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

At the same time, the usefulness of Ciclosporin against various autoimmune diseases and inflammatory conditions has been intensively studied, especially inflammatory conditions with an etiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, and there is an extensive literature with reports and results in vitro, on animal models and clinical trials. Specific autoimmune diseases for which cyclosporine therapy has been proposed or applied include autoimmune hematological disorders (including, for example, hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (including, for example, ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, 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 minimal change nephropathy).

Other areas of investigation have been potential utility as an antiparasitic, particularly anti-protozoal agent, with proposed potential uses including treatment of malaria, coccidiomycosis and schistosomiasis, and more recently use in cancer therapy, e.g. as an agent to reverse or abrogate resistance to other anti-neoplastic or cytostatic therapy. \ x in m Since the original 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 application of modified culture techniques.

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 (1982); Kobel et al., Europ. J. Applied Microbiology and Biotechnology 14, 273-240 (1982); and von Wartburg et al., Progress in Allergy/ åå, 28-45 (1986)], as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins, including the so-called the dihydrocyclosporins [in which the -x-y- moiety of the -MeBmt group (formula B above) is saturated so that -x-y- = -CH2-CH2-]; derivatized cyclosporins (e.g. those in which an additional substituent has been introduced at the α-carbon atom of the sarkosyl group in the 3-position of the cyclosporin molecule); cyclosporins in which the -MeBmt group is present in isomeric form (e.g. in which the configuration over positions 6' and 7' of 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.; US-A- 4,108,985, 4,210,581 and 4,220,641; European Patent Publications 0034567, 0056782 and 0296122; International Patent Publication WO 86/02080; Wenger 1, Transp. Proc. 15, Suppl. 1:2230 (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- and (Nva-[Nva-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-Ciclosporin (also known as dihydrocyclosporin D), [3'-desoxi-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 20 25 30 35 511598 4 [MeIle]11-Ciclosporin, [(D)MeVal]11-Ciclosporin (also known as cyclosporin H), [MeAla]6-Ciclosporin, [(D)Pro]3-Ciclosporin, etc.

[According to the now conventional nomenclature for cyclosporins, these are defined with reference to the structure of Ciclosporin (i.e., cyclosporin A). This is done by first stating the amino acid groups present that differ from those found in Ciclosporin (e.g., "[(D)Pro]3" to denote that the cyclosporin in question has a -(D)Pro- instead of a -Sar- group in the 3-position) and then using 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 to Ciclosporin or more specific utility, for example, in particular activity in reversing tumor resistance to cytostatic therapy, and the literature is flooded with proposals for use as therapeutic agents.

Despite the very important progress that Ciclosporin has made, especially in the fields of organ transplantation and therapy of autoimmune diseases, difficulties have been encountered regarding more effective and convenient administration routes and methods and undesirable side effects have been reported, especially nephrotoxic reactions, which have obviously posed a serious obstacle to widespread use or application. Characteristic of Ciclosporins is that they are very hydrophobic. Proposed liquid preparations, e.g. for oral administration of Ciclosporins, have so far been mainly based on the use of ethanol and oils or similar excipients as carriers. Thus, in the commercially available Ciclosporin drink solution, ethanol and olive oil are 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 necessity of using oils or oil-based carriers can give the formulations an unpleasant taste or otherwise reduce palatability, especially in connection with long-term therapy. These effects can be masked by formulation in the form of gelatin capsules. However, to keep the cyclosporin in solution, a high ethanol content is required. Evaporation of the ethanol, e.g. from capsules or from other forms, e.g. when they are 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 necessity of packaging the encapsulated product in an airtight compartment, for example an airtight blister or aluminum foil blister pack. This in turn leads to the product being 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 dosage systems are also low and vary greatly between individuals, individual patient types and even for individual individuals at different times during the course of therapy. Literature reports thus show that currently available therapy, which utilizes the commercially available Ciclosporin drinking solution, provides an average absolute bioavailability of only about 30%, with marked variation between individual groups, e.g. between liver transplant recipients (relatively low bioavailability) and bone marrow transplant recipients (relatively high bioavailability).

