CH680650A5 - - Google Patents

Description

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description

The invention relates to new pharmaceutical formulations containing cyclosporin as an active ingredient.

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

rHeBmt-aAbu-Sar-HeLeu-Val-HeLeu-Ala- (D) Ala-HeLeu-XeLeu-HeVal-

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(A)

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

CB3

(B)

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

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

At the same time, ciclosporin has been used intensively for various autoimmune diseases and inflammatory conditions, in particular inflammatory conditions with an etiology including an autoimmune component such as arthritis (such as rheumatoid arthritis, progressive arthritis chronic and arthritis deformans) and rheumatic diseases. The literature contains numerous reports and results on in vitro tests, animal models and clinical studies. Specific autoimmune diseases for which cyclosporin therapy has been proposed or used include autoimmune haematological disorders (including, for example, hemolytic anemia, aplastic anemia, pure erythrocyte anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodomoma lamenose pathogen , Dermatomyositis, chronic active hepatitis, severe myasthenia, psoriasis, Steven-John-son syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (including ulcerative colitis and Crohn's disease, for example), endocrine ophthalmopathy, Graves disease,

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Sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (type I diabetes mellitus), uveitis (anterior and posterior), sicca keratoconjunctivitis and spring keratocunjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (for example, with or without nephrotic syndrome, with or without nephrotic syndrome, with or without nephrotic syndrome, including nephrotic syndrome, with or without nephrotic syndrome with minimal change).

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

Since the original discovery of ciclosporin, a variety of naturally occurring cyclosporins have been isolated and identified, and numerous other non-natural cyclosporins have been made by total or semi-synthetic methods or by using modified breeding techniques. The class of cyclosporins is now very extensive and includes, for example, the naturally occurring cyclosporins A to Z (cf. Traber et al. 1, Helv. Chim. Acta. Vol. 60 (1977), pages 1247 to 1255; Traber et al. 2 , Helv. Chim. Acta, Vol. 65, No. 162 (1982), pages 1655 to 1667; Kobel et al., Europ. J. Applied Microbiology and Biotechnology, Vol. 14 (1982), pages 273-240 (1982 ); and by Wartburg et al., Progress in Allergy, vol. 38 (1986), pages 28-45, as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins including the so-called dihydrocyclosporins (in which the rest -xy- of the -MeBmt residue (formula B above) to form -xy = -CH2-CH2-); derivatized cyclosporins in which, for example, another substituent on the a-carbon atom of the sarcosyl residue in the 3-position of the cyclosporin mole -küls is introduced); Cyclosporins in which the -MeBmt residue is present in isomeric form (where, for example, the configuration at positions 6 'and T of the MeBmt residue is ice instead of trans); and cyclosporins, in which different amino acids are introduced at specific positions within the peptide sequence, using, for example, the total synthesis process developed by R. Wenger for the production of cyclosporins (see, for example, Traber 1, Traber 2 and Kobel loc. cit.; US Pat , 4 210 581 and 4 220 641, European patent publications 0 034 567, 0 056 782 and 0 296 122; International patent publication WO 86/02 080; Wenger 1, Transp. Proc., Vol. 15; Suppl. 1 (1983), Page 2230; Wenger 2, Angew. Chem. Int. Ed., Vol. 24 (1985), p. 77 and Wenger 3, Progress in the Chemistry of Organic Natural Products, Vol. 50 (1986), p. 123.

The class of cyclosporins now includes, for example, [Thr] 2-, [Val] 2-, [Nva] 2- and [Nva] 2- [Nva] 5-ciclosporin (also known as cyclosporins C, D, G and M, respectively) , [3'-0-Acyl-MeBmt] 1-cyclosporin (also known as Cyclosporin A acetate), [Dihydro-MeBmt] 1- [Val] 2-cyclosporin (also known as Dihydro-cyclosporin D), [ 3'-deoxy-3'-oxo-MeBmt] 1- [Val] 2- and - [Nva] 2-ciclosporin, [(D) fluoromethyl-Sar] 3-ciclosporin [(D) Ser] 8-ciclosporin, [ Melle] 11-ciclosporin, [(D) MeVaI] 11-cicIosporin (also known as Cyclosporin H), [MeAlap-Ciclosporin, [(D) ProP-Ciclosporin and the like.

