CH679277A5 - - Google Patents

Description

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description

The invention relates to new gaienische formulations containing cyciosporin as an active ingredient.

The cyclosporins comprise a class of structurally characteristic, cyclic, poly-N-methylated endecapeptides, which usually have a pharmacological, in particular an immuno-suppressive, anti-inflammatory and / or antiparasitic effect. The cyclosporins were the first to isolate the naturally occurring fungal metabolite ciclosporin or cyciosporin, which is also known as cyciosporin A and is commercially available under the trade name SANDIMMUN® or SANDIMMUNE®. Ciclosporin is the cyciosporin of formula A.

-HeBm t- ccAbu-Sar-MeLeu-Val-HeLeu-Ala- (D) Ala-MeLeu-MeLeu-MeVal- »

10 11

(A)

in the -MeBmt- means the N-methyl- (4R) -4-but-2E-en-1-yl-4-methyl- (L) -threonyl radical of the formula B.

(B)

in which-x-y-has the meaning -CH = CH- (trans).

As the parent compound of the class, ciclosporin has received the most attention so far. The primary clinical studies on ciclosporin dealt with the immunosuppressive effect, particularly in relation to its use in organ transplant recipients, e.g. cardiac, pulmonary, combined cardiopulmonary, liver, kidney, pancreas, bone marrow, skin and corneal transplants and in particular allogeneic organ transplants. Ciclosporin has achieved considerable success and recognition in this area.

At the same time, ciclosporin has been used intensively for various autoimmune diseases and inflammatory conditions, in particular inflammatory conditions with an etiology including an autoimmune component such as arthritis (such as rheumatoid arthritis, progressive arthritis chronic and arthritis deformans) and rheumatic diseases. The literature contains numerous reports and results on in vitro tests, animal models and clinical studies. Specific autoimmune diseases for which therapy with cyciosporin has been proposed or used include autoimmune haematological disorders (including, for example, hemolytic anemia, aplastic anemia, pure erythrocyte anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodomoma pathways , Dermatomyositis, chronic active hepatitis, severe myasthenia, psoriasis, Steven-John-son syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (including ulcerative colitis and Crohn's disease, for example), endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary Biliary cirrhosis, juvenile diabetes (type I diabetes mellitus), uveitis (anterior and posterior), keratoconjunctivitis sicca and spring keratocunjunctivitis, intersti-

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tial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or nephropathy with minimal change).

Further areas of investigation with potential applicability are as an antiparasitic, in particular antiprotozoal agent, the possible fields of application being suggested for the treatment of malaria, coccydiomycosis and schistosomiasis and more recently also for use in cancer therapy, e.g. as a means of reversing or removing resistance to other anti-neoplastic or cytostatic therapies.

Since the original discovery of ciclosporin, a variety of naturally occurring cyclosporins have been isolated and identified, and numerous other non-natural cyclosporins have been made by total or semi-synthetic methods or by using modified breeding techniques. The class of cyclosporins is now very extensive and includes, for example, the naturally occurring cyclosporins A to Z (cf. Traber et al. 1, Helv. Chim. Acta. Vol. 60 (1977), pages 1247 to 1255; Traber et al. 2 , Helv. Chim. Acta, Vol. 65, No. 162 (1982), pages 1655 to 1667; Kobel et al., Europ. J. Applied Microbiology and Biotechnology, Vol. 14 (1982), pages 273-240 (1982 ); and by Wartburg et al., Progress in Allergy, vol. 38 (1986), pages 28-45, as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins including the so-called dihydrocyclosporins (in which the rest -xy- of the -MeBmt radical (formula B above) to form -xy = -CH2-CH2-); derivatized cyclosporins in which, for example, another substituent on the a-carbon atom of the sarcosyl radical in the 3-position of the cyclosporin mole -küls is introduced); Cyclosporins in which the -MeBmt residue is present in isomeric form (where, for example, the configuration at positions 6 'and 7' of the MeBmt residue is ice instead of trans); and cyclosporins, in which different amino acids are introduced at specific positions within the peptide sequence, using, for example, the total synthesis process developed by R. Wenger for the production of cyclosporins (see, for example, Traber 1, Traber 2 and Kobel loc. cit.; US Pat. No. 4,108,985) , 4 210 581 and 4 220 641, European patent publications 0 034 567, 0 056 782 and 0 296 122; International patent publication WO 86/02 080; Wenger 1, Transp. Proc. Vol. 15; Suppl. 1 (1983), page 2230; Wenger 2, Angew. Chem. Int. Ed., Vol. 24 (1985), p. 77 and Wenger 3, Progress in the Chemistry of Organic Natural Products, Vol. 50 (1986), p. 123.

The class of cyclosporins now includes, for example, [Thr] 2-, [Val] 2-, [Nva] 2- and [Nva] 2- [Nva] 5-ciclosporin (also known as cyclosporins C, D, G and M, respectively) [3'-0-Acyl-MeBmtJi-Ciclosporin (also known as Cyciosporin A-acetate), [Dihydro-MeBmt] i- [Val] 2-Ciclosporin (also known as Dihy-dro-cyclosporin D), [3'- Deoxy-3'-oxo-MeBmt] 1- [Val] 2- and - [Nva] 2-ciclosporin, [(D) fluoromethyl-Sar] 3-ciclosporin [(D) Ser] 8-ciclosporin, [Melle] 11 -Ciclosporin, [(D) MeVaip-Ciclosporin (also known as Cyciosporin H), [MeAla] 6-Ciclosporin, [(D) Pro] 3-Ciclosporin and the like.

(In accordance with the now agreed nomenclature for cyclosporins, the name is given with reference to the structure of ciclosporin (ie cyciosporin A). This is carried out by first denoting the amino acid residues present which differ from those in ciclosporin (eg «[ (D) Pro] 3 »to indicate that the cyciosporin in question has a - (D) Pro residue instead of the -Sar residue in the 3-position and then uses the term« ciclosporin »to express ensure that the remaining residues are identical to those of ciclosporin. The individual residues are numbered, starting with the residue -MeBmt-, -Dihydro-MeBmt- or the equivalent thereof in position 1).

Many of these additional cyclosporins have a pharmaceutical utility comparable to ciclosporin or a more specific utility, for example a special activity in the reversion of tumor resistance to cytostatic therapy. There are numerous proposals in the literature for the use of these compounds as therapeutic agents.

Despite the very important contribution that ciclosporin has made, particularly in the area of organ transplantation and the therapy of autoimmune diseases, difficulties arise in providing more effective and convenient means of administration. Furthermore, the reports of the occurrence of undesirable side reactions, in particular of nephrotoxic reactions, represent a serious obstacle to the extended use of these compounds. Characteristic of the cyclosporins is their highly hydrophobic nature. Proposed liquid formulations, e.g. for oral administration of cyclosporins have so far been based predominantly on the use of ethanol and oils or similar vehicles as carrier media. Thus the commercially available ciclosporin drinking solution uses methanol and olive oil as a carrier medium in connection with labrafil as a surface-active agent; see. e.g. U.S. Patent 4,388,307. However, the use of the drinking solution and similar compositions as proposed in the prior art is accompanied by numerous difficulties.

First, the need to use oils or oil-based carriers can result in unpleasant taste preparations or otherwise affect taste, particularly in long-term therapy. These effects can be masked by a presentation in the form of gelatin capsules. However, to keep the cyciosporin in solution, the ethanol content must be high. Evaporation of the ethanol, e.g. from capsules or from other dosage forms, if they are open, for example, leads to the development of a cyclospo

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rin precipitation. When such compositions are presented in the form of so-called soft gelatin capsules, this particular difficulty makes the packaging of the encapsulated product in an airtight container, e.g. an airtight blister pack or an aluminum foil blister pack. This in turn leads to a voluminous nature of the product and to an increase in the cost of manufacture. The storage properties of the aforementioned formulations are therefore far from ideal.

The bioavailability levels achieved with existing oral cyclosporin dosing systems are also low and show strong fluctuations between individuals, individual patient types and even with the same individuals at different times in the course of therapy. Reports in the literature show that the currently available therapy using the commercially available ciclosporin drinking solution gives an average absolute bioavailability of only 30%, with considerable fluctuations between individual groups, e.g. between recipients of liver transplants (relatively low bioavailability) and of bone marrow transplants (relatively high bioavailability). The reported variations in bioavailability between patients vary from 1 or a few% for certain patients to 90% or more for other patients. As already mentioned, a pronounced change in bioavailability over time is often observed in individuals.

