JPH01211598A - Novel cyclosporine crystal, its production, pharmaceutical composition containing the same and use thereof - Google Patents

Abstract

PURPOSE: To obtain a cyclosporin compd. having a new crystal form useful as an immunosuppressor and an antiinflammatory agent for autoimmune diseases such as rheumatoid arthritis from which sustained release drugs and delayed active drugs are provided in a stable fine particulate form having a non-solvated orthorhombic system.

CONSTITUTION: Amorphous cyclosporin is dissolved in polyethylene glycol at 50°C with stirring to obtain a solution. The solution is allowed to stand at about 35-40°C for 24-48 hours to form crystals of CY-A/X-III type. Thereafter the solution is diluted with a plenty of water with vigorously stirring and the formed precipitates are filtered off. They are washed to remove remained polyethylene glycol and dried. Non-solvated orthorhombic system cyclosporin is obtained which has crystal lattices of a=12.7 angstrom, b=15.7 angstrom, c=36.3 angstrom and a volume per one asymmetric unit = 1804 cubic angstrom.

COPYRIGHT: (C)1989,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to a novel pharmaceutical composition containing cyclosporine as an active ingredient.

[Prior Art and Problems to be Solved by the Invention] Cyclosporin Cyclosporin A is a known fungal intermediate metabolite that has valuable pharmaceutical uses. Cyclosporin has the formula [wherein -McBmL- is N-methyl-(4R)-4
-but-2E-en-1-yl-4-methyl-(L)threonyl residue] It is a cyclic poly-N-methylated endecapeptide represented by the following formula.

Cyclosporin and methods for its production are described, for example, in US Pat. No. 4,117,118. The main area of clinical research on cyclosporine concerns its application as an immunosuppressant, especially in the treatment of recipients of organ transplants, such as heart, lung, cardiopulmonary, liver, kidney, pancreas, bone marrow, skin and corneal transplants, especially atypical organ transplants. It was something. In this field, cyclosporin has achieved significant success and reputation, for example in the form of an injectable concentrate, an oral solution and a gelatin-encapsulated solution (the latter two forms are described, for example, in U.S. Pat. No. 4,388,307 and are included in the claims. It is currently widely used in clinical practice and is commercially available under the registered trade name SANDIMMUN or SANDIMMUNE.

At the same time, various autoimmune diseases and inflammatory conditions, especially those with an etiology that includes an autoimmune component, such as arthritis (
The applicability of cyclosporin for rheumatoid arthritis (e.g., rheumatoid arthritis, chronic progressive arthritis and osteoarthritis) has been thoroughly investigated, and reports and results in vitro, animal models and clinical trials have been widely published in the literature. Are listed. Specific autoimmune diseases for which cyclosporine therapy is proposed or indicated include autoimmune blood diseases (including, for example, hemolytic anemia, nonregenerative anemia, congenital aplastic anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, multiple sclerosis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic acute hepatitis, myasthenia gravis, psoriasis, Steven-Nyonson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. , ulcerative colitis and Crohn's disease), ovarian cancer, endocrine eye disease, Grages' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, secondary juvenile diabetes (diabetes mellitus summer type)
, Birchiet's disease, uveitis (anterior and posterior), vernal conjunctivitis, keratoconjunctivitis sicca, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. idiopathic) (including sexual nephrotic syndrome or microlesional nephropathy).

Another area of research is the promising applicability of antiparasitic drugs, especially as antiprotozoal drugs, with proposed possible uses including the treatment of malaria, coccidioidomycosis and schistosomiasis, as well as chemotherapy, e.g. Includes uses in reducing tumor resistance to cytostatic therapy and promoting hair growth, for example in the treatment of alopecia.

In the solid state, cyclosporin exists in both amorphous and crystalline forms. In the crystalline state, both tetragonal and orthorhombic forms are known.

Square product deformation (P 4 ,X For convenience, in this specification [C
Y-A/X-IJ) is described, for example, in Austrian Patent Specification No. 353,961, together with its method of preparation. CY-A / , with approximately two 14,0 molecules per molecule of cyclosporin.

The first orthorhombic deformation (p2+2+20 is [Sandrama J
(S andorama) 1984 / In, "Total Synthesis Change in Molecular Structure - Biological Effects: Cyclosporine as Example J" by Wenger.
Total synthesis-change in
molecular structure-biol
logical effect: C1clospori
It can be produced by recrystallization from diisopropyl ether as described in the article entitled (nasexample).

This particular form has a=12.5 angstroms, b=
It has a crystal lattice of 22.9 angstroms, c=28.4 angstroms, volume per 1 asymmetric unit=2027 cubic angstroms, and contains a cyclosporin/diisopropyl ether (approximately 1:2) solvate with a melting point of 150°C. Orthorhombic cyclosporine solvate crystals can be produced by recrystallization of a supersaturated cyclosporine solution in a suitable solvent over an extended period of time. Namely, Wenger? The orthorhombically modified cyclosporine/diisopropyl ether solvate form produced from this method is obtained by adding a concentrated solution of cyclosporine dissolved in methylene chloride (cyclosporine is fairly easily soluble) to diisopropyl ether (cyclosporine is relatively sparingly soluble), Obtained by concentrating.

Crystallization from the remaining diisopropyl ether is then continued at ambient temperature for about 7 days. Further, for convenience, the orthorhombic form containing the cyclosporin solvate is referred to as rCY-A/X-II J in this specification.

[DESCRIPTION OF THE INVENTION] Another orthorhombic modification (P2.2,2υ) is herein characterized in that it is free of any or substantially no solvent component, i.e. substantially or essentially free of cyclosporin. confirmed.

The dimensions of the crystal lattice in solvent-free or non-solvent compatible orthorhombically modified cyclosporine are: a = 12.7 angstroms, b = 15.7 angstroms, c = 36.3 angstroms, volume per asymmetric unit = 1804
It is a cubic angstrom.

The melting point is on the order of about 180 to about 190° C. to about 195° C. or less, depending on, for example, the purity/source shown in Examples 1 and 2 below, where the specific preparation of this variation is described. Also, for convenience, the non-solvent compatible (or solvent-free) orthorhombic form of cyclosporine is referred to herein as rCY-
A/X-I[[Referred to as J. Furthermore, CY-A/X −
The characteristic data of CY-A/X-1 and CY-
It is shown in Table 3 and FIG. 4 below together with the corresponding data of A/X-11.

Despite the very significant achievements and reputation that cyclosporine has achieved, and despite the important contributions it has made to medicine, especially organ transplant technology, its practicality is still far from ideal or perfect. do not have. The specific field obstacles that have been encountered to date do not allow for convenient or overall satisfactory administration, or for the treatment of specific diseases or conditions for which cyclosporine has already been identified as a particularly good and promising drug. The aim is to provide the most suitable herbal medicine forms.

These obstacles can be attributed in part to certain physical properties of cyclosporine, such as its relatively limited solubility or (as previously experienced) compatibility with available pharmaceutically acceptable carrier media. . These obstacles are compounded by the very nature of certain disease states for which cyclosporine exhibits the most significant possible therapeutic effect as well as by the occurrence of undesirable side effects that cyclosporine can induce when administered orally. For example, cyclosporine has been shown to be effective in treating psoriasis by oral administration. It is a widespread condition that afflicts psoriasis and other patients, and there is currently no generally accepted and effective treatment. Those who suffer from psoriasis clearly represent a troubled patient population. Available evidence suggests that
Cyclosporin can overcome this situation, but
It is unlikely that transrocyclosporine therapy can be justified as a routine means of treating psoriasis. A similar consideration is
This also applies, for example, to the treatment of eye diseases (eg posterior uveitis and keratoconjunctivitis sicca).

Topical or dermal application or ocular application, which can be used for example in the treatment of psoriasis, other skin diseases and conditions, such as atopic dermatoses and alopecia or in the treatment of uveitis,
Various systems have been proposed for the administration of cyclosporin, including herbal forms intended for topical application to the eye. However, these systems have so far not provided much significant benefit and have not proven to be entirely satisfactory.

Thus, among the various reported attempts to treat psoriasis patients by direct application of known oral solutions at the superficial sites of the psoriasis, there have been very few or no successful attempts, and the results for patients with atopic dermatoses have been very limited. It was limited to.

Similarly, topical application to the eye has been found to be widely effective, e.g. as a means of preventing corneal transplant rejection or treating diseases in the anterior part of the eye, but so far only In the general treatment of inflammation, no topical formulations have been reported that may allow easy, safe or effective treatment of diseases or conditions that attack deep within the eye.

Other cyclosporin drug delivery systems, e.g. in injectable forms, or e.g. modified organisms, suitable for e.g. intra-articular injection in the local treatment of joint diseases (e.g., the diseases mentioned above), or intralesional injection, e.g. in the treatment of severe psoriatic lesions. Comparable obstacles have been encountered with the development of other oral delivery systems with biological availability or drug release characteristics.

