DE3843054C2 - Ciclosporin in unsolvated orthorhombic crystal form, process for its preparation and pharmaceutical composition containing it - Google Patents

Description

The invention relates to cyclosporin in non-solvated orthorhombic crystal form, process for its preparation position and containing pharmaceutical Composition according to the claims.

Ciclosporin, also called cyclosporin A, is a known fungal metabolite with valuable pharmaceutical properties. Ciclosporin is a cyclic poly-N-methylated undecapeptide of the formula

wherein -MeBmt- is an N-methyl- (4R) -4-but-2E-en-1-yl-4 methyl (L) threonyl radical.

Ciclosporin and methods for its production are included For example, in US-A 4 117 118 described. The clinical ver Search with Ciclosporin mainly ranged its use as an immunosuppressant, in particular on its application in the treatment of recipients of Organ transplants, such as heart transplants, lung transplant did, heart-lung transplants, liver transplants, never transplants, pancreas transplants, bone marrow trans implants, skin grafts and corneal transplants, and here in particular of allogeneic organ transplants. On the Ciclosporin has proven to be very successful in its field of application enforced, so that today it is widely used clinically is turned. Ciclosporin is commercially available under the names SANDIMMUN® or SANDIMMUNE® available. Suitable galenic  Forms are for example infusion concentrates, oral solution and gelatin encapsulated solutions, the two latter forms, for example, in US-A 4,388,307 be be written.

At the same time, Ciclosporin was also in depth regarding its Suitability for the treatment of various autoimmune diseases and inflammatory conditions, in particular ent inflammatory states with an autoimmune component as ill cause of illness, such as arthritis (for example arthritis rheumatism tica, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, and in the literature will be out in detail about the in vitro, in these studies in animal models and results obtained in clinical trials directed. On autoimmune diseases for whose treatment Ciclo sporin has been proposed or applied, for example wise autoimmune hematologic disorders (such as hemolytic Anemia, aplastic anemia, anemia with pure erythrocytes waste and idiopathic thrombocytopaenia), more systemic Lupos Erythematosus, Polychondritis, Scleroderma, Wegener's Granulamotosis, dermatomyositis, chronic acute hepatitis, Myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory diseases of the Intestines (such as colitis ulcerosa and Crohn's disease), pemphigus, endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary cirrhosis, juvenile Diabetes (diabetes mellitus type I), Behcet's disease, uveitis (anterior and posterior), vernal conjunctivitis, keratoconus junctivitis sicca, interstitial pulmonary fibrosis, psoriatic Arthritis and glomerulonephrosis (with and without nephrosesyn drom, including idiopathic nephrosis syndrome or Minimalschadennephropathie).

Ciclosporin was also already considering its potential feasibility in other areas, as a means  against parasites, in particular antiprotozoal agents, wherein it also as a possible means of treating malaria, Coccidioidomycosis and schistosomiasis have been considered was, and also as a means of reversing the resistance of Tumors against chemotherapeutic treatment, for example wise a treatment with cytostatics, and as an agent for Promote the growth of hair, as for the treatment of Alopecia.

When solid, cyclosporin is both amorphous in form as well as in crystalline form. As crystalline forms are both a tetragonal modification and an orthorhomic Bic modification known.

The tetragonal modification (P4 ₁ ), which is also referred to herein as CY-A / XI for simplicity, is described together with methods for their preparation, for example in AT-A 353 961. CY-A / XI has a crystal lattice with a = b = 13.8 × 10 ^-10 m (13.8 Å) and c = 41.2 × 10 ^-10 m (41.2 Å), has one volume per asymmetry unit from 1974 x 10 ^-30 m ³ (1974 Å ³ ), has a melting point of about 140 to 150 ° C and contains about 2 molecules of H ₂ O per molecule of cyclosporin.

A first orthorhombic modification (P2 ₁ 2 ₁ 2 ₁ ) can be obtained by crystallization from diisopropyl ether, and reference is made to the paper by R. Wenger entitled "Total synthesis - change in molecular structure - biological effect: ciclosporin as example" in Sandorama 1984 / III pointed out. This particular paper is a solvate of cyclosporin and diisopropyl ether (ratio about 1 to 2) with a crystal lattice a = 12.5 × 10 ^-10 m (12.5 Å), b = 22.9 × 10 ^{. 10} m (22.9 Å) and c = 28.4 × 10 ^-10 m (28.4 Å), a volume per unit of asymmetry of 2027 × 10 ^-30 m ³ (2027 Å ³ ) and a melting point of about 150 ° C. Orthorhombic ciclosporin solvate crystals can be obtained by recrystallizing supersaturated solutions of cyclosporin in a suitable solvent medium for a longer period of time. The modification of ortho rhombic ciclosporin / diisopropyl ether solvate produced by Wenger can thus be obtained by adding a concentrated solution of ciclosporin in methylene chloride (in which cyclosporin is rather readily soluble) to diisopropyl ether (in which cyclosporin is relatively poorly soluble) and the methylene chloride is then evaporated from this solution. By leaving the diisopropyl ether freed from methylene chloride for a period of about 7 days at ambient temperature then it comes to crystallization. The orthorhombic crystal forms thereby formed, which contain the solvates of cyclosporin obtained in the process, are also referred to herein as CY-A / X-II for the sake of simplicity.

A further orthorhombic modification (P2 ₁ 2 ₁ 2 ₁ ) has now been found, which is characterized in that no or practically no solvent component is present in it, so that it consists practically or essentially of free cyclosporin.

The dimensions of the crystal lattice of this solventless or non solvating orthorhombic modification of ciclosporin are a = 12.7 × 10 ^-10 m (12.7 Å), b = 15.7 × 10 ^-10 m (15.7 Å), and c = 36.3 × 10 ^-10 m (36.3 Å), and this modification has a volume per unit of asymmetry of 1804 × 10 ^-30 m ³ (1804 Å ³ ). The melting point of this crystal form is on the order of about 180 to about 190 ° C and up to about 195 ° C, and depends, for example, on the degree of purity and starting material as shown in Examples 1 and 2 below which methods for producing this orthorhombic modification of Ciclo sporin be described. Ciclosporin in the form of these ortho rhombic crystals, which are not a solvate and thus solvent-free, is also referred to herein as CY-A / X-III for the sake of simplicity. Further characteristic data (X-ray diffraction data in powder form) for CY-A / X-III are shown in Table III and Fig. IV below, and there are also the corresponding data for the modifications of ciclosporin with the designations CY-A / XI and Specify CY-A / X-II.

Despite the great success and recognition of Ciclosporin and despite the great contribution to medical knowledge and in particular for the technique of organ transplantation tion that Ciclosporin has already delivered is its prak table application not yet ideal and free of problems. On The provision of galenicals encounters particular difficulties Shapes that are simple or completely satisfactory Allow administration or be particularly good for Be treatment of specific diseases or conditions, for which Ciclosporin already recognized as a possible drug of choice has been.

These difficulties are partly due to the particular physika attributed to ciclosporin, as in For example, its relatively limited solubility or (previously observed) compatibility with the usual pharma ceutically applicable carrier media. These difficulties are a consequence of the special nature of certain disease states, which is primarily a therapeutic treatment with Ciclosporin is indicated, and also the appearance of unwanted Side effects of cyclosporine in oral administration can cause. For example, psoriasis can be achieved effectively combat oral administration of cyclosporine. at Psoriasis is a widespread disease, which leaves the affected person with a lot of complaints and for which it is still not sufficiently effective Therapeutic treatment gives. An effective treatment of Psoriasis sufferers is therefore a serious problem. Ciclosporin could indeed be based on the data available so far suitable for solving this problem  but this should fail because of the fact that for a treat treatment of psoriasis with oral therapeutic treatment Ciclosporin probably does not come into question. Similar considerations also apply to the treatment of, for example, eye disease diseases such as posterior uveitis and keratoconjunctivitis sicca.

For the administration of cyclosporine ver most diverse systems, including galenic forms proposed for topical or dermal application or for ophthalmic use, namely a topical application to the eyes, to thereby example psoriasis or other skin diseases or skin conditions to treat, such as atopic dermatosis and alopecia, or to Treatment of uveitis. However, such systems have ent neither brought any apparent advantage or not as overall satisfactory.

The various attempts to treat psoriasis suffering patients by direct order of the known oral Solutions to the surface of the psoriatic herd have one shown only minimal or no success, being one Success in patients suffering from atopic dermatosis severe was limited. By topical application to the eyes For example, although a rejection of a cornea trans Plantats effectively prevented or a disease in the front The area of the eye can be effectively treated, but there are So far no topically applicable formulation, the one simple, safe and effective treatment at deeper levels Location of the eye-related diseases or conditions made possible such as a general treatment of Uveitis including uveitis posterior.

