 1 : 2.5 parts by weight.

These compositions will also advantageously comprise:

d) a surfactant.

Components (d) include, among others:

d ¹ Triglyceride trans-esterification products from natural vegetable oils with polyalkylene polyols. Said trans-esterification products are known in the art and can be obtained, for example, according to the general processes described in Strong American Patent IT ² 3 288 824. They include the trans-esterification products of various natural vegetable oils (eg (eg, non-hydrogenated) such as, for example, corn oil, walnut kernel oil, almond oil, milled walnut oil, olive oil, and palm oil, as well as mixtures of such oils with polyethylene glycols, in particular with polyethylene glycols having an average molecular weight between 200 and 800. Products obtained by transesterification of 2 molar parts of a natural vegetable oil triglyceride with a molar part of polyethylene glycol (for example, with an average molecular weight are preferred) 200 to 800). Several forms of trans-esterification product of the defined class are known and commercially obtained under the Commercial label labrafil

/ see Piedler, lexikon der Hilfsstoffe ”, 2 ^. edition, Revista e Completada (1981), Volume 2, p. 539? ·

Of special use as components of the compositions of the invention are the products:

iahrafil If 1944 CS, a trans-esterification product of walnut "core" oil with polyethylene glycol having an acid number of approximately 2, a saponification number of 145-175 and an iodine number of SC-20; and Labrafil M 2130 CS, a transesterification product of a glyceride with 12 to 18 carbon atoms with polyethylene glycol having a melting point of approximately 35 to 40 ° C, an acid index <2, a saponification index of approximately 185 to 200 and an iodine index <3.

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 reacting a natural or hydrogenated castor oil with ethylene oxide, for example, in a molar ratio between approximately 1: 35 and approximately 1: 60, with elimination option of the product's polyethylene glycol component, for example, according to the methods described in German Patent Applications 1 182 388 and 1 518 819. Especially suitable are the various surfactants sold under the Trademark Cremophor. Cremophor RH 40 products are particularly suitable, having a saponification index of approximately 5C-S0, an acid index <1, an iodine index <íl, a water content (fischer) <2 $ £, a η ^ value βΟ of approximately 1.453 to 1.4578 and a HEB value of approximately 14 to 16; Cremophor RHSO having a saponification index of approximately 40 to 50, an index r <!

acid <1, an iodine index <1, a water content (pischer) of 4.5 to 5.5, a n ^ 25 value of approximately 1.453 to 1.57 and an HLB value of approximately 15 to 17; and Cremophor EI having a molecular weight (sol vapor osmometry) of approximately 1630, a saponification index of approximately 65 to 70, an acid index of approximately 2, an iodine index of approximately 28 to 32 and an n _D 25 value of approximately 1,471. The various surfactants sold under the NIKKOL Trademark, for example ο ΕΣΕΕΟΙ HC0-60, are also suitable.

said product uIEECE HC0-60 and a reaction product of hydrogenated castor oil with ethylene oxide having the following characteristics: acid index of 0.3 saponification index of 47.4 hydroxyl value 42.5; pH (5 ') of 4.6; Apha color = 40; melting point of 36.0 ° C; freezing point of 32.4 ° 0; 0.03 B ^ O (^ kP) content;

fatty acid esters with polyoxyethylene sorbitan ethers or polysorbates, for example, those known and marketed, for example, under the Trademark, Comercial Tisreen and Armotan (see Piedler, 2, p. 745-746 and 972-975 ) products comprising Tween 20 ^ polyoxyethylene (20) sorbitan? monolaurate / polyoxyethylene (20) sorbitan monopalmitate ?, / polyoxyethylene (20) sorbitan? monostearate / polyoxyethylene (20) sorbitan? tristearate ?,

SO / polyoxyethylene (20) sorbitan? Monooleate / polyoxyethylene (20) sorbitan? Trioleate / polyoxyethylene (4) sorbitan? Monolaurate / polyoxyethylene (4) sorbitan monostearate? and

/ polyoxyethylenc (5) sorbitan monooleate7.

d ^ Fatty acid esters of polyoxyethylene ethers, for example, esters of stearic acid with polyoxyethylene ethers of the type known and marketed under the trade name Myrj (see Fiedler, 2, p. S3> 5) as well as fatty acid esters of polyoxyethylene ethers known and marketed under the Trade Mark Getiol ΗΞ (see Piedler, 1, p. 228) and polyoxyethylene ethers of fatty alcohols, for example stearyl, oleyl, or cetyl ethers, polyoxyethylene, for example, those known and marketed under the Trademark Brij (see iiedler 1, 184-186), for example Brij 78 θ 95 and Cetomacrogel 1000 (see Biedler, 1, 229) j d ' 'Polyoxyethylene-polyoxypropylene copolymers, for example those known and marketed under the Trade Mark Pluronic and Smkalyx (see Piedler, 2, p. 720-722);

d 'Sorbent fatty acid esters, for example those of the known type and commercially available under the Trade Mark Span, comprising, for example, monolauryl, monopalmityl, monostearyl, tristearyl, monooleyl, and trioleyl esters sorbitan (see Piedler, 2, p. 850-851);

d 'Partial glycerides, for example products comprising mono- and / or di-glycerides components, for example, surfactants based on mixtures of monc- / di- / tri-glycerides / glycerol, as well as by example, glycerol monostearates and mono25

glycerol oleates. Examples of such products include the products known and marketed under the Commercial Earphones IMUITOR (see Fiedler 1, 491), for example Iiraritor 191 and ImmLtor 780 and Softigen (see Fiedler, 2, 833) for example Softigen 701);

Q d

Ionic surfactants or emulsifying agents, such as sodium lauryl sulfate and sodium keto stearyl sulfate.

The components (d), when present, are advantageously present in an amount up to a maximum of 30%, preferably up to a maximum of 15% by weight, based on the total weight of the composition. 32 is particularly suitable when components (d) are present in an amount of approximately C, 5 to approximately 10%, for example approximately 1.0% by weight, based on the total weight of the composition.

Such compositions also advantageously comprise:

and A thickener component.

The appropriate components (e) comprise, for example, the following components:

ΐ e Polymethylacrylic resins, for example, of the type known and marketed under the trademark Eudispert (see Fiedler, 1, 371-372).