Previous attempts at formulating cyclosporin have been limited to solutions or, less commonly, amorphous or CY-
The A/X-1 form of the compound was used, for example the latter being the crystalline form identified for example for drug registration. Also, a great deal of effort has been expended in the search for new or improved alternative forms, or the already mentioned oral solutions and infusion concentrates remain the only and widely applied cyclosporine delivery systems.

[Aspects and Effects of the Invention] According to the present invention, surprisingly, orthorhombic forms of cyclosporin, such as CY-A/X-It and especially CY
-A/X-DI has been found to exhibit particular advantages and advantages in the manufacture of a wide variety of cyclosporin formulations.

In particular, it has been discovered that by using the crystallographic variation described above, it is possible to produce formulations containing cyclosporine in a stable particulate form and/or having enhanced stability or release characteristics. This discovery makes it suitable, for example, for the treatment of diseases or conditions that have long-acting or slow-acting cyclosporine delivery properties and/or that are previously antigenic to cyclosporine therapy or for which conventional cyclosporine therapy is inherently unsuitable. This opens the door to the production of new and improved cyclosporine drug delivery systems. More particularly, by use of said crystalline modification, e.g. said particulate form,
Topical or dermal application, for example in the treatment of diseases or conditions affecting the skin or eyes mentioned above, in particular psoriasis, atopic dermatoses, contact dermatitis, intraocular manifestations of Behcet's disease, uveitis and keratoconjunctivitis sicca; It has been found that formulations suitable for topical ophthalmic application can be produced. Also,
By using these crystalline variants, they have sustained or delayed release properties, such as for the treatment of diseases or conditions whose usefulness may otherwise be hampered by the frequency of administration required, such as arthritis by intra-articular injection. Alternatively, it becomes possible to produce an injectable form of cyclosporin that has particular use in the treatment of similar diseases of the joints or in the treatment of psoriasis or similar diseases of the skin by intralesional injection.

In those applications, the orthorhombic form, especially CY-A/X
-III has better physicochemical properties, in particular stability, release properties, i.e. release of cyclosporine from the crystal lattice, and necessary formulation, than other usable forms, in particular amorphous cyclosporin or CY-A/X-1. It has been found to be quite suitable in terms of sensitivity to the method. C
Y-A/X-■ is a novel and preferred orthorhombic form for formulations and/or therapeutic uses according to the invention.

Accordingly, a first aspect of the invention provides A C1-A/X-111, i.e., non-solvent compatible orthorhombic cyclosporin, in particular C Y -A having an A1 crystal lattice or other physical properties substantially as described above. /X-III, and/or A
2 This relates to CY-A/X-[ having the X-ray powder diffraction characteristics substantially as listed in Table 3 or shown in FIG.

The present invention also provides a method for producing B CY-A/X-[1,
A method is provided comprising crystallizing cyclosporin from an A/X-111 containing medium and recovering the resulting CY-A/X-111.

C Y -A/X-III suitable for use in the above method
The containing medium is, in particular, a cyclosporine solvent medium containing a high molecular weight solvent component, for example having a molecular weight>200. Particularly suitable are media containing high molecular weight ethers, especially polymeric ethers, such as polyalkyl ethers, such as polyethylene and polypropylene glycols. Examples of polymer ethers which have proven suitable include, for example, polyethylene and polypropylene glycols with a molecular weight >200, glycerin-polyethylene glycol esters, such as glycerin-polyethylene glycol lysyl ate and glycerin-polyethylene glycol esters.
Polyethylene glycol oxystearate, e.g. [
Cremophor EL J and "Cremophor RH and Reference, Fiedler-1" Lexikon der Hilfstoffe
polyoxyethylene-sorbitan esters, such as Tween
2-975), polyoxyethylene esters, e.g. polyoxyethylene-stearate, e.g.
Fiedler 1 Vol. 2, p. 636), as well as transesterification products of natural oil triglycerides and polyalkylene polyols, such as corn oil, kernel oil,
almond oil, ground nuts
ut) transesterification products of oils, olive oil, palm oil and mixtures thereof with polyethylene glycols, in particular polyethylene glycols with a molecular weight of 200 to 800, for example under the trade name "Labrafi J"
1) (Reference, Fiedler, p. 1539) is commercially available. Especially suitable is about 200 to about 600,
In particular, a medium comprising polyethylene glycol having a molecular weight of about 300 to about 400.

However, in addition to the above components, the CY-A/X--containing medium may contain one or more components, such as low molecular weight alcohols and/or water, as a means of modifying the solvent/crystal properties. .

A particularly suitable CY-A/X ~ ■ containing medium has been found to be one containing about 0.5 parts by volume of ethanol, about 8.0 parts by volume of polyethylene glycol (300) and about 1.0 parts by volume of HtO. Ta.

The method of the invention first involves dissolving, for example, an amorphous or tetragonal cyclosporin in a selected C Y -A/X--containing medium at an elevated temperature. The dissolution temperature will, of course, vary depending on the particular medium chosen, but is generally >40°C, more specifically >50'C. For polyethylene-glycol based media, the melting temperature is generally >70
°C, for example about 75-130 °C. Suitably the solution obtained contains >5% by weight, preferably >10% by weight, such as not more than about 40-60%, preferably not more than 20% by weight of cyclosporin, relative to the total weight of the solution. . Crystallization of the cyclosporine is then allowed to continue with cooling, preferably for a relatively long period of time, for example approximately 10-35 minutes or more depending on the degree of crystal growth desired.

If desired, the nucleation process can be initiated, for example by sonication or seeding. For example, when using the aforementioned ethanol/polyethylene glycol/H10 crystal-containing medium,
For example, it has been found that nucleation can be readily initiated at temperatures of about 60-90°C, such as about 65-85°C, by application of sonic vibrations at about 20,000 cpc. As shown in Example 2 below, by continuing sonication in this manner throughout the crystallization process, microcrystals with very fine but relatively constant particle size can be produced.

Of course, the rate of crystal growth and the size of the crystals obtained will vary depending on the particular medium chosen and the conditions under which the crystallization is carried out, such as whether or not sonication is applied and what frequency of vibration is used. In the use according to the invention, for example in the preparation of the formulations described below, CY-A/X-II [is preferably, for example <200 μM1, for example 0.5 to 200 μM
It is used in fine particle form with an average particle size of .

If the initially obtained crystals are of relatively large size, the particle formulation with the desired size characteristics can of course be prepared using conventional comminution methods, such as grinding, milling, comminution, micronization to reduce the size or It can be produced by other crushing methods. The use of grinding or milling or equivalent techniques is often not preferred, although the particle formulations obtained in this way may be perfectly suitable for some purposes, such as the production of topical compositions for skin application.

The reason for this is that products from those methods exhibit a relatively broad particle size distribution and tend to have a relatively coarse structure as a result of crystal fragmentation.

Furthermore, milling tends to destroy the physical properties at the natural crystal surface and is anyway difficult or expensive to carry out while maintaining the aseptic conditions required, for example in the manufacture of intra-articular formulations. . For the reasons stated above, crystals having dimensions within the desired final particle size range,
For example, it is generally preferred to carry out the process of the invention in a manner that results in fine crystals. That is, when used, for example, in the preparation of compositions for intra-articular or other parenteral applications, CY-A/X-III particle formulations in an unground, microcrystalline state (i.e., in a native or unbroken state, e.g., by grinding, milling, Preference is given to using CY-A/X-111 microcrystals) which have not been subjected to micronization or other reduction methods.

CY-A/X that can be used directly in the unpulverized state in the above method
In order to obtain -IIIIn microcrystals, the method of the present invention comprises:
Suitable? During the crystallization period e.g. 200-30 O
rpm to, for example, 7 Q Orpm, and with vibration, in particular by applying ultrasonic vibrations, for example in the range of 10,000-30,000 cycles per second, preferably on the order of about 20,000 cycles per second.

By modifying the CY-A/X-III-containing medium and adjusting the cooling rate and degree of vibration during the recrystallization process according to techniques known in the art and specifically mentioned below, formulations according to the invention can be prepared, for example. C Y -A/X-In microcrystals can be produced with various average particle sizes as described above or below with respect to the use depending on the particular type of CY-A/X-In.

As mentioned above, crystallization according to the method of the invention is preferably carried out under aseptic conditions. Obtained CY-A/X −
Purification of DI can be carried out in conventional manner, for example by rinsing with polyethylene glycol (300):water (eg 3-4:1 weight ratio)/washing with hot water as described in the Examples. The resulting CY-A/X-■ is preferably recovered free or substantially free of other forms of cyclosporin, preferably in pure or substantially pure form. The above rinsing step helps prevent amorphous cyclosporin formation.

