CH677926A5 - - Google Patents

Description

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description

The invention relates to new pharmaceutical compositions containing ciclosporin as an active ingredient.

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

~ MeBmt-ceAbu-Sar-MeLeu-Val-MeLeu-Ala- (D) Ala-MeLeu-MeLeu-MeVal-j 1 2 3 4 5 6 7 8 9 10 11

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

In the solid state, ciclosporin occurs in both amorphous and crystalline form. Both a tetragonal modification and an orthorhombic modification are known as crystalline forms.

The tetragonal modification (P4i), which for the sake of simplicity is also referred to herein as CY-A / X-I, is described together with processes for its preparation, for example in AT-A 353 961. CY-A / XI has a crystal lattice with a = b = 13.8 x 10-10 m and c = 41.2 x 10-1o m, has a volume per asymmetry unit of 1974 x 10 ~ 30 m3, has one Melting point of about 140 to 150 ° O and contains about 2 molecules of H2O per molecule of ciclosporin.

A first orthorhombic modification (P2i2i2i) can be obtained by crystallization from diisopropyl ether, and for this purpose R. Wenger's treatise entitled "Total synthesis-change in molecular structure - biological effect: Cyclosporin as example" in Sandorama 1984 / 111 pointed out. This special treatise is a solvate of ciclosporin and diisopropyl ether (ratio about 1 to 2) with a crystal lattice of a = 12.5 x 1 (H ° m 22.9 x 10-1 ° m and c = 28.4 x tO-10 m, a volume per asymmetry unit of 2027 x 10-30 m3 and a melting point of about 150 ° C. Orthorhombic ciclosporin solvate crystals can be recrystallized from supersaturated solutions of ciclosporin in a suitable solvent medium over a longer period The modification of orthorhombic ciclosporin / dilsopropyl ether solvate made by Wenger can therefore be obtained by adding a concentrated solution of ciclosporin in methylene chloride (in which ciclosporin is fairly readily soluble) to diisopropyl ether (in which ciclosporin is relatively poorly soluble and the methylene chloride is then evaporated from this solution by allowing the methylene chloride freed from dilsopropyl ether crystallization then occurs over a period of about 7 days at ambient temperature. The orthorhombic crystal forms thus formed, which contain the solvates of ciclosporin obtained in this way, are also referred to herein as CY-A / X-II for the sake of simplicity.

A further orthorhombic modification (P2i2i2i) has now been found, which is characterized in that no or practically no solvent component is present in it, so that it consists practically or essentially of free cyclosporin.

The dimensions of the crystal lattice of this solvent-free or non-solvate orthorhombic modification of ciclosporin are a = 12.7 x 10 ~ 10 m, b = 15.7 x 10_1 ° m and c = 36.3 x 10-10 mi and this modification indicates a volume per asymmetry unit of 1804 x 10-30 m3.

The melting point of this crystal form ranges from about 180 to about 190 ° C and up to about 195 ° C, and depends, for example, on the degree of purity and starting material, as can be seen in Examples 1 and 2 below, in which Methods for producing this orthorhombic modification of ciclosporin are described. Ciclosporin in the form of these orthorhombic crystals, which are not a solvate and are therefore solvent-free, is also referred to herein as CY-A / X-I II for the sake of simplicity. Further characteristic data (X-ray diffraction values in powder form) for CY-A / X-III are shown in Table III below, and there are also the corresponding data for the modifications of ciclosporin with the designations CY-A / XI and CY-A / X-II specified.

According to the invention, it has now surprisingly been recognized that orthorhombic crystalline forms of cyclosporin, such as CY-A / X-II and especially CY-A / X-III, are particularly well suited for the preparation of pharmaceutical formulations of the most varied types of cyclosporin.

Above all, it was recognized that such crystal modifications can be used to produce pharmaceutical formulations which contain cyclosporin in a stable and finely divided form and / or which have better stability or have more favorable release characteristics. This opens the way to the production of new and better release systems for the active ingredient ciclosporin, by means of which this active ingredient can be released, for example, in an extended or delayed manner and / or by which diseases or conditions can be treated whose therapeutic treatment with ciclosporin was previously not possible or for which is a conventional thera2

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Treatment with ciclosporin inevitably was not particularly suitable. In particular, it has now been recognized that the use of such crystal modifications in, for example, the fine-particle form mentioned makes it possible to produce galenic forms which are suitable for topical or dermal use or for topical ophthalmic use, in order to thereby, for example, treat diseases or conditions of the skin or eyes described above Type of treatment, such as psoriasis, atopic dermatitis, contact dermatitis, ocular symptoms of Behcet's disease, uveitis and keratoconjunctivitis sicca. The use of such crystal modifications also enables the production of injectable forms of ciclosporin with prolonged or delayed release characteristics, so that these forms can be used above all for the treatment of diseases or conditions for which the necessary frequency of administration is otherwise an obstacle, such as, for example Treatment of arthritis and similar joint diseases by intra-articular injection or for the treatment of psoriasis or similar skin diseases by intralesional injection.

For such applications, orthorhombic crystal forms, and in particular CY-A / X-III, have proven to be inherently much more suitable than other available forms, such as, in particular, amorphous ciclosporin or CY-A / XI, mainly due to the special physicochemical Properties such as the stability, the release characteristics, namely the release of ciclosporin from the crystal lattice, and the particular balance of these crystal forms in relation to the measures necessary for the preparation of the pharmaceutical formulations. CY-A / X-III is a new and preferred orthorhombic crystal form which is used according to the invention for galenic and / or therapeutic purposes.

