KR100188305B1 - Orthorhombic ciclosporin crystal form, process for its production and pharmaceutical compositions containing it - Google Patents

Abstract

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Description

Novel cyclosporin crystal forms, preparation methods thereof, pharmaceutical compositions containing the same and uses thereof

1 to 3 compare the results of using the composition of the present invention containing 0.1% by weight of cyclosporin as CY-A / X-III and applying 0.1% cyclosporine in placebo and conventional oral solution forms. It is shown.

4 shows the X-ray diffraction data of CY-A / X-III.

The present invention relates to a novel pharmaceutical composition containing cyclosporin as the active ingredient.

Cyclosporin or cyclosporin A is a known fungus metabolite with valuable pharmaceutical use. Cyclosporine is a cyclic poly-N-methylated endocapeptide of the general formula:

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

Cyclosporins and methods for their preparation are described, for example, in US Pat. No. 4,117,118. Clinical studies on cyclosporin relate mainly to its function as immunosuppressive agents, in particular organ transplants such as heart, lung, coalesced heart-lung, liver, kidney, pancreas, bone marrow, skin, corneal transplants, and especially allogeneic It has been used to treat patients receiving allogenic organ transplants. Cyclosporine has been a tremendous success in this field and is currently widely used in clinical practice and is marketed under the trademark SANDIMMUN ^R or SANDIMMUNE ^R in the form of infusion concentrates, oral solutions and gelatin capsule solutions, the latter two variants being described in US Pat. No. 4,388,307. Described and claimed. At the same time, the application of cyclosporin to various autoimmune diseases and inflammatory symptoms, in particular inflammatory diseases associated with aetiology, including autoimmune components such as arthritis (eg rheumatoid arthritis, chronic progressive arthritis and modified arthritis) and rheumatic diseases Has been intensively studied, and reports and results from in vitro, animal models, and clinical trials are well known in the literature. Certain autoimmune diseases in which cyclosporine treatment has been discussed or applied include, but are not limited to, autoimmune hematological diseases (e.g., hemolytic anemia, aplastic anemia, pure erythrocyte anemia, reduction of unknown thrombocytopenia (systemic lupus erythematosus, polychondritis, scleroderma) , Wegener's granulomatosis, dermatitis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, unspecified sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease ( Crohn's disease), pemphigus, endocrine eye disease, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, primary childhood diabetes mellitus (diabetes type I), Behcet's disease, uveitis (allergic uveitis and posterioritis), Nephropathy, including spring conjunctivitis, dry keratoconjunctivitis, interstitial pulmonary fibrosis, dry arthritis, glomerulonephritis (e.g., unexplained kidney syndrome or nephropathy with minimal changes) (With or without a syndrome) Another area for potential applicability is anti-parasitic agents, in particular antiprotozoal agents, including the treatment of malaria, coccidiosis and schistosomiasis, and chemotherapeutic agents ( Eg, to reverse tumor resistance to cellular embolism) and to promote hair growth (eg alopecia treatment).

In the solid state, cyclosporine exists in amorphous and crystalline forms. As the crystalline state, tetragonal and tetragonal variants are known.

The tetragonal variants (P4 ₁ ) are referred to herein as CY-A / X-I for convenience and are described together with their preparation in Austrian patent specification 353,961, for example. CY-A / X-Ⅰ lattice a = b = 13.8Å, c = 41.2Å , and an asymmetric per unit volume = 1974Å ^3, the melting point is about 140-150 ℃, cyclosporin 1 H ₂ of about 2 molecules per molecule Contains O. The primary tetragonal variant (P2 ₁ 2 ₁ 2 ₁ ) is a cyclosporine di-iso, as described in Wegner's Total synthesis-change in molecular structure-biological effect: Ciclosporin as example, Sandrama 1984 / III. Obtained by recrystallization from propyl ether. This includes cyclosporine / di-isopropyl ether (about 1: 2) solvation, crystal lattice a = 12.5 mm 3, b = 22.9 mm ³ , c = 28.4 mm ³ , volume per asymmetric unit = 2027 mm ³ and melting point is About 150 ° C. Orthotropic cyclosporine solvability crystals can be obtained by recrystallization of a supersaturated cyclosporin solution in a suitable solvent medium over time. Thus, the tetragonal cyclosporine / di-isopropylether solvable variant produced by Wegner is a solution of concentrated cyclosporine solution in methylene chloride (cyclosporine is relatively easily dissolved). Less soluble), followed by evaporation of methylene chloride. Crystallization with the remaining di-isopropyl ether then proceeds at ambient temperature for about 7 days. The tetragonal crystal form including the cyclosporin solvation is collectively referred to herein as CY-A / X-II for convenience.

Another tetragonal (P2 ₁ 2 ₁ 2 ₁ ) variant has been identified in the present invention, which is characterized by having little or no solvent component, i.e., consisting almost or mainly of free cyclosporin.

The crystal lattice dimensions for a solvent-free or non-solvable tetragonal cyclosporine variant are a = 12.7 kPa, b = 15.7 kPa, c = 36.3 kPa, volume per asymmetric unit = 1804 kPa ³ , melting point from about 180 to about 190 [deg.] C. and below about 195 [deg.] C., the specific method of obtaining the modified body is determined by purity / source as described in Examples 1 and 2 described. Cyclosporin in the form of non-solvable (or solvent free) tetragonal crystals is referred to herein as CY-A / X-III for convenience. Characteristic data for CY-A / X-III (X-ray powder diffraction) are presented in Tables 3 and 4 with corresponding data of CY-A / X-I and CY-A / X-II. have.

Although cyclosporine has made a significant contribution to the field of medicine, especially organ transplantation, it has not been ideal or trouble-free in its use. Particularly difficult is that it is difficult to provide a convenient or fully satisfactory dosage or to provide the most suitable herbal form for treating a particular disease or condition for which cyclosporin has already been found to be a suitable drug. This difficulty is due in part to the relatively low physical properties of cyclosporin, such as compatibility or solubility with commercially available pharmaceutically acceptable carrier media. These difficulties are complicated by the nature of some of the disease symptoms in which cyclosporine is the primary treatment regimen as well as the occurrence of undesirable side effects that may occur when oral administration of cyclosporin. Cyclosporin, for example, has been shown to be effective in treating psoriasis upon oral administration. Psoriasis causes considerable pain and is a widespread disease that currently has no effective treatment. Psoriasis patients are clearly a group of patients in need of treatment. While it has been found that cyclosporin can meet this need, oral cyclosporin therapy cannot be demonstrated as a conventional means of treating psoriasis. The same is true for the treatment of eye diseases such as posterior uveitis and dry keratoconjunctivitis.

Several systems are conceivable for the administration of cyclosporin, either in the form of herbal or eye drops for topical or dermal application, ie in the form of herbal for topical application to the eye, for example psoriasis or other dermatological diseases (e. ) Forms for the treatment, or herbal forms for the treatment of uveitis. However, these systems have so far had no significant advantages or were not satisfactory enough.

Thus, several attempts to treat psoriasis patients by applying known oral solutions directly to the surface of the psoriasis lesions have been almost unsuccessful, with very limited success when used for patients with irritable dermatitis. Similarly, topical application to the eye is known to be widely effective as a means of preventing, for example, corneal graft rejection or treating diseases in the front of the eye, but cyclosporin affects the inner depth of the eye, such as uveitis (including posterior uveitis). Topical formulations that are convenient, safe and effective in the general treatment of) have not been reported to date.

Other cyclosporine drug delivery systems, such as intraarticular injections suitable for topical treatment of arthritis diseases as described above, or in the form of injections such as intralesional injections for the treatment of severe psoriasis lesions, or with altered bioavailability or drug release properties Significant difficulties exist with the development of drug delivery systems, such as alternative oral delivery systems.

