SE503174C2 - Ciclosporin crystal forms, process for its preparation, pharmaceutical compositions containing the same and its use - Google Patents

Abstract

Novel pharmaceutical compositions, in particular topical forms, e.g. for intra-lesional or intra-articular injection, comprising Ciclosporin as active ingredient in orthorhombic crystal form. Ciclosporin in non-solvate orthorhombic crystal form is preferred for use in the compositions of the invention, is new and also part of the invention together with its use and processes for its production.

Description

10 15 20 25 30 35 7. [-,.

Eïl: 1! ¿; q g I a disorders or diseases (including, for example, hemolytic anemia, aplastic anemia, thrombocytopenia), systemic lupus erythematosus, sclerodoma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, psoriasis, pure red blood cell anemia and idiopathic polycondrite, chronically active Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including ulcerative colitis and Crohn's disease), pemphigus, endocrine ophthalmopathy, Graves' disease, type bile duct, primary biliary cirrhosis, (type I diabetes mellitus), poeterior), vernal conjunctivitis, sarcoids, mul- primary juvenile diabetes Behcet's disease, uveitis (anterior and keratoconjunctivitis sicca, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome. for example inclusivef idiopathic nephrotic syndrome or minimal change nephrotic ropati).

Other investigated areas have included potential uses. as an anti-parasitic agent, average, act of malaria, cocciodiomucosis and schistoeomiasis, in particular anti-protozoa where possible proposed uses have included like- as a use for reversing tumor resistance to chemotherapy peutic, for example cytostatic, hair growth, for example for the treatment of alopecia. therapy and to promote In the solid state, Ciclosporin exists in both amorphous and crystalline form. tetragonal as an orthorhombic modification known.

The tetragonal modification (P41), which herein for the sake of simplicity also referred to as "CY-A / X-I", X the crystalline state is as well one for described together with processes for its production in, for example, Austrian U.S. Patent No. 353,961. CY-A / X-I has a grid a = b = 41.2 Å, 13.8 Å c = one volume per asymmetric unit = 1974 A3, a melting point at about 140-150 ° C and comprises about two molecules of H 2 O per Ciclosporin molecule.

A first orthorhombic medication (P212121) can be obtained by recrystallization from diisopropyl ether, as discussed in an article entitled 'Total synthesis - change in molecular structure - biological effetc: Wenger in "Sandorama" 1984 / III.

Ciclosporin as an example "by R.

This-special modification n- -W comprises a Ciclosporin diisopropyl ether (about 1: 2) solvate with a crystal lattice with a = 12.5 Å, b = 22.9 Å, c = 28.4 Å, volume 10 15 20 25 30 _35 O? k ...__ \ W fi IN-. l CTI per asymmetric unit = 2027 A3 and a melting point at about 150 ° C.

Orthorombic Ciclosporin Solvate Crystals can be obtained by crystallization from supernatant Ciclosporin solutions in a lamp solvent medium for long periods of time. Salunda er- the orthorhombic Ciclosporin / diisopropyletherol modification made by Wenger by adding a con- concentrated solution of Ciclosporin in methylene chloride (wherein Ciclosporin rin is relatively easily soluble) to diisopropyl ether (var Ciclosporin is relatively less soluble) and evaporation of methylene chlorides. Crystallization from the remaining diisopropyl the ether is then allowed to take place for a period of about 7 days at ambient temperature. Orthorombic crystal forms comprising such The Ciclosporin Solvate is designated V herein also for the sake of simplicity generically "CY-A / X-II".

Another orthorhombic (P212121) modification has now been identified. which is characterized by the absence or substantial absence of any solvent component, ie it consists essentially of of or mainly of free Ciclosporin.

The dimensions of the crystal lattice for the solvent free or non-solvate form of the orthorhombic Cicloeporin mo- the specification is a = 12.7 A, b = 15.7 A, c = 36.3 A and the volume per asymmetric unit = 1804 A3. The melting point is of the order of from about 180 to about 190 ° C up to about 195 ° C, for example depending on the degree of purity / source, as indicated in Example 1 and 2 below, where specific methods for obtaining this modi- fiction is described. Ciclosporin in orthorhombic, non-solvate (or solvent-free) crystalline form is also referred to herein as hets skull "CY-A / X-III". Additional characterization (X-ray powder diffraction) data for CY-A / X-III are given in Table III and Figure IV below together with the corresponding data for CY-A / X-I and CY-A / X-II.

Despite the considerable success and the very good reputation Ciclosporin has received and despite the large contribution to the Chinese science, in particular as regards the field of transplants, which it has entailed, is its use in practice still not ideal or hassle-free. One special area, in which difficulties have arisen, is to-_ handling of galenic forms which enable simple or completely satisfactory administration or which are best 10 15 20 25 30 35 fn ”4flfl 4 u 1 'w IN. ( (_: for the treatment of specific diseases or conditions, for which Ciclosporin has already been identified as a potential selected drug.

These difficulties can be partly attributed to the special ones physical characteristics of Ciclosporin, to example its relatively limited solubility or (hitherto compatibility with available, pharmaceutically applicable only carrier media. These responsibilities are exacerbated by the nature of some of the disease states for which Ciclosporin represents it potential therapy in the first instance, as well as the behavior of undesirable side or side effects that Ciclosporin may cause cause when administered orally. For example, Ciclosporin identified as effective in treating psoriasis after oral administration. Psoriasis is a common condition, which causes considerable suffering to patients and for which it does not currently find any generally accepted, effective therapy. People who suffer from psoriasis represent without doubt a patient population in need of further assistance. Also if the evidence or results currently available would be able to indicate that Ciclosporin represents this help, it is unlikely that oral Ciclosporin therapy could be defended as a conventional way of treating psoriasis. Similar considerations apply to the treatment of, for example, judgments, such as posterior uveitis and keratoconjunctivitis sicca.

Various systems have been proposed for the administration of Ciclosporin, including galenic forms intended for topical use or dermal application or for ophthalmic application, it that is, topical application to the eye, for example, for possible use in the treatment of psoriasis, by other dermatologists diseases and conditions, such as atopic dermatosis and alopecia, or for the treatment of uveitis. Such systems have so far has not brought any particular benefit or has not proved to be completely satisfactory.

Salunda has various reported attempts to treat individuals psoriasis by applying the known oral solution directly at the superficial site of the psoriasis has involved success or no success at all, and_the successes of the bands with individuals suffering from atopic dermatosis have been particularly limited. Similarly, even if topiek 10 15 20 25 30 _35 ñ '"4 W - oo: M- (_31 application to the eye has been found to be very effective as a way of preventing, for example, the rejection of a corneal graft or to treat a disease of the eye mentum anterius, no topical preparation has so far been reported which could enable convenient, safe or efficient effective treatment of diseases or conditions, since they deeper lying places inside the eye, for example for all treatment of uveitis, including posterior uveitis.

Comparable responsibilities have occurred in connection with the country of other Ciclosporin drug delivery systems, to injectable forms, for example suitable for intra-articular teach injection for local treatment of arthritic diseases, to examples as mentioned above, or for intra-leeional injection for example for the treatment of black psoriasis, or alternative oral delivery systems, such as those with modified bioavailability or drug release characteristics.

So far, Ciclosporin has been used in attempts to prepare Ciclosporin of the compound in solution or, which has been less usually, in amorphous form or C 1 -A / X-I form, the latter for example, the crystal form identified for example is for drug registration purposes. Despite the very significant efforts that have been made to try to produce new or improved alternatives, remains the already mentioned oral solution and infusion concentrates are the only more widely used systems for Ciclosporin.

According to the present invention, it is now surprising found, that orthorhombic crystalline forms of Ciclosporin. for example CY-A / X-II, and in particular CY-A / X-III, is off special advantage and utility in the production of galenic Ciclosporin preparations of different and diversified types. In particular, it has been found that such crystal modifiers cations can be used for the preparation of galenic preparations comprising Ciclosporin in stable, fine particulate form and / or with improved stability or release characteristics.

This finding opens the way to the production of new ones and improved CieloepbrinlätemedeisavgivningsystemT ~ tiil = ~ == ~ ¿'~ -e such as those exhibiting delayed Ciclosporin delivery characteristics and / or are adapted to or suitable for 10 l15 20 25 30 35 5GB act of disease or condition, which has hitherto been instead of Ciclosporin therapy or for which the conventional The cyclospor therapy itself has been less suitable. More spe- In particular, it has been found that by using such crystal modifications, for example in fine particulate form such as have been mentioned above, may obtain galenic forms which are suitable for topical or dermal application or for topical ophthalmic application, for the treatment of diseases or conditions which affects the skin or eye, for example as has been mentioned above, in particular for the treatment of psoriasis, atopic dermatitis, contact dermatitis, keratoconjunctivitis sicca. Use of such crystal modifiers ocular symptoms of Behcet's disease, uveitis and cations also enable the production of injectable forms for Ciclosporin with delayed release characteristics, and these are hence of special usefulness for example in the treatment of diseases or conditions for which the required administration the administrative frequency may otherwise impede or impede the for example in the treatment of arthritis or the like diseases of the joints by intra-articular injection or for treatment of psoriasis or similar diseases of the skin by intra-lesional injection.