Cellulose derivatives including, for example, ethyl cellulose, xoropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and carboxymethyl cellulose;

Polyvinyl resins, comprising, for example,

polyvinyl alcohols and polyvinylpyrrolidones, as well as other polymeric materials, including gelatins, alginates, pectins, tragacanth gum, arabic gum, xanthan gum, and pliacrylic acids, such as those known and marketed under the Commercial brand Carbopol (see Fiedler,

1, 206-207);

materials such as silica gel, bentonite, magnesium silicate and aluminum.

Cumulent Cs b (e), if present, are advantageously present in a maximum amount of 20 most preferably up to 10 by weight based on the total weight of the composition. Advantageously, the components (e) are present in an amount between approximately 0.5 θ approximately 15, especially between approximately

1, C and approximately 3.0 by weight, based on the total weight of the composition.

In addition, such compositions advantageously also comprise an antimicrobial agent, such as methylparaben, propylparaben, benzalkonium chloride, and benzyl alcohol, for example in an amount comprised between 0.05 and 0.5% or, in the case of alcohol benzyl, up to 2.0 for example approximately 1.0 by weight, calculated on the total weight of the composition.

As alternative carrier media, hydrophobic materials are taken into account, for example those which meet the solubility criteria in relation to the active ingredient previously specified. Other preferred compositions according to the invention, for example, for topical application, therefore require:

U. a r ·

Q ~ a) Cyclosporine in orthorhombic crystalline form,

27.

preferably in unsolvated orthorhombic crystalline form, for example, G -A / X-III, as defined 73 'under A to A' above; and

f) a hydrophobic carrier, for example, as previously indicated.

The amount of component (a) is advantageously as described above in relation to the compositions as defined under the appropriate components (f). For example, petroleum derivatives, comprising mineral oils, fats and gelatines, such as, for example, petrolatum (fat, mineral or petroleum gelatin), liquid petrolatum (white mineral oil or liquid paraffin), or any products known and commercially available under the Veseline Trademark / see Fiedler, loc. cit. 2, 9857, as well as lanolin-based nonionic derivatives, such as those obtainable under the Amerchol Trademark, for example Amerchol GAE (see Fiedler, 1, · 119-120).

Further suitable components (f) comprise, for example, natural or saturated vegetable or fats and oils, for example, fractionated coconut oils known and marketed under the Miglyol commercial market, 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 known and marketed under the Brand Commercial Eutanol G (see Fiedler, 1, 375).

Such compositions may also comprise one or more of any of the components (d) and (e) mentioned above, as well as one or more anti-microbial agents, for example as described above.

Said compositions may additionally comprise one or more components (d), advantageously in an amount up to a maximum of 30%, more preferably up to a maximum of 20%, advantageously an amount comprised between approximately 1 / and approximately 15% by weight, calculated on the total weight ds. composition.

The hydrophobic compositions, according to 0 and comprising an emulsifying component (d), can also be prepared in the form of creams or emulsions by adding water. The creams or emulsions obtained can be of the oil-in-water type or of the water.-in-oil type. The amount of water present in such compositions can therefore vary, for example, from 5% to 80%, preferably from 20% to 70% based on the total weight of the composition.

The amounts of components (e) and anti-microbial agent, if incorporated, will be of the same order or identical to the amounts indicated for the compositions of the invention according to 0, above.

The amount of any form used for topical application will vary, depending on the concentration of the composition, the condition to be treated and the treatments. desired effects and, in the course of a dermal application, also of the area to be covered, as in the case of compositions intended for dermal application, for example for the treatment of psoriasis or atopic dermatosis, the quarters applied will generally be sufficient to provide a dosage of Cyclosporine between approximately 0.1 and approximately 5 mg / cm, for example approximately 0.5 mg / cm, applied, for example twice a day over the desired area. In the case of ophthalmic preparations, administration is advantageously carried out using preparations containing approximately 0.1 to approximately 10 for example 1.0% or 2% by weight of Ciclosporin applied to each eye in the form of 1 to 3 drops times a day.

IMPROVABLE SCHEDULE, for example, for subcutaneous, intra-muscular or other parenteral injection, including, in particular, intra-articular injection, for example, for the treatment of arthritis diseases, such as rheumatoid arthritis, or for Intra-injury injection, for example, for the treatment of psoriasis.

Δε 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 in general in the art, for example, by dispersion, suspension or any distribution of the Cyclosporine in the orthorhombic crystalline form of fine particles in an appropriate liquid carrier medium, by adding appropriate emulsifying agents, surfactants, stabilizers or flocculating agents, etc. In these compositions, the said Cyclosporine component will have, preferably, an average particle size less than 100 µm, in particular less than 50, more preferably less than 20 k, average particle size will advantageously be between 0.1 and 0.5 and up to the indicated maximum of 20, 50 or ICC yUlÕ.

If you want the injectable forms to have, for example, a depot effect ”, for example for a subI injection

-cutaneous or intramuscularly, larger particles may be used. If these forms are intended for intra-lesion application or, in particular, for intra-articular injection, it is recommended to use finer nartinuery preparations. For these uses, the particle size, 'irod.içí, d. £ ts, is advantageously comprised, for example, between approximately 0.1 or approximately 0.5 and even approximately: between 20 µm, for example approximately 5 at approximately 15 / ff

In order to stabilize the particles in the injectable forms, for example, to prevent an increase in the size of the larger crystalline particles at the expense of the smaller crystalline particles, the particle size should preferably be as uniform as possible. Advantageously, the variation between the maximum and minimum particle size will not exceed approximately 50 yUM, more preferably, will not exceed approximately 20

Although it is possible to achieve the desired size of the particles through the appropriate fragmentation processes, for example, by micronisation, it will generally be preferable to use non-fragmented micro-crystals, that is, crystals that have developed up to the dimensions (as described above) to minimize variations in particle sizes, to prevent the presence of fragmented particles and to modify the surface of crystals, for example to preserve moisture characteristics and to more easily meet the required sterility requirements .

Accordingly, the injectable compositions according to the invention advantageously comprise:

^c a) Cyclosporine in orthorhombic crystalline form, preferably in unsolvated orthorhombic crystalline form, for example, C-A / X-III, for example such as 7 as defined under any of points A to A, in particular under A ° and A 'above, distributed or likely to be distributed,

b) in a vehicle for injection.