Previous attempts to formulate cyclosporin have been to use this compound in solution or, more rarely, in amorphous or CY-A / X-I form, the CY-A / X-I form for drug approval purposes. It is a confirmed crystalline form. Efforts have been made to find new or improved alternatives, but only oral solutions and infusion concentrates have been widely applied as cyclosporine drug delivery systems.

It is surprisingly possible by the present invention that the tetragonal crystal forms of cyclosporin, such as CY-A / X-II and in particular CY-A / X-III, are particularly advantageous for the preparation of various different types of cyclosporine herbal preparations. Turned out.

In particular, it has been found that such crystal modifications can be used for the preparation of herbal preparations containing cyclosporin and having stable and fine particulate form and / or improved stability or release properties. The findings indicate that new and improved cyclosporine drug delivery systems, such as drugs that are adapted for the treatment of sustained cyclosporine release properties and / or diseases in which conventional cyclosporine treatment was inadequate or difficult to treat with cyclosporin It is now possible to produce a delivery system. In particular, by using the crystal modifications in the form of fine particulate as described above, it is possible to obtain a herbal form suitable for topical or skin application or topical eye application, such as skin or eye diseases, in particular psoriasis, irritable dermatitis, contact dermatitis. There are also herbal forms for the treatment of eye diseases of Behcet's disease, uveitis and dry keratoconjunctivitis. The use of such crystalline variants has sustained release properties, and as a result, frequent administration is required to treat diseases that have not been useful, for example, treatment of psoriasis or similar skin diseases by intra-lesion injection, or arthritis or similar joints by intraarticular injection. Particularly useful in the treatment of diseases of the patient is the preparation of injectable preparations of cyclosporin.

For this purpose the tetragonal crystalline form, in particular CY-A / X-III, is more useful than other useful forms, in particular amorphous cyclosporin or CY-A / X-I, physicochemical properties, in particular stability, emission properties, ie its crystal lattice It has been found to be much more suitable in terms of the release of cyclosporin from and the sensitivity to the essential process of the herbal preparation. CY-A / X-III is a preferred tetragonal crystal form for herbal and / or therapeutic uses according to the present invention. In a first embodiment the invention provides:

A. CY-A / X-III, ie cyclosporin in the form of non-solvable tetragonal crystals; Especially:

A ¹ CY-A / X-III (has the crystal lattice or other physical properties defined above)

And / or

A ² CY-A / X-III (having X-ray powder diffraction characteristics as shown in FIG. 4 or listed in Table 3).

The invention also provides:

B. A process for producing CY-A / X-III characterized in that the obtained CY-A / X-III is recovered after crystallizing the cyclosporin from the CY-A / X-III containing medium.

Suitable CY-A / X-III containing media suitable for use in the process are, for example, solvent media for cyclosporines containing high molecular weight solvent components having a molecular weight of at least 200. Especially suitable are media containing high molecular weight ethers, in particular polymerizable ethers such as polyalkyl ethers such as polyethylene glycol and polypropylene-glycol. Examples of polymerizable ethers that have been found suitable are polyethylene glycols and polypropylene glycols such as those having a molecular weight of 200 or more; As glycerin-polyethyleneglycol esters, for example, glycerin-polyetherglycolysinate and glycerin-polyethyleneglycoloxystearate, such as the trademarks Cremophor EL and Cremophor RH (see Fiddler, Lexikon der Hilfstoffe 2nd edition, first Vol. 1, pp. 257-258); Polyoxyethylene-sorbitan esters sold, eg, under the trademark Tween (cf. Fiddler, Vol. 2, pp. 972-975); Corn oil, supernuclear oil, almond oil, peanut oil, olive oil, palm oil and mixtures thereof are trans- converted into polyethylene-glycol, in particular polyethylene-glycol having a molecular weight of 200 to 800 sold under the trademark Labrafil (cf. Fiddler, p. 539). There are trans-esterified products of natural oil triglycerides and polyalkylene polyols, including products obtained by esterification. Particularly suitable are media comprising polyethylene-glycol having a molecular weight of about 200 to about 600, especially about 300 to about 400.

The CY-A / X-III-containing medium may contain one or more components other than those described above as a means for changing the solvent / crystallization properties, such as low molecular weight alcohols and / or water. Particularly suitable CY-A / X-III containing media have been found to contain about 0.5 vol. Ethanol, about 8.0 vol. Polyethylene-glycol 300 and about 1.0 vol. H ₂ O.

The process of the invention is once put into cyclosporin in amorphous or tetragonal form in a selected CY-A / X-III containing medium and dissolved at high temperature. The dissolution temperature, of course, depends on the particular medium chosen but is usually above 40 ° C, in particular above 50 ° C. In the case of polyethylene-glycol medium the dissolution temperature is usually at least 70 ° C, such as about 75-130 ° C. The resulting solution is usually at least 5%, preferably at least 10%, such as up to about 40-60% and preferably contains up to 20% by weight of cyclosporin based on the total weight of the solution. The cyclosporin is then crystallized with cooling for a relatively long time, eg, 10-35 minutes or more (depending on the desired crystal growth). If necessary, the nucleation process can be started by, for example, ultrasonic waves or seeding. When an ethanol / polyethylene-glycol / H ₂ O crystal containing medium as described above is used, the nucleation process can be easily initiated by applying ultrasonic vibration at about 20,000 cpc, at a temperature of about 60-90 ° C., such as about 65-85 ° C. Can be. As shown in Example 2 below, by continuing the sonication in this manner during the crystallization process, it is possible to obtain very fine and relatively constant particle size microcrystals.

The rate of crystal growth and the size of the crystal obtained naturally vary depending on the particular selection medium and the conditions under which its crystallization has taken place, such as whether ultrasound has been applied and its frequency. The use of the present invention, for example CY-A / X-III, for use in the preparation of the herbal preparations described above, preferably has a fine particulate form, such as an average particle size of 200 μm or less, such as 0.5 to 200 μM. If the crystals initially obtained are relatively large, the particulate formulation having the desired size properties can be obtained by conventional grinding methods, for example by grinding, milling, grinding, micronizing, or fragmenting to a smaller size. The particulate preparations obtained in this way are well suited for some purposes, such as formulations of topical compositions for skin application, but in most cases it would be undesirable to use grinding or milling or equivalent techniques. The reason is that the particle size distribution of the product of the above process is relatively wide and has a rough structure or abrasive structure as a result of crystal crushing. In addition, grinding may destroy the properties of the natural crystal surface and grinding is difficult or expensive, while maintaining the desired sterile state (such as in the preparation of a herbal formulation for intra-articular administration). For this reason, it is preferable to carry out the method of the present invention by a method for obtaining a crystal having a preferred final particle size and in-dimension, for example, a crude crystal. Thus CY-A / in the non-grinding microcrystalline state (ie, CY-A / X-III microcrystals in natural or non-crushed state, such as without grinding, milling, micronization or other size reduction process) It is preferable to prepare and use the X-III particle formulations in a composition suitable for use in intraarticular or other injections.

The process of the invention for obtaining CY-A / X-III microcrystals, which can be used directly in a non-milling state by the above-described method, is for example stirred while increasing from 200-300 rpm to 700 rpm during crystallization and in particular ultrasonic Vibration is preferably carried out with shaking, for example, by applying about 10,000-30,000 cycles / second, suitably about 20,000 cycles / second.

By varying the CY-A / X-III containing media and adjusting the degree of vibration and cooling rate during the recrystallization process by techniques known in the art, CY-A / X in connection with the individual types of herbal preparations of the present invention The average particle size of the -III microcrystals can be varied, for example to the size described above or below.

