DE3843054A1 - NEW CYCLOSPORINE CRYSTAL SHAPE, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THIS CRYSTAL SHAPE AND ITS USE - Google Patents

Abstract

Pharmaceutical compositions, in particular topical forms, e.g. for dermal or topical ophthalmic use, and injectible forms, e.g. intra-lesional or intra-articular injection, comprising Ciclosporin as active ingredient in orthorhombic crystal form. Ciclosporin in non-solvate orthorhombic crystal form is also described together with its use and processes for its production.

Description

The invention relates to new pharmaceutical compositions, which contain ciclosporin as an active ingredient.

Cyclosporin, which is also called cyclosporin A, is a well-known fungal metabolite with valuable pharmaceutical Properties. Ciclosporin is a cyclic poly-N-methylated Undecapeptide of the formula

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

Ciclosporin and processes for its preparation are, for example in US-A 41 17 118. The clinical trials with ciclosporin primarily extend to its use as an immunosuppressant, in particular on its application in the treatment of recipients of Organ transplants, such as heart transplants, lung transplants, Heart-lung transplants, liver transplants, kidney transplants, Pancreas grafts, bone marrow grafts, Skin grafts and corneal grafts, and especially allogeneic organ transplants. On this Application area, ciclosporin has been very successful enforced so that it is widely used clinically today becomes. Ciclosporin is commercially available under the names SANDIMMUN® or SANDIMMUNE® available. Suitable galenic  Forms are, for example, infusion concentrates, oral solutions and solutions encapsulated in gelatin, the two the latter forms described for example in US-A 43 88 307 will.

At the same time, ciclosporin was also in depth regarding its Suitability for the treatment of various autoimmune diseases and Inflammatory conditions examined, especially inflammatory Conditions with an autoimmune component as the cause of the disease, we arthritis (for example arthritis rheumatica, Arthritis chronic progressive and arthritis deformans) and rheumatic diseases, and is detailed in the literature about the in vitro studies on animal models and results obtained in clinical trials. About autoimmune diseases, for their treatment ciclosporin has been proposed or applied, for example autoimmune haematological disorders (such as haemolytic Anemia, aplastic anemia, anemia with pure erythrocyte drop and idiopathic throhombocytopaenia), more systematic Lupos erythematosus, polychondritis, scleroderma, pathogen Granulamotosis, dermatomyositis, chronic acute hepatitis, Myasthenia gravis, psoriasis, Steven Johnson syndrome, idiopathic sprue, autoimmune inflammatory disease of the Intestines (such as ulcerative colitis and Crohn's disease), pemphigus, endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary billary cirrhosis, juvenile Diabetes (type I diabetes mellitus), Behcet's disease, uveitis (anterior and posterior), vernal conjunctivitis, keratoconjunctivitis sicca, interstitial pulmonary fibrosis, psoriatic Arthritis and glomerulonephrosis (with and without nephrosis syndrome including idiopathic nephrosis syndrome or Minimal damage nepropathy).

Cyclosporine has also been discussed regarding its potential applicability examined in other areas, such as as a means  against parasites, in particular agents against protozoa, where it also as a possible treatment for malaria, Coccidioidomycosis and schistosomiasis considered and also as a means to reverse the resistance of Tumors against chemotherapy treatment, for example treatment with cytostatics, and as a means of Promote hair growth as for the treatment of Alopecia.

In the solid state, ciclosporin comes in both amorphous form as well as in crystalline form. As are crystalline forms both a tetragonal modification and an orthorhombic one Modification known.

The tetragonal modification (P4₁), which is used here for simplicity is also called CY-A / X-I for the sake of, together with Processes for their preparation, for example in AT-A 353 961 described. Cy-A / X-I has a crystal lattice with a = b = 13.8 Å and c = 41.2 Å, has a volume per unit of asymmetry of 1974 ų, has a melting point of about 140 to 150 ° C and contains about 2 molecules of H₂O per molecule of ciclosporin.

A first orthorhombic modification (P2₁2₁2₁) can be obtained by crystallization from diisopropyl ether, and this is based on the treatise by R. Wenger "Total synthesis - change in molecular structure - biological effect: Ciclosporin as an example "in Sandorama 1984 / III. This particular treatise is about a solvate of ciclosporin and diisopropyl ether (ratio about 1 to 2) with a crystal lattice of a = 125 Å, b = 22.9 Å and c = 28.4 Å, a volume per unit of symmetry of 2027 Å and a melting point of about 150 ° C. Orthorhombic Ciclosporin solvate crystals can be recrystallized supersaturated solutions of ciclosporin in a suitable Solvent medium for a long period of time  hold. Wenger's modification of orthorhombic Ciclosporin / diisopropyl ether solvate can therefore obtained by using a concentrated solution of ciclosporin in methylene chloride (in which ciclosporin is fairly easy is soluble) is added to diisopropyl ether (in which Ciclosporin is relatively poorly soluble) and that Methylene chloride is then evaporated from this solution. By Allow the diisopropyl ether freed from methylene chloride to stand for a period of about 7 days at ambient temperature crystallization then occurs. The educated orthorhombic crystal forms, which the resulting Solvates of ciclosporin are included herein Also called CY-A / X-II for simplicity.

Another orthorhombic modification has now been made (P2₁2₁2₁) found, which is characterized in that in it no or practically no solvent component present is so that it is practical or essentially free Ciclosporin exists.

The dimensions of the crystal lattice of this solvent-free or non-solvate orthorhombic modification of ciclosporin are a = 12.7 Å, b = 15.7 Å and c = 36.3 Å, and this modification has a volume per unit of asymmetry of 1804 ų. The melting point of this crystal form ranges from approximately 180 to approximately 190 ° C. and up to approximately 195 ° C., and depends, for example, on the degree of purity and starting material, as can be seen in Examples 1 and 2, in which later Methods for producing this orthorhombic modification of ciclosporin are described. Ciclosporin in the form of these orthorhombic crystals, which are not a solvate and are therefore solvent-free, is also referred to herein as CY-A / X-III for the sake of simplicity. Further characteristic data (X-ray diffraction values 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 huge contribution to medical science and especially for the technique of organ transplantation, the ciclosporin has already delivered is its practical one Application not yet ideal and free of problems. On The provision of galenic poses particular difficulties Forms that are simple or completely satisfactory Allow administration or which are particularly good for treatment special diseases or conditions are suitable for what Ciclosporin already recognized as a possible active ingredient of choice has been.

These difficulties are partly due to the particular physical Properties of cyclosporin attributed, such as its relatively limited solubility or (previously observed) compatibility with the usual pharmaceutical applicable carrier media. These are difficulties a consequence of the special nature of certain disease states, where primarily a therapeutic treatment with Cyclosporine is indicated, and also the occurrence of undesirable Side effects of ciclosporin when administered orally can cause. For example, psoriasis can be diagnosed Combat oral ciclosporin effectively. At Psoriasis is a common disease which causes quite a few complaints to those affected and for which it is still not sufficiently effective therapeutic treatment there. An effective treatment from Patients suffering from psoriasis is therefore a serious problem. Based on the data available so far, ciclosporin could suitable for solving this problem  be, but this should fail because of treatment of psoriasis using an oral therapeutic treatment Ciclosporin is probably out of the question. Similar considerations also apply to the treatment of eye diseases, for example, such as posterior uveitis and sicca keratoconjunctivitis.

For the administration of ciclosporin the most varied Systems including galenic forms suggested for topical or dermal use or come into question for an ophthalmic application, namely a topical application to the eyes, for 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 so far either brought no discernible advantage or not as proven satisfactory overall.

The various attempts to treat psoriasis suffering patients by direct application of the known oral Solutions to the surface of the psoriatic herd have one shown minimal or no success, being a Strictly occurs in patients suffering from atopic dermatosis was limited. Through topical application to the eyes for example, a rejection of a corneal transplant effectively prevents or an illness in the front Area of the eye can be treated effectively, but there is So far no topically applicable formulation, the one simple, safe and effective treatment of deep ones Enable diseases or conditions located in the eye, such as general treatment of Uveitis including posterior uveitis.