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

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

Despite the very important contribution that ciclosporin has made, particularly in the area of organ transplantation and the therapy of autoimmune diseases, difficulties arise in providing more effective and convenient means of administration. In addition, reports of adverse side effects, particularly nephrotoxic reactions, are a serious obstacle to the extended use of these compounds.

Cyclosporins are characterized by their highly hydrophobic nature. Proposed liquid formulations, e.g. for oral administration of cyclosporins have so far been based predominantly on the use of oils together with solvent systems which contain, for example, ethanol and labrafile and similar vehicles as carrier media. The commercially available Ciclospo-rin drinking solution uses ethanol and olive oil as a carrier medium in conjunction with Labrafil as a surface-active agent; see. e.g. U.S. Patent 4,388,307. However, the use of the drinking solution and similar compositions as proposed in the prior art is accompanied by numerous difficulties.

First, the use of oil-based systems has required the use of high ethanol concentrations to maintain solubility. The use of ethanol is naturally undesirable, especially if it is intended to be administered to children. Furthermore leads

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evaporation of the ethanol, e.g. capsules or other dosage forms (if they are open, for example) to develop a precipitate. When such compositions are presented in the form of so-called soft gelatin capsules, this particular difficulty makes the packaging of the encapsulated product in an airtight container, e.g. an airtight blister pack or an aluminum foil blister pack or container. This in turn leads to a voluminous nature of the product and to an increase in the cost of manufacture. The storage properties of the aforementioned formulations are therefore far from ideal.

The use of such dosage forms is also characterized by extreme fluctuations in the dosage required for the patient. In order to achieve effective immunosuppressive therapy, the cyclosporin levels in the blood or blood serum must be maintained within a certain range. Again, this range can vary depending on the particular condition being treated, e.g. depending on whether the therapy is used to prevent transplant rejection or to combat an autoimmune disease or condition and depending on whether or not other immunosuppressive therapy is used at the same time as the cyclosporin therapy. Experience shows, however, that, for example, when using the available ciclosporin drinking solution, the daily dosages required to achieve the required blood serum levels vary from person to person and also with the same individual at different times. For this reason, it is necessary to monitor the blood / blood serum levels of the patients undergoing cyclosporine therapy at regular and frequent intervals in order to adjust the daily dose in such a way that blood / blood serum levels are maintained within the required range. Monitoring blood / blood serum levels, generally by RIA or an equivalent immunoassay technique, e.g. using the technique based on monoclonal antibodies must be carried out regularly in every patient who is subjected to cyclosporine therapy. This is necessarily time consuming and troublesome and adds to the overall cost of the therapy.

Furthermore, the blood / blood serum cyclosporin levels achieved using available dosing systems show extreme fluctuations between maximum and minimum levels. This means that effective cyclosporin levels in the blood vary widely between doses of each dose for each individual patient. It has been found that this variation in patient response is significantly related to a variation in the availability of naturally occurring surfactant components, e.g. Bile acids and salts thereof can be attributed to the gastrointestinal tract of the patient to be treated. In the known formulations for cyclosporins known hitherto, the presence of such natural surface-active agents in sufficient quantity is necessary if a satisfactory absorption is to be achieved. However, it cannot be avoided that the availability of such surfactants in the gastrointestinal tract varies from one patient to another and also in an individual patient with time.

Apart from such inconsistencies in therapy, this also means that the individual patient must be monitored at every opportunity within a relatively narrow time window to ensure that, for example, a maximum level is not accidentally recorded as a strong response to a dose. In addition to all of these obvious practical difficulties, there are the occurrence of the aforementioned undesirable side effects that are observed when using available oral dosage forms.