For such purposes, orthorhombic crystal forms, i in particular CY-A / X-III, much better suited than other available molds, for example as regards found to be inherent or in itself especially amorphous Ciclosporin or CY-A / X-I, physico-chemical properties, in particular stability, release characteristics, ie release of Cicloeporin from crystal lattice, and susceptibility or suitability for the necessary procedures for galenic preparation. CY-A / X-III is new and the preferred orthorhombic crystal form for galeniek and / or therapeutic use in accordance with the invention.

According to a first embodiment, the present invention provides finning ealunda the following: A CY-A / X-III, ie Ciclosporin in orthorhombic non-solvate crystal form; especially, A1 CY-A / X-III with a crystal lattice or other physical physical characteristics essentially as defined above and / or 10 15 20 25 30 35 A2 CY-A / X-Ill with X-ray powder diffraction characteristic essentially as reported in Table III or illustrated in Figure IV.

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

Suitable CY-A / X-III bearing or containing media for use in the above process is in particular solution Ciclosporin solvent media comprising solvent components higher molecular weight, for example those with a molecular weight cooling weight> 200. Particularly suitable are media comprising ethers with higher molecular weight, especially polymeric ethers, for example polyalkyl ethers, for example polyethylene and polypropylene glycols.

Examples of polymeric ethers which have been found to be suitable are polyethylene and polypropylene glycols, for example with a molecular cooling weight of> 200; glycerol-polyethylene glycol esters, for example glycerol-polyethylene glycol ricinol ether and glycerol-polyethylene- glycol oxystearates, such as, for example, those available in under the trademarks "Cremophor EL" and "Cremophor RH" (compare Fiedler, "Lexikon der Hilfstoffe", second edition, vol. ¿, P 257 and 258); polyoxyethylene sorbitan esters, for example available under the trademark "Tween" (compare Fiedler, Q, pp. 972-975); polyoxyethylene esters, for example polyoxyethylene esters len stearic acid esters, for example those available under the trademark "Myrj" (compare Fiedler, Q, p. 636); and trans-esterification products of natural oil triglycerides and polyalkylene polyols, including the transesterification products of maize oil, kernel or seed oil, almond oil, peanut oil, olive oil, palm oil and mixtures thereof with polyethylene glycols, in particular polyethylene glycols having a molecular weight of from 200 to 800, such as those available during the registered trademark "Labrafil" (compare Fiedler, page S39).

Particularly suitable are media comprising polyethylene glycols with a molecular weight of from about 200 to about 600, in particular from about 300 to about 400. 10 15 20 25 30 35 É: “7”: 7Å As indicated, the CY-A / X-III bearing medium may comprise a or more components in addition to those listed above, for example lower molecular weight alcohols and / or water, as a method to modify solvent / crystallization characteristics.

A particularly suitable CY-A / X-III support medium has been found be one comprising about 0.5 parts by volume of ethanol, about 8.0 parts by volume parts of polyethylene glycol (300) and about 1.0 part by volume of H 2 O.

The method of the invention first comprises dissolving Ciclosporin, for example in amorphous or tetragonal form, in the selected CY-A / X-III support medium at elevated temperature.

The dissolution temperature naturally varies depending on it special medium that is selected but is usually> 40 ° C, even better > 50 ° C. The temperature is usually> 70 ° C, for example about 75-130 ° C.

In the case of polyethylene glycol-based media, the dissolution Suitably the solution obtained comprises> 5% by weight, preferably> 10% by weight, for example up to about 40-60 weight percent, preferably up to a maximum of 20 weight percent, Ciclosporin calculated on the total weight of the solution. The crystallization of Ciclosporin is then allowed to proceed under cooling, suitably over a relatively long period of time, for example of the order of l0-35 minutes or more depending on the desired crystal growth.

If desired, nucleation or germination procedures may be begin, for example, through sound processing or the use of sprouts. When ethanol / polyethylene glycol / H 2 O crystalline media, for example, as described above, is used, it has proved that the nucleation or germination can easily be initiated. at a temperature of about 60-90 ° C, for example about 65-85 ° C, by applying sound vibrations at about 20,000 c.p.s. As indicated in Example 2 below, by continuing sound processing, obtained in this way during the crystallization process microcrystals with very fine and relatively constant particles size.

The heat for crystal growth and the size of the The held crystals are, of course, dependent on the special medium selected and the conditions under which the crystallization is performed, for example, whether sound processing or sonication is applied and at what frequency. For use in single- in accordance with the present invention, for example, for 10 15 20 25 30 _35 : G5 \ .4 'â7f-'å- galenic preparations as will be described below. CY-A / X-III is preferably used in fine particulate form, for example pile with an average particle size of (200 μl, for example from 0.5 to 200 ul. Then the crystals initially obtained have relatively large size, particulate preparations can with desired size characteristics are of course obtained by conventional atomization procedures, for example by grinding rolling, pulverizing, micronizing or fragmentation otherwise for size reduction. While on this particulate preparations obtained in this way can be completely satisfactory for certain purposes, for example in production of topical compositions for application to the skin, are in manga use of grinding or rolling or equivalent slow technology not preferred. The reasons for this are that the products of such procedures tend to exhibit relative wide particle size distribution and have a relatively coarse or structure as a result of the crystal decomposition. In addition the atomization tends to destroy physical characteristics bitch at the natural crystal surface, and it is in any case difficult or costly to carry out while maintaining the adverse sterility conditions, for example in the manufacture of galenic preparations for intra-articular administration. Of For these reasons, it is usually preferred to perform the process according to the invention in such a way that one obtains crystals, such as microcrystals, with dimensions within the desired final particle size range. For use with manufacture of, for example, compositions for intra-articular or other parenteral application, use is thus preferred. of CY-A / X-III particle preparations in non-atomized micro- crystalline state (i.e. CY-A / X-III microcrystals in native or non-southern state, for example such as have not been subjected to grinding, rolling, micronizing or others reductive procedures). In order to obtain CY-A / X-III microcrystals, which can be used directly in the non-atomized state of the written method, the method according to the invention is carried out suitably gene by mixing, for example by stirring, for example at 200-300 rpm rising to, for example, 700 rpm below crystallization, and in particular by the application of ultrasonic 10 15 20 25 30 35 10 "Vf" vibration, for example in the range 10,000-30,000 cycles / sec, in preferably of the order of 20,000 cycles / sec.

By varying the CY-A / X-III bearing medium and adjusts the cooling rate and degree of mixing during recrystallization procedures according to the prior art and As exemplified below, one can prepare C crystals of varying average particle size, to examples as given above or as described below for use in connection with individual types of galenic preparations in accordance with the invention.

As previously mentioned, crystallization is carried out in one according to the method according to the invention suitably under rila conditions. Purification of the obtained CY-A / X-III can be performed on conventional way, for example by rinsing with polyethylene long glycol (300) water, for example in a ratio of 3-4: 1 parts by weight (p.p.w.) / Washing with hot water, as determined written in the examples. The resulting CY-A / X-III is conveniently recovered freely or substantially free of Ciclosporin in any other form, preferably in pure or substantially pure form. The above rinsing steps help prevent the formation of amorphous Ciclosporin.

In accordance with the above, in addition, according to present invention: Ciclosporin manufacturable by any of the procedures described above as well as: A3 CY-A / X-III according to any of A to A2 above, free or essentially free from Ciclosporin in someone else form, for example free or substantially free from Ciclosporin in amorphous form, from CY-A / X-I or from CY-A / X-II; a * cY-A / x-xxx enngz nagøn av A: in A3 above i: en enar substantially pure form, A5 cY-A / x-xrz .young nagøn of A and A4 above i: in particle shape, for example with particle size characteristics as previously indicated or as described below, for example in connection with Galenic forms comprising CY-A / X-III; A5 CY-A / X-IIT'enIïgï'nown from A to A5'ovan for consideration the part consisting of either entirely or in the head thing entirely and the hall consisting of not finely divided 10 15 20 25 30 §5 11 IN! (_T1 (Q / ¿V7 | .EI: e- 5 crystal material, for example CY-A / X-III according to A5 above, wherein the component particles predominantly or completely and preferably or essentially completely and preferably consists of non-atomized microcrystals; and A7 cr-A / x-111 according to the name ev A: ill A6 even 1 sterile: or essentially sterile condition, for example in a condition suitable for pharmaceutical use, particularly suitable for psrenteral application, to examples for administration by parenteral injection, for example, intra-articular injection.

In addition, according to the present invention, ning: A pharmaceutical composition comprising a) Ciclosproin in orthorhombic crystal form as active ingredient together with (b) a pharmaceutically acceptable diluent; or a pharmaceutically acceptable carrier therefor.

Ciclosporin may be present in the compositions of the invention in any suitable orthorhombic crystal form, for example as CY-A / X-II or CY-A / X-III. Use of However, CY-A / X-II is generally less preferred with respect to its physico-chemical properties, which are less well suited for use both in terms of tolerability and utility for the preparation of effective pharmaceuticals Ciclosporin-based products. Most preferably, Ciclosporin is present in the compositions of the invention as cr-A / x-111, for example according to: nine if A to A7 even. Although Ciclosporin is present in the compositions of invention in solid (crystalline) form, the compositions themselves themselves be of any suitable constitution or Construction. Compositions of the invention thus include solid forms, such as capsules, tablets, dragees, powders and granules, semi-solid forms, such as ointments, gels, creams and pastors, as well as liquid forms, such as those includes the defined Ciclosporin component -in fine (e.g., micronized or microparticulate form) suspended or dispersed in a liquid pharmaceutical 10 15 20 25 30 35 12 3 » , 7 i I 5133 43 diluent or a liquid pharmaceutical carrier, wherein the selected crystal shape can be maintained.