Comparable difficulties also arise for the development of others Systems for the release of ciclosporin, for example  wise injectable forms for intra-articular injection for the local treatment of arthritic diseases of the the type already mentioned above can be applied or the are suitable for intralesional injection, such as for treatment a severe psoriatic lesion, and the same applies also for other oral release systems with, for example, modified ones Bioavailability properties or Release of the active substance.

In previous attempts to formulate ciclosporin will this connection either in solution or what is not so is usually used in amorphous form or in the form of CY-A / X-I, the latter being the crystal form, on the basis of which this medicine is registered. Despite the enormous effort in the search for new or better alternatives have so far been practical as release systems for cyclosporin only oral solutions and infusion concentrates are used.

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

It was mainly recognized that using of such crystal modifications produce pharmaceutical formulations let the ciclosporin in more stable and finely divided Contain form and / or have a better stability or have more favorable release characteristics. This will make the way to making new and better ones Release systems for the active ingredient ciclosporin opened by which this active ingredient prolongs or delays, for example can be released and / or through which diseases or have conditions treated, their therapeutic treatment with ciclosporin was previously not possible or for which  a conventional therapeutic treatment with cyclosporine inevitably not particularly suitable. In particular, was now recognized that by using such crystal modifications in, for example, the fine-particle mentioned Form galenic forms that can be made for a topical or dermal application or for a topical ophthalmic application are suitable to treat diseases, for example or conditions of the skin or eyes of those described above Type of treatment, such as in particular psoriasis, atopic Dermatitis, contact dermatitis, ocular symptoms of disability Illness, uveitis and keratoconjunctivitis sicca. The application Such crystal modifications also enable the production Injectable forms of prolonged cyclosporin or shifted release characteristic, so that this Forms especially for the treatment of diseases or Let states be used where the necessary frequency 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 due to intralesional Injection.

Orthorhombic crystal forms have been used for such purposes, and especially CY-A / X-III, as inherently much better proven suitable as other available forms, such as in particular amorphous ciclosporin or CY-A / X-I, mainly as a result the special physico-chemical properties, like the stability, the release characteristics, namely the Release of ciclosporin from the crystal lattice, and the particular balance with respect to these crystal shapes those necessary for the preparation of the pharmaceutical formulations Activities. CY-A / X-III is a new and preferred one orthorhombic crystal form, according to the invention too galenic and / or therapeutic purposes is used.  

A first embodiment of the invention is therefore

• A CY-A / X-III, namely ciclosporin in an unsolvated orthorhombic crystal form, namely before everything
• A¹ CY-A / X-III with a crystal lattice or other physical properties of those practically defined above Type and / or
• A² CY-A / X-III with an X-ray diffraction spectrum in powder form of the type specified in Table III or in Fig. IV.

The invention also relates to

• B a process for the preparation of CY-A / X-III by Crystallization of ciclosporin from a CY-A / X-III containing medium and recovery of the thus obtained CY-A / X-III.

Suitable media that contain CY-A / X-III can be in the above process, especially solvent media for cyclosporine use the solvent components with higher Contain molecular weight, for example a molecular weight of over 200. Are particularly suitable as media higher molecular weight ethers, especially polymeric ethers, for example Polyalkyl ethers such as polyethylene glycols and polypropylene glycols. Examples of polymeric ethers that have been found to be suitable have proven to be polyethylene glycols and polypropylene glycols with, for example, a molecular weight of over 200, Gly cerium polyethylene glycol esters, such as glycerol polyethylene glycol ricinoleates and glycerol polyethylene glycol oxystearates as they for example under the trademarks Cremophor EL and Cremophor RH (see Fiedler, Lexicon of auxiliary materials, 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 to 975) are polyoxyethylene esters, such as polyoxyethylene stearic acid esters, as for example under the trademark Myrj (see Fiedler, Volume 2, page 636) are available, and transesterification products from natural oil triglycerides and polyalkylene polyols including the transesterification products of corn oil, seed oil, Almond oil, nut flour oil, olive oil, palm oil and mixtures thereof with polyethylene glycols, especially with polyethylene glycols a molecular weight of 200 to 800, as for example available under the trademark Labrafil (see Fiedler, page 539) are. Particularly suitable media include polyethylene glycols with a molecular weight of about 200 to 600, especially from about 300 to about 400.

The media containing CY-A / X-III can also additionally contain one or more other components, for example low molecular weight alcohols and / or water, which are used as agents to modify the solvent / crystallization properties serve. A CY-A / X-III containing has been found to be particularly suitable Medium, which contains about 0.5 parts by volume of ethanol, about 8.0 parts by volume of polyethylene glycol (300) and about 1.0 Contains parts by volume of water.

In the process according to the invention, ciclosporin is first used, for example in amorphous or tetragonal form in the selected and medium containing CY-A / X-III at elevated temperature. The solution temperature naturally fluctuates depending on of the medium chosen in each case, and it is generally above 40 ° C and especially above 50 ° C. In the case of media on The solution temperature is based on polyethylene glycols generally at over 70 ° C and for example between about 75 and 130 ° C. The solution obtained advantageously contains over 5 percent, preferably over 10 percent, for example up to  about 40 to 60 percent, and preferably up to a maximum of 20 weight percent ciclosporin, based on the total weight the solution. The crystallization of Ciclosporin with cooling while appropriate and relative long period of time, for example of the order of magnitude from 10 to 35 minutes or more, depending on the desired crystal growth.

If necessary, core formation procedures can also be initiated like a sound system or a vaccination. When using crystal-containing media based on ethanol, polyethylene glycol and water as described above nucleation occurs at temperatures of around 60 to 90 ° C, for example from 65 to 85 ° C, by using a sound vibration of about 20,000 vibrations per second. By continuing this sonication during the course of crystallization result, as the later example 2 shows, microcrystals with a very fine and relatively constant particle size.

The extent of crystal growth and the size of the obtained Crystals are of course dependent on the medium chosen and the conditions under which the crystallization is carried out is like the question of whether or not working under sound and if so, with what frequency. For one application according to the present method, for example for the production of the galenic to be described later Formulations, CY-A / X-III is preferably in finely divided Form used, for example in a form with a medium Particle size of less than 200 microns, such as from 0.5 to 200 microns .. Show the originally obtained crystals proportionately large particle size, then preparations can with the desired particle size, of course, by usual Receive crushing processes, such as by crushing, grinding, pulverizing, micronizing and other grinding processes. The particulate zu obtained in this way  Preparations can be quite sufficient for certain applications be how to make topical compositions for use on the skin, but can in some cases the application of a shredding technique or grinding technique not be preferred. The reasons for this are that those caused by such Measures received products are usually proportionate have broad particle size distribution and as a result breaking the crystals over a relatively coarse and sharp one Structure. Furthermore, the size reduction physical properties of the natural crystal surface destroyed, and in addition, such procedures are difficult and expensive under the necessary conditions of sterility feasible, such as for manufacturing pharmaceutical formulations for intra-articular administration needs. For these reasons, the method according to the invention usually preferably carried out so that crystals, for example microcrystals, with dimensions within the finally give desired particle size range. For the Production of, for example, compositions for intra-articular or other parenteral use preferably particulate preparations of CY-A / X-III in non-crushed microcrystalline state used (namely Microcrystals of CY-A / X-III in native or unbreakable Condition, which does not require crushing, grinding, Micronization or other particle size reduction have been).

For the formation of microcrystals of CY-A / X-III, directly in used in the uncrushed state described above can be, the inventive method expediently with thorough mixing, such as by stirring, for example at a speed of 200 to 300 revolutions per minute that during crystallization on for example 700 revolutions per minute is increased, and in particular using an ultrasonic vibration, for example  wise in the range of 10,000 to 30,000 vibrations per second, expediently in the order of about 20,000 vibrations per second.