The crystallization by the method of the present invention is preferably carried out under sterile conditions. The obtained CY-A / X-III can be purified by conventional methods such as rinsing with polyethylene glycol 300: water in a 3-4: 1 (p.p.w.) ratio and washing with warm water as described in the examples. The obtained CY-A / X-III is suitably recovered in a form free or almost free of other forms of cyclosporine, preferably in pure or nearly pure form. The rinsing step helps to suppress amorphous cyclosporin formation.

As noted above, the present invention additionally provides cyclosporines that may be produced by the foregoing as well as the following A ³ -A ⁷ :

A ³ CY-A / of one of the above A to A ² , with or without other forms of cyclosporin, such as CY-A / X-I or CY-A / X-II VII, with or without amorphous cyclosporin X-III;

A ⁴ CY-A / X-III of one of A to A ³ in pure or nearly pure form;

CY-A / X-III of any one of A to A ⁴ , having an A ⁵ microparticulate form, such as the above-mentioned or as described below, particle size characteristics (such as associated with a herbal form containing CY-A / X-III) ;

A ^{6, wherein} the component particles thereof consist mainly of, or wholly or almost entirely of non-milling crystalline material, such as CY-A / X-III of A ⁵ , consisting mainly or wholly or almost entirely of non-milling microcrystals. CY-A / X-III of one of A ⁵ ;

A ⁷ CY-A of any one of A to A ⁶ above, sterile or near sterile, for example suitable for pharmaceutical use, especially for parenteral injection such as parenteral injection, for example. / X-III .

The present invention also provides the following.

C. A pharmaceutical composition comprising a) cyclosporine in the form of tetragonal crystals as an active ingredient and b) a pharmaceutically acceptable diluent or carrier

Cyclosporines may be present in the compositions of the present invention in suitable tetragonal crystal forms such as CY-A / X-II or CY-A / X-III. However, the use of CY-A / X-II is generally less preferred because it has less suitable physicochemical properties for use in the preparation and acceptability of effective cyclosporine-based pharmaceutical products. Cyclosporin is most preferably present in the composition of the invention as one of CY-A / X-III, such as A to A ⁷ above.

Although cyclosporin is present in the composition of the present invention in solid (crystal) form, the composition itself may be in any suitable form. Therefore, the compositions according to the invention can be prepared in solid forms such as capsules, tablets, dragees, powders and granules; Semisolid forms such as ointments, gels, creams, pastes; For example, liquid forms containing cyclosporin components which are distinguished in microparticulate form (eg micronized or microparticulate form) suspended or dispersed in liquid pharmaceutical diluents or carriers.

The composition according to the invention comprises one cyclosporine-containing phase or compartment (e.g., a simple cream, gel, ointment, etc. or a simple one-compartment capsule or ampoule as described above, such as hard or soft gelatin capsules). Or a scanning ampule) as well as a system comprising a plurality of phases or compartments. Accordingly, the present invention relates to cyclosporin in combination with one or more phases or compartments that do not contain cyclosporin (eg, coatings, carriers, delayed or placebo phases) or with phases or compartments that contain other drug ingredients or auxiliaries. It is to be understood to include compositions comprising the phase or compartment it contains. Accordingly, the present invention provides a coated tablet having a core containing cyclosporine in a tetragonal crystal form surrounded by, for example, a coating phase containing no other cyclosporin; Mantle tablets containing a core or mentle containing cyclosporine in a tetragonal form and provided with a mentle or core containing no cyclosporine; Mixed granules comprising a primary granular phase containing cyclosporin in a tetragonal crystal form and a secondary granular phase not containing cyclosporin; It is to be understood, for example, to include split capsules having two or more compartments which are divided by an inner wall and one of which contains cyclosporine in tetragonal form and the other. Other alternatives and variants will be apparent to those skilled in the art. Cyclosporin is preferably present in the composition of the invention, mainly, or preferably wholly or almost entirely in tetragonal crystalline form, such as CY-A / X-III.

The composition of the present invention contains cyclosporine in a tetragonal crystal form (eg, CY-A / X-III), and at least one phase or compartment in which the crystal form is or may be uniformly distributed throughout. It is suitable to include. Such systems include, for example, homogeneous creams, ointments, gels and the like, as well as liquid systems which can be easily and homogeneously distributed when, for example, by shaking the contained crystalline cyclosporin.

Compositions of the present invention may be in, for example, forms suitable for topical administration of skin or topical ocular administration; Forms suitable for parenteral administration, eg by infusion or injection, including subcutaneous or intramuscular injection, especially intralesional or intraarticular injection; And intestinal dosage forms such as suppositories, parsley, and oral dosage forms. However, enteric dosage forms, such as oral dosage forms, are generally less preferred.

The tetragonal crystalline cyclosporin, such as CY-A / X-III, is preferably present in the composition of the invention in the form of fine particulates, such as micronized or microparticulates or non-milled microcrystals as described above. Suitable particle size depends on the nature of the composition and its use, dosage form, and desired effect. In general, however, it is appropriate that the average particle size be on the order of 0.5-200 μM. Specific ranges are discussed below, for example in connection with oral, topical or injectable preparations.

Topical form: Skin or topical eye administration to treat psoriasis or irritable dermatitis or diseases of the eye that require immunosuppressive treatment (eg, uveitis, conjunctivitis including dry keratitis and spring keratoconjunctivitis, or symptoms of corneal transplantation) Mode for.

Topical or dermal gels, creams, ointments and the like can be prepared by methods known and widely used in the art, for example, cyclosporine in the form of tetragonal crystals can be prepared in a suitable flowable substrate such as an aqueous gel (e.g. aqueous Cellulose-ether-based gels) and prepared by adding suitable surfactants, thickening agents such as aerosols.

The cyclosporine component is preferably present in the form of fine particles with an average particle size of 0.5-200 μM. Preferred average particle sizes are 60-80 μM or less, more preferably 40 μM or less, even more preferably 30 μM or less, most preferably 20 μM or less. It is advantageous for the particles to have as narrow a particle size distribution as possible. It is preferable that almost all particles are 60-80 μM or less.

The compositions of the present invention for topical ophthalmic use, ie for application to the eye, may comprise suitably thickened suspensions or dispersants, for example in the form of viscous eye drops or creams or gels for eye applications. In the case of compositions for ophthalmic administration, the average particle size for the crystalline cyclosporin material is preferably 25 μM or less. More preferably, almost all particles are 25 μM or less. The average particle size of the eye drop formulations suitably ranges from about 0.1, preferably from about 0.5 to about 20 μM, preferably from about 10 μM. The hydrophilic / lipophilic content of the carrier system for use in ophthalmic formulations or for skin application forms will depend, for example, on the particular surface to which the composition is applied, for example on the nature of the particular skin area being treated.

Compositions for topical application, in particular particular skin applications, preferably comprise a carrier medium in which the active ingredient (cyclosporin component) is almost insoluble. The solubility of the cyclosporin component (eg CY-A / X-III) in the composition is preferably 10% or less, and preferably 1.0% by weight or less. The solubility is more preferably 0.1% or less, and most preferably 0.001% by weight or less.

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

Hydrophilic and water miscible carrier components are preferably relatively low in volatility. Examples of suitable carrier components belonging here are liquid polyalkylene glycols, propylene glycol, glycerol and ethylene glycol. Suitable polyalkylene glycols especially include liquid polyethylene glycols having an average molecular weight of about 600 or less, such as about 250 to 450, in particular about 300.

Representative compositions of the present invention for topical application include the following ingredients.

C ¹ a) cyclosporine in a tetragonal, preferably non-solvable, tetragonal crystal form, such as CY-A / X-III of any one of A to A ⁷ above;

b) a hydrophilic and water miscible carrier as described above; And

c) any pharmaceutical grade of water.