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

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

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

Various proposals have been made in the art to overcome these problems, including both solid and liquid oral dosage forms. Thus, Japanese Patent Application No. 71682/1985 (Takada et al.) proposes the application of agents to increase the lymphatic delivery of cyclosporins, especially by administration together with surfactants. A general list of surfactants which may 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 sorbitan oleate, palmitate or stearate. Although the use of both mono- and poly-esters is indicated, preference is generally suggested for mono- or di-esters. Other listed surfactants include polyoxyethylated hydrogenated vegetable oils such as the products known and commercially available under the trade names Cremophore RH and Nikkol HCO 60, and these are clearly stated to be preferred, for example, to the sucrose ester surfactants listed.

Example 3 of the said Japanese application describes the preparation of an aqueous formulation comprising a sucrose fatty acid ester, identified as Fl60, as the surfactant component. The formulation comprises 3.5 mg of Ciclosporin and 2 mg of sucrose ester in 1 ml of H20. To achieve dispersion of the Ciclosporin, sonication is required for 5 minutes at 100W. The resulting formulation, described as "a transparent solution", is used directly in animal models to investigate relative lymphatic resorption. In view of the very low solubility of Ciclosporin in H20 and the small amount of surfactant used, it is obvious that the claimed solution is an artefact of the sonication procedure. Not only is the Ciclosporin concentration achieved inappropriately low for e.g. an oral dosage form, but the preparation is inherently unstable and therefore practically excluded as a practical or commercial galenic form of any kind. It is essentially an experimental system, enabling laboratory investigation and nothing more. There is no suggestion of using surfactants in any other context than in connection with lymphatic delivery.

Japanese Patent Application No. 193129/1987 (Publication No. 038029/1989), also here Takada et al., describes powder preparations 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 methyl cellulose phthalate, together with minor amounts of a surfactant. Again, the surfactant is added for the purpose of increasing lymphatic delivery and the application is, in this respect, clearly directed to providing a means of implementing the teachings of 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 a list of possible surfactant components has been retained.

Nikkol HCO 60 products 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 claimed increase in lymphatic drainage provides any practical advantage or overcomes any of the difficulties in cyclosporine therapy which have been encountered in the art, e.g. as discussed above.

The present invention provides novel galenic formulations of cyclosporin comprising fatty acid saccharide monoesters as primary carrier components which eliminate or substantially reduce the difficulties in cyclosporin therapy, e.g. Ciclosporin therapy, which have been encountered heretofore. It has been found in particular that the compositions of the invention permit the preparation of solid, semi-solid and liquid compositions containing a cyclosporin in a sufficiently high concentration to permit e.g. convenient oral administration while achieving improved efficacy e.g. in terms of bioavailability properties.

More particularly, it has been found that compositions according to the present invention make it possible to achieve effective cyclosporin dosing with concomitant increase in resorption/bioavailability levels, as well as less variation in the achieved resorption/bioavailability levels both for individual patients receiving cyclosporin therapy and between individuals. By applying the teachings of the present invention, dosage forms of cyclosporin can be achieved 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 closer standardization and optimization of ongoing daily dosage requirements for individual patients on cyclosporin therapy, as well as for groups of patients undergoing comparable therapy.

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

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

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

More particularly, the present invention provides: A pharmaceutical composition comprising a) a cyclosporin as an 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 present in said composition in 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-(C2-4alkylene)glycol having an average molecular weight of not more than 7,000 or a viscosity at 50°C of not more than 15,000 mPa~s. or comprises a C3-5alkylene polyol ether or ester; or v) said composition is anhydrous or substantially anhydrous; or vi) component (c) comprises a solid polymer carrier, a nu x m M H| ml) x w MMH 511 398 10 15 20 25 30 35 10 organic silicone polymer or paraffinum per- or sub-liquidium and component (a) is included in said composition in solid solution in (b).

The compositions defined above are new and particularly advantageous variants of those generically claimed in French patent application No. 88 11953 and corresponding applications in other countries worldwide, including US patent application 07/243 577, DOS 38 304945, JP application No. 231 396/88 and UK application No. 88 21443.9 (first published in France on 17 March 1989 under No. 2 620 336).

The definitions (i) to (vi) above are to be understood as not mutually exclusive. The compositions according to the invention thus include compositions according to the definitions which satisfy one or more of the stated limitations (i) to (vi). Preferred compositions according to the invention are thus, for example, 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 contemplated, are acceptable for oral use, or when topical administration is contemplated, are topically acceptable.

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

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

The fatty acid moiety of 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), myristic 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) comprise 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 monopalmitate and raffinose monooleate. Most preferred components (b) are raffinose monolaurate and, in particular, sucrose monolaurate.