By changing the medium containing CY-A / X-III and adjusting the cooling rate and the extent of mixing during those to be performed using known techniques and recrystallization described later by way of example can be microcrystals of CY-A / X-III with produce different average particle size, for example with particle sizes as mentioned above or as will be described in the following, where these crystals in the aforementioned galenic Formulations apply.

The crystallization process according to the invention is, as 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 becomes. The CY-A / X-III obtained is expedient won in a form that has no or practically no Ciclosporin contains any other form, and thus represents preferably pure or practically pure CY-A / X-III. The above-mentioned level of rinsing contributes to the formation is prevented by amorphous ciclosporin.

The invention therefore also includes a cyclosporin, which is based on have any of the measures described above made, and also

• A³ CY-A / X-III of the type described above under A to A₂, that is free or practically free of ciclosporin in any other form, like free or practically free of Cyclosporine in amorphous form, such as in the form of CY-A / X-I or from CY-A / X-II,
• A⁴ CY-A / X-III of the type described above under A to A³, in pure or practically pure form,
• A⁵ CY-A / X-III of the type described above under A to A⁴, in finely divided form, for example particle size properties of the type described above or in has the following type to be described, as they the galenic forms containing CY-A / X-III are,
• A⁶ CY-A / X-III of the type described above under A to A⁵, predominantly or completely or practically completely consists of non-crushed crystal material, for example from CY-A / X-III that described above under A⁵ Type where the component parts predominantly or completely or practically completely from non-shredded Microcrystals exist, and
• A⁷ CY-A / X-III of the type described above under A to A⁶, in a sterile or practically sterile state, for example in a suitable for a pharmaceutical application Condition, especially one for parenteral use suitable condition, for example for administration by parenteral injection or by intra-articular Injection.

Another part of the invention

• C is a pharmaceutical composition that
  • a) Ciclosporin in orthorhombic crystal form as an active ingredient together with
  • b) a pharmaceutically acceptable diluent or carrier therefor
• contains.

The ciclosporin can be used in the compositions according to the invention in any suitable orthorhombic crystal form be present, such as in the form of CY-A / X-II or CY-A / X-III. in the general is the use of CY-A / X-II because of this physicochemical properties, however, less preferred, because this crystal shape is not so good for making pharmaceutical products based on ciclosporin. The compositions according to the invention therefore contain cyclosporin especially in the form of CY-A / X-III, namely a cyclosporin of the type specified under A to A⁷ above.

The ciclosporin is in the compositions of the invention present in solid (crystalline) form, but can Compositions themselves any suitable pharmaceutical Show shape. Compositions according to the invention include hence solid forms, such as capsules, tablets, coated tablets, powders and granules, semi-solid forms such as ointments, gels, creams and Pastes, and also liquid forms, which the respective ciclosporin component in finely divided form (for example in micronized or microparticulate form) in a liquid pharmaceutical Diluent or carrier in which the particular Crystal form is retained, suspended or dispersed contain.  

Compositions according to the invention include both systems, containing ciclosporin as a single phase or arrangement, such as simple creams, gels, ointments and other forms of type 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 cyclosporine in the form of several phases or arrangements contain. The invention therefore encompasses compositions which a phase or arrangement containing cyclosporin together with one or more phases not containing ciclosporin or Contain arrangements such as with coating phases, carrier phases, Prolonged-release phases or placebo phases, or with phases or arrangements, which contain other active substances or auxiliary substances. The invention therefore includes coated materials, for example Tablets with a core of ciclosporin in orthorhombic Crystal form, for example that of others not ciclosporin containing coating phases or the like is surrounded, Coated tablets with a ciclosporin in orthorhombic Core or cladding containing crystal form and one not Ciclosporin containing shell or core, mixed granules a first granulate phase of ciclosporin in orthorhombic Crystal form and a second one containing no ciclosporin Granulate phase, as well as split tablets with two or more sections, which is separated, for example, by an inner wall are, with a section of ciclosporin in orthorhombic Contains crystal form and the other does not contain ciclosporin. Further possibilities and modifications of such pharmaceutical Shapes are within the usual professional Can s.

The ciclosporin is in the compositions of the invention preferably predominantly or in particular completely or practically completely present in orthorhombic crystal form, for example in the form of CY-A / X-III.  

The compositions according to the invention advantageously contain at least one phase or section of ciclosporin in orthorhombic crystal form, for example in Form of CY-A / X-III, in which this crystal form is uniformly distributed or is distributable. Such systems include, for example homogeneous creams, ointments, gels and the like and also liquid systems in which the existing crystalline Ciclosporin homogeneously distributed or easily homogeneously distributable is, for example by shaking by hand.

Compositions according to the invention include pharmaceutical Forms that are topical, such as dermal or topical ophthalmic administration, perenterally, such as by infusion or injection including subcutaneous or intramuscular Injection and especially an intralesional or intra-articular injection, can be administered and also pharmaceutical forms which are administered enterally can, such as suppositories, pessaries and the like, and oral Dosage forms. Enteral forms, such as oral dosage forms, are generally less preferred, however.

In the compositions according to the invention this is orthorhombic crystalline cyclosporin, such as CY-A / X-III, preferably available in finely divided form, such as micronized, micro-divided or non-crushed microcrystallized form of type described above. The respective particle size is natural depending on the type of composition, the intended use and the type and Mode of application and the desired effect. In general is the average particle size of the respective orthorhombic crystalline ciclosporins, however, in the order of magnitude from 0.5 to 200 µm. Special particle size ranges, as for example for the manufacture of oral, topical or injectable pharmaceutical forms are used further described below.  

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

Gels, creams, ointments and the like for a topical or Dermal administration can be carried out using any technique customary for this purpose are made by ciclosporin in orthorhombic Crystal form with a suitable flowable base, for example an aqueous gel, such as an aqueous gel Base of a cellulose ether, with the addition of suitable surfactants, Thickeners and the like including, for example an aerosil is mixed.

The ciclosporin component is preferably finely divided therein Form available, for example in a form with a average particle size from 0.5 to 200 microns. The ciclosporin component preferably has an average particle size of less than 60 to 80 µm, more preferably less than 40 µm, even stronger preferably less than 30 µm and especially less than 20 µm. The particles are expediently as narrow as possible Particle size distribution. Virtually everyone preferably 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, include, for example, suitable thickened suspensions or Dispersions in the form of viscous eye drops or creams or gels for ocular use. For compositions to treat the eyes has the existing crystalline cyclosporine expediently an average particle size of below  25 µm. Virtually all of the particles present preferably have a size of less than 25 µm. The average particle size for Eye drops are conveniently in the range of about 0.1 up to about 20 µm and preferably from about 0.5 to about 10 µm.

The carrier system, which is in pharmaceutical forms for a dermal use or in preparations for use used in the eyes may vary in content fluctuate in hydrophilic and lipophilic components, and this depends, for example, on the respective surface, to which the composition is to be applied like the properties of the skin to be treated area.

Compositions for a topical and especially a dermal Applications expediently contain a carrier medium, in which the active ingredient (ciclosporin component) is only weak is soluble. The solubility of the cyclosporine component, such as of CY-A / X-III, in such compositions generally lies at less than 10 percent by weight, preferably below 1.0 weight percent, more preferably less than 0.1 weight percent and especially below 0.001 percent by weight.

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

The hydrophilic and water-miscible carriers have expediently a relatively low volatility. To Examples of suitable carrier components, which of these Belong to class include liquid polyalkylene glycols, propylene glycol, Glycerin and ethylene glycol. Suitable polyalkylene glycols belong above all to liquid polyethylene glycols with an average molecular weight of, for example, up to about 600, being polyethylene glycols with an average molecular weight from about 250 to 450 and especially from about 300 are preferred.  