Various proposals to overcome these difficulties are known from the prior art, including both solid and liquid oral dosage forms. The main difficulties remain the inherently insolubility of cyclosporins, e.g. of ciclosporin, in aqueous media and thus the provision of a dosage form which cyclosporins can contain in a concentration which is sufficiently high for an expedient application and yet meet the necessary criteria with regard to bioavailability, which are, for example, effective absorption from the stomach or intestinal tract and the Achieve uniform and suitably high blood / blood serum levels.

As previously mentioned, current commercial oral dosage forms for ciclosporin are disclosed and claimed, for example, in U.S. Patent 4,388,307. The early phase of this development is represented by Swiss Patent Application No. 8634 / 78-8, which serves as a priority document for the patent mentioned. This application is based on pharmaceutical formulations which contain cyclosporin as an active ingredient together with a carrier medium containing one or more of the following components:

i) Sesamöi;

ii) a non-ionic surfactant such as Tween 80, Cremophore EL, 40 or 60 or lecithins;

iii) a transesterified, nonionic triglyceride, e.g. Labrafil;

iv) mixtures of a lecithin (e.g. epicuron), components (iii) and ethyl oleate;

v) neutral oils, e.g. saturated C & -12 triglycerides such as Miglyol 812; and vi) mono- and / or diglycerides, such as glycerol monooleate, glycerol monostearate and glycerol distearate,

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The text and examples describe (i) sole use for oral and parenteral administration; are described (ii) for use in combination with ethanol for oral or parenteral administration and in combination with components (v) for parenteral use; are described (iii) for sole use and in conjunction with a vegetable oil and additionally with ethanol for oral or parenteral administration; (iv) regarding the defined combination with possible further additives, e.g. Preservatives, described for oral administration; are (v) for use in combination with solvents such as ethanol, benzoic acid benzyl ester, 1,2-butylene glycol 1-methyl ether and components (iii) (Labrafil) and in combination with the above-mentioned components (ii) especially for described parenteral administration; and are described (vi) for use alone or in combination with thickeners such as Aerosil or cellulose for oral administration in encapsulated or pelletized form. No specific proposal is made to combine components (vi) (mono- / diglycerides) with any other components (i) to (vi) or vice versa.

In the patent application from which US Pat. No. 4,388,307 originated, the focus of the development set out in the above CH application is on compositions containing cyclosporins as active ingredient together with a carrier medium containing one or more of the components (iii) (Labrafile and the like), (v) (neutral oils) and (vi) (mono- / diglycerides, especially stearic acid or oleic acid mono / diglycerides, especially glycerol monooleate). With regard to oral dosage forms, the use of cosolvents, ethanol and vegetable oils such as olive oil and corn oil is preferred. The components (v) are specifically stated to be preferred with respect to parenteral dosage forms. For components (vi), use with lecithins, optionally with other components (iii) in orally administered aqueous or aqueous / ethanolic emulsions, is proposed.

BE-PS 895 724, which is mainly focused on the use of [Dihydro-MeBmt] 1- [Val] 2-Cic! Osporin (or Dihydro-cyclosporin D) in the treatment of multiple sclerosis, also describes two oral formulations are suitable for the administration of this special compound. Both are based on commercially available Ciclosporin (Sandimmun®) drinking solution with adaptation to the requirements of the special cyclosporin active ingredient. The first formulation comprises 5 to 10% [Dihydro-MeBmfp- [Val] 2-ciclosparin, 10 to 12% ethanol, 30 to 40% Maisine, about 4% Cremophore and 51 to 30% Labrafil (i.e. ad 100%). This corresponds to the composition of the Sandimun® drinking solution, but with the replacement of the natural vegetable oil component by Maisine and with the addition of a minor percentage of the surfactant Cremophore. Maisine is the transesterification product of corn oil with glycerin, with a more detailed composition given below. It contains triglycerides and mono- / diglycerides derived from corn oil in a ratio of about 1: 8 parts by weight (TrkMono- / diglyceride). The ratio of cyclosporin: surfactant in the disclosed composition is approximately 1: 0.4-0.8 and the ratio of cyclosporin: triglycerides: mono- / diglycerides is approximately 1.0: 0.4-0.9: 2. 6-7.1. No proposal is made for a possible increase in the surfactant component or for any measures to avoid the use of labrafil or ethanol components as cosolvents.