From the foregoing, the present invention further provides cyclosporin that can be produced by any one of the above methods, as well as A 3 , free or substantially free of other forms of cyclosporin, such as CY- to/X-1 or CY-A
CY-A/X-II according to any one of A to A above, which is free or substantially free of amorphous cyclosporin of /X-If [, A4 = pure or substantially CY-A/X-■ according to any one of A-A' above in pure form, AS, e.g. CY-A/X-II [with particle size characteristics as described above or below for the containing formulation CY according to any one of the above A-A', which is in the form of fine particles.
- A / consists essentially entirely of unground microcrystals)
or completely or substantially completely consists of C as described in any one of A to A% above.
Y-A/X-I[[,A? CY- according to any one of the above A-A'', in a sterile or substantially sterile condition, e.g. in a condition suitable for pharmaceutical use, especially for parenteral application, e.g. administration by parenteral injection, e.g. intraarticular injection. A/
Provide X −■.

Furthermore, the invention provides a pharmaceutical composition comprising: C2a) orthorhombic cyclosporin as an active ingredient together with b) a pharmaceutically acceptable diluent or carrier.

Cyclosporine is available in the appropriate orthorhombic form (e.g., CY-A/X
-n or CY-A/X-III) may be present in the compositions of the invention. However, cY-A/X-■
The use of cyclosporine is generally not preferred as it exhibits poor physicochemical properties, making it less suitable for use both in terms of tolerability and usability in the preparation of effective pharmaceutical products based on cyclosporin. More preferably, cyclosporin is, for example, CY- as described in any one of AA' above.
It is present in the composition of this invention as A/X-■.

Although cyclosporine is present in the compositions of this invention in solid (crystalline) form, the composition itself may assume any suitable structure.

Thus, the composition according to the invention can be used in solid forms, such as capsules, tablets, dragees, powders and granules, in semi-solid forms, such as ointments, gels, creams and pastes,
and a liquid form containing, for example, the above-mentioned cyclosporine component in finely divided form (e.g., micronized or particulate form!14) suspended or dispersed in a liquid pharmaceutical diluent or carrier capable of retaining the selected crystalline form. include.

The compositions according to the invention are suitable for use in systems comprising a single cyclosporine-containing phase or compartment, such as the aforementioned simple creams, gels, ointments, etc. or simple one-compartment capsules or ampoules, such as gelatin hard or soft capsules or ampoules for injection; It encompasses both systems containing multiple phases or compartments. That is, the invention includes, for example, a cyclosporin-containing phase or compartment together with one or more non-cyclosporine-containing phases or compartments, such as a coating, a carrier, a delay or placebo phase, or a phase or compartment containing other drug substances or adjuvant materials. is to be understood as encompassing compositions containing. That is, the present invention includes a coated tablet having a core containing, for example, orthorhombic cyclosporin, surrounded by, for example, another non-cyclosporin-containing coating phase, a skeleton or mantle containing orthorhombic cyclosporin, A mantle tablet with a cyclosporine-containing mantle or skeleton, a mixed granule having a first phase containing orthorhombic cyclosporine and a second non-cyclosporine containing phase, and separated by, for example, an inner wall, one containing orthorhombic cyclosporine. is to be understood as encompassing split capsules having two or more compartments, one containing the other without. Other alternatives and modifications will be apparent to those skilled in the art. Preferably the cyclosporin is present in the compositions of the invention predominantly or preferably completely or substantially completely as an orthorhombic system, e.g. CY-A/X-In.

The composition of the invention preferably comprises at least one orthorhombic cyclosporin, such as CY-A/X-III.
three phases or compartments throughout which the crystalline form is uniformly distributed or distributable. These systems include, for example, homogeneous creams, ointments, gels, etc., as well as liquid systems in which the contained crystalline cyclosporine is or can be easily and evenly distributed, for example by hand shaking.

The compositions according to the invention are suitable for topical administration, e.g. dermal or topical ocular administration, parenteral administration by infusion or injection, including e.g. subcutaneous or intramuscular injection and especially intralesional or intraarticular injection, as well as e.g. suppositories. , enteric-coated forms for administration, such as pessaries, and oral dosage forms. However, enteric forms, such as oral dosage forms, are generally less preferred.

Preferably, orthorhombic cyclosporin, such as CY-
A / Suitable particle sizes will, of course, vary depending on the particular nature of the composition, its intended use and method of application, and the desired effect. However, in general the average particle size is preferably on the order of 0.5-200 μM. For example, specific areas relating to the manufacture of oral, topical or injectable forms are discussed further below.

(e.g. used in the treatment of dry skin or atopic dermatoses or eye diseases or conditions requiring immunosuppressive treatment, e.g. conjunctivitis including uveitis, external keratoconjunctivitis sicca or vernal keratoconjunctivitis or corneal transplants, e.g. skin Gels, creams, ointments, etc. for topical or dermal administration (or topical forms for topical use in the eye) may be prepared by preparing, for example, orthorhombic cyclosporin in a suitable water-dispersible concentrated suspension base material, according to well-known techniques commonly used in the art. , for example with an aqueous gel, e.g. an aqueous cellulose-ether based gel, and at the same time with a suitable surfactant, thickener, etc.
For example, it can be produced by adding Aerosil.

The cyclosporine component is preferably e.g. 0.5-20
Exists in fine particle form with an average particle size of 0 μM. Preferably the average particle size is <60-80 μM, more preferably 40 μM, even more preferably 30 μM.
M1 is most preferably 20 μM. Advantageously, the particles have as narrow a particle size distribution as possible. Preferably substantially all particles present are less than 60-80 μM.

Compositions of the invention for topical ophthalmic use, i.e. for application to the eye, may take the form of, for example, viscous eye drops or ocular creams or gels, including, for example, moderately concentrated suspensions or dispersions. obtain.

For compositions administered to the eye, the average particle size of the crystalline cyclosporin material present is preferably 25 μM. More preferably substantially all particles present are less than 25 μM. The average particle size in the eye drop formulation is suitably from about 001 to about 0.5
In the range of ˜about 20 μM or preferably ˜about 10 μM.

The hydrophilic/lipophilic content of the carrier system used in dermal or ophthalmic formulations may vary, for example depending on the characteristics of the particular surface to which the composition is applied, eg the particular skin area to be treated.

Topical, especially dermal, compositions preferably include a carrier medium in which the active ingredient (tucrosvorin component) is only slightly soluble.

Suitably, the solubility of the cyclosporine component (eg, CY-A/X-III) in these compositions is <10% by weight, preferably 1.0% by weight. More preferably the solubility is <o, 1% by weight, most preferably <0.0
01% by weight.

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

Hydrophilic, water-miscible carrier components suitably exhibit relatively low volatility. Examples of suitable carrier components belonging to this class are polyalkylene glycols, propylene glycol and ethylene glycol. Suitable polyalkylene glycols include, in particular, liquid polyethylene glycols, such as having an average molecular weight of less than about 600, such as from about 250 to 45o1, especially about 300.

Thus, for example, a typical composition according to the invention, applied topically, comprises: C1a) an orthorhombic, preferably non-solvent compatible, orthorhombic cyclosporin, such as CY-A/X-111, such as AA'above; b) a hydrophilic, water-miscible carrier, eg as described above, and optionally C) pharmaceutical water.

The amount of component (a) present is suitably from about 0.1% to about 30.0% based on the total weight of the composition, especially about 0.5 or 1%.
．． 0 to 20%, for example about 1.012.0°5.0 or 10.0%. Components (b) and (C) are preferably present in a weight ratio of 1:o to 1:20. More preferably, component (b) and processing (c) are 1:065 to 1:5.
, for example III~1:3, most preferably lfl:1.5~
It is present in a weight ratio of l:2.5.

These compositions preferably further include: d) Surfactant Contains.

