SE511398C2 - Composition containing cyclosporin and sucrose or raffinose monolaurate - Google Patents

Abstract

Pharmaceutical compositions comprising (a) a cyclosporin as active ingredient (b) a fatty acid saccharide monoester and (c) a diluent or carrier. Components (c) are typically ethanol, an alkylene glycol (e.g. 1,2-propylene glycol), an alkylene polyol (e.g. glycerol), a polyalkylene glycol (e.g. PEG), an alkylene polyol ether or ester (e.g. a Gelucir product), paraffinum per- or sub-liquidum or an organosilicon oxide polymer, ethanol being less preferred.

Description

511 398 2 especially in connection with its application to recipients of organ transplants, e.g. heart, lung, combined heart / lung, liver, kidney, pancreas, bone marrow, skin and corneal transplants and, especially, allogeneic organ transplants. 5 In this field, Ciclosporin has gained remarkable success and reputation.

At the same time, the applicability of Ciclosporin to various autoimmune diseases and inflammatory conditions, especially inflammatory conditions with an etiology including an autoimmune component such as arthritis, (for example rheumatoid arthritis, chronic arthritis and chronic arthritis) and rheumatic diseases, has been extensively studied. , and there is an extensive literature with reports and results in vitro, on animal models and clinical trials. Specific autoimmune diseases for which Ciclosporin therapy has been proposed or applied include autoimmune haematological disorders (including, for example, hemolytic anemia, aplastic anemia, pure erythrocyte anemia and ideopathic thrombocytopenia), systemic lupus erythondritus, , sclerodoma, Wegener's granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, Idiopathic sprue, autoimmune inflammatory bowel diseases (including ulcerative colitis and Chrohn's disease) endocrine ophthalmopathy, Graves 'disease, sarcoidosis, multiple sclerosis, ~ n | www 25 primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimally altering nephropathy).

Other areas that have been investigated have been potential uses as antiparasitic, especially antiprotozoal agents, with proposed possible uses including treatment of malaria, coccidiomycosis and schistosomiasis, and more recently use in cancer therapy, e.g. as a means of reversing or reversing resistance to other anti-neoplastic or cytostatic therapies. After the initial discovery of Ciclosporin, many different naturally occurring cyclosporins have been isolated and identified and many additional non-natural cyclosporins have been prepared by total or semi-synthesis or by the application of modified cultivation technician.

Thus 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. QQ, 1247-1255 (1977); Traber et al. 2, Helv. Chim. Acta. 65 No. 162, 1655-1667 (l982); Kobel et al., Europ. J. Applied Microbiology and Biotechnology 14, 273-240 (l982); and von Wartburg et al., Progress in Allergy / yy, 28-45 (1986)], as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins, including the so-called the dihydro-cyclosporins [in which the moiety -x-y- in the -MeBmt group (formula B above) is saturated such that -x-y- = -CH 2 -CH 2 -]; derivatized cyclosporins (eg those in which an additional substituent has been introduced at the α-carbon atom of the sarcosyl group in the 3-position of the cyclosporin molecule); cyclosporins in which the -MeBmt- group is in isomeric form (eg in which the configuration of positions 6 'and 7' in the -MeBmt group is cis instead of trans); and cyclosporins in which different amino acids have been incorporated into specific positions in the peptide sequence, e.g. using the total synthesis method for the production of cyclosporins, developed by R. Wenger - see e.g.

Traber '1, Traber 2 and Kobel loc. cit .; U.S. Patent Nos. 4,108,985, 4,210,581 and 4,220,641; European Patent Publications 0034567, 0056782 and 0296122; International Patent Publication WO 86 / O2080; Wenger 1, Transp. Proc. 15, Suppl. 1: 223O (1983); Wenger 2, Angew. Chem. Int. Ed., 24, 77 (1985); and Wenger 3, Progress in the Chemistry of Organic Natural Products 50, 123 (1986).

Thus, the class of cyclosporins now includes, for example, [Thr] 2-, [val] 2-, [Nva fi- øch (Nva fl- [Nva fi- cyclosporin (also known as cyclosporin C, D, G and M, respectively)), [3'-O- acyl-MeBmt] 1- Ciclosporin (also known as cyclosporin A-acetate), [dihydro-MeBmt] 1- [Val] 2-Cyclosporin (also known as dihydrocyclosporin D), [3'-desoki-3'-oxo-MeBmt ] 1- [Val] 2- and - [Nva] 2-Ciclosporin, [(D) fluoromethyl-Sar] 3-Ciclosporin, [(D) Ser] 8-Ciclosporin, .zkàm Hj r Hvrw - ~ 10 15 5 [MeIle] 11-Cyclosporin, [(D) MeVal] 11-Ciclosporin (also known as cyclosporin H), [MeAla] 6-Cyclosporin, [(D) Pro] 3-Cyclosporin and so on.

[According to the now conventional nomenclature for cyclosporins, these are defined by reference to the structure of Ciclosporin (ie cyclosporin A). This is done by first indicating the amino acid groups present, which differ from those found in Ciclosporin (eg "[(D) Pro] 3" to indicate that the cyclosporin in question has a - (D) Pro- instead of a -Sar group in the 3-position) and then uses the term "Ciclosporin" to characterize the remaining groups that are identical to those found in Ciclosporin. Individual groups are numbered starting from the residue -MeBmt- or -dihydroMeBmt- or its equivalent in the 1-position.] A large number of these additional cyclosporins have comparable pharmaceutical utility as Ciclosporin or more specific utility, for example special activity to reverse tumor resistance against cytostatic therapy, and the literature is flooded with suggestions for use as therapeutic agents.

Despite the very important progress made by Ciclosporin, especially in the areas of organ transplantation and autoimmune disease therapy, difficulties have been encountered in more effective and convenient routes and methods of administration and undesirable side effects have been reported, especially nephrotoxic reactions, which have been a serious obstacle. against extended use or application. Characteristic of cyclosporins is that they are very hydrophobic. Proposed liquid preparations, e.g. for oral administration of cyclosporins, has hitherto been based mainly on the use of ethanol and oils or similar excipients as carriers. In the commercially available Ciclosporin drink solution, ethanol and olive oil are thus used as carriers together with labrafil as surfactant - see e.g. US-A-4,388,307. However, the use of the drink solution and similar compositions proposed in the art is accompanied by several different difficulties.

First, the need to use oils or oil-based carriers can give the formulations an unpleasant taste or otherwise reduce the palatability, especially in connection with long-term therapy. These effects can be masked by preparation in the form of gelatin capsules. However, a high ethanol content is required to keep the cyclosporin in solution. Evaporation of ethanol, e.g. from capsules or from other forms, e.g. when opened, leads to the development of a cyclosporin precipitate. When such compositions are given the form of e.g. soft gelatin capsules, this difficulty leads to the need to package the encapsulated product in an airtight compartment, such as an airtight blister or aluminum foil blister pack. This in turn leads to the product becoming both bulky and more expensive to produce. The storage properties of the above preparations are far from ideal.

The bioavailability levels achieved using existing oral cyclosporine dosing systems are also low and vary widely between individuals, individual patient types and even for individuals at different times during therapy. Literature reports thus show that currently available therapy, which utilizes the commercially available Ciclosporin drink solution, gives an average value of the absolute bioavailability of only about 30%, with marked variation between individual groups, e.g. between. recipients of liver transplants (relatively low bioavailability) and bone marrow transplants (relatively high bioavailability).

Reported variations in bioavailability between different patients have ranged from anything between one or a few percent for some patients to as much as 90% or more for others. As already noted, one can often observe a marked change in the bioavailability of the same individuals over time.