The second composition disclosed contains: 15-25% [Dihydro-MeBmt] 1- [Val] 2-ciclosporin, 2-5% ethanol, 40-60% Maisine and 10-40% Imwitor 742, a coconut oil monoglyceride product with a content of> 45% monoglycerides with additional di- and triglyceride components. Again, the use of ethanol is not avoided, and no suggestion for the incorporation of any surfactant component is made.

AU patent application No. 87 335 122 describes the use of surfactants from the group poly-ethoxylated castor oils, polyethoxylated, hydrogenated, castor oils and polyethoxylated fatty acids derived from castor oil or hydrogenated castor oil, such as Cremophore, Myrj and Nikkol HCO-60, as Solubilizers for incorporating poorly soluble pharmaceutical agents into controlled release systems, such as hydrophilic gel systems. The poorly soluble drugs mentioned include cyclosporin, although no example of the application of the system to cyclosporins is given. Furthermore, there is no teaching regarding the use of the solubilizers / surfactants listed in connection with simple fatty acid mono-, di- or triglycerides.

According to the invention, it has now surprisingly been found that pharmaceutical compositions containing cyclosporins, in particular ciclosporin, as the active ingredient, by means of which the previously encountered difficulties in dosage, for example the problems discussed above, can be eliminated or substantially reduced, can be obtained by using carrier systems containing fatty acid triglycerides and mono- / diglycerides in combination and in combination with a hydrophilic surfactant. In particular, it was found that using the defined carrier systems, it is possible to obtain oil-based compositions which are not aqueous emulsions and which do not require the presence of additional solvents, cosolvents or solubilizers, such as ethanol or labrafile or the like, and that high stability and improved bioavailability properties in comparison to known cyclosporin / fatty acid triglyceride / solvent cosolvent systems, for example compared to the well-known Sandimmun® drinking solution. According to a special aspect, the present invention provides

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pharmaceutical oil-based compositions, particularly oil-based pharmaceutical compositions other than aqueous emulsions, which are free or substantially free of ethanol.

In particular, it has been found that the compositions according to the invention enable an effective cyclosporin dosage with simultaneous increase in the absorption / bioavailability levels and / or reduced fluctuation in the absorption / bioavailability levels, both in relation to individual patients who receive cyclosporin therapy and also in with respect to different patients. In particular, it was surprisingly found that the composition according to the invention enables cyclosporins to be resorbed in a manner which is independent or substantially less dependent on the relative availability of natural surface-active materials, such as bile acids or their salts, in the gastrointestinal tract of the treated patient. Applying the teaching of the present invention, cyclosporin dosage forms are obtained with reduced variation in the cyclosporin blood / blood serum levels achieved between the dosages and between different patients. The invention thus enables the cyclosporin dosage level required to achieve effective therapy to be reduced. It also enables closer standardization and optimization of the requirements for continuous daily dosing for individual patients receiving cyclosporine therapy and for groups of patients undergoing appropriate therapy.

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

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

Furthermore, the compositions according to the invention have improved storage stability compared to compositions based on ethanol or equivalent alkanols and, in particular, are more suitable, for example for administration in capsules, such as hard or soft gelatin capsules. Compositions according to the findings of the present invention which are free or substantially free of ethanol have the particular advantage that packaging difficulties, such as have been discussed above, e.g. with regard to packaging in the form of soft gelatin capsules can be eliminated or significantly reduced. According to its broadest aspect, the following is provided according to the invention:

A. A pharmaceutical composition containing:

a) a cyclosporin as active ingredient in a carrier medium, containing b) a fatty acid triglyceride,

c) a glycerol-fatty acid partial ester or a full or partial ester of propylene glycol (e.g. 1,2-propylene glycol) or sorbitol and d) a surfactant with a hydrophile-lipophile balance (HLB value) of at least 10;

with the proviso that when components (b) and (c) consist wholly or essentially of the individual components of a transesterification product of a vegetable oil with glycerol, the composition:

i) free or substantially free of ethanol; or ii) contains ciclosporin or [Nvap-ciclosporin as component (a); or iii) components (a) and (d) in a ratio of 1 contains at least 1 part by weight.