Comparable difficulties are also the development ande counteracts systems for the release of ciclosporin, for example  Injectable forms suitable for intraarticular In tion for the local treatment of arthritic diseases already mentioned above can be applied or the are suitable for intralesional injection, such as for treatment severe psoriatic lesion, and so on also for other oral release systems with, for example, modes fied properties in terms of bioavailability or Release of the active substance.

In previous attempts to formulate cyclosporin This compound will either be in solution or what not is usual, in amorphous form or in the form of CY-A / X-I ange turns, which in the latter case is the crystal form, on the basis of which this medicine is registered. Despite the Huge effort in finding new or better age Native are currently available as release systems for Ciclosporin only oral solutions and infusion concentrates are used.

According to the invention, it has now surprisingly been found that orthorhombic crystalline forms of cyclosporine, such as CY-A / X-II and especially CY-A / X-III, especially good for Her position of galenic formulations of various kinds of ciclosporin.

This was especially recognized that using of such crystal modifications, galenic formulations let the ciclosporin in stable and finely divided Contain the form and / or ver the better stability ver add or have more favorable release characteristics. This will be the way to make new and better ones Release systems for the active ingredient Ciclosporin opened, by For example, this drug extends or ver reluctant to release and / or illnesses or treat conditions whose therapeutic treatment with ciclosporin was previously not possible or for which  a conventional therapeutic treatment with Ciclo sporin was not necessarily well suited. In particular, wur de now recognized that by using such crystal modifications in, for example, the mentioned finely divided Form galenic forms that are suitable for a topical or dermal application or for a topical ophthalmic application, to hereby, for example, Er diseases or conditions of the skin or eyes described above kind of treat, in particular psoriasis, atopic Dermatitis, contact dermatitis, ocular symptoms of Disease, uveitis and keratoconjunctivitis sicca. The users Such crystal modifications also allow the Her Injection of injectable forms of cyclosporine with prolonged or shifted release characteristic, so that the especially for the treatment of diseases or Use conditions where the necessary frequency the administration is otherwise an obstacle, such as for the treatment of arthritis and similar joint diseases by intra-articular injection or for the treatment of Psoriasis or similar skin diseases by intralesional Injection.

For such applications have become orthorhombic crystal form, and in particular CY-A / X-III, as inherently much better proved suitable as other available forms, in particular amorphous ciclosporin or CY-A / X-I, especially in following the particular physicochemical properties, like the stability, the release characteristics, namely the Release of cyclosporin from the crystal lattice, and the particular balance of these crystal forms in terms of necessary for the preparation of the galenic formulations Activities. CY-A / X-III is a new and be Preferred orthorhombische crystal form, which according to the invention to galenic and / or therapeutic purposes.  

A first embodiment of the invention is therefore
A CY-A / X-III, namely ciclosporin in a non-solvated orthorhombic crystal form, and especially
A ¹ CY-A / X-III with a crystal lattice or with other physical properties of the type defined in practice above and / or
A ² CY-A / X-III with an X-ray diffraction spectrum in powder form of practically in Table III or in Fig. IV type given.

The invention is also also
B is a process for producing CY-A / X-III by crystallization of cyclosporin from a medium containing CY-A / X-III and recovering the CY-A / X-III thus obtained.

Suitable media containing CY-A / X-III can be in the above method, especially solvent media for Ciclo sporin, the solvent components with higher Contain molecular weight, such as polymeric ethers with a molecular have weight of over 200. They are suitable as media higher molecular weight ethers, for example example, polyalkyl ethers, such as polyethylene glycols and polypropylene glycols. Examples of polymeric ethers that are suitable have proven to be polyethylene glycols and polypropylene glycols with a molecular weight of over 200, Gly cerium polyethylene glycol esters, such as glycerol polyethylene glycol ricinoleates and glycerol polyethylene glycol oxystearates, as they are for example under the trademarks Cremophor® EL and Cremo phor® RH (see Fiedler, Lexikon der Hilfsstoffe, 2nd edition,  Volume 1, pages 257 and 258) are available, polyoxyethylene sorbitan esters, as for example under the trademark Tween® (see Fiedler, Volume 2, pages 972-975) are polyoxyethylene esters, such as polyoxyethylene stearate, as described, for example, under the trademark Myrj® (see Fied Vol. 2, page 636), and transesterification pro from natural oil triglycerides and polyalkylene polyols including the transesterification products of corn oil, seed oil, Almond oil, nut meal oil, olive oil, palm oil and mixtures thereof with polyethylene glycols with a molecular weight of 200 to 800, as for example under the trademark Labrafil® (see Fiedler, page 539) he are available. Particularly suitable media include polyethylene glycols having a molecular weight of about 200 to about 600, in particular from about 300 to about 400.

The CY-A / X-III containing media may additionally contain one or more other components, for example low molecular weight alcohols and / or water, which as an agent for modifying the solvent / crystallization property serve. Particularly suitable is a CY-A / X-III ent holding medium containing about 0.5 volume of ethanol, about 8.0 parts by volume of polyethylene glycol (300) and about 1.0 Volumes of water.

Ciclosporin is first included in the method of the invention For example, in amorphous or tetragonal form in the selected and CY-A / X-III containing medium at elevated temperature ge solves. The solution temperature of course varies depending on from the chosen medium, and it is generally over 40 ° C and especially at over 50 ° C. In the case of media on Basis of polyethylene glycols is the solution temperature in general at over 70 ° C and for example between about 75 and 130 ° C. The resulting solution conveniently contains 5 percent, preferably over 10 percent, for example up to  about 40 to 60 percent, and preferably up to a maximum of 20% by weight of cyclosporin, based on the total amount weight of the solution. Then let the crystallization of Ciclosporin under cooling during a suitable and rela for a long period of time, for example of the order of magnitude from 10 to 35 minutes or more, depending on that desired crystal growth, proceed.

If desired, nucleation processes can also be initiated be like a sound or inoculation. When using crystal-containing media based on ethanol, polyethylene glycol and water as described above nucleation at temperatures of about 60 to 90 ° C, for example, from 65 to 85 ° C, by applying a sound initiate vibration of about 20,000 oscillations per second. By Fort This sonication during the course of crystallization As shown in Example 2, microcrystals result with very fine and relatively constant particle size.

The extent of crystal growth and the size of the obtained Of course, crystals are dependent on the selected medium and the conditions under which crystallization took place leads, as the question of whether at all under sonication ge is working and if so, with what frequency. For an An Use according to the present method, for example the preparation of the later to be described galenic Formulations, CY-A / X-III is preferably in finely divided Form used, for example, in a form with a mittle ren particle size of less than 200 microns, such as from 0.5 to 200 microns. Do the originally obtained crystals have a ratio moderately large particle size, then can be preparations of course with the desired particle size by üb obtained by crushing, as by crushing, grind, pulverize, micronize and other shreds approximately procedures. The particulate preparations obtained thereby  can look completely out for certain uses be sufficient as for the preparation of topical compositions for an application on the skin, however, in some cases the application of a shredding technique or milling technique not preferred. Reasons for this are that by sol usually receives a proportional have moderately broad particle size distribution and as a result of breaking the crystals over a relatively coarse and sharp Structure. Furthermore, by a crushing the physical properties of the natural crystal surface destroyed, and moreover, such procedures are difficult and up agile under the required conditions of sterility feasible, as you can for example for the production galenic formulations for intra-articular administration needs. For these reasons, the Verfah inventive usually carried out preferably so that crystals, For example, microcrystals, with dimensions within the finally give desired particle size range. For the Preparation of, for example, compositions for intra Articular or other parenteral use therefore preferably particulate preparations of CY-A / X-III in undecomposed microcrystalline state (Nam Microcrystals of CY-A / X-III in native or not broken state, which no comminution, grinding, Micronization or other particle size reduction un have been withdrawn).

To form microcrystals of CY-A / X-III, which are directly in the manner described above in non-comminuted ver can be used, the method of the invention expediently with thorough mixing, such as by stirring at For example, at a speed of 200 to 300 revolutions per minute during crystallization For example, 700 revolutions per minute is increased, and in particular special using an ultrasonic vibration, for example  in the range of 10,000 to 30,000 oscillations per second, suitably on the order of about 20,000 swine conditions per second.

By altering the medium containing CY-A / X-III and Ein Setting the cooling rate and the extent of through mixture while using known techniques by feeding and later described by way of example Um crystallization can be microcrystals of CY-A / X-III with produce different average particle size, at For example, with particle sizes, as mentioned above or as they are described below, where these crystals in the aforementioned galeni invention formulations are used.