In order to achieve effective immunosuppressive therapy, cyclosporine levels in blood or blood serum must be kept within a specific range. The required range may in turn vary depending on the particular condition being treated, e.g. if the therapy is to prevent transplant rejection or to control an autoimmune disease, or if the cyclosporine therapy is simultaneously combined with any alternative immunosuppressive therapy or not. Due to the large variations in bioavailability levels achieved with conventional dosage forms, the daily doses required to achieve the required blood serum levels will also vary considerably from individual to individual and even for one and the same individual. For this reason, it is necessary to monitor blood / blood serum levels in patients receiving cyclosporine therapy at regular intervals. The monitoring of blood / blood serum levels, which is generally performed by RIA or techniques based on equivalent immunoassay techniques, e.g. use of monoclonal antibodies, must be performed regularly. This inevitably becomes time consuming and inconvenient and significantly increases the total cost of therapy.

In addition to all these very obvious practical difficulties, the occurrence of undesirable side effects, which are observed when using available oral dosage forms and as indicated above, is included.

In the field of technology, various proposals have emerged to master these problems, including both solid and liquid oral dosage forms. Thus, Japanese Patent Application No. 71682/1985 (Takada et al.) Application of agents to increase the lymphatic release of cyclosporins, especially by co-administration with surfactants. A general list of surfactants that can be used includes sucrose (sucrose) fatty acid esters such as sucrose oleate, palmitate or stearate as well as other fatty acid esters, especially sorbitan fatty acid esters such as sorbitanolate, palmitate or stearate. Although the use of both mono- and poly-esters is stated, preference is generally given to mono- or di-esters. Other listed surfactants include polyoxyethylated hydrogenated vegetable oils such as those products which are known and commercially available under the trade names Cremophore RH and Nikkol HCO 60, and these are clearly stated to be preferred, e.g. in front of the indicated sucrose ester type surfactants.

Example 3 of the said Japanese application describes the preparation of an aqueous preparation comprising a sucrose fatty acid ester, identified as F160, as the component surfactant. The preparation comprises 3.5 mg of Ciclosporin and 2 mg of sucrose ester in 1 ml of H 2 O. To achieve dispersion of the Ciclosporin, sonication is required for 5 minutes at 100W. The resulting preparation, described as a "transparent solution", is used directly in animal models to examine relative lymphatic resorption. In view of the very low solubility of Ciclosporin in H 2 O and the small amount of surfactant used, it is obvious that the alleged solution is an artifact of the sonication procedure. Not only is the Ciclosporin concentration reached inappropriately low for e.g. an oral dosage form, but the preparation is inherently unstable and therefore in practice excluded as a practical or commercial galenic form of any kind. It is essentially an experimental system, which enables laboratory testing and nothing more. There is no suggestion to use surfactants in any other context than in connection with lymphatic delivery.

Japanese patent application no. 193129/1987 (Publication No. 038029/1989), also herein Takada et al., Describe powder formulations comprising a ciclosporin dispersed in a solid carrier phase which is not a surfactant, e.g. containing sucrose, sorbitol, succinic acid, urea, cellulose acetate phthalate, methacrylic acid / methyl methacrylate or hydroxypropyl methylcellulose phthalate, together with minor amounts of a surfactant. Again, the surfactant is added for the purpose of increasing the lymphatic release and the application is, in this respect, clearly aimed at providing an intended practical means for applying the teachings according to the above-mentioned Japanese application no. 71682/1985. In this case, there is no reference to sucrose esters as possible surfactant components. The reference to sorbitan esters among an enumeration of possible surfactant components has been retained.

Products of the type Nikkol HCO 60 are again stated to be preferred as surfactants and Nikkol HCO 60 is the only surfactant used in the examples. There is no indication that the alleged increase in lymphatic delivery provides any practical benefits or overcomes any of the difficulties of cyclosporine therapy which have hitherto emerged in the art. 10 15 20 25 30 35 511 398 8 area, e.g. as discussed above.

The present invention provides novel gallic preparations of cyclosporin comprising fatty acid saccharide monoesters as primary carrier components which eliminate or substantially reduce the difficulties of cyclosporin therapy, e.g. Cyclosporine therapy, which has been encountered so far. In particular, it has been found that the compositions of the invention allow the preparation of solid, semi-solid and liquid compositions containing a cyclosporin in a sufficiently high concentration to allow e.g. convenient oral administration while achieving improved efficacy, e.g. in terms of bioavailability characteristics.

More specifically, it has been found that compositions of the present invention make it possible to achieve effective cyclosporine dosage with concomitant increase in resorption / bioavailability levels, as well as minor variations in the levels of resorption / bioavailability achieved both for individual patients receiving cyclosporine therapy and between individuals. . By applying the teachings of the present invention, one can achieve dosage forms of cyclosporin, which provide less variation in the achieved blood / blood serum levels of cyclosporin between dosages for individual patients as well as between individuals / individual patient groups. The invention thus makes it possible to reduce the cyclosporin dosage levels required to achieve effective therapy. In addition, it allows for tighter standardization and optimization of ongoing daily dose needs for individual patients on cyclosporine therapy, as well as for groups of patients undergoing comparable therapy.

Through tighter standardization of the dosage rate and the blood / blood serum level response for individual patients, as well as the dosage and response parameters for patient groups, the requirements for monitoring can be reduced and the cost of therapy thereby greatly reduced.

By reducing the required cyclosporine dosage / standardization of achieved bioavailability properties, the present invention also provides a means of reducing the incidence of undesirable side effects, especially nephrotoxic reactions, in patients undergoing cyclosporine therapy.

In addition, the present invention enables the preparation of compositions which are not alkanol-based, e.g. which may be free or substantially free of ethanol. Such compositions avoid the difficulties of stability discussed above and associated processing difficulties which are inherent in known alkanolic compositions. The invention thus provides e.g. compositions, which are better suited for e.g. preparation in capsule form, for example as hard or soft gelatin capsules, and / or which eliminates or significantly reduces the packaging difficulties, for example as previously discussed for e.g. soft gelatin encapsulated forms.

More particularly, the present invention provides: A pharmaceutical composition comprising a) a cyclosporin as active ingredient, b) a fatty acid saccharide monoester and c) a diluent or carrier, wherein i) component (c) is a solvent with respect to both components ( a) and (b), wherein components (a) and (b) each independently have a solubility in component (c) of at least 10% at room temperature; or ii) component (c) is a solvent with respect to both components (a) and (b), and components (a) and (c) are included in said composition i. a ratio of 1:05 to 50 parts by weight [( a) :( c)]; or iii) component (c) is a solvent with respect to both components (a) and (b) and said composition is prepared in solid unit dosage form suitable for oral administration; or iv) component (c) comprises a poly- (C 2-4 alkylene) glycol having an average molecular weight of at most 7,000 or a viscosity at 50 ° C of at most 15,000 mPa ~ s. or comprises a C 3-5 alkylene polyol ether or ester; or v) said composition is anhydrous or substantially anhydrous; or vi) component (c) comprises a solid polymeric support, a now x m M H | ml) x w MMH 511 398 10 15 20 25 30 35 10 organic silicone polymer or paraffin per- or sub-liquidium and component (a) are included in said composition in solid solution in (b).

The compositions defined above are new and particularly advantageous variants of those which are generically claimed in French patent application no. 88 11953 and corresponding applications in other countries worldwide, including US patent application O7 / 243 577, DOS 38 304945, JP application no. 231 396/88 and UK application no. 88 2l443.9 (first publication in France 1989-03-17 under no. 2 620 336).

The definitions (i) to (vi) above shall be understood in such a way that they do not exclude each other. The compositions according to the invention thus comprise compositions according to the definitions, which meet one or more of the stated limitations (i) to (vi). Thus, for example, preferred compositions of the invention are such that they satisfy two or more of (i) to (v).