Typical compositions according to the invention, for example can be applied topically

• C¹ a) a ciclosporin in orthorhombic and preferably unsolvated orthorhombic crystal form, like CY-A / X-III, for example that under A to above A⁷ defined type,
• b) a hydrophilic and water-miscible carrier, for example of the type described above, and possibly
• c) Water of pharmaceutical purity.

Component a) is generally in an amount of approximately 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 approximately 1.0, 2.0, 5.0 or 10.0 percent based on the total weight of the composition present. Components b) and c) are generally in a ratio of 1 to 0 to 1 to 20 parts by weight present. The ratio of components b) and c) is preferably 1 to 0.5 to 1 to 5 parts by weight, for example 1 to 1 to 1 to 3 parts by weight and makes in particular 1 to 1.5 to 1 to 2.5 parts by weight.

Such compositions expediently also contain still

• d) a surfactant.

Suitable components d) include

• d¹ Transesterification products from natural vegetable oil triglycerides and polyalkylene glycols. Such transesterification products are well-known materials that stand out  for example according to those described in US-A 32 88 824 Have the process made. They include transesterification products various natural, for example non-hydrogenated, vegetable oils, such as corn oil, Kernel oil, almond oil, nut meal oil, olive oil and palm oil or Mixtures of these with polyethylene glycols, in particular an average molecular weight of 200 to 800 to have. Preferred are those by transesterification of 2 molar parts a natural vegetable oil triglyceride with 1 mole part of polyethylene glycol, for example a has an average molecular weight of 200 to 800 Products. Transesterification products in this class are known in various forms and for example commercially available under the Labrafil trademark (see Fiedler, Lexicon of auxiliary substances, 2. revised and expanded edition, 1981, volume 2, Pages 539). As a component in the invention Compositions are particularly suitable for the products Labrafil M 1944 CS (this is a transesterification product of seed oil and polyethylene glycol with an acid number of about 2, a saponification number of 145 to 175 and an iodine number of 60 to 90), and Labrafil M 2130 CS (this is a transesterification product from a C₁₂ to C₁₈ glyceride and Polyethylene glycol with a melting point of about 35 up to 40 ° C, an acid number of less than 2, a saponification number from about 185 to 200 and an iodine number of under 3).
• d² reaction products of natural or hydrogenated Castor oil and ethylene oxide. Such products are known in the Obtainable, for example by implementation a natural or hydrogenated castor oil with ethylene oxide in a molar ratio of about 1 to 35 to about 1 to 60 and at optional distance  the polyethylene glycol component of the product like this is described in DE-B 11 82 388 and DE-B 15 18 819. The various surfactants, the are available under the trademark Cremophor. Of that the products with the designations are particularly suitable Cremophor RH 40 (with a saponification number from 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  from about 1.453 to 1.457 and an HLB value of about 14 to 16), Cremophor RH 60 (with a saponification number from about 50 to 60, an acid number below 1, an iodine value of less than 1, a water content (according to Fischer) from 4.5 to 5.5 percent, one Refractive index from about 1.453 to about 1.457 and an HLB value of about 15 to 17) and Cremophor EL (with a molecular weight (by vapor osmometry) from about 1630, a saponification number from about 65 to 70, an acid number of about 2, an iodine number of about 28 to 32 and a refractive index of about 1,471). Products are also suitable as such the various surfactants under the trademark Nikkol are available, such as Nikkol HCO-60. Nikkol HCO-60 is a Reaction product from hydrogenated castor oil and Ethylene oxide: acid number 0.3, saponification number 47.4, Hydroxyl number 42.5, pH (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.
• d³ polyoxyethylene sorbitan fatty acid esters or polysorbates, for example the products commercially available under the trademark Tween and Armotan (see Fiedler, volume 2, pages 745 to 746 and 972 to 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].
• d⁴ polyoxyethylene fatty acid esters, for example the known Types of polyoxyethylene stearic acid esters, as commercially available under the Myrj trademark are (see Fiedler, Volume 2, page 636) and also the known polyoxyethylene fatty acid esters, as in Available under the trademark Cetiol HE (see Fiedler, Volume 1, page 228), as well as polyoxyethylene fatty alcohol ethers, for example polyoxyethylene stearyl ether, Polyoxyethylene oleyl ether or polyoxyethylene cetyl ether, as under the trademark Brÿ are available (see Fiedler, Volume 1, pages 184 to 186), for example Brÿ 78 and Brÿ 96, or also Cetomacrogel 1000 (see Fiedler, Volume 1, Page 229).
• d⁵ copolymers of polyoxyethylene and polyoxypropylene the various known types, such as under the Pluronic and Emkalyx are available (see Fiedler, Volume 2, pages 720 to 722).
• d⁶ sorbitan fatty acid esters of various known Types, such as those under the trademark Span are commercially available and include them for example sorbitan monolauryl esters, sorbitan mono  palmitylester, sorbitan monostearyl ester, sorbitan tristearyl ester, Sorbitan Monooleylester and Sorbitantrioleylester (see Fiedler, Volume 2, pages 850 to 851).
• d⁷ partial glycerides, for example mono- and / or diglyceride components containing products such as surfactants Mixtures based Monoglycerides, diglycerides, triglycerides and free glycerin, and also glycerin monostearate and Glycerin monooleate. It is also here to commercially available products, for example under the trademark 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.
• d⁸ ionic surfactants or emulsifiers, such as sodium lauryl sulfate or sodium ceto stearyl sulfate.

If present, components d) are present 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 added. At the Components d) are most favorable in an amount of approximately 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 advantageously also contain also

• e a thickener.

Thickeners suitable as component e) include for example

• e 1 polymethylacrylate resins of various known Types, such as those under the trademark Eudispert (see Fiedler, Volume 1, pages 371 to 372) are commercially available,
• e² cellulose derivatives including, for example Ethyl, propyl, methyl, hydroxypropylmethyl and Carboxymethyl celluloses,
• e³ polyvinyl resins such as polyvinyl alcohols and polyvinyl pyrrolidones and also other polymeric materials below Inclusion of gelatin, alginates, pectins, Tragacanth gum, gum arabic, xanthan gum and Polyacrylic acids, such as those under Carbopol trademark (see Fiedler, Volume 1, pages 206 to 207) are commercially available;
• e⁴ materials such as silica gels, bentonites and Magnesium aluminum silicates.

If present, components e) are expedient in an amount of up to 20 percent and preferably up to 10 percent based on the total weight of the composition present. The components e) are expediently shown in an amount from about 0.5 to about 15 weight percent, for example from about 1.0 to about 3.0 percent based on total weight the composition. Furthermore, such Compositions expediently also antimicrobial Contain agents such as methyl paraben, propyl paraben, 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 up to 2.0 percent, for example about 0.1 percent by weight based on the total weight the composition.

Other carrier media include hydrophobic materials that for example the solubility criteria described above for the active ingredient fulfill.

For further preferred compositions according to the invention, that can be applied topically, for example

• C² a) a ciclosporin in orthorhombic and preferably unsolvated orthorhombic crystal form, like CY-A / X-III, for example that under A to above A⁷ defined type, and
• f) a hydrophobic carrier, for example that described above Art.

The amount of component a) suitably corresponds to that Amount as defined above in connection with those under C¹ Compositions have already been described.

Suitable components f) include, for example, petroleum derivatives including mineral oils, fats and gels, such as petrolatum (mineral fat or petroleum gel), liquid petrolatum (White mineral oil or liquid paraffin) or other known commercial products, such as those under the trademark Vaseline (see Fiedler, Volume 2, page 986) are available, or the non-ionic derivatives based on lanolin, such as those under the trademark Amerchol (Fiedler, Volume 1, pages 119 to 120) is available are, for example 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 Miglyol trademark (see Fiedler, Volume 2, Page 616), such as Miglyol 812, and peanut oils as well saturated nut oils, and also the higher fatty alcohols or branched chain alcohols and fatty esters, such as Stearic alcohol, cetyl palmitate and 2-octyldodecanol as they under the trademark Eutanol G (see Fiedler, Volume 1, page 375) are commercially available.