Suitable carrier media comprise, in particular, pharmaceutical grade water.

In addition, the compositions as defined under C comprise 31

will give advantageously;

g) air, surfactants as a dispersing or emulsifying agent and / or a flocculating agent, to ensure or maintain the distribution of particles in the carrier.

As appropriate surfactant components (g), mention may be made of sorbitan polyoxyethylene fatty acid esters or polysorbates, for example as indicated in (d ^J ) above, for example, Tween 80 or Polysorbate 80 ( see Eiedler, 2, page 746). Suitable flocculating agents (g) include ethylenediamine-tetraacetic acid and its salts, for example ELSA calcium and 33ΤΔ sodium, coconut and other equivalent chelating agents, and peptizing agents such as acid succinic and citric acid.

To maintain the particle size distribution, a stabilizing agent is also incorporated. Suitable stabilizing agents include, for example, gelatins or modified gelatins, such as plasma substitutes known and marketed under the Trademarks Gelafundin and Haemaccel, or cold water-soluble gelatins, of highly collagen hydrolysates. Purifiable compositions according to GC, may also contain one or more anti-microbial agents, for example such as those described above, and also peptizing agents, such as

The Swedish action is the chemical acyl.

weighting between components (a); (b) in the compositions', 3 definitions defined under C, this one advantageously included

2T; 10 and 1:

; > C O O ·; 1,000, preferably between 1; 50 for example approximately 1; 100 pieces in

200, JC / ^st order not to unduly affect the stability of the pair · particulates, will be used, preferably the surfactants present as component (g), only in minute concentrations, for example from 0, 1 to 2.0 /, advantageously approximately 1 γ by weight, based on the weight of component (a). If a flocculating agent is present, the relationship between the flocculating agent and component (a) • -J. ,

-There.

It will advantageously comprise between 1: 3 and 1: 8 parts by weight, for example, approximately 1: 5 parts by weight, if a stabilizing agent is present, the relationship between component (a): agent stabilization, it will be advantageously between 1: 5 and 1: 30, more preferably between 1 ί 10 and 1 ί 30, for example, of approximately 1:20 parts by weight. If a peptizing agent is used, the ratio between the peptizing agent and component (a) will be advantageously comprised between 1: 1 and 1: 10, for example approximately 1: 15 parts by weight.

The amount of Oiclosporin present in the unit dosage forms intended for injection according to the invention will vary from the first, depending, for example, on the condition to be treated, the injection zone and the desired effect, for example, when wishes to obtain a prolonged release effect or a relatively quick release in neighboring tissues. Suitable individual unit dosage forms will comprise approximately 10 to 500 milligrams of Oiclosporin, in particular approximately 20 to 100 milligrams per dosage.

As can be seen, the unit dosage forms according to the invention also comprise more complex systems, for example double-compartment syringes, in which the Oiclosporin particles as well as the other appropriate components, for example the stabilizing agent or the anti-microbial agent, are contained in a first compartment and the carrier medium is in a second compartment, the components of the two compartments will be mixed, for example, through the action of the syringe piston. Such double-compartment syringe systems are well known in the art and the unit dosage forms comprised therein should be understood to form part of the present invention as well.

FOBI1AS ΗΞ DOSAGE FOR ORAL ADMINISTRATION, for example, for the treatment of autoimmune diseases and conditions and other conditions as specified above, for example, for the prevention of transplant rejections according to the interest but there are dosage forms for, oral administration with the present invention generally has a minor and is therefore less preferred, such forms are also included within the scope of the present invention. Forms for oral administration according to the Invention can be prepared using any appropriate carrier or carrier, as known and used in the art. Liquid or semi-liquid forms intended for administration- by vis. oral, they may comprise, for example, Oiclosporin in orthorhombic crystalline form, for example, C -Α / Σ-ΙΙΙ association with formally acceptable diluents or carrier agents in which the crystalline form is, in itself, insoluble or substantially insoluble

Said carrier agents and diluents comprise, for example, the trans-esterification products of triglycerides from natural vegetable oils with polyoxyalkylene polyols, such as those described above under (d), for example those

Labraíils, as well as products obtained by reacting natural or hydrogenated castor oil with ethylene oxide, • o 1 as described above under (d ^z ), in particular products

Liquid Jremophors, for example the product Círemophore EI.

n Oiclcsporin is preferably present in the form of fine particles having, for example, an average size between 0.5 θ 20G ^ uE, in particular between, for example, 5 s 30 yUli, preferably less than 20 yUll, comprised by example, between 0.5 and 10 / UlI.

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

unit dosage forms according to the invention for oral administration will advantageously comprise an amount of Ciclosporin between approximately 25 and approximately 75, or up to 200, for example 1 and approximately 50 to 100 mg of Ciclosporin. Such forms are administered for example, 1 to 4 times a day to achieve concentrations of Ciclosporin in the plasma of the individual patient (for example, as determined by RIA) identical or equivalent to the concentrations obtained by a fabitus.l treatment with Ciclosporin, for example, using a drinking solution of Cyclosporine.

; ingredients indicated in this Memorandum or defined as components of the pharmaceutical compositions of the invention are to be understood as being suitable for pharmaceutical application, for example in the case of ingredients or compositions intended for oral administration (as they are pharmaceutically acceptable) , or, in the case of ingredients of compositions intended for topical application, leonforme are acceptable or downloadable from a topical point of view

for example from a dermal or ophthalmic point of view.

galore rorsias intended for administration by equivalent or alternative routes to those described above, will be known to a person skilled in the art.

BXfhPLQ _m 1 ^: Preparation of 0 -A / X-lII 'Τ''™-' * - · ' ^! J

a) Dissolve 100 g of Ciclosporin in amorphous form with stirring in 400 g of polyethylene glycol 300 at 50 ° G. The formation of C ^ -A / 1-ΙΙΙ begins shortly after the dissolution is completed. The solution is left to stand for 24 to 48 hours, at a temperature of approximately 35 to 40 ° C, to finish the crystallization and immediately diluted the solution with 1000 ml of water, with vigorous stirring. The precipitate obtained by filtration is separated, washed with HgO to remove the remaining polyethylene glycol and dried, obtaining 0 -Α / Σ-ΙΙΙ in essentially pure form: melting point = 195 0, dimension particle size = approximately 100 - 200 yuM.