The crystallization process according to the invention, as be already mentioned, expediently under sterile conditions carried out. The obtained microcrystals of CY-A / X-III can be cleaned in the usual way, such as by rinsing with mixtures of polyethylene glycol (300) and water, which for example, these two components in a ratio from 3 to 4 parts by weight to 1 part by weight, and Wash with warm water as described in the examples is written. The obtained CY-A / X-III becomes more convenient Wise in a form that has no or virtually no Contains ciclosporin of any other form, and put such with preferably pure or virtually pure CY-A / X-III. The mentioned rinsing step contributes to the formation is prevented by amorphous ciclosporin.

The invention therefore also includes a cyclosporin, which can be prepared by any of the above-described measures, and also
A ³ CY-A / X-III of the type described above under A to A ² , which is free or practically free of cyclosporin in any other form, such as free or substantially free of cyclosporin in amorphous form, such as in the form of CY-A / XI or CY-A / X-II,
A ⁴ CY-A / X-III of the type described above under A to A ³ , in pure or virtually pure form,
A ⁵ CY-A / X-III of the type described above under A to A ⁴ , in finely divided form, having, for example, particle size properties of the type described above or of the type to be described below, as the CY-A / A- III containing galenic forms are ent,
A ⁶ CY-A / X-III of the type described above under A to A ⁵ , which consists predominantly or completely or practically completeness dig of non-crushed crystal material, for example, CY-A / X-III of the type described above under A ⁵ enclosed type, where the component particles consist predominantly or completely or practically completely of non-cracked microcrystals, and
A ⁷ CY-A / X-III of the type described above under A to A ⁶ , in sterile or practically sterile condition, example, in a ge suitable for a pharmaceutical application state, in particular a parenteral to use suitable state, for example for administration administration by parenteral injection or by intra-articular injection.

Next belongs to the invention as well
C is a pharmaceutical composition which

• a) Ciclosporin in orthorhombic crystal form as Active ingredient together with
• b) a pharmaceutically acceptable diluent or carrier for this

contains.

The cyclosporin may be present in the compositions of the invention in any suitable orthorhombic crystal form, such as in the form of CY-A / X-II or CY-A / X-III. In general, however, the use of CY-A / X-II is less preferable because of its physico-chemical properties, since this crystal form is not well suited for the preparation of ciclosporin-based pharmaceutical products. The compositions according to the invention therefore contain cyclosporin in the form of CY-A / X-III, namely a cyclosporin of the type indicated above under A to A ⁷ .

The cyclosporin is in the compositions of the invention Although in solid (crystalline) form, but the Compositions themselves any suitable pharmaceutical Form form. Gehö to compositions of the invention gehö Therefore, solid forms, such as capsules, tablets, dragees, powders and granules, semi-solid forms such as ointments, gels, creams and Pastes, and also liquid forms, which the respective Ciclo Sporin component in finely divided form (for example, in micro niger or microparticulate form) in a liquid pharma ceutical diluent or carrier in which the remaining crystal form is retained, suspended or dis included pergiert.  

Compositions according to the invention include both systems, containing ciclosporin as a single phase or arrangement, like simple creams, gels, ointments and other forms of described above, or simple one-piece capsules or Ampoules, for example hard gelatin capsules, soft gelatin capsules or ampoules for injection, and also systems which ciclosporin in the form of multiple phases or arrangements contain. The invention therefore comprises compositions which a cyclosporin-containing phase or assembly together with one or more non-cyclosporin-containing phases or Arrangements, as with coating phases, carrier phases, Retard phases or placebo phases, or with phases or Anord tions containing other active substances or excipients. The invention therefore includes, for example, coated Tablets with a core of ciclosporin in orthorhombic Crystal form, for example, not of other ciclosporin surrounded by coating phases or the like, Coated tablets with a Ciclosporin in orthorhombischer Crystal form containing core or shell and a not Ciclosporin-containing sheath or core, mixed granules, a first granule phase of ciclosporin in orthorhombic Crystal form and a second no Ciclosporin containing Granule phase, as well as split tablets with two or more Ab cut, which, for example, separated by an inner wall are, with a section ciclosporin in orthorhombic Contains crystal form, and the other contains no Ciclosporin. Other possibilities and modifications of such pharmi Shear forms are within the scope of the usual expert Can s.

The cyclosporin is in the compositions of the invention preferably predominantly or in particular completely or practically complete in orthorhombic crystal form in the form of CY-A / X-III available.  

The compositions of the invention contain more useful have at least one phase or section of Ciclo sporin in orthorhombic crystal form, in Form of CY-A / X-III wherein this crystal form is uniform shares or is distributable. Such systems are included For example, homogeneous creams, ointments, gels and the like and also liquid systems in which the existing crystalline Ciclosporin homogeneously distributed or easily distributed homogeneously is, for example, by shaking by hand.

Compositions according to the invention include pharmi various forms that are topically, such as dermal or topical ophthalmic administration, parenterally, as by infusion or injection, including subcutaneous or intra muscular injection and in particular an intralesional or intra-articular injection, and also administer pharmaceutical forms which are administered enterally can, like suppositories, pessaries and the like and oral Dosage forms. Enteric forms, such as oral dosage forms, however, are generally less preferred.

In the compositions of the invention, the orthorhom Bic crystalline ciclosporin, such as CY-A / X-III, preferably present in finely divided form, as in micronized, micro part or uncomminuted microcrystallized form of the type described above. The respective particle size is na Of course, depending on the type of composition, the intended use and the type and Way of application as well as the desired effect. In general Mean is the average particle size of the respective orthorhombic crystalline ciclosporins, however, in the order of magnitude rich from 0.5 to 200 microns. Special particle size ranges, as for example for the production of oral, topical or Injectable pharmaceutical forms are applied further described below.  

Topical forms, for example for a dermal or topical ophthalmic administration, such as for the treatment of psoriasis or atopic dermatosis or diseases or conditions of the eyes, where a therapeutic treatment with a Immunosuppressant is necessary, as from uveitis, conjunctivitis including keratoconjunctivitis sicca or vernal keratoconjunctivitis or a corneal graft

Gels, creams or ointments for a topical or dermal administration may be by any conventional technique be prepared by ciclosporin in orthorhombic Crystal form with a suitable flowable base, at For example, an aqueous gel, such as an aqueous gel Base of a cellulose ether, with the addition of suitable surfactants, Thickening agents and the like, including at For example, an Aerosil is mixed.

The cyclosporin component is preferably in finely divided therein ger form present, for example in a form with a average particle size of 0.5 to 200 microns. The cyclosporin component preferably has an average particle size of below 60 to 80 microns, more preferably below 40 microns, even stronger preferably less than 30 microns and especially less than 20 microns. Conveniently, the particles have as close as possible Particle size distribution. Preferably, virtually all existing particles have a particle size of less than 60 to 80 μm.

To compositions according to the invention for a topical ophthalmic application, such as an application to the eyes, For example, include suitable thickened suspensions or Dispersions in the form of viscous eye drops or creams or gels for an ocular application. For compositions to treat the eyes has the existing crystalline Ciclo Sporin expediently a mean particle size of below  25 μm. Preferably, virtually all particles present a size of less than 25 microns. The mean particle size for Eye drops are suitably in the range of about 0.1 to about 20 microns, and preferably from about 0.5 to about 10 microns.

The vehicle system used in pharmaceutical forms for a dermal application or in preparations for use used in the eyes can, in terms of its content vary in hydrophilic and lipophilic components, and this depends, for example, on the respective upper surface to which the composition is to be applied as according to the properties of each skin to be treated surface.

Compositions for a topical and especially one of male application suitably contain a carrier medium, in which the active ingredient (Ciclosporinkomponente) only weakly is soluble. The solubility of the cyclosporin component, such as of CY-A / X-III, in such compositions is generally mine at less than 10 weight percent, preferably below 1.0 weight percent, more preferably less than 0.1 weight percent and in particular less than 0.001% by weight.

Suitable carrier media include hydrophilic and water miscible carriers and also hydrophobic carriers.

The hydrophilic and water-miscible carriers have purpose moderately a relatively low volatility. To Examples of suitable carrier components which this Classes include liquid polyalkylene glycols, propyne glycol, glycerin and ethylene glycol. To suitable polyal Kylene glycols are mainly liquid polyethylene glycols with an average molecular weight of, for example, up to about 600, with polyethylene glycols having a middle molecule largeweight of about 250 to 450 and especially about 300 are preferred.  

Typical compositions of the invention, the example, can be applied topically include
C ¹

• a) a cyclosporin in orthorhombic and preferably unsolvated orthorhombic crystal form, such as CY-A / X-III, for example of the type defined above under A to A ⁷ ,
• b) a hydrophilic and water-miscible carrier, for example, the type described above, and possibly
• c) water in pharmaceutical grade.