The above conditions (i) to (iii) are not mutually exclusive. Thus, the present invention encompasses compositions that meet any or more of the above conditions.

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

Component (a) is suitably present in the compositions according to the invention in an amount of about 2-20% and preferably about 5-15%, based on the total weight of components (a) up to and including (d). Component (a) can be any therapeutically applicable cyclosporin, e.g. to the products listed above. The preferred component (a) in the compositions of the invention is cyclosporine. Another preferred component (a) in the compositions according to the invention is [Nva] 2-cyclosporin, which

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also known as cyclosporin G.

Examples of suitable components (d) in the compositions according to the invention are:

d.1 reaction products of natural or hydrogenated castor oil and ethylene oxide. Such products can be obtained in a known manner, for example by reacting a natural or hydrogenated castor oil with ethylene oxide, e.g. in a molar ratio of from about 1:35 to about 1:60, the polyethylene glycol component being optionally removed from the product, e.g. according to the processes in DE-ASen 1 182 388 and 1 518 819. The various surfactants available under the trade name Cremophor are particularly suitable. The products Cremo-phor RH 40 with a saponification number of approximately 50-60, an acid number <1, an iodine number <1, a water content (Fischer) <2%, an nD60 value of approximately 1.453-1.457 and one are very particularly suitable HLB value of about 14-16; Cremophor RH 60 with a saponification number of about 40-50, an acid number <1, an iodine number <1, a water content (Fischer) of 4.5-5.5% and an nD25 value of about 1.453-1.457 and an HLB- Worth about 15-17; and Cremophor EL with a molecular weight (by vapor osmometry) of about 1630, a saponification number of about 65-70, an acid number of about 2, an iodine number of about 28-32 and an nD25 value of about 1.471. The various surfactants sold under the trade name Nikkol, e.g. Nikkol HCO-40 and HCO-60, are available. The Nikkol HCO-60 product is a reaction product of hydrogenated castor oil and ethylene oxide with the following properties: acid value about 0.3; Saponification number about 47.4; Hydroxyl value about 42.5; pH (5%) about 4.6; Color APHA = about 40; F. about 36.0 ° C; Freezing point about 32.4 ° C; H20 content (%), RF) 0.03.

d.2 polyoxyethylene sorbitan fatty acid esters, e.g. Mono- and tri-lauryl, palmityl, stearyl and oleylesters, for example the known products available under the name Tween (cf. Fiedler, "Lexicon of auxiliary substances", 2nd revised and extended edition (1981), Vol. 2, pages 972-975) including the products Tween

20 (polyoxyethylene (20) sorbitan monolaurate),

40 (polyoxyethylene (20) sorbitan monopalmitate),

60 (polyoxyethylene (20) sorbitan monostearate)

65 (polyoxyethylene (20) sorbitan tristearate)

85 (polyxoxyethylene (20) sorbitan trioleate),

21 (polyoxyethylene (4) sorbitan monolaurate),

81 (polyoxyethylene (5) sorbitan monooleate).