In order to achieve effective immunosuppressive therapy, cyclosporin levels must be maintained in a specific range in the blood or in the serum. The required range can in turn depend on the specific condition to be treated, for example depending on whether the therapy is used to prevent the rejection of transplants or to combat an autoimmune disease and depending on whether another immunosuppressive therapy is used simultaneously with the cyclosporin therapy. or not, vary. Due to the strong fluctuations in the bioavailability levels achieved with conventional dosage forms, the daily doses required to achieve the required blood serum levels also vary considerably from one person to another and also with one and the same person. For this reason, it is necessary to monitor the blood / blood serum levels of the patients undergoing cyclosporin therapy at regular and frequent intervals. Monitoring blood / blood serum levels, generally by RIA or an equivalent immunoassay technique, e.g. using the technique based on monoclonal antibodies, must be carried out regularly. This is necessarily time consuming and troublesome and adds to the overall cost of the therapy. In addition to all of these clearly recognizable practical difficulties, there is the occurrence of the undesirable side reactions already mentioned, which are observed with all available oral dosage forms.

Various proposals to overcome these difficulties are known from the prior art, including both solid and liquid oral dosage forms.

For example, JP-A-71 682/1985 (Takada et al.) Suggests the use of agents which increase the lymphatic supply of cyclosporins, in particular by administration in conjunction with surface-active agents. A general list of surfactants that can be used includes sucrose fatty acid esters, such as sucrose oleate, palmitate or stearate, and other fatty acid esters, especially sorbitan fatty acid esters, such as sorbitan oleate, palmitate or stearate. Although the use of mono- as well as polyesters is indicated, the proposal goes in the direction of a general preference for mono- or diesters. Other surface-active agents listed are polyoxyethylated, hydrogenated vegetable oils and commercially known products known under the trade names Cremophore RH and Nikkol HCO 60. For these products it is clearly stated that, for example, they are preferred over the surface-active agents based on sucrose ester.

Example 3 of the aforementioned Japanese patent application describes the provision of an aqueous preparation containing a sucrose fatty acid ester with the designation F160 as a surface-active component. The preparation contains 3.5 mg ciclosporin and 2 mg sucrose ester in 1 ml H2O. To achieve a dispersion of the ciclosporin, a 5 minute ultrasound treatment with 100 W is required. The preparation, described as a "transparent solution", is used directly in animal experiments to investigate the relative lymphatic absorption. Due to the very low solubility of ciclosporin in H2O and the minor amount of surfactant used, it is clear that the claimed solution is an artificial result of the ultrasound treatment. Not only is the ciclosporin concentration achieved inadequate, for example for an oral dosage form, but the preparation is also inherently unstable, so that the use as any practical or commercial galenic form is de facto excluded for this reason. It essentially represents only an experimental system that enables laboratory examinations and is also not applicable. There is no suggestion to use surfactants in any context other than lymphatic delivery.

Japanese Patent Application No. 193 129/1987 (Publication No. 038 029/1989) (also Takada et al.) Discloses powdered preparations containing ciclosporin which are in a solid, non-surface-active carrier phase, e.g. containing sucrose, sorbitol, tartaric acid, urinary

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Cloth, cellulose acetophthalate, methacrylic acid / methyl methacrylate or hydroxypropylmethyl cellulose phthalate, is dispersed together with minor amounts of a surfactant. Again, the surfactant is added to increase lymphatic delivery. In this connection, the application is clearly aimed at providing practical means for applying the teaching of the aforementioned Japanese application No. 71 682/1985. In this case, there is no reference to sucrose esters as possible surface-active components. The reference to sorbitan esters when listing possible surface-active components is retained. However, products of the Nikkol HCO 60 type are again indicated as preferred surfactants. Nikkol HCO 60 is used as the only surfactant in the examples. There is no evidence that the alleged increase in lymphatic delivery provides practical benefits or resolves any of the difficulties previously discussed with cyclosporin therapy.

According to the invention, new pharmaceutical cyclosporin formulations are provided which contain fatty acid resaccharide monoesters as primary carrier components. These formulations address the difficulties encountered in the prior art in therapy with cyciosporin, e.g. with ciclosporin, overcome or significantly reduced. In particular, it has been found that the compositions according to the invention allow the production of solid, semi-solid and liquid compositions containing cyciosporin in a sufficiently high concentration so that, for example, convenient oral administration is possible and at the same time an improved effectiveness, e.g. in terms of bioavailability properties.

In particular, it has been found that the compositions according to the invention reduce an effective cyclosporin dosage while simultaneously increasing the absorption / bioavailability level and reducing the fluctuation in the absorption / bioavailability level both in individuals who receive cyclosporin therapy and between different individuals. Applying the teachings of the present invention, cyclosporin dosage forms are obtainable which ensure a reduced fluctuation in the cyclosporin / blood / blood serum levels achieved in doses for individual patients and for individual patients / groups of individual patients in comparison with one another. The invention thus enables the cyclosporin dosage level required to achieve effective therapy to be reduced. It also enables closer standardization and optimization of the requirements for continuous daily dosing for individual patients receiving cyclosporin therapy and for groups of patients undergoing appropriate therapy.

The monitoring requirements can be reduced by a closer standardization of the dosage amounts for individual patients and the blood / blood serum level reaction as well as the dosage and reaction parameters for patient groups, which considerably reduces the costs of the therapy.

By reducing the required cyclosporin dosage standardization of the bioavailability properties achieved, the present invention also offers a possibility of reducing the occurrence of undesirable side effects, in particular of nephrotoxic reactions, in patients who receive cyclosporin therapy.

Furthermore, the present invention enables the preparation of non-alkanol-based compositions, i.e. that are free or substantially free of ethanol. With such compositions, the stability problems discussed above and the associated processing difficulties which are inherent in known alkanolic compositions are avoided. Thus, the invention provides, among other things, compositions which are better for administration in the form of capsules, i.e. hard or soft gelatin capsules are suitable and in which the packaging difficulties, for example the problems described above for soft gelatin capsules, are eliminated or substantially reduced.

In particular, according to the invention a pharmaceutical composition is provided which contains the following components:

a) a cyciosporin as active ingredient,

b) a fatty acid saccharide monoester and c) a diluent or carrier,

where i) component (c) is a solvent for the two components (a) and (b), components (a) and (b) each independently of one another having a solubility in component (c) of at least Own 10% at ambient temperature; or ii) component (c) is a solvent for the two components (a) and (b) and components (a) and (c) in the composition in a ratio of 1: 0.5 to 50 Parts by weight (a) :( c) are present; or iii) component (c) is a solvent for both components (a) and (b) and the composition is formulated in a solid unit dosage form suitable for oral administration; or iv) component (c) a poly (C2-4 alkylene) glycol with an average molecular weight

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of at most 7000 or a viscosity at 50 ° C of at most 15000 mPa.s or contains a C3-5-alkylene polyol ether or ester; or v) the composition is non-aqueous or substantially non-aqueous; or vi) the composition contains as component (c) a solid polymeric carrier, an organosilicon oxide polymer or paraffin per- or sub-liquidum and component (a) is present in the composition in solid solution in component (b).

The compositions thus defined represent new and particularly advantageous variants of those generally described in French patent application No. 8 811 953 and the corresponding patent applications in other countries (including USSN 07/243 577, DE-OS 38 304 945, Japanese patent application 231 396/88 and GB application 8 821 443.9 (first publication in France, March 17, 1989 under the number 2 620 336).

The above definitions (i) to (vi) are to be understood in such a way that they are not mutually exclusive. The compositions of the inventions thus comprise compositions which are defined to correspond to one or more of the conditions defined under (i) to (vi). Preferred compositions of the invention are those which, for example, meet any two or more of conditions (i) to (v).

The term "pharmaceutical composition" used here and in the appended claims is to be understood to define compositions, the individual components or constituents of which are themselves pharmaceutically acceptable, for example when intended for oral administration for oral use or for intended topical administration for topical application are tolerated.