The forms of 0 -A / Z-III can be prepared in a manner analogous to the process described above, but using the following materials as a solvent, instead of the 30C polyethylene glycol used above:

P.F. FOR THE C -A / Z-III OBTAINED (° C)

T.WTs? V TDx '»i

B) Polyethylene glycol 300 / Cremoph.ore EH 40 (1: 1) volume) ç) Cremopliore EL 190 d) Solutol HS 15 188 and) Gelucire 44/14 180 f) Eyrj 52 184 g) Tveen 80 186 li) Cremophor EH 40 190

Pr: each of the chaos, the average particle size is between approximately 50 and approximately 200 1 / uA. K determined reticular structure is as defined before river rr

The X-ray diffraction data is as described below in Table III and Fig. IV.

20 2: Preparation of C _y -A / X-III

Dissolve 20 g of Cielosporin as 0 -Α / Σ-Ι in 60 ml of ethanol and concentrate the solution to 1/6 of its original volume by distillation, under reduced pressure, at a temperature greater than 50 ° C. Then, 160 ml of polyethylene glycol (molecular weight 300) + 20 ml of liquid are added slowly at a temperature of 50 - 85 ° C, with stirring at 300 revolutions per minute. An ultrasound vibrator / mixer is installed in the solution, operating at 20,000 revolutions per second. Nucleation begins at 55-75 ° C for 3 to 5 minutes. Harness37

then the dispersion obtained for 10 to 20. minutes is

s. 4C ° C, with continuous agitation at 700 revolutions per minute and ultrasound vibration. The thick, pasty mixture obtained is then filtered, rinsed with polyethylene glycol (molecular weight 300) / H ₂ 0 (3: 1 parts by volume), washed with hot water (30 ° 0) and dried at 50 ° 0 in high vacuum with which it is obtained at 0 -Α / Σ-ΙΙΙ in pure form: melting point = 192 ° 0. Diy measurement of particles = 3-15 yuM. The lattice structure is determined as described above. The diffraction data of the li rays are described below in Table III and Pigu. IV.

Experiments carried out repeatedly show that the size of the crystals depends more on the core temperature and the speed of growth of the crystals than on the duration of the process. In this way, starting the nucleation at approximately 75 ° C and continuing the crystallization at the same temperature, an average size of the crystalline particles of approximately 50 µm is obtained. -v

REPAIR OF PEA PORÍÍA GALELTICA PAF.A ADEIRISTRAÇÃO BY VIA

ORAL

3 · 1 Preparations I encapsulated in gelatin /

t

At a high temperature (using a colloidal mill), a suspension comprising 20% by weight of the obtained C-A / X-III is used. according to the procedure of Example 1 in Gelucire 44/14,

Cí- θ 40 '3 obtain a particle size of 0 -A / X-III comprised between 0.5 and 10 µP.

250 mg portions of the obtained ground suspension, in ητ κχ U.-X - n. * · size 2 hard gelatin insulas, each capillary comprising 50 mg of Cyclosporine (in the form of C -A / Z-III) as ingredient agent.

3.2 Preparation 11 encapsulated in Gelatin the C ^ -A / Z-III is obtained, obtained according to the procedure of Example 1, in a colloidal mill, until there is a particle size of Is C ^ -A / X-III between 0.5 and 20. Then 50 mg portions are intimately mixed with 200 g of Crsmophorí and placed in size 2 hard gelatin capsules, each capsule comprising 50 mg of Cyclosporine <in the form of C, -A / Z -III) as an active ingredient.

^ hEPAPAQAQ IF PQPKAS GÀhEdICAS FOR TOPICAL APPLICATION

PHEPAEAÇAO I DS GEL a C -A / X-III obtained according to the procedures of Example 1, in an air-jet mill ”. The micronised product is then combined, having a maximum particle size of 60-70 dd and an average particle size of 2 - 10 hM. e / n, it is mixed in the usual way with the ingredients listed in the following table, to provide an aqueous gel comprising 10% by weight of Cyclosporine (such as C -Α / Σ-ΪΙΙ) suitable for topical application, for example for the treatment of psoriasis.

IN WEIGHT

IMCREDIEHTE

The) CIOLOSPORIEA (C_-A / X-III y micronized) 10.0 B). Polyacrylic acid (Carbopol 934 ??) 0 , 5 and) ITaOH solution (at 5 m) 3 , 0 d) Tilparah me 0 , 07 •s) Pro pilparaben 0 , 03 f) 20 (pharmaceutical grade) up until 100 , 0% 4.2 GEL PREPARATION II 144 ED13ETE IN WEIGHT Composition THE Composition The) GIOCOSPOEIEA (0 -A / X-III micronized) 10.0 1.0 B) Polyethylene glycol 300 30.0 30.0 ç) Labrafil M 2130 OS 1.0 1.0 d) Carbopol 934 P 1.0 1.0 and) 5% sodium hydroxide 6.0 6.0 f) Me tiIparaben 0.07 0.07 g) Propylparaben 0.03 0.03 H) H ₉ 0 (degree of purity) 51χΐ 60.9

100.0% 100.0%

Component a) was preached as described in 4.1 above; components c), f) and g) are dissolved in component b) with heating and the mixture obtained is cooled to room temperature. This solution is then dispersed in water h). Component d) is added and the whole is homogenized to make the dispersion. Component a) is added and the mixture is homogenized again. To neutralize, add the component

e) with agitation and the resulting gel is introduced into rollable tubes ”pare, gel, for topical application, for example, in the treatment of psoriasis.

4.3 PREPARATION OF WT & DENIO LAGRZDIalTTE IS IN WEIGHT

The) CICL03P0EIDA (0 -Α / Σ-ΙΙΙ micronisa.da) Composition The Composition 1.0 10.0 B) Amerchol OAB 2.0 2.0 ç) Liquid paraffin 42.0 37.5 The) letrola.to white 55.0 100.0 t 50 ^ 5 100.0 φ

Component a) is prepared as described in 4.1 above. Components b), c) and d) are combined together, agitated and component a) is added to them at approximately 30 ° C; the particles are distributed using a homogenizer. The obtained ointment is cooled and introduced into rollable tubes ”intended for topical application, for example, in the treatment of. psoriasis.