Particularly preferred products of this class for use in the compositions according to the invention are the above products Tween 40 and Tween 80.

d.3 polyoxyethylene fatty acid esters, e.g. Polyoxyethylene stearic acid esters of the known type, which are available under the trade name Myrj (cf. Fiedler, op. Cit., Vol. 1, page 228). A particularly preferred product of this class for use in the compositions according to the invention is the product Myrj 52 with a D25 value of approximately 1.1, an F. of approximately 40-44 ° C., an HLB value of approximately 16.9 Acid number of about 0-1 and a saponification number of about 25-35.

d.4 polyoxyethylene-polyoxypropylene copolymers and block copolymers, e.g. well-known and commercially available products under the names Pluronic, Emkalyx and Poloxamer (see Fiedler, op. cit., vol. 2, pages 720-723). A particularly preferred product of this class for use in the compositions according to the invention is the product Pluronic F68, with an F of about 52 ° C. and a molecular weight of about 6800-8975. Another preferred product of this class for use in the compositions according to the invention is the product Poloxamer 188. d.5 dioctyl succinate or di (2-ethylhexyl) succinate (cf. Fiedler, op. Cit., Vol. 1, page 307). d.6 phospholipids, in particular lecithins (cf. Fiedler, op. cit., vol. 2, pages 559 to 560). Lecithins that can be used in the compositions according to the invention include, in particular, soybean lecithins.

d.7 propylene glycol mono- and difatty acid esters, such as propylene glycol dicaprylate (known and commercially available under the name Miglyol 840), propylene glycol dilaurate, propylene glycol hydroxystate, propylene glycol isostearate, propylene glycol iaurate, propylene glycol propic glycolate stearate and the like (see Fiedler, loc. cit., vol. 2, pages 760 ff.).

d.8 sodium auryl sulfate.

The ratio of components (a) :( d) in the compositions according to the invention is suitably in the range from 1: 1 to 25 parts by weight, in particular from 1: 1.25 to 20 parts by weight and very particularly from 1: 1.5 to 8 or 10 parts by weight, e.g. 1: 2 to 5 parts by weight. In particular, the ratio of components (a) :( d) is 1: at least 2 parts by weight. Component (a) is thus suitably present in the compositions according to the invention in an amount of, for example, about 20-50% and preferably 25-40%, based on the total weight of components (a) and (d).

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As is clear from the above definition (A), components (b) and (c) in the compositions according to the invention may contain the individual components (b) and (c) in the form of a single component, e.g. contained as a single material or product, or consist wholly or essentially of this. Examples of ingredients suitable according to the invention containing both components (a) and (b) are known mixed fatty acid triglyceride and fatty acid mono / diglyceride products. Suitable products of this type include, in particular, transesterification products of vegetable oils, saturated, including hydrogenated, or unsaturated oils, e.g. Almond oil, peanut oil, palm oil or preferably corn oil, with glycerin, propylene glycol (e.g. 1,2-propylene glycol) or sorbitol.

Such transesterification products are generally obtained by treating the vegetable oil, e.g. Corn oil, with glycerin, propylene glycol or sorbitol, heated to high temperatures in an inert atmosphere with constant stirring, for example in a stainless steel reactor, to carry out the transesterification, e.g. perform the glycerolysis, glycolysis or sorbitolysis.

The transesterification products suitable according to the invention include mixtures of mono-, di- and triglycerides (i.e. glycerol mono-, di- and triesters) with generally minor amounts of free glycerol.

If constituents containing both components (b) and (c) for use according to the invention have been obtained by transesterification of a vegetable oil with propylene glycol or sorbitol, they also contain minor amounts of free propylene glycol or sorbitol. They also contain substantial amounts of esters thereof, for example in the case of transesterification products with propylene glycol, such as propylene glycol mono- and diesters and in the case of transesterification products with sorbitol, the sorbitol mono-, di- and tetraesters.

The amount of triglyceride contained in the components used according to the invention containing the two components (b) and (c) is a substantial amount, e.g. more than 5% and in particular 7.5 to 12% or more, based on the total weight of [(b) + (c)] in the constituent mentioned.

The amount of free glycerin plus, if appropriate, free propylene glycol or sorbitol, which is present in the components used according to the invention with a content of both components (b) and (c), is preferably less than 10%, in particular less than 5% and very particularly 1 up to 2% or less, based on the total weight of the ingredient mentioned. The amount of monoglyceride present in the components used according to the invention with a content of both components (b) and (c) is preferably about 25 to 50%, in particular about 30 to 45%, based on the total weight of the component mentioned.