The preferred cyciosporin in the context of component (a) is cyclosporin. Another preferred component (a) is [Nva] 2-ciclopsorin, which is also known as Cyciosporin G.

Preferred components (b) for use in the compositions of the invention are water-soluble fatty acid saccharide monoesters, e.g. fatty acid monoesters of saccharides with a solubility in water of at least 3.3% at ambient temperature, i.e. which are soluble in water at ambient temperature in an amount of at least 1 g monoester per 30 ml water.

The fatty acid residue of components (b) can contain saturated or unsaturated fatty acids or mixtures thereof. Particularly suitable components (c) are C6-i8 fatty acid saccharide monoesters, in particular water-soluble C6-i8 fatty acid saccharide monoesters. Particularly suitable components (c) are caproic acid (C6) -, caprylic acid (Cs) -, capric acid (Cio) -, lauric acid (C12) -, myristic acid (C14) -, palmitic acid (Cm) -, oleic acid (Cis) -, ricinoleic acid (Cis) - and 12-hydroxystearic acid (cis) saccharide monoesters, especially lauric acid saccharide monoesters.

The saccharide residue of component (b) may comprise any suitable sugar residue, e.g. Mono-, di- or trisaccharide residues. The saccharide residue preferably comprises di- or trisaccharide residues. Preferred components (b) include C6-i4 fatty acid disaccharide monoesters and Cs-is fatty acid trisaccharide monoesters.

Particularly suitable saccharide residues are sucrose and raffinose residues. Particularly suitable components (b) are therefore sucrose monocaproate, sucrose monolaurate, sucrose monomyrate, sucrose monooleate, sucrose monoricinoleate, raffinose monocaproate, raffinose monolaurate, raffinose monomyristate, raffino monoplamitate and raffinose monooleate. Particularly preferred components (b) are raffinose monolaurate and in particular sucrose monolaurate.

Components (b) preferably have a hydrophile-lipophile balance (HLB) of at least 10.

Components (b) preferably have a purity of the ester residue of at least 80%, in particular at least 90% and very particularly at least 95%. Components (b) preferably have a melting point of from about 15 to about 60 ° C. and in particular from about 25 to about 50 ° C.

According to the above definitions for the compositions of the invention (ii) and (iii) components (c) are defined as materials in which both components (a) and (b) are at ambient temperature, e.g. have a substantial solubility at temperatures of about 20 ° C. Preferred components (c) are materials in which (a) and (b) independently of one another have a solubility of at least 10% (according to the requirement of definition (i)), preferably of at least 25% and in particular of at least 50% (in which for example, components (a) or (b) independently of one another have a solubility on the order of at least 100 mg, preferably 250 mg and in particular at least 500 mg / ml) at room temperature. Particularly preferred are materials in which component (a) has a solubility of at least 10%, preferably at least 25% and in particular at least 50%, and / or in which component (b) has a solubility of at least 100%, preferably at least 200 % and in particular at least 300% (in which, for example, component (b) has a solubility of the order of at least 1000, preferably 2000 and in particular at least 3000 mg / ml).

Components (c) which are suitable for use in the compositions according to the invention include

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c1) ethanol;

c2) C2-4 alkylene glycols;

c3) C3-5 alkylene polyols;

c4) poly (C2-4 alkylene) glycols; and c5) C3-5 alkylene polyethers or esters, and any mixtures thereof.

However, according to the general objectives of the invention, the use of ethanol either alone or in admixture with any other component (c) is generally less preferred.

If component (c) contains a C2-4-alkylene glycol (c2), it is preferably a propylene glycol, in particular 1,2-propylene glycol. If component (c) comprises a C3-5 alkylene polyol (c3), it is preferably a C3-5 alkylene triol, in particular glycerin.

If component (c) comprises a poly (C2-4 alkylene) glycol (c4), it is suitably a polyethylene glycol. For use in the compositions of the invention, these components preferably have an average molecular weight of no more than about 7000 (see definition (iv)), e.g. up to 6600, especially not more than about 2000, e.g. up to 1600 and especially not more than about 500. Such components preferably have a viscosity of at most about 15,000 mPa.s, in particular of at least about 1000 mPa.s and very particularly of at least about 200 mPa.s at 50 ° C. or in particular at ambient temperatures (cf. definition (iv)) . Suitable polyethylene glycols for use as components (c) are described, for example, in Fiedler, Lexikon der Hilfsstoffe, 2nd revised and extended edition, (1981), Vol. 2, pages 726 to 731, in particular the products PEG (polyethylene glycol) 200, 300, 400 and 600, and PEG 1000, 2000, 4000 or 6000, and in particular 200, 300 and 400, which have, for example, the following physical properties:

PEG 200

PEG 300

PEG 400

PEG 600

Molecular weight about 190-210

approx. 285-215

about 380-420

about 570-630

Viscosity, mPa.s approx. 46-53

about 66-74

about 85-95

about 130-150

Freezing point approx. -50 ° C

approx. 16 bis-12 ° C

approx. -3 to 8 ° C

approx. 15 to 25 ° C

n ^ D

about 1,459

about 1,465

about 1,465

about 1,467

If component (c) comprises a C3_5 alkylene pololyether or ester (es), it is suitably a C3-5 alkylene triol, in particular glycerol, ether or ester. Suitable components (c5) include mixed ethers or esters, i.e. Components including other ether or ester constituents, for example the transesterification products of C3-5-alkylene triolesters with other mono-, di- or polyols.

Particularly suitable components (c5) are mixed C3-5-alkylene triol / poly (C2-4-alkylene) glycol fatty acid esters, in particular mixed glycerol / polyethylene or polypropylene glycol fatty acid esters.

The particularly suitable components (c5) for the use according to the invention include products which are obtained by transesterification of glycerides, e.g. Triglycerides with poly (C2-4 alkylene) glycols, e.g. Polyethylene glycols, and optionally glycerin are available. Such transesterification products are generally made by alcoholysis of glycerides, e.g. Triglycerides, in the presence of a poly (C2-4 alkylene) glycol, e.g. Polyethylene glycol, and optionally obtained from glycerol (i.e. to carry out the transesterification from the glyceride to the polyalkylene glycol / glycerol component, i.e. via polyalkylene glycolysis / glycerolysis). In general, such a reaction is carried out by reacting the specified components (glyceride, polyalkylene glycol and optionally glycerin) at elevated temperatures under an inert atmosphere with constant agitation.

Preferred glycerides are fatty acid triglycerides, e.g. (Cio-22 fatty acid) triglycerides, including natural and hydrogenated oils, especially vegetable oils. Suitable vegetable oils include, for example, olive oil, almond oil, peanut oil, coconut oil, palm oil, soybean oil and wheat germ oil and in particular natural or hydrogenated oils which are rich in (Ci2-i6 fatty acid) ester residues.

Preferred polyalkylene glycol materials are polyethylene glycols, especially polyethylene glycols with a molecular weight from about 500 to about 4000, e.g. from about 1000 to about 2000.

Suitable components (es) thus include mixtures of C3-5 alkylene triol esters, e.g. Mono-, di- and triesters in variable relative amounts; and poly (C2-4 alkylene) glycol mono- and diesters, along with minor amounts of free C3-5 alkylene triol and free poly (C2-5 alkylene) glycol. As mentioned above, the preferred alkylene triol residue is glyceryl. Preferred polyalkylene glycol residues are polyethylene glycol residues, in particular with a molecular weight of about 500

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to about 4000. Preferred fatty acid residues are Cio-22 fatty acid ester residues, especially saturated Cio-22 fatty acid ester residues.

Components (cS) which are particularly suitable can thus alternatively be defined as follows: transesterification products of a natural or hydrogenated vegetable oil and of a polyethylene glycol and, if appropriate, of glycerol; or compositions which contain or consist of the following constituents: glyceryl mono-, di and tri-Cio-22 fatty acid esters and polyethylene glycyl mono and di-Cio-22 fatty acid esters (optionally together with, for example, minor proportions free glycerin and free polyethylene glycol).