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

The components (b) suitably have an ester residue purity of at least 80%, more preferably at least 90%, most preferably at least 95%. The 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 definitions (ii) and (iii) above as applied to the compositions of the invention, 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 wherein component (a) has a solubility of at least 10%, preferably at least 25%, most preferably at least 50% and/or wherein component (b) has a solubility of at least 100%, more preferably at least 200%, most preferably at least 300% (e.g. wherein component (b) has a solubility of the order of at least 1,000, more preferably 2,000, most preferably at least 3,000 mg/ml).

Components (c) suitable for use in the compositions of 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 polyol ethers or esters, as well as any mixtures thereof.

However, in accordance with the general objectives 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 C2-4alkylene glycol (c2), it is preferably a propylene glycol, most preferably 1,2-propylene glycol. When component (c) comprises a C3-5alkylene polyol (c3), it is preferably a C3-5alkylene triol, most preferably glycerol.

When component (c) comprises a poly-(C2-4alkylene)glycol (C4), this is suitably a polyethylene glycol. For use in the compositions of the invention, these components preferably have an average molecular weight of not more than about 7,000 [cf. definition (iv)], e.g. up to 6,600, more preferably not more than about 2,000, e.g. up to 1,600, most preferably not more than about 500. Such components preferably have a viscosity of not more than about 15,000 mPa.s., more preferably not more than about 1,000 mPa.s., most preferably not more than about 200 mPa.s., at 50°C or, more suitably, at room temperature [cf. definition (iv)]. Suitable polyethylene glycols for use as components (c) are, e.g. de sonx are 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 meet 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. about 46-53 about 66-74 about 85-95 about 130-150 freezing- about -16 to about -3 to about 15 to point about -so°c -12°c 8°c 25°c 25 n about 1.459 about 1.463 about 1.465 about 1.467 D When component (c) comprises a C3_5alkylene polyol ether or ester (c5), this is suitably a C3_5alkylene triol, especially -glycerol, ether or ester. Suitable components (c5) include mixed ethers or esters, i.e. components which comprise other ether or ester ingredients, e.g. transesterification products of C3_5alkylene triol esters with other mono-, di- or polyols.

Particularly suitable components (c5) are mixed C3-5alkylenetriol/poly-(C2-4alkylene)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 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-(C2-4alkylene)glycol, e.g. polyethylene glycol and, optionally, glycerol (i.e., carrying out transesterification from the glyceride to the polyalkylene glycol/glycerol component, i.e., via polyalkylene glycolysis/glycerololysis). 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 l0 15 20 25 30 35 14 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, almond, peanut, coconut, palm, soybean and wheat germ oils, and, especially, 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, for example from about 1,000 to about 2,000.

Suitable components (c5) thus include mixtures of C3-5alkylenetriol esters, e.g. mono-, di- and triesters in varying relative amounts, and poly-(C2-5alkylene)glycol mono- and diesters, together with minor amounts of free C3-5alkylenetriol and free poly-(C2-5alkylene)glycol. As indicated above, the preferred alkylenetriol moiety is glycerol; preferred polyalkyleneglycol moieties are especially those with a molecular weight of from about 500 to about 4,000; and preferred fatty 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) according to the description 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 has mp. = about 33-38°C and a saponification number = about 240/260; 10 15 20 25 30 35 511 398 15 ii) Gelucir 35/10, mp. = about 29-34°C, saponification number = about 120-140; iii) Gelucir 37/02, mp. = 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. = approx. 42-46°C, saponification number = approx. 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. = ca 46-41°C, saponification value = ca 65-85; x) Gelucir 53/10, mp. = ca 48-53°C, saponification value = ca 95-115; xi) Gelucir 62/05, mp. = ca 60-65°C, saponification value = ca 70-90; The products (i) to (x) above all have an acid value = <2.

The product (xi) has an acid value = <5. The products (ii), (iii) and (vi) to (x) above all have an iodine value = <3. The product (i) has an iodine value = S8. The 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 in scmx can also be used in the compositions of the invention.