Such compositions can also include one or more components 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 expediently in an amount of about 1 to about 15 percent by weight, based on the total weight of the together settlement.

Compositions based on hydrophobic agents of the above C² described type, as component d) an emulsifying agent can also contain water by further addition in the form of creams or emulsions. The received Creams or emulsions can either be oil-in Belong to water or water-in-oil. Those in such compositions the amount of water present can therefore be 5 up to 80 percent, suitably 20 to 70 percent on the total weight of the composition.

The quantities of components e) and any present antimicrobial correspond to or resemble the amounts, such as they already above in connection with the compositions of the invention C¹ have been specified.  

The amount of topical form used is natural depending on the active ingredient concentration of the composition, the condition to be treated and the desired effect and in the case of a dermal application also from the one to be covered Area. For compositions for dermal use, such as to treat psoriasis or atopic Dermatosis, amounts are generally applied, the one Cyclosporine dose on the order of about 0.1 to about 5 mg per cm², for example of about 0.5 mg per cm² an application twice a day, for example, on the desired one Surrender. Ophthalmic preparations with a Ciclosporin content from about 0.1 to about 10 percent by weight, for example of 1.0 or 2.0 weight percent, for example in drops on each eye one to three times applied daily.

Injectable pharmaceutical forms, for example for subcutaneous, intramuscular or other parenteral injection, especially including an intra-articular injection, which, for example, is used to treat arthritic Diseases such as rheumatoid arthritis, or for intralesional injection, for example for treatment of psoriasis

Dispersions, suspensions, emulsions and the like, for one Compositions suitable for injection may also be known Be prepared, for example by dispersion, Suspension or other distribution of ciclosporin in finely divided orthorhombic crystal form in one suitable liquid carrier medium with the addition of suitable Emulsifying agents, surfactants, stabilizers, Flocculants and the like. The ciclosporin component in such compositions preferably have an average particle size of less than 100 µm, especially less than 50 µm and especially less than 20 µm. The appropriate middle particles  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.

Would you like to use injectable forms like those through subcutaneous or intramuscular injection, for example achieve a depot effect, then particles with larger particle size can be used. Such forms there by intralesional application or in particular by administered intra-articular injection, but then the Use of more finely divided preparations is indicated. To do this the ciclosporin component then expediently a medium one Particle size from about 0.1 µm or about 0.5 µm up to about 20 µm, for example from about 5 µm to 15 µm.

To achieve particle stability in injectable Forms, for example to avoid increasing the size of larger crystalline particles at the expense of smaller ones Particles, the particles should preferably be one have the same size. The deviation between the maximum and the minimum particle sizes should suitably not more than about 50 microns, and preferably no more than about 20 microns be.

The desired particle size can be determined by suitable ones Achieve comminution processes, such as by micronization, however, the application is generally not crushed Microcrystals, such as from crystals mentioned to and desired particle sizes have grown, preferably to a To keep particle size change to a minimum, the presence of fragmented To avoid changing the particles Prevent crystal surface, such as the Be maintain wettability properties, and the required Sterility conditions easier to meet.  

Injectable compositions according to the invention contain forth

• C³ a) a ciclosporin in fine-particle orthorhombic and preferably unsolvated orthorhombic Crystal form, such as CY-A / X-III, listed above under A to A⁷ defined type, and in particular the above under A⁶ and A⁷ defined type that is distributed or redistributable is in
• b) an injectable carrier medium.

Suitable carrier media include in particular water pharmaceutical purity.

Furthermore, the above compositions suitably contain C3 also

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

Surfactants suitable as component g) include Polyoxyethylene sorbitan fatty acid esters or polysorbates of the type described above under d³), such as Tween 80 or Poly sorbate 80 (see Fiedler, Volume 2, page 746). To suitable Flocculants g) include ethylenediaminetetraacetate and Salts thereof, for example calcium EDTA and sodium EDTA, and also other comparable chelating agents and peptizing agents, like succinic acid or citric acid.

To maintain the particle size distribution is expedient also used a stabilizing agent. About this suitable stabilizers include gelatins and  modified gelatins, such as those under the Gelafundin trademark and Haemaccel available plasma extender, or Gelatine of highly purified collagen soluble in cold water hydrolysates.

Compositions according to C³ can also contain one or more antimicrobial Means, for example of the type described above and also peptizing agents, such as succinic acid or citric acid, contain.

The compositions C³ contain the components a) to b) expediently in a ratio of about 1 to 10 to about 1 in 1000, preferably from about 1 in 50 to about 1 in 200, and for example from about 1 to 100 parts by weight.

In order not to disturb the particle stability too much, they are surface-active agents corresponding to component g) preferably only in a low concentration, for example in a concentration of 0.1 to 2.0 percent by weight, advantageously in a concentration of about 1 percent by weight on the weight of component a). In presence of a flocculant is the ratio of Flocculants for component a) expediently in the Magnitude of 1.3 to 1 to 8 parts by weight and corresponds for example about 1 to 5 parts by weight. In the present of a stabilizing agent makes the ratio of Component a) to the stabilizing agent expediently about 1 in 5 to 1 in 30 parts by weight, preferably 1 in 10 up to 1 to 30 parts by weight, and it is, for example 1 to 20 parts by weight. In the presence of a peptizing agent is the ratio of peptizer to component a) expediently in the order of 1 to 1 to 1 to 15 parts by weight, and is for example about 1 to 10 parts by weight.  

The amount of cyclosporin used in unit dosage forms according to the invention available for injection fluctuates of course, depending on what to treat, for example Condition, location of injection and desired effect, for example whether you have a custody account effect or a proportionate one have rapid release into the surrounding tissue would like to. Suitable unit dosage forms contain about 10 up to 500 mg ciclosporin and in particular about 20 to 100 mg Cyclosporin per dose.

Of course, unit dosage forms according to the invention include also more complex systems, such as double-chamber syringes or spray batteries, in which the finely divided ciclosporin along with other suitable components, such as one Stabilizer, or an antimicrobial, in one first chamber, and the carrier medium in a second Chamber is present, with those present in the two chambers Components, for example, by operating the piston the syringe to be mixed together. Such double chamber syringes are known in the art and unit dosage forms based on this 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 Graft rejection

Oral dosage forms, as mentioned above, are generally less interesting and therefore less preferred, but of course such forms belong also to the invention. Oral dosage forms according to the invention can be taken at Use of any known media or media in a conventional manner getting produced. Liquid or semi-solid oral dosage forms can be taken with for example a ciclosporin in orthorhombic crystal form, such as CY-A / X-III, ent together with pharmaceutically acceptable diluents or carriers hold in which the crystal form itself is insoluble or practically insoluble. Such carriers and diluents include  for example transesterification products from natural vegetable oil triglycerides and polyalkylene polyols as described above under d¹) Kind of like those sold under the Labrafil trademark Products, and also reaction products from natural or hydrogenated castor oil and ethylene oxide of the above d²) described type, in particular that under the trademark Cremophor, such as liquid products available from 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 less than 20 µm, and in particular from 0.5 to 10 µm.

For ease of administration, those mentioned above are Compositions expediently in hard gelatin capsules or filled with soft gelatin capsules.

Unit dosage forms according to the invention which are for an oral Administration used conveniently included about 25 to 75 mg or up to 200 mg, for example about 50 mg or 100 mg ciclosporin per unit dose. Such forms are, for example, one to four times a day administered so that it is in the serum of each patient Cyclosporin concentrations (e.g. by radioimmunoassay determined) result, the same or comparable to the concentrations which are using a conventional achieved therapeutic treatment with cyclosporine be, for example, by administration of the usual oral Ciclosporin solutions.