The amount of component (a) is suitably about 0.1 to about 30.0%, in particular about 0.5 or 1.0 to 20%, such as about 1.0, 2.0, 5.0 or 10.0% (based on the total weight of the composition). Components (b) and (c) are suitably present in a ratio of 1: 0 to 1:20 (p.p.w). Components (b) and (c) are more suitably present in a ratio of 1: 0.5 to 1: 5, such as 1: 1 to 1: 3, and most suitably present at 1: 1.5 to 1: 2.5 (ppw). Do.

The compositions additionally

d) it is suitable to include a surfactant.

Suitable components (d) include in particular the following d ¹ to d ⁸ .

d ¹ : Trans-esterification product of natural vegetable oil triglycerides and polyalkylene polyols.

Such trans-esterification products are known in the art and can be obtained, for example, by the general methods described in US Pat. No. 3,288,824. These products include a variety of natural (eg non-hydrogenated) vegetable oils such as corn oil, supernuclear oil, almond oil, peanut oil, olive oil, palm oil and mixtures thereof and polyethylene glycols, especially polyethylene glycols having an average molecular weight of 200 to 800. And trans-esterification products. Preference is given to products obtained by trans-esterifying 2 mole parts of a natural vegetable oil triglyceride with 1 mole part of polyethylene glycol (e.g., an average molecular weight of 200 to 800). Several forms of trans-esterification products of the class defined above are known and are sold under the trademark Labrafil (Reference, Fiddler Lexikon der Hilfstoffe, 2nd Rev., Definitive Edition (1981), Vol. 2, p539). Particularly useful as components of the compositions of the present invention include Labrafil M 1944CS, a trans-esterification product of supernuclear oil and polyethylene glycol, having an acid value of about 2, a saponification degree of 145-175 and an iodine of 60-90; And Labrafil M 213OCS, a trans-esterification product of C ₁₂ -C ₁₈ glycerides and polyethylene glycols, having a melting point of about 35-40 ° C., an acid value of 2 or less, a saponification degree of about 285-200, and an iodine of 3 or less.

d ² : The reaction product of natural or hydrogenated castor oil and ethylene oxide. This product can be prepared by known methods, for example by reacting natural or hydrogenated castor oil with ethylene oxide in a molar ratio of about 1:35 to 1:60, optionally removing the polyethylene glycol component from the product, examples of which It may be prepared by the method described in German Publication Nos. 1,182,388 and 1,518,819.

Particularly suitable are various surfactants sold under the trademark Cremophor. Cremophor RH 40 having a saponification degree of about 50-60, an acid value of 1 or less, an iodine value of 1 or less, a Fischer of 2%, an nD 60 of about 1,453-1,4578 and an HLB of about 14-16; Cremophor having a saponification degree of about 40-50, an acid value of 1 or less, an iodine value of 1 or less, a Fischer of 4.5-5.5%, an nD ²⁵ of about 1,453-1,57 and an HLB of about 15-17. RH 60; Cremophore EL having a molecular weight (by steam osmometer) of about 1630, a saponification degree of about 65-70, an acid value of about 2, an iodine value of about 28-32 and an nD ²⁵ of about 1,471 are particularly suitable. Also suitable for use in this category are various surfactants sold under the trademark Nikkol, such as Nikkol HCO-60.

The Nikkol HCO-60 exhibits the following properties as a reaction product of hydrogenated castor oil and ethylene oxide; Acid value of 0.3: saponification degree of 47.4; Fishery value of 42.5; PH of 4.6 (5%); Color APHA = 40; Melting point = 36.0 ° C .; Freezing point = 32.4 ° C .; H ₂ O content (%, KF) = 0.03.

d ³ : known types of polyoxyethylene-sorbitan-fatty acid esters or polysorbates sold under the trademarks Tween and Aromtan (cf. Fettler, No. 2, pages 745-746 and 972-975) such as Tween 20 [ Polyoxyethylene (20) sorbitan monolaurate], Tween 40 [polyoxyethylene (20) sorbitan monostearate], Tween 60 [polyoxyethylene (20) sorbitan tristearate], Tween 65 [polyoxy Ethylene (20) sorbitan tristearate], Tween 80 [polyoxyethylene (20) sorbitan monooleate], Tween 85 [polyoxyethylene (20) sorbitan trioleate], Tween 21 [polyoxyethylene (4 ) Sorbitan monolaurate], Tween 61 [polyoxyethylene (4) sorbitan monostearate], and Tween 81 [polyoxyethylene (5) sorbitan monooleate],

d ⁴ : polyoxyethylene fatty acid esters such as the polyoxyethylenestearic acid ester known under the trade name Myrj (see Fiddler, 2, p. 636) and the trademark Cetiol HE. (See Fiddler, 1.p. 228) and known polyoxyethylene fatty acid esters, and polyoxyethylene fatty acid alcohol ethers such as polyoxyethylene stearyl ether, oleyl ether, or cetyl ether, such as the trademark Brij ( See fiddler, 1, 184-186 (e.g., Brij 78 and 96), a type known as Cetomacrogel 1000 (see fiddler, 1, 229),

d ⁵ : Polyoxy ethylene-polyoxy propylene copolymers known and sold under the trademarks Pluronic and Emkalyx (see Fiddler, 2, pp 720-722).

d ⁶ : sorbitan fatty acid esters of the type sold and known under the trademark Span, such as sorbitan monolauryl,-monopalmityl,-monostearyl,-tristearyl,-monooleyl and-trioleyl ester ( See Fiddler, 2, pp 850-851).

d ⁷ : partial glycerides such as mono- and / or di-glyceride components (eg mixed mono-di- / tri-glycerides / freeglycerol based surfactants), and for example glycerol monostearate and glycerol monool Products containing rates, examples of such products are known and are sold under the trademarks Imwitor (cf. Fiddler, 1, 491), such as those sold under Imwitor 191 and Imwitor 780, and Softigen (cf. Fiddler, 2, 833), such as Softigen 701. Some are commercially available.

d ⁸ : Ionic surfactants or emulsifiers such as sodium lauryl sulphate and sodium cetostearyl sulphate.

If present, component (d) is preferably present in an amount up to 30%, more preferably up to 15%, based on the total weight of the composition. Component (d) is most suitably present in an amount of about 0.5 to about 10% (eg, about 1.0%) based on the total weight of the composition. The composition also

e) it is suitable to include thickening agents.

Examples of suitable component (e) are e ¹ to e ⁴ :

e ¹ : Polymethylacrylate resin, eg marketed and known under the trademark Eudispert (see Fiddler, 1, 371-372)

e ² : cellulose derivatives including ethyl-, propyl-, methyl-, hydroxy-, propylmethyl- and carboxymethyl-cellulose.

e ³ : polyvinyl resins (e.g. polyvinyl alcohol and polyvinylpyrrolidone), gelatin, alginate, pectin, gum tragant, gum arabic, gum pellets, and the trademark Carbopol (cf. Fiddler, 1, 206- 207) and other polymeric materials comprising polyacrylic acid known and known.

e ⁴ : materials such as silica gel, bentonite, magnesium-aluminum silicate.

When present, component (e) is suitably present in an amount of up to 20%, more preferably up to 10%, based on the total weight of the composition. Component (e) is most suitably present in an amount of about 0.5 to about 15% (eg, about 1.0 to about 3.0%) based on the total weight of the composition.

The composition may also suitably contain antibiotics such as methylparaben, propylparaben, benzalconium chloride or benzyl alcohol, such as in an amount of 0.05 to 0.5% based on the total weight of the composition, up to 2.0% in the case of benzyl alcohol ( Eg, about 0.1%), in the case of benzyl alcohol, it is suitable to include about 1.0% by weight.