When using a component (c) as specifically described above (i.e. a component meeting any of the definitions (i) to (iv) above or any component as defined under (c1) to (c5)], the compositions of the invention will generally comprise component (a) in a carrier medium comprising components (b) and (c). Each of components (a) and (b) will generally be present in the compositions of the invention in dispersion or solution, e.g. molecular or micellar ........ '"_........... ... _ _ i 511 398 10 15 20 25 30 35 16 dispersion or solution (including solid solution where applicable). 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 (c). Component (b) will generally act in the compositions of the invention as carrier or solubilizer (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 being limited in any way to any particular functional relationship between components (a), (b) and (c) unless otherwise stated.) When a component (c) as above is used, it is further preferred that the compositions of the invention are formulated 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 dosage.

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 of from 1:0.5 to 50 parts by weight [(a):(c)] [cf. definition (ii)]. The 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 according to the invention are anhydrous or substantially anhydrous [cf. definition (v)], e.g. have 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 specific 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 meets 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 specific 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, the components (a) and (c) are suitably included in said compositions in a ratio of about 1:0.5 to 50 parts by weight. More suitably, the components (a) and (c) are suitably included 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)]. The 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 suitably, 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 according to the invention comprise sucrose monolaurate as component (b) and 1,2-propylene glycol as component (c), components (a) and (b) are preferably present in a ratio of from about 1:6 to 7 parts by weight [(a):(b)] and components (a) and (c) are preferably present 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 formulated into any suitable dosage form, e.g. for oral, parenteral or topical application, e.g. for dermal or ophthalmic application, e.g. for application to the surface of the eye, e.g. 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 or other administration.

The amount of component (a) contained in such unit dosage forms will of course vary depending, for example, on 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, for example, liquids, granules and the like. However, solid unit dosage forms, for example, tablets or soft gelatin encapsulated dosage forms, are preferred, such as hard capsule forms, especially capsules or 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, for example, 15, 20, 25, 50, 75 or 100 mg of component (a), for example, Ciclosporin, per unit dose.

Compositions of the present invention, which comprise a component (c) as above, 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) over a longer period of time, for example after oral administration. Such compositions further comprise (d) a component capable of modifying the release of the composition. Such components (d) include, for example, polymeric excipients, in particular thickeners, for example polymeric or colloidal setting properties with respect to the thickener component, as well as agents which are swellable in water, for example 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 known and commercially available under the trade name Carbopol (cf. Fiedler loc. cit. 1, pp. 206-207), especially the products Carbopol 934, 940 and 941, p. L, p. 372-373), especially the products Eudragit E, L, S, and Eudragit (cf. Fiedler loc. cit. 10 15 20 25 30 35 511 398 19 RL and RS, especially the products Eudragit E, L and S; Cellulose and cellulose derivatives including: alkyl cellulose, for example methyl, ethyl and propyl cellulose; hydroxyalkyl cellulose, for example hydroxypropyl cellulose and hydroxypropyl alkyl cellulose such as hydroxypropyl methyl cellulose; acetylated cellulose, for example cellulose acetates, cellulose acetate phthalates, cellulose acetate succinates and hydroxypropyl methyl cellulose phthalates; and salts thereof such as sodium carboxymethyl 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), especially the products Klucel LF, MF, GF and HF and Methocel K 100, K l5M, K l00M, E 5M, E 15, E l5M and E l00M; including vinylpyrrolidones and vinylpyrrolidone copolymers such as Polyvinylpyrrolidones, for example poly-N-vinylpyrrolidone vinyl acetate copolymers. Examples of such compounds suitable for use according to the present invention are those which are known and commercially available, Kollidon (cf.

Fiedler loc. cit. 1, pp. 526 and 527), especially the products Kollidon 30 and 90; e.g. under the trade name Polyvinyl resins, including e.g. polyvinyl acetates and alcohols, as well as other polymeric materials including gum tragacanth, gum arabic, alginates, e.g. alginic acid and salts thereof, e.g. sodium alginates; Silicas, including hydrophilic silica products, e.g. alkylated silica gels, especially colloidal silica products which are (e.g. methylated) known and commercially available 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 components (a) + (b) + (C) + (d)- _ When component (c) in the compositions of the invention comprises: (c6) a solid carrier polymer as required by definition (vi) above, this 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 in particular crosslinked polyvinylpyrrolidones. Examples of such materials suitable for use in the present invention are those known and commercially available under the trade name Kollidon [cf. Fiedler, loc. cit., 1, p. 5271, Kollisept [cf. Fiedler, loc. cit., 2, pp. 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 having 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 as (C6) are: Plasdone XL, Plasdone XL 10 and Crospovidone.