As used herein and in the appended claims, the term "pharmaceutical composition" refers to compositions in which the individual components or ingredients themselves are pharmaceutically acceptable, e.g. when oral administration is envisaged are acceptable for oral use or when topical administration is envisaged are topically acceptable.

The preferred cyclosporin as component (a) is Ciclosporin. A further preferred component (a) is [Nva] 2-Cyclosporine, also known as cyclosporin G.

Preferred. components (b) for use in the compositions of the invention are water-soluble fatty acid sac- e.g. fatty acid monoesters of saccharides such as carid monoesters, have a solubility in water of at least 3.3% at room temperature, ie. which are soluble in water at room temperature in an amount of at least 1 g of monoester per 30 ml of water.

The fatty acid moiety in components (b) may comprise saturated or unsaturated fatty acids or mixtures thereof. Particularly suitable components (c) are C6_18 fatty acid saccharide monoesters, especially water-soluble C6_18 fatty acid saccharide monoesters.

Particularly suitable components (c) are caproic acid (C5) -, caprylic acid (C8) -, capric acid (C10) -, lauric acid (C12) -, myris-10 (514398) tinic acid (C14) -, palmitic acid (C15), oleic acid (C18), ricinoleic acid (C18) and 12-hydroxystearic acid (C18) saccharide monoesters, especially lauric acid saccharide monoesters.

The saccharide moiety in component (b) may comprise any suitable sugar residue, e.g. mono-, di- or trisaccharide residue. The saccharide moiety suitably comprises a di- or trisaccharide residue. Preferred components (b) include C5_14 fatty acid disaccharide monoesters and C8_18 fatty acid trisaccharide monoesters. Particularly suitable saccharide moieties are sucrose and raffinose residues. Particularly suitable components (b) are thus: sucrose monocaproate, sucrose monolaurate, sucrose monomyristate, sucrose monooleate, sucrose monoricinoleate, raffinose monocaproate, raffinose monolaurate, raffinose monomyristate, raffinose monopalmonite. Most preferred components (b) are raffinose monolaurate and, in particular, sucrose monolaurate.

Components (b) suitably have a hydrophilic-lipophilic balance (HLB) of at least 10.

Components (b) suitably have an ester purity of at least 80%, more preferably at least 90%, most preferably at least 95%. Components (b) suitably have a melting point of from about 15 to about 60 ° C, more preferably from about 25 to about 50 ° C.

By the definitions (ii) and (iii) as applied above to the compositions according to the invention, the components (c) are defined as materials in which both components (a) and (b) exhibit significant solubility at room temperature, e.g. at temperatures of about 20 ° C. Preferred components (c) are materials in which (a) and (b) independently have a solubility of at least 10% [as required by definition (i)], preferably at least 25%, most preferably at least 50% (e.g. where components (a) or (b) independently have a solubility of the order of at least 100 mg, preferably 250 mg, most preferably 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%, most preferably at least 50% and / or in which component (b) has a solubility of at least 100%, more preferably at least 200%. %, most preferably at least 300% (eg wherein component (b) has a solubility of the order of at least 1,000, more preferably LN 511 398 10 15 20 25 30 35 12 preferably 2,000, most preferably at least 3,000 mg / ml).

Components (c) suitable for use in the compositions of the invention include: cl) ethanol; c2) C2-4alkylene glycols; C3) C3-5 alkylene polyols; c4) poly (C 2-4 alkylene) glycols; and c5) C3-5 alkylene polyol ethers or esters, as well as any mixtures thereof.

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

When component (c) comprises a C 2-4 alkylene glycol (cz), this is preferably a propylene glycol, most preferably 1,2-propylene glycol. When component (c) comprises a C 3-5 alkylene polyol (c3), this is preferably a C 3-5 alkylene triol, most preferably glycerol.

When component (c) comprises a poly- (C 2-4 alkylene) glycol (C 4), this is suitably a polyethylene glycol. For use in the compositions of the invention, these components preferably have an average molecular weight not greater than about 7,000 [cf. definition (iv)], e.g. up to 6,600, more preferably not greater than about 2,000, e.g. up to 1,600, most preferably not greater than about 500. Such components preferably have a viscosity of at most about 15,000 mPa ° s, more preferably at most about 1,000 mPa-s., most preferably at most about 200 mPa's., at 50 ° C or , more suitable, at room temperature [cf. definition (iv)]. Suitable polyethylene glycols for use as components (c) are e.g. de sonx is described in Fiedler, Lexikon der Hilfstoffe, second revised and expanded edition, [1981] Vol. 2, pages 726 to 731, especially the products PEG (polyethylene glycol) 200, 300, 400 and 600, as well as PEG 1,000, 2,000, 4,000 or 6,000, but especially 200, 300 and 400, e.g. which meets the following approximate physical properties: 10 15 20 25 30 35 40 511 398 13 PEG 200 PEG 300 PEG 400 PEG 600 molecular weight approx. 190-210 approx. 285-215 approx. 380-420 approx. 570-630 viscosity mPa's. ca 46-53 ca 66-74 ca 85-95 ca 130-150 freezer- ca -16 to ca -3 to ca 15 to point ca -so ° c -12 ° c 8 ° c 25 ° c 25 n ca 1,459 ca 1.463 about 1.465 about 1.467 D When component (c) comprises a C 3-5 alkylene polyol ether or ester (c5), this is suitably a C 3-5 alkylene triol, especially -glycerol, ether or ester. Suitable components (c5) include mixed ethers or esters, i.e. components comprising other ether or ester ingredients, e.g. transesterification products of C3-5 alkylene triol esters with other mono-, di- or polyols.

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

Particularly suitable components (c5) for use in accordance with the present invention include those especially products which can be obtained by transesterification of glycerides, e.g. triglycerides, with poly- (C2-4alkylene) glycols, e.g. polyethylene glycols and, optionally, glycerol. Such transesterification products are generally obtained by alcoholysis of glycerides, e.g. triglycerides, in the presence of a poly- (C 2-4 alkylene) glycol, e.g. polyethylene glycol and, optionally, glycerol (ie to perform transesterification from the glyceride to the polyalkylene glycol / glycerol component, ie via polyalkylene glycolysis / glycerolysis). In general, such a reaction is carried out by reacting the indicated components (glyceride, polyalkylene glycol and, optionally, glycerol) at elevated temperature under an inert atmosphere with continuous stirring. 511 398 10 15 Preferred glycerides are fatty acid triglycerides, e.g.

(Cl0_22 fatty acid) -triglycerides, including natural and hydrogenated oils, in particular vegetable oils. Suitable vegetable oils include, for example, olive, almond, peanut, coconut, palm, soybean and wheat germ oils, and, in particular, natural or hydrogenated oils rich in (C12_16 fatty acid) ester residues.

Preferred polyalkylene glycol materials are polyethylene glycols, especially polyethylene glycols having a molecular weight of from about 500 to about 4,000, e.g. from about 1,000 to about 2,000.

Suitable components (c5) thus comprise mixtures of C3-5 alkylene triol esters, e.g. mono-, di- and triesters of varying relative importance, and poly- (C 2-5 alkylene) glycol mono- and diesters, together with minor amounts of free C 3-5 alkylene triol and free poly- (C 2-5 alkylene) glycol. As stated above, the preferred alkylene triol moiety is glycerol; preferred polyalkylene glycol moieties are especially having a molecular weight of from about 500 to about 4,000; and preferred fatty- especially saturated polyethylene glycyl, acid moieties are C10-22 fatty acid ester residues, C10-22 fatty acid ester residues.