Compositions of the invention include both eyetem comprising a single Cicloeporin-containing fae or compartment ning, for example simple creams, gels, elves, etc. eom mentioned or simple single compartment capsules or ampoules, for example hard or soft gelatin capsules or ampoules for injection, and eyetem comprising a plurality of faer or compartments.

Thus, the invention is embodied as comprising, for example, compositions comprising a Cicloeporin-containing fae or department together with one or more non-Cicloeporin containing feathers or compartments, for example coating: -, barbaric, retarded or placebo faeces, or faeces or including other medicinal products or adjuvants material. The invention is intended to be comprehensive for example: coated tablets with a core comprising Cicloeporin in orthorombic crystalline form surrounded, for example, by other non-Cicloeporin-containing coating agents or similar nande; mantle tablets comprising a core or mantle containing taking Cicloaporin in orthorhombic form and provided with a non-Cicloeporin-containing shell or core; mixed granules lat comprising a granular phase comprising Cicloeporin in orthorhombic crystalline form and a second non-Cicloeporin pouring granules; and divided chapels with two or more departments, for example, the means divided an inner wall, of which one contains Cicloeporin in orthorhombic form and one does not contains eadant. Other alternatives and variants should be obvious to those skilled in the art.

Preferred is Cicloeporin present in the compositions according to the invention predominantly or preferably entirely and hallowed or essentially entirely in ortorombiek crystal form, for example eom CY ~ A / X-III.

The compositions of the invention suitably comprise a phase or compartment comprising Cicloaporin in the ortho- biek crystalline form, for example CY-A / X-III, over which said crystalline form is distributed or distributable on a homogeneous eätt. Such eyetems include, for example, homogeneous creams, elves, gels and the like as well as also hydrogen-containing 'eyatems, wherein the inert crystalline Cicloeporin is distributed or 10 15 20 25 30 35 13 Ffï7 can be easily distributed homogeneously, for example by stirring for hand.

Compositions in accordance with the invention may include: forms suitable for topical administration, for example dermal or topical ophthalmic administration; for parenteral administration administration, for example by infusion or injection, including subcutaneous or intramuscular injection and in particular intra-lesonial or intra-articular injection; as well as for- more for enteral administration, such as suppositories, and the like, as well as oral dosage forms. Enteral forms, for example, oral dosage forms are usually less preferred.

Preferably orthorhombic crystalline is Ciclosporin, for example CY-A / X-III, present in the compositions of the invention in fine particulate form, for example micronized, microparticulate or non-atomized microcrystalline form as previously described. The appropriate particle size varies, of course, depending on the particular nature of the the situation, its intended use and the method of application and desired effect. In general, however, the average particle size is suitably of the order of magnitude 0.5-200 uñ. Special areas, for example in connection with position of oral, topical or injectable forms, is discussed more below.

P KA 0 '"e take " sis or atgpisk gegmatos or of gjgkggggg or gillgtggg; U t iv. .V. _. _ jgngtivit, igklggeggndg kegatokogjgnctivitig gigca gllgg vgggal oco 't' 't' e e r 'e a creams, ointments and the like for topical or dermal Geler, administration can be prepared in accordance with any of the techniques known and commonly used within technology, for example by mixing Ciclosporin in ortho- bis crystal form with a suitable flowable base material, to for example aqueous gel, for example aqueous cellulose ether-based gel, with the addition of suitable surfactants, thickening agents, etc., including, for example, aerosil. 10 15 20 25 30 35 14 f! C., Z fi'7 É v-.Is/ il; The cyclosporin component is preferably present in fine particle shape, for example with an average particle size of 0.5-200 u fi .. Preferably the average particle size is (80-80 nm, even better (40 uk, even more preferred (30 ul, preferably) (20 ul. Preferably, the particles have such a narrow particle size distribution as possible. Preferably, substantially all of the particles less than 60-80 ul.

Compositions of the invention for topical ophthalmic use, that is, application to the eye, can, for example include suitably thickened suspensions or dispersions, present, for example, in the form of viscous eye drop preparations ions or creams or gels for ocular application. In the fall with compositions for administration to the eye are the size of the crystalline Ciclosporin material present preferably <25 ul. Even better, essentially everyone is present particles less than 25 pH. The average particle size for such eye drop preparations is suitably within the range of about 0.1, or preferably from about 0.5, to about 20 μl or preferably to about 10 p.

The hydrophilic / lipophilic content of the carrier system for use in forms for dermal application or for use in preparations for application to the eye may vary, for example depending on the particular surface on which the composition is to be applied applied, for example, depending on the characteristics that apply for the particular skin surface to be treated.

Compositions for topical, especially dermal, application suitably comprises a carrier medium in which the active the stand part (Ciclosporin component) is only slightly soluble.

Suitably, the solubility of the Ciclosporin component (e.g. CY-A / X-III) in such compositions (10% by weight, preferably step by step weight percent, most preferably <0.00 in weight percent Suitable carrier media include hydrophilic, with water miscible carriers as well as hydrophobic carriers.

Hydrophilic, water-miscible carrier components have suitable relatively low volatility. Examples of suitable carrier components components belonging to this class include liquid polyalkylene glycols, propylene glycol, glycerol and ethylene glycol. Suitable polyalkylene glycols include in particular liquid polyethylene 10 15 20 25 30 35 15 (HRS (2 5 ”27- / 5- glycols, for example those with an average molecular weight of up to ce 600, for example with an average molecular weight of from about 250 to 450, in particular about 300.

Representative compositions according to the invention, to examples of topical application, consequently include: C1 a) Ciclosporin in orthorhombic, preferably orthorhombic non-solvate, crystalline form, for example CY-A / X-III, for example as defined under any of A to A7 above; b) a hydrophilic, water-miscible carrier, for example as described above; and possibly c) water of pharmaceutical grade.

The amount of component (a) present is suitably off from the order of about 0.1 to about 30.0 L, especially from about 0.5 or 1.0 to 20 l, for example about 1.0, 2.0, 5.0 or 10.0 I calculated on the composition total weight. Components (b) and (c) is suitably present in a ratio of from 1: 0 to 1:20 parts by weight (p.p.w.). Even more preferably, the components (b) and (c) present in a ratio of from 1: 0.5 to 1: 5, to examples from 1: 1 to 1: 3, more preferably from 1: 1.5 to 1: 2.5 parts by weight (p.p.w.) Such compositions suitably further comprise: d) a surfactant.

Suitable components (d) include, but are not limited to dl trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols. Sadana trans-etherification products are known in the art and can be obtained, for example, in accordance with the general ones procedures described in U.S. Patent 3,288,624 includes trans-esterification products of various natural (for example, non-hydrogenated) vegetable oils, for example corn oil, seed oil, almond oil, peanut oil, olive oil and palm oil, and mixtures thereof polyethylene glycols, in particular polyethylene glycols with a average molecular weight of from 200 to 800. Preferred are products obtained by trans-etherification of two mold parts of a natural vegetable bljetriglyceride with one part polyethylene glycol (for example with a 10 15 20 25 30 35 (N (D ¿2 (J ~ š "Labrafil # Cse Fiedler, na \ ._ 3 .pt 16 average molecular weight of from 200 to 800). Different forms of trans-esterification products of the defined class are known and commercially available under the trademark “Lexicon of Auxiliaries”, 2nd a revised and expanded edition (1981), vol. 2, p 5391. Especially useful as components in the compositions according to the invention are the products: "Labrafil M 1944 CS: a trans-esterification product of seed oil and polyethylene glycol having an acid number of about 2, a preselection number of 145-175 and an iodine number of 60-90; and "Labrafil M 2130 CS: a trans-esterification product of a C12 to C53 glyceride and polyethylene glycol with a one melting point of about 35-40 ° C, an acid number of <2, preselection number of about 185-200 and an iodine number of <3.

Reaction products of a natural or hydrogenated castor oil and ethylene oxide. Such products can be obtained at known manner, for example by a natural or hydrogenated castor oil is reacted with ethylene oxide, for example in a molar ratio of from about 1:35 to about 1:60, with one optionally removing the polyethylene glycol component from the product, for example in accordance with the methods used described in German Offices 1,182,388 and 1,518,819. Particularly suitable are the various surfactants which are available under brand t Cremopho Special the products Cremophor RH 40 with one an acid number <1, an iodine number .appropriate are pre-selection numbers of about 50-60, <1, a water content (Fischer) <2 I, a nš5 ° of approx 1,453-1.457 and an HLB value of about 14-15; Cremophor RH60 an acid number <1, one an nd25- with a default number of about 40-50, iodine value <1, a water content (Fischer) of 4.5-5.5 X, value of 1.453-1.457 and an HLB value of about 15-17; and Cremophore EL with a molecular weight (by angosmometry) of about 1,630, a preselection number of about 65-70, an acid number of about 2, an iodine value of about 28-32 and a n¿25 value of about 1,471. Suitable for use in this category the various surfactants available below tiil exempe1 "niiu ° 1 nco-sof Nämnda is also va: umarket "Nixx ° 1f product 'Nikkol HCO-60' is a reaction product of 10 15 20 25 30 35 f fl CD U fl .reach \\ J .ia 17 generated castor oil and ethylene oxide having the following characteristics: acid number 0.3; pre-selection number 47.4; hydroxy value 42.5; pH (5 Z) 4.8; color APHA = 40; s.m.p. = 36.0 ° C; freezing point = 32.4 ° C; H20 content (X, KF) = 0.03.