With regard to the above definitions, the above statements apply to the preferred vegetable oils, polyethylene glycols or polyethylene glycol residues. Particularly suitable components (c5), as described above for the use according to the invention, are known and commercially available under the trade name Gelucir, in particular the following products:

i)

Gelucir 33/01,

F: = about 33-38 ° C saponification number = about 240/260;

ii)

Gelucir 35/10,

F. = about 29-34 ° C; Saponification number = about 120-140;

iii)

Gelucir 37/02,

F. = about 34-40 ° C, degree of saponification = about 200-220;

iv)

Gelucir 42/12,

F. = about 41-46 ° C,

Saponification number = 95-115;

V)

Gelucir 44/14,

F. = about 42-46 ° C, saponification number = 75-95;

vi)

Gelucir46 / 07,

F. = about 47-52 ° C, saponification number = about 125-145 ° C;

vii)

Gelucir48 / 09,

F. = about 47-52 ° C, saponification number = about 105-125;

viii)

Gelucir 50/02,

F. »about 48-52 ° C, saponification number = about 180-200;

ix)

Gelucir 50/13;

F. = about 46-41 ° C, saponification number = about 65-85;

X)

Gelucir 53/10,

F. = 48-53 ° C,

Saponification number = about 95-115;

xi)

Gelucir 62/05,

F: = about 60-65 ° C, saponification number = about 70-90.

The above products (i) to (x) all have an acid number of <2. The product (xi) has an acid number of <5. Producers (ii), (iii) and (vi) to (x) have an iodine number of <3. The product (i) has an iodine number of s 8. Products (iv) and (v) have an iodine number of <5. The product (xi) has an iodine number of <10. Components (es) with an iodine number of <1 are generally preferred. It should be noted that mixtures of components (c5) as defined above can also be used in the compositions according to the invention.

When a component (c) according to the above specific description (ie a component which satisfies any of the above definitions (i) to (iv) or any components according to the definition (c1) to (c5)) is used, the compositions of the In general, the invention component (a) in a carrier medium containing components (b) and (c). Typically, components (a) and (b) are each present in the compositions of the invention in dispersion or solution, e.g. as a molecular or multicellular dispersion or solution (possibly including a solid solution). Thus component (a) is generally present in dispersion or solution in the two components (b) and (c) and component (b) is again in solution in (c). Component (b) in the compositions according to the invention generally serves as a carrier or solubilizer (before and / or after administration) for component (a), and component (c) serves as a carrier or fluidizing agent (the present invention is of course in in no way limited to a specific functional relationship between components (a), (b) and (c) unless expressly stated otherwise).

It is further preferred that when using component (c) according to the above statements, the compositions of the invention are in solid unit dosage forms for oral administration.

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be formulated, i.e. that they are presented, for example, in encapsulated form in hard or soft gelatin which are suitable for oral administration (cf. definition (iii)). These unit dosage forms preferably contain e.g. 2 to 200 mg of component (a) per unit dose.

When using component (c) according to the above, components (a) and (c) in the compositions according to the invention are preferably in a ratio of 1: 0.5 to 50 parts by weight (a) :( c) (cf. definition (ii)). Components (a) and (b) are preferably present in a ratio of 1: 3 to 200 parts by weight (a) :( b).

If a component (c) according to the above statements is used, it is further preferred that the compositions according to the invention are non-aqueous or essentially non-aqueous (cf. definition (v)), i.e. for example, they have a water content of less than 20%, in particular less than 10% and very particularly less than 5.2 or 1%, based on the total weight of the composition.

In accordance with the above statements, a number of special embodiments are also provided according to the invention:

- A pharmaceutical composition containing a component (a) and a component (b) as defined above, and a diluent selected from any of components (c1) to (c *) as defined above or from any mixture thereof where any of the above definitions (ii) to (v) are met;

a pharmaceutical composition containing a component (a), (b) and (c2) according to the above definitions, the above definitions (ii), (iii) or (v) being fulfilled; and a pharmaceutical composition containing component (a), (b) and (c5) as defined above.

If a component (c) according to the above special statements (ie a component which corresponds to any of the definitions (i) to (iv), or any component (c1) to (c5)) is used in the compositions according to the invention, the components lie (a) and (c) suitably in the compositions in a ratio of 1: 0.5 to 50 parts by weight. Components (a) and (c) are preferably present in a ratio of about 1: 1 to 10, in particular 1: 1 to 5 and very particularly about 1: 1.5 to 2.5, i.e. approximately in the ratio of 1: 1.6 or 1: 2 parts by weight (a) :( c). Components (a) and (b) are preferably present in the compositions in a ratio of about 1: 3 to 200, preferably from about 1: 3 to 100 and in particular from about 1: 3 to 50 parts by weight. In particular, components (a) and (b) are present in a ratio of approximately 1: 5 to 20, preferably approximately 1: 5 to 10 and in particular approximately 1: 6.0 to 6.5, for example in a ratio of 1: 6.25 parts by weight (a) :( b).

If the compositions according to the invention contain sucrose monolaurate as component (b) and 1,2-propylene glycol as component (c), components (a) and (b) are preferably in a ratio of about 1: 6 to 7 parts by weight (a) :( b) and components (a) and (c) preferably in a ratio of about 1: 1.5 to 2.5, for example of about 1: 2 parts by weight (a) :( c).

Compositions according to the invention containing a component (c) as described above can be prepared in any suitable dosage form, e.g. for oral, parenteral or topical use, such as for dermal or ophthalmic use, e.g. for use on the surface of the eye, for example for the treatment of autoimmune diseases of the eye as set out above, or for intralesional injections, e.g. in the treatment of psoriasis.

Preferably such compositions are provided in unit dosage forms for both oral administration and other routes of administration.

The amount of component (a) present in such a unit dosage form can of course vary depending on the condition to be treated, the intended route of administration and the desired effect. Generally, however, such unit dosage forms contain from about 2 to about 200 mg of component (a), e.g. Cyclosporine, per unit dose.

Suitable dosage forms for oral administration include, for example, liquids, granules and the like. However, solid unit dosage forms, e.g. Tablets or capsules, in particular hard or soft gelatin capsules. Such oral unit dosage forms preferably contain about 5 to about 200 mg, especially about 10 or 20 to about 100 mg, e.g. 15, 20, 25, 50, 75 or 100 mg of component (a), e.g. Cyclosporine, per unit dose.

Compositions according to the invention which contain a component (c) according to the above statements have the further advantage that they can form the basis for compositions with modified release properties, e.g. for a delayed release of component (a) or a release of component (a) over a long period of time, for example following oral administration. Such compositions additionally contain a component (d) which is capable of modifying the release properties of the composition with respect to component (a). Such components (d) include, for example, polymeric vehicles, especially thickeners, e.g. polymeric or colloidal thickeners, as well as agents that can swell in water, e.g. water-swellable polymers or colloids.

Suitable components (d) are known from the prior art. These include:

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d1) polyacrylate and polyacrylate copolymer resins, e.g. Polyacrylic acid and polyacrylic acid-methacrylic acid resins, such as the known and commercially available products with the name Carbopol (cf. Fiedler, loc. Cit., Vol. 1, pages 206 to 207), in particular the products Carbopol 934, 940 and 941 , and Eudragit (Fiedler, loc. cit., vol. 1, pp. 372-373), in particular the products Eudragit E, L, S, RL and RS and in particular the products Eudragit E, L and S;

d2) celluloses and cellulose derivatives including: alkyl celluloses, such as methyl, ethyl and propyl celluloses; Hydroxyalkylceiluloses such as hydroxypropylcelluloses and hydroxypropylalkylcelluloses, e.g. Hydroxypropylmethyl celluloses; acylated celluloses such as cellulose acetates, cellulose acetophthalates, cellulose acetosuccinates and hydroxypropylmethyl cellulose phthalates; and salts thereof, such as sodium carboxymethyl celluloses. Examples of such products which are suitable according to the invention are known and commercially available, e.g. under the names Klucel and Methoce! (Vergi. Fiedler, loc. cit., vol. 1, p. 521 and vol. 2, p. 601), in particular the products Klucel LF, MF, GF and HF as well as Methocel K100, K15M, K100M, E 5M, E 15, E15M and E 100M.

d3) polyvinylpyrrolidones, including, for example, poly-N-vinylpyrrolidones and vinylpyrrolidone copolymers, such as vinylpyrrolidone-vinyl acetate copolymers. Examples of such compounds which are suitable according to the invention are known and commercially available, e.g. under the name Kollidon (Vergi. Fiedler, op. cit., Vol. 1, pp. 526 and 527), in particular the products Kollidon 30 and 90.

d4) polyvinyl resins, for example including polyvinyl acetates and polyvinyl alcohols, as well as other polymeric materials including tragacanth gum, gum arabic, alginates, e.g. Alginic acid and salts thereof, e.g. Sodium alginates.

d5) silica, including hydrophilic silica products such as alkylated (e.g. methylated) silica gels, especially colloidal silica products as are known and commercially available, e.g. Aerosil (Vergi. Handbook of Pharmaceutical Excipients, published by Pharmaceu-tical Society of Great Britain, pp. 253 to 256) in particular the products Aerosil 130, 200, 300, 380, O, OX 50, TT 600, MOX 80, MOX170, LK 84 and the methylated Aerosil R 972.