Suitable components (d) include in particular the following substances:

dl Transesterification products of natural vegetable oil triglycerides and polyalkylene polyols. These transesterified products are known in the art and can be prepared, for example, according to the general procedure described in US Pat. No. 3,288,824. They include various natural (e.g., non-hydrogenated) oils such as corn oil, kernel oil, almond oil, ground nut oil,
Contains transesterification products of olive oil and palm oil and mixtures thereof with polyethylene glycols, especially polyethylene glycols having an average molecular weight of 200-800. 2 molar parts of natural vegetable oil triglyceride and 1 molar part of polyethylene glycol (e.g. 200-8
Preference is given to products obtained by transesterification with (having an average molecular weight of 0.00). Various forms of transesterification products belonging to said class are known and are commercially available under the trade name Labrafil [Fiedler-1 "Lexicon.
Der Hilfstoffe J (Lexikon der
HilfstofTe) 2nd revised and expanded edition (198
3), Vol. 2, p. 539]. A particularly useful product as a component of the compositions of this invention is LabraFil M1944C
8° kernel oil and polyethylene glycol with an acid value of about 2, a saponification loss of 145-175 and an iodine G11i of 60-90, transesterification products, and Labrafil M2130CS-C+t to CII glycerides and melting points of 35 -40℃, acid value 2, saponification approximately 185-20
0 and an iodine number <3.

d' Reaction product of natural or hydrogenated castor oil and ethylene oxide. These products can be prepared by known methods, for example West German Publication No. 1182388 and German Publication No. 1518.
No. 819, for example natural or hydrogenated castor oil and ethylene oxide (e.g. about 1=35 to
(molar ratio of about 1:60) and optionally removing the polyethylene glycol component from the product. Particularly suitable are the surfactants sold under the trade name Cremophor. Particularly suitable products have a saponification ratio of about 50-60 and an acid value of about 50-60! , iodine number<1. Moisture content (Fisher) 2%, nD@O approx. 1453-14
578 and HL, B about 14-16 Talemophor RH40, saponification about 40-50, acid value 1, iodine number <1, water content (Fisher) 4.5-5.5%, b.
fi11 about 1453-157 and HLB about 15-17
Cremophor RI-160 with a molecular m (by vapor osmolality) of about 1630, saponification of about 65-To, acid number 2, iodine number 28-32 and n, ts, about 14
Cremophor EL with 71. Additionally, products suitable for use in this category include Nikko
l) various surfactants commercially available under the trade name Nibucol 14GO-60.

The product Nibucol HCO-60 is made of hydrogenated castor oil, acid value of 0.3, saponification number of 47.4, hydroxyl value of 42.5, ptl (5%) of 4.6, color AP) IA = 40
, melting point 36.0°C, freezing point = 32.4°C, H1O containing M
(%, Kt') = 0'.

It is a reaction product with ethylene oxide that exhibits characteristics such as 03.

d3 For example, belongs to a known type, such as Tween (
Tween and Armotan trade names (Fiedler - Vol. 12, pp. 745-746 and 9)
Polyoxyethylene-sorbitan-fatty acid ester or polysorbate, commercially available as (see pages 72-975). Tween has the following products:

20 [Polyoxyethylene (20) Sorbitan Monooletoko, 40 [Polyoxyethylene (20) Sorbitan Monopalmitate], 60 [Polyoxyethylene (20) Sorbitan Monostearate], 65 [Polyoxyethylene (20) Sorbitan tristearate], 80 [polyoxyethylene (20) sorbitan monooleate], 85 [polyoxyethylene (20) sorbitan tristearate], 21 [polyoxyethylene (4) sorbitan monolaurate], 61 [polyoxyethylene (20) sorbitan monooleate], oxyethylene (4) sorbitan monostearate, and 81 [polyoxyethylene (5) sorbitan monooleate].

d4 Polyoxyethylene fatty acid esters, such as polyoxyethylene stearate of known type commercially available under the trade name Mildi (Reference, Fiedler Vol. 12, p. 636), as well as cetiol (Get 1
ol) HE (Reference, Fiedler Vol. 11, p. 228) known polyoxyethylene fatty acid esters and polyoxyethylene aliphatic alcohol ethers, such as Brino (BrijX reference,
Polyoxyethylene stearyl ether, oleyl ether or cetyl ether, such as Breasif 8 and 96, of known types, commercially available under the trademarks of Fiedler, Vol. 11, pp. 184-186), and Cetomacrogel 1000 (Ref. , Fiedler, Vol. 11, p. 229).

d5 Commercially available, for example, under the trade names Pluronic and Emkalyx (Reference, Fiedler Vol. 12, 720-72
Page 2) Polyoxyethylene-polyoxypropylene copolymers of known types.

d6 Sorbitan fatty acid esters of known types, such as those sold under the trade name Span, such as sorbitan-monolauryl, -monobalmityl, -
Monostearyl, -tristearyl, -monooleyl and mono-trioleyl esters (reference, Fiedler-1
2, pp. 850-8'51).

d7 Partial glycerides, e.g. products containing mono- and/or di-glyceride components, e.g. mixed mono-
/G/Trieglyceride/Free glycerin-based surfactants and, for example, glycerin monostearate and glycerin monooleate. Examples of such products include the known products marketed under the trade name Imwitor (see Fiedler Vol. 11, p. 491), such as Invitor 191 and Impitor 80, and the trade name Softigen. i
gen) (Reference, Fiedler Vol. 12, p. 833),
For example, there is Softigen 701.

d” Ionic surfactants or emulsifiers, such as sodium lauryl sulfate and sodium ketostearyl sulfate.

If component (d) is present, it preferably accounts for at most 30%, more preferably at most 15%, based on the total weight of the composition.
% or less. Most preferably component (d) is
It is present from about 0.5% to about 10%, such as about 1.0%, based on the total weight of the composition.

Also, those compositions preferably include e) Thinner Contains.

Suitable components (e) include, for example, the following substances:

el For example, the trade name Eudispe
rt) (Reference, Fiedler Volume 1L, pages 371-372).

e2 For example ethyl-, propyl-, methyl-, hydroxy-, propylmethyl- and carboxymethyl-
Cellulose derivatives containing cellulose.

e3 Polyvinyl resins, including for example polyvinyl alcohols and polyvinylpyrrolidones, as well as gelatin, alginate, pectin, gum tragacanth, gum arabic, gum xanthan and polyacrylic acids, such as the trade name Carbopol (Reference, Fiedler Vol. 11, Other polymeric materials, including known products commercially available (pages 206-207).

e4 For example silica gel, bentonite and magnesium-aluminum silicate materials.

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. Most preferably, component (e) is present in an amount of about 0.5% to about 15%, such as about 1.0% to about 3.0%, based on the total weight of the composition.

Furthermore, these compositions suitably contain an antimicrobial agent, such as methylparaben, propylparaben, benzalkonium chloride or benzyl alcohol, in an amount of, for example, 0.05 to 0.5% relative to the total weight of the composition. Or, in the case of benzyl alcohol, it is contained in a proportion of 2.0% or less, for example, about 0.1%, or in the case of benzyl alcohol, in a proportion of 1.0%.

Alternative carrier media include, for example, hydrophobic materials that meet the solubility criteria for the active ingredient. Further preferred compositions of the invention, for example for topical application, therefore include C''a) orthorhombic, preferably non-solvating orthorhombic cyclosporins, such as CY-A/X-[[, such as the above-mentioned A -A', and f) a hydrophobic carrier, for example as described above.

The amount of component (a) present is preferably the amount mentioned above for the composition according to item 01. Appropriate ingredients (``) include
For example petroleum derivatives, such as mineral oils, fats and jellies, such as petrolatum (mineral fats or petroleum jelly), liquid petrolatum (liquid paraffin or liquid paraffin)
, or the trade name Vaseline (Vasel 1neX reference,
Fiedler 1 supra, vol. 2, p. 986), as well as non-ionic lanolin-based derivatives, such as those sold under the trade name Amerchol, e.g. Amerchol. CAB (Fiedler Vol. 11, pp. 119-120).

Further suitable components (f) include, for example, natural or saturated vegetable oils and fats, such as Miglyol.
) known fractionated Cocoyashiura, such as Miglyol 812 (Reference, Fiedler Vol. 12, 6
p. 16) and peanuts and saturated peanut oil, and higher aliphatic or branched chain alcohols and aliphatic esters,
For example, stearyl alcohol, cetyl palmitate and 2-octyldodecanol [Eutanol]
nol) G (Reference, Fiedler volume 11, page 375)
There is a well-known commercially available product under the trade name of

These compositions also contain the components (d) and (e).
and, for example, one or more of the antimicrobial agents mentioned above.

In particular, these compositions further comprise one or more components (d) in an amount preferably not more than 30% by weight, more preferably not more than 20% by weight relative to the total weight of the composition; It may suitably be present in an amount of about 1 to about 15% by weight.

Furthermore, the composition with a hydrophobic base containing the emulsifier component (d) described in C2 can be produced in the form of a cream or emulsion by further adding water. The resulting cream or emulsion may be of either oil-in-water or water-in-oil type. That is, the amount of water present in those compositions may vary, for example, from 5 to 80%, preferably from 20 to 70%, relative to the total weight of the composition.

When component (e)/antibacterial agents are mixed, their amounts are:
The values are the same or of a similar order to those stated for the composition of the invention described in cl above.

The dosage of topical forms will, of course, vary depending on the concentration of the composition, the condition to be treated and the desired effect, and, in the case of dermal application, the area to be covered. For skin application compositions, for example in the treatment of psoriasis or atopic dermatoses,
Generally, the dosage will be from about 001 to about 5 H/c1, e.g. about 0,5
This amount is sufficient to provide a dose of ncrosvorin on the order of xtg/cm'. For ophthalmic formulations, administration is preferably once per day.
It may be practiced with a formulation containing about 0.1 to about lθ%, such as 1.0 or 2.0% by weight, of cyclosporin, applied in eye drop form to each eye ~3 times.