Particularly suitable components (c5) can thus alternatively be defined as: transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and, optionally, glycerol; or compositions comprising or consisting of am / glyceryl mono-, di- and tri-C10-22 fatty acid esters and polyethylene glycol mono- and di-C10-22 fatty acid esters (optionally together with, for example, minor amounts of free glycerol and free polyethylene glycol).

Preferred vegetable oils, polyethylene glycols or polyethylene glycol moieties and fatty acid moieties j. Relation to the above definitions are as previously stated. Particularly suitable components (c5) as described above for use in the present invention are those known and commercially available under the trade name Gelucir, especially the products i) Gelucir 33/01, which have m.p. = about 33-38 ° C and a saponification number = about 240/260; 10 15 20 25 30 35 511 398 15 ii) Gelucir 35/10, m.p. = about 29-34 ° C, saponification number = about 120-140; iii) Gelucir 37/02, m.p. = about 34-40 ° C, saponification number = about 200-220; iv) Gelucir 42/12, m.p. = about 41-46 ° C, saponification number = about 95-115; v) Gelucir 44/14, m.p. = about 42-46 ° C, saponification number = about 75-95; vi) Gelucir 46/07, m.p. = about 47-52 ° C, saponification number = about 125-145; vii) Gelucir 48/09, m.p. = about 47-52 ° C, saponification number = about 105-125; viii) Gelucir 50/02, m.p. = about 48-52 ° C, saponification number = about 180-200; ix) Gelucir 50/13, m.p. = about 46-41 ° C, saponification number = about 65-85; x) Gelucir 53/10, m.p. = about 48-53 ° C, saponification number = About 95-115; xi) Gelucir 62/05, m.p. = about 60-65OC, saponification number = about 70-90; The products (i) to (x) above all have an acid number = <2.

The product (xi) has an acid number = <5. The products (ii), (iii) and (vi) to (x) above all have an iodine value = <3. The product (i) has an iodine value = S8. Products (iv) and (v) have an iodine value = <5. The product (xi) has an iodine value = <10. Components (c5) having an iodine value = <1 are generally preferred.

As will be appreciated, mixtures of components (c5) as defined by scmx may also be used in the compositions of the invention.

When using a component (c) as specifically described above (ie, a component that meets any of the definitions (i) to (iv) above or any component as defined under (cl) to (c5)], the composition will The compositions of the invention will generally comprise component (a) in a carrier medium comprising components (b) and (c) Each of the components (a) and (b) will generally be present in the compositions of the invention. in dispersion or solution, eg molecular or miscellular ........ '“_........... ... _ _ in 511 398 10 15 20 25 30 35 16 dispersion Thus, component (a) will generally be present in dispersion or solution in both components (b) and (c) and component (b) will in turn be present in solution in Component (b) will generally act as a carrier or solubilizer in the compositions of the invention (either before and / or after administration) for component (a), and component (c) will act as a carrier or fluidizer. (The present invention should, of course, not be construed as limiting in any way any particular functional relationship between components (a), (b) and (c) unless otherwise indicated.) When a component (c) as used above is further preferred, the compositions according to the invention are prepared in solid unit dosage form suitable for oral administration, for example presented in hard or soft gelatin capsule form suitable for oral administration [cf. definition (iii)]. As will be described in more detail below, such unit dosage forms suitably comprise, for example, from 2 to 200 mg of component (a) per unit dose.

When a component (c) as above is used, the components (a) and (c) are preferably included in the compositions according to the invention in a ratio from 1: 0, 5 to 50 parts by weight [(a) :( c)] [cf. definition (ii)]. Components (a) and (b) are suitably included in a ratio of from 1: 3 to 200 parts by weight [(a) = (b)]. When a component (c) as above is used, it is further preferred that the compositions of the invention are aqueous. ten-free or mainly water-free [cf. definition (v)], e.g. has a water content of less than 20%, more preferably less than 10%, even more preferably less than 5%, 2% or 1%, based on the total weight of the composition.

In accordance with the foregoing, the present invention also provides, in a series of particular embodiments: A pharmaceutical composition comprising a component (a) and a component (b) as defined above and a diluent selected from any of the components (c1) to (c4) as defined above, or any mixture thereof, and which satisfies any of the definitions (ii) to (v) above; A pharmaceutical composition comprising a component (a), (b) and (c2) as defined above and compatible with the definitions (ii), (iii) or (V) above; and - A pharmaceutical composition comprising a component (a), (b) and (C5) as defined above.

When a component (c) according to the above special description [i.e. a component which is compatible with any of the definitions (i) to (iv) or any of the components (c1) to (c5)] is used in said compositions according to the invention, components (a) and (c) are suitably included in said compositions in a ratio of about 1: 0.5 to 50 parts by weight. More preferably, components (a) and (c) are present in a ratio of about 1: 1 to 10, more preferably 1: 1 to 5, most preferably about 1: 1.5 to 2.5, e.g. about 1: 1, 6 or 1: 2 parts by weight [(a) :( c)]. Components (a) and (b) are suitably included in said compositions in a ratio of about 1: 3 to 200, preferably about 1: 3 to 100, more preferably about 1: 3 to 50 parts by weight. More preferably, components (a) and (b) are present in a ratio of about 1: 5 to 20, preferably about 1: 5 to 10, most preferably about 1: 6.0 to 6.5, e.g. . about 1: 6.25 parts by weight [(a) :( b)].

When the compositions of the invention comprise sucrose monolaurate as component (b) and 1,2-propylene glycol as component (c), components (a) and (b) are preferably included in a ratio of from about 1: 6 to 7 parts by weight [(a): (b)] and components (a) and (c) are preferably included in a ratio of from about 1: 1.5 to 2.5, e.g. about 1: 2 parts by weight [(ê) = (C)] - Compositions according to the present invention comprising a component (c) as above can be prepared into any suitable dosage form, e.g. for oral, parenteral or topical application, for example for dermal or ophthalmic application, e.g. for application to the surface of the eye, for example for the treatment of autoimmune conditions of the eye as previously indicated or for intralesional injection, e.g. in the treatment of psoriasis. Such compositions are conveniently formulated in unit dosage form, whether for oral administration or otherwise.

The amount of component (a) included in such unit dosage forms will, of course, vary depending upon, e.g. the condition to be treated, the intended route of administration and the desired effect. In general, however, such unit dosage forms suitably contain from about 2 to about 200 mg of component (a), e.g. Ciclosporin, per unit dose.

Suitable dosage forms for oral administration include e.g. liquids, granules and the like. However, solid unit dosage forms, for example tablet or soft gelatin encapsulated, are preferred. preferably contains from about 5 to about 200 mg, more suitably from about 10 or 20 to about 100 mg, e.g. 15, 20, 25, 50, 75 or 100 mg of component (a), e.g. Ciclosporin, per unit dose.

Compositions of the present invention, which comprise a component (c) as above, have the further advantage that they may form the basis of compositions which according to the invention show properties with modified release, for example delayed release of component (a) or release of component (a) for a longer period of time, e.g. after oral administration. Such compositions further comprise (d) a component capable of modifying the release (a) of the composition. Such components (d) include, for example, polymeric excipients, especially thickeners, e.g. polymeric or colloidal settling properties with respect to component thickeners, as well as agents which are swellable in water, e.g. water-swellable polymers or colloids.