Alternative carrier media include hydrophobic materials, such as those that meet the solubility criteria for the active ingredients described above.

Preferred compositions according to the invention for topical application include:

C ² a) cyclosporines in tetragonal, preferably non-solvable, tetragonal crystal form, such as Cy-A / X-III, such as those defined by any of A to A ⁷ above; And

f) hydrophobic carriers (such as those described above).

The amount of component (a) is suitably present as described above for the composition defined in C ¹ above.

Suitable examples of component (f) include petroleum derivatives (eg mineral oils, fats and jelly), petrolatum (mineral fat or petroleum jelly), liquid petrolatum (white mineral oil or liquid paraffin) or the trademark Vaseline ( See, known products sold under Fiddler, loc.cit, 2, 986) and non-ionic lanolin based derivatives such as those sold under the trademark Amerchol, for example Amerchol CAB (Fiddler, 1, 119-120). .

Examples of other suitable components (f) are saturated with natural or saturated vegetable oils and fats, such as fractionated coconut oil and peanut oil, sold and known under the trademark Miglyol, such as Miglyol 812 (see Fiddler, 2, 616). In addition to peanut oil, there are higher fatty or branched chain alcohols and fatty esters such as stearin alcohol, cetyl palmitate and 2-octyldodecanol sold and known under the trademark Eutanol G (cf. Fiddler, 1, 375).

The composition may also comprise one or more of components (d) and (e) and one or more of the antibiotics.

In particular the compositions may additionally contain at least one component (d) in an amount of preferably at most 30%, more preferably at most 20%, suitably in an amount of about 1 to 15% by weight, based on the total amount of the total composition. It may include.

Hydrophobic compositions of C ² containing the emulsifier component (d) can also be prepared in the form of creams or emulsions by the addition of water. The resulting cream or emulsion may be in oil-in-water or water-in-oil form. The amount of water present in the composition varies, for example, within 5 to 80%, suitably 20 to 70%, based on the total amount of the composition.

When mixed, the amount of component (e) / antibiotic is to the same or as described or similar to that described in connection with the composition of C ¹ above.

The amount of topical form applied depends on the concentration of the composition, the condition to be treated, the desired effect and, in the case of skin application, the area to be applied. The amount of the composition of the skin application used, for example, for the treatment of psoriasis or irritable dermatitis, is generally administered at about 0.1 to about 5 mg / cm ² (eg, about 0.5 mg / cm ² ) of cyclosporin, for example, twice daily It should be enough to provide minutes. For ophthalmic formulations, it is suitable to administer a formulation containing from about 0.1 to about 10%, such as 1.0 or 2.0% by weight of cyclosporin, one to three drops daily to the eye.

Forms of injection: for example subcutaneous, intramuscular or other parenteral injections, especially intraarticular injections for the treatment of joint diseases such as rheumatoid arthritis or intralesional injections for the treatment of psoriasis

Compositions such as dispersions, suspensions, emulsions and the like suitable for injection may be prepared by methods known and widely used in the art, for example, by dispersing, suspending or distributing cyclosporine in the form of microparticulate tetragonal crystals in a suitable liquid carrier medium, It may be prepared by the addition of a surfactant, stabilizer or coagulant. Preferably the cyclosporin component in the composition has an average particle size of 100 μM or less, more preferably 50 μM or less and most preferably 20 μM or less. The average particle size is suitably from 0.1 or 0.5 to 20,50 or up to 100 μM.

Larger particle sizes may be used if the injection form is, for example, subcutaneous or intramuscular injection form to have a dissemination effect. If the injection form is an intralesional application, especially an intraarticular injection form, finer particulate preparations are used. Suitable average particle sizes for such use are, for example, from about 0.1 or 0.5 to about 20 μM (eg, about 5 to 15 μM).

In order to stabilize the particles in the injection form, for example, so that fewer particles gather to increase in size to larger crystal grains, the particles are preferably as uniform as possible. The change between the maximum and minimum particle sizes is suitably about 50 M or less, more preferably about 20 μM or less.

A suitable particle size can be obtained by a suitable grinding process, such as micronization, but it minimizes particle size changes, prevents fragmentation of the particles, prevents changes in the crystal surface (e.g. retains wettability properties) and easily meets certain sterilization requirements. In order to obtain, it is generally preferred to use non-pulverized microcrystals, ie crystals grown to the desired size described above.

It is therefore suitable for the injectable compositions of the invention to comprise:

C ³ : a) Cyclosporines in the form of tetragonal, preferably non-solvable, tetragonal crystals of fine particulates, for example Cy-A as defined in any of A to A ⁷ above, in particular A ⁶ and A ⁷ / X-III; And

b) An injectable carrier medium in which a) is distributed.

Suitable carrier media are specifically pharmaceutical grade water.

In addition, the composition defined as C ³

g) it is suitable to include surfactants as dispersants or emulsifiers and / or coagulants to assist or maintain the distribution of particles throughout the carrier phase.

Suitable surfactant components (g) include polyoxyethylene-sorbitan fatty acid esters or polysorbates such as tween 80 or polysorbate 80 (see Fiddler, 2, pp 746) as described in (d ³ ) above. Include. Suitable coagulants (g) include ethylene diamine tetra-acetate and salts thereof, such as calcium EDTA and sodium EDTA, other equivalent chelating agents and peptising agents (eg succinic acid or citric acid).

In order to maintain the particle size distribution, it is appropriate to incorporate stabilizers. Examples of suitable stabilizers are gelatin or modified gelatin, such as plasma extenders sold and known under the trademarks Gelafundin and Haemaccel, or cold water soluble gelatin of purified collagen hydrolysate.

The composition of C ³ may also comprise one or more antibiotics (such as those described above) and peptising agents (such as succinic acid or citric acid).

The ratio of component (a) :( b) in the composition defined in C ³ is suitably about 1:10 to 1: 1000, preferably about 1:50 to 1: 200 (eg, about 1: 100 ppw). to be.

In order not to disturb particle stability, the surfactant present in component (g) is preferably present in a small concentration, such as from 0.1 to 2.0%, preferably about 1% by weight based on the weight of component (a). When a coagulant is present, a ratio of coagulant to component (a) to component (a) is suitably in the range of 1: 3 to 1: 8 p.p.w, such as about 1: 5 p.p.w. When a stabilizer is present, the ratio of component (a) to stabilizer is suitably about 1: 5 to 1:30, more preferably about 1:10 to 1:30 (e.g., about 1:20 p.p.w). When the peptizer is present, the ratio of peptizer to component (a) is suitably in the range of 1: 1 to 1:10 (e.g., about 1:15 p.p.w).

The amount of cyclosporin present in the unit dosage form for injection according to the invention depends on the condition to be treated, the site of injection and the desired effect (e.g. whether rapid release to the surrounding tissue or a dissemination effect is required).

Each unit dosage form suitably comprises about 10 to 500 mg, in particular about 20 to 100 mg of cyclosporin / dosage.

The unit dosage form according to the invention also comprises a complex system, such as a dual chambered syringe or syringe cylinder, in which the particulate cyclosporin stays in the first chamber together with other suitable components (eg stabilizers or antibiotics) and the carrier The medium is retained in the second chamber and the components of the two chambers are mixed, for example as the syringe piston acts. Such dual chamber syringe systems are well known in the art, and it is to be understood that a single dosage form comprising the system falls within the scope of the present invention.

Oral dosage form: for example, the above-described auto-immune and other disease treatments, such as oral dosage forms for preventing transplant rejection

As mentioned above, oral dosage forms of the present invention are generally less important and less preferred, but such forms also fall within the scope of the present invention.