A first embodiment of the invention is therefore A CY-A / X-lil, namely ciclosporin in a non-solvated orthorhombic crystal form, above all

A1 CY-A / X-III with a crystal lattice or with other physical properties of the type practically defined above and / or

A2 CY-A / X-III with an X-ray diffraction spectrum in powder form of the type practically given in Table III

The invention also relates to

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

Suitable media containing CY-A / X-III can be used in the above process, especially solvent media for cyclosporin, which contain solvent components with a higher molecular weight, which have a molecular weight of over 200, for example. Higher molecular weight ethers, in particular polymeric ethers, for example polyalkyl ethers such as polyethylene glycols and polypropylene glycols, are particularly suitable as media. Examples of polymeric ethers which have proven to be suitable are polyethylene glycols and polypropylene glycols with, for example, a molecular weight of more than 200, glycerol polyethylene glycol esters, such as glycerol polyethylene glycol ricinoleates and glycerol polyethylene glycol oxystearates, as described, for example, under the trademarks Cremophor EL and Cremophor Lex (see Auxiliaries, 2nd edition, volume 1, pages 257 and 258) are available, polyoxyethylene sorbitan esters, such as are available, for example, under the trademark Tween (see Fiedler, volume 2, pages 972 to 975), polyoxyethylene esters, such as polyoxyethylene stearic acid esters, as they are For example, available under the trademark Myrj (see Fiedler, Volume 2, page 636), and transesterification products from natural oil triglycerides and polyalkylene polyols, including the transesterification products of corn oil, kernel oil, almond oil, nut meal oil, olive oil, palm oil and mixtures thereof with polyethylene glycols, in particular polyethylene glycols with a molecular weight of 200 to 800, as are available, for example, under the trademark Labrafil (see Fiedler, page 539). Particularly suitable media include polyethylene glycols with a molecular weight from about 200 to about 600, in particular from about 300 to about 400.

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

In the process according to the invention, ciclosporin, for example in amorphous or tetra-gonal form, is first dissolved in the selected medium containing CY-A / X-III at elevated temperature. The solution temperature naturally fluctuates depending on the medium chosen, and is generally above 40 ° C and in particular above 50 ° C. In the case of media based on polyethylene glycols, the solution temperature is generally above 70 ° C. and for example between about 75 and 130 ° C. The solution obtained advantageously contains over 5 percent, preferably over 10 percent, for example up to about 40 to 60 percent, and preferably up to a maximum of 20 percent by weight of ciclosporin, based on the total weight of the solution. The ciclosporin is then allowed to crystallize with cooling for a suitable and relatively long period of time, for example in the order of 10 to 35 minutes or more, depending on the desired crystal growth.

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If desired, core formation processes can also be initiated, such as sonication or inoculation. When using crystal-containing media based on ethanol, polyethylene glycol and water, as described above, nucleation can be carried out at temperatures of about 60 to 90 ° C, for example from 65 to 85 ° C, by using a sound vibration of about 20 Initiate 000 vibrations per second. Continuing this sonication during the course of the crystallization, as the later example 2 shows, results in microcrystals with a very fine and relatively constant particle size.

The extent of the crystal growth and the size of the crystals obtained are, of course, dependent on the medium chosen in each case and the conditions under which the crystallization is carried out, such as the question of whether work is carried out under sonication and, if so, with a soft frequency. For an application according to the present method, for example for the preparation of the galenic formulations to be described later, CY-A / X-III is preferably used in finely divided form, for example in a form with an average particle size of less than 200 μm, as of 0.5 to 200 jim. If the crystals originally obtained have a relatively large particle size, then preparations with the particle size desired in each case can of course be obtained by customary refining methods, such as by comminuting, grinding, pulverizing, micronizing and other comminuting methods. The particulate formulations thus obtained may be sufficient for certain uses, such as for the manufacture of topical compositions for use on the skin, but in some cases the use of a grinding or grinding technique may not be preferred. The reasons for this are that the products obtained by such measures usually have a relatively broad particle size distribution and, due to the breaking of the crystals, have a relatively coarse and sharp structure. Furthermore, the physical properties of the natural crystal surface are destroyed by comminution and, moreover, such processes are difficult and expensive to carry out under the necessary conditions of sterility, as are required, for example, for the preparation of galenical formulations for intra-articular administration. For these reasons, the method according to the invention is usually preferably carried out in such a way that crystals, for example microcrystals, with dimensions within the ultimately desired particle size range result. For the preparation of, for example, compositions for intra-articular or other parenteral use, therefore, preference is given to using particulate preparations of CY-A / X-IIt in the non-comminuted microcrystalline state (namely microcrystals of CY-A / X-III in the native or non-broken state, which ones no crushing, grinding, micronization or other particle size reduction).

To form microcrystals of CY-A / X-III, which can be used directly in the above-described manner in the non-comminuted state, the process according to the invention is expediently mixed, such as by stirring, for example at a speed of 200 to 300 revolutions per minute , which is increased during the crystallization to, for example, 700 revolutions per minute, and in particular using an ultrasonic vibration, for example in the range from 10,000 to 30,000 vibrations per second, expediently in the order of about 20,000 vibrations per second.