If component (d) is present, it is preferably in an amount of approximately 0.5 to 50%, in particular approximately 1 to 20% and very particularly approximately 2 to 10% by weight, based on the total weight of the components (a) + (b) + (c) + (d) before.

If component (c) in the compositions according to the invention contains as component (c6) a solid polymeric carrier as defined above (vi), it is preferably a water-insoluble or essentially water-insoluble polymeric carrier.

Particularly preferred as components (c6) are polyvinylpyrrolidones (Vergi. Fiedler, op. Cit., Vol. 2, pp. 748 to 750), including in particular crosslinked polyvinylpyrrolidones. Examples of such materials which are suitable according to the invention are known and commercially available, for example under the name Kollidon (ref. Fiedler, loc. Cit., Vol. 1, p. 527), Kollisept (coll. Fiedler, loc. Cit., Vol. 2, Pp. 719 to 720), Povidone and Crospovidone (Vergi. Fiedler, loc. Cit., Vol. 2, p. 751).

Particularly suitable components (c6) are polyvinylpyrrolidones with a molecular weight of at least about 10,000 and very particularly of at least about 20,000 or about 25,000, that is to say, for example, products with a molecular weight of about 40,000 or more.

Crosslinked polyvinylpyrrolidones are of particular interest. Examples of special products which are suitable according to the invention as component (c6) are Plasdone XL, Plasdone XL 10 and Cropovido-ne.

When the compositions of the invention contain a component (cß), they preferably also contain (d) a water-swellable or water-soluble component, e.g. Cellulose or cellulose derivatives as defined above (d2).

Further examples of such materials of particular interest for the compositions of the invention containing component (c6) are known and commercially available products, e.g. under the designation Avicel (Vergi. Fiedler, loc. vol. 1, pp. 160 to 161), Elcema (vergi. Fiedler, loc. vol. 1, p. 326) and Pharmacoat (vergi. Fiedler, loc. cit., vol. 2 , P. 707), e.g. the products Avicel PH 101 and PH 102, Elcema and Pharmacoat 603.

In the case of compositions according to the invention containing component (cß), component (a) is present in component (b) in solid solution including a solid, multicellular solution, i.e. completely or essentially completely in molecular or multicellular dispersion. (In practice, components (b) often have at least a certain fluidity, for example at ambient temperature or slightly elevated temperatures, and are therefore strictly speaking not “solid” is to be interpreted accordingly, for example including viscous or highly viscous systems.) The solid solution containing (a) and (b) is dispersed in a suitable manner, for example in particle form, for example in the form of fine particles within the entire component (c®). The components (c6) thus generally serve in the compositions according to the invention as a decay-accessible matrix for [(a) + (b)]. Component (d) usually serves as an agent that supports decay, e.g. upon contact with the contents of the gastrointestinal tract.

Compositions of the invention containing one component (cβ) further contain 10 appropriately

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a binder and / or lubricant as component (s). Materials suitable for use as binders / lubricants are in particular fatty acids and alkyl sulfonate salts such as metal salts, e.g. those with 10 or more carbon atoms in the fatty acid / alkyl radical, such as Cio-22 fatty acid and C10-22 alkyl sulfonate alkali metal or alkaline earth metal salts, such as sodium, calcium or magnesium salts. Examples of such materials suitable for use in the present invention are sodium lauryl sulfate and magnesium stearate (Vergi. Fiedler, op. Cit., Vol. 2, p. 584).

When the compositions of the invention contain component (c6), components (a) and (b) are suitably in a ratio of about 1: 2 to 20, preferably about 1: 2.5 to 10, and most preferably 1 : 3 to 8 before, (a) :( b).

Components (c6) are suitably present in the compositions according to the invention in an amount of at least 10%, preferably at least 15% and in particular at least 20%, based on the total weight of the composition. Suitable components (cβ) are in the compositions according to the invention in an amount of 10 to 60%, preferably 15 to 50% by weight, e.g. from about 20 to 40% by weight, such as about 25, 30 or 35% by weight, based on the total weight of the composition.

If component (d) is present, components (d) and (c6) are suitably in a ratio of 1: 0.5 to 4, preferably about 1: 1 to 3 and especially about 1: 1.5 to 2.5, e.g. about 1: 2 or about 1: 2.5 parts by weight before, [(d) i (c6)].

If a component (e) is present, the components (e) and (c6) are suitably present in a ratio of about 1: 5 to 25, preferably from about 1: 5 to 20 and in particular from 1: 7 to 15 parts by weight. [(e ^ c6)].

If the compositions according to the invention contain all three components (c6), (d) and (e), these are suitably together in an amount of about 25 to 75%, preferably about 30 to 65% and in particular 40 to 65%, based on the Total weight of the composition present. The ratio of components (a) + (b): (c) + (d) + (e) is suitably in the order of 1: 0.25 to 7.5 and preferably 1: 0.5 to 5 and in particular from 1: 0.5 to 2, e.g. about 1: 0.8, 1: 1.2 or 1: 1.3 parts by weight.

The compositions according to the invention containing a component (cβ) can be in any suitable dosage form, e.g. for oral, parenteral or topical use. Such compositions according to the invention are suitably provided in unit dosage form, either for oral or other administration.

The amount of components (a) present in such unit dosage forms will of course vary, for example, depending on the condition of the patient to be treated, the intended route of administration and the desired effect. In general, this amount suitably ranges from about 2 to about 200 mg of component (a), e.g. Cyclosporine, per unit dose.

Suitable dosage forms for oral administration include granules and the like. However, solid unit dosage forms, e.g. tableted or encapsulated forms. Such oral unit dosage forms suitably contain from about 5 to about 200 mg, preferably 10 or 20 to about 100 mg, e.g. 15.20, 25.50.75 or 100 mg, component (a), e.g. Cyclosporine, per unit dose.

If component (c) in the compositions according to the invention contains, as component (c7), an organosilicon oxide polymer or paraffin per- or subliquidum as defined above (vi), the component (c7) is preferably at temperatures up to 150 ° C. preferably easily flowable up to 100 ° C and in particular up to 50 ° C. Suitable components (c7) have a maximum viscosity of 15,000 mPa.s and preferably of 1000 mPa.s at the temperatures indicated.

Paraffinic hydrocarbons suitable for use as component (c7) are liquid and semi-solid paraffins and mixtures thereof, e.g. Paraffinium subliquidum and Paraffinum periiquidum (Vergi. Fiedler, op. Cit., Vol. 2, pp. 690 to 691). To ensure easy formulation, component (c7) suitably consists wholly or essentially of fluid or semi-solid paraffins, i.e. Paraffinum periiquidum or Paraffinum subliquidum or mixtures thereof. However, if it is desired to make compositions with, for example, slower drug release, this can be accomplished by additionally adding a solid paraffin, i.e. Paraffinum durum, adds.

If the compositions according to the invention contain only liquid or semi-solid paraffins as component (c7), these are preferably present in a ratio of about 1: 0.5 to 1.0 [liquid: semi-solid]. In this case, components (a) and (c7) are suitably in a ratio of about 1: 6 to 200, preferably about 1: 6 to 100 and especially 1: 6 to 20, e.g. 1: 8 parts by weight, available, [(a) :( c)].