Oral dosage forms according to the invention can be prepared using suitable carriers or carrier media known in the art. Liquid or semisolid oral dosage forms may, for example, comprise cyclosporine in tetragonal crystalline form (eg, Cy-A / X-III) with a pharmaceutically acceptable diluent or carrier (the crystalline form is insoluble). These carriers and diluents are for example trans-esterified products of natural vegetable oil triglycerides and polyalkylene polyols as described above in (d ¹ ) (eg Labrafils), and natural or hydrogenated as described above in (d ² ). Reaction products of castor oil and ethylene oxide, in particular liquid Cremophore products (eg Cremophore EL).

The cyclosporine is preferably in microparticulate form, for example having an average particle size of 0.5 to 200 μM, in particular 0.5 to 30 μM, preferably up to 20 μM (eg 0.5 to 10 μM).

For the convenience of administration, the above-mentioned compositions are suitably filled in hard or soft-gelatin capsules.

Unit dosage forms for oral administration according to the present invention preferably comprise from about 25 to about 75, or up to 200 (eg, about 50 or 100 mg) of cyclosporin per unit dose. This form is 1 to 1 per day to obtain cyclosporin concentrations in the patient's serum (e.g., measured by RIA) at the same or similar levels obtained using conventional cyclosporine treatment (e.g., commercially available oral solution of cyclosporin). Four times.

The components mentioned above as components of the pharmaceutical composition according to the present invention should be understood to be suitable for the required pharmaceutical use, for example in the case of compositions for oral administration, pharmaceutically acceptable and in the case of compositions for topical administration. It is to be understood locally, for example, as skin or eye applicability, acceptable or tolerant.

Herbal forms for administration by equivalent or alternative routes to those described above will be apparent to those skilled in the art.

The following examples illustrate various aspects of the invention.

Example 1

Preparation of Cy-A / X-III

a) 100 g of amorphous cyclosporin was dissolved while stirring 400 g polyethylene glycol 300 at 50 ° C. As soon as dissolution is finished, Cy-A / X-III begins to form. The solution was left at about 35-40 ° C. for 24-48 hours to complete crystallization and then diluted with 1000 ml of water with vigorous stirring. The precipitate obtained was isolated by filtration, washed with H ₂ O to remove the remaining polyethylene glycol and dried, with a nearly pure form of Cy-A / X-III having a melting point of 195 ° C. and a particle size of about 100-200 μM. Got.

Various forms of Cy-A / X-III can be prepared by carrying out a similar process to the above process using the following materials instead of polyethylene glycol 300 as a solvent.

In each case, the average particle size obtained is about 50- about 200 μM. The measured grating structure is as defined above.

X-ray diffraction data are as described below with reference to Tables 3 and 4.

Example 2

Preparation of Cy-A / X-III

20 g of Cysporin in the form of Cy-A / X-I were dissolved in 60 ml of ethanol and distilled under reduced pressure at 60 ° C. or higher to concentrate to 1/6 of the initial volume. Then 160 ml of polyethylene glycol (molecular weight 300) + 20 ml of HO were slowly added at 50-85 ° C. with stirring at 300 r.p.m. An ultrasonic vibrator / mixer was installed and operated at 20,000 c.p.c. Nuclei began to form over 3-5 minutes at 65-75 ° C. The resulting dispersion was then ultrasonically vibrated and cooled to 40 ° C. over 10-20 minutes with continuous stirring at 700 r.p.m. The resulting thick paste mixture was filtered, rinsed with polyethylene glycol (molecular weight 300) / HO (3: 1 pp volume), washed with warm water (30 ° C.) and dried at 50 ° C. under high vacuum, with a melting point of 192 ° C. and a particle size CY-A / X-III in pure form, 3-15 M, was obtained. The measured lattice structure is as defined above. X-ray diffraction data are described later with reference to Tables 3 and 4.

Repeated experiments indicate that crystal size is affected by crystal growth rate and nucleation temperature rather than processing time. Thus nucleation was initiated at about 75 ° C. and crystallization continued at the same temperature, yielding an average grain size of about 50 μM.

Example 3

Preparation of herbal form for oral administration

3.1 Formulation I encapsulated in gelatin capsules

A suspension containing 20% by weight of Cy-A / X-III obtained according to the process of Example 1 in Zelusir 44/14 was milled at high temperature using a colloid mill to obtain an average particle size of Cy-A / X-III. Bring to 0.5-10 μM.

250 mg of the obtained milling suspension was filled into hard gelatin capsule dimension 2 containing 50 mg of cyclosporine (Cy-A / X-III) as the active ingredient.

3.2 Formulation Enclosed in Gelatin Capsules II

CY-A / X-III obtained in Example 1 was milled in a colloidal mill so that the average particle size of CY-A / X-III was 0.5-20 μM. The 50 mg was then mixed with 200 g of Cremophor EL and filled into hard gelatin capsule dimension 2 containing 50 mg of cyclosporin (CY-A / X-III) as the active ingredient.

Example 4

Preparation of herbal forms for topical application

4.1 Gel Formulation I

Cy-A / X-III obtained in Example 1 was micronized using an air-jet mill. Micronized products having a maximum particle size of 60-70 μM and an average particle size of 2-10 μM were combined and mixed with the components shown in the table by conventional methods to obtain 10% by weight of cyclosporine (Cy-A / X-III). ) And gels suitable for topical application, for example for the treatment of psoriasis and the like.

a) is prepared as in 4.1 above. After dissolving c), f) and g) in b) with warming, the resulting mixture was cooled to room temperature. This solution was then dispersed in water h). To this d) was added and the whole was homogenized and dispersed. To this a) was added and the mixture was homogenized again. E) was added to neutralize with stirring, and the resulting gel was filled into topical compressible tubes such as psoriasis treatment and the like.

4.3 ointment preparations

a) was prepared as in 4.1 above. b), c) and d) were melted together and added, after which a) was added at about 30 ° C. where the particles were distributed using a homogenizer.

The resulting ointment was cooled and filled into compressible tubes for topical application such as psoriasis treatment and the like.

4.4 Cream Formulations

a) was prepared as in 4.1 above and mixed with components b) -h) similarly to 4.3 above and then filled into topically applied compressible tubes such as psoriasis treatment and the like.

4.5 ointment preparations

A suspension containing 20% by weight of Cy-A / X-III (obtained according to Example 1) in polyethylene glycol 300 was wet milled to give an average particle size of Cy-A / X-III of 2-10 μM. . 10 g of the obtained milled product is mixed with 50 g of polyethylene glycol 300 and 40 g of molten polyethylene glycol 1500 by a conventional method, containing 10% by weight of cyclosporin (Cy-A / X-III) and treating psoriasis. A flowable paste suitable for topical application was obtained.

4.6 Gel Formulation

a) was prepared as in 4.1 above. b), c) and d) were mixed and mixed after the addition of f). Thereafter a) was suspended in the resulting mixture by homogenization. E) was added slowly with stirring until gel formation was complete. The gel was then injected into compressible tubes for topical application such as psoriasis treatment.

4.7 Gel Formulation

A) was prepared as in 4.1 above. C), d) and e) were dissolved in b) while warming. The warmed mixture was homogenized, dispersed in h) and cooled to room temperature. Then a) and f) were added thereto and the whole was homogenized. G) was added thereto to complete the gel formation. The gel obtained was injected into compressible tubes for topical application such as psoriasis treatment and the like.

4.8 Cream Formulation (Water-in-Water)

a) was prepared as in 4.1 above and dispersed in e) using b) while warming and homogenizing. After c) and d) were melted together and mixed, the mixture was added to the previously obtained dispersion while strongly homogenizing and the whole was cooled to give a fatty white cream. It was injected into compressible tubes for topical application such as psoriasis treatment and the like.

4.9 Gel / Cream Formulations

The process of Examples 4.1-4.8 was repeated using the crystalline product of Example 2 directly as the cyclosporine component.