Those described herein and as components of the invention pharmaceutical compositions defined ingredients are of course intended for the pharmaceutical required in each case Suitable application, namely in the case of components 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 tolerable be.

Other pharmaceutical forms for administration by the ways described above result in the same or alternative ways itself for the specialist.

The various aspects of the invention are described in the following examples are further described.

Example 1 Production of CY-A / X-III

• a) 100 g of ciclosporin are dissolved in amorphous form with stirring in 400 g polyethylene glycol 300 at 50 ° C. Shortly after finishing the dissolution begins the development of CY-A / X-III. The solution becomes 24 to for crystallization Let stand at about 35 to 40 ° C for 48 hours and then diluted with 1000 ml of water with vigorous stirring. The precipitate obtained is separated off by filtration, to remove residual polyethylene glycol Washed and dried water, making CY-A / X-III in a practically pure form that has a melting point of 195 ° C and a particle size of about 100 to 200 µm.
• Analogous to the above procedure, other shapes can be created of CY-A / X-III, for which purpose instead of polyethylene glycol 300 as a solvent, however, the following Materials are used.

This results in crystals with an average particle size of approximately 50 to approximately 200 μm. The particular grid structure corresponds to the structure already given above. The X-ray diffraction data correspond to the values given in the later following Table III and FIG. IV.

Example 2 Production of CY-A / X-III

20 g of ciclosporin in the form of CY-A / XI are dissolved in 60 ml of ethanol and the solution is concentrated to one sixth of its original volume by distillation under reduced pressure at a temperature above 60 ° C. 160 ml of polyethylene glycol (molecular weight 300) and 20 ml of water are then slowly added at 50 to 85 ° C. with stirring at a speed of 300 revolutions per minute. An ultrasonic vibrator / ultrasonic mixer operating at a rate of 20,000 vibrations per second is then put into operation and core formation is hereby initiated for 3 to 5 minutes at 65 to 75 ° C. The dispersion obtained is then linearly cooled to 40 ° C. over a period of 10 to 20 minutes with further stirring at 700 revolutions per minute and further ultrasound treatment. The thick paste-like mixture formed is then filtered, rinsed with a mixture of 3 parts by volume of polyethylene glycol (molecular weight 300) and 1 part by volume of water, washed with warm water (30 ° C.) and dried under high vacuum at 50 ° C., thereby making CY-A / X-III in pure form with a melting point of 192 ° C and a particle size of 3 to 15 microns. This material has the lattice structure already mentioned. Its X-ray diffraction values correspond to the data given in Table III and Fig. IV.

Repeating the experiments shows that the Crystal size rather by the nucleation temperature and the Crystal growth rate is affected by the duration of the proceedings. By initiating core formation at about 75 ° C and continued crystallization at the same Temperature gives crystals with an average particle size of about 50 µm.

Example 3 Preparation of a galenical form for oral administration 3.1 Preparation encapsulated in gelatin I

A suspension of 20 weight percent CY-A / X-III, which according to the procedure of Example 1, in Gelucir 44/14 is so long in a colloid mill at elevated temperature grind until the CY-A / X-III has an average particle size from about 0.5 to 10 µm. Then 250 mg the ground suspension thus obtained in hard gelatin capsules the size 2 filled that each 50 mg of ciclosporin (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 kept in for as long as a colloid mill until the CY-A / X-III is medium Has particle size in the order of 0.5 to 20 microns. Amounts of 50 mg each are then thoroughly 200 g Cremophor EL mixed and so in hard gelatin capsules Size 2 filled that each 50 mg of ciclosporin (in Form of CY-A / X-III) contained as an active ingredient.

Example 4 Production of galenic forms for topical use 4.1 Gel preparation I

CY-A / X-III made by the procedure of Example 1 is micronized with an air jet mill. The received micronized product with a maximum particle size of 60 to 70 µm and an average particle size of 2 to 10 µm becomes like this with the components listed in the following table combines and mixes that an aqueous gel shows that 10 weight percent ciclosporin (in the form of CY-A / X-III) contains and for a topical application, such as Treatment of psoriasis.

4.2 Gel preparation II

The preparation of a) is as described under 4.1 above carried out. Components c), f) and g) are in the component b) dissolved with heating, and the mixture obtained is cooled to room temperature. The solution is then in Water h) dispersed. Component d) is added to the solution, and the whole is homogenized to effect dispersion. Component a) is added and the mixture is homogenized again. The component is then stirred e) added for neutralization, and the gel obtained is then squeezed into tubes for topical application, for example for the treatment of psoriasis.  

4.3 Ointment preparation

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

4.4 Cream preparation

Component a) is produced as described under 4.1 above and then as described above under 4.3 with the  Components b) to h) combined, whereupon the whole in compressible Tubes for topical use, for example for the treatment of psoriasis.

4.5 Ointment preparation

A suspension of 20 weight percent CY-A / X-III (obtained following the procedure of Example 1) in polyethylene glycol 300 is wet-milled until it has an average particle size on the order of 2 to 10 µm. Then mixed up 10 g of the ground product obtained in the usual way Way with 50 g polyethylene glycol 300 and 40 g melted Polyethylene glycol 1500, which makes it flowable Paste with 10 weight percent ciclosporin (in the form of CY-A / X-III) results which, for a topical application, for example for the treatment of psoriasis.

4.6 Gel preparation

Component a) is produced as described under 4.1 above. Components b), c) and d) are mixed together, whereupon component f) is added and mixed. In the mixture obtained, component a) is then homogenized mixed. Then slowly while stirring component e) was added until the gel formation ended  is. The gel is then squeezed into tubes for one topical application, for example for the treatment of Bottled psoriasis.

4.7 Gel preparation

Component a) is produced as described under 4.1 above. Components c), d) and e) are heated in component b) solved. The warm mixture is homogenized dispersed in component h) and then on Cooled to room temperature. Then the components a) and f) and homogenizes the whole. Then the component g) added and the gel formation ended. The received Gel comes in compressible tubes for topical use, for example for the treatment of psoriasis.  

4.8 Cream preparation (water-in-oil)

Component a) is produced as described under 4.1 above and with component b) in component e) below Dispersing heating and homogenization. Components c) and d) are fused and mixed together, and that The mixture is then intensively homogenized before dispersion obtained. By subsequent cooling the result is a greasy white cream. This cream is in compressible tubes for topical use, for example for the treatment of psoriasis.

4.9 Preparation of gels and creams

The measures described in examples 4.1 to 4.8 above are repeated, but here the crystalline product of Example 2 used directly as a ciclosporin component becomes.

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

A suspension of CY-A / X-III is made under sterile conditions using conventional techniques and application of the following ingredients produced:  

The release characteristics of the active ingredient from the thus obtained Formulations depend on the average particle size component a). So you need a longer lasting one Duration of action, then a CY-A / X-III with a large medium particle size used, for example a product with an average particle size of 100 to 200 microns, how to it receives directly by the method described in Example 1. On the other hand, one would like effectiveness only during a relative have a short period of time, then is called CY-A / X-III Product with a relatively smaller average particle size used as for example by micronization or grinding the product of Example 1, namely for example a product with an average particle size from 0.5 to 10 µm. The suspension obtained is in each case in injection ampoules for parenteral administration or for an intralesional injection to treat psoriasis bottled, for example to create a deposit effect achieve.

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

5.2 Injectable forms, for example for an intra-articular one injection

Injectable forms that are suitable for intra-atricular administration are made using the following ingredients produced:

The formulation is made using standard techniques and sterile conditions. Component a) contains Non-crushed microcrystals that are under sterile conditions prepared according to the procedure of Example 2 are and have an average particle size of 3 to 15 microns. The compositions obtained are under sterile conditions filled into ampoules for injection, for example for intra-articular injection to treat rheumatoid arthritis to treat.

The advantageous properties of the compositions according to the invention can be used on animal models and also in the clinic will. The particular suitability of the combination according to the invention  settings for dermal use, for example for treatment of psoriasis or dermatosis, can be caused by the following Experimental model are shown.