If the compositions according to the invention additionally contain a solid paraffin as component (c7), the ratio of liquid / semi-solid paraffin components: solid paraffin components is suitably about 1: 0.06 to 0.1 part by weight. In this case, components (a) and (c7) are suitably in a ratio of 1: 6 to 200, preferably 1: 6 to 100 and especially 1: 8 to 20, e.g. about 1:10 parts by weight, before, (a) :( c7).

The organosilicon oxide polymers which are suitable as component (c7) include, in particular, fluid, i.e. liquid and semi-solid, polymer materials with structural units of the form (-R) zSi-O, in which

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each of the radicals R is a monovalent organic radical, such as Ci-4-alkyl, in particular methyl, or phenyl. Organosiloxane polymers with a viscosity of approximately 0.65 to 105 cP and in particular of 10 or 50 to 500 or 1000 cP are particularly preferred.

To enable easy formulation, component (c7) suitably contains liquid organosiloxane polymers, e.g. Polymethylsiloxane polymers, such as any of the various known silicone oils, such as silicone oil 550, DC 200, SF-1066 and SF-1091 (Vergi. Fiedler, op. Cit., Vol. 2, p. 826). If the compositions according to the invention contain only liquid organosiloxane polymers, the components (a) and (c7) are suitably in a ratio of about 1: 6 to 200, preferably from 1: 6 to 100 and in particular from 1: 6 to 20, e.g. of about 1: 8 parts by weight before, (a) :( c7).

Compositions with, for example, slower drug release, can be prepared using semi-solid organosiloxane polymers, e.g. of any of the various known silicone pastes, such as silicone paste A (ref. Fiedler, op. cit., vol. 2, p. 826), as component (c7) or by adding these components, e.g. to other organosilicon oxide polymers as described above. In the latter case, the ratio of liquid: semi-solid organosilicon polymers in the composition according to the invention is suitably in the order of about 1: 0.5 to 1. In this case, the ratio of components (a) :( c7) is suitably in the order of magnitude from about 1: 6 to 100 and preferably from 1: 6 to 20 parts by weight (a): ^ 7).

It should be noted that mixtures of components (c7) according to the given definition can also be used in the compositions according to the invention.

If the compositions according to the invention contain a component (c7), the components (a) and (b) are suitably in a ratio of approximately 1: 6 to 20 and preferably approximately 1: 6 to 10 and in particular approximately 1: 6.0 up to 6.5, e.g. about 1: 6.25 parts by weight before, (a) :( b).

In the case of the compositions according to the invention containing a component (c7), component (a) in component (b) is completely or substantially completely in molecular or miscelilar dispersion, e.g. in the form of a solid solution or a solid multicellular solution (the term "solid solution" being used broadly as in the case of the compositions with a component (c6)). The solid solution containing (a) and (b) is suitably in the form of particles, e.g. of fine particles, with component (c7), e.g. dispersed in the entire component (c7).

Compositions according to the invention containing a component (c7) can be in any suitable dosage form, e.g. for oral, parental or topical use, e.g. for dermal or ophthalmic use e.g. for application to the surface of the eye, e.g. for the treatment of autoimmune conditions of the eye as set out above, or for intralesional injections, e.g. for the treatment of psoriasis. Suitably they are provided in unit dosage forms for either oral administration or other routes of administration.

The amount of component (a) present in such unit dosage forms will of course depend, for example, on the condition to be treated, the intended route of administration and the desired effect. Generally these amounts suitably range from about 2 to about 200 mg of component (a), e.g. Cyclosporine, per unit dose.

Suitable dosage forms for oral administration include liquids, granules and the like. However, solid unit dosage forms, e.g. tableted or encapsulated forms, especially in the form of hard or soft gelatin capsules. Such oral unit dosage forms suitably contain about 5 to about 200 mg, preferably about 10 or 20 to about 100 mg, e.g. 15, 20, 25.50, 75 or 100 mg of component (a), e.g. Cyclosporine, per unit dose.

Compositions according to the invention containing a component (c7) have the further advantage that they can be used as the basis for compositions with modified release properties, for example for delayed release of component (a) or for release of component (a) over extended periods of time , e.g. following oral administration. Such compositions can be obtained in the manner described above by incorporating solid or semi-solid components (c7) in suitable amounts. Another possibility for the preparation of these compositions is to incorporate, as additional component (d), a component which is capable of modifying the release properties of the compositions with respect to component (a). Such components (d) include, for example, polymeric vehicles, especially thickeners, e.g. polymeric or colloidal thickeners, as well as agents that are swellable in water, e.g. water-swellable polymers or colloids, e.g. the materials defined above under (d1) to (d5).

If component (d) is present, it is suitably present in an amount of approximately 0.5 to 30%, preferably 1 to 20% and in particular approximately 1 to 10%, based on the total weight of components (a) + ( b) + (c7) + (d) before.

The components (ds) are particularly indicated for use in compounds according to the invention containing an organosilicon oxide polymer as component (c7).

Compositions according to the invention containing a component (c6) or (c7) are

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preferably non-aqueous or substantially non-aqueous, i.e. the above statements apply with regard to the compositions containing other components (c).

The compositions according to the invention can contain any additional additives, regardless of the component (c) chosen (for example regardless of whether component (c) contains one of components (c1) to (c7) according to the above statements or any mixture thereof), such as they are known from the prior art and are used conventionally, for example Antioxidants (e.g. ascorbyl palmitate, tocopherols, butylated hydroxyanisole (BHA) or butylatedroxy toluene (BHT)), flavorings and the like.

In particular, the compositions according to the invention suitably also contain one or more stabilizers or buffer substances, in particular in order to prevent hydrolysis of component (b) or degradation of component (a) during processing or during storage. Such stabilizers can include acidic stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid, and basic stabilizers such as potassium hydrogen phosphate, glycine, lysine, arginine or tris (hydroxymethyl) aminomethane.

Suitable stabilizers or buffering agents are expediently added in an amount sufficient to have a pH in the range from about 3-8, preferably from about 5-7, e.g. between 6 and 7, to achieve or maintain. Such stabilizers are generally present in an amount of up to 5% by weight, based on the total weight of the composition, before or up to 10% by weight, for example when using citric acid or acetic acid. The compositions according to the invention, in particular compositions in which component (a) is cyclosporin, with a pH within the ranges specified above are preferred.

Compositions according to the invention suitably also contain a polyoxyalkylene-free surfactant, e.g. Dioctyl succinate, dioctyl sulfosuccinate, di- [2-ethylhexyl] succinate, sodium lauryl sulfate or phospholipids such as lecithins. If a surfactant as described above is present, it is suitably present in an amount of 50, preferably 5-50, e.g. of 10-25%, based on the weight of component (b).

In the case of compositions according to the invention containing a component (a) in solid solution in component (b), e.g. if component (c) is a component (c6) or (c7) according to the foregoing, any of the aforementioned stabilizers, buffers and / or surfactants can be suitably incorporated into the solid solution phase. Such materials can also be incorporated into component (c) and the like.

The compositions according to the invention are in turn independent of the selected component (c) free or essentially free of ethanol and contain, for example, less than 5.0%, preferably less than 2.5%, for example 0-1.0% ethanol, based on the total weight of the composition.

In addition to the above explanations, a method for producing a pharmaceutical composition according to the above definition is also provided according to the invention, the method possibly involving the intimate mixing or compounding of components (a), (b) and (c) together with a component (d) and / or other components, for example Stabilizers, buffers and surfactants according to the above, comprises, where appropriate the composition obtained in unit dose form, e.g. into a unit dosage form for oral administration, e.g. by tableting, filling into gelatin capsules or other suitable measures.

If component (c) is a solvent for components (a) and (b) or contains component (c1), (c2), (c3), (c4) or (c5) as defined above , components (a), (b) and (c) are suitably brought together in the above process by dissolving components (a) and (b) together in component (c), e.g. while heating to temperatures up to 50 or 150 ° C, preferably not above 70 or 75 ° C. The mixture thus obtained can then be further compounded with components (d) and the like by making an intimate mixture according to known techniques. The filling, for example in hard or soft gelatin capsules, is suitably carried out at elevated temperatures, e.g. at temperatures up to 50 ° C to maintain fluidity of the composition, e.g. to reach in the warmth.