The component a) is generally in an amount of about 0.1 to about 30 percent, especially in an amount of about 0.5 or 1.0 to 20 percent, for example, in amounts of about 1.0, 2.0, 5.0 or 10.0 percent, based on the total weight the composition is present. The components b) and c) are generally in a ratio of 1 to 0 to 1 to 20 Ge present in parts. The ratio of components b) and c) is preferably 1: 0.5 to 1: 5 parts by weight, for example 1 to 1 to 1 to 3 parts by weight and makes into particular 1 to 1.5 to 1 to 2.5 parts by weight.

Conveniently, such compositions also contain

• a) a surfactant.

Suitable components d) are, inter alia

• 1. d ¹ transesterification products of natural vegetable oil tri glycerides and polyalkylene glycols. Such transesterification products are known materials which can be prepared, for example, by the method described in US Pat. No. 3,288,824. They include esterification products of various natural, for example non-hydrogenated, vegetable oils, such as corn oil, seed oil, almond oil, Nussmahlöl, olive oil and palm oil or mixtures thereof with polyethylene glycols, in particular a special average molecular weight of 200 to 800. Preferred are those obtained by transesterification of 2 moles of a natural vegetable oil triglyceride with 1 part by mole of polyethylene glycol, which has, for example, an average molecular weight of 200 to 800, obtained products. Transesterification products of this class are known in various forms and example, under the trademark Labrafil® in the trade he holds (see Fiedler, Lexikon der Hilfsstoffe, 2nd revised and expanded edition, 1981, Volume 2, page 539). Suitable components in the compositions according to the invention are, in particular, the products Labrafil® M 1944 CS (this is an esterification product of core oil and polyethylene glycol having an acid number of about 2, a saponification number of from 145 to 175 and an iodine value of from 60 to 90). and Labrafil® M 2130 CS (which is an esterification product of a C ₁₂ to C ₁₈ glyceride and polyethylene glycol having a melting point of about 35 to 40 ° C, an acid number of less than 2, a Versei index of about 185 to 200 and an iodine value of less than 3).
• 2. d ² reaction products of natural or hydrogenated castor oil and ethylene oxide. Such products are obtainable in any known manner, for example by reacting a natural or hydrogenated castor oil with ethylene oxide at a molar ratio of from about 1 to 35 to about 1 to 60 and selectively removing the polyethylene glycol component from the product as described in DE-B 11 82 388 and DE-B 15 18 819 will be described. Particularly suitable are the various surfactants available under the trademark Cremophor®. Particularly suitable here are the products with the names Cremophor® RH 40 (with a saponification number of about 50 to 60, an acid number of less than 1, an iodine value of less than 1, a water content (according to Fischer) of less than 2 percent, a refractive index of n _D ⁶⁰ about 1.453 to 1.457 and an HLB value of about 14 to 16), Cremophor® RH 60 (with a Versei number of about 50 to 60, an acid number of un ter 1, an iodine value of less than 1, a water content (by Fischer) of 4.5 to 5.5 percent, a refractive index n _D ²⁵ of about 1.453 to about 1.457, and an HLB of about 15 to 17) and Cremophor® EL (having a molecular weight (by vapor osmometry ) of about 1630, a saponification number of about 65 to 70, an acid number of about 2, an iodine value of about 28 to 32 and a refractive index n _D ²⁵ of about 1.471). Also suitable as such products are the various surfactants available under the trademark Nikkol®, such as Nikkol® HCO-60. Nikkol® HCO-60 is a reaction product of hydrogenated castor oil and ethylene oxide: acid number 0.3, saponification number 47.4, hydroxyl value 42.5, pH value (5 percent) 4.6, APHA color = 40, Melting point 36.0 ° C, freezing point 32.4 ° C, water content (according to Karl Fischer) 0.03 percent.
• 3. d ³ Polyoxyethylene sorbitan fatty acid esters or polysorbates, for example the products commercially available under the trademarks Tween® and Armotan® (see Fiedler, Volume 2, pages 745-746 and 972-975), and examples of such tweens are the following products
  20 [polyoxyethylene (20) sorbitan monolaurate],
  40 [polyoxyethylene (20) sorbitan monopalmitate],
  60 [polyoxyethylene (20) sorbitan monostearate],
  65 [polyoxyethylene (20) sorbitan tristearate],
  80 [polyoxyethylene (20) sorbitan monooleate],
  85 [polyoxyethylene (20) sorbitan trioleate],
  21 [polyoxyethylene (4) sorbitan monolaurate],
  61 [polyoxyethylene (4) sorbitan monostearate] and
  81 [polyoxyethylene (5) sorbitan monooleate].
• 4. d ⁴ Polyoxyethylene fatty acid esters, for example the any known types of polyoxyethylene stearic acid esters, as are commercially available under the trademark Myrj® (see Fiedler, Volume 2, page 636) and also the known polyoxyethylene fatty acid esters, as are commercially available under the trade name Cetiol ® HE are available (see Fiedler, Volume 1, page 228), and polyoxyethylene fatty alcohol ethers, for example, polyoxyethylene stearyl ether, Polyoxyethylenoleylether or polyoxy ethylene cetyl ethers, such as those available under the trademark Brij® (see Fiedler, Volume 1, pages 184 to 186), for example, Brij® 78 and Brij® 96, or else Cetomacrogel® 1000 (see Fiedler, Volume 1, page 229).
• 5. d ⁵ copolymers of polyoxyethylene and polyoxypropylene of various known types, as they are available for example under the trademarks Pluronic® and Emkalyx® (see Fiedler, Volume 2, Be th 720 to 722).
• 6. d ⁶ sorbitan fatty acid esters of various known types, such as those commercially available under the trademark Span®, and these include, for example sorbitan monolauryl, sorbitan monopalmitylester, sorbitan monostearyl, sorbitan tristearylester, sorbitan monooleylester and Sorbi tantrioleylester (see Fiedler, Volume 2, pages 850 to 851).
• 7. d ⁷ partial glycerides, for example mono- and / or di glyceride components containing products, such as surface-active agents based on mixtures of monoglycerides, diglycerides, triglycerides and free glycerol, and also glycerol monostearates and glycerol monooleate. These are also commercially available products, for example, under the trademarks Imwitor® (see Fiedler, Volume 1, page 491), such as Imwitor® 191 or Imwitor® 780 and Softigen® (see Fiedler, Volume 2, page 833), such as Softigen® 701, are available.
• 8. d ⁸ ionic surfactants or emulsifiers, such as sodium lauryl sulfate or sodium ceto stearyl sulfate.

Components d), if present, are in an amount of up to a maximum of 30 percent, and preferably a maximum of 15 percent, based on the total weight of the composition present. At the most favorable are the components d) in an amount of about 0.5 to about 10 percent, for example, an amount of about 1.0 percent, based on the total weight of the composition, available.

Such compositions also suitably contain further

• 1. a thickener.

Examples of thickeners suitable as component e) include

• 1. e ¹ polymethylacrylate resins of the various known types, such as are commercially available, for example, under the trade mark Eudispert® (see Fiedler, Volume 1, pages 371 to 372),
• 2. e ² cellulose derivatives including, for example, ethyl, propyl, methyl, hydroxypropylmethyl and carboxymethylcelluloses,
• 3. e ³ Polyvinyl resins, such as polyvinyl alcohols and polyvinyl pyrrolidones and also other polymeric materials, including gelatin, alginates, pectins, tragacanth gums, gum arabic, xanthan gum and polyacrylic acids, as described, for example, under the trademark Carbopol® (see Fiedler, Volume 1, Pages 206 to 207) are commercially available;
• 4. e ⁴ materials such as silica gels, bentonites and magnesium aluminum silicates.

The components e), if present, are expediently in an amount of up to 20 percent and preferably up to 10 percent, based on the total weight of the together present. Conveniently, the components e) in in an amount of about 0.5 to about 15 weight percent, for example from about 1.0 to about 3.0 percent, based on Ge total weight of the composition, present. Furthermore, sol che compositions expediently even antimicroes contain bielle agents, such as methylparaben, propylparaben, Benzalkonium chloride or benzyl alcohol, and these agents are then, for example, in amounts of 0.05 to 0.5 percent, for example, in an amount of 0.1 percent, or in the case  of benzyl alcohol in amounts of up to 2.0 percent, at For example, about 0.1 percent by weight, based on the total Weight of the composition, present.

Other media include hydrophobic materials For example, the Lös described above for the drug meet the criteria of eligibility.

Other preferred compositions according to the invention which can be applied topically, for example, belong
C ²

• a) a ciclosporin in unsolvated orthorhombic crystal form, such as CY-A / X-III, for example of the type defined above under A to A ⁷ , and
• b) a hydrophobic carrier, for example the above be written style.