Polyoxyethylene sorbitan fatty acid esters or polysorbates, for example, of the type that is known and comes iellt available under, for example, the brands Tween and "Armotan" (compare Fiedler, ¿, pages 745-746 and 972-975) inclusive the following Tween products [polyoxyethylene (20) sorbitan monolaurate], [polyoxyethylene (20) sorbitan monopalmitatl, [polyoxyethylene (20) sorbitan monostearate], [polyoxyethylene (20) sorbitan tristearate], (polyoxyethylene (20) sorbitan monooleate, [polyoxyethylene <20) sorbitan trioleate, Palm (him ou a w mn o nn o <3 o polyoxyethylene (4) sorbitan monolaurate, [polyoxyethylene (4) sorbitan monostearate] and (D01 now [polyoxyethylene <5) sorbitan monooleate.

Polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters of the type known and commercial available under the trademark Myrj (compare Fiedler, 2, p 636) as well as polyoxystylene fatty acid esters known and commercially available under the Cetiol HE brand (compare Fiedler, ¿, page 228 and polyoxyethylene fatty alcohol holethers, for example polyoxyethylene stearyl ether, -oleyl- ether or cetyl ether, for example of the type which is xänd under varumärxeUhrL-Wcjämföz Fiedler, _1 __, _ xa-a-xas), for example, "8" and 96, and "Cetomacrogel 1000" (compare Fiedler, ¿, 229).

Polyoxyethylene-polyoxypropylene copolymers, for example of the type known and commercially available under the Pluronic and Emkalyx brands (compare Fiedler, Z, pp. 720-722). 10 15 20 25 30 35 CH (4 OH 18 Sorbide fatty acid esters, for example of the type which are known and commercially available under the trademark Span, for example including sorbitan monolauryl-, -tristearyl-, -monooleyl- 3, sia aso-as1>. -monopalmityl-, -monostearyl-, and trioleyl esters (compare Fiedler, Partial glycerides, for example products including mono- and / or di-glyceride components, for example mixed mono- / di- / tri-glyceride / free glycerol-based surfactants substances as well as glycerol monostearates and glycerol monooleater. Examples of such products includes those that are known and commercially available under the trademarks Imwitor (compare Fiedler, 1, 491) to examples Imwitor 191 and Imwitor 780 and Softigen (compare Fiedler, 2, 833) for example Softigen 701.

Ionic surfactants or emulsifiers, such as sodium lauryl sulfate and sodium cetostearyl sulfate. suitably 30 Z, total weight.

Components (d) are, when present, even better Very lasting in an amount of up to a maximum maximum 15 X, calculated on the compositions preferably the components (d) are present in an amount of from about 0.5 to about 10 l, for example about 1.0 X, calculated pa the total weight of the composition.

Such compositions also suitably include: e) A thickener.

Suitable components (e) include, for example: Polymethyl acrylate resins, for example of the type is known and commercially available under the trademark Eudispert "(cf. Fiedler, L, 371-372).

PI ° PYl '. and carboxymethyloellulose Cellulose derivatives including, for example, ethyl, methyl, hydroxypropylmethyl- sorts. 10 15 20 25 30 35 40 m <_> -x u-Ä \ '| ! \ l9 Polyvinyl resins, for example including polyvinyl resins alcohols and polyvinylpyrrolidones, as well as others polymeric materials including gelatin, alginates, pectins, tragacanth, gum arabic, xanthan gum, and polyacrylic acids, such as those known and commercially available under the Carbopol brand (compare Fiedler, L, 206-207).

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

When the components (e) are present, they are suitable present in an amount of up to 20 X, more preferably up to 10 1, based on the total weight of the composition.

Most preferably, the component (s) are present in an amount of from about 0.5 to about 15 X, for example from about 1.0 to about 3.0 1, calculated on the total weight of the composition.

In addition, such compositions also suitably include. an antimicrobial agent, such as methyl paraben, propyl paraben, benzalkonium chloride or benzyl alcohol, for example in an amount of from 0.05 to 0.5% by weight, or in the case of benzyl alcohol up to 2.0% by weight, for example about 0.1% by weight, or in the case of benzyl alcohol about 1.0% by weight, based on the composition total weight of the tion.

Alternative carrier media include hydrophobic materials, to such as those which meet the solubility criteria with looking at the previously described active component.

Furthermore, preferred compositions according to the invention include the finding, for example for topical application, a) Ciclosporin in orthorhombic, preferably orthorhombic non-solvate, crystalline form, for example CY-A / X-III for example as defined under any of A to A7 above; and f) A hydrophobic carrier, for example as mentioned OVÄD. 10 15 20 25 30 35 (TI (IN) 'v 174 20 The amount of component (a) present is suitably that which have been described above in connection with the compositions as defined under C1. Suitable components (f) includes, for example, petroleum derivatives, including the mineral oils, fats and gel products, as well as for example petrolatum (mineral fat or petroleum jelly), liquid petrolatum (white mineral oil or liquid paraffin) or any of the known products and commercially available under the trademark Vaselineuícompare Fiedler loc. cit. 2, 986] as well as nonionic lanolin-based derivatives, such as those that are available under the trademark Amerchol, for example Amercho CAB (Fiedler, ¿, 119-1203.

Furthermore, suitable components (f) include, for example natural or saturated vegetable oils and fats for example, fractionated coconut oils such as those known and commercially available under the trademark Miglyol, for example Miglyol 812 (compare Fiedler, 2, and saturated peanut oils, as well fat- 616) and peanut also higher fat or branched chain alcohols and esters, such as stearic alcohol, cetyl palmitate and 2-octyldodecanol, ng under the trademark fi eutanol e fl compares Fiedler, _1_, known and commercially available 375).

Such compositions may also comprise one or more of any of the previously described components (d) and (e) as well as one or more antimicrobial agents, for example, those previously described.

In particular, such compositions may also comprise one or more components (d), suitably in one even better at most in to approx amount of up to 30% by weight, 20% by weight, preferably in an amount of from about 15% by weight, based on the total weight of the composition.

Hydrophobic-based compositions according to C2 and comprising an emulsifier component (d) may also prepared in the form of creams or emulsions by 10 15 20 25 30 35 21 em additional addition of water. The hugs received or the emulsions may be either of the oil-in-type type. -water or water-in-oil. The amount of water present in such compositions may thus vary from to example S to 80 1 calculated on the total weight of the composition, preferably from 20 to 70 1.

The amounts of the component (s) / antimicrobial agent, when incorporated, are of the same or similar size rules of procedure such as those mentioned in connection with according to the invention in accordance with C1 above.

The amount of any applied topical form varies. naturally depends on the concentration of the tion, the condition to be treated and the desired one the effect as well as, in the case of dermal application, the area to be covered. In the case of compositions for dermal application or application, for example in the treatment of psoriasis or atopic dermatosis, is the amounts applied are usually sufficient to give a Cicloeporine dosage of the order of about 0.1 to about 5 mg / cm 2, for example about 0.5 mg / cm 2, with administration for example twice daily to it desired place. In the case of ophthalmic preparations the administration may conveniently be performed during use of preparations comprising from about 0.1 to about 10% by weight, for example 1.0 or 2.0% by weight Ciclosporin, applied in drop form to each eye '1 to 3 times daily.

I J C R ARA FO R t '1 X "k t' ntr B U- ä er e t '' '' e nner et i t Dispersions, auapeneions, emulsions and the like compositions suitable for injection may be prepared in 10 15 20 25 30 35 U1 (JJ 22 17 f: - in accordance with any of the techniques known and commonly used in technology, for example by that one disperses, suspends or otherwise distributes Ciclosporin in fine particulate orthorhombic crystalline form in a suitable liquid carrier medium with the addition of suitable emulsifiers, surfactants, stabilizers or flocculants, etc. vis has the Ciclosporin component in such compositions an average particle size of (100 μl, more preferably smaller) than 50 ul, particle size of the order of 0.1 or 0.5 up to the specified maximum of 20, 50 or 100 u fi.

Preferred Since injectable forms are intended for subcutaneous use, for example or intramuscular injection, for example for coming of a depot effect, the use of is greater particle size possible. Since such forms are intended for intra-lesional application or in particular intra-arti- ocular injection, desirable. For such uses one is suitable average particle size, for example of the order of magnitude from about 0.1 or 0.5 to about 20 nä for example from about 5 to 15 pH.

To achieve stability of the particles in the injection certifiable forms, for example to avoid an increase in size of larger crystalline particles at the expense of smaller particles, the particles are preferably off said uniform size as possible. the variation between the maximum and minimum particle sizes not about 50 nä, even better about 20 ul.

Suitably exceeds Although the desired particle size can be achieved by use of appropriate atomization procedures, to example micronization, to minimize particle size play variations, in order to avoid the presence of mented particles; ~% to avoid mcdrfiering'tv - "-" crystal surface, for example to maintain wettability properties, and to more easily meet the requirements is the use of finer particulate matter preferably less than 20 pä. Suitably, medium 10 15 20 25 30 35 Efïï \ - 'k; \ J 411.1 ~ l 23 the sterility requirements, it is usually preferred to use non-comminuted microcrystals, that is say crystals that have been allowed to grow to the desired one size, as previously described. " Injectable compositions of the invention include thus suitably: a) Cicloeporin in fine particulate, orthorhombic, present orthorhombic non-solvate, crystal form, to Example CY-A / X-III, for example as defined under any of A to A7, 2 in particular A5 and A7, above, distributed or distribution heart in b) an injectable carrier medium.