Suitable components (d) are known in the art and include: dl) Polyacrylate and polyacrylate copolymer resins, for example polyacrylic acid and polyacrylic acid / methacrylic acid resins e.g. those which are known and commercially available under the trade name Carbopol (cf. Fiedler loc. cit. 1, pp. 206-207), in particular the products Carbopol 934, 940 and 941, p. L, p. 372-373), in particular the products Eudragit E, L, S, and Eudragit (cf. Fiedler loc. Cit. 10 15 20 25 30 35 511 398 19 RL and RS, in particular the products Eudragit E, L and S; Cellulose and cellulose derivatives including : alkylcellulose, for example methyl, ethyl and propylcellulose; hydroxyalkylcellulose, eg hydroxypropylcellulose and hydroxypropylalkylcellulose such as hydroxypropylmethylcellulose; acetylated cellulose, egcellulose acetates, cellulose acetate phthalates, cellulose acetate succinates and hydroxypropylmethyl cellulose Examples of such products suitable for use in accordance with the present invention are those which are known and commercially available, for example under the trade names Klucel and Methocel (cf. Fiedler loc. cit. 1, p. 521 and 2, p. 601), in particular the products Klucel LF, MF, GF and HF and Methocel K 100, K15M, K100M, E5M, E15, E15M and E100M, including vinylpyrrolidones and vinylpyrrolidone samples polymers such as polyvinylpyrrolidones, for example poly-N-vinylpyrrolidone vinyl acetate copolymers. Examples of such compounds suitable for use in the present invention are those which are known and commercially available, Kollidon (cf.

Fiedler loc. cit. l, p. 526 and 527), in particular the products Kollidon 30 and 90; for example under the trade name Polyvinyl resins, including e.g. polyvinyl acetates and alcohols, as well as other polymeric materials including tragacanth, gum arabic, alginates, for example alginic acid and salts thereof, e.g. sodium alginates; Silica, including hydrophilic silica products, e.g. alkylated silica gels, especially colloidal silica products which are (for example methylated) known and commercially Handbook of Pharmaceutical Excipients, published by the Pharmaceutical Society of Great Britain, p. 253-256], in particular the products Aerosil 130, 200, 300, 380, o, ox 50, TT 600, Mox 80, Mox 170, LK 84 and the methylated product Aerosil R 972. available under the trade name Aerosil [cf. When a component (d) is present, it is suitably present in an amount of from about 0.5 to 50% by weight, more preferably from about 1 to 20% by weight, most preferably from about 2 to 10% by weight, based on the total weight of the components (a) + (b) + (C) + (d) - When component (c) in the compositions of the invention comprises: (c6) a solid carrier polymer as required by the definition (vi) above, it is preferably a water-insoluble or substantially water-insoluble polymeric carrier.

Particularly preferred as components (c6) are polyvinylpyrrolidones (cf. Fiedler, loc. Cit., 2, pp. 748-7501, including especially crosslinked polyvinylpyrrolidones. Examples of such materials suitable for use in the present invention are those known and commercially available under the tradename Kollidon [cf. Fiedler, loc. cit., 1, page 5271, Kollisept [cf. Fiedler, loc. cit., 2, pages 719-7201, Povidone and Crospovidone [cf. Fiedler, loc. cit., 2, p. 7511.

Particularly suitable components (c6) are polyvinylpyrrolidones having a molecular weight of at least about 10,000, more preferably at least about 20,000 or 25,000, e.g. those that have a molecular weight of about 40,000 or more. Crosslinked polyvinylpyrrolidones are of particular interest. Examples of specific products suitable for use in the present invention such as (C6) are: Plasdone XL, Plasdone XL and Crospovidone.

When the compositions of the invention comprise a component (c6), they preferably also comprise (d), a water-swellable or water-soluble component, for example cellulose or cellulose derivatives as defined in (dz) above.

Further examples of such materials which are of special interest in connection with the compositions according to the invention, which comprise a component (C6), are those which are known and commercially available under the trade names Avicel [cf.

Fiedler, loc. cit., 1, p. 160-1611, Elcema [cf. Fiedler, loc. cit., 1, p. 326] and Pharmocoat [cf. Fiedler, loc. 10 15 20 25 30 35 511 398 21 cit., 2, p. 707], for example the products Avicel PH 101 and PH 102, Elcema and Pharmacoat 603.

In the case of compositions according to the invention comprising a component (c6), component (a) is present in component (b) in solid solution, including solid miscellular solution, e.g. wholly or substantially wholly in molecular or miscellular dispersion. [In practice, components (b) will often exhibit a certain degree of fluidity, e.g. at room temperature or slightly elevated temperature, and therefore are not "solid" in the strict sense. As the term "solid solution" is used in the present specification and claims, it is to be understood accordingly, e.g. such as comprising viscous or highly viscous systems.] The solid solution comprised by (a) and (b) is suitably dispersed, for example in particulate matter, e.g. fine particulate form in, e.g. throughout, component (c5). Thus, components (c6) will generally serve in the compositions of the invention as a disintegratable matrix for [(a) + (b)]. Components (d) will generally serve as disintegration promoting agents, e.g. in contact with the contents of the gastrointestinal tract.

Compositions of the invention comprising a component (c6) also suitably comprise (e), a binder and / or lubricant. Suitable materials for use as binders / lubricants are in particular fatty acid and alkyl sulfonate salts, e.g. metal salts, for example those having 10 or more carbon atoms in the fatty acid / alkyl moiety, for example C10-22 fatty acid and C10-22 alkylsulfonate alkali metal or alkaline earth metal salts, e.g. sodium, calcium or magnesium salts. Examples of such materials suitable for use in the present invention are: sodium lauryl sulfate and magnesium stearate [cf. Fiedler, loc. cit., 2, p. 5841.

When the compositions of the invention comprise a component (c5), the components (a) and (b) are suitably included in a ratio of about 1: 2 to 20, preferably about 1: 2.5 to 10, most preferably about 1: 3 to 8 [ (a) :( b)].

Components (c6) are included in the compositions according to the invention suitably in an amount of at least 10% by weight, more preferably at least 15% by weight, and more preferably at least 20% by weight 511398 10 15 20 25 30 35 22 based on the total weight of the composition. It is suitable that components (c5) are included in compositions according to the invention in an amount from 10 to 60% by weight, more preferably from 15 to 50% by weight, e.g. from about 20 to 40% by weight, for example about 25, 30 or 35% by weight, based on the total weight of the composition.

When a component (d) is present, components (d) and (c5) are suitably included in a ratio of about 1: 0.5 to 4, more preferably about 1: 1 to 3, most preferably about 1: 1.5. to 1: 2.5 parts by weight of Hdmcön- When a component (s) is present, the component- (C6) is suitably included in a ratio of about 1: 5 to 25, more preferably about 1: 5 to 20, most preferably about 1: 7 to 15 parts by weight [(e) :( c6)].

When the compositions according to the invention include all, it is suitable that the 2.5, e.g. about 1: 2 or about the elements (e) and the three components (C6), (d) and (e) together are present in an amount from about 25 to 75%, more preferably about 30 to 65%, most preferably about 40 to 65% calculated The ratio of the components the order of magnitude of the total weight of the composition. [(ä) + (b)] = [(C) + (d) + (@)] is 1: 0.25 to 7.5, more preferably 1: 0.5 to 5, most preferably 1: 0.5 to 2, about 1: 0, 8, 1: 1, 2 or 1: 1.3 parts by weight. suitably of e.g.

Compositions of the invention comprising a component (C5) may be formulated in any suitable dosage form, e.g. for oral, parenteral or topical application. Such compositions of the invention are conveniently formulated in unit dosage form, whether for oral administration or otherwise.

The amount of component (a) included in such a unit dosage form will, of course, vary depending upon, e.g. which condition is to be treated, the intended mode of administration and the desired effect. In general, however, preferably from about 2 to about 200 mg of component (a), e.g. Ciclosporin, per unit dose. The suitable dosage forms for oral administration include granules and the like. However, solid unit dosage forms are, for example, tableted or encapsulated forms.