The amount of component a) expediently corresponds to the amount already described above in connection with the compositions defined under C ¹ .

Suitable components f) include, for example, petroleum derivatives including mineral oils, fats and gels, like petrolatum (mineral fat or petroleum gel), liquid petro latum (white mineral oil or liquid paraffin) or other known commercial products, such as under the trademark Vaseline® (see Fiedler, Volume 2, page 986) are available, or else the nonionic derivatives based on lanolin, such as under the goods Amerchol® (Fiedler, vol. 1, pages 119 to 120) such as Amerchol® CAB.

Other suitable components f) include, for example  natural or saturated vegetable oils or vegetable fats, For example, the known fractionated coconut oils, such as under the trademark Miglyol® (see Fiedler, Volume 2, Page 616), such as Miglyol® 812, and peanut oils like saturated peanut oils, and also the higher fat alcohols or branched chain alcohols and fatty esters, such as Stearic alcohol, cetyl palmitate and 2-octyldodecanol, as they are under the trademark Eutanol® G (see Fiedler, vol. 1, p te 375) are commercially available.

Such compositions may also contain one or more compo nents of the type described above under d) and e), and further also one or more of the above-mentioned antimicrobial Contain funds.

Above all, such compositions additionally contain one or more of the components d) in an amount of at most 30 percent and preferably at most 20 percent, and indeed suitably in an amount of about 1 to about 15 Ge percent by weight, based on the total weight of the combination setting.

Compositions based on hydrophobic agents of the type described above under C ² , which contain an emulsifier as component d) can be prepared by further addition of water in the form of creams or emulsions. The creams or emulsions it contains can either be of the oil-in-water or water-in-oil type. The amount of water present in such compositions can therefore be, for example, 5 to 80 percent, advantageously 20 to 70 percent, based on the total weight of the composition.

The amounts of components e) and of any antimicrobial agent present correspond or are similar to the amounts already mentioned above in connection with the compositions C ¹ according to the invention.

The amount of the topical form used in each case is of course dependent on the active substance concentration of the composition, the condition to be treated and the desired effect and, in the case of dermal application, also of the area to be covered. Compositions for dermal use, such as for the treatment of psoriasis or atopic dermatosis, generally employ amounts of a cyclosporin dose of the order of about 0.1 to about 5 mg per cm ² , for example about 0.5 mg per cm ² , resulting in an example twice daily use at the desired ge site. Ophthalmic preparations having a ciclosporin content of from about 0.1 to about 10 percent by weight, for example from 1.0 or 2.0 percent by weight, are applied, for example, in drop form to each eye one to three times daily.

Injectable pharmaceutical forms, for example for subcutaneous, intramuscular or other parenteral Injection, in particular including an intra-articular Injection, which, for example, for the treatment of arthritic Diseases such as rheumatoid arthritis, or for intralesional injection, for example for treatment of psoriasis

Dispersions, suspensions or emulsions for a Injection suitable compositions may also be in be be known manner, for example by Disper gation, suspension or other distribution of Ciclo sporin in finely divided orthorhombic crystal form in one suitable liquid carrier medium with addition of suitable Emulsifying agents, surface-active agents, stabilizers, Flocculants and the like. The cyclosporin component in such compositions preferably have a middle part chengröße of less than 100 microns, in particular of less than 50 microns and especially below 20 μm. The appropriate average particle sizes  range from about 0.1 μm or about 0.5 μm up to the specified maximum values of 20 μm, 50 μm or 100 μm.

One would like to use injectable forms, such as those by subcutaneous or intramuscular injection, for example se achieve a depot effect, then also particles with larger particle size can be used. Become such forms by intralesional application or in particular by administered intra-articular injection, but then the Application of feinteiligerer preparations indicated. For this purpose should the cyclosporin component then suitably a middle one Particle size of about 0.1 microns or about 0.5 microns up to about 20 microns, for example, from about 5 microns to 15 microns have.

To achieve a stability of the particles in injectables Shapes, for example, to avoid an increase in the off of larger crystalline particles at the expense of smaller ones Particles, the particles should preferably one as possible have the same size. The deviation between the maximum and the minimum particle size should not be appropriate more than about 50 μm, and preferably not more than about 20 μm be.

The desired particle size can indeed be determined by suitable Achieve comminution processes, such as by micronization, but in general the application is not crushed Microcrystals, as of crystals, to the mentioned and desired particle size are grown, preferably to a Minimize particle size change, the presence question to avoid a change in the particle Prevent crystal surface, such as the Be maintain wettability characteristics, and the required easier to fulfill sterility conditions.  

Injectable compositions of the invention contain since
C ³

• a) a ciclosporin in finely divided unsolvated orthorhombic crystal form, such as CY-A / X-III, of the type defined above under A to A ⁷ , and in particular the type defined above under A ⁶ and A ⁷ , which is distributed or distributable in
• b) an injectable carrier medium.

Suitable carrier media include, in particular, water pharmaceutical purity.

Furthermore, the above compositions C ³ expediently also still

• a) as a dispersant or emulsifier serving surfactant and / or a Flocculant, which is a distribution of particles supported or sustained by the carrier phase.

Polyoxyethylene sorbitan fatty acid esters or polysorbates of the type described above under d ³ ), such as Tween® 80 or Poly sorbat® 80 (see Fiedler, Volume 2, page 746), are suitable as surface-active agents as component g). Suitable flocculants g) include ethylenediamine tetraacetate and salts thereof, for example calcium EDTA and sodium EDTA, and also other comparable chelating agents and peptizers, such as succinic acid or citric acid.

To maintain the particle size distribution is zweckmäßi gerweise a stabilizer also used. To here suitable stabilizers include gelatins and  modified gelatins, such as those under the trademark Gela fundin® and Haemaccel® available plasma extenders, or cold water soluble gelatins of highly purified collagen hydrolysates.

Compositions according to C ³ may also contain one or more anti-microbial agents, for example of the type described above, and also peptizers, such as succinic or citric acid.

The compositions C ³ suitably contain the components a) to b) in a ratio of from about 1: 10 to about 1: 1000, preferably from about 1: 50 to about 1: 200, and for example from about 1 to 100 parts by weight.

To not disturb the particle stability too much, are the Component g) corresponding surface active agent preferably only in low concentration, for example in a concentration of 0.1 to 2.0 weight percent, zweckmäßi in a concentration of about 1% by weight, be based on the weight of component a), present. At An The presence of a flocculant is the ratio of Flocculant for component a) expediently in the Order of magnitude of 1.3 to 1 to 8 parts by weight and ent For example, speaks about 1 to 5 parts by weight. At counter The presence of a stabilizer makes the ratio of Component a) to the stabilizing agent expediently about 1 to 5 to 1 to 30 parts by weight, and preferably 1 to 10 to 1 to 30 parts by weight, and it is for example 1 to 20 parts by weight. In the presence of a peptization by means of the ratio of peptizer to Kom Component a) expediently in the order of 1 to 1 to 1 to 15 parts by weight, for example, about 1 to 10 parts by weight.  

The amount of cyclosporin, which in Ein Ein dosage forms for injection varies of course, depending on, for example, the treat the condition, the site of the injection and the desired we kung, for example, whether a depot effect or ver have relatively rapid release into the surrounding tissue would like to. Suitable unit dosage forms contain about 10 to 500 mg ciclosporin and in particular about 20 to 100 mg Ciclosporin per dosage.

Self-contained dosage forms of the invention are themselves understandably more complex systems, such as dual-chamber syringes or spray batteries, in which the finely divided Ciclo sporin along with other suitable components, like one Stabilizer or an antimicrobial agent, in one located first chamber, and the carrier medium in a second Chamber is present, wherein the INAN chambers in the two chambers which components, for example, by pressing the piston the syringe are mixed together. Such double chamber Syringes are known in the art, and unit dosage Forms on the basis of which also belong to the invention.

Oral dosage forms, for example for the treatment of Autoimmune diseases and other diseases and conditions of the type described above, how to prevent a transplant rejection

Although oral dosage forms, as mentioned above, are generally less interesting and thus less preferred, such forms naturally also belong to the invention. Oral dosage forms of the invention may be prepared in a conventional manner using any known carrier or carrier media. Liquid or semi-solid oral dosage forms may be a cyclosporin in orthorhombic crystal form, such as CY-A / X-III, together with pharmaceutically acceptable. Contain diluents or carriers in which the crystal form itself is insoluble or practically insoluble. Such carriers and diluents include, for example, transesterification products of natural vegetable oil triglycerides and polyalkylenepolyols of the type described above under d ¹ ), such as the products sold under the trademark Labrafil®, and also reaction products of natural or hydrogenated castor oil and ethylene oxide of the above under d ² ), in particular the liquid products obtainable under the trademark Cremophor®, such as Cremophor® EL.