When the compositions according to 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 under (dz) above.

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

Fiedler, loc. cit., 1, pp. 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 micellar solution, e.g. entirely or substantially entirely in molecular or micellar 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 description and claims, it should be understood correspondingly, e.g. as including viscous or highly viscous systems.] The solid solution comprised by (a) and (b) is dispersed in a suitable manner, e.g. in particulate, e.g. finely particulate form in, e.g. throughout, component (c5). Components (c6) will thus generally serve in the compositions according to the invention as a disintegrable matrix for [(a)+(b)]. The components (d) will generally serve as disintegration promoting agents, e.g. upon contact with the contents of the gastrointestinal tract.

Compositions according to 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 alkylsulfonate salts, e.g. metal salts, e.g. those having 10 or more carbon atoms in the fatty acid/alkyl moiety, e.g. 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), 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, even 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 of 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. When a component (e) is present, 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 comprise all of them, it is suitable that the three (e) and the three components (C6), (d) and (e) together are included in an amount of from about 25 to 75%, more preferably about 30 to 65%, most preferably about 40 to 65% calculated on the order 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) contained in such a unit dosage form will of course vary depending, for example, on the condition to be treated, the intended route of administration and the desired effect. In general, however, it is convenient to contain from about 2 to about 200 mg of component (a), e.g. Ciclosporin, per unit dose. Suitable dosage forms for oral administration include granules and the like. Solid unit dosage forms are, however, for example, tableted or encapsulated 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.

When component (c) of the compositions according to the invention comprises: (c7) an organic silicone polymer or paraffinum per- or subliquidum as required by definition (vi), component (c7) is preferably readily flowable at temperatures up to 150°C, preferably up 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 temperatures specified. above, Paraffin 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, pp. 690-6911. To enable easy preparation, component (c7) suitably consists entirely or essentially of liquid or semi-solid paraffins, i.e. paraffinum perliquidum or paraffinum subliquidum or mixtures thereof, but when it is desirable to prepare compositions which, for example, have a slower release of active ingredient, this can be achieved by further adding a solid paraffin, i.e. paraffinum durum.

When the compositions according to the invention comprise only liquid or semi-solid paraffins as component (c7), these are preferably present in a ratio of from about 1:0.5 to 1.0 [liquid semi-solid]. In this case, components (a) and (c7) are suitably present 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)].

When the compositions according to the invention further comprise a solid paraffin as component (c7), the ratio of liquid/semi-solid paraffin:solid paraffin 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 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)]. Organic silicone polymers suitable for use as component (c7) include in particular liquid, i.e. liquid and semi-solid polymer materials having a structural unit of the formula -(R)2Si-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 for ease of formulation, component (c7) comprises poly- any of the various known, for example C1-4 alkyl, preferably liquid organic silicone polymers, e.g. methylsiloxane polymers, e.g. 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 polymers alone, components (a) and (C7) are from about 1:6 to 200, most preferably 1:6 to 20, [cf. Fiedler, loc. polymers alone, preferably present in a ratio of more than 100, e.g. about 1:8 parts by weight [(a):(c7)]. 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 adding these, 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 components (a):(c7) is suitably of the order of from 1:6 to 100, preferably about 1:6 to 20 parts by weight [(a):(c7)].

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

When the compositions of the invention comprise a component (c7), 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 comprising a component (c7), component (a) is present in component (b) completely or substantially completely in molecular or micellar dispersion, e.g. in the form of a solid solution or solid micellar solution [wherein the term "solid solution" is used herein in the same broad sense as in connection with compositions comprising a component (c5)]. The solid solution comprising (a) and (b) is suitably dispersed in particulate form, e.g. fine particulate form with component (c7), e.g. throughout component (c7).

Compositions of the invention comprising a component (c7) may be formulated in any suitable dosage form, e.g. for oral, parenteral or topical application, e.g. for dermal or ophthalmic application, e.g. for application to the surface of the eye, e.g. 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, for example, on the condition to be treated, the intended route of administration and the desired effect. In general, however, they suitably contain from about 2 to about 200 mg of component (a), e.g. Ciclosporin, per unit dosage.

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) over longer periods of time, e.g. after oral administration. As previously described, such compositions can be obtained by incorporating solid or semi-solid components (c7) in suitable amounts. Alternatively, they can be obtained by incorporating a further 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, in particular thickeners, e.g. polymeric or colloidal thickeners, as well as agents which are swellable in water, e.g. water-swellable polymers or colloids, for example any of the materials defined above under (d1) to (d5).