In the case of compositions according to the invention containing a component (a) in solid solution in component (b), e.g. in the case of compositions containing a component (c®) or (c7) as defined above, this method suitably comprises firstly preparing a solid solution of (a) in (b), followed by intimate mixing or compounding of the Solid solution obtained with the remaining components (c) and optionally (d) and the like. Solid solutions containing components (a) in (b) can be prepared by known techniques, for example by solidifying a melt containing (a) in solution in (b) or by removing the solvent from a solution of components (a) and (b). For the purposes of the invention, the latter alternative is generally preferred.

Examples of suitable solvents for components (a) and (b) are lower alkanols, e.g. Ethanol. Stabilizers, buffers and / or surfactants can be suitably added in the solution step.

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The solid solution thus obtained is then suitably compounded with component (c) and optionally with components (d) and (e) and the like, e.g. in the form of fine particles, for example by distribution in component (c).

Although ethanol can be used to prepare the compositions of the present invention, as set forth above for example in the preparation of the solid solutions, this ethanol is removed prior to completion of the final dosage form, for example by evaporation, to give an ethanol-free or substantially ethanol-free product. as set out above.

The following examples serve to illustrate the invention.

The product sucrose monolaurate L-1969 used in the examples is the commercial product from Mitsubishi-Kasei Food Corp, Tokyo 104, Japan: HLB value = at least 12.3; Purity of the lauryl ester residue = at least 95%; F. about 35 ° C; Decomposes at about 235 ° C; Surface tension in 0.1% by weight; aqueous solution = 72.0 dynes / cm at 25 ° C.

Examples 1-10

Components relative proportion (mg)

1. a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

312.5

c)

1,2-propylene glycol

100.0

total

462.5

2. a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

312.5

c)

Glycerin

100.0

total

462.5

3. a) Cyciosporin (e.g. ciclosporin) 50.0

b) Sucrose monolaurate L-1695 312.5

c) PEG 200 100.0

total 462.5

4. a) Cyciosporin (e.g. ciclosporin) 50.0

b) Sucrose monolaurate L-1695 312.5

c) PEG 400 100.0

total 462.5

5. a) Cyciosporin (e.g. ciclosporin) 50.0

b) Sucrose monolaurate L-1695 350.0

c) 1,2-propylene glycol 100.0

d) Eudragit E 50.0

total 550.0

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6. a) Cyciosporin (e.g. ciclosporin) 50.0

b) Sucrose monolaurate L-1695 350.0

c) 1,2-propylene glycol 100.0

d) Methocel K100 110.0

total

610.0

7.

a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

350.0

c)

1,2-propylene glycol

100.0

d)

Aerosi! 200

15.0

total

515.0

8th.

a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

350.0

c)

PEG 400

200.0

d)

Eudragit L

2.5

total

602.5

9.

a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

312.5

c)

Gelucir, e.g. Gelucir 42 / 12,44 / 14 or 35/10

100.0

total

462.5

10th

a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

312.5

c)

Gelucir

100.0

d)

Klucel LF

50.0

total

512.5

The composition of Example 1 is prepared by dissolving components (a) and (b) in component (c) with stirring and heating in an oil bath at 100 ° C. The compositions of Examples 2-10 are prepared in an analogous manner. In the case of Examples 5 and 8, component (d) is dissolved in the mixture of components (a) to (c) originally obtained. In the case of Examples 6, 7 and 10, component (d) is suspended in (a) to (c).

The compositions obtained are filled with heating in size 1 hard gelatin capsules (Examples 1-4 and 9) or size 0 (Examples 5-7 and 10). Encapsulated end products are obtained, the capsules each containing 50 mg of cyciosporin (e.g. ciclosporin) and suitable for administration to prevent graft rejection or in the treatment of autoimmune diseases, for example administration of 1 to 5 capsules per day.

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Examples 11-13

Components relative proportion (mg)

11. a)

Cyciosporin (e.g. ciclosporin)

100.0

b)

Sucrose monolaurate L-1695

300.0

c)

Plasdone L

350.0

d)

Avicel PH 102

150.0

e)

Sodium lauryl sulfate

25.0

total 925.0

12. a)

Cyciosporin (e.g. ciclosporin)

50.0

b1)

Sucrose monolaurate L-1695

350.0

b2)

Sucrose monostearate

50.0

c)

Crospovidone

250.0

d)

Elcema

150.0

s)

Magnesium stearate

30.0

total

980.0

13. a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

160.0

c)

Plasdone XL 10

200.0

d1)

Pharmacoate 603

25.0

d2)

Avicel PH 101

75.0

e)

Magnesium stearate

20.0

total

605.0

Compositions 11-13 above each additionally contain 25 mg (f) tartaric acid and / or 50 mg (g) dioctyl succinate and preferably both components, with a final weight of 1000 mg for composition 11, 1055 mg for composition 12 and 680 mg for composition 13 results.

Compositions 11-13 are prepared in the following manner: Components (a) and (b) are dissolved in absolute ethanol and the ethanol is thoroughly evaporated at 50 ° C under reduced pressure. Components (c) through (e) are mixed thoroughly (adding (f) and (g) if used) using conventional mixing techniques. The solid solution containing (a) + (b) is ground to a fine powder and mixed evenly into (c) to (g). The uniform mass obtained is compressed into tablets which each contain 100, 50 or 25 mg (a) and are suitable for administration to prevent graft rejection or in the treatment of autoimmune diseases, for example 1-5 tablets being administered daily.

Examples 14 and 15

Components relative proportion (mg)

14. a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

312.5

c)

Paraffinum periiquidum

397.5

total

760.0

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15. a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

312.5

c)

Siliconö [DC200

397.5

total

760.0

Components (a) and (b) are dissolved in absolute ethanol and the ethanol is then evaporated off thoroughly at 50 ° C. under reduced pressure. The solid solution obtained is ground to a fine powder and uniformly suspended in component (c). The liquid suspension obtained is filled into size 0 hard gelatin capsules. An encapsulated end product is obtained, each capsule containing 50 mg of cyciosporin (e.g. ciclosporin) and suitable for administration to prevent graft rejection or in the treatment of autoimmune diseases, for example 1-5 capsules per day.

Examples 16 and 17

Components relative proportion (mg)

16.

a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

312.5

c)

Paraffinum periiquidum

397.5

d)

Paraffinum durum

25.0

total

760.0

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a)

Cyciosporin (e.g. ciclosporin)

50.0

b)

Sucrose monolaurate L-1695

312.5

c)

Paraffinum periiquidum

397.5

d)

Aerosil

10.0

total

770.0

Compositions 16 and 17 are prepared in an analogous manner to compositions 14 and 15 above. In the case of composition 16, (c) and (d) are first combined by melting and intimate stirring. The solid solution containing (a) + (b) is then suspended in (c) + (d). In the case of compositions 17, (d) is suspended together with (a) + (b) in (c).

Equivalent compositions to those of Examples 1-17 can be prepared by substituting any other cyclosporins, e.g. [Nva) 2-ciclosporin, or by using any other fatty acid saccharide monoesters, such as those listed above, for example raffinosemonolaurate, instead of sucrose monolaurate as component (b), the same or equivalent amounts or relative amounts being used in the respective cases .

The usability of the compositions according to the invention is explained below by animal experiments or clinical studies, which are carried out, for example, in the following manner.

Examination of the bioavailability of the compositions according to the invention in dogs

(ai Test compositions

Composition I as in Example 1 Composition II as in Example 14

(bi test procedure

Groups of 8 beagle dogs (male, approximately 11-13 kg) are used. The animals are given no feed 18 hours prior to administration of the test composition, but have free access to water until administration. The test compositions are administered by a probe followed by the administration of 20 ml of 0.9 NaCl solution. 3 hours after administration of the test composition, the animals have free access to food and water.

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Blood samples of 2 ml (or 5 ml for the blank value) are taken from the saphenous vein and placed in 5 ml plastic tubes containing EDTA at the time point -15 min (blank value), 30 min and 1, 1,5, 2, 3, 4, 6, 8, 12 and 24 hours after administration. The blood samples are stored at -18 ° C before determination. The blood samples are analyzed by RIA. The areas under the curves where the blood drug concentration is plotted against time are calculated according to the trapezoidal rule. The variance analysis is carried out in relation to AUC (area under the curve), Cmax (maximum concentration) and Tmax (maximum time).