4.4 PREPARATION OF PREME TACABDIEATE

a) OICIOSPORIRA (C -Α / Σ-ΡΙΙ micronised)

b) Polysorbate 50

c) alcohol, cetylstearyl

d) 0-lioerol at 85 á

1.0

5.0

10.0

10.0

e) White detrolate (white petroleum jelly)

f) Methylparaben

g) Propylparaben hj? Γ * 0 (degree of purity)

24.0

0.07

0.03

49.0

100.0 φ

Component a) is prepared as described in 4.1 above, combined with components b) to h.) In a manner similar to that described in 4.3 above and the mixture is then introduced into rollable tubes ”for topical application, for example example, for the treatment of psoriasis.

• 5. PREPARATION OF THE OINTMENT a suspension consisting of 20% by weight is added to life; „- A / Z-II ± (obtained according to the procedures of Example 1): oliethylene glycol 300, until an average dimension of the r-children is obtained ds C „-A / Z-III comprised between 2 and 10 μm. Mix 10 g of the ground product obtained with 50 g of polyethylene glycol 300 and 40 g of polyethylene glycol 1500 in the molten state in the usual way, with which a paste is obtained. fluid comprising 10% by weight of Cyclosporine (in the form of 0-0 / Σ-III) intended for topical application, for example for 0 treatment of psoriasis.

1EPAPACA0 DE GEL 'I · - II A.lll - ........................

IGRZDlEDfE <BY WEIGHT

3) \

ç;

λ j

u.)

u..OajLo _ ''>. · ϊιΧ »<& (C ^ _— A / a— ± 11 mi c oniz aua) iabrofil M 1944 CS Dolietilenogiicol 300 benzyl ileocl

1.0

1.0

30.0 1.0

hydroxypropylmethylcellulose (Zetocel E4L)

H ‘“ 0 (degree of purity)

2.5

64.5

100.0 hp

Γ Prepare component a) as described for 4.1. Components b), c) and d) are listed, component f) is added and the whole is mixed. Component a) is then suspended in the resulting mixture by homogenization. Then, component e) is slowly added with stirring • 5 is continued. shake until gel formation is complete. The gel is immediately inserted into rollable gel tubes for topical application, for example for treatment

z I r ”fi '· * c n-s τ cj \ J - n_C „kb · 4.7 GEL PREPARATION IIC1ZDIEIT3 % Eh WEIGHT The) CIOLOSPORIEA (0 -Α / Σ-ΙΙΙ p 5.0 micronized) B) Poiethylene glycol 300 30.0 ç) G / glyceryl onostearate 5.0 d) Letilparaben 0.07 Θ ') Iropilparaben 0.03 Carbopol 934 D 1.0 and) 5% sodium hydroxide 6.0 H) h? C (degree of purity) 52.9 100.0% Go ps component a) as described himself to bad. 1 Components c) are issued, d) and e) in b) with

ment. The hot mixture is dispersed in h) by homogenization and

β immediately cools down to room temperature. Then add 35, components a and f) and mix the mixture. Component g) is then added and the gel formation is completed. The gel obtained was introduced into rollable gel tubes for topical application, for example in the treatment of nsoriasis.

4.ε

V-EM-ÕIEO) / WEIGHT

IfOnfDIEETE

The) GICLOSfOPIHA (C.-A / & - III micronized) 2.0 B) Amercho1 CAB 5.0 and 3 niglyol 312 .10.0 d) White Petrolatum (White Vasslina) 53.0 and) H _c 0 (degree of purity) .30.0

$ 100.0

Component a) is prepared as described in 4.1 above and immediately dispersed with component b) in component e) with heating and homogenization. Components c) and d) are melted together, mixed and the mixture is added to the dispersion prepared before with intense homogenization and then the whole is cooled, thus obtaining a greasy white cream. This is introduced in rollable cre · me tubes ”intended for topical application, for example in the treatment of psoriasis.

4.9

ÍA9Ã0 EE GEL / CREAM

See Examples 4.1 to 4.8 above but using the crystalline product of Example 2 directly as the Cyclosporine component.

FCEEA lEJECTÁVSL, POE EXAMPLE AS PARENTERIC APPLICATION to · MMMΜΜΜΜ * · »™ ΙΙΙΙΙΙΜΜ« ΜΜΜΜΜβΜΒ «MenuZ ·. — ΟΧΜΜΒΜηΐΜ« ΠΗΜΒαΜΜΜηΜ * ΜΜ »Μ« Mf ——— OMCT — r— I 1 '^ t -! - «-« ΜΚΜηΜΜΜΜ · —Μ ™ ΜΒΗΜ *! » - epe.ra suspension of C -A / X-III, under sterile conditions

V ceedsrdo according to usual techniques and using the following ingredients:

EGEEDIEETES

WEIGHT IN (mg) adj uiOrOi ^ PvEniA (C __— Α / λ — Iii) J

b) Polysorbate 80

20.0

Ί)

-a · vz -L

s) benzyl alcohol

f) (degree of injection) up to a final volume of

4.0

5.0

9.0

9.0

1.0 ml

The release characteristics of the active ingredient of the formulation obtained depend on the average particle size of component a). Thus, when ss requires activity for a longer period of time, the product C -Α / Σ-ΙΙΙ with an average particle size y will be chosen

greater (for example 100-200 / & :, as obtained directly through the procedures of Example 1). When you want a

activity for relatively shorter time periods, product C -A / x-IIII with a relatively smaller average particle size (eg obtained by mieronizing or milling the product of Example 1, for example at a particle size of 0.5 - 10 µM). The suspension obtained in ampoules for injection for parenteral administration or for intra-lesion injection for the treatment of psoriasis is introduced, for example to provide an after effect.

According to an especially preferred variant, the example is carried out using the 0 -A / Z-III prepared according to Example 2 described above, having a particle size between 5 and 15 µm and proceeding under sterile conditions.