(injectable forms, e.g. for subcutaneous, intramuscular or other parenteral injection, e.g. especially intra-articular injection, e.g. in the treatment of joint diseases, e.g. rheumatoid arthritis, or intralesional injection, e.g. in the treatment of psoriasis) Compositions such as suitable dispersions, suspensions, emulsions etc. can be prepared according to known techniques commonly used in the art, for example by adding suitable emulsifiers, surfactants, stabilizers or flocculants, etc. Particulate orthorhombic forms of cyclosporine may be prepared by dispersing, suspending, or otherwise dispensing the particulate orthorhombic form in a suitable liquid carrier medium. Preferably the cyclosporine component in those compositions has an average particle size of <100 μM, more preferably 50 μM, and most preferably 20 μM. Preferably the average particle size ranges from 0.1 or 0.5 up to the indicated 20.50 or 100 μM maximum.

The use of large particle sizes is possible, for example when it is intended to achieve a devo-action, for example in injectable forms for subcutaneous or intramuscular injection. If their form is intended for intralesional application or especially intraarticular injection, the use of even finer particle formulations is indicated. In these uses, suitable average particle sizes are, for example, in the range of about 0.1 or about 0.5 to about 20 μM, such as about 5 to 15 μM.

In order to stabilize the particles in injectable form, for example to avoid increasing the size of large crystalline particles at the expense of smaller particles, it is preferred that the particles have as uniform a size as possible. Preferably the variation between maximum and minimum particle size is about 50 μM, more preferably about 20 μM
not exceed.

Achieving the desired particle size using suitable grinding methods, e.g. micronization, minimizes particle size variations, avoids the presence of fragmented particles, avoids modification of crystal surfaces, and improves, e.g. wetting properties. - For boat fishing, it is possible to maintain and more easily meet the required sterility requirements - for boat fishing, it is possible to use unground microcrystals, i.e. crystals grown to such an extent that they meet the desired size requirements mentioned above. Use is preferred.

That is, the injectable composition according to the invention comprises C3a)
Fine-grained orthorhombic form, preferably unsolvated orthorhombic form of cyclosporin, such as CY-A/X-■, such as the above-mentioned A
-A', particularly those described in paragraphs A6 and A7 above, suitably comprising b) distributed or distributable in an injectable carrier medium.

Suitable carrier media include, inter alia, pharmaceutical water.

Furthermore, the composition according to item 03 preferably contains g) a surfactant, such as a dispersant or an emulsifier and/or a flocculant, to assist or maintain the distribution of the particles throughout the carrier phase.

Suitable surface-active ingredients (g) include polyoxyethylene-
Sorbitan fatty acid esters or polysorbates, such as those described in section (d3) above, such as Tween 80 or polysorbate 80 (reference, Fiedler Vol. 12,
746 pages). Suitable flocculants (g) include ethylenediaminetetraacetate and its salts, such as calcium EDTA and sodium EDTA, and other equivalent chelating agents, and peptidizing agents, such as succinic or (citric acid).

Stabilizers are also preferably incorporated to maintain particle size distribution. Suitable stabilizers include, for example, gelatin or modified gelatins, such as gelafundin (Gela
fundin) and Haemaccel
) known whey (plasma
) Cold water soluble gelatin is a bulking agent or highly purified collagen hydrolyzate.

The composition according to C3 above may also contain one or more antimicrobial agents, such as said antimicrobial agents, and a peptidizing agent, such as succinic acid or citric acid.

The ratio of components (a):(b) in the composition described in C3 above is suitably in the range of 1:10 to 1:1000, preferably in the range of 1:50 to I:200, for example about 1= 1
00 (weight ratio).

In order not to interfere unduly with particle stability, the surfactants present as component (g) are preferably present in very low concentrations, e.g. 0.1-2.0% relative to the weight of component (a), preferably is present at a concentration of about 1% by weight. If a flocculant is present,
The weight ratio of flocculant to component (a) is preferably from 1:3 to 1:
8 degrees, for example about 1:5 (weight ratio). If a stabilizer is present, the ratio of component (a) to stabilizer is preferably l:
About 5 to 1:30, more preferably 1:10 to 1:3
0, for example a weight ratio of approximately 1=20. When a peptidizing agent is present, the ratio of other peptide agents to component (a) is preferably about 1:I to 1:10, for example about 1:15.

Of course, the amount of cyclosporine present in the injectable unit dosage form according to the invention will depend, for example, on the condition being treated, the site of injection and the desired effect, e.g. whether devo-action or relatively rapid release into the surrounding tissue is desired. It depends.

Preferably individual unit dosage forms! Approximately 10~ per dose
50o119, especially about 20 to 10 (lyy) of cyclosporin.

The unit dosage form according to the invention can also be used in combination systems such as double chamber syringes or injection parts (i.e., the particulate cyclosporine is held in the first chamber together with other suitable ingredients, such as stabilizers or antimicrobial agents, and the carrier medium is is held in a second chamber), and it is also conceivable that the components of the two chambers are mixed, for example by moving the plunger of a syringe. These double chamber syringe systems are well known in the industry and
It is to be understood that unit dosage forms containing them are also included within the scope of this invention.

(Oral dosage forms, e.g. for the purpose of preventing transplant rejection, e.g. in the treatment of autoimmunity and other diseases and conditions mentioned above) As mentioned above, oral dosage forms according to the present invention are of general interest and less preferred. Although not limited, these forms are also within the scope of this invention.

Oral dosage forms according to the invention may be prepared using suitable carriers or carrier media that are well known and in practice in the art. Liquid or semi-solid oral dosage forms are suitable, for example for orthorhombic cyclosporine, e.g. CY-A
/X-III with a pharmaceutically acceptable diluent or carrier, provided that the crystalline form is itself insoluble or substantially insoluble. These carriers and diluents include, for example, transesterification products of natural vegetable oil triglycerides and polyalkylene polyols as described in (dl) above, such as labrafyl, and natural or hydrogenated castor oil and ethylene oxide as described in (dl) above. and, in particular, liquid cremophor products such as cremophor BL.

Cyclosporine preferably has a 0.5 to 200
μM1, especially about 0.5 to 30 uM, preferably 2
It is present in fine particle form, developing an average particle size of less than 0 μM, such as 0.5-10 μM.

For convenient administration, the composition is preferably filled into hard or soft gelatin capsules.

The unit dosage form for oral administration according to the invention preferably comprises 1
Contains from about 25 to about 75, or less than 200, such as about 50 or 10019 cyclosporins per unit dose. Administration of these forms, e.g., 1 to 4 times per day, results in serum cyclosporine concentrations (e.g.,
(measured by radioimmunoassay) is achieved.

The components described or indicated in this specification as constituents of the pharmaceutical compositions according to the invention are suitable for the required pharmaceutical application, e.g. in the case of components of compositions for oral administration. It is to be understood as acceptable or, in the case of a component of a composition for topical administration, as capable of being applied topically, eg dermatologically or ophthalmically, as acceptable or tolerable.

Additionally, formulations for administration by equivalent or alternative routes to those described above will be apparent to those skilled in the art.

Hereinafter, various aspects of the present invention will be explained with reference to examples.

[Example 1 Preparation of CY-A/X-III a) 100 g of amorphous cyclosporin was heated at 50'C for 4 hours.
009 in polyethylene glycol 300 with stirring. Immediately after dissolution is completed, CY-A/X-111
1 begins to form. Leave the solution for about 35-40 hours for 24-48 hours.
C. to complete crystallization, then diluted with 1000.times.f water without vigorous stirring. The resulting precipitate was separated by filtration and H.

Washing with 0 to remove residual polyethylene glycol and drying yields CY-A/x-■ in substantially pure form. tap = 195°C, particle size - approx. 100-2
The 00 μM0 CY-A/X-m form can also be produced using the same procedure as above, but using the following materials as solvents instead of polyethylene glycol 300.

b) Polyethylene glycol 300/Cremophor RH40 (1:1 volume ratio)-1-C) Cremofu*-EL190 d) Tsurutol HS15 188e) Jerusha 44/14 180r) Milzi 52
184g)) Vienna 80
凰86h)Fure%7t-RH4019
0 winter case, the average particle size obtained is approximately 50 to
It is about 200 μM. The measured lattice structure is as described above. XllA diffraction data are shown in Table 3 and FIG. 4 below.