Example 5

5.1 Injectable forms (eg parenteral injection)

The following components were used to prepare Cy-A / X-III suspensions under sterile conditions by conventional techniques.

The active ingredient release characteristics of the obtained formulations depend on the average particle size of component a). Therefore, if activity is to be sustained for a long time, select a larger average particle size Cy-A / X-III product (eg 100-200 μM as can be obtained directly through the process of Example 1). . If activity should be maintained for a relatively short time, a relatively small average particle size of the Cy-A / X-III product (eg 0.5-10 μM particle size obtained by milling or micronizing the product of Example 1) is selected.

For example, to provide a dissemination effect, the resulting suspension is placed in an injection or ampoules for injection or parenteral administration in the lesion during the treatment of psoriasis.

In a particularly preferred embodiment, CY-A / X-III with a particle size of 5-15 μM prepared according to Example 2 under sterile conditions is used.

5.2 Injectable forms (eg intraarticular injection)

The following components were used to prepare suitable injectable forms for intraarticular administration.

The formulation was carried out according to standard techniques under sterile conditions.

Component (a) is produced sterile according to the process of Example 2 and comprises uncrushed micro-crystals having a particle size of 3-15 μM. The resulting composition was placed in an ampoule for injection, such as intraarticular injection for the treatment of rheumatoid arthritis under sterile conditions.

The advantages of the compositions according to the invention can be demonstrated in animal testing models as well as clinical trials. The particular utility of the compositions of the invention used for skin application, such as for treating psoriasis or dermatitis, can be demonstrated by the following test model.

Allergic Contact Dermatitis in Guinea Pigs (DTH-Test)

50 μl of 2% dinitrofluorobenzene (DNFB) in acetone / olive oil (1: 1) was sensitized inside the right ear of a guinea pig (Gartley species, male, 400-500 g). After 7 days, 20 µl of 0.5% DNFB in acetone / olive oil (4: 1) was applied to the marks on the left and right flanks of the guinea pig, and then treated again. Exposure to this secondary attack causes allergic inflammation, infiltrating (thickening) the cells with redness of the skin. 200-250 mg of test composition was applied to the DNFB treated portion of the right flank with a weak spoon. The left flank is similarly treated with placebo as a control. Test compositions / Placebos are applied five times at 20 minute, 8 hour, 24 hour, 32 hour, 48 hour post attack time. The thickness of the skin at the site of application is measured before each application and 8 hours after the last application. The skin is lifted, folded and weighed. The extent of redness or inflammation is also assessed visually on a scale of 0-4. The efficacy of the test formulation to inhibit the inflammatory response is determined compared to the results recorded for the placebo-treated flanks.

The results obtained in the test model using the compositions of Examples 4.1 and 4.5 containing 0.1% by weight of cyclosporin of CY-A / X-III were applied topically in the form of results for placebo and conventional oral solutions. The results are shown in FIGS. 1, 2 and 3 with the results for 0.1% cyclosporin. (0.1% concentration of CY-A / X-III is used in this test model as it has the highest sensitivity. Almost similar to Examples 4.1 and 4.5, the cyclosporin component is reduced to 0.1 g, 9.9 g of water is added for Example 4.1 and polyethylene glycol component is added for Example 4.5.)

In each figure, the measured skin thickness is plotted against time. In FIG. 1, the results using 0.1% (weight) cyclosporin, which is applied in the form of conventional commercial oral drinking solution, were compared with those of placebo. A slight decrease in response occurs in oral solutions when compared to placebo. The results using the compositions according to Examples 4.1 and 4.5, containing 0.1% (weight) cyclosporin in FIGS. 2 and 3, are compared with the results of placebo respectively. In both cases, a significant reduction in skin thickness as compared to placebo is still obtained after the first application and during the treatment duration after the first application, and until the completion of the experiment.

The usefulness of the compositions according to the invention can also be demonstrated in clinical trials as carried out below.

Clinical trial: Treatment of dryness by topical (skin) application

Experiment with a randomized, placebo-controlled, double-blind design. In each patient, the active composition and placebo (vehicle only) are fed simultaneously on two symmetrical lesions. The assignment of active and placebo compositions is randomized to the right and left lesions.

Patients were selected from a group of 12 to 24 people, including men and women aged 18-70 years, including menopausal surgical infertility or women whose pregnancy test was negative and using oral contraceptives. The calculation criteria are as follows:

a) consent to written information; And

b) Clinically defined, stable chronic plaque psoriasis.

Two or more severe lateral symmetric lesions with a severity of 5 or more are controlled by areas of 4 to 25 cm 2 and scales ranging from 0 to 9, respectively.

The score by this scale is a combination of individual scores from 0 (weakest) to 3 (most severe) for the three parameters: erythema, scab and skin thickness. Both lesions should be compared for the same patient (i.e. no change more than 20% in severity scale or area).

The following exclusion criteria were applied:

a) a medical condition that, in the opinion of the investigator, makes the study difficult

b) Psoriasis systemic treatment in the last two months (PUVA, methotrexate, steroids, retinoids, cyclosporine)

c) Excluding non-significant substances (eg white petrolatum) containing specific topical treatment-salicylic acid (up to 10%) for the lesion selected for the study within two weeks prior to entry into the study. However, these palliatives can be used for lesions not selected for the study.

d) Patients with psoriasis naturally healed, reddened without treatment or worsened with discontinuation of treatment.

e) known hypersensitivity to any of the test drug components

f) non-cooperative patients who do not appear to have correctly followed medical instructions and who may or may not make regular visits;

g) treatment with test drug within one month of study incidence

h) serious concomitant diseases, particularly renal failure with serum creatinine of at least 130 μMol / L

i) Hypertension (diastolic BP 95 mmHg after 5 minutes in the failure position). Drug controlled hypertension patients are included in the study.

j) History of malignant or malignant diseases including skin cancer

k) skin lesions associated with acute bacteria, viruses or fungi

l) pregnancy, lactation

m) alcoholics, substance abuse, psychosis or patients with emotional or intellectual problems

n) Other immunosuppressants, chemotherapeutic agents, compounds with renal toxicity potential (e.g. aminoglycosides) and drugs known to interact with the pharmacokinetics of cyclosporin (ketoconazole, erythromycin, phenytoin, phenobarbitone, rifampicin, INH , Carbamazepine, sodium valproate)

o) Patients with abnormal baseline readings above 15%, the normal limit of the trial

p) Patients found to have a clinically significant effect upon physical investigation.

The test composition used is any one of Examples 4.1-4.9 described above, such as 1% Composition B of Example 4.2 or 10% Composition B of Example 4.3. Each patient is supplied with a pair of 20 g coded tubes with 2-panel labels. This label is blue for materials to be applied on the right side and red for materials to be applied on the left side. In addition, the side being treated, left or right, study code, investigator name, patient number, and treatment start date are recorded in each panel of the label. Attach the panel removed from the label to the case report.

The test medication is applied twice daily in the morning and in the evening (the dose depends on the size of the lesion) to give a daily dosage of 0.2 to 2.0 mg cyclosporine per cm 2 (eg, about 0.5 mg per cm 2 in one trial). Cyclosporin).

Placebo is applied in equal amounts. No test composition or placebo is applied to the body surface of 25 cm 2 or more, and up to 1 g of cyclosporin is applied per week. In each clinical visit, the medication / placebo tube is weighed and the daily dose applied topically is determined. The patient can simply take a bath before the medication application. Replace disposable gloves to avoid cross contamination of each test composition and placebo. At least 3 hours have elapsed between administration to the treatment area and washing. The primary application is overseen and the patient is provided with instruction sheets. The treatment period is 4 weeks. Even if the lesion disappears before then, treatment continues for four weeks. Patients are examined before the start of the study (one week before), the start of the study (week 0), and after 1,2,3 and 4 weeks.

