AT404552B - NEW GALENIC FORMULATIONS CONTAINING CYCLOSPORINE - Google Patents

Description

AT 404 552 B

The invention relates to new gaienische formulations containing cyclosporin 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 immunosuppressive, anti-inflammatory and / or antiparasitic effect. The cyclosporins were the first to isolate the naturally occurring fungal metabolite ciclosporin or cyclosporin, which is also known as cyclosporin A and is commercially available under the trade name SANDIMMUNR or SANDIMMUNE *. Ciclosporin is the cyclosporin of the formula A. -MeBmt-aAbu-Sar-MeLeu-Val-HeLeu-Ala- (D) Ala-HeLeu-MeLeu-MeVal-. (A) 2345 6 7 8 9 10 11 in the -MeBmt- the N-methyl- (4R) -4-but-2E-en-1-yl-4-methyl- (L) -threonyl radical of the formula B. means CB} x

ch2

HO

-N-CH-CO- (B) (S) CB, 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 were concerned with the immunosuppressive activity, 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. There are numerous reports and results in the literature on in vitro tests, animal models and clinical studies. it has been proposed to the specific autoimmune diseases for which treatment with cyclosporine or applied include, autoimmune hematological disorders (including eg hemolytic anemia, apiastische anemia, pure Erythrozytenanaemie and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener Granulamtose, dermatomyositis , chronic active hepatitis, severe myasthenia, psoriasis, Steven Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (including, for example, ulcerative colitis and Crohn's disease- 2

AT 404 552 B heit), 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, interstitial pulmonary pulmonary fibrosis (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 the treatment of malaria, coccidiomyosis and schistosomiasis, and more recently also the use in cancer therapy, e.g. as a means of reversing or removing resistance to other antineoplastic 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 synthesized using total or semi-synthetic methods or 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, and various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins including the so-called dihydro-cyclosporins (in which the residue -xy- of the -MeBmt residue (formula B above) is saturated to form -xy = -CH2-CH2-); derivatized cyclosporins in which, for example, another substituent on the a-carbon atom of the sarcosyl residue in the 3-position of the cyclosporin molecule is introduced); Cyclosporins in which the -MeBmt residue is present in isomeric form (in which, for example, the configuration at positions 6 'and 7' of the MeBmt residue is cis 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 86/02080; 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 in the structural characterization in Römpp Chemie-Lexikon, 9th edition, page 842 now includes, for example, [Thrp-, [Val] 2-, [Nva] 2- and [Nvap-fNva] 5-ciclosporin (also known as cyclosporins C, D, G and M) [3'-0-acyl-MeBmt] 1-cyclosporin (also known as cyclosporin A-acetate), [dihydro-MeBmtMValp-cyclosporin (also known as dihydro-cyclosporin D), [3 * -Desoxy-S'-oxo-MeBmt] 1 - [Val J2- and - [Nva] 2-ciclosporin, ((D) fluoromethyl-sarp-ciclosporin [(D) Ser] 8-ciclosporin, [Melle] 11-Ciclosporin, [(D) Meval] 11-Ciclosporin (also known as Cyclosporin H), [MeAla] 6-Ciclosporin, [(D) Prop-Ciclosporin and the like. (In accordance with the now agreed nomenclature for Cyclosporins Term referring to the structure of ciclosporin (ie cyclosporin A) This is done by first denoting the amino acid residues present that differ from those in ciclosporin (e.g. " [(D) Pro] 3 " to indicate Admit that the cyclosporin in question has a - (D) pro residue instead of the -Sar residue in the 3-position and then the expression " Ciclosporin " applied to express 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 that of ciclosporin or a more specific utility, for example a particular 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 field 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. The commercially available ciclosporin drinking solution uses metha- 3

AT 404 552 B nol and olive oil as a carrier medium in conjunction 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 cyclosporin in solution, the ethanol content must be high. Evaporation of the ethanol, e.g. from capsules or from other dosage forms, for example when opened, leads to the development of a cyclosporin precipitate. 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 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 also with the same individuals at different times in the course of therapy. For example, reports in the literature show that the therapy currently available 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 depending on time is often observed in individuals.