Example 2 Preparation of CY-A/X-[209 Cyclosporine (as CY-A/X-I) was dissolved in 60yQ of ethanol and reduced to one-sixth of its original volume by distillation under reduced pressure at >60°C. Concentrate. Then 16
0d polyethylene glycol (molecule 1i300) +
Slowly add 20x (l of H,O) at 50-85°C while stirring at 30 rpm.

Install an ultrasonic vibrator/stirrer and run at 20,000 cpC. Nucleation is initiated over a period of 3-5 minutes at 65-75°C. Next, the obtained dispersion was heated at 700 r
Continue stirring and ultrasonic vibration at 10-2 pm.
Cool linearly to 40°C over 0 minutes. The resulting thick pasty mixture was filtered, rinsed with polyethylene glycol (molecular weight 300)/H,0 (3:l, volume ratio), washed with warm water (30 °C) and dried on high vacuum at 50 °C. , CY-A/X-II [ is obtained in pure form (mp = 192 °C, particle size = 3-15 μM). The measured lattice structure is as described above. X-ray diffraction data are shown in conjunction with Table 3 and FIG. 4 below.

Repeated experiments showed that crystal size was influenced by the nucleation temperature and crystal growth rate rather than the duration of the process. That is, by starting nucleation at about 75° C. and continuing crystallization at the same temperature, an average crystal grain size of about 50 μM is obtained.

Example 3 Production of a formulation for oral administration 3.1 Gelatin-encapsulated formulation I A suspension containing CY-A/X-III (20% by weight) obtained according to the procedure of Example 1 was added to Gelucia 44/14.
Average CY-A/X-I [[Particle size is 0°5-1
Grind at high temperature using a colloidal mill until it reaches approximately 0 μM. Nine amounts of 250JI of the resulting ground suspension are charged into hard gelatin capsules (size 2). Each contains 50zy cyclosporin (CY-A/X-II) as an active ingredient.
as I).

3.2 Gelatin-encapsulated preparation■ CY-A/X-■ obtained according to the procedure of Example 1
, the average CY-A/X-l11 particle size is 0.5~
Grind with a colloidal mill until it reaches about 20 μM. The 50u quantity is then intimately mixed with 2009 Taremofo-EL and filled into hard gelatin capsules (size 2).

Each contains 50 cyclosporine (CY-A) active ingredients.
/X-I [as 1].

Example 4 Manufacture of topical formulation 4.1 Gel formulation! C Y-A/X-■ obtained according to the procedure of Example 1 is pulverized using an air jet mill.

By combining the micronized product with a maximum particle size of 60-70 μM and an average particle size of 2-10 μM and mixing in the conventional manner with the ingredients shown in the table below, a product suitable for topical application in the treatment of psoriasis, for example, can be prepared. An aqueous gel containing 10% by weight of cyclosporin (CY-A/X-■) is obtained.

Ingredients Weight %a) Cyclosporin (micronized CY-A/X-In) 10.0b) Polyacrylic acid (Carbobol 934P) 0.5c) NaO
H solution (5%)3. .

d) Methylparaben 0.070) Propylparaben 0.030HtO (for pharmaceuticals) Add appropriate amount to 100.0% 4.2 Gel formulation ■ Ingredients Heavy weight % Composition ^
Composition B a) Cyclosporine (micronized CY-A/X-DI) 10.0 1
．． Ob) Polyethylene glycol 300 30.0 30. Oc) Lavra Ile M2130C81,01, Od) Carbo Ball 934P 1.0 1. Oe) Sodium hydroxide 5% 6.0 6. Of) Methylbarabea 0.07 0.07g) Propylparaben 0.03 0.03h) I(to (for pharmaceuticals) 51.9 60.9100.0
% 100.0% a) is produced in the same manner as in 4.1 above. C), f)
and g) are dissolved in b) with warming and the resulting mixture is cooled to room temperature. This solution is then dispersed in water h). Add d) and homogenize the whole to perform dispersion. Add a) and homogenize the mixture again. e)
12 and the resulting gel is filled into collapsible tubes used for topical application in the treatment of psoriasis, for example.

4.3 Ointment formulation ingredients Weight % to composition
Composition B a) Cyclosporine (micronized CY-A/X-I [1) 1.0 1
0. Ob) Amarcall CAB 2.0
2. OC) Liquid paraffin 42.0 37
．． 5d) White petrolatum 55.0 50.
5too, o% 100.0% a) is manufactured according to the procedure of 4.1 above. Dissolve b), C) and d) together and stir, add a) at about 30°C and distribute the particles using a homogenizer. The resulting ointment is cooled and filled into collapsible tubes used for topical application, for example in the treatment of psoriasis.

4.4 Cream formulation components Weight %a) Cyclosporin (micronized CY-A/X-111) 1.0b) Polysorbate 60 5.OC) Cetylstearyl alcohol 10. Od) Glycerin 85%
l01Oe) White petrolatum
24, Or) Methylparaben
0.078) Propylparaben 0.0
3f) H, O (for pharmaceuticals) 49.0
100.0% 4 above. ! Prepare a) according to the procedure 4 and 3 above and combine components b) to h) and fill into collapsible tubes used for topical application in the treatment of psoriasis, for example.

4.5 Ointment formulation 20% by weight CY-A in polyethylene glycol 300
/X-1 (obtained according to the procedure of Example 1) with an average CY-A/X-III particle size of 2 to
Pulverize by immersion until the concentration is about 10 μM. 10 g of the obtained pulverized product was mixed with 509 polyethylene glycol 300 and 409 molten polyethylene glycol 15 in a conventional manner.
When mixed with 00, it is used for example in the treatment of psoriasis.
10% by weight cyclosporine (CY) suitable for topical application
A water-dispersible thick suspension paste is obtained containing -A/X-■).

4.6 Gel formulation components Weight % a) Cyclosporine (micronized CY-A/X-1) 1.0b) Labrafil M1944CS I, OC)
Polyethylene glycol 300 30.0d) Benzyl alcohol! , Oe) Hydroxypropyl methylcellulose (Methosel E4M) 2,5''
) HtO (for pharmaceuticals) 64.510
0.0% a) is prepared as in 4.1 above. b), C)
Mix and d), add r) and mix. Then a
) is suspended in the mixture produced by homogenization. Then add e) slowly with stirring until gel formation is complete. The gel is then filled into a collapsible tube for topical application, for example in the treatment of psoriasis.

4.7 Gel formulation components Weight % a) Cyclosporin (micronized CY-A/X-III) 5,0b
) Polyethylene glycol 300 30. OC) Glyceryl monostearate 5. Od) Methylparaben 0.07e) Propylparaben
0.03f) Carbo Ball 934P
1.0g) Sodium hydroxide 5%
6.0h) I(, O (for pharmaceuticals)
52.9100.0% Produce a) according to the procedure of 4.1 above. Dissolve C), d) and e) in b) while warming. The warmed mixture is dispersed in h) by homogenization and cooled to room temperature. Then add a) and r) and homogenize the whole. g) is then added to complete the gel formation. The resulting gel is filled into collapsible tubes for topical application, for example in the treatment of psoriasis.

4.8 Cream formulation (water in oil) Ingredients Weight % a) Cyclosporine (micronized CY-A/X-I [1) 2,0
b) Amarcor CAB 5. O.C.)
Miglyol 812 10. Od) White petrolatum 53. Oe) Ht 2 O (for pharmaceuticals) 30.0100.0% a) is prepared in the same manner as in 4.1 above, warmed and homogenized, and then dispersed in e) by b).

C) and d) are melted together, mixed, the mixture is added to the dispersion obtained earlier with strong homogenization and the whole is cooled to give a fatty white cream. This is filled into a collapsible tube for topical application, for example in the treatment of psoriasis.

4.9 Gel/Cream Formulation Examples 4.1-4.8 above are repeated, but using the crystalline product of Example 2 directly as the cyclosporine component.

Example 5 5.1 Injectable forms for e.g. parenteral application A CY-A/X-■ suspension is prepared under sterile conditions by conventional techniques using the following ingredients.

Component Weight (Town Oa)
Cyclosporine (CY-A/X-111) 2
0.0b) Polysorbate 80 4. O
C) Carboxymethyl cellulose sodium 5.0d) Na
C(! 9.O
e) Benzyl alcohol 9.0r)H
,0 (for injection) The active ingredient release characteristics of the resulting formulation with a final volume of 1.06 depend on the average particle size of component a). That is, when long-term action is required, C Y-A with a large average particle size
/X-III product (eg, 100-200 gM obtained directly by the procedure of Example I) is selected. When action over a relatively short period of time requires, C Y -A/X-III products having a relatively small average particle size (e.g. obtained by micronization or grinding of the Example 1 product, e.g. particle size 0 .5-10 gM) is selected. The suspension obtained is filled into injection ampoules for parenteral administration or intralesional injection in the treatment of psoriasis, e.g. to provide a devoting effect.