(c) results

The calculated average AUC values (in ng.h / mM) and Cmax values (in ng / mM) of typical test batches are shown in the table below together with the calculated variation (CV) in relation to the response between test animals that were the same Received composition, specified.

composition

AUC (0-24h)

CV <%)

Cmax

CV (%)

I.

3058

19.9

583

30.9

II

2894

14.91

544

19.7

From the table above it can be seen that the compositions according to the invention have a high bioavailability (AUC and Cmax) together with a relatively small fluctuation in the reaction for both AUC and Cmax.

Comparable favorable results can be obtained when using the other compositions according to Examples 1-17 and in particular according to Examples 1-10.

Clinical examinations

The advantageous properties of the compositions of the invention when administered orally can also be demonstrated in clinical studies which are carried out in the following manner.

The test subjects are adult volunteers, for example male people with higher education from 30 to 55 years. The test groups suitably comprise 12 subjects.

The following detection / imposition criteria are applied. Acquisition: normal screening ECG; normal blood pressure and normal heart rate; Body weight = 50-95 kg.

Exclusion: clinically significant, inter competitive medical condition that could interfere with absorption, distribution, metabolism, excretion or safety of the drug; Symptoms of a significant clinical illness within 2 weeks before the examination; clinically relevant abnormal laboratory values or electrocardiograms; Need for simultaneous medication for the entire duration of the experiment; Administration of any drugs that have a well-defined potential toxicity to an important organ system within the previous 3 months; Administration of any investigational drug within 6 weeks of the start of the study; Medical history of drug or alcohol abuse; Loss of 500 ml or more blood within the past 3 months; adverse drug reactions or hypersensitivity; allergic medical history with the need for drug therapy; Hepatitis B / HIV positive.

A complete physical examination and an ECG are carried out before and after the test. The following parameters are evaluated 1 month before and after the examination: Blood: number of red blood cells, hemoglobin, hematocrit, erythrocyte sedimentation, number of white blood cells, smear, number of platelets and glucose when fasted; Serum / Plasma: total protein and electrophoresis; Cholesterol, triglycerides, Na +, Ka +, Fe ++, Ca-1 "1-, Cl ~, creatinine, urea, uric acid, SGOT, SGPT, gamma-GT, alkaline phosphatase, total bilirubin, a-amylase;

Urine: pH, microaibumin, glucose, erythrocytes, keto body, sediment. Furthermore, the creatinine clearance is determined 1 month before the start of the experiment.

The test subjects each receive test compositions in an arbitrary sequence. The compositions are administered all at once in a total dose of 150 mg cyciosporin, e.g. Ciclosporin, administered, with at least 14 days between the individual administrations.

The administration is carried out in the morning after a fasting period of 10 hours, during which only water intake is allowed. Only decaffeinated drinks are allowed within 24 hours of administration. Subjects should not smoke within 12 hours of administration. The subjects received a standardized lunch meal 4 hours after the administration.

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Blood samples (2 ml) are taken 1 hour before administration and after administration at times 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 9, 12, 14, 24, 28 and 32 hours. Blood samples of 2 ml are taken immediately before administration and 12, 24 and 48 hours after administration to determine creatinine. The samples for the cyclosporin determination are obtained in 2 EDTA-coated polystyrene tubes (1 ml each) at the respective times and, after massive movement, frozen at -20 ° C. Cyciosporin is determined in whole blood by RIA using a specific and / or non-specific MAB test, the detection limit in both cases being approximately 10 ng / ml.

In the tests carried out according to the above procedure, for example, when comparing the composition of Example 1 in the form of a hard gelatin capsule with the current ciciosporin drinking solution (ciclosporin = 50 mg, labrafil = 150 mg, ethanol = 50 mg), corn oil = 213 mg, in the form of soft gelatin capsules with a final weight of 463 mg / dose) as standard significantly increased bioavailability concentrations for the composition of Example 1 compared to the standard both in terms of AUC values (0-32 h) and in terms of Cmax Values determined. Furthermore, a comparison of the temporal change in ciclosporin concentrations in whole blood (determined by specific monoclonal RIA) following a single administration of the test compositions with a ciclosporin dose of 150 mg shows a marked reduction in the variability of the response among all subjects who made up the composition of Example 1 compared to all subjects who received the standard composition.

Similar or equivalent results can be obtained following oral administration of other compositions of the invention as described in the present examples.

Claims (1)

Claims 1. Pharmaceutical composition containing a) a cyciosporin as active ingredient, b) a fatty acid saccharide monoester and c) a diluent or carrier, where i) component (c) is a solvent for the two components (a) and (b), components (a) and (b) in each case independently of one another have a solubility in component (c) of at least 10% at ambient temperature; or ii) component (c) is a solvent for the two components (a) and (b) and components (a) and (c) in the composition in a ratio of 1: 0.5 to 50 Parts by weight (a) :( c) are present; or iii) component (c) is a solvent for both components (a) and (b) and the composition is formulated in a solid unit dosage form suitable for oral administration; or iv) component (c) a poly (C2-4-alkylene) glycol with an average molecular weight of at most 7000 or a viscosity at 50 ° C. of at most 15000 mPa.s or a C3-5-AI-kylenpolyolether contains or esters; or v) the composition is non-aqueous or substantially non-aqueous; or vi) the composition contains as component (c) a solid polymeric carrier, an organosilicon oxide polymer or paraffin per- or sub-liquidum and component (a) is present in the composition in solid solution in component (b). 2. Pharmaceutical composition according to claim 1, comprising a) a cyciosporin as active ingredient, b) a fatty acid saccharide monoester and c) a diluent selected from the following group: c1) ethanol; c2) C2-4 alkylene glycols; c3) C3-5 alkylene polyols; c4) poly (C2-4 alkylene) glycols; and mixtures thereof, wherein ii) components (a) and (c) are present in the composition in a ratio of 1: 0.5 to 50 parts by weight (a) :( c); or iii) the composition is formulated in a solid unit dosage form suitable for oral administration; or iv) component (c) contains a component (C *) with an average molecular weight of at most 7,000 or a viscosity at 50 ° C. of at most 15,000 mPa.s; or v) this composition is non-aqueous or substantially non-aqueous. 3. Pharmaceutical composition according to claim 1, comprising a) a cyciosporin as active ingredient, b) a fatty acid saccharide monoester and c2) 1,2-propylene glycol 19th 5 10th 15 20th 25th 30th 35 40 45 50 55 CH 679 277 A5 wherein ii) components (a) and (c2) are present in the composition in a ratio of 1: 0.5 to 50 parts by weight (a) :( c2); or iii) the composition is in solid unit dosage form suitable for oral administration; or (v) the composition is non-aqueous or substantially non-aqueous. 4. Composition according to one of claims 1-3, characterized in that components (a) and (b) are present in a ratio of 1: 3 to 200 parts by weight (a) :( b). 5. Pharmaceutical composition according to claim 1, comprising a) a cyciosporin as active ingredient in solid solution in, b) a fatty acid saccharide monoester and cß) a polymeric carrier containing polyvinylpyrrolidone. 6. The composition according to claim 5, characterized in that components (a) and (b) are present in a ratio of 1: 2 to 20 parts by weight (a) :( b) and component (c6) in an amount of at least 10 % By weight, based on the total weight, is present. 7. Composition according to one of claims 1-6, characterized in that it is in unit dosage form and contains 2-200 mg component (a) per unit dose. 8. Pharmaceutical composition according to claim 1, containing a) a cyciosporin as active ingredient b) a fatty acid saccharide monoester and c2) 1,2-propylene glycol, the composition being in unit dose form and containing 20 to 100 mg component (a) per unit dose, the components ( a) and (b) in the composition in a ratio of 1: 3 to 200 parts by weight (a) :( b) and the components (a) and (c2) in the composition in a ratio of 1: 0.5 to 50 parts by weight (a) :( c) are present. 9. Composition according to one of claims 1-8, characterized in that component (a) is ciclosporin or [Nva] 2-ciclosporin. 10. The composition according to any one of claims 1-9, characterized in that component (b) contains raffinose or sucrose monolaurate. 20th