In order to achieve an effective immunosuppressive therapy, cyclosporin levels in the blood or in the serum must be maintained in a special area. The required range can in turn be dependent 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 will or will 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 immunoas-say 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 in the art, including both solid and liquid oral dosage forms.

For example, JP-A-61 280 435 (Takada et al.) Proposes 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, palmate 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 products known and commercially available under the trade names Cremophore RH and Nikkol HCO 60. These products are clearly stated to be preferred, for example, over the sucrose ester-based surfactants mentioned.

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 4 ΑΤ 404 552 Β is required. That as " see-through solution " The preparation described 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 for this reason the use as any practical or commercial galenic form is excluded. 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 JP-A-01 038 029 (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. Urea, 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 of applying the teaching of the aforementioned JP-A-61 280 435. In this case, there is no reference to sucrose esters as possible surface-active components. The reference to sorbitan esters in the list of 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 galenic cyclosporin formulations are provided which contain fatty acid saccharide monoesters as primary carrier components. These formulations address the difficulties encountered in the prior art in therapy with cyclosporin, 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 cyclosporin 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 increasing the absorption / bioavailability levels and reducing the fluctuation in the absorption / bioavailability levels both in individuals receiving cyclosporin therapy and between different individuals. Applying the teaching of the present invention, cyclosporin dosage forms are obtainable which ensure a reduced fluctuation in the achieved cyclosporin / blood / blood serum levels in dosages for individual patients and for individual patients / individual patient groups 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 cyclosporine 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 production of non-alkanol based compositions, i.e. that are free or essentially free of ethanol. With such compositions, the stability problems discussed above and the associated processing difficulties 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. 5

AT 404 552 B

In particular, according to the invention, a pharmaceutical liquid or semi-liquid composition is provided in a capsule, which contains the following components: a) a cyclosporin as active ingredient, b) a fatty acid saccharide monoester and c) a second auxiliary, i) being the second auxiliary (c) is a solvent for the two components (a) and (b), the components (a) and (b) each independently having a solubility in component (c) of at least 10% at ambient temperature; or ii) the second auxiliary (c) is a solvent for the two components (a) and (b), the components (a) and (c) in the composition in a ratio of 1: 0.5 up to 50 parts by weight [(a) :( c)] are present; or iii) the second excipient (c) is a solvent for the two components (a) and (b) and the composition is formulated in a solid unit dosage form suitable for oral administration; or iv) the second auxiliary substance (c) contains a poly (C2-4-alkylene) glycol with an average molecular weight of at most 7000 or a viscosity at 50 * C of at most 15,000 mPa.s or a C3_5-alkylene polyol ether or ester ; or v) the composition is non-aqueous or substantially non-aqueous; or vi) the composition (c) contains a solid polymeric carrier, an organosilicon oxide polymer or paraffinum per- or sub-liquidum in an amount of 1 to 50% by weight, based on the total weight of the composition, and the component ( a) dissolved in the composition in (b) and (b) suspended in (c).

The compositions defined above represent new and particularly advantageous variants of the products generally claimed in FR-A1 2,620,336 published on March 17, 1989.

The above definitions (i) to (vi) are to be understood so 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 in (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 " as used herein and in the appended claims. It is to be understood that it defines compositions, the individual components or constituents of which are themselves pharmaceutically acceptable, which, for example, are intended for oral use when intended for oral administration or for topical use when intended for topical administration.

The preferred cyclosporin in component (a) is cyclosporin. Another preferred component (a) is [NvaF-Ciclopsorin, which is also known as Cyclosporin G.

Preferred components (b) for use in the compositions according to 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 Ce. ^ Fatty acid saccharide monoesters, in particular water-soluble C6-ie * fatty acid saccharide monoesters. Particularly suitable components (c) are caproic acid (Ce) -, caprylic acid (Cs) *, capric acid (Cio) -, lauric acid (C12) -, myristic acid (Cu) -, palmitic acid (Cie) -, oleic acid (Ci8) -, ricinoleic acid (Ci8 > - and 12-hydroxystearic acid (Cisj-saccharide monoester, especially lauric acid saccharide monoester.

The saccharide residue of component (b) can 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 Ce-u fatty acid disaccharide monoesters and C8-18 fatty acid trisaccharide monoesters.