The cyclosporin preferably has a finely divided form an average particle size of, for example, 0.5 to 200 microns, for example, from 0.5 to 30 microns, preferably from we niger than 20 microns, and in particular from 0.5 to 10 microns.

For purposes of ease of administration, the above are he Expected compositions were conveniently in hard gelatin filled capsules or soft gelatin capsules.

Unit dosage forms of the invention suitable for oral administration Administration used conveniently from about 25 to about 75 mg, or up to 200 mg, for example about 50 mg or 100 mg ciclosporin per unit dose. Such forms become, for example, one to four times a day administered in the serum of each patient Ciclosporin concentrations (for example, by a radio immunoassay determined), which are the same or comparable to the concentrations which are produced using a achieved conventional therapeutic treatment with cyclosporine be, for example by administration of the usual oral Solutions of Ciclosporin.

Those described herein and as components of the invention Be defined in accordance with pharmaceutical compositions Be Of course, components should be available for the required phar be suitable for use in the pharmaceutical industry, namely in the case of Be components of a composition for oral administration  be pharmaceutically acceptable or in the case of ingredients a composition for topical administration topically, namely dermal or ocular, applicable, acceptable or ver be tolerant.

Other galenic forms for administration through to the described above, equal or alternative ways yourself for the expert.

The various aspects of the invention will be appreciated the following examples further described.

example 1 Preparation of CY-A / X-III

• a) Dissolve 100 g of cyclosporin in amorphous form with stirring in 400 g of polyethylene glycol 300 at 50 ° C. Shortly after termination of the dissolution, the development of CY-A / X-III begins. The solution is allowed to crystallize for 24 to 48 hours at about 35 to 40 ° C and then diluted with vigorous stirring with 1000 ml of water. The resulting precipitate is separated by filtration, washed with water to remove residual polyethylene glycol, and dried to give CY-A / X-III in a substantially pure form having a melting point of 195 ° C and a particle size of about 100 to 200 has μm.
  Other forms of CY-A / X-III can be prepared analogously to the above method, but instead of polyethylene glycol 300 as the solvent, the following materials are used.

solvent Melting point of the obtained CY-A / X-III in ° C b) Polyethylene glycol 300 / Cremophor® RH 40 (volume ratio 1 to 1) --- c) Cremophor® EL 190 d) Solutol® HS15 188 e) Gelucir® 44/14 180 f) Myrj® 52 184 g) Tween® 80 186 h) Cremophor® RH 40 190

This results in each case crystals having an average particle size of about 50 to about 200 microns. The particular lattice structure corresponds to the structure already given above. The X-ray diffraction data correspond to the values given in Table III and Figure IV below.

Example 2 Preparation of CY-A / X-III

Dissolve 20 g Ciclosporin in the form of CY-A / XI in 60 ml Etha nol and the solution is concentrated by distillation under reduced pressure at a temperature of about 60 ° C to one sixth of its original volume. While stirring at a rate of 300 revolutions per minute, 160 ml of polyethylene glycol (molecular weight 300) and 20 ml of water are then added slowly at 50 to 85 ° C. Then, under a performance of 20,000 oscillations per second working tender ultrasonic vibrator / ultrasonic mixer in operation ge taken and hereby initiated for 3 to 5 minutes at 65 to 75 ° C nucleation. The dispersion obtained is then cooled linearly for 10 to 20 minutes with further stirring at 700 revolutions per minute and further sonication to 40 ° C. The resulting thick pasty mixture is filtered, rinsed with a mixture of 3 volumes of polyethylene glycol (molecular weight 300) and 1 volume of water, washed with warm water (30 ° C) and dried under high vacuum at 50 ° C to give CY-A / X-III in pure form with a melting point of 192 ° C and a particle size of 3 to 15 microns receives. This material has the already mentioned lattice structure. Its X-ray diffraction values correspond to the data given in Table III and Fig. IV.

A repetition of the experiments shows that the Crystal size rather by the nucleation temperature and the Crystal growth rate is affected by the duration of the procedure. By initiating the nucleus formation at about 75 ° C and continuing the crystallization at the same Temperature is obtained crystals with a medium particle size of about 50 microns.

Example 3 Preparation of a galenic form for oral administration 3.1. Gelatin encapsulated preparation I

A suspension of 20% by weight of CY-A / X-III after obtained in the method of Example 1, in Gelucir® 44/14 is so long in a colloid mill at elevated temperature milled until the CY-A / X-III is a medium particle size of about 0.5 to 10 microns has. This is followed by 250 mg each the obtained ground suspension in hard gelatin bottled capsules size 2, that each 50 mg Ciclo sporin (in the form of CY-A / X-III) as an active ingredient.  

3.2 Preparation encapsulated in gelatin II

CY-A / X-III obtained by the method of Example 1 is so long in grind a colloid mill until the CY-A / X-III medium re particle size in the order of 0.5 to 20 microns has. Amounts of 50 mg each are then thoroughly mixed with 200 g Cremophor® EL mixed and so in hard gelatin capsules of Size 2 bottled, that these each 50 mg Ciclosporin (in Form of CY-A / X-III) as an active ingredient.

Example 4 Preparation of galenic forms for topical application 4.1 Gel preparation I

CY-A / X-III prepared by the method of Example 1 is micronized with an air jet mill. The obtained micronized product with a maximum particle size of 60 to 70 microns and a mean particle size of 2 to 10 microns becomes such with the Be mentioned in the following table parts combined and mixed, that an aqueous gel 10% by weight of cyclosporin (in the form of CY-A / X-III) and for topical application, such as Treatment of psoriasis, is appropriate.

ingredients weight a) cyclosporin (micronized CY-A / X-III) 10.0 b) polyacrylic acid (Carbopol 934 P) 0.5 c) sodium hydroxide solution (5%) 3.0 d) methylparaben 0.07 e) Propylparaben 0.03 f) water (pharmaceutically pure) to 100.0%

4.2 Gel preparation II

The preparation of a) is described in 4.1 above carried out. The components c), f) and g) are in the Kom Component b) dissolved with heating, and the resulting mixture is cooled to room temperature. The solution is then in Water h) dispersed. The solution is ver with the component d) sets, and the whole is Homo to effect a dispersion genisiert. Component a) is added, and the mixture is homogenized again. Then the comm component e) was added for neutralization and the resulting gel is then placed in compressible tubes for a topical application tion, for example for the treatment of psoriasis.  

4.3 Ointment preparation

Component a) is prepared as described above under 4.1 provides. The components b), c) and d) are fused and stirred, and the component a) is added at about 30 ° C, wherein the particles are distributed with a homogenizer. The resulting ointment is cooled and compressible Tubes for topical use, for example for treatment psoriasis, bottled.

4.4 Cream preparation

ingredients weight a) cyclosporin (micronized CY-A / X-III) 1.0 b) Polysorbate® 60 5.0 c) cetylstearyl alcohol 10.0 d) Glycerol (85%) 10.0 e) white petrolatum 24.0 f) methylparaben 0.07 g) Propylparaben 0.03 h) water (pharmaceutically pure) 49.0 100.0%

Component a) is prepared as described above under 4.1 and then analogously as described above under 4.3 with the  Components b) to h) united, whereupon the whole in together pushable tubes for topical use, for example for the treatment of psoriasis.

4.5 ointment preparation

A suspension of 20% by weight of CY-A / X-III (obtained by the method of Example 1) in polyethylene glycol 300 is wet-ground until it is a medium particle size of the order of 2 to 10 microns has. Hereupon ver 10 g of the resulting milled product are mixed in Licher manner with 50 g of polyethylene glycol 300 and 40 g molten zenem polyethylene glycol 1500, resulting in a flowable 10% by weight ciclosporin paste (in the form of CY-A / X-III), which are useful for topical application For example, for the treatment of psoriasis, is suitable.

4.6 Gel preparation

ingredients weight a) cyclosporin (micronized CY-A / X-III) 1.0 b) Labrafil® M 1944 CS 1.0 c) Polyethylene glycol 300 30.0 d) benzyl alcohol 1.0 e) Hydroxypropylmethylcellulose (Methocel E4M) 2.5 f) water (pharmaceutically pure) 64.5 100.0%

Component a) is prepared as described above under 4.1 provides. The components b), c) and d) are ver together mixes, whereupon the component f) is added and mixed. In the resulting mixture, component a) is then replaced by homo mixed genization. This is done while stirring long the component e) is added until the gel formation ends  is. The gel is then put into compressible tubes for a topical application, for example for the treatment of Psoriasis, bottled.