Dermatological evaluations (local psoriasis index or LPSI) are measured by the same investigator, regardless of medication, using a numerical scale of 0-3 below.

The value of the total LPSI range = erythema + scab + thickness = 0 to 9 is evaluated. To enter the study, two or more symptoms must appear moderate to severe for two selected lesions (LPSI5).

At the beginning and at each clinical visit, the area of the treated lesion is assessed (start size: 4-25 cm 2 at each plaque). The area indicates the presence of three or more criteria, erythema, scab and skin thickening. Pigmentation within the lesion area was not considered in the area evaluation.

The plaques are photographed before treatment (1 week before) and after treatment (4 weeks). Take three pictures. One was taken of both lesions, and the other two were taken of each lesion.

Pruits are assessed from interviews with patients using the following scales.

0 = none

1 = minimum: I want to scratch sometimes.

2 = Normal: I want to scratch often.

3 = Severe: I want to scratch very often, disturbed sleep.

At the end of the study, the response to treatment is assessed according to the following criteria.

Clean = 100% Resolution

Significant improvement = at least 66% LPSI reduction, and / or at least 66% plaque area reduction

Mild refurbishment: 65% to 33% LPSI reduction, and / or 65% to 33% plaque area reduction

Insufficient: less than 32% LPSI reduction, and / or less than 32% plaque area

-Poor: Disease worsened.

Lesions that exhibit clean or significant improvement are defined as therapeutically successful.

Doctors and patients exhibit their preference for left or right drug treatment according to the following criteria.

The left definitely got better.

The left side is slightly better.

There is no difference.

The right side is slightly better.

The right definitely got better.

LPSI scores and lesion area of patients were tested for baseline to 4 weeks post-treatment by Wilcoxon-symptom rank test for a pair of cyclosporin-treated and placebo treated sections to test efficacy at the end of treatment. Compare in relation.

All other comparisons (other time points and remaining parameters of efficacy), including the attached P-values, describe the progress in this test.

In this test, the patient shows a marked improvement in the LPSI score for psoriasis lesions such as erythema, scab and skin thickening, where the site to which the test composition containing cyclosporin was applied is compared with the placebo treated portion. Subjective improvements are recorded along with improvements in recorded values for pruritus in the placebo treated and cyclosporine treated portions.

Positive results are also obtained in tests designed in parallel for patients exhibiting contact dermatitis as diagnosed through three or more of the criteria below.

-Pruritus

Typical shape and distribution:

Flexible limbing or linearization in adults

Facial and Extensor Involvement in Infants and Children

Chronic or chronic-recurring dermatitis

= Hypersensitivity history of an individual or family (asthma, allergic rhinitis, irritable dermatitis); And at least three small features, including:

Dryness, young / myelination / pore keratosis, direct (type 1) skin test reactivity, elevated serum IgE, onset young age (under 5 years), tendency to skin infections (especially with Staphylococcus aureus) Herpes simplex) / damaged cell-mediated immunity, non-specific limb dermatitis tendency, papillary eczema, cleft lip, recurrent conjunctivitis, Denny-Morgan orbital wall, keratoconus, subcapsular cataract, orbital sensitization, facial window / facial erythema, White nasal mucus, anterior neck wall, sweating on both sides, susceptibility to wool and lipid solvents, hyperalgemic salts, food susceptibility, progression affected by environmental / emotional factors, white skin myopathy / persistent blight.

The trial period is three weeks and is evaluated on a scale of 0 to 3 for parameters such as pruritis, erythema, effusion, peeling and thyroiditis.

Topical formulations described above in Examples 4.1 to 4.9 and containing 1-10% cyclosporin, such as 5.0% of the compositions according to Example 4.7, have been shown to be effective against allergic contact dermatitis and alopecia.

As mentioned above, the present invention provides:

In administering D cyclosporine to a patient in need thereof or in treating cyclosporine in a patient in need thereof, the cyclosporine in tetragonal crystal form is an effective amount, in particular a non-solvable crystal form, such as CY-A / X-III (e.g., A to A To a patient).

More detailed embodiments are as follows:

D Tetragonal crystal forms, in particular non-solvable crystal forms such as CY-A / X-III (A to A above) A method of administering immunosuppression or anti-inflammatory treatment by administering to the patient an effective amount of cyclosporin.

For the purposes of applying these methods, the treatment of diseases or conditions as described above in connection with the use of cyclosporin, such as prevention of transplant rejection, treatment of auto-immune or rheumatic diseases, unfavorable high of the immune system Treatment of other diseases or symptoms including reactivity, treatment of parasitic infections, treatment of chemotherapy resistance (eg, reversal of tumor resistance to anti-neoplastic chemotherapy), and treatment of alopecia areata. The method is particularly used for the treatment of skin or eye diseases such as psoriasis, irritable or contact dermatitis, corneal transplantation, keratoconjunctivitis, uveitis by topical administration, as well as for the treatment of rheumatoid arthritis or other joint diseases by intraarticular administration. Can be.

Alternatively, the present invention provides:

E. Use as a drug, such as D or D above Cyclosporin in the form of non-solvable tetragonal crystals, such as A to A, for use in therapeutic use (eg, immunosuppressant or anti-inflammatory agents) of the diseases or symptoms described in connection with CY-A / X-III as defined by any of the above.

F. Cyclosporines in tetragonal crystal form for use in preparing pharmaceutical compositions for the use as defined in E above, such as A to A CY-A / X-III as defined in any one of the following.

X-ray powders for CY-A / X-III, CY-A / X-I and CY-A / X-II, for the identification of cyclosporins in tetragonal crystal form, in particular CY-A / X-III Diffraction data is shown in Tables 1 to 3 below. 3 shows a representative X-ray half diffraction diagram with the data in Tables 1-3.

The diffraction diagram was obtained using a Guinier-Dewolff II camera and obtained with CuKα-radiation, λ = 1.542 Hz.

Claims (16)

Cyclosporine in the form of a non-solvable tetragonal crystal with crystal lattice m of a = 12.7 Hz, b = 15.7 Hz, c = 36.3 Hz and a volume of 1804 Hz ³ per asymmetric unit. The cyclosporine of claim 1 having the following X-ray diffraction characteristics:

The cyclosporine of claim 1 free of other forms of cyclosporin. The cyclosporine according to claim 1, which is in pure form. The cyclosporine according to claim 1, which is in the form of microparticulates. The cyclosporin according to claim 5, wherein the particle size of the component particles is 200 µM or less. 7. The cyclosporine according to claim 6, wherein the component particles have an average particle size of 0.5 to 200 m. The cyclosporin according to claim 5, wherein an average particle size of the component particles is 25 µM or less. The cyclosporin of claim 1, wherein the cyclosporin is composed of non-milled crystalline material. 6. The cyclosporin of claim 5, wherein the component particles consist of non-milled microcrystalline material. The cyclosporine according to claim 1, which is sterile. A pharmaceutical composition for use as an immunosuppressant, anti-inflammatory or antiparasitic agent, comprising a) the cyclosporin of claim 1 and b) a pharmaceutically acceptable diluent or carrier. 13. The pharmaceutical composition of claim 12, wherein the cyclosporin present in the composition is the cyclosporin of claim 1. The pharmaceutical composition of claim 12, wherein the cyclosporine of claim 1 has one or more compartments or phases, or can be distributed throughout the compartment or phase. The pharmaceutical composition of claim 12, which is applied or topically applied by injection or infusion. 13. A pharmaceutical composition according to claim 12 containing from 0.05 to 30% by weight of cyclosporin, based on the total weight of the composition.

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