Particularly suitable saccharide residues are sucrose and raffinose residues. Particularly suitable components (b) are thus sucrose monocaproate, sucrose monolaurate, sucrose monomyristate, saccharose monooleate, sucrose monoricinoleate, raffinose monocaproate, raffinose monolaurate, raffinose mono-myristate, raffinose mono-pleatate and raffinose mono-oleate. Particularly preferred components (b) are raffinose monolaurate and in particular sucrose monolaurate. 6

AT 404 552 B

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%. The components (b) preferably have a melting point of about 15 to about 60'C and in particular of about 25 to about 50 ° C.

According to the above definitions for the compositions of the invention (ii) and (iii), component (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 of 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 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-s-alkylene polyol (c3), it is preferably a C3-s-alkylene triol, in particular glycerol.

When 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 7,000 (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 Hilfsmittel, 2nd revised and extended edition, (1981), Vol. 2, pages 726 to 731, in particular the products PEG (polyethylene glycol) 200, 300, 400 and 600, as well as 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 viscosity, mPa.s freezing point n ^ o approx .190-210 approx. 46-53 approx. -50 * C approx. 1.459 approx. 285-215 approx. 66-74 approx. 16 to -12 * C approx. 1.465 approx. 380-420 approx. 85-95 approx .-3 to 8 * C approx.1.465 approx. 570-630 approx. 130-150 approx. 15 to 25C approx. 1.467

If component (c) comprises a C3-5 alkylene pololyether or ester (c5), 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 components, for example the transesterification products of C3-s-alkylene triol esters with other mono-, di- or polyols. 7

AT 404 552 B

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

The particularly suitable components (c?) 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. (C10_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_, 6-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 (c5) thus comprise 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, together 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 to about 4000. Preferred fatty acid residues are C 1-22 fatty acid ester residues, in particular saturated Cio-22 fatty acid ester residues.

Components (c5) 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-C10-22 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 have been described above for the use according to the invention, are known and commercially available under the trade name Gelucir, in particular the following products: >) Gelucir 33/01, F: = about 33-38 C saponification number = about 240/260; ») 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 * 0, saponification number = 95-115; v) Gelucir 44/14, F. = about 42-46 * C, saponification number = 75-95; vi) Gelucir 46/07, F. = about 47-52 * C, saponification number = about 125-145 * C; vii) Gelucir 48/09, 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 46-410 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 80-65 * 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. Products (ii), (iii) and (vi) to (x) have an iodine number of <3. The product (i) has an iodine number of 28. Products (iv) and (v) have an iodine number of <5. The product (xi) has an iodine number of <10. Components (c5) 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 specific description above (ie a component which satisfies any of the above definitions (i) to (iv) or any component according to the definition (c1) to (c5)) is used, the compositions contain the In general, the invention component (a) in a carrier medium containing components (b) and (c). Usually 8

AT 404 552 B, 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 (optionally 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) as set forth above, the compositions of the invention are formulated in solid unit dosage forms for oral administration, 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)] (see definition (ii)). Components (a) and (b) are preferably present in a ratio of 1: 3 to 200 parts by weight of [(a) :( b)].

If a component (c) is used as described above, it is further preferred that the compositions according to the invention are non-aqueous or essentially non-aqueous (see 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, a number of specific embodiments are also provided according to the invention: A pharmaceutical composition containing a component (a) and a component (b) according to the above definitions, and a diluent, which is among any components (c1 ) to (c4) is selected according to the above definitions or from any mixture thereof, any of the above definitions (ii) to (v) being fulfilled; 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 specific 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 a 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 9