I0P1IA3 IRJAOTAVRIS, BY ΞΣΞΕΡΙΌ FOR IUTRA-ART1CU1AR INJECTION, the appropriate forms for intra-air administration are repaired using the following ingredients:

ICREDIEfli;

T> T? Q; Q3I-ão A

ECIISRCRILTA (Cf-A / Z-III «y

Oarboxinetyl-cellulose sodium

RjTA of Ra

SSO EE (mg)

10.0

10.0

2.0

d) No 0 (injection grade) to a sale volumes fineide

1.0 ml zcmposigão B

a) OICLCSECRINA (C ^ -Α / Σ-ΙΙΙ)

t) Eoliserbate SO

c) Citric acid

e) H _O C (degree of injection) up to a final volume of

2.0

1.0 ml

The formulation is carried out in accordance with standard techniques in sterile conditions. Component (a) comprises non-fragmented micro-crystals, produced under sterile conditions according to the processes described in Example 2 and having a particle size of 3 to 15 / UN. Compositions' obtained in ampoules for injection (always under sterile conditions) are introduced, for example, for intra-articular injection for the treatment of rheumatoid arthritis.

The advantageous properties of the compositions according to the invention can be demonstrated in test models carried out on the animal core effect, as well as in clinical studies. In this way, the particular utility of the compositions of the invention, intended for dermal application, for example for the treatment of psoriasis or dermatosis, can be demonstrated in the following test model:

ALLERGIC CONTACT LENNAAITE IN THE COEAIA RETARDED HYPERSENAIETLISADN TEST

Guinea pigs are used (Hartley or weighing 400 to 500

e) by applying 50 µl of dinitrofluorbenzene (DNEB) to 2 (in a mixture of acetone 'olive oil (1: 1) in the inner ear of the right ear. 7 days later, animals are treated again with 20 µl of DNEB at 0.5% in a mixture of acetone and olive oil (4: 1) applied in lighter areas of the left loin and

of the shaved right loin. The second exposure causes an allergic inflammation with erythema and cellular infiltration (swelling) on the skin. The composition to be tested is applied with a spatula to an amount between 200 and 250 mg in the area treated with DEPB (dinitrofluorbenzene) of the right loin. As a control, the left loin is treated similarly with placebo, k application of the composition to be tested and the placebo is performed 5 times oh either at intervals of 20 minutes, 8 hours, 24 hours, 32 hours and 48 hours after the challenge. . The thickness of the skin at the application sites is determined before each application and again at 8 hours after the last application, by lifting the skin in a crease and measuring the thickness of the crease. The degree of erythema or inflammation of p-ie and also assessed visually according to a scale of values from 0 to 4. The effectiveness of the test preparation in preventing inflammation is determined by comparison with the results obtained on the treated loins with placebo.

of Figures I, II and III attached to this Order, the results obtained in the test model described above using the compositions in the Examples are indicated

4.5 but comprising 0.1 by weight of Ciclosporin at / 1 -J * · -

COEI 0

Π £? r ¹ r.

-A / P-ili, in comparison with the results obtained with lacebo and with 0.1 g of Cyclosporine by application of known drinkable topical solution, this test model is used due to> and C -A / z-III in a concentration of 0.1 7: shake sensitivity. The compositions from en0.1 to exo are prepared in a completely analogous manner to that described in the Examples

4.1 and 4.5 'but by reducing the content of Cyclosporine for and compensating' by adding 9 _S 9 g of water in the case of 4.1.3 polyethylene glycol in the case of Example 4.5.

In each of the figures the average skin thickness with respect to time is indicated. A? Ig. I presents the results obtained for the use of 0.1 by weight of Ciclosporin, applied

each in the form of a commercial drinkable solution, compared to z results obtained with placebo. In relation to the drinkable solution, there is a weak but significant reduction in the reaction compared to the placebo, the Eiguras II and III compare the results obtained with the compositions containing 0.1% by weight of Cyclosporine according to Examples 4.1 θ 4.5 respectively with placebo. In both cases, one is achieved. substantial reduction in skin swelling compared to placebo after the first application and which continues throughout the treatment until the experience is complete.

The usefulness of the compositions according to the present invention can also be demonstrated through the following clinical trials:

CLINICAL ETSION

PC OF ISORIASE BY TOPICAL APPLICATION (DSRNICA)

The trial is carried out as a randomized, double-blind, placebo-controlled study. Each patient receives simultaneously the active composition to test the placebo (vehicle attachments) on two symmetrical lesions. The active composition and the placebo are applied to the left and right lesions according to randomization.

The chosen patients are divided into groups of 12 to 24 people, 12 to 70 years old and comprising men and women in postmenopause, sterile due to an operation or who use oral contraceptives and whose pregnancy test is negative.

The criteria for participation in the trial are as follows:

written consent and b) a chronic, stable and clinically defined psoriatic plaque. Each patient must have at least two bilateral symmetrical lesions between moderate and severe, measuring each of the referred lesions 4 to 25 cnf · and with a degree of severity ”> 5 on a scale of 0 to 9. This score” is a comparison individual scores from 0 (absence of severity) to 3 (very severe) for each of the following three parameters: erythema, desquamation and skin inflammation. lesions on both sides must be comparable for the same patient (that is to say, they should not differ by more than one cu in surface).

The following exclusion criteria apply:

Any medical condition that, according to the researcher's opinion, would compromise the study.

b) Systemic psoriasis therapy. (PUVA, methotrexate steroids, retinoids, cyclosporine) within the past two months.

c) A specific topical treatment - with the exception of neutral substances (eg white petroleum jelly) or formulations containing salicylic acid (not more than 10 $) on the lesions selected for the study and carried out during the last 2 weeks prior to the beginning of the study . These emollients can, however, be used on non-selected lesions for the study.

d) Patients whose psoriasis appears to improve spontaneously, increase without treatment, or return after treatment is stopped.

e) A known hypersensitivity to any of the ingredients of the product to be tested.

f) Cooperation by patients who do not stop5

hundred willing to follow medical instructions exactly well. as patients who do not want, or are not able to make regular medical visits.

A participation in another clinical trial during the month prior to inclusion in the study.

hj A serious concomitant disease, especially renal failure with serum creatinine greater than 130 / iUol / 1.

/

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

j) Patients who have had or have malignancies including skin carcinoma.

acute skin lesions associated with bacteria, viruses or o>

Pregnancy, lactation.

Alcoholic patients, drug abusers, who have psychosis or emotional or intellectual problems.