Suitable carrier media include in particular water of pharmaceutical grade.

In addition, the compositions defined under C3 include conveniently g) a surfactant as a dispersant or emulsifier and / or a flocculant to facilitate or maintain the distribution of the particles over or in the carrier phase.

Suitable surfactant components (g) include polyoxyethylene sorbitan fatty acid esters or polysorbates, for example those mentioned in (d3) above, for example pelvis Tween 80 or "Polysorbate 80" (compare Fiedler, 2, page 746). Suitable flocculants (g) include ethylenediaminetetraacetate and salts thereof, for example calcium EDTA and sodium EDTA, as well as others equivalent chelating agents, as well as peptizing agents. agents such as succinic acid or citric acid.

In order to maintain the particle size distribution a stabilizer is also suitably incorporated.

Suitable stabilizers include, for example gelatins or modified gelatins, such as plasma 10 15 20 25 30 35 C fl CD 041 24 expander means edge and commercial to angelic under the trade name'šelafundin and Haemaccel, or cold water soluble gelatins of highly purified collagen hydrolysates.

Compositions according to C3 above may also include one or more antimicrobial agents, such as those mentioned above, as well as peptizing agents, such as succinic acid or citric acid.

The ratio of the components = (a) :( b> in compositions defined under C3 is suitably of the order of magnitude 1:10 and '1: 1 ooo, preferred of 1:50 to 1: 200, for example about 1: 100, of the order of magnitude parts by weight (p.p.w.).

In order not to disturb the particle stability too much surfactants are present as component (g) preferably present only in minor concentrations or concentrations, for example of the order of magnitude from 0.1 to 2.0% by weight, preferably about 1% by weight, calculated on the weight of component (a). When a flocking agent is present, the ratio is flocculant to component (a) suitably of the order of 1: 3 to 1: 8 parts by weight (p.p.w.), for example about 1: 5 parts by weight (p.p.w.). When a stabilizer is approached being is the ratio component (a): stabilizer preferably of the order of 1: 5 to 1:30, even better from 1:10 to 1:30, for example about 1:20, parts by weight (p.p.w.). When a peptizing agent is is, the ratio of peptizing agent to com- component (a) suitably of the order of 1: 1 to 1:10, for example about 1: 5, parts by weight (p.p.w.).

The amount of Ciclosporin present in unit dosage forms for injection in accordance with the invention varies of course depending on, for example, the condition that to be treated, the injection site and the desired the effect, for example whether depot effect or relative 10 15 20 25 30 35 25 : oz 1? ¿ \ / \ J \ J enabb release to the surrounding tissues aveee.

Suitably, individual unit dooering forms include from about 10 to 500 mg, in particular from about 20 to 100 mg, Cicloeporin / dose.

Saeom torde ineee includes enbetedoeeringeformer i according to the invention also more complex eyetem, for example eprutes or eprut cylinders with double chamber in which the particulate Cicloeporin is eammane with other suitable components, for example stabilizer or antimicrobial agent, be in an undertaking chamber and the carrier medium store in a second chamber, the components of the two chambers bring them to mix with each other, for example inpreeening of the eprut flask. Sadana epruteyetem with double chambers are well known in the art, and forms including eadana far aneee are within the scope of present invention. Although, eaeom has previously mentioned, oral dosage forms of the present invention eellt is of less intreeee and thus less pre- drawn, eadana forms are also within the framework of the invention.

Oral dosage forms of the invention may present using any suitable carrier or which is the most suitable carrier medium known and used in technology. Liquid or semi-fat oral dosage forms may include, for example, Cicloeporin in orthorhombic crystalline form, for example as CY-A / X-III. tilleammane med_pharmaceutiekt acçeptabl; _ntepädninge- .____ ~ ____ : man .nu carrier, in vina kriuzaiiførmn in itself »jan is insoluble or essentially insoluble. Such carriers 10 15 20 25 30 35 G1 CD -a -: | l m 26 and diluents include, for example, trans- -esterification products of natural vegetable oil triglycerides and polyvalkylene polyols as defined in written above under (dï), for example 'Labrafiflpro- products, as well as reaction products of natural or hydrogenated castor oil and ethylene oxide as such described previously under (dz), in particular liquid Cremophore products, such as Cremophore EL.

The cyclosporin is preferably present in fin particle shape, for example with an average particle size ranges from 0,5 to 200 un, in particular of the order from, for example, 0.5 to 30 μM, preferably less than 20 μM, for example from 0.5 to 10 μM.

To facilitate administration, the composition is the ions described above are suitably filled with hard or soft gelatin capsules.

Unit dosage forms according to the invention for oral administration suitably comprises from about 25 to about 75 or up to 200, for example about 50 or 100 mg Ciclosporin / unit dose. Such forms administered, for example, from 1 to 4 times daily gene for the delivery of individual patient sera -Ciclosporin concentrations (for example such as those determined by RIA) of the same order of magnitude or an order of magnitude equivalent to those using conventional Ciclosporin therapy, for example using the available oral Ciclosporin solution.

Ingredients or constituents referred to herein defined as components of pharmaceutical compositions according to the invention is to be understood as being suitable for pharmaceutical application in dependence on what is required, for example in the case of stock parts for compositions for oral administration, as being pharmaceutically acceptable or in the case 10 15 20 25 30 CW LD OH year!! 27 with ingredients for compositions for topical administration stration as being topical, for example dermal or ocular, applicable, acceptable, or tolerable.

Additional galenical forms of administration via paths equivalent to or alternative to those described above should be apparent to those skilled in the art in the area.

The following examples are intended to illustrate the present invention invention in each aspect of each avïd.

EXAMPLE 1 Preparation of CY-A / X-III a) 100 g of Ciclosporin in amorphous form are dissolved with stirring in 400 g of polyethylene glycol 300 at 50 ° C.

CY-A / X-III development begins shortly after completed resolution. The solution is left to stand in 22-48 hours at about 35-40 ° C for the crystallization to take place is completed and then diluted with 1,000 ml of water underneath vigorous stirring. The resulting precipitate is separated by filtration, washed with H 2 O to remove residual polyethylene glycol and dried to form of CY-A / X-III in substantially pure form: m.p. = 195 ° C, particle size = 100-200 μM.

CY-A / X-III forms can be prepared analogously to the above standing procedure but using the following as a solvent instead of polyethylene glycol 300. 10 15 20 25 30 35 5% 174. 28 Lggginggggggl Smp. for obtained CY-A / X-III (° C) b) Polyethylene lycol 300 / Cremophore RH 40 (volume ratio 1: 1) --- c) Cremophore EL 190 a> "soiutoi us 15" 1as e) "Gelucire 44/14" 180 f) Myr; 2 184 g) Two 0 3 186 h) Cremophor RH40 3 190 In all cases, the average particle size is on the order of about 50 to about 200 u fl. The established the lattice structure is the one previously defined. X-ray diffraction data are those presented below in connection with Table III and Figure IV.

EXAMPLE 2 Production of cv-A / x-111 20 g of Ciclosporin as CY-A / X-I are dissolved in 60 ml of ethanol and condensed to 1/8 of the original volume by distillation under reduced pressure at> 60 ° C. 160 ml polyethylene glycol (molecular weight 300) + 20 ml of H 2 O are then slowly added at 50-85 ° C with stirring at 300 rpm. An ultrasound a mixer is installed, which operates at 20,000 cps.

Germination is initiated at 65-7S ° C for 3 to 5 minutes. The the resulting dispersion is then cooled linearly over 10-20 minutes to 40 ° C with continued stirring at 700 rpm and ultrasonic vibration. The resulting thick pasty mixture is filtered. co-oil with polyethylene glycol (molecular weight 300) / H 2 O (3: 1) washed with hot water (30 ° C) and dried at 50 ° C race, volume parts), under high vacuum to give CY-A / X-III in pure form: 192 ° C. Particle size = 3-15uM. The definite lattice structure m.p. = is the previously defined. X-ray diffraction data are given below 1 connection iili Table 111 ash Figure lv. 10 15 20 25 30 35 G1 LD Cd _ a \ _J Yes. 29 Repeated experiments show that the crystal size is affected by the germination temperature and the rate of crystal growth rather than the time of the process or processing. If you say lunda initiates nucleation at about 75 ° C and if the crystallization continues at the same temperature, it is obtained an average crystal particle size of about 50 u fl.

EXAMPLE 3 Preparation of a galenic form for oral administration .

Y 3 e t 'a lade re A suspension comprising 20% by weight of CY-A / X-III u ion r held in accordance with the procedures of Example 1 in “Gelucire 44/14 is ground at elevated temperature using a until the average CY-A / X-IIl batch 250 mg colloid mill, The cell size is of the order of 0.5 to 10 pH. portions of the obtained ground suspension are filled into hard size 2 gelatin capsules, each containing 50 mg Ciclosporin (as CY-A / X-III) as active ingredient. 3.2 Gelatin encapsulation prepagation II CY-A / X-III obtained according to the procedures of Example pile 1 is ground in a colloid mill, until the average The CY-A / X-III particle size is of the order of 0.5 to 20 μM. SO mg portions are then intimately mixed with 200 g Cremophore EL and filled into size 2 hard gelatin capsules, each containing 50 mg of Ciclosporin (as CY-A / X-III) as active ingredient.