Such oral unit dosage forms suitably contain from about 5 to about 200 mg, more preferably from about 10 or 20 to about 100 mg, e.g. 15, 20, 25, 50, 75 or 100 mg of component (a), e.g. Ciclosporin, per unit dose.

When component (c) of the compositions of the invention comprises: (c7) an organic silicone polymer or paraffinic per- or subliquid as required by the definition (vi), component (c7) is preferably readily flowable at temperatures up to 150 ° C, preferably up to to 100 ° C, more preferably up to 50 ° C. Suitable components (c7) have a maximum viscosity of 15,000 mPa's, more preferably 1,000 mPa's. at the specified temperatures. above, Paraffinic hydrocarbons suitable for use as component (c7) are liquid and semi-solid paraffins and mixtures thereof, i.e. paraffinum subliquidum and paraffinum perliquidum [see Fiedler, loc. cit., 2, p. 690-6911. To enable simple preparation, component (c7) suitably consists wholly or mainly of liquid or semi-solid paraffins, i.e. paraffin perliquidum or paraffinum subliquidum or mixtures thereof, but when it is desirable to prepare compositions such as e.g. has a slower release of the active ingredient, this can be achieved by further addition of a solid paraffin, ie. paraffin durum.

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

In addition, when the compositions of the invention most preferably 1: 6 comprise a solid paraffin as component (c7), the liquid / semi-solid paraffin solid paraffin ratio is suitably about 1: 0.06 to 0.1 parts by weight. In this case, components (a) and (c7) are suitably present in a ratio of from about 1: 6 to 200, more preferably 1: 6 to 100, most preferably 1: 8 to 20, e.g. about 1:10 parts by weight [(a) :( c7)]. In Organic Silicone Polymers which are suitable for use as component (c7) include especially liquid, i.e. liquid and semi-solid polymeric materials having a structural unit of the formula - (R) 2 Si-O-, where each R is a monovalent organic group, especially methyl, or phenyl. Particularly preferred are organosilicon polymers having a viscosity of from about 0.65 to 105 cP, especially from about 10 or 50 to 500 or 1,000 cP.

To allow simple preparation, component (c7) comprises poly- any of the various known, for example C1-4alkyl, suitably liquid organic silicone polymers, e.g. methylsiloxane polymers, for example the silicone oils such as silicone oil 550, DC 200, SF-1066 and SF-1091 cit., 2, p. 826]. When the compositions of the invention comprise liquid organosiloxane, the components (a) and (C7) are from about 1: 6 to 200, most preferably 1: 6 to 20, [cf. Fiedler, loc. polymers alone, suitably present in a ratio of more than 100, for example about 1: 8 parts by weight [(a) :( c7)]. slower release of the preferred about 1: 6 to Compositions having e.g. active ingredient can be obtained using semi-solid organosiloxane polymers, e.g. any of the various known silicone pastes, e.g. silicone paste A [cf. Fiedler, loc. cit., 2, p. 826] as component (c7) or by their addition, e.g. to other organic silicone polymers as described above. In the latter case, the ratio of liquid semi-solid organic silicone polymers in the composition according to the invention is suitably of the order of from about 1: 0.5 to 1. In this case, the ratio of the components (a) :( c7) is suitably of the order of 1: 6 to 100, preferably about 1: 6 to 20 parts by weight [(a) :( c7)].

Mixtures of components (c7) as defined may also be used in the compositions of the invention.

When the compositions of the invention comprise a component (c7), the components (a) and (b) are suitably present in a ratio of about 1: 6 to 20, preferably about 1: 6 to 10, 1 = 6, 0 to 6, 5, 1: 6.25 parts by weight [(a) :( b)].

In the case of compositions according to the invention most preferably about t-eX-Ca 10 15 20 25 30 35 511 398 25 comprising a component (c7), component (a) is present in component (b) completely or substantially completely in molecular or miscellular dispersion, e.g. in the form of a solid solution or solid miscellular solution [where the term "solid solution" is used herein in the same broad sense as in the case of compositions with a component (c5)]. The solid solution comprising (a) and (b) is suitably dispersed in particulate form, e.g. fine particle shape with component (c7), e.g. through the whole component (c7).

Compositions of the invention comprising a component (c7) may be formulated into any suitable dosage form, e.g. for oral, parenteral or topical application, for example for dermal or ophthalmic application, e.g. for application to the surface of the eye, for example for the treatment of autoimmune conditions of the eye as previously indicated, or for intralesional injection, e.g. in the treatment of psoriasis. They are conveniently formulated in unit dosage form, whether for oral administration or otherwise.

The amount of component (a) in such unit dosage forms will, of course, vary depending upon, e.g. which condition is to be treated, the intended. the route of administration and the desired effect. In general, however, they suitably contain from about Ca 2 to about 200 mg of component (a), e.g. Ciclosporin, per unit dose.

Suitable dosage forms for oral administration include liquids, granules and the like. However, solid unit dosage forms are preferred, for example tableted or encapsulated forms, especially hard or soft gelatin capsule forms. Such oral unit dosage forms suitably contain from about 5 to about 200 mg, more suitably from about 10 or 20 to about 100 mg, e.g. 15, 20, 25, 50, 75 or 100 mg of component (a), e.g. Ciclosporin, per unit dose.

Compositions according to the invention comprising a component (c7) have the further advantage that they can form the basis for compositions which exhibit modified release properties, for example delayed release of component (a) or release of component (a) for longer periods of time, for example after oral administration. As previously described, such compositions may be obtained by incorporating solid or semi-solid components (c7) in appropriate amounts. Alternatively, they may be obtained by incorporating an additional component (d): a component capable of modifying the release properties of the composition with respect to component (a). Such components (d) include, for example, polymeric excipients, especially thickeners, e.g. polymeric or colloidal thickeners, as well as. agents that are swellable in water, e.g. water-swellable polymers or colloids, for example any of the materials defined above under (dl) to (d5).

When a component (d) is present, it is suitably present in an amount of from about 0.5 to 30%, more preferably from about 1 to 20%, most preferably from about 1 to 10% based on the total weight of the components (a) + ( b) + (c7) + (d).

The components (d5) are particularly indicated for use in compositions in accordance with the invention which comprise an organic silicone polymer as component (c7).

Compositions of the invention comprising a component (c6) or (c7) are preferably anhydrous or substantially anhydrous, i.e. as previously described in connection with compositions containing other components (c).

Compositions of the invention may, independently of the selected component (c) [e.g. whether or not component (c) comprises any of the components (c1) to (c7) above or any mixture thereof], include additional additives, e.g. as is known and conventionally used in the art, for example antioxidants [e.g. ascorbyl palmitate, tocopherols, butylhydroxyanisole (BHA) or butylhydroxytoluene (BHT)], flavoring agents, etc.

In particular, the compositions of the invention also suitably contain one or more stabilizers or buffering agents, especially to prevent hydrolysis of component (b) or degradation of component (a) during processing or storage. Such stabilizers may include acid stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid as well as basic stabilizers such as potassium hydrogen phosphate, glycine, lysine, arginine or tris (hydroxymethyl) aminomethane. Such stabilizers or buffering agents are suitably added in an amount sufficient to give or maintain a pH in the range of from about 3 to 8, more preferably about 5 to 7, e.g. between 6 and 7. Such stabilizers are generally present in an amount of up to 5% by weight based on the total weight of the composition, or up to 10% by weight, for example when citric or acetic acid is used. Preferred composition compositions in which 27 ions according to the invention, in particular component (a) are Ciclosporin, have a pH in the above ranges.