When a component (d) is present, it is suitably included in an amount 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 components (a)+(b)+(c7)+(d).

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

Compositions according to 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 according to the invention may, regardless of the selected component (c) [e.g. regardless of whether component (c) comprises any of the components (c1) to (c7) above or any mixture thereof], comprise further 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)], flavourings, etc.

In particular, the compositions of the invention also suitably contain one or more stabilizers or buffering agents, particularly 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. 10 15 20 25 30 35 511398 Such stabilizers or buffering agents are suitably added in an amount sufficient to provide 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 compositions according to the invention, especially component (a) is Ciclosporin, have a pH in the above-mentioned range.

Compositions according to the invention also suitably contain a polyoxyalkylene-free surfactant such as dioctyl succinate, dioctyl sulfosuccinate, di[2-ethylhexyl] succinate, sodium lauryl sulfate or phospholipids, e.g. lecithins. a surfactant according to the invention 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) according to the invention, any stabilizers, buffers and/or surfactants above are suitably included in the solid solution phase. Such materials may also be included in component (c) etc.

Compositions according to the invention, again independently of the selected component (c), are preferably free or substantially free of 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 preparation of a pharmaceutical composition, which process also includes a process for composition as previously defined, comprising intimately mixing or compounding components (a), (b) and (c) together with a component (d) and/or other component, e.g. stabilizer, buffer or surfactant as described above, and, if necessary, preparing the resulting composition as defined above, optionally in unit dosage form, e.g. unit dosage form for oral administration, e.g. by tabletting, filling into gelatin capsules or other suitable means.

When component (c) is a solvent for components (a) and (b) or comprises a component (c1), (c2), (c3), (c4) or (c5) as defined above, components (a), (b) and (c) are suitably brought together in the above process by sufficiently dissolving components (a) and (b) in component (c), e.g. by 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 is suitably carried out 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 comprising or with components etc., e.g. by intimate mixing in ting 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) in (b) can be prepared by techniques known in the art, e.g. by allowing (a) (b) 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 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 solubilization stage.

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

The following examples illustrate the present invention.

Product examples, Food Corp., Tokyo 104, Japan: lauryl ester residue = 100%: at about 235°C: surface tension of 0.1 wt% aqueous solution 72.0 dyne/cm at 25°C.

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

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

Sucrose monolaurate Glycerol Cyclosporine (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 EXAMPLES Ciclosporin) L~l695 TOTAL Ciclosporin) L-1695 TOTAL Ciclosporin) L-1695 TOTAL Ciclosporin) L-1695 TOTAL Ciclosporin) L-1695 TOTAL L-1969, is commercially available from Mitsubishi-Kasei at least 12.3: decomposition HLB value m.p. = ca 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 50.0 350.0 100.0 50.0 550.0 removed 10 15 20 25 30 35 511398 30 6. a) Cyclosporine (e.g. 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) Cyclosporine (e.g. 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 (e.g. Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) PEG 400 200.0 d) Eudragit L __2¿§ TOTAL 602.5 9. a) Cyclosporine (e.g. Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelucir (e.g. Gelucir 42/12, 44/14 or 35/10 10000 TOTAL 462.5 10. a) Cyclosporine (e.g. Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelucir 100.0 d) Klucel LF _0000 TOTAL 512.5 The composition according to Example 1 is prepared by dissolving components (a) and (b) under stirring and heating over an oil bath at 100OC in component (c). The compositions according to 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) is suspended in (a) to (c).

The resulting compositions are filled under heating into hard gelatin capsules, size 1 (Examples 1 to 4 and 9) or size 0 (Examples 5 to 7 and 10) to give an encapsulated final product, each capsule containing 50 mg of cyclosporine (e.g. Ciclosporin) and which is suitable for administration for the prevention of transplant rejection or in the treatment of autoimmune diseases, e.g. by administering 1 to 5 capsules daily.