EXAMPLE 5 Preparation of galenic forms for tcpic application re a t 'n Cy-A / X-III obtained in accordance with the procedures of 4 e pile 1 is micronized during use of an air jet mill.

Micronized product with a maximum particle size of 60-70 u fl and an average particle size of 2-10 px is combined and 10 15 20 25 30 35 40 95 174 C? 30 blandae pa conventionally one with the beetandedelar com vieae in the following table to form an aqueous gel, which The composition comprises 10% by weight of Cicloeporin (a CY-A / X-III) and is suitable for topical application, for example for the treatment of peoriaeie. ß5§IAED§DEL Xikizxnssnå a) Cicloeporin (micronized t CY-A / X-III) 10.0 b) Polyacrylic acid (Carbopol 934P> 0.5 c) XaOH solution (5 L) '; 3.0 e> xezyiparaben '0.01 e) Propyl paraben 0.03 f) H 2 O (pharmaceutical grade) to 100.0 X 4.2 Gel separation 11 geetandgdel Weight percentage Composition A Composition B a) Cycloeporin CY-A / X-III) 10.0 1.0 b) Polyethylene glycol 300 30.0 30.0 => "Labrafi1 M 2130 cs" 1.0 1.0 d) Carbopol 934 P 1.0 1.0 e) Sodium hydroxide 5 Z 6.0 6.0 f) Ethyl paraben 0.07 0.07 g) Propyl paraben 0.03 0.03 h) H 2 O (pharmaceutical grade) 51.9 60.9 100.0 X 100.0 1 a) is prepared eaeom for 4.1 above. c), f) and g) are solved in b) during heating and the resulting mixture kylee to runs * temperature. This solution is then dispersed in water h). d) is added and the whole mixture is hemogenieerae for aetadkommande of diepereion. a) tilleättee, and the mixture homogenieerae pa new. (e) neutralization action, with stirring, and obtained crazy fyllee in jumpreeeneable tubes for topiek app- licensing, for example in the treatment of peoriaeie. 10 15 20 25 30 35 Alfta 31 o \ JJ E in Eaannsl fl al liksnmsans.

Composition A Composition B a) Ciclolporin (micronized CY-A / X-I I) 1.0 10.0 b) Amerchol CAB _ 2.0 2.0 c) Liquid paraffin 42.0 37.5 d) Vit petrolatum §§, 0 __§g¿§ 100.0 X 100.0 X a) is prepared as for 4.1 above. b), c) and d) were fused to together and stirred, and a) quenched at about §0 ° C, the particles are distributed using a homogenizer. It is- keep the ointment in the refrigerator and fill into a compressible tube: for topical application, for example in the treatment of psoriasis.

H E 31: ” ßesgàgdggel Xigtgggggnt a) Ciolosporin (micronized CY-A / X-III) 1.0 b) "Polysorbate 60'l 5.0 o) Cetylstearyl alcohol 10.0 d) Glycerol 85 X 10.0 e) Vit petrolatum 24.0 f) Methyl paraben 0.07 g) Propyl paraben 0.03 h) H20 (pharmaceutical grade) §§, Q 100.0 I a) is prepared as for 4.1 above, combined with the components b) to h) by analogy with 4.3 above and fill in compressible only tubes for topical application, for example in the treatment of psoriasis. l0 15 20 25 30 Ü! J 04 ... x “Sl . | \ _. 32 A_§_§alx2rs2ara3ian A suspension comprising 20% by weight of CY-A / X-III (obtained in accordance with the procedures of Example 1) in ethylene glycol 300 vatmales, until the average The CY-A / X-III particle size is of the order of 2 to 10 LLM. 50 g of polyethylene glycol 300 and 40 g of molten polyethylene ethylene glycol 1500 to form a flowable paste comprising 10% by weight of Ciclosporin (as CY-A / X-Ill) and suitable for for example = for the treatment of psoriasis. 10 g of the obtained ground product are mixed at a conventional topical application, âssttndndal Eikånrsssnt a) Ciolosporin (micronized 1.0 cv-A / x-111) b> "Labrafi1 M 1944 cs" 1,0 c) Polyethylene glycol 300 30.0 d) Benzyl alcohol 1.0 e) Hydroxypropylmethylcellulose (Hethoce EQH) 2.5 f) B20 (pharmaceutical quality) §§, § 100.0 X and d) mixed, and f) a) is prepared as for 4.1 above. b), o) is added and mixed. a) is then suspended in the obtained the mixture by homogenization. e) is then added elongated while stirring, until gel formation is complete.

The gel is then filled into compressible tubes for topical application. licensing, for example in the treatment of psoriasis. 10 15 20 25 30 35 33 503 âuianslmsl. likiamami a) Ciclosporin (micronized CY-A / X-III) 5.0 b) Polyethylene glycol 300 30.0 c) Glyceryl monostarate 5.0 d) Mothylparaben 0.07 e) Propyl paraben 0.03 I) Carbopol 934 P, 1.0 g> nau-iumhydraxia s x 6.0 m H20 (ramaceuusx: vant-u '§2, g '100.0 x a) is prepared as for 4.1 above. c), d) and e) are solved in b) during heating. The hot mixture is dispersed in h) through homogenization and cooled to room temperature. (a) and (i) is then added, and the whole mixture is homogenized. g) till- is then added, and gel formation is completed. The obtained the gel is filled into compressible tubes for topical application, for example in the treatment of psoriasis. 8 "m e t '(v t' ') fi own part Vigtgrogegt a) Ciclosporin (micronized CY-A / X-III) 2.0 b) Amerchod§CAB 5.0 => xiglyoéeiz '10.0 d) Vit petrolatum _ 53.0 e) H 2 O (pharmaceutical grade) 30.0 100.0 X a) is prepared asom for 4.1 above and dispersed with b) in e) during heating and homogenization. c) and d) melted! together and mixed, and the mixture is added to the previously obtained kept the dispersion under intensive homogenization, and whole 10 15 20 25 30 35 (17 i c-) (N ~ 1 '\ .. 34 the mixture is cooled to form a greasy white cream. This drunk on jumpable tubes for topical application, for example in the treatment of psoriasis.

Examples 4.1 to 4.8 above are repeated the crystalline product of Example 2 directly as ciclosporin but using component.

EDGä flfl üaJí A CY-A / X-III suspension is prepared under sterile conditions using conventional technology and the following parts - Ee flfi ågdg fl gl VÅRQ (gg) a) Cicloeporin (CY-A / X-Ill) 20.0 b) "Polysorbate '80" 4.0 c) Ratium carboxymethylcellulose 5.0 d) NQCI 9.0 e) Benzyl alcohol 9.0 f) H 2 O (injection quality) to a final volume of 1.0 ml Characteristics of the release of the active compound the component from the preparation obtained depends on the average particle size of component a). Salunda applies that, when activity for longer periods of time is required, CY-A / X-Ill product with large average particle size (e.g. 100-200 μm as it can be obtained directly via the procedures from Example 1) is selected. Since activity over a relatively short period of time periods are required, CY-A / X-Ill product is selected with relative smaller average particle size (e.g. product from Example 1, It received as it is obtained by micronization or grinding of for example to a particle size of 0.5-10 μm). the suspension is filled into ampoules for parenteral administration 10 15 20 25 30 35 U1 (IN UI ... Ju \ 1 ¿M 35 nitration or for intra-leeional injection in the treatment of peoriaeie, for example for the addition of a depot effect.

According to an especially preferred embodiment the example using CY-A / X-III above according to with Example 2 above and with a particle size of 5-15 μm eamt produced under ethereal conditions. Injectable forms suitable for intra-articular administration tion is prepared using any of the following ingredients: Beetàndgdgl Weight (gg) K2m221i1i2n_A_ a) Cicloeporin (CY-A / X-III) 10.0 b) Sodium carboxymethylcellulose 10.0 c) Na BDTA 2.0 a> H20 cxnjexziens- quality) to an electrical volume of 1.0 ml K2m221itien_E a) Cicloeporin (CY-A / X-Ill) 10.0 b> fpøiysorbace ao "o, 1 c) Citroneura 2.0 d) H 2 O (Injection quality) to an electrical volume of 1.0 ml The preparation is carried out in accordance with standard technology below ethereal conditions. Component (a) includes non-atomized microcrystals prepared under sterile conditions in accordance with with the procedures of Example 2 and with a particle size of 3-15 pm. The resulting compositions filled, again during the rila conditions, on ampoules for injection, for example intra-articular injection for the treatment of rheumatoid arthritis. 10 15 20 25 30 35 36 FF17 3a; J »= 7p the beneficial properties of compositions according to the finding can be demonstrated in animal test models as well as at clinical trials. Thus, particular utility of compositions ions according to the invention intended for dermal application, to examples in the treatment of psoriasis or dermatosis, ascites made according to the following test model: Guinea pigs (HartleY, ¿?, 400-500 g) are seneibilized by application of 50 μl of 2% dinitrofluorobenzene (DNFB) in 2 acetone / olive oil (lzl) on the inside of the right ear. Seven days later the animals are tested again with 20 ul of 0.5% DRFB in acetone / olive oil (4: 1> applied to marked areas on it shaved, left and right flanks. This second inducing ex- ponation causes an allergic inflammation, which leads to redness and cellular infiltration (thickening) of the skin. Test- composition in an amount of 200-250 mg is applied with a spatula to the DNFB-treated area of the right flank.