AT 404 552 B

Effect vary. 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, especially 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: 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. Redler, loc. Cit., Vol. 1, pp. 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; Hydroxyalkyl celluloses such as hydroxypropyl celluloses and hydroxypropylalkyl celluloses e.g. Hydroxypropylmethyl celluloses; acylated celluloses such as cellulose acetates, cellulose acetophthalates, cellulose acetosuccinates and hydroxypropyl methyl cellulose phthalates; and salts thereof, such as sodium carboxymethyicelluloses. Examples of such products which are suitable according to the invention are known and commercially available, e.g. under the names Klucel and Methocel (see 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 K 100, K 15M, K 100M, E 5M, E 15, E 15M 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 (cf. Redler, loc. vol. 1, pp. 526 and 527), in particular the products Koliidon 30 and 90. d4) polyvinyl resins, for example including polyvinyl acetates and polyvinyl alcohols, and other polymeric materials including tragacanth gum , Gum arabic, alginates, e.g. Alginic acid and salts thereof, e.g. Sodium alginates. ds) 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 (cf. Handbook of Pharmaceutical Excipients, published by Pharmaceutical Society of Great Britain, pp. 253 to 256) in particular the products Aerosil 130, 200, 300, 380, Ο, OX 50, TT 600, MOX 80, MOX 170, 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 (cs) a solid polymeric carrier as defined above (vi), this is preferably a water-insoluble or essentially water-insoluble polymeric carrier.

Particularly preferred as components (c6) are polyvinylpyrrolidones (cf. Redler, loc. 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 (cf. Redler, loc. Vol. 1, p. 527), Kollisept (cf. Fiedler. Loc., Vol. 2, p . 719 to 720), Povidone and Crospovidone (see Redler, 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. 10th

AT 404 552 B

Cross-linked polyvinyl pyrrolidones are of particular interest. Examples of special products which are suitable as component (c6) according to the invention are Plasdone XL, Plasdone XL 10 and Cropovidone.

When the compositions of the invention contain a component (c6), they preferably also contain (d) a water-swellable or water-soluble component, e.g. Cellulose or cellulose derivatives as defined above (d2).

Other examples of such materials of particular interest for the compositions of the invention containing component (c8) are known and commercially available products. e.g. under the designation Avicel (cf. Fiedler, op. cit., vol. 1, pp. 160 to 161), Elcema (comp. Redler, loc. cit., vol. 1, p. 326) and Pharmacoat (comp. Redler, 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 (c6), component (a) is present in component (b) in a 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 ''. The expression `` solid solution '' as used in the present description and the claims used 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 particulate form, for example in the form of fine particles within the entire component (c8). The components (c8) 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 component (c8) also suitably contain a binder and / or lubricant as component (e). 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 Ci0-22 fatty acid and Ci o-22 alkysulfonate alkali metal or alkaline earth metal salts, such as sodium, calcium or magnesium salts. Examples of such materials that are suitable for use in the present invention are sodium lauryl sulfate and magnesium stearate (see Fiedler, op. Cit., Vol. 2, p. 584).

When the compositions of the invention contain component (c8), 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 (c8) 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 (c8) are present 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.

When component (d) is present, components (d) and (c8) 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) :( ce)].

If a component (e) is present, the components (e) and (c8) are suitably present in a ratio of about 1: 5 to 25, preferably about 1: 5 to 20 and in particular 1: 7 to 15 parts by weight. [(6) :( 08)].

If the compositions according to the invention contain all three components (c8), (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 the components [(a) + (b)]: [(c) + (d) + (e)] is suitably on 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, for example about 1: 0.8, 1: 1.2 or 1: 1.3 parts by weight.

The compositions according to the invention containing a component (c8) can be in any suitable dosage form, e.g. for oral, parenteral or topical use. Suitably, such compositions according to the invention are 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. Generally, this amount suitably ranges from about 2 to about 200 mg of component (a), e.g. Cyclosporine, per unit dose. 11

AT 404 552 B

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 of 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 paraffinum per- or subliquidum as defined above (vi), the component (c7) is preferably at temperatures up to 150 ° C. preferably easily flowable up to 10CTC and in particular up to 50'C. Suitable components (c7) have a maximum viscosity of 15,000 mPa.s and preferably 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 perliquidum (see Fiedler, op. Cit., Vol. 2, pp. 690 to 691). To ensure easy formulation, component (c7) suitably consists entirely or essentially of fluid or semi-solid paraffins, i.e. Paraffinum perliquidum 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 from about 1: 6 to 100 and especially from 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 in particular 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 formula (-R) iSi-0, in which 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 10s cP and in particular of 10 or 50 to 500 or 1000 cP are particularly preferred.

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 (see Fiedler, loc. 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, [(a) :( c7)].