By changing the medium containing CY-A / X-III and adjusting the cooling rate and the extent of the mixing during the recrystallization to be carried out using known techniques and described later by way of example, microcrystals of CY-A / X-III with different average Produce particle size, for example with particle sizes, as have already been mentioned above or as will be described below, where these crystals are used in the pharmaceutical formulations according to the invention mentioned.

As already mentioned, the crystallization process according to the invention is expediently carried out under sterile conditions. The microcrystals of CY-A / X-III obtained can be purified in a conventional manner, such as by rinsing with mixtures of polyethylene glycol (300) and water, which contain these two components, for example in a ratio of 3 to 4 parts by weight to 1 part by weight, and Wash with warm water as described in the examples. The CY-A / X-III obtained is expediently obtained in a form which contains no or practically no ciclosporin in any other form, and thus preferably represents pure or practically pure CY-A / X-III. The rinsing step mentioned bears help prevent the formation of amorphous cyclosporine.

The invention therefore also includes a cyclosporin, which can be produced by any of the measures described above, and also

A3 CY-A / X-III of the type described above under A to A2, which is free or practically free of ciclosporin in any other form, such as free or practically free of ciclosporin in amorphous form, such as in the form of CY-A / XI or from CY-A / X-ll, is,

A4 CY-A / X-III of the type described above under A to A3, in pure or practically pure form,. As CY-A / X-III of the type described above under A to A4, in finely divided form which, for example, has particle size properties of the type described above or of the type to be described below, as described in the CY-A / X-III galenic forms containing,

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A6 CY-A / X-III of the type described above under A to A5, which consists predominantly or completely or practically completely of non-crushed crystal material, for example from CY-A / X-III of the type described above under A5, where the component particles predominantly or consist entirely or practically entirely of non-comminuted microcrystals, and

A7 CY-A / X-III of the type described above under A to A6, in a sterile or practically sterile state, for example in a state suitable for pharmaceutical use, in particular a state suitable for parenteral use, for example for administration by parenteral injection or by intra-articular injection.

The invention also includes C a pharmaceutical composition which contains a) cyclosporin in orthorhombic crystal form as active ingredient together with b) a pharmaceutically acceptable diluent or carrier therefor.

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

The ciclosporin is present in solid (crystalline) form in the compositions according to the invention, but the compositions themselves can be any suitable pharmaceutical form. Compositions according to the invention therefore include solid forms, such as capsules, tablets, dragees, powders and granules, semi-solid forms, such as ointments, gels, creams and pastes, and also liquid forms which contain the respective cyclosporin component in finely divided form (for example in micronized or microparticulate form) ) suspended or dispersed in a liquid pharmaceutical diluent or carrier in which the respective crystal form is retained.

Compositions according to the invention include systems which contain ciclosporin as a single phase or arrangement, such as simple creams, gels, ointments and other forms of the type described above, or simple one-piece capsules or ampoules, for example hard gelatin capsules, soft gelatin capsules or ampoules for injection, and also also Systems that contain cyclosporin in the form of several phases or arrangements. The invention therefore encompasses compositions which contain a ciclosporin-containing phase or arrangement together with one or more non-ciclosporin-containing phases or arrangements, such as with coating phases, carrier phases, sustained release phases or placebo phases, or with phases or arrangements which contain other active substances or auxiliaries. The invention therefore includes, for example, coated tablets with a core of ciclosporin in orthorhombic crystal form, which is surrounded, for example, by other coating phases or the like not containing ciclosporin, coated tablets with a core or shell containing ciclosporin in orthorhombic crystal form and a shell or core not containing ciclosporin, mixed granules from a first granulate phase of ciclosporin in orthorhombic crystal form and a second granule phase containing no ciclosporin, as well as split tablets with two or more sections which are separated, for example, by an inner wall, one section containing ciclosporin in orthorhombic crystal form and the other containing no ciclosporin. Further possibilities and modifications of such pharmaceutical forms are within the scope of the usual professional skill.

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

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

Compositions according to the invention include pharmaceutical forms which can be administered topically, such as by dermal or topical ophthalmic administration, parenterally, such as by infusion or injection, including subcutaneous or intramuscular injection and in particular intralesional or intra-articular injection, and also pharmaceutical forms, which can be administered enterai, such as suppositories, pessaries and the like, and oral dosage forms. However, enteral forms such as oral dosage forms are generally less preferred.

In the compositions according to the invention, the orthorhombic crystalline ciclosporin, such as CY-A / X-III, is preferably present in finely divided form, such as in micronized, microparticulate or non-comminuted microcrystallized form of the type described above. The particular particle size is of course dependent on the particular one Type of composition, the intended use5

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Purpose and the way of application and the desired effect. In general, however, the average particle size of the respective orthorhombic crystalline cyclosporin is in the order of magnitude in the range from 0.5 to 200 μm. Particular particle size ranges, such as are used for example for the production of oral, topical or injectable pharmaceutical forms, are described further below.

Topical forms, for example for dermal or topical ophthalmic administration, such as for the treatment of psoriasis or atopic dermatosis or for diseases or conditions in the eyes which require therapeutic treatment with an immunosuppressive agent, such as uveitis, conjunctivitis including keratoconjunctivitis sicca or vernal keratoconjunctivitis or a comea transplant.

Gels, creams, ointments and the like for topical or dermal administration can be prepared by any technique customary for this purpose by adding cyclosporine in orthorhombic crystal form with a suitable flowable base, for example an aqueous gel, such as an aqueous gel based on a cellulose ether, with the addition of suitable ones Surfactants, thickeners and the like including, for example, an Aerosi! is mixed.