Patients requiring continuous concomitant therapy with other immunosuppressants, chemotherapeutic agents, compounds with a nephrotoxic potential (for example aminoglucosides) and active substances known to exert an interaction on the pharmacoainetics of Cyclosporine (ketoconazole, erythromycin, phenytoin, phenobarbitone, ramp INH, Oarbamazepine, sodium valproate).

Patients with laboratory results

O;

£ ιλ *** λ 15 d initial higher than normal limits for the laboratory performing the test.

Patients with an abnormality found on clinical examination.

The test pieces used correspond to any temples 4.1 to 4.9 described above, for example:

compositions and fields. Leão E jao n 10% corresponds to Example 4.2 or the corresponding to Example 4.3.

The patient receives two 20 g coded tubes provided i- a double label. The label is blue to designate the substrate if applied on the right side, and red on the left side. In addition, it is written about li'® ·· votiva ±, pns.um. u sOS of the label the side to be treated, eslerio .u right, the coding of the study, the name of the doctor, the name of the patient and the date of the beginning of the treatment, the separable part of the label is affixed in the clinical history do pari ·.

-k _the substance to be tested twice a day, in the morning and, depending on the amount applied to the extent of the lesion, which corresponds to a daily dosage of Oiclosporin

r.

, 2:, 0 mg of Oiclosporin per cm, per; lc in a test series of approximately 0.5 mg of OiO jorina per cnT. Placebo is applied in equiXI C S S · j c amounts. G S Θ ct, j 2 a body surface greater than 25 cmX, and Oiclosporin is not applied per week. At each visit, the tubes containing the drug and the placebo will not contain either the composition or the placebo. 2 vile · · de te:

(The P-i-f

Pocient for i! .O

Γ

d. J · the daily dose applied topically. Passers can take a bath just before the application of medication, for the application of the placebo, as for the application of the test composition, are available and move

disposable gloves, in order to avoid cross contamination. It is necessary to allow at least three hours to pass between administration and washing of treated surfaces. The first application takes place under medical supervision, and the patient is given an instruction sheet. The treatment lasts 4 weeks. If an elimination of the lesions occurs more quickly, treatment is continued until the fourth week. Patients are examined prior to the start of the trial (one week before the trial = week -, 1) at the start of the trial (week 0) after 1, 2, 3 and 4 weeks.

) 1 dermatological evaluation (local psoriasis severity index or LPSI (local psoriasis severity index) is carried out by the same doctor, not involved in the treatment application, using the following numerical scales o to 3:

• ·: ΐτρρ; P

C = none

- language:

erythema only leteotével; very light pink ΐ 2 ™ moderate: distinguishable opaque red

- Pronounced: deep red / alive

DRAINING

- None = Minimum:

poorly defined skinning = lodged well-defined scaling giving thick scales = Severe:

well-defined beds; very thick to compact

GU1ANEA INFLAMMATION = None = Minimum:

barely noticeable elevation = Moderate: clearly noticeable elevation = Severe: significant elevation

I,

-n ^ X ~ _{o Ci}

- G _-Xii L-íw ·. uz b Ca <_ ·> _>

total LPSI (local psoriasis severity index) - erythema value -í »peeling + thickness = 0 to 9 Sara will participate in the study, at least two signs must be moderate, and severe for the two selected lesions (LPSI> 5).

 start the trial and at each clinical visit, the surface of the treated lesions is evaluated (size at the beginning: 4 to 25 cmá for each plate). k surface refers to one or more of the three criteria, erythema, scaling, skin inflammation. k pigmentation inside the lesion is not considered in the evaluation.

The plates were recorded one week before the trial (week -1) after treatment was completed (week 4).

Three photographs were taken: one showing the two injuries together and one for each injury.

lo.this pruritus ends during an interview with the patient, using the following scale:

C = none;

= minimum; occasionally experience the need for ras:? QT5 · o 9

- moderate: often experiences the need to rmsgar;

= severe: you often experience the need for air, which can disturb sleep.

„·. K_ ...

b at the end of the treatment, an evaluation of the treatment is carried out according to the following criteria:

- cleaning of the lesion = resolution 100 7;

- marked improvement = LPSI reduction of 65 / at least and / or

at least a reduction of 66? the surface of the plates;

moderate improvement = LPSI reduction between 65 / θ 33? and / or reduction of 65? at 33? the surface of the plates; weak improvement = reduction less than 32? LPSI and / or minor redoubt) 2 / from the surface of the plates.

worsening: exacerbation of the disease.

I Issue ^J -.therapeutic and defined by the elimination or a marked improvement of the disease.

Indicator ~ patient also indicate their preference between trotnreate on the left and right according to the following criteria:

left definitely improved left side slightly better no visible difference right ledo slightly better right side definitely improved.

effectiveness at the end of treatment,

of the patient's LPSI and the surfaces of the lesions in the Wilcoxon LlLCOLCòT - sign Rank ”trial and compare treatments on the side treated with Cyclosporine 0 side treated with the placebo, depending on the variations in results between the start of treatment and after 4 weeks of treatment.

All subsequent comparisons (at other time intervals and for the other parameters of effectiveness), including the p values adjacent to those, are considered as indices of

LrG;

In the rehearsal described above, the patients showed a marked improvement in psoriatic injury, for example, relatively? the results of the LPSI for erythema, skin and skin inflammation on the sides to which the composition to be tested according to the invention, containing Giclosporin, had been applied, in comparison with the side to which it had been applied c. placebo. There was also a subjective improvement in Peo as well as an improvement in values for the itching for the sides treated with Cyclosporine, compared to the sides treated with placebo.

Positive results are also obtained in the tests performed and at ppm: a parallel protocol with patients who present. atopic dermatitis diagnosed on the basis of 3 or more of the following criteria:

- itching

- typical horphology and distribution: lichenification by flexions or linearity in adults: lesions of the face and faces of exemption in infants and children;

- Chronic relapse dermatitis

- personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis);

plus three or more of the following minor criteria:

Zerosis, ichthyosis / palmary hyperlinearity / keratosis pilare, immediate type hypersensitivity (type I, after skin test, high serum IgE index, early appearance (<3 years), propensity for skin infections (especially Staph, aureus and Herpes simplex) / deficiency immunize ^the itOJ '

οοον cell measurement, propensity to nonspecific dermatitis or lo pe; Nipple eczema, cheilitis, conjunctivitis r3corrente, Sennie-Morgan fold the level of the lower eyelid keratoconus, anterior subcapsular cataract, i-.i-t-orbital pigmentation, facial pallor / facial erythema, pityriasis ^alba! .s of the anterior neck, itching when sweating, intolerance to wool and lipid solvents, worsening of the follicle, nutrition, worsening of lesions under the influence of emotional and environmental factors and delayed white / bleaching dermographism. The test lasts 3 weeks, with an evaluation on a scale of 0 to 3 for the following parameters: pruritus, erythema, exudation, excoriation and lichenification.