The left flank is treated in a similar way with placebo as comparison. Application of test composition / placebo is performed Sx at intervals of 20 minutes, 8 hours, 24 hours, 32 hours and 48 hours after exposure. Skin thickness at application the place is determined before each application and again 8 hours after the last application by lifting the skin to a fold and measure the thickness of this. The degree of redness of inflammation is also determined visually according to a scale from 0 to 4. The effectiveness of the test preparation when it comes to prevent inflammatory response is determined by comparison with results registered for each flank treated with placebo.

Results obtained in the above test model during use compositions in accordance with Examples 4.1 and 4.5 above but comprising 0.1% by weight of Ciclosporin as CY-A / X-III i comparison with placebo and with topically applied 0.1% Ciclosporin in conventional oral solution form is shown in the figures I, II and III attached the present application. (A 0.1 percent CY-A / X-Ill concentration was used in this test model against due to its extreme sensitivity. Test compositions are prepared 10 15 20 25 30 35 37 completely and analogously with examples 4.1 and 4.5 but by The cyclosporin component is reduced to 0.1 g and by pension is carried out by adding 9.9 g of water for example 4.1 and polyethylene glycol components for Example 4.5).

In each figure, the measured skin thickness is plotted against the time. Figure 1 compares results, where 0.1 I has been used (weight) Ciclosporin applied in the form of a conventional, commercial oral drinking solution, with placebo. A certain but still insignificant reduction in reaction compared to placebo ascertained for the oral solution. In Figures II and III, results are obtained, where 0.1 l (weight) of Ciclosporin has been used containing compositions in accordance with Examples 4.1 and 4.5, with placebo. In both cases, a significant reduction is achieved skin thickening compared to placebo after the first application and continued during the treatment compared to the cebo until the experiment is completed.

The utility of compositions of the present invention findings can also be neutralized in clinical trials, which pelvis is performed as follows: placebo-regulated This experiment is performed according to random, double-blind model. Each patient receives active composition and cebo (carrier only) on two symmetrical wounds simultaneously. Advantage- active compositions and placebo compositions are used randomly to the left and right wound.

Selected individuals are taken in groups of from 12 to 24 patients. who are 18-70 years old, including men and women nor, which are postmsnopausal, surgically sterile or use ter, oral contraceptives with a negative pregnancy test.

The inclusion criteria include: a) written consent and b) clinically defined, stable, At least two moderate to black bilateral symmetrical wounds, chronic plaque psoriasis. each having an area of from 4 to 25 cm 2 and a serious degree of severity> 5 on a scale from 0 to 9. This severity .unit degree or this score is the total score for individual scores from 0 (least responsive) to 3 (most responsive 10 15 20 25 30 35 503 tad) for each of three parameters: 38 7 erythema, flaking and skin thickness. The wound or damage to both sides must be for the same patient (that is to say, they must not distinguish between with more than 20 I in terms of severity or area). a) b) c) d) G) f) g) hrs) in) j) k) 1) m) The following exclusion criteria apply: any medical permit which, in the opinion of the underserved would jeopardize the study. systemic peoriaeiotherapy (PUVA, methotrexate, within the last two months. specific topical treatment - with the exception of indifferent steroids, retinoids, Cicloaporin) substances (for example white vaaelin) or preparations containing salicylic acid (not more than 10 l) - except selected for the study within the last two weeks before e the study in question begins. These emollients may, however, be used in cases which have not been selected for current study. patients whose psoriasis is found to improve spontaneously, flares up without treatment or regenerates after completion therapy. known hypersensitivity to any of the components of test medicine. non-cooperating patients who are not expected to follow the medical instructions exactly, and patients who are not willing or unable to go on regular visits. treatment with a study drug within one month before the start of the study. severe concomitant disease, especially renal dysfunction with serum creatinine above 130 μmol / l. hypertension (diastolic blood pressure> 95 mm Hg after 5 minutes in a sitting position). Patients undergoing with hypertension drugs are included in the study in question. malignancy or previous malignancy, including skin cancer. acute bacterial, viral or fungal associated skin damage. pregnancy, patients with known alcoholism, drug abuse, lactation. 10 15 20 25 30 35 39 (HRS Q) 3 peykoe or emotional or intellectual problems.

... A w -TÉ .. \ .. . n) patients in need of continuous concomitant therapy with other immunoeuppressive agents, chemotherapeutic agents, compounds with nephrotoxic potential (for example amminoglycoides) and medicines known for to interact with the pharmacokinetics of Cicloeporin (ketoconazole, erythromycin, phenytoin, phenobarbitone, rifamipcin, INR, carbamazepine. sodium valproate). o) patients with abnormal baeli line laboratory values> 15 I outside the normal limits of the testing laboratory toriet. p) patients with clinically significant results in physical examination.

The experimental compositions used correspond to something of the previously described Examples 4.1 to 4.9, for example: the 1% composition B from Example 4.2 or the 10% composition B from Example 4.3.

Each patient receives a pair of 20 g labeled tubes with an ethical kett with two fields. The label is, among other things, for the substance that should applied on the right side and red for the left side. Further applies that on each field of the label is indicated that side to be processed, left or right, the code or marking for the study in question, the name of the researcher, the patient number and date of commencement of treatment. The tear field of the label is attached to the medical record form.

The test medication is applied twice daily, morning and evening, the amount applied depending on the wound size, said that one obtains a daily Ciclosproine dosage of from 0.2 to 2.0 mg Ciclosporin / cm 2, for example in a test series about 0.5 mg Ciclosporin / cm2. Placebo is applied in equivocal slow amount. Neither experimental composition nor placebo is applied on a body surface area> 25 cm2 and not more than 1 g Ciclosporin applied race per week. At each clinic visit, the medicine / placebo tube is weighed, and the topically applied daily dose is determined. Trial the sons may bathe shortly before the application of the drug. Disposable gloves are used and changed to apply each test compound. position and placebo to avoid cora contamination. Least three hours may elapse between administration and washing the treated areas. The first application is monitored and 10 15 20 25 30 35 40 585 a patient instruction card is provided. Permanent baits of the treatment is 4 weeks. If complete healing of the wounds occurs earlier, treatment is continued until week 4. The patient examine before starting the experiment (week -1), at the jat trial (week 0) and after 1, 2, 3 and 4 weeks.

Dermatological evaluation (local peoriasis duration index or LPSI) is performed by the same examiner, who is not involved in the medication, using the following numerical scales 0-3.

Eumn fl mriins 0 = none 0 = none 0 = none 1 = minimal: 1 = minimal: 1 = minimal: weakly detectable weak flaking only perceptible erythema; much or mountain formation increase light pink 2 = moderate: 2 = moderate: 2 = moderate: dull red well-defined increase clearly separable rock begins to be built separable UP 3 = strong: 3 = difficult: 3 = difficult: dark / bright red well-defined scales; strong increase built to com- pact mass The total LPSI range = the value of the erythema plus flaking plus thickness = 0 to 9 are evaluated. To be included in this study, at least two values must be moderate to the the for the both selected wounds (LPSI> 5).

At the beginning of studies and at each clinic visit is evaluated the surface of the treated wounds (entrance size: 4 to 25 cmz for each plaque). The surface refers to the presence of one or more of the following three criteria, erythema, flaking or scaling, thickening. The pigmentation within the scar area is not considered evaluation of the surface. 10 15 20 25 30 35 41 5:35 p.m. I I The plaques or ear surfaces in question are registered using photographs before (week -1) and after treatment (week 4).

Three pictures tee, one vieande bada earen tilleammane and one for every wound.

Evaluation of klada do through interviews with patients using the following scale: 0 = none 1 minimal: only temporarily the patient needs to tear 2 = moderate: the patient needs to tear frequently 3 = preserved: the patient needs to tear very often, can disrupt sleep ' After completing the study, a total evaluation of response to the therapy in question in accordance with the following criteria: terier: liberation = 100 X resolution or effect - marked improvement = at least 66% reduction of LPSI and / or at least a 66% reduction in plaque or saryta - moderate improvement: between 65% and 33% reduction of LPSI and / or between 65% and 33% reduction in plaque or surface area poor: less than 32% of LPSI and / or less than 32% reduction of plaque or sary surface ~ - worse: the disease worsened.

Therapeutic success is defined as the patient having " friate ”from something sar or where“ significant improvement ”has natts.

The doctor and the patient also indicate their preference for medication on the left or right side in accordance with the following the criteria: - left side definitely better - left side slightly better - no detectable difference - right side slightly better - right side definitely better To test the effectiveness at the end of treatment, LPSI values and sites of the subjects are entered using WILCOXOH-Sign Rank test for paired treatments between 10 15 20 25 30 35 42 : oz ukiu 74- Ciclosporin-treated sides and placebo-treated sides bet concerns changes in points from the baseline to after 4 weeks of treatment.

All further comparisons (at other times and for remaining efficiency parameters), including the associated man-dependent p-values, tee as descriptive attempt forward-critical dande.

In the above experiments, the subjects show markedly improvement of psoriasis, for example of LPSI score values for erythema, scaling and skin thickness, on the sides, the test composition comprising Ciclosporin has been applied, on which brought with the site receiving placebo. Subjective improvement also registered together with an improvement of registered itch values for Ciclosporin - treated sides compared to pages treated with placebo.