The cyclosporine component is preferably present therein in a finely divided form, for example in a form with an average particle size of 0.5 to 200 μm. The ciclosporin component preferably has an average particle size of less than 60 to 80 µm, more preferably less than 40 µm, even more preferably less than 30 µm and in particular less than 20 µm. The particles expediently have the narrowest possible particle size distribution. Virtually all of the particles present preferably have a particle size of less than 60 to 80 µm.

Compositions according to the invention for topical ophthalmic use, such as application to the eyes, include, for example, suitable thickened suspensions or dispersions in the form of viscous eye drops or creams or gels for ocular use. In the case of compositions for treating the eyes, the crystalline cyclosporin present advantageously has an average particle size of less than 25 μm. Preferably, virtually all of the particles present have a size of less than 25 μm. The average particle size for eye drops is suitably in the range from about 0.1 to about 20 µm and preferably from about 0.5 to about 10 µm.

The carrier system used in pharmaceutical forms for dermal use or in preparations for use in the eye can vary in its content of hydrophilic and lipophilic components, and this depends, for example, on the particular surface to which the composition is applied should, as according to the properties of the skin area to be treated.

Compositions for a topical and in particular a dermal application expediently contain a carrier medium in which the active ingredient (cyclosporine component) is only slightly soluble. The solubility of the ciclosporin component, such as CY-A / X-III, in such compositions is generally below 10% by weight, preferably below 1.0% by weight, more preferably below 0.1% by weight and in particular below 0.001% by weight.

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

The hydrophilic and water-miscible carriers expediently have a relatively low volatility. Examples of suitable carrier components belonging to this class include liquid polyalkylene glycols, propylene glycol, glycerin and ethylene glycol. Suitable polyalkylene glycols include, above all, liquid polyethylene glycols with an average molecular weight of up to about 600, for example, polyethylene glycols with an average molecular weight of about 250 to 450 and in particular about 300 being preferred.

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

C1 a) a ciclosporin in orthorhombic and preferably non-solvated orthorhombic crystal form, such as CY-A / X-III, for example of the type defined above under A to A7,

b) a hydrophilic and water-miscible carrier, for example of the type described above, and optionally c) water in pharmaceutical purity.

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

Such compositions expediently also contain d) a surface-active agent.

The components d) are, if available, in an amount of up to a maximum of 30 percent and above6

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preferably a maximum of 15 percent, based on the total weight of the composition. The components d) are most preferably present in an amount of about 0.5 to about 10 percent, for example an amount of about 1.0 percent, based on the total weight of the composition.

Such compositions advantageously also contain e) a thickener.

If present, components e) are expediently present in an amount of up to 20 percent and preferably up to 10 percent, based on the total weight of the composition. The components e) are expediently present in an amount of approximately 0.5 to approximately 15 percent by weight, for example approximately 1.0 to approximately 3.0 percent, based on the total weight of the composition. Furthermore, such compositions may also expediently also contain antimicrobial agents, such as methylparaben, propylparaben, benzalkonium chloride or benzyl alcohol, and these agents are then, for example, in amounts of 0.05 to 0.5 percent, for example in an amount of 0.1 percent, or Case of benzyl alcohol is present in amounts up to 2.0 percent, for example about 0.1 percent by weight based on the total weight of the composition.

Other carrier media include hydrophobic materials which, for example, meet the solubility criteria described above for the active ingredient.

Other preferred compositions according to the invention which can be applied topically, for example, include

C2 a) a ciclosporin in orthorhombic and preferably non-solvated orthorhombic crystal form, such as CY-A / X-III, for example of the type defined above under A to A7, and f) a hydrophobic carrier, for example of the type described above.

The amount of component a) suitably corresponds to the amount as has already been described above in connection with the compositions defined under C1.

Such compositions may also contain one or more components of the type described above under d) and e) and also one or more of the above-mentioned antimicrobial agents.

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

Compositions based on hydrophobic agents of the type described above under C2, which contain an emulsifying agent as component d), can also be prepared in the form of creams or emulsions by further addition of water. The creams or emulsions obtained can either be of the oil-in-water or water-in-oil type. The amount of water present in such compositions can therefore be, for example, 5 to 80 percent, advantageously 20 to 70 percent, based on the total weight of the composition.

The amounts of components e) and any antimicrobial agent present correspond or are similar to the amounts as have already been stated above in connection with the compositions C1 according to the invention.

The amount of the topical form used in each case is of course dependent on the concentration of active substance in the composition, the condition to be treated and the desired effect and, in the case of dermal application, also on the area to be covered. Compositions for dermal use, such as for treating psoriasis or atopic dermatosis, generally use amounts that have a dose of ciclosporin on the order of about 0.1 to about 5 mg per cm2, for example about 0.5 mg per cm2, result in, for example, twice a day application at the desired location. Ophthalmic preparations with a ciclosporin content of about 0.1 to about 10 percent by weight, for example of 1.0 or 2.0 percent by weight, are applied, for example, in the form of drops to each eye one to three times a day.

Injectable pharmaceutical forms, for example for subcutaneous, intramuscular or other parenteral injection, in particular including an intra-articular injection, which are suitable, for example, for the treatment of arthritic diseases, such as rheumatoid arthritis, or for intra-lesional injection, for example for the treatment of psoriasis.