Topical formulations as previously described in Examples 4.1 to 4.9 containing 1/10/10 of Cyclosporine, for example the 5.0 composition according to Example 4.7, are

i.puaimenta effective for the treatment of contact dermatitis as well as alopecia.

In accordance with what has been said above, the present invention thus offers:

D. A method of administering Ciclosporin to, or to perform. of a therapy with Ciclosporin, in a patient who receives or needs such therapy, said method comprising administering to that patient a quantity of Ciclosporin in the orthorhombic crystalline form, in particular in the unsolvated orthorhombic crystalline form, for example C - A / X-III, for example, such as y 7 as defined under any of the points A to A anteriox * es ·

According to a specific variant, the invention offers:

π

D ^a , A method for carrying out immunosuppressive therapy

anilinflammatory drug in a patient in need of such therapy, said method comprising administering o, that patient an effective amount of Cyclosporine in the crystallized orthorhombic form, in particular in the unsolvated orthorhombic crystalline form, for example to C.-A / X-III, for example, as defined under 47 any of the above points A to A.

The objectives for which the methods described above can be applied include the treatment of any disease or condition described above in relation to the use of cyclosporine, for example, the prevention of trans · plantation rejection, the treatment of a disease of the autoimmune system cu of a rheumatic disease, the treatment of any of the diseases or conditions that involve a highly undesired response of the immune system, for the treatment of an infection by parasites, the treatment of, resistance to quinieotherapeutic agents, for example , the inversion of tumor resistance to anti-neoplastic chemotherapy, as well as the treatment of alopecia. The aforementioned methods are particularly applicable in the treatment of diseases or conditions of the eye skin, for example, psoriasis, atopic contacrnatiie dermatitis, cornea transplantation, conjunctivitis and uveitis, by topical application, as well as rheumatoid arthritis, or other diseases mount OR do o to or 1 treatment of,; s from to:

—Articular.

.and another, variant, the present invention offers:

cyclosporine in unsolvated orthorhombe crystalline form, for example, in the form of G.-A / X-III, for example, y 7 as defined under any of the points A to A above, for use with the drug, for example, for use in the treatment of any disease or joint condition, by administration

medication;

previously in connection with D or D above for example for use as an immunosuppressive agent or as an anti-inflammatory qen-cc, as well as

Cyclosporine in orthorhombic crystalline form, for example, in the form of CL-A / 2-III, for example as defined in any of points A to A above, for using XXct and stopping a pharmaceutical composition for use as was defined in clC jLRicl «

X IA ilii b 331 the identification of Oiclosnorina. in the crisΖ.-Ϊ / v_p orthorhombic form, in particular the identification of C -Α / Σ-111, in Tables I to III, below, the data for powder for a. C -A / 2-III and for both

Cg-A / 2-ΙΙ also referred to in this Descriptive Memorandum. The attached Figure IV provides a representation of the diffraction diagram of the rays 2 in the powder from which the data shown in Tables I to III were obtained. The diffraction diagram was obtained using a G-uinie2f · de-V / olff II camera, employing Cuk <Y, X = 1,542 ÍL radiation

3 37 RAYS Σ TO Οϊ-Α / Σ-Ι Xylílha. i; -. d (£) intensity 1. 13.0 VS 2. 11.4 VS O P · 10.3 ' VS 4. 9.7 VS ΓΣ > · 9.4 vs £ 8.25 VS 7. 7.1 s P (♦ 1 6.1 M 1 1 9 · I 5.85 s ¹⁰ ' 5.6 s 11. 5.25 VS 12. 4.81 s 1 13. 4.58 s 14. 4.25 M 15. 4.0 K 16. 3.67 M 17. 3.45 M

beautiful

II

DIAGIAL1A. 15 Z RAYS FOR OY-A / Z-II

Claims (3)

ΌΣΑ? ΡΑΓΑ PB Z RAYS FOR 0Ϊ-Α / Χ-ΙΙΙ K. - Process for the preparation of a new crystalline form of unsolvated Ciclosporin crystallized in the orthorhombic system, characterized by the fact that Ciclosporin crystallizes from a dissolving medium that originates, the formation of unsolvated orthorhombic crystalline Cyclosporine and recovering the Unsolvable crystalline orthorhombic cyclosporin1 thus obtained. i '. Process' according to claim 1, characterized in that the solvent medium comprises a high molecular weight ether. 3-- ·. Process according to claim 2, characterized in that the solvent medium comprises a polymeric ether. O · 4 '~. Process according to claim 3, characterized in that the solvent medium includes a polyethylene glycol or a polypropylene glycol. ’’ ’. Process according to any one of claims 1 to 4, characterized in that Cyclosporine is dissolved in said solvent medium at a temperature above 40 ° C. d '. Process according to any one of the preceding claims, characterized in that, as a final product, a Cyclosporine À is obtained in the unsolvated orthorhombic crystalline form, having the following parameters of the cristali network63 Cl 12.7 b = 15.7 S, c - 36.3 S, and the volume asymmetrical is 1804 cubic pounds. - Process according to claim 5, characterized in that it is possible to obtain as final product Cielosporina S under na in unsolvated orthorhombic crystalline which has the same characteristics of dif ray diffraction in each case. Very strong intensity means strong intensity intensity average. Ç'. - Process for the preparation of pharmaceutical compositions containing a Ciclosporin especially suitable for the immunosuppressive or anti-inflammatory treatment of a patient who needs that treatment, as an active ingredient, oarac · terisadc by the intimacy of at least one Ciclosporin, under the orthorhombic crystalline form according to any of the preceding claims with a diluent agent and / or a pharmaceutically acceptable carrier. process according to claim 8, characterized in that Ciclosporin is Ciclosporin A in unsolvated orthorhombic crystalline form.