Compositions according to also suitably contain a polyoxyalkylene-free surfactant such as dioctyl succinate, dioctyl sulfosuccinate, di [2-ethylhexyl] succinate, sodium lauryl- In the presence of the invention sulfate or phospholipids, e.g. lecithins. a surfactant as above is suitably included in an amount of from 5 to 50, for example 10 to 25% based on the weight of component (b). more preferably 10 to 50. In the case of compositions according to the invention comprising component (a) in solid solution in component (b), e.g. when component (c) is a component (c5) or (c7) as above, any stabilizers, buffers and / or surfactants above are included as such, suitably in the solid solution phase. material can also be included in component (c) etc.

Compositions according to the invention, again independent of the selected component (c), are preferably free or substantially contain less than 5.0%, more from 0 to 1.0% ethanol gene free from ethanol, e.g. preferably less than 2.5%, e.g. based on the total weight of the composition.

In addition to the foregoing, the present invention provides the manufacture of a pharmaceutical which process also comprises a process for composition as previously defined, comprising intimately mixing or compounding components (a), (b) and (c) together with a component (d) and / or another component, e.g. stabilizer, buffer or surfactant as described above, and if necessary, prepare the resulting composition into, as defined above, any unit dosage form, for example, unit dosage form for oral administration, e.g. by tableting, filling into gelatin capsules or other suitable agents.

When component (c) is a solvent for components (a) and (b) or comprises a component (c1), (c2), (c3), (c4) or (c5) as defined above, the components (a), (b) and (c) suitably together in the above process by dissolving components (a) and (b) together in component (c), e.g. with heating at temperatures up to 50 150 ° C, preferably not above 70 or 75 ° C. The mixture thus obtained can then be further compounded (Ö) in accordance with techniques known in the art. Filling of e.g. hard or soft gelatin capsules are suitably made at elevated temperature, e.g. up to 50 ° C, to achieve fluidity of the composition, e.g. in heat.

In the case of compositions according to the invention including or with components etc., e.g. by intimate mixing in tooth component (a) in solid solution in component (b), e.g. compositions comprising a component (c5) or (c7) as previously described, said process suitably comprises first preparing a solid solution of (a) in (b) followed by intimate mixing or compounding of the resulting solid solution with the remaining components ( c) and, optionally, (d) etc.

Solid solutions containing component (a) of (b) may be prepared by techniques known in the art, e.g. by (a) (b) is allowed to solidify or by removing the solvent from a solution of (a) (b). For the purposes of the present invention, the latter alternative is generally preferred. and that a melt containing in solution in components and Suitable solvents for components (a) (b) include alkanols, e.g. ethanol. Stabilizers, buffering agents and / or surfactants are suitably incorporated in the lowering stage.

The solid solution thus obtained is then suitably compounded, e.g. in fine particulate form, with component (c) and, optionally, components (d) and (e) etc., e.g. by distribution in component (c). Although ethanol can be used to prepare the compositions of the invention, e.g. in the preparation of solid solutions as described above, preferably, e.g. by evaporation, before the final dosage form is completed, to give an ethanol-free or substantially ethanol-free product as indicated above.

The following examples illustrate the present invention.

Product examples, Food Corp., Tokyo 104, Japan: lauryl ester residue = at least 95%: at about 235 ° C: surface tension of 0.1 wt% aqueous solution 72.0 'dynes / cm at 2s ° c.

INGREDIENT 1. 8) b) C) 2. a) b) C) b) C) Cyclosporine (e.g.

Sucrose monolaurate 1,2-propylene glycol Cyclosporin (e.g.

Sucrose monolaurate Glycerol Cyclosporin (e.g.

Sucrose monolaurate PEG 200 Cyclosporine (e.g.

Sucrose monolaurate PEG 400 Cyclosporine (e.g.

Sucrose monolaurate 1,2-propylene glycol Eudragit E sucrose monolaurate EXAMPLE Ciclosporin) L ~ 1695 TOTAL Ciclosporin) L-1695 TOTAL Ciclosporin) L-1695 TOTAL Ciclosporin) L-1695 TOTAL Mit-Ciclosporin) Casein at least 12.3: decomposition HLB value m.p. = approx. 35 ° C: used RELATIVE AMOUNT (mg) 1: ___ + _ 462.5 50.0 312.5 100.0 462.5 I 462.5 50.0 312.5 L00.0 462.5 50 350.0 100.0 50.0 550.0 is removed 6. a) Cyclosporine (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) 1 , 2-propylene glycol 100.0 d) Methocel Kl00 11000 TOTAL 610.0 7. a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) 1,2-propylene glycol 100.0 d) Aerosil 200 _0000 TOTAL 515.0 8. a) Cyclosporine (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) PEG 400 200.0 d) Eudragit L __2¿§ TOTAL 602, 9. a) Cyclosporine (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelucir (eg Gelucir 42/12, 44/14 or 35/10 10000 TOTAL 462.5 10. a) Cyclosporine (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelucir 100.0 d) Klucel LF _0000 TOTAL 512.5 The composition of Example 1 is prepared by dissolving the components ( a) and (b) while stirring and heating over an oil bath vi d 100 ° C in component (c). The compositions of Examples 2 to 10 are prepared in an analogous manner. In the case of Examples 5 and 8, component (d) is dissolved in the initially obtained mixture of components (a) to (c). In the case of Examples 6, 7 and 10, component (d) of (a) to (c) is suspended.

The resulting compositions are filled while heating on hard gelatin capsules, size 1 (Examples 1 to 4 and 9) or size 0 (Examples 5 to 7 and 10) to give a capped final product where each capsule contains 50 mg 'cyclosporin (eg Ciclosporin) and which is suitable for administration for the prevention of transplant rejection or for the treatment of autoimmune diseases, e.g. when administering 1 to 5 capsules daily.

EXAMPLE INGREDIENT R§LATIVE AMOUNT (mg) 11. a) Cyclosporine (eg Ciclosporin) 100.0 b) Sucrose monolaurate L-1695 300.0 c) Plasdone XL 350.0 d) Avicel PH 102 150.0 e) Sodium lauryl sulphate _2âiQ TOTAL 925.0 12. a) Cyclosporine (eg Ciclosporin) 50.0 bl) Sucrose monolaurate L-1695 350.0 b2) Sucrose monostearate 50.0 c) Crospovidone 250.0 d) Elcema 150.0 e) Magnesium stearate _§Q¿Q TOTAL 980.0 13. a) Cyclosporine (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 160.0 c) Plasdone XL 10 200.0 dl) Pharmacoate 603 25, 0 C12) Avicel PH 101 75.0 e) Magnesium stearate _20¿Q TOTAL 605.0 Each of the above compositions ll to 13 additionally suitably contains 25 mg (f) of tartaric acid and / or 50 mg (g) of dioctyl succinate, preferably both, giving a final weight of 1,000 mg for composition 11, 1.055 mg for composition 12 and 6180 mg for composition 13.

Compositions 11 to 13 are prepared as follows: components (a) and (b) are dissolved in absolute ethanol and ethanol. ... uun._. | .__ L.;.; . .. 511 398 10 15 20 25 30 32 evaporates to a great extent at 50 ° C under reduced pressure. Components (c) to (e) are thoroughly mixed [with the addition of (f) and (g) when used]. use of conventional mixing technology. The solid solution comprising [(a) + (b)] is ground to a fine powder and mixed uniformly in [(c) - (g)] and the uniform mass formed is compressed into tablets, each containing 100, 50 or 25 mg of (a) and are suitable for administration for the prevention of transplant rejection or for the treatment of autoimmune diseases, e.g. when administering 1 to 5 tablets daily.