Dispersions, suspensions, emulsions and similar compositions suitable for injection can also be prepared in a known manner, for example by dispersing, suspending or otherwise distributing ciclosporin in finely divided orthorhombic crystal form in a suitable liquid carrier medium with the addition of suitable emulsifiers, surface-active agents, stabilizers, Flocculants and the like. The cyclosporin component in such compositions preferably has an average particle size of less than 100 µm, in particular less than 50 µm and especially less than 20 µm. The suitable average particle sizes range from about 0.1 µm or about 0.5 µm up to specified maximum values of 20 µm, 50 µm or 100 µm.

For example, if you want to achieve a depot effect with injectable forms, such as those administered by subcutaneous or intramuscular injection, then particles with larger particle sizes can also be used. However, such forms are by intralesional application or

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administered particularly by intra-articular injection, then the use of finely divided preparations is advisable. For this purpose, the ciclosporin component should then expediently have an average particle size of approximately 0.1 μm or approximately 0.5 μm up to approximately 20 μm, for example approximately 5 μm to 15 μm.

In order to achieve stability of the particles in injectable forms, for example to avoid an increase in the size of larger crystalline particles at the expense of smaller particles, the particles should preferably have the same size as possible. The difference between the maximum and the minimum particle size should expediently not be more than about 50 μm and preferably not more than about 20 μm.

Although the desired particle size can be achieved by suitable comminution methods, such as by micronization, the use of non-comminuted microcrystals, such as crystals that have grown to the mentioned and desired particle size, is generally preferred in order to keep a change in particle size to a minimum to avoid fragmented particles, to prevent a change in the crystal surface, such as maintaining the wettability properties, and to more easily meet the required sterility conditions.

Injectable compositions according to the invention therefore contain C3 a) a ciclosporin in finely divided orthorhombic and preferably unsolvated orthorhombic crystal form, such as CY-A / X-III, of the type defined above under A to A7, and in particular of the type defined above under A6 and A7, which distributes or can be distributed in b) an injectable carrier medium.

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

Furthermore, the above compositions C3 also expediently also comprise g) a surface-active agent which serves as a dispersant or emulsifier and / or a flocculant which supports or maintains a distribution of the particles through the carrier phase.

To maintain the particle size distribution, a stabilizing agent is also expediently used. Stabilizers suitable for this purpose include gelatins and modified gelatins, such as the plasma extenders available under the trademarks Gelafundin and Haemaccel, or cold water-soluble gelatins of highly purified collagen hydrolyzates.

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

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

In order not to disturb the particle stability too much, the surface-active agents corresponding to component g) are preferably only in a low concentration, for example in a concentration of 0.1 to 2.0 percent by weight, expediently in a concentration of about 1 percent by weight, based on the Weight of component a), available. In the presence of a flocculant, the ratio of flocculant to component a) is expediently in the order of 1.3 to 1 to 6 parts by weight and corresponds, for example, to about 1 to 5 parts by weight. In the presence of a stabilizing agent, the ratio of component a) to the stabilizing agent suitably amounts to about 1 to 5 to 1 to 30 parts by weight and preferably 1 to 10 to 1 to 30 parts by weight, and is, for example, 1 to 20 parts by weight. In the presence of a peptizing agent, the ratio of peptizing agent to component a) is expediently in the order of 1 to 1 to 15 parts by weight, and is, for example, approximately 1 to 10 parts by weight.

The amount of ciclosporin that is present in unit dosage forms for injection according to the invention naturally varies depending on, for example, the condition to be treated, the location of the injection and the desired effect, for example whether one wishes to have a depot effect or a relatively rapid release into the surrounding tissue . Suitable unit dosage forms contain about 10 to 500 mg ciclosporin and in particular about 20 to 100 mg ciclosporin per dose.

Unit dosage forms according to the invention naturally also include more complex systems, such as double-chamber syringes or spray batteries, in which the finely divided ciclosporin is located in a first chamber together with other suitable components, such as a stabilizer or an antimicrobial agent, and the carrier medium is present in a second chamber. the components present in the two chambers being mixed with one another, for example, by actuating the plunger of the syringe. Such double chamber syringes are known in the art and unit dosage forms based thereon also form part of the invention.

Oral dosage forms, for example for the treatment of autoimmune diseases and other diseases and conditions of the type described above, such as for the prevention of graft rejection.

Oral dosage forms, as mentioned above, are generally less interesting and therefore less interesting

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less preferred, but of course such forms are also within the scope of the invention. Oral dosage forms according to the invention can be prepared in the usual manner using any known carrier or carrier medium. Liquid or semi-solid oral dosage forms can include, for example, ciclosporin in orthorhombic crystal form, such as CY-A / X-III, along with pharmaceutically acceptable diluents or carriers in which the crystal form itself is insoluble or practically insoluble. Such carriers and diluents include, for example, transesterification products from natural vegetable oil triglycerides and polyalkylene polyols of the type described above under d1), such as the products sold under the trademark Labrafil, and also reaction products made from natural or hydrogenated castor oil and ethylene oxide of the type described above under d2), in particular the liquid products available under the trademark Cremophor, such as Cremophor EL.

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

For ease of administration, the above-mentioned compositions are conveniently packaged in hard gelatin capsules or soft gelatin capsules.

Unit dosage forms according to the invention, which are used for oral administration, expediently contain about 25 to about 75 mg or up to 200 mg, for example about 50 mg or 100 mg, ciclosporin per unit dosage. Such forms are administered, for example, one to four times a day, so that ciclosporin concentrations (for example determined by a radioimmunoassay) result in the serum of the respective patient, which are the same or comparable to the concentrations which are achieved using conventional therapeutic treatment with ciclosporin, for example by administration of the usual oral solutions of ciclosporin.