Positive results are also obtained with parallel experiments on persons exhibiting contact dermatitis according to diagnosis via three or several possible following criteria: itching - typical morphology and distribution: flexural likenification or linearity in adults - facial and extensor effects in infants and other children chronic or chronic recurrent dermatitis personal or family history as regards atopy (asthma, allergic rhinitis, atopic dermatitis); plus 3 or more minor features included: ichthyosis / palmar hyperlinearity / keratosis pilaris, immediate early age Xeros, bar (type 1) skin test reactivity, elevated serum IgB, for infestation (<5 years), tendency to cutaneous infections (in particular the Steph. aureus and Herpes simplex) / impaired cell-mediated immunity, tendency to non-specific hand or foot dermatitis, nipple eczema, keilitis, recurrent conjunctivitis, Denis-Morgan infraorbital fold, keratoconus, anterior subcapital eular cataract, orbital darkening, anterior neck folds, itching when sweating, facial pallor / facial ery- tem, pityriasis alba, intolerance to wool and lipid solvents, perifollicular accentuation, intolerance to certain foods, processes affected by environmental / emotional factors and white dermography / delayed 10 15 20 25 30 35 43 __ _ 505 "íïf fl ï- fading. The pre-increase period is three weeks with evaluation according to a scale from 0 to 3 for the following parameters: klada, erythema, exudation, excoriation and lichenification.

Topical preparations as described above in Examples 4.1 to 4.9 containing 1-10 X Cioloeporin, for example the The 5.0% composition in accordance with Example 4.7, found may also be effective in treating or treating allergic tact dermatitis as of alopecia.

In accordance with the above provides the present invention also: D. A route of administration of Ciclosporin to or effect Ciclosporin therapy in an individual receiving or requires either therapy, which method includes administration to said individual of an effective amount of Ciclosporin in orthorhombic crystal form, in particular orthorhombic non-solvate crystalline form, for example as CY-A / X-III, for example as defined below any of A to A7 above.

According to a more specific embodiment,: D1 A way to produce immunosuppressive or anti-inflammatory therapy in an individual in need thereof, which method comprises administering to said individual at of an effective amount of Ciclosporin in orthorhombic crystalline form, in particular orthorhombic non-solvate crystal form, for example as CY-A / X-III, for example said as defined under any of A to A7 above.

Purposes for which the above methods are applicable take treatment of any disease or any preferably condition as described earlier in connection with use of ciclosporin, for example to prevent transplant rejection, treat autoimmune or rheumatic diseases, treat any other disease or condition involving undesirably high response of the immune system, treat parasitic infections, treat chemotherapeutic resistance reversal of tumor resistance to anti-neonatal plastic chemotherapy, as well as treatment of alopecia. Above- Standing methods are particularly applicable to the treatment of 10 15 20 25 30 44 1533 '174 judgments or condition hoe skin or eye, etopiek or contact dermatitis, corneal implant, for example peoriaeie, conjunctivitis and uveitis, through topical administration, as well as on the treatment of rheumatoid arthritis or other disease or other condition of the joints, by intra-articular administration tion. _ As an alternative, the present invention provides ning: E. Cicloeporin in orthorhombic non-eolvate crystalline form, to example com CY-A / X-III, for example ea which has defined below any of A to A7 above, for use as a pharmaceutical, to examples for use in the treatment of any disease or any condition mentioned above in connection with D or D1, for example for use as an immunosuppressive agent or anti-inflammatory agent; as well as F. Ciclosporin in orthorhombic crystalline form, for example as CY-A / X-III, any of A to A7 above, for use in preparation for example said as defined below of a pharmaceutical composition for use according to definition E above.

To facilitate or strengthen the identification of Ciclosporin in orthorhombic crystal form, in particular CY-AIX-III, give X-ray powder diffraction data for CY-A / X-III and for both forms CY-A / X-I and CY-A / X-II, which have also been mentioned herein, in the following Tables I to III. a representation of the X-ray powder diffraction diagram from Attached Figure IV provides which obtained the data in Tables I to III.

The diffraction diagram was obtained using a Guinier DeWolff II camera using CuKG radiation, Ä = 1,542 Å. 45 OH _ -x '\ f | -fim 59 IQMAJJ X-ray diagram for CY-A / X-I Line no. d (A) Intonnitot 1. 13.0 'VS 2. 11.4 US 3. 10.3 US 4. 9.7 US 5. 9.4 US 6. 8.25 US 7. 7.1 S 8. 6.1 H 9. 5.85 S 10. 5.6 S 11. 5.25 US 12. 4.81 S 13. 4.58 S 14. 4.25 H 15. 4.0 M 16. 3.67 H 17. 3.45 H 10 15 20 25 30 35 (HRS C) 04 ..- Å \ ~ 3 F: - 46 ILDLILIJ.

X-ray frame for CY-A / X-II Line no. D (A) Intonsitot 1. 17.9 S 2. 11.4 US 3. 11.0 S 4. 10.6 M 5. 10.2 S 6. 8.9 M 7. 8.7 M 8. 8.1 H 9. 7.2 US 10. 6.3 M 11. 5.95 H 12. 5.7 H 13. 5.35 M 14. 5.1 S 15. 4.85 S 16. 4.8 M 17. 4.55 M 18. 4.4 M 47 X-ray diagonal for CY-A / X-III to O 6.- in M fl ßS-è fl s flfl s flfl ss fi n flflfi C L .. n IN O ) 3 ° .8n8 r.8 Å Û467977ÛB329854 ° 53 t "|, III | '|,' |, ', |' 2Û987766555ÅÅ44433 .d 11 n hrs G .m .I 123Å56789Û12345678 .L 111111111 0 5 0 5 0 1 1 2 2 3 VS = very strong S M 35 = strong = medium

Claims (19)

(H CD 'Ud 10 15 20 25 30 35 le »J Jß Ciclosporin characterized H6 PATENT REQUIREMENT that it is in orthorhombic crystal form with a crystal lattice asymmetric unit a 12.7 Å, b 15.7 Å, c 1804 Å. 36.3 Å, volume per characteristic - 2. Ciclosporin according to claim 1, that it exhibits the following X-ray diffraction characteristics: AI Línjß no. d (Å) Intenity 1- 12.0 H 2. 10.4 vs 3- 9.6 S 4. 6.7 s S. 7.9 H 6. 7.7 s 7. 6.7 H 8. 6.0 H 9. s, a3 s 10. 5.3 M 11. 5.2 M 12. 4.92 S 13. 4, ae s 14. 4.58 3 15- 4.48 H 16. 4.0 H 17. 3.59 H 18. 3, 33 H VS = very strong S = strong H = medium 10 15 20 25 30 35 (eg (f) 04 -Fin Ciclosporin according to any one of claims 1 to 2, characterized in that it is free or substantially free of Ciclosporin in some other form or that it is in pure or substantially pure form. Ciclosporin according to any one of claims 1 to 3, characterized in that it is present in fine particulate form. Ciclosporin according to claim 4, in that the component particles have a mean particle size of S200 pM. Ciclosporin according to claim 5, in that the component particles have an average particle size of from 0.5 to 200 pM. Ciclosporin according to claim 5 or 6, characterized in that the component particles have an average particle size of <25 pM. Ciclosporin according to any one of claims 1 to 7, characterized in that it consists predominantly or wholly or substantially entirely of non-comminuted crystal material. Ciclosporin according to any one of claims 5 to 7, characterized in that the component particles predominantly or wholly or substantially wholly comprise non-atomized microcrystalline material. Ciclosporin according to any one of claims 1 to 9, characterized in that it is present in a sterile or substantially sterile state. Process for the preparation of Ciclosporin in orthorhombic crystal form with a crystal lattice = a = 12.7 Å, b = 15.7 Å, c = 36.3 Å, volume per asymmetric unit = 1804 Å, characterized in that a solution of Ciclosporin in a medium capable of yielding Ciclosporin in said orthorombic crystal form upon crystallization and from this solution said Ciclosporin crystallizes in orthorhombic crystal form and extracts the orthorombic crystals thus obtained. Uï (L) .. .S -: 1 -fx 10 15 20 25 30 35 50 Pharmaceutical composition, characterized in that it comprises a) Ciclosporin in orthorhombic crystal form with a crystal lattice 12.7 Å, b 15.7 Å, c 36.3 Å, volume per asymmetric unit 1804 Å as active ingredient together with b) a pharmaceutically acceptable diluent a or a pharmaceutically acceptable carrier therefor. Pharmaceutical composition according to claim 12, characterized in that the Ciclosporin present in the composition is predominantly or wholly or substantially wholly in orthorombic crystal form. Pharmaceutical composition according to claim 12 or 13, characterized in that it has at least one compartment or phase comprising Ciclosporin in orthorhombic crystal form, said crystal form being distributed or distributable in or over said compartment or phase or homogeneous or in mainly homogeneously distributed or distributable in or over this department or phase. Pharmaceutical composition according to any one of claims 12 to 14, characterized in that it comprises Ciclosporin as defined in any one of claims 2 to 10. Pharmaceutical composition according to any one of claims 12 to 15, characterized in that it is in liquid form, which enables topical application or application by injection or infusion. Pharmaceutical composition according to any one of claims 12 to 16, characterized in that it comprises from 0.05 to 30% by weight of Ciclosporin based on the total weight of the composition. Ciclosporin according to any one of claims 1 to 10, characterized in that it is used as a pharmaceutical. 10 15 20 25 30 35 5l (fi CD L; s Use of Ciclosporin according to any one of claims 1 to 10 for the manufacture of an immunosuppressive or anti-inflammatory agent.