Allergic contact dermatitis in guinea pigs (DTH test)

Guinea pigs (Hartley, male, 400 to 500 g) by applying 50 µl of 2 percent dinitrofluorobenzene (DNFB) in a 1 to 1 mixture of acetone and olive oil sensitized the inside of the right ear. After 7 days the animals are treated with 20 μl of 0.5 percent dinitrofluorobenzene in a 4 to 1 mixture of acetone and olive oil by applying to marked and sheared areas on the left and right. This second treatment is calling an allergic inflammation that turns red and cellular infiltration (thickening) of the skin leads. On the area treated with DNFB on the right side thereupon the composition to be examined is added in a quantity from 200 to 250 mg applied in a spatula. The left Page is treated and served in a similar way with placebo as a control. Treatment of the composition to be examined or with placebo is five times at intervals of 20 minutes, 8 hours, 24 hours, 32 hours and 48 Hours after causing the allergic inflammation second treatment repeated. The thickness of the skin on the treated Spot is before each application and then again 8 hours after the last application determined by the skin raised to a crease and measured the thickness of that crease becomes. The extent of the redness or inflammation also becomes visual rated on a rating scale from 0 to 4. The effectiveness of the preparation to be examined for prevention an inflammatory response is by comparison with the results of the sites treated with placebo only Right.  

Those in the above test model using compositions according to Examples 4.1 and 4.5 above, which, however, only contain 0.1% by weight ciclosporin in the form of CY-A / X-III, in comparison to placebo and topically applied 0.1% ciclosporin in the form Results obtained from a conventional oral solution are shown in Figs. I, II and III of the drawing. In view of the extreme sensitivity in this test model, the CY-A / X-III is only used in a concentration of 0.1 percent. The compositions to be investigated are prepared in complete analogy to Examples 4.1 and 4.5, but the cyclosporine component is reduced to 0.1 g, and in the case of Example 4.1 compensation is carried out by adding 9.9 g of water, and in the case of Example 4.5 is compensated by the polyethylene glycol components.

The measured skin thickness is plotted against time in each figure . In Fig. I the results obtained using 0.1% by weight ciclosporin, which is in the form of the conventional, commercially available oral drinking solution and is used, are compared with the results of the placebo. The oral solution showed a slight but insignificant reduction in the response compared to placebo. Figs. II and III show a comparison between the inventive compositions according to the Examples 4.1 and 4.5, respectively, each containing 0.1 percent by weight cyclosporine, and placebo. In both cases there is a significant reduction in the swelling of the skin compared to placebo after the first application, and this also continues during the further treatment and until the end of the trial.

The suitability of the compositions according to the invention will also shown by clinical trials performed as follows will:  

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

This attempt is called an arbitrary, placebo-controlled Double blind test carried out. Every patient receives one effective composition and placebo (carrier alone) simultaneously on two symmetrical lesions. Treatment with active ingredients Compositions and with placebo are arbitrary on lesions located on the left and right sides.

The selected subjects are in groups of 12 to 24 patients divided, which have an age of 18 to 70 years and are both male and female, whereby the female patients either postmenopausal or in Are sterile or as a result of a surgical procedure oral contraceptives negative Show pregnancy test.

The inclusion criteria include a) a written one Consent and b) a clinically defined stable chronic patch psoriasis with at least two medium to strong bilateral symmetrical lesions, each one Have an area of 4 to 25 cm² and an evaluation value of over 5 on a rating scale from 0 to 9. This evaluation value is a total of 0 (very weak) to 3 (very strong) individual assessments for each of the following three parameters: erythema, Dandruff and swelling of the skin. The lesions on both sides must be comparable in the same patient and they may therefore by no more than 20 percent in the assessment differ in strength or in area.

The following exclusion criteria are applied:

• a) Any medical condition that, in the opinion of the examiner would endanger the attempt.  
• b) a systemic, therapeutic treatment of Psoriasis (e.g. with PUVA, methotrexate, Steroids, retinoids or ciclosporin) within the last two months.
• c) A special topical treatment except with indifferent ones Substances such as with white vaseline or with salicylic acid formulations (not more than 10 percent), of lesions selected for this trial within the last two weeks before the start of the experiment. However, these softening substances can Lesions are used which are not for this trial have been selected.
• d) patients with psoriasis that appears to improve spontaneously, or which spreads without treatment or by discontinuing therapeutic treatment declines.
• e) Known hypersensitivity to any of the components of the active ingredient to be investigated.
• f) Non-cooperative patients receiving medical instructions don't exactly obey or patients who are unwilling or unable to regularize themselves To undergo visits.
• g) treatment with an active substance to be investigated within one month before the start of the experiment.
• h) Serious coexisting diseases, such as one renal dysfunction with serum creatinine levels above 130 µmol per liter.
• i) hypertension (diastolic blood pressure of over 95 mm Hg after 5 minutes in a sitting position). Patients, at  who have hypertension controlled by drugs, are admitted in this attempt.
• j) Malignancy or past malignancy including inclusion of skin cancer.
• k) Acute and bacterial, viral or fungal skin lesions.
• l) pregnancy and lactation.
• m) patients who are alcoholics or drug addicts, suffer from psychosis or emotional or intellectual Having trouble.
• n) Patients who are constantly taking other immunosuppressive Agents, chemotherapeutic agents, compounds with a nephrotoxic potential, such as aminoglycosides, and medicines need to be treated by who are known to have pharmacokinetics of Cyclosporine interact, such as from ketoconazole, Erythromycin, phenytoin, phenobarbiton, rifampicin, INH, carbamazepine or sodium valproate.
• o) Patients with abnormal baseline laboratory values who um over 15 percent outside of normal limits for the test laboratory values are.
• p) Patients with clinically significant findings in the physical examination.

The compositions to be examined correspond to the compositions the above examples 4.1 to 4.9, and examples this is 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 one Double label are provided. The substance for treatment the right side bears a blue label while the substance intended for the treatment of the left side is marked with a red label. In addition to the the right or left hand side is each label also with the test code, the name of the examiner, the name of the patient and the date of the start of the Treatment labeled. The tearable part of the label is in attached to the fall area shape.

The active ingredient to be examined is twice daily, namely applied in the morning and in the evening, the applicable of which Amount depends on the size of the lesion and is a daily one Cyclosporine dose of 0.2 to 2.0 mg ciclosproin per cm² results, for example in a series of tests 0.5 mg ciclosporin per cm². Placebo will be comparable Amount applied. Body areas with more than 25 cm² are neither with the composition to be examined nor treated with placebo, and weekly treatment with Ciclosporin is not more than 1 g. With every visit in The clinic will either contain the active ingredient or placebo Weighed tubes and the topically applied daily doses certainly. Patients may just before the application of the Bath active ingredient. Disposable gloves are put on and after application of the composition to be examined in each case or of the placebo, and to prevent cross-contamination. Between administration and washing of the treated Areas are allowed to pass at least 3 hours each. The first application is monitored and the patient receives a corresponding information sheet. The duration of treatment is 4 weeks. The lesions completely disappear before then the treatment is continued for a total of 4 weeks. Patients will be at the start of the trial (week -1) Start of experiment (week 0) and then after 1, 2, 3 and 4 Weeks examined.  

The dermatological evaluation (local psoriasis severity Index or LPSI) is from the same examiner, which of course has not undergone treatment after from 0 to 3 rating scale.

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

At the beginning and at every clinical visit, the area of the treated lesions (the initial size for each Stain is 4 to 25 cm²). The area refers to the Presence of one or more of the three criteria erythema, Dandruff and swelling of the skin. A pigmentation inside The lesion area is used when assessing the skin area disregarded.