Compositions with, for example, slower drug release, can be prepared using semi-solid organosiioxane polymers, e.g. any of the various known silicone pastes, such as silicone paste A (see Fiedler, loc. cit., vol. 2, p. 826), as component (c7) or by adding these components, e.g. to other organosilica 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 on the order of about 1: 6 to 100 and preferably from 1: 6 to 20 parts by weight [(a) :( c7)].

It should be noted that mixtures of components (c7) as defined 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 about 1: 6 to 20 and preferably about 1: 6 to 10 and in particular about 1: 6.0 up to 6.5, e.g. about 1: 6.25 parts by weight, [(a) :( b)].

In the case of the compositions according to the invention containing a component (c7), component (a) in component (b) is wholly or substantially completely in molecular or multicellular 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). 12th

AT 404 552 B

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 either for oral administration or for 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. In general, 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, in particular 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) also have the 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 production of these compositions is to incorporate, as additional component (d), a component which is able to modify 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.

Components (d5) are particularly indicated for use in compounds according to the invention containing an organosilicon polymer as component (c7).

Compositions according to the invention containing a component (c6) or (c7) are preferably non-aqueous or essentially non-aqueous, i.e. the above statements apply with regard to the compositions containing other components (c).

The compositions according to the invention can, 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), contain any additional additives, such as they are known from the prior art and are used conventionally, for example Antioxidants (e.g. ascorbyl palmitate, tocopheroie, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (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 the hydrolysis of component (b) or the 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 ciclosporin, 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 according to the above statements is present, it is suitably 13

AT 404 552 B se 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. when component (c) is a component (c6) or (c7) according to the above, 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 statements, 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 foregoing, where the composition obtained may be in unit dosage 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 a component (c1), (c2), (c3), (c4) or (&lt;?) according to The above definition, 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 component (c6) or (c7) as defined above, this method suitably involves first preparing a solid solution of (a) in (b), followed by intimately mixing or compounding the resulting ones solid solution 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 alkanoic e.g. Ethanol. Stabilizers, buffers and / or surfactants can be suitably added in the solution step.

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 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 of 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; Decomposition at about 235 * C; Surface tension in 0.1% by weight; aqueous solution = 72.0 dynes / cm at 25 * C. 14

AT 404 552 B

Examples 1-10 relative

Ingredients 1. a) Cyclosporin (e.g. ciclosporin) b) Sucrose monolaurate L-1695 c) Total 1,2-propylene glycol 2. a) Cyclosporin (e.g. ciclosporin) b) Sucrose monolaurate L-1695 c) Total glycerin 3. a) Cyclosporin (e.g. Ciclosporin) b) sucrose monolaurate L-1695 c) total PEG 200 a) cyclosporin (e.g. ciclosporin) b) sucrose monolaurate L-1695 c) PEG 400 total 15

AT 404 552 B 5. a) Cyclosporin (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 6. a) Cyclosporin ( e.g. ciclosporin) 50.0 b) sucrose monolaurate L-1695 350.0 c) 1,2-propylene glycol 100.0 d) Methocel Kl00 110.0 total 610.0 7. a) cyclosporin (e.g. ciclosporin) 50.0 b) sucrose monolaurate L -1695 350.0 c) 1,2-propylene glycol 100.0 d) Aerosil 200 15.0 total 515.0 8. a) Cyclosporin (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) Cyclosporin (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 10. a) Cyclosporin (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). 16

AT 404 552 B

The resulting compositions are filled with heat 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 cyclosporin (e.g. ciclosporin) and are suitable for administration to prevent graft rejection or in the treatment of autoimmune diseases, for example administration of 1 to 5 capsules per day.

Examples 11-13

Components relative proportion (mg) 11 a) Cyclosporin (e.g. ciclosporin) b) Sucrose monolaurate L-1695 c) Plasdone L d) Avicel PH 102 e) Sodium lauryl sulfate 100.0 300.0 350.0 150.0 25.0 total 925.0 12 a) Cyclosporin ( e.g. ciclosporin) b1) sucrose monolaurate L-1695 b2) sucrose monostearate c) crospovidone d) Elcema e) magnesium stearate 50.0 350.0 50.0 250.0 150.0 30.0 total 980.0 13 a) cyclosporin (e.g. ciclosporin) b) sucrose monolaurate L-1695 XL 10) d1) Pharmacoate 603 d2) Avice! PH 101 e) Magnesium stearate 50.0 160.0 200.0 25.0 75.0 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. 17th