4.7 Gel preparation

ingredients weight a) cyclosporin (micronized CY-A / X-III) 5.0 b) Polyethylene glycol 300 30.0 c) glyceryl monostearate 5.0 d) methylparaben 0.07 e) Propylparaben 0.03 f) Carbopol® 934 P 1.0 g) Sodium hydroxide (5%) 6.0 h) water (pharmaceutically pure) 52.9 100.0%

Component a) is prepared as described above under 4.1 provides. The components c), d) and e) are added with heating in the component b) dissolved. The warm mixture is made by homo genisierung in the component h) and then dispersed Room temperature cooled. Then you give the components a) and f) and homogenize the whole. Then the compo nent g) was added and the gelation ended. The obtained Gel is made into squeezable tubes for a topical application tion, for example for the treatment of psoriasis.  

4.8 Cream preparation (water-in-oil)

ingredients weight a) cyclosporin (micronized CY-A / X-III) 2.0 b) Amerchol® CAB 5.0 c) Miglyol® 812 10.0 d) white petrolatum 53.0 e) water (pharmaceutically pure) 30.0 100.0%

Component a) is prepared as described above under 4.1 and with component b) in component e) Heating and homogenization dispersed. The components c) and d) are fused together and mixed, and that Mixture is then preceded by intensive homogenization given dispersion. By subsequent cooling results in a fat-like white cream. This cream is in compressible tubes for topical application, for example wise for the treatment of psoriasis, bottled.

4.9 Preparations of gels and creams

The measure described in the above examples 4.1 to 4.8 men are repeated, but here the crystalline Pro Use the product of Example 2 directly as a cyclosporin component it becomes.

Example 5 5.1 Injectable form, for example for a parenteral application

A suspension of CY-A / X-III is administered under sterile conditions under conventional techniques and application of the following Be manufactured components:  

ingredients Amount by weight (mg) a) Ciclosporin (CY-A / X-III) 20.0 b) Polysorbate® 80 4.0 c) sodium carboxymethylcellulose 5.0 d) sodium chloride 9.0 e) benzyl alcohol 9.0 f) water (injection-pure) to a final volume of 1.0 ml

The release characteristics of the drug from the so erhal The formulation depends on the average particles size of component a). So you need a longer stop tende duration of action, then a CY-A / X-III with a large mean particle size used, for example, a product with an average particle size of 100 to 200 microns, how to it directly obtained by the method described in Example 1. On the other hand, if you want to be effective during one only may have a short duration, then becomes CY-A / X-III Product with a relatively smaller middle part used, for example, by Mikroni tion or milling of the product of Example 1 receives, näm For example, a product with a medium particle size of 0.5 to 10 microns. The suspension obtained is respectively in injection vials for parenteral administration or for intralesional injection for the treatment of psoriasis bottled to thereby, for example, a depot effect achieve.

A particularly preferred embodiment consists in the Ver use of produced according to Example 2 CY-A / X-III, the one average particle size of 5 to 15 microns and under sterile Conditions has been established.  

5.2 Injectable forms, for example for a intra-articular injection

Injectable forms suitable for intraarticular administration are prepared using the following components:

ingredients Amount by weight (mg) AL = L <composition A a) Ciclosporin (CY-A / X-III) 10.0 b) Sodium carboxymethylcellulose 10.0 c) sodium EDTA 2.0 d) water (injection-pure) to a final volume of 1.0 ml

AL = L <composition B a) Ciclosporin (CY-A / X-III) 10.0 b) Polysorbate® 80 0.1 c) citric acid 2.0 d) water (injection-pure) to a final volume of 1.0 ml

The formulation is made using conventional techniques and sterile conditions. Component a) contains non-shredded microcrystals under sterile condition conditions were prepared by the method of Example 2 are and have a mean particle size of 3 to 15 microns. The resulting compositions are administered under sterile conditions bottled in ampoules for injection, for example for intra-articular injection to treat rheumatoid arthritis to treat.

The advantageous properties of the combination according to the invention Settlements can be found on animal models and also in the clinic become. The particular suitability of the compositions according to the invention  for a dermal application, for example Be The treatment of psoriasis or dermatosis may be due to the following Experimental model will be shown.

Allergic contact dermatitis in guinea pigs (DTH test)

Guinea pigs (Hartley, male, 400 to 500 g) by applying 50 μl of 2% dinitrofluorobenzene (DNFB) in a 1 to 1 mixture of acetone and olive oil the inside of the right ear sensitized. After 7 days the animals are treated with 20 μl of 0.5% dinitro fluorobenzene in a 4 to 1 mixture of acetone and olive oil by applying to marked and shorn surfaces at the left and right side. This second treatment is calling an allergic inflammation resulting in redness and to a cellular infiltration (thickening) of the skin leads. On the DNFB treated area on the right side is then the composition to be examined in a Men 200-250 mg with a spatula. The left Page is similarly treated with placebo and serves as a control. Treatment with the to be examined composition or with placebo is repeated five times that of 20 minutes, 8 hours, 24 hours, 32 hours and 48 Hours after which the allergic inflammation is causing repeated second treatment. The thickness of the skin at the be acted before each application and then again 8 hours after the last application determined by the skin lifted to a fold and measured the thickness of this fold becomes. The extent of redness or inflammation also becomes visual rated according to a rating scale from 0 to 4. The effectiveness of the preparation to be examined for sub Binding of an inflammatory reaction is by comparison with the results of the placebo-treated pages only Right.  

The above experimental model using compositions according to the above examples 4.1 and 4.5, which contain only 0.1 percent by weight Ciclosporin in the form of CY-A / X-III, compared to placebo and topically applied 0.1- percent cyclosporin in the form of a her conventional oral solution obtained results are shown in FIGS . I, II and III of the drawing. In view of the extreme sensitivity of this experimental model, the CY-A / X-III is used only in a concentration of 0.1 percent. The compositions to be tested are prepared in complete analogy to Examples 4.1 and 4.5, but the Cyclosporinkomponente is reduced to 0.1 g, and in the case of Example 4.1 compensation by adding 9.9 g of water, and in the case of Example 4.5 compensation is made by the polyethylene glycol components.

In each figure, the measured skin thickness is worn over time. In Fig. I, the results obtained using 0.1% by weight cyclosporin, which is in the form of the conventional commercial oral drinking solution and is used, are compared with the results of the placebo. This shows a slight but not significant reduction in the response compared to placebo for the oral solution. FIGS. II and III show a comparison between the compositions according to the invention according to Examples 4.1 and 4.5, each containing 0.1% by weight of cyclosporin, and placebo. In both cases, there is a significant reduction in swelling of the skin compared to placebo after the first application, and this persists during further treatment and until termination of the experiment.

The suitability of the compositions of the invention will also demonstrated by clinical trials performed as follows become:  

Clinical trial: Treatment of psoriasis by topical (dermal) application

This trial is considered arbitrary, placebo controlled Double blind trial performed. Each patient receives one effective composition and placebo (vehicle alone) simultaneously on two symmetrical lesions. Treatment with active ingredient containing compositions and with placebo is arbitrary lesions on the left and right sides.

The selected subjects are in groups of 12 to 24 Pa divided into patients aged 18 to 70 years and both male and female are where in the female patients either postmenopausal or in Result of a surgical procedure are sterile or through oral intake of contraceptive means a negative Show pregnancy test.

Inclusion criteria include a) written consent and b) clinically defined stable chronic stain psoriasis with at least two moderate to severe bilateral symmetric lesions, each with an area of 4 to 25 cm ² and an assessment score above 5 on one of 0 to 9 reaching assessment scale. This score is a total of 0 (very weak) to 3 (very strong) individual assessments for each of the following three parameters: erythema, dandruff, and skin swelling. The lesions on both sides must be comparable in the same patient, and therefore they should not differ by more than 20 percent in the assessment of their strength or area.