In a particularly preferred embodiment, this example corresponds to Example 2 above.
CY-A/X-1 (manufactured under sterile conditions) with a particle size of 5-15 μM, prepared according to I.

5.2 Injectable Forms For Intra-Articular Injection Injectable forms suitable for intra-articular administration are prepared using the following ingredients.

Ingredients Heavy 1i C119
) Composition A a) Cyclosporine (CY-A/X-I [I)
10.0b) Sodium carboxymethyl cellulose 10.0c) Na
EDTA 2.0d)H*
0 (for injection) Composition Ba with a final volume of 1 OmQ a) Cyclosporin (CY-A/X-l11)
10.0b) Polysorbate 80
0.1c) Citric acid 2.
0d) H*O (for injection) Final volume 1, 0 m
(1) is carried out according to standard techniques under aseptic conditions. Ingredient (a) is an unmilled micronized powder having a particle size of 3-15 μM, prepared under aseptic conditions according to the procedure of Example 2. The resulting composition is again filled under sterile conditions into ampoules for injection, for example for intra-articular injection used in the treatment of rheumatoid arthritis.

The advantageous properties of the composition according to the invention can be demonstrated in animal test models and in the clinic. Thus, the special utility of the compositions according to the invention intended for dermal application, for example in the treatment of psoriasis or skin diseases, can be demonstrated in the following test models.

Allergic contact dermatitis in guinea pigs (DTH test) Guinea pigs (Hartley, male, 400-
500g). After 7 days, animals are re-treated by applying 820 μg of 0.5% DNF in acetone/olive oil (1:4) to the marked areas of the shaved right and left flanks.

This second challenge exposure induces allergic inflammation, leading to redness and cellular infiltration (thickening) of the skin.

200-250. A quantity of w9 of the test composition is applied with a spatula to the DNFB treated area of the right flank. The left flank is treated similarly with a placebo as a control.

Application of test composition/bracebo was carried out for 20 minutes after challenge at 8
5 times at intervals of 1 hour, 24 hours, 32 hours and 48 hours. The skin thickness at the application site is measured before each application and again 8 hours after the final application by folding the skin and measuring its thickness. The degree of redness or inflammation is also visually evaluated on a scale of 0 to 4. The effectiveness of the test formulation in preventing inflammatory reactions is determined by comparison with the results recorded for the placebo-treated flank.

Compositions according to Examples 4.1 and 4.5 above (provided that
Comparison of the results obtained in the above test model with O, tii% cyclosporine (containing CY-A/X-m) with placebo and with topical application of O 91% cyclosporine regular liquid form The results are shown in attached drawing 1.
．． Shown in Figures 2 and 3. (In this test model, 0.1%C'l-A/X-1
111 concentration is used. The test compositions were exactly as in Examples 4.1 and 4.5, but the cyclosporine component was reduced to 0.19, and in the case of Example 4.1 water,
and in the case of Example 4.5, by supplementing the polyethylene glycol component by adding 9.9 g each.

) In each figure, the measured skin thickness is plotted against time. FIG. 1 compares the results with 0.1% by weight Ncrosvorin, commonly applied in the conventional commercially available oral drinkable liquid form, with that of a placebo. A small but insignificant decrease in response is shown with the oral solution compared to the placebo. In Figures 2 and 3, 0, 1% by weight according to Examples 4.1 and 4.5, respectively.
Results using cyclosporine-containing compositions are compared to those of Bracevo. In both cases, a significant reduction in skin thickness compared to placebo is achieved after the first application and throughout the treatment period until the end of the experiment.

Further, the usefulness of the composition according to the present invention can be demonstrated, for example, in a clinical trial conducted as follows.

Clinical Trial: Treatment of Psoriasis by Topical (Skin) Application This trial will be conducted in a randomized, bracebo-controlled, double-blind design.

Each patient receives the active composition and placebo (vehicle only) simultaneously in two symmetrical lesions. Assignment of active and placebo compositions will be randomized to left and right lesions.

Selected subjects are taken in groups of 12 to 24 patients, including men and women (postmenopausal, surgically sterilized or using oral contraceptives, with negative pregnancy tests) aged 18 to 70 years.

Inclusion criteria include a) documented consent and b) clinically defined, stable chronic plaque psoriasis. Requires at least two moderately to severely symmetrical lesions;
Each has an area of 4 to 25 CI” and a severity score of >5 on a scale ranging from 0 to 9. This score ranges from 0 (the mildest) to It is a composite of individual scores of 3 (most severe).

Bilateral lesions must be comparable within the same patient (i.e., 20% in severity score or area).
(There is no difference exceeding .)

The following exclusion criteria apply:

a) Medical conditions that, in the investigator's opinion, affect the study.

b) Systemic psoriasis treatment (puvA1 methotrexate, steroids, retinoids, cyclosporine) within the last 2 months.

C) Specific topical treatment at the lesions selected for the study within the last two weeks before the start of the study [irrelevant substances e.g.
white petrolatum) or salicylic acid-containing preparations (10% or less)].

d) Patients whose psoriasis appears to be improving spontaneously, expanding without treatment, or reversing upon discontinuation of treatment.

e) Known hypersensitivity to the test pharmaceutical ingredient.

r) Uncooperative patients who do not seem to follow the doctor's instructions accurately or who are unwilling or unable to undergo regular check-ups.

g) Treatment with an experimental drug within one month prior to study entry.

h) Severe concomitant diseases, especially renal insufficiency with serum creatinine above 130 micromol/12.

i) Hypertension (diagnosed blood pressure >95 mmHg after 5 minutes in sitting position)
). Patients whose hypertension is controlled with medication will be included in the trial.

j) Malignant tumor or history of malignant tumor, including skin cancer.

k) Acute bacterial, viral or fungal related skin lesions.

l) Pregnancy and lactation period.

l) Patients with a history of alcoholism, drug abuse, mental illness or emotional or intellectual problems.

n) other immunosuppressants, chemotherapeutics, compounds with nephrotoxic potential (e.g. aminoglycosides) and drugs known to interact with the pharmacokinetics of cyclosporin (ketoconazole, erythromycin, phenytoin, Patients requiring continuous concomitant treatment with phenobarbitone, rifampicin, INH, carbamazepine, sodium palproate).

0) Patients presenting with abnormal baseline test values >15% outside normal limits in the testing laboratory.

p) Patients with clinically significant findings on physical examination.

The test compositions used were those of Example 4 above. ! ~4.9. Example, Example 4.2-1
% Composition B or lθ% Composition B0 of Example 4.3 Each patient receives a set of 209 coded tubes with 2-panel labels. The color of the label shall be blue for substances to be applied on the right side and red for those on the left side. In addition, write the left or right side to be treated, study code, study name, patient number, and treatment start date on each panel of the label. Attach the label cutout panel to the case record form.

The study drug is applied twice a day, in the morning and in the evening, with application 1
The amount varies depending on the size of the lesion and gives a daily cyclosporine dose of 0.2 to 2.01 (cyclosporine) 7 cm'' (e.g., approximately 0,5 cm per Icx'' in a series of studies).
mg of cyclosporine). Blasebo is applied in equal amounts. Neither the test composition nor the bracebo will be applied to body surfaces larger than 25 C1'' and no more than 19 cyclosporine will be applied per week. For each clinical diagnosis, weigh the medication/bracebo tube and calculate the topically applied daily dose. Avoid cross-contamination by wearing disposable gloves and changing between each application of test composition and placebo. Allow at least 3 hours to elapse between administration and cleaning of treatment area.

Monitor initial application and give patient instruction sheet. Treatment duration is 4 weeks. If complete or complete clearance of the lesion occurs earlier, treatment is continued until week 4. Patients are examined before the start of the study (Week 1), at the start of the study (Week 0) and at Weeks 1, 2.3 and 4 after the start of the study.

Dermatological evaluation (local psoriasis severity index or LPS)
I) will be assessed by the same investigator not involved in the drug therapy using the 0-3 numerical scale described below.

Erythema Catechism Skin thickness 〇-None 〇-None 0=None.

Total LPS I range 1 erythema + scale 10 thickness 1 θ to 9 values are evaluated. At least two symptoms must be moderate to severe in both selected lesions (LPSI>5) to initiate the study.

At the start and at each clinical diagnosis, the treated lesion area is evaluated (starting size: 4 to 2
5 cm. Areas are evaluated by the presence of one or more of three criteria: erythema, size, and thickness. Pigmentation within the lesion area is not considered in area evaluation.

Plaques are photographically recorded before (1st week) and after (4th week) treatment. Three photographs are taken, one showing both lesions together and one showing each lesion.

Rate the photos from the patient interview using the scale below.

0=none.

! = Minimal: Occasionally scratches impulsively.

2 = Moderate: Frequent compulsive scratching.