EXAMPLE INGREDIENT RELATIVE AMOUNT (mg) 11. a) Cyclosporine (e.g. Ciclosporin) 100.0 b) Sucrose monolaurate L-1695 300.0 c) Plasdone XL 350.0 d) Avicel PH 102 150.0 e) Sodium lauryl sulfate _2âiQ TOTAL 925.0 12. a) Cyclosporine (e.g. 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 (e.g. 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 preferably additionally contains 25 mg (f) tartaric acid and/or 50 mg (g) 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 ll to 13 are prepared as follows: components (a) and (b) are dissolved in absolute ethanol and the ethanol . ...uun._. |.__L.;.; . .. 511 398 10 15 20 25 30 32 is largely evaporated at 50°C under reduced pressure. Components (c) to (e) are thoroughly mixed [with the addition of (f) and (g) when used] using conventional mixing techniques. The solid solution comprising [(a)+(b)] is ground to a fine powder and uniformly mixed into [(c)-(g)] and the resulting uniform mass 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 in the treatment of autoimmune diseases, e.g. when administering 1 to 5 tablets daily.

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

The usefulness of the compositions according to the invention can be demonstrated in animal experiments or clinical trials, for example carried out as follows: BIOAVAILABILITY TESTS FOR COMPOSITIONS ACCORDING TO THE INVENTION a) Tested compositions COMPOSITION I according to example 1 COMPOSITION II e.g. as indicated 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, approx. 11-13 kg) are used. The animals are fasted 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 h after administration of the test compound. 2 ml blood samples (or 5 ml for the blank samples) are taken from the saphenous vein and collected in 5 ml plastic tubes containing EDTA -15 min. (blank), 1.5, 2, 3, 4, 6, 8, 12 and 24 h after administration. The blood samples are stored at -18°C pending examination.

The blood samples are analyzed by RIA. The areas under the curves of drug concentration in the blood versus time are calculated according to the trapezoidal rule. Analysis of variance is performed finding AUC, area under the curve, Cmax (maximum concentration) and Tmax (time to 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 exhibit high bioavailability (AUC and Cmax) and at the same time relatively little variation in patient response for both AUC and Cmax.

Comparable beneficial results can be obtained using other compositions according to Examples 1 to 17, especially the compositions according to Examples 1 to 10. 10 15 20 25 30 35 511 398 35 ginlsg EöRsöK The beneficial properties of the compositions according to the invention when administered orally can also be demonstrated in clinical trials, e.g. carried out as follows: The test subjects are adult volunteers, e.g. professionally trained men from 30 to 55 years of age. The test groups suitably comprise 12 persons.

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 heart rate; Exclusion: clinically significant intercurrent medical condition that could affect the absorption, distribution, metabolism, excretion or safety of the drug; symptoms of significant clinical illness during the two-week period prior to the trial; clinically relevant abnormal laboratory values or ECG; need for concomitant medication throughout the trial; administration of any drug known to have well-defined potential toxicity to any of the major organ systems; administration of any pre- histamine within the past 3 months; weeks prior to the start of the trial; loss of 500 ml of blood or more adverse reaction to the drug; history of drug or alcohol abuse; history of allergic disease requiring drug therapy; Hep-B/HIV- positive.

A complete medical examination is performed and an ECG is taken before and after the trial. The following parameters are evaluated within 1 month before and after the trial: Blood: erythrocyte sedimentation rate, hemoglobin, hematocrit, blood cells, red blood cell count, white blood cell count, platelet count and fasting glucose. electrophoresis, cholesterol, Cl' 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 trial.

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

Administration is performed in the morning after a 10-hour overnight fast with only water allowed. Only caffeine-free beverages are allowed for 24 hours after administration. Subjects are not allowed to smoke for 12 hours after administration. Subjects are given 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 32 h. For creatinine determination, 2 ml blood samples are taken immediately before administration and 12, 24 and 48 h after administration, respectively. Samples for cyclosporine determination are collected in two EDTA-coated polystyrene tubes (1 ml each) at each time point and frozen at -20°C after gentle mixing. Cyclosporine is tested in whole blood using RIA with specific and/or non-specific MAB assay - the detection limit is in both cases about 10 ng/ml.

In experiments carried out in accordance with the above protocol, e.g. comparing the composition according to 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 capsule form: final weight = 463 mg/dose) as standard, significantly increased bioavailability levels are recorded for the composition according to Example 1 compared to the standard, reflected in both established AUC (0-32h) and Cmax values. Comparison of the variation in time of Ciclosporin concentration in whole blood (determined by specific monoclonal RIA) after administration of the test compositions to a Ciclosporin dose of 150 mg also showed a marked reduction in the variation in response between all patients who received 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, eg 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.