The constituents described herein and defined as components of the pharmaceutical compositions according to the invention should of course be suitable for the pharmaceutical application required in each case, namely in the case of constituents of a composition for oral administration or pharmaceutically acceptable in the case of constituents of a composition for topical administration, namely dermal or ocular, applicable, acceptable or compatible.

Other galenic forms for administration by the same or alternative routes to the routes described above will be apparent to those skilled in the art.

The various aspects of the invention are further described by the following examples,

example 1

Production of CY-A / X-III

a) 100 g of ciclosporin in amorphous form are dissolved with stirring in 400 g of polyethylene glycol 300 at 50 ° C. The development of CY-A / X-III begins shortly after termination of the resolution. The solution is left to crystallize at about 35 to 40 ° C. for 24 to 48 hours and then diluted with 1000 ml of water with vigorous stirring. The precipitate obtained is separated off by filtration, washed with water to remove residual polyethylene glycol and dried, giving CY-A / X-III in practically pure form which has a melting point of 195 ° C. and a particle size of about 100 to 200 um has.

Analogous to the above process, other forms of CY-A / X-III can be produced, for which purpose the following materials are used instead of polyethylene glycol 300 as solvent.

solvent

Melting point of the obtained CY-A / X-III in ° C

b) polyethylene glycol 300 /

-

Cremophor RH 40

(Volume ratio 1 to 1)

c) Cremophor EL

190

d) Solutol HS15

188

e) Gelucir 44/14

180

f) Myrj 52

184

g) Tween 80

186

h) Cremophor RH 40

190

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This results in crystals with an average particle size of about 50 to about 20Q (im. The determined lattice structure corresponds to the structure already given above. The X-ray diffraction data correspond to the values given in Table III and IV below.

Example 2

Production of CY-A / X-III

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

Repetition of the experiments shows that the crystal size is influenced more by the nucleation temperature and the crystal growth rate than by the duration of the process. By initiating the nucleation at about 75 ° C. and continuing the crystallization at the same temperature, crystals with an average particle size of about 50 μm are obtained.

Example 3

Preparation of a galenical form for oral administration

3.1 Preparation encapsulated in gelatin l

A suspension of 20% by weight of CY-A / X-III, which was obtained by the process of Example 1, in Gelucir 44/14 is ground in a colloid mill at elevated temperature until the CY-A / X-III is a has an average particle size of about 0.5 to 10 μm. 250 mg of the ground suspension obtained are then filled into size 2 hard gelatin capsules such that they each contain 50 mg of ciclosporin (in the form of CY-A / X-III) as the active ingredient.

3.2 Preparation encapsulated in gelatin II

CY-A / X-III obtained by the method of Example 1 is ground in a colloid mill until the CY-A / X-III has an average particle size of the order of 0.5 to 20 µm. Quantities of 50 mg each are then mixed thoroughly with 200 g Cremophor EL and filled into size 2 hard gelatin capsules so that they each contain 50 mg ciclosporin (in the form of CY-A / X-III) as the active ingredient.

Example 4

Preparation of galenic forms for topical use 4.1 Gel preparation l

CY-A / X-III produced according to the procedure of Example 1 is micronized with an air jet mill. The resulting micronized product with a maximum particle size of 60 to 70 μm and an average particle size of 2 to 10 (in which it is combined and mixed with the constituents listed in the table below, gives an aqueous gel which contains 10% by weight of ciclosporin (in Form of CY-A / X-III) contains and is suitable for topical use, such as for the treatment of psoriasis.

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Components

Weight percent a) ciclosporin

10.0

(micronized CY-A / X-III)

b) polyacrylic acid

0.5

(Carbopol 934 P)

c) Sodium hydroxide solution (5%)

3.0

d) methyl paraben

0.07

e) propyl paraben

0.03

f) water (pharmaceutically pure)

to 100.0%

4.2 Gel preparation II

Ingredients weight percent

Put together

tongue A

settlement B

a)

Ciclosporin

(micronized CY-A / X-III)

10.0

1.0

b)

Polyethylene glycol 300

30.0

30.0

c)

Labrafil M 2130 CS

1.0

1.0

d)

Carbopol 934 P.

1.0

1.0

e)

Sodium hydroxide (5%)

6.0

6.0

f)

Methyl paraben

0.07

0.07

G)

Propyl paraben

0.03

0.03

H)

Water (pharmaceutically pure)

51.9

60.9

100.0%

100.0%

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

4.3 Ointment preparation

Ingredients weight percent

Together- together-

settlement A

settlement B

a)

Ciclosporin

(micronized CY-A / X-III)

1.0

10.0

b)

Amerchol CAB

2.0

2.0

c)

Liquid paraffin

42.0

37.5

d)

Weisspetrolatum

55.0

50.5

100.0%

100.0%

Component a) is produced as described under 4.1 above. Components b), c) and d) are melted and stirred, and component a) is added at about 30 ° C., the particles being distributed using a homogenizer. The ointment obtained is cooled and filled into compressible tubes for topical use, for example for the treatment of psoriasis.