If a transesterification product of a vegetable oil, e.g. of corn oil and of glycerin as a component for providing [(b) + (c)], the amount of free glycerol present in this product is preferably less than 10% by weight, in particular less than 5% by weight and very particularly less than about 4% by weight. The amount of monoglyceride present is preferably about 30 or 35 to 50% by weight, preferably about 35 or 40 to 45% by weight. The amount of diglyceride present is preferably less than about 60% by weight, and especially less than 40% by weight. The amount of triglyceride present is preferably about 10% by weight, e.g. 7.5 to 14% by weight (all percentages refer to the total weight of the product). The ratio of components (b) :( c) in the defined transesterification products is therefore suitably in the order of about 1: 8 to about 1: 9 parts by weight.

If a transesterification product of a vegetable oil, e.g. of corn oil, and sorbitol, as an ingredient for providing [(b) + (c)], the amount of free glycerin plus free sorbitol in this product is preferably less than 5% by weight, and particularly about 1 to 2% % By weight. The amount of monoglyceride present is preferably about 30 to 40% by weight and in particular about 35% by weight (all percentages relate to the total weight of the product).

Particularly suitable transesterification products according to the above statements, which are suitable for use according to the invention, are transesterification products made from corn oil and glycerol, as are available, for example, under the trade name Maisine. These products mainly consist of linoleic acid and oleic acid mono-, di- and triglycerides together with minor amounts of palmitic acid and stearic acid mono-, di- and triglycerides (corn oil itself consists of about 56% by weight linoleic acid -, about 30 wt .-% oleic acid, about 10 wt .-% palmitic acid and about 3% stearic acid components). The physical properties of Maisine (available from Etablissements Gattefossé, 36, Chemin de Genas, Postfach 603, 69 804 Saint-Priest, Cedex (France)) are given below:

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free glycerin

- 10% max. (typically 3.9-4.9% or about 0.2% in newer batches)

Monoglycerides

- about 40% (typically 41 to 44.1% or about 38% in newer batches)

Diglycerides

- about 40% (or about 46% in newer batches)

Triglycerides

- about 10% (or about 12% in newer batches)

Free oleic acid content

- about 1%

Other physical properties of Maisine are: acid value = max. about 2, iodine number = about 85-105, saponification number = 150-175, mineral acid content = 0.

The fatty acid content of maizeine is typically: palmitic acid: about 11%; Stearic acid: about 2.5%; Oleic acid: about 29%, linoleic acid: about 56%; others: about 1.5%.

Further transesterification products according to the above statements, which are suitable for use according to the invention, are the transesterification products made from corn oil and sorbitol, as are available, for example, under the trade name Sorbito Glycerides from the company Etablissements Gattefossé, e.g. Sorbito Glycerides WL 713, which has the following approximate composition:

Product: transesterification product from about 2 moles of corn oil and about 1 mole of sorbitol:

Approximate composition:

free glycerin about 1 to 2%

free sorbitol about 1 to 2%

Monoglycerides about 35%

plus: di- and triglycerides and sorbitol mono-, di-, tri- and tetraesters

Color (Echelle Garner) = <8. Freely soluble in ethanol and chloroform / slightly soluble in diethyl ether / insoluble in H2O. Acid number = <1; Saponification number = about 160-185; Iodine number = about 110-140.

In the case of compositions according to the invention, the components (b) and (c) of which consist entirely or essentially of the individual components (b) and (c) in the form of a single constituent, components (b) and (c), for example, completely or in the essentially consist entirely of transesterification products according to the above statements, the ratio of (a): [(b) + (c)] is suitably in the order of 1: 0.75-35, preferably 1: 1-25 parts by weight and in particular in the order of 1: 3-10 and especially about 1: 6 parts by weight. If only constituents which contain both (b) and (c) are used, [(b) + (c)] is suitably in the compositions according to the invention in an amount of about 15-70% by weight and preferably of about 20-50 wt .-%, based on the total weight of components (a) up to and including (d) present.