The following exclusion criteria are applied:

• a) Any medical condition which, in the opinion of the searchers would endanger the experiment.  
• b) A systemic, therapeutic treatment of Psoriasis (for example with PUVA, methotrexate, Steroids, retinoids or ciclosporin) within the last two months.
• c) A special topical treatment except with indifferent substances such as white vaseline or salicyl containing acid (not more than 10 percent) of lesions selected for this trial within the last two weeks before the start of the Ver suchs. However, these softening substances may be added Lesions are not used for this Ver have been selected.
• d) Patients with psoriasis who appear to be spontaneously ver mends or spreads without treatment or by stopping the therapeutic treatment too back goes.
• e) Known hypersensitivity to any of the Be constituents of the active substance to be investigated.
• f) Non-cooperative patients receiving medical care do not want to follow the instructions exactly or patients, who are unwilling or unable to meet regularly to undergo visits.
• g) treatment with an active substance to be investigated half a month before the start of the experiment.
• h) serious co-existing diseases, such as a renal dysfunction with serum creatinine levels of over 130 μmol per liter.
• i) hypertension (diastolic blood pressure greater than 95 mm Hg after 5 minutes in a sitting position). Patients, at  Hypertension controlled by drugs, however, are allowed in this experiment.
• j) Malignancy or past malignancy, including of skin cancer.
• k) Acute and bacterial, viral or fungal related skin lesions.
• l) pregnancy and lactation.
• m) patients who are alcoholics or addicted to drugs, suffering from psychosis or emotional or intellek have real problems.
• n) Patients who are constantly at the same time as other immunosuppres active agents, chemotherapeutic agents, with a nephrotoxic potential, such as aminogly kosiden, and medicines must be treated by which are known to interact with the pharmacokinetics of Ciclosporin, as described by Ketocon azole, erythromycin, phenytoin, phenobarbitone, rifampi cin, INH, carbamazepine or sodium valproate.
• o) Patients with abnormal baseline laboratory scores around over 15 percent outside the normal limits for the experimental laboratory values are.
• p) Patients with clinically significant findings in the physical examination.

The compositions to be tested correspond to the co Compositions of the above examples 4.1 to 4.9, and examples these are the 1 percent composition B of Example 4.2 or the 10 percent composition B of Example 4.3.  

Each patient receives a pair of 20 g tubes, each with a Double label are provided. The substance for the Be The right side of the action carries a blue label while the substance intended for the treatment of the left side marked with a red label. In addition to the each right or left side to be treated is each eti Also link with the test code, the name of the Exam the name of the patient and the date of onset of the Treatment labeled. The tearable part of the label is in attached to the case report form.

The active substance to be tested is applied twice a day, morning and evening, the amount to be used being dependent on the size of the lesion and giving a daily dose of cyclosporin of 0.2 to 2.0 mg ciclosporin per cm ² , which, for example, in a test series is about 0.5 mg ciclosporin per cm ² . Placebo is used in a comparable amount. Body areas greater than 25 cm ² are not treated with either the composition under study or with placebo, and the weekly treatment with cyclosporin does not exceed 1 g. At each visit to the clinic, the tubes containing either drug or placebo are weighed and the topically applied daily doses are determined. Patients may take a bath just prior to use of the active substance. Disposable gloves are put on and changed after the order of the composition or the placebo to be examined in order to prevent cross-contamination. Between administration and washing of the treated surfaces, at least 3 hours are allowed to elapse. The first application is monitored and the patient receives a corresponding instruction sheet. The treatment duration is 4 weeks. If the lesions disappear completely in advance, the treatment will nevertheless be continued for a total of 4 weeks. Patients are examined before the beginning of the experiment (week -1), at the beginning of the experiment (week 0), and then after 1, 2, 3 and 4 weeks.

The dermatological evaluation (local psoriasis severity) Index or LPSI) is from the same examiner who na Of course no treatment has been given after one ranging from 0 to 3 rating scale.

The entire LPSI area is identified and assessed, viz resulting from the erythema plus the dandruff plus the Swelling of the skin resulting area, which is from 0 to 9 enough. At the beginning of the experiment must have at least two characters be moderate to severe for both selected lesions (LPSI over 5).  

At the beginning and at each clinical visit, the area of the treated lesions is evaluated (the initial size for each spot is 4 to 25 cm ² ). The area refers to the presence of one or more of the three criteria erythema, dandruff and swelling of the skin. Pigmentation within the lesion area is disregarded in skin area assessment.

The patches are before (week -1) and after the treatment (Week 4) photographed. Here are three pictures taken, namely an image that shows both lesions together, and each a picture that shows each lesion individually.

The itching of the skin (pruritus) is evaluated on the basis of a survey of the patients according to the following assessment scale:
0 = none
1 = minimal, occasional need for scratching
2 = mediocre, frequent need for scratching
3 = strong, very frequent need for scratching, which may even disturb sleep

At the end of the trial, a global assessment of the response to the therapeutic treatment will be made, using the following criteria:

• - Purity = 100 percent resolution
• - pronounced improvement = at least 66 percent He LPSI and / or at least 66% Reduction of the stain area
• - medium improvement = lowering of the LPSI to values between 65 and 33 percent and / or reduction in the Stain area to values between 65 and 33 percent
• - bad = lowering of LPSI by less than 32 Pro cent and / or reduction of stain area by less than 32 percent  
• - Deterioration = exacerbation of the disease

Therapeutic success is defined as any lesion that has disappeared or has significantly improved.

The physician and the patient also evaluate the respective preference for the treatment of the left side or the right side with active ingredient according to the following criteria:

• - The left side is clearly better
• - The left side is a little better
• - There is no difference
• - The right side is a little better
• - The right side is clearly better

To test the efficacy at the end of treatment, the respective assessment data of the LPSI and the lesional areas based on the so-called WILCOXON Sign Rank experiment for paarwei Treatments between ciclosporin-treated Se and placebo-treated pages with regard to Change in rating from baseline to 4 Compared to weeks after treatment.

All other comparisons (at other times and for the remaining parameters of effectiveness) including the with these associated p-values are considered to be for the course of the experiment descriptively viewed.

In the above experiment results in the patients a ausge marked improvement in the psoriatic lesion, such as the LPSI-who for the erythema, dandruff and swelling of the skin on the sides containing a cyclosporin-containing compound If you do this with the pages compared with placebo only. Furthermore, there is also a subjective improvement in the  Assessment of itching of the head (pruritus) by Ciclo sporin compared to those treated with placebo alone Pages.

Positive results are also obtained in parallel experiments on patients with contact dermatitis for whom three or more of the following criteria have been diagnosed:

• - pruritus
• - Typical morphology and distribution:
  Lichens and linearity in the flexural area in adults
  Inclusion of face and extensor in children and adolescents
• - Chronic or Chronic Recurrent Dermatitis
• - Personal or family history Atophy (Asthma, allergic rhinitis, atopic dermatitis),

plus three or more subordinate features, such as:
Xerosis, ichthyosis / palmaris perlinearity / keratosis pilaris, immediate (type I) skin reaction, increased serum IgE, early onset of aging (less than 5 years), predisposition to cutaneous infections (mainly Staphylococcus aureus and herpes simplex) and poorer cell-mediated immunity , Tendency to nonspecific dermatitis on hands and feet, nipple eczema, cheilitis, recurrent conjunctivitis, Dennie-Morgan infraorbital folds, keratoconus, anterior subcapsular cataracts, orbital obscuration, facial paleness, facial erythema, pityriasis alba, anterior cervical fold, itching on sweating , Intolerance of wool and fat solvents, perifollicular accentuation, food intolerance, period affected by environmental factors and emotional factors, dermographism albus and delayed blanching.

The trial period is 3 weeks, with the following para meters are judged by a scale ranging from 0 to 3 the: pruritus, erythema, exudation, and excoriation Lichenification.

Formulations as described above in Examples 4.1 to 4.9 be have been written and the 1 to 10 percent ciclosporin ent like the 5.0% composition according to example 4.7, are also suitable for the treatment of allergic con tact dermatitis and alopecia.  

For the identification of cyclosporin in orthorhombic crystal form, in particular in the form of CY-A / X-III, those given herein are for CY-A / X-III and for the two forms CY-A / XI and CY-A / X-II X-ray diffraction data, as shown in the following Tables I to III. FIG. 4 shows a representation of the X-ray diffraction spectrum, from which the data given in Tables I to III emerged. This X-ray diffraction spectrum was obtained with a Guinier-DeWolff II camera using CuKα radiation with a wavelength of λ = 1.542 Å.

TABLE I

X-ray diffraction diagram of CY-A / XI

TABLE II

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

TABLE III

X-ray diffraction diagram for CY-A / X-III

Claims (4)

1. Ciclosporin in unsolvated orthorhombic crystal form with a crystal lattice a = 12.7 × 10 ^-10 m (12.7 Å), b = 15.7 × 10 ^-10 m (15.7 Å) and c = 36, 3 × 10 ^-10 m (36.3 Å) and a volume per unit of asymmetry of 1804 × 10 ^-30 m ³ (1804 Å ³ ). 2. A process for the preparation of cyclosporin according to claim 1, characterized in that Ciclosporin from a Ci closporin in unsolvated orthorhombic crystal form containing solvent medium, which consists of poly selected ethers having a molecular weight above 200 is crystallized and the resulting solva orthorhombic crystals of ciclosporin wins. 3. Pharmaceutical composition, characterized that they ciclosporin according to claim 1 together with a pharmaceutically acceptable diluent or carrier contains. 4. Pharmaceutical composition according to claim 3, characterized characterized in that it contains 0.05 to 30% by weight of cyclosporin, based on the total weight of the composition.