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4.4 Cream preparation

Components

Weight percent a) ciclosporin

1.0

(micronized CY-A / X-III)

b) polysorbate 60

5.0

c) cetylstearyl alcohol

10.0

d) glycerin (85%)

10.0

e) white petrolatum

24.0

f) methyl paraben

0.07

g) propyl paraben

0.03

h) water (pharmaceutically pure)

49.0

100.0%

Component a) is prepared as described above under 4.1 and then combined with components b) to h) in the same way as described above under 4.3, whereupon the whole is filled into compressible tubes for topical use, for example for treating psoriasis.

4.5 Ointment preparation

A suspension of 20 percent by weight CY-A / X-III (obtained by the process of Example 1) in polyethylene glycol 300 is wet-milled until it has an average particle size in the order of 2 to 10 pm. Then 10 g of the ground product obtained are mixed in a conventional manner with 50 g of polyethylene glycol 300 and 40 g of molten polyethylene glycol 1500, resulting in a pourable paste with 10% by weight of ciclosporin (in the form of CY-A / X-III), which is suitable for a topical application, for example for the treatment of psoriasis, is suitable.

4.6 Gel preparation

Components

Weight percent a) ciclosporin

1.0

{micronized CY-A / X-Ill)

b) Labrafil M 1944 CS

1.0

c) polyethylene glycol 300

30.0

d) benzyl alcohol

1.0

e) hydroxypropylmethyl cellulose

2.5

(Methocel E4M)

f) water (pharmaceutically pure)

64.5

100.0%

Component a) is produced as described under 4.1 above. Components b), c) and d) are mixed together, whereupon component f) is added and mixed. In the mixture obtained, component a) is then mixed by homogenization. Then component e) is slowly added with stirring until the gel formation has ended. The gel is then filled into squeezable tubes for topical use, for example to treat psoriasis.

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4.7 Gel preparation

Components

Weight percent a) ciclosporin

5.0

(micronized CY-A / X-Ill)

b) polyethylene glycol 300

30.0

c) Glyceryl monostearate

5.0

d) methyl paraben

0.07

e) propyl paraben

0.03

f) Carbopol 934 P.

1.0

g) sodium hydroxide (5%)

6.0

h) water (pharmaceutically pure)

52.9

100.0%

Component a) is produced as described under 4.1 above. Components c), d) and e) are dissolved in component b) with heating. The warm mixture is dispersed in component h) by homogenization and then cooled to room temperature. Then components a) and f) are added and the whole is homogenized. Then component g) is added and the gel formation is ended. The gel obtained is filled into compressible tubes for topical use, for example for the treatment of psoriasis.

4.8 Cream preparation for water-in-oil

Components weight percent a) ciclosporin

2.0

(micronized CY-A / X-III)

b) AmercholCAB

5.0

c) Miglyol 812

10.0

d) white petrolatum

53.0

e) water (pharmaceutically pure)

30.0

100.0%

Component a) is prepared as described above under 4.1 and dispersed with component b) in component e) with heating and homogenization. Components c) and d) are melted together and mixed, and the mixture is then added to the previously obtained dispersion with intensive homogenization. Subsequent cooling results in a fat-like white cream. This cream is filled into compressible tubes for topical use, for example for the treatment of psoriasis.

4.9 Preparations of gels and creams

The measures described in Examples 4.1 to 4.8 above are repeated, but here the crystalline product from Example 2 is used directly as the cyclosporine component,

Example 5

5.1 Initiable form, for example for parenteral use

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

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Components weight (mg)

a) Ciclosporin (CY-A / X-III)

20.0

h) polysorbate 80

4.0

c) sodium carboxymethyl cellulose

5.0

d) sodium chloride

9.0

e) benzyl alcohol

9.0

f) water (injection-free)

to a final volume

of 1.0 ml

The release characteristics of the active ingredient from the formulation thus obtained depend on the average particle size of component a). If a longer duration of action is therefore required, a CY-A / X-III with a large average particle size is used, for example a product with an average particle size of 100 to 200 μm, as is obtained directly by the process described in Example 1 . If, on the other hand, one would like to have an efficacy for only a relatively short period of time, then a product with a relatively smaller average particle size is used as CY-A / XI il, as is obtained, for example, by micronizing or grinding the product from Example 1, namely, for example, a Product with an average particle size of 0.5 to 10 µm. The suspension obtained is filled into injection ampoules for parenteral administration or for intralesional injection for the treatment of psoriasis in order to achieve a depot effect.

A particularly preferred embodiment consists in the use of CY-A / X-III prepared according to Example 2, which has an average particle size of 5 to 15 μm and has been produced under sterile conditions.

5.2 Initiable forms, for example for an intra-articular injection

Injectable forms suitable for intra-articular administration are made using the following ingredients:

Components

Amount of weight (mg)

Composition A

a) Ciclosporin (CY-A / X-III)

b) sodium carboxymethyl cellulose cj sodium EDTA

d) water (injection-free)

Composition B

a). Ciclosporin (CY-A / X-III)

b) polysorbate SO

c) citric acid d) water (injection-free)

10.0 10.0 2.0

to a final volume of 1.0 ml

10.0

0.1

2.0

to a final volume of 1.0 ml

Formulation is done using standard techniques and sterile conditions. Component a) contains non-comminuted microcrystals which have been produced under sterile conditions by the process of Example 2 and have an average particle size of 3 to 15 μm. The compositions obtained are filled under sterile conditions into ampoules for injection, for example for intra-articular injection, in order to treat rheumatoid arthritis.

The advantageous properties of the compositions according to the invention can be demonstrated on animal models and also in the clinic.