AT 404 552 B

Examples 14 and 15

Components relative proportion (mg) 14 a) Cyclosporin (e.g. ciclosporin) b) Sucrose monolaurate L-1695 c) Paraffinum perliquidum 50.0 312.5 397.5 total 760.0 15 a) Cyclosporin (e.g. ciclosporin) b) Sucrose monolaurate L-1695 c) Silicone oil DC 200 50.0 312.5 397.5 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 into a fine powder and suspended uniformly 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 cyclosporin (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) Cyclosporin (e.g. ciclosporin) b) Sucrose monolaurate L-1695 c) Paraffinum subliquidum d) Paraffinum durum 50.0 312.5 372.5 25.0 total 760.0 17 a) Cyclosporin (e.g. ciclosporin) b) Sucrose monolaurate L-1695 c) Paraffinum perliquidum d) Aerosil 50.0 312.5 397.5 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 in (c) together with [(a) + (b)].

Equivalent compositions to those of Examples 1-17 can be prepared by substituting any other cyclosporins, e.g. [Nva ^ -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. 18th

AT 404 SS2 B

Examination of the bioavailability of the compositions according to the invention in dogs (a) test compositions

Composition I as in Example 1 Composition II as in Example 14 (b) Test Procedure

Groups of 8 beagle dogs (male, about 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.

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 the 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 analysis of variance 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 / mr1) and Cmax values (in ng / ml'1) of typical experimental approaches are shown in the table below together with the calculated variation (CV) in relation to the response between test animals that obtained the same composition.

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 of the invention have high bioavailability (AUC and Cmax) along with a relatively small variation in response 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 entry / exclusion 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 19

Claims (31)