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

The itching of the skin (pruritus) is based on a survey of patients rated according to the following assessment scale:

• 0 = none
• 1 = minimal, occasional need to scratch
• 2 = mediocre, frequent need to scratch
• 3 = strong, very common need for scratching, which if necessary even disturbs sleep

At the end of the trial there is a global assessment of the response performed on the therapeutic treatment for what the following criteria are used:

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

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

The doctor and patient also determine the respective preference for the treatment of the left side or the right Page with active ingredient evaluated 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 effectiveness at the end of treatment, the respective assessment data of the LPSI and the lesional areas using the so-called WILCOXON Sign Rank test for pairs Treatments between the pages treated with ciclosporin and the placebo treated pages regarding Change in valuation from baseline to after 4 Compared weeks after treatment.

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

In the above experiment, the patient developed a pronounced one Improvement of the psoriatic lesion, such as LPSI values for the erythema, dandruff and swelling of the skin on the sides with a composition containing ciclosporin have been dealt with when looking at the pages compares that have only been treated with placebo. There is also a subjective improvement in the  Ciclosporin assesses the itchiness of the head (pruritus) compared to those treated with placebo only Pages.

Positive results can also be achieved with parallel tests on patients with contact dermatitis for whom three or more have been diagnosed with the following criteria:

• - pruritus
• - Typical morphology and distribution:
  Braiding 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 sub-features, such as:

Xerosis, ichthyosis / palmar hyperlinearity / keratosis pilaris, immediate (type I) skin reaction, increased serum IgE, early onset of aging (under 5 years), tendency to cutaneous infections (especially from Staphylococcus aureus and herpes simplex) and worse cell-mediated immunity, tendency to a non-specific Dermatitis of the hands and feet, nipple eczema, Cheilitis, recurrent conjunctivitis, Dennie Morgan infraorbital folds, keratoconus, anterior subcapsular cataracts, orbital darkening, facial pallor, Facial erythema, pityriasis alba, front neck wrinkles, Itching when sweating, intolerance of Wool and fat solvents, perifollicular accentuation, Food intolerance, due to environmental factors and emotional factors influenced period, dermographism albus and delayed pale.

The trial period is 3 weeks, taking the following parameters can be judged on a scale from 0 to 3: Pruritus, erythema, exudation, excoriation and Lichenification.

Formulations as described above in Examples 4.1 to 4.9 that contain 1 to 10 percent ciclosporin, like the 5.0 percent composition according to example 4.7, are also suitable for the treatment of allergic contact dermatitis and from alopecia.

The invention therefore also belongs

• D a method for the therapeutic treatment of patients, suffering from such diseases, with ciclosporin, which is characterized in that such patients Ciclosporin in orthorhombic crystal form, in particular in unsolvated orthorhombic crystal form, as as CY-A / X-III, according to the above under A to A⁷ defined type administered in an effective amount becomes.

Above all, part of the invention

• D¹ a method of immunosuppressive or anti-inflammatory therapeutic treatment of patients, who need such treatment because of that is characterized that such patients an effective Amount of ciclosporin in orthorhombic crystal form, especially in unsolvated orthorhombic Crystal form, such as in the form of CY-A / X-III, for example the type defined below 04501 00070 552 001000280000000200012000285910439000040 0002003843054 00004 04382r A to A⁷ becomes.

The above methods are used, for example, for loading  act of any disease or condition described above The way ciclosporin has been used so far how to prevent graft rejection, for treatment autoimmune or reheumatic diseases, for treatment other diseases or conditions with an undesirable high response of the immune system Treatment of parasite infections, for the treatment of a chemotherapeutic resistance, such as a reversal of tumor resistance versus antineoplastic chemotherapy, and also for the treatment of alopecia. The above procedures find particular application for the treatment of diseases or skin or eye conditions such as psoriasis, atopic dermatitis or contact dermatitis, corneal transplants, Conjunctivitis and uveitis, by topical administration and also for the treatment of rheumatoid arthritis and other diseases or conditions of the joints intra-articular administration.

The invention therefore also belongs

• E ciclosporin in unsolvated orthorhombic Crystal form, such as in the form of CY-A / X-III, for example of the type defined above under A to A⁷, for use as a pharmaceutical, as for the treatment of any Diseases or conditions described in D or D 1 above Art, for example for use as immunosuppressive or anti-inflammatory agent, and also
• F ciclosporin in orthorhombic crystal form, as in Form of CY-A / X-III, for example the one under A to A⁷ defined type, for use in manufacturing a pharmaceutical composition for an application of the type defined under E above.

The ciclosporin in orthorhombic crystal form, in particular in the form of CY-A / X-III, is used to identify ciclosporin 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 Tables I to III below. Fig. IV is an illustration of the X-ray diffraction spectrum from which emerged in Tables I to III specified data. This X-ray diffraction spectrum was obtained with a Guinier-DeWolff II camera using CuK α radiation with a wavelength of g = 1.542 Å.

Table I

X-ray diffraction pattern of CY-A / XI

Table II

X-ray diffraction pattern of CY-A / X-II

Table III

X-ray diffraction pattern of CY-A / X-III

Claims (21)

1. Ciclosporin in unsolvated orthorhombic Crystal shape. 2. Ciclosporin according to claim 1, characterized in that there is a crystal lattice with a = 12.7 Å, b = 15.7 Å and c = 36.3 Å and a volume per asymmetry unit of 1804 Å. 3. ciclosporin according to claim 1 or 2, characterized in that it has the following X-ray diffraction data: 4. ciclosporin according to any one of claims 1 to 3, characterized characterized that it is free or practically free Ciclosporin is in any other form and is pure or practically pure form. 5. Ciclosporin according to any one of claims 1 to 4, characterized characterized in that it is in finely divided form. 6. ciclosporin according to claim 5, characterized in that its particles have an average particle size of less than 200 µm to have. 7. ciclosporin according to claim 6, characterized in that its particles have an average particle size of 0.5 to 200 µm to have. 8. ciclosporin according to claim 6 or 7, characterized in that its particles have an average particle size of less than 25 microns to have. 9. ciclosporin according to any one of claims 1 to 8, characterized characterized that it is predominantly or wholly or practically consists entirely of non-crushed crystal material. 10. ciclosporin according to any one of claims 6 to 8, characterized characterized in that its particles predominantly or entirely or practically entirely from non-crushed microcrystalline Material existed. 11. ciclosporin according to any one of claims 1 to 10, characterized characterized in that it is sterile or practically sterile Condition is present.   12. Process for the production of ciclosporin in unsolvated orthorhombic crystal shape, characterized in that that ciclosporin from a ciclosporin in unsolvated solvent medium containing orthorhombic crystal form is crystallized and the unsolvated so obtained orthorhombic crystals of ciclosporin obtained will. 13. Pharmaceutical composition, characterized in that it

• a) Ciclosporin in orthorhombic crystal form as an active ingredient together with
• b) a pharmaceutically acceptable diluent or carrier therefor

contains. 14. Pharmaceutical composition according to claim 13, characterized characterized in that the ciclosporin predominantly therein or entirely or practically entirely in orthorhombic crystal form lies. 15. Pharmaceutical composition according to claim 13 or 14, characterized in that it has at least one section or Has phase, the ciclosporin in orthorhombic crystal form contains, this crystal form by the section or Phase is distributed or redistributable or through the section or phase homogeneously or practically homogeneously distributed or distributable is. 16. A pharmaceutical composition according to any of the claims 13 to 15, characterized in that they are ciclosporin as defined in any of claims 1 to 11.   17. A pharmaceutical composition according to any of the claims 13 to 16, characterized in that they are flowable Form for a topical application or application by injection or infusion. 18. A pharmaceutical composition according to any of the claims 13 to 17, characterized in that they 0.05 to 30 weight percent ciclosporin, based on the total weight of the composition. 19. Ciclosporin according to any one of claims 1 to 11 Use as a pharmaceutical. 20. ciclosporin according to claim 19 for use as immunosuppresives or anti-inflammatory agent.