The invention also belongs

D) Ciclosporin in unsolvated orthorhombic crystal form, such as in the form of CY-A / X-III, for example of the type defined above under A to A7, as a pharmaceutical, in particular as an immunosuppressive or anti-inflammatory agent.

For the identification of ciclosporin in orthorhombic crystal form, in particular in the form of CY-A / X-III, the ones given here for CY-A / X-III and for the two forms CY-A / XI and GY-A / X-II are used X-ray diffraction data as shown in Tables I to III below.

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Table I

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

Line No.

d in 10 ~ 10m

intensity

1.

CO

O

VS

2nd

1t, 4

VS

3rd

10.3

VS

4th

9.7

VS

5.

9.4

VS

6.

8.25

VS

7. ■

• 7.1

S

8th.

6.1

M

9.

5.85

S

10th

5.6

S

11.

5.25

VS

12.

4.81

S

13.

4.58

S

14.

4.25

M

15.

4.0

M '

16.

3.67

M

17th

3.45

M

Table II

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

Line No.

din10 ~ 10m

intensity

1.

17.9

S

2nd

11.4

VS

3rd

11.0

S

4th

10.6 •

M

5.

10.2

S

6.

8.9

M

7.

8.7

M

8th.

8.1

M

9.

7.2

VS

10th

6.3

M

11.

5.95

M

12.

5.7

M

13.

5.35

M

14.

5.1

S

15.

4.85

S

16.

4.8

M

17th

4.55

M

18th

4.4

M

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Table IH

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

Line No. d in10 "" 1 ° m intensity

1.12 m

2. 10.4 VS *

3.9.6 p

4. 8.7 p

5.7.9 sts

6. 7.7 p

7. 6.7 m

8. 6.0 m

9. 5.83 p

10.3 m

11.5 m

12. 4.92 p

13. 4.88 p

14. 4.58 s

15. '4.48 m

16. 4.0 m

17.3.5 M

18. 3.38 s

VS s very strong S = strong M = medium

Claims (1)

Claims 1. Cyclosporin in unsolvated orthorhombic crystal form. 2. ciclosporin according to claim 1, characterized in that it is a crystal lattice with a = 12.7 x 10-10 mi b = 15.7 x 10-1 ° m and c = 36.3 x 10 ^ 1 ° m and a volume per asymmetry unit of 1804 x 10-30 m3. 3. ciclosporin according to claim 1 or 2, characterized in that it has the following X-ray diffraction data; 16 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 677 926 A5 Line No. din1O ~ 10m intensity 1. 12.0 M 2nd 10.4 VS 3rd 9.6 S 4th 8.7 S 5- 7.9 M 6. 7.7 S 7. 6.7 M 8th. 6.0 M 9, 5.83 S 10th 5.3 M 11. 5.2 M 12. 4.92 S 13. 4.88 S 14. 4.58 M 15. 4.48 M 16. ■ 4.0 M 17th 3.59 M 18th 3.38 M VS = very strong S = strong M = middle! 4. ciclosporin according to any one of claims 1 to 3, characterized in that it is free or practically free of ciclosporin in any other form and is in pure or practically pure form. 5. ciclosporin according to any one of claims 1 to 4, characterized in that it is in finely divided form. 6. ciclosporin according to claim 5, characterized in that its particles have an average particle size of less than 200 jxm. 7. ciclosporin according to claim 6, characterized in that its particles have an average particle size of 0.5 to 200 (im. 8. ciclosporin according to claim 6, characterized in that its particles have an average particle size of less than 25 (im. 9. ciclosporin according to one of claims 1 to 8, characterized in that it consists predominantly or wholly or practically entirely of non-comminuted crystal material. 10. ciclosporin according to any one of claims 6 to 8, characterized in that its particles consist predominantly or wholly or practically entirely of non-comminuted microcrystalline material. 11. ciclosporin according to any one of claims 1 to 10, characterized in that it is in a sterile or practically sterile state. 12. ciclosporin according to any one of claims 1 to 11 as a pharmaceutical. 13. ciclosporin according to claim 12 as an immunosuppressive or anti-inflammatory agent. 14. A process for the preparation of ciclosporin in unsolvated orthorhombic crystal form, characterized in that ciclosporin is crystallized from a solvent medium containing ciclosporin in unsolvated orthorhombic crystal form and the unsolvated orthorhombic crystals of ciclosporin obtained in this way are obtained. 15. Pharmaceutical composition, characterized in that it contains a) ciclosporin in orthorhombic crystal form as active ingredient together with b) a pharmaceutically acceptable diluent or carrier therefor. 16. Pharmaceutical composition according to claim 15, characterized in that the ciclosporin is present predominantly or wholly or practically entirely in orthorhombic crystal form. 17. Pharmaceutical composition according to claim 15 or 16, characterized in that it has at least one section or phase containing ciclosporin in orthorhombic crystal form, this crystal form being distributed or distributable by the section or phase or homogeneous or practical by the section or phase is homogeneously distributed or distributable. 18. Pharmaceutical composition according to one of claims 15 to 17, characterized in that it contains ciclosporin according to the definition of one of claims 1 to 11. 17th 5 10th 15 20th 25th 30th 35 40 45 50 55 60 CH 677 926 A5 19, Pharmaceutical composition according to one of claims 15 to 18, characterized in that it is in a flowable form for topical use or use by injection or infusion. 20. Pharmaceutical composition according to one of claims 15 to 18, characterized in that it contains 0.05 to 30 weight percent ciclosporin, based on the total weight of the composition. 18th