AT 404 552 Pie; 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 in the fasted state; Serum / Plasma: total protein and electrophoresis; Cholesterol, triglycerides, Na +, Ka +, Fe ++, Ca ++, CI ', creatinine, urea, uric acid, SGOT, SGPT, gamma-GT, alkaline phosphatase, total bilirubin, <* amylase; Urine: pH, microalbumin, glucose, erythrocytes, keto body, sediment. The creatinine clearance is also 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. Subjects are given a standardized midday meal 4 hours after administration. Blood samples (2 ml) are taken 1 hour before administration and after administration at the 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 moderate agitation, 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 investigations 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 ciclosporin 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 in comparison with 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. 1. Pharmaceutical liquid or semi-liquid compositions in a capsule, containing a) a cyciosporin as active ingredient, b) a fatty acid saccharide monoester and c) a second auxiliary, i) the second auxiliary (c) being a solvent for the two components (a) and (b), components (a) and (b) each independently having a solubility in component (c) of at least 10% at ambient temperature; or ii) the second auxiliary (c) is a solvent for the two components (a) and (b), the components (a) and (c) in the composition in a ratio of 1: 0.5 up to 50 parts by weight of [(a) :( c)] are present; or iii) the second excipient (c) is a solvent for the two components (a) and (b) and the composition is formulated in a solid unit dosage form suitable for oral administration; or 20 AT 404 552 B iv) the second auxiliary (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 15,000 mPa.s or a C3- contains s-alkylene polyol ether or ester; or v) the composition is non-aqueous or substantially non-aqueous; or vi) the composition (c) contains a solid polymeric carrier, an organosilicon oxide polymer or paraffinum per- or sub-liquidum in an amount of 1 to 50% by weight, based on the total weight of the composition, and the component ( a) is present in the composition dissolved in (b) and (b) suspended in c). 2. Pharmaceutical composition containing a) a cyclosporin 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 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 (c4) with an average molecular weight of at most 7000 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. Composition according to claim 2, characterized in that component (c) is selected from the following group: c2) 1,2-propylene glycol, c3) glycerol and c4) polyethylene glycols with an average molecular weight of at most 7000 or a viscosity at 50 · C. of a maximum of 15,000 mPa.s. 4. Pharmaceutical composition containing a) a cyclosporin as active ingredient, b) a fatty acid saccharide monoester and c2) 1,2-propylene glycol, where ii) components (a) and (c2) in the composition in a ratio of 1: 0.5 up to 50 parts by weight of [(a) :( c2)]; or iii) the composition is formulated in solid unit dosage form suitable for oral administration; or (v) the composition is non-aqueous or substantially non-aqueous. 5. Pharmaceutical composition containing a) a cyclosporin as active ingredient, b) a fatty acid saccharide monoester and c5) a C3_5 alkylene polyol ether or ester. 6. Composition according to claim 5, characterized in that component (c5) contains a transesterification product of a natural or hydrogenated vegetable oil and a polyethylene glycol. 7. Composition according to claim 6, characterized in that component (c5) contains a transesterification product of a natural or hydrogenated vegetable oil and a polyethylene glycol with a molecular weight of 500-4000. 21 AT 404 552 B 8. Composition according to claim 6 or 7, characterized in that component (c5) contains a transesterification product of a natural or hydrogenated vegetable oil, a polyethylene glycol and glycerol. 9. Composition according to one of claims 5-8, characterized in that components (a) and (c5) are present in a ratio of 1: 0.5 to 50 parts by weight. 10. Composition according to one of claims 1-9, characterized in that the components (a) and (c) or in the case of claim 4 the component (c2) or in the case of claims 5-9 the component (c5) in a ratio from 1: 1 to 10 parts by weight of [(aMcKfc2) / ^)]. 11. The composition according to claim 10, characterized in that the ratio is 1: 1.5 to 2.5 parts by weight. 12. The composition according to any one of claims 1-11, characterized in that components (a) and (b) are present in a ratio of 1: 3 to 200 parts by weight of [(a) :( b)]. 13. The composition according to claim 12, characterized in that the ratio is 1: 5 to 20 parts by weight. 14. The composition according to claim 13, characterized in that the ratio is 1: 6 to 6.5 parts by weight. 15. Pharmaceutical composition containing a) a cyclosporin as active ingredient in solid solution in b) a fatty acid saccharide monoester and c6) a solid polymeric carrier. 16. The composition according to claim 15, characterized in that component (c6) contains polyvinyl pyrrolidone. 17. The composition according to claim 15 or 16, characterized in that components (a) and (b) are present in a ratio of 1: 2 to 20 parts by weight of [(a): (b)]. 18. The composition according to claim 17, characterized in that the ratio is 1: 3 to 8 parts by weight. 19. The composition according to any one of claims 15-18, characterized in that it additionally (d) contains a water-soluble, but water-absorbing component. 20. The composition according to claim 19, characterized in that components (d) and (c8) are present in a ratio of 1: 0.5 to 4 parts by weight [(d) :( c *)]. 21. The composition according to any one of claims 1 to 20, characterized in that it is in unit dose form containing 2 to 200 mg of component (a) per unit dose. 22. The composition according to claim 21, characterized in that it contains 10 to 100 mg of component (a) per unit dose. 23. Pharmaceutical composition containing a) a cyclosporin as active ingredient, b) a fatty acid saccharide monoester and c2) 1,2-propylene glycol, the composition being in unit dosage form and containing 20 to 100 mg component (a) per unit dose, components (a) and (b) in the composition in a ratio of 1.3 to 200 parts by weight of [(a): (b) J and components (a) and (c) in the composition in a ratio of 1: 0.5 to 50 parts by weight are present. 22 AT 404 552 B 24. The composition according to claim 23, characterized in that components (a) and (b) are in a ratio of 1: 5 to 10 parts by weight and components (a) and (c) in a ratio of 1: 1.5 up to 2.5 parts by weight. 25. Composition according to one of claims 1 to 24, characterized in that it is encapsulated in an oral dosage form in soft or hard gelatin. 26. The composition according to any one of claims 1 to 25, characterized in that it additionally contains a stabilizer or a buffering agent. 27. Summary according to claim 26, characterized in that it is buffered to a pH of 3 to 8. 28. Composition according to one of claims 1 to 27, characterized in that component (a) is ciclosporin or [Nvap-ciclosporin. 29. The composition according to any one of claims 1 to 28, characterized in that component (b) contains a water-soluble fatty acid saccharide monoester. 30. The composition according to claim 29, characterized in that component (b) contains a Ce-ie fatty acid di or tri-saccharide monoester. 31. The composition according to claim 30, characterized in that component (b) contains raffinose or sucrose monolaurate. 23