3- Severe: Very frequent and compulsive scratching, sleep may be disturbed.

At the end of the study, an overall evaluation of the treatment will be performed according to the following criteria.

One wipe - 100% dissipation.

One significant improvement = at least 66% reduction in LPSI and/or at least 66% reduction in plaque area.

- Moderate improvement - 65% to 33% reduction in LPSI and/or 65% to 33% reduction in plaque area.

−2 new improvements = less than 32% reduction in LPS I, and/
or less than 32% reduction in plaque area.

- Exacerbation - flare-up of the disease.

Treatment success is defined as when the lesion is "cleared" or exhibits "significant improvement."

Physicians and patients also indicate a preference for left- or right-sided drug effects according to the criteria below.

・The left side is clearly better.

・The left side is slightly better.

・Differences cannot be detected.

・The right side is slightly better.

・The right side is clearly better.

To test efficacy at the end of treatment, the target LPS
Compare I scores and lesion areas.

All further comparisons (comparisons at other time points and remaining parameters of efficacy), including their associated p-values, are taken as a record of the study progress.

In the above study, subjects showed that the side to which the cyclosporine-containing composition was applied compared to the side to which the placebo was administered;
There is a significant improvement in psoriatic lesions, such as significant improvement in LPS I scores for erythema, size and skin thickness. Subjective improvement was also noted, along with an improvement in recorded itch values on the cyclosporine treated side compared to the placebo treated side.

Positive results are also obtained in parallel design studies in subjects presenting with contact dermatitis diagnosed according to three or more of the following criteria.

- Itching, - Typical organization and distribution: soft or linear flexural lesions in adults, combined facial and extensor lesions in infants and children, - chronic or chronically recurrent dermatitis, - atopic dermatitis (asthma, allergic Personal or family history of rhinitis, atopic dermatitis), xerosis, ichthyosis/palmar hyperplasia/keratosis pilaris, immediate (type I) skin test reactivity, high serum IgE, disease onset. young onset (5 years old), skin infections [especially Staphylococcus aureus]
, aureus) and acne simplex]/damaged cell (mediated) immune tendency, non-specific pediculitis or foot dermatitis tendency, papillary eczema, cheilitis, anticanthus conjunctivitis, Denny Morgan's eyelid. Heki (infraorbital f
old), keratoconus, anterior supracapsular cataract, unclear orbit, facial pallor/erythema, white rash, anterior neck itching, swelling when sweating, hypersensitivity to wool and lipid solvents, perifollicular worsening, food sensitivities, course influenced by environmental/emotional factors and dermatographia albinism/delayed albinism (d
Add three or more of the small features, including (layered branches). The test period is 3 weeks and the parameters consisting of itching, erythema, exudation, epidermal peeling and lichenification are evaluated on a scale of θ~3.

1-10% cyclosporine-containing topical formulations as described in Examples 4.1-4.9 above, e.g. 5.0% according to Example 4.7.
The compositions have also been found to be effective in treating allergic contact dermatitis and alopecia.

From the foregoing, this invention also provides D. a method of administering cyclosporine or carrying out cyclosporine therapy in a subject undergoing or in need of treatment, comprising administering to said subject an orthorhombic form, particularly an unsolvated Orthorhombic cyclosporin (e.g. A-A7 above)
CY-A/X-I[
[as] a method comprising administering an effective amount of [as].

In a more specific embodiment, a method of administering Dl, immunosuppressive or anti-inflammatory therapy in a subject in need of treatment, comprising administering to said subject an orthorhombic form, particularly an unsolvated orthorhombic cyclosporine (e.g., as described above). A-
C Y −A/X − described in any one of A′
(as III) is provided.

Applications to which the above method may be applied include the use of cyclosporin, for example in the treatment of the diseases or conditions mentioned above in connection with the prevention of transplant rejection, in the treatment of autoimmune or rheumatic diseases, and in other diseases involving an undesirably high response of the immune system. or treatment of conditions, treatment of parasitic infections, treatment of chemotherapy resistance, such as reversal of tumor resistance to antitumor chemotherapy, and treatment of alopecia. The above methods are suitable for the treatment of diseases or conditions of the skin or eyes, such as psoriasis, atopic or contact dermatitis, corneal transplants, conjunctivitis and uveitis, in particular by topical administration and rheumatoid arthritis or other diseases of the joints by articular administration. or may be applied in the treatment of conditions.

The invention provides, in another aspect, E. a non-solvent-phasic orthorhombic cyclosporine for pharmaceutical use, e.g. as an immunosuppressive or anti-inflammatory agent, for use in the treatment of diseases or conditions as described above or with respect to Dl; For example, CY-A / Crystalline forms of cyclosporine, e.g. CY-A
/X-nl (for example, as described in any one of the above A-A').

To aid in the identification of orthorhombic cyclosporins, particularly CY -A/X -■, CY -A/X -II [as well as the two forms CY-A/X-1 and CY
- X-ray powder diffraction data regarding A/X-11 is shown below.
- Shown in Table 3. The attached FIG. 4 shows the X-ray powder diffraction diagram from which the data in Tables 1 to 3 were obtained. This diffraction diagram was obtained using a Guinea de Wolff ■ camera with CuKα radiation (λ-1,542 angstroms).

1. X-ray diagram 2 regarding Table CY-A/X-1
X-ray diagram for table CY-A/X-I+ 11 X-ray diagram for table 3 CY-A/X-II+ VS
-Very strong S-Strong M-Moderate

[Brief explanation of the drawing]

Figures 1, 2 and 3 are graphs comparing the commercially available product, the product of Example 4.1 and the product of Example 4.5, respectively, to Bracevo in a DTH test using a guinea pig model. Figures 4a, 4b and 4c are
It is an X-ray photograph showing powder diffraction of the crystal used in this invention. Patent applicant Sand Akchengesellschaft representative Patent attorney Aoyama Aoyama and 1 other person! 1 ko = 41st) Fgl Cy-A/X-11 2nd...K

Claims (23)

[Claims] (1) Unsolvated orthorhombic cyclosporine (Ciclos)
porin). 2. The cyclosporine of claim 1, having a crystal lattice in which: (2) a=12.7 angstroms, b=15.7 angstroms, c=36.3 angstroms, and volume per asymmetric unit=1804 cubic angstroms. (3) The cyclosporine according to claim 1, which exhibits the following X-ray diffraction characteristics. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ VS = Very strong. S=strong. M=moderate. (4) The cyclosporin according to claim 1, which does not contain any or substantially no other forms of cyclosporin. (5) Claim 1 is in pure or substantially pure form.
Cyclosporine as described. (6) Cyclosporin according to claim 1, which is in the form of microparticles. (7) Cyclosporin according to claim 6, wherein the constituent particles have an average particle size of <200 μM. (8) The cyclosporine according to claim 7, wherein the constituent particles have an average particle size of 0.5 to 200 μM. (9) Cyclosporin according to claim 6, wherein the constituent particles have an average particle size of <25 μM. 10. The cyclosporin of claim 1, wherein the cyclosporin is comprised primarily of, or is comprised entirely or substantially completely, of unground crystalline material. 11. The cyclosporin of claim 6, wherein the constituent particles are comprised primarily, or completely or substantially completely, of non-ground microcrystalline material. (12) Claim 1 is sterile or substantially sterile.
Cyclosporine as described. (13) A pharmaceutical composition containing a) orthorhombic cyclosporine as an active ingredient, and b) a pharmaceutically acceptable diluent or carrier. 14. The pharmaceutical composition of claim 13, wherein cyclosporin is present in the composition primarily or completely or substantially completely in orthorhombic form. 15. The pharmaceutical composition of claim 13, having at least one compartment or phase comprising orthorhombic cyclosporin, and wherein the crystalline form is distributed or distributable throughout the compartment or phase. (16) The pharmaceutical composition according to claim 13, which contains unsolvated orthorhombic cyclosporine. (17) The pharmaceutical composition according to claim 13, which is in the form of a water-dispersible concentrated suspension that can be applied topically or by injection or infusion. (18) 0.05 to 30% by weight based on the total weight of the composition
14. The pharmaceutical composition according to claim 13, comprising cyclosporin. (19) A method of administering cyclosporine or performing cyclosporine treatment in a subject undergoing or in need of cyclosporine therapy, the method comprising administering to the subject an effective amount of orthorhombic cyclosporine. (20) A method for administering immunosuppressive or anti-inflammatory treatment in a subject in need of treatment, comprising administering to said subject an effective amount of orthorhombic cyclosporine.
9. The method described in 9. (21) The method according to claim 19, wherein the cyclosporin is a nonsolvating orthorhombic cyclosporin. (22) The method according to claim 19, wherein the administration is local or by injection. (23) Claim 19, wherein the administration is by topical ocular or dermal application, or intralesional or intraarticular injection.
Method described.