EXAMPLE RELATIVE AMOUNT (mg) 14. a) Cyclosporine (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Paraffinum perliquidum 397.5 TOTAL 760.0 15. a) Cyclosporin (t. eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Silicone oil Dc 200 397.5 TOTAL 760.0 Components (a) and (b) are dissolved in absolute ethanol and the ethanol is largely evaporated at 50 ° C under reduced pressure.

The resulting solid solution is ground to a fine powder and suspended uniformly in component (c). The resulting liquid suspension is filled into hard gelatin capsules, size 0 to give an encapsulated end product where each capsule contains 50 mg of cyclosporin (eg Ciclosporin) and is suitable for administration in order to prevent transplant rejection or for the treatment of autoimmune diseases, e.g. ex. when administering 1 to 5 capsules daily. 10 15 20 25 30 35 511398 33 XEMP L INGREDIENT RELATIVE AMOUNT (mg) 16. a) Cyclosporine (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Paraffinum subliquidum 372.5 d ) Paraffinum durum _åålQ TOTAL 760.0 17. a) Cyclosporine (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Paraffinum perliquidum 397.5 d) Aerosil 10.0 TOTAL 770.0 The compositions 16 and 17 are prepared analogously to 14 and 15 above. In the case of composition 16, first (c) and (d) are combined by melting and intimate stirring. The solid solution [(a) + (b)] then in [(c) + (d)]. In the fall. with composition 17 together with [(a) + (b)] in (C) - Compositions equivalent to those in Examples 1 to 17 above can be prepared by substituting as component (a) containing suspended (d) Ciclosporin with any other cyclosporin, e.g. [Nva] 2-Ciclosporin or using any other fatty acid saccharide monoester, raffinose monolaurate, (b), cases in the same or equivalent amount or relative proportion.

The utility of the compositions of the invention can be demonstrated in animal or clinical trials, for example, performed as follows: BIO-AVAILABILITY PREPARATIONS BA EQEQ FOR. COMPOSITIONS ACCORDING TO THE INVENTION a) Tested compositions COMPOSITION I according to Example 1 COMPOSITION II e.g. as stated above, for example instead of sucrose monolaurate as a component in each according to Example 14 b) Test method 511 398 10 15 20 25 30 35 C) 34 Groups of 8 beagle dogs (males, about 11-13 kg) are used. The animals are not fed for 18 hours before the administration of the test composition, but are given free access to water until the administration. The test compositions are administered by gavage, followed by 20 ml of 0.9% NaCl solution.

The animals are given free access to food and water 3 hours after the administration of the test compound. 2 ml blood samples (or 5 ml for the blank samples) are taken from the vena saphena and collected in 5 ml plastic tubes containing EDTA -15 min. (blank), 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after administration. The blood samples are stored at -18 ° C pending examination.

The blood samples are analyzed with RIA. The areas under curves with drug concentration in the blood against time are calculated according to 30 min., And 1, according to the trapezoid rule. Analysis of variance is performed using AUC, area under the curve, Cmax (maximum concentration) and Tmax (time for maximum).

Results Calculated mean values for 'AUC (in ng h / ml'1) and Cmax (in ng / ml' 1) typical test runs are shown in the following table, the response between test animals receiving the same composition (CV). from together with calculated variation in COMPOSITION AUC cv <9) cmax cv% (o-24h) I 3058 19.9 583 30.9 11 2894 14.91 544 19.7 As can be seen in the table above, compositions according to the invention show high bioavailability (AUC and Cmax) and at the same time relatively little variation in patient response for both AUC and Cmax.

Comparable advantageous results can be obtained using other compositions according to Examples 1 to 17, in particular the compositions according to Examples 1 to 10. 10 15 20 25 30 35 511 398 35 GENESAL EXAMPLE The advantageous properties of the compositions according to the invention when administered orally in clinical trials, e.g. performed as follows: The subjects are adult volunteers, e.g. professionally trained men from 30 to 55 years. The experimental groups suitably comprise 12 people.

The following criteria were applied for inclusion / exclusion for the trials: normal ECG; frequency; body weight = 50-95 kg.

Inclusion: normal blood pressure and normal cardiac Exclusion: clinically significant intermittent medical condition that may affect the absorption, distribution, metabolism, excretion or safety of the drug; symptoms of significant clinical disease during the two-week period prior to the trial; clinically relevant abnormal laboratory values or ECG; need for concomitant medication throughout the trial period; administration of any drug known to have well-defined potential toxicity to any of the major organys- administration of any pre-histemene in the last 3 months; weeks before the start of the trial; loss of 500 search drugs within 6 toria with drug or alcohol abuse; during the last 3-month period; drugs or hypersensitivity; ml of blood or more adverse reaction to an allergic history requiring drug therapy; Hep-B / HIV-positive.

A complete medical examination is performed and the ECG is taken before and after the experiment. The following parameters are evaluated within 1 month before and after the experiment: Blood: erythrocyte sedimentation, hemoglobin, hematocrit, blood cells, red blood cell count, white blood cell count, platelet count and fasting glucose. electrophoresis, cholesterol, C1 'creatinine, Serum / plasma: total protein and triglycerides, Na +, K *, Fe ++, Ca ++, urea, uric acid, SGOT, SGPT, -GT, alkaline phosphatase, total bilirubin, α-amylase; Urine: pH, microalbumin, glucose, erythrocytes, ketone bodies, sediment. w u Åx n. 511 398 36 10 15 20 25 30 35 Creatinine clearance is also determined 1 month before the start of the experiment.

Each of the subjects receives test compositions in random order. The compositions are administered orally, once to a total dose of 150 mg of cyclosporin, e.g. Cyclosporine, and at least 14 days may elapse between each administration.

Administration is performed in the morning after a 10h fast overnight with only water allowed. Only decaffeinated beverages are allowed for 24 hours after administration. Subjects should not smoke for l2h after administration. The subjects receive a standardized lunch 4 hours after administration.

Blood samples (2 ml) are taken 1 h before administration and after administration at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 9 , 12, 14, 24, 28 and 32h. For determination of creatinine, 2 ml of blood sample is taken immediately before administration and 12, 24 resp. 48 hours after administration. Samples for cyclosporin determination are collected in two EDTA-coated polystyrene tubes (1 ml each) at each time point and deep-frozen at -20 ° C after gentle stirring. Cyclosporine is tested in whole blood using RIA with specific and / or nonspecific MAB assay - the detection limit in both cases is about 10 ng / ml.

In experiments performed in accordance with the above protocol, e.g. Comparison of the composition of Example 1 in hard gelatin capsule form with today's Ciclosporin drink solution (Ciclosporin = 50 mg, Labrafil = 150 mg, ethanol = 50 mg, corn oil = 213 mg, in soft gelatin encapsulated form: final weight = 463 mg / dose) as standard, is significantly recorded increased bioavailability levels for the composition of Example 1 compared to the standard, reflected in both established AUC (O-32h) and Cmax values. In addition, comparison of the variation in time of the Ciclosporin concentration in whole blood (determined by specific monoclonal RIA) after administration of the test compositions to a Ciclosporin dose of 150 mg showed a marked reduction in the variation in response between all patients receiving the composition. according to Example 1 compared to the corresponding 511 398 37 for all patients who received the standard composition.

Similar or equivalent results may be obtained after oral administration of other compositions of the invention, e.g. as described in the examples.

Claims (2)

I fi iiíš 511 398 5% Patent Application No. 9000041-7 P A T E N T K R A V A non-alcoholic composition containing cyclosporin in a solid solution of sucrose monolaurate or raffinose monolaurate, wherein cyclosporin: sucrose monolaurate or raffinose monolaurate is present in a ratio of 1: 3 to 200 parts by weight. A composition according to claim 1, in which the cyclosporin is in a solid solution of sucrose monolaurate.