In accordance with the foregoing, according to a particular embodiment, the invention also provides the following.

B. A pharmaceutical composition containing:

a) a cyclosporin as an active ingredient in a carrier medium, comprising:

b + c) a transesterification product of a vegetable oil and of glycerol, propylene glycol or sorbitol and d) a surfactant with an HLB value of at least 10;

provided that if the composition does not contain any other component (b) or (c) as defined in section (A) above, the composition:

i) free or substantially free of ethanol; or ii) contains cyclosporin or [Nva] 2-cyclosporin as component (a); or iii) contains components (a) and (d) in a ratio of 1: at least 1 part by weight.

To provide a combination of components (b) and (c) in the compositions according to the invention in the preferred ratio described below, component (b) in the compositions according to the invention preferably contains at least one constituent which can be defined as fatty acid retriglyceride (for example a material or product) which is the components (b) (ie fatty acid triglycerides) defined above, or which consists wholly or essentially of these components (which, for example, at least 75% by weight, preferably at least 90% by weight and in particular at least 95 Component (c) in the compositions according to the invention preferably contains at least one constituent which can be defined as glycerol fatty acid partial ester or complete or partial ester of propylene glycol or sorbitol, in which it is are, for example, the components (c) defined above t,

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or which consists wholly or essentially entirely of these components (which contains, for example, at least 75% by weight, preferably at least 90% by weight and in particular at least 95% by weight of components (c)).

In particular, components (b) and (c) in the compositions according to the invention contain separate constituents which, according to the explanations below, can be combined in a selected ratio (b) :( c). With regard to components (b) and (c), the compositions according to the invention thus preferably contain a two-part combination of constituents according to definition (b) and constituents according to definition (c), e.g. a combination of one or more first constituents which consist wholly or essentially wholly of components (b) and one or more second constituents which wholly or substantially entirely consist of components (c).

Suitable components (b) include both saturated (including hydrogenated) and unsaturated fatty acid triglycerides, especially of animal or vegetable oils. The fatty acid constituents of components (b) suitably include saturated or mono-, di- or polyunsaturated acids with, for example, a chain length of 6 to 22 carbon atoms. Fatty acid triglycerides with a high content of unsaturated fatty acid constituents, in particular mono-, di- and polyunsaturated fatty acids with at least 16 carbon atoms and preferably 18 carbon atoms or more, and very particularly those with a high content of oleic acid, linoleic acid, are particularly suitable for use according to the invention. or linolenic fatty acid components. Of particular interest are fatty acid triglycerides with a linoleic and / or linolenic acid component of at least 45%, preferably at least 60% and up to 65 or 80%, which includes, for example, the use of super-refined oils.

A first group of fatty acid triglycerides suitable according to the invention are saturated C & -12 vegetable oil fatty acid triglycerides, e.g. Caprylic acid-capric acid triglycerides. Examples of constituents suitable as component (b) are fractionated vegetable oils, e.g. fractionated coconut oils, as are known for example under the trade name Miglyol (cf.Fiedler, loc. cit., vol. 2, pages 615 and 616), including Miglyol 810, a fractionated coconut oil-caprylic acid-capric acid triglyceride with a molecular weight of approximately 520 and the fatty acid composition: C6 max. about 2%; Os about 65-75%, Gio about 25-35%, C12 max. about 2%. Miglyol 810 has the following additional physical properties: <xd20 = 1.4490-1.4510, acid number = max. 0.1, saponification number = about 340-360, iodine number = max. 1. Particularly preferred is Miglyol 812, a fractionated coconut oil-caprylic acid-capric acid triglyceride with a molecular weight of about 520 and the following fatty acid composition: C6 max. about 3%, Os about 50-65%, C10 about 35-40%, C12 max. about 5%. Miglyol 812 has the following additional physical properties: c®20 = 1.4480-1.4500, saponification number = approx. 330-345, iodine number = max. 1.

Other components of a similar class which are suitable as component (b) are the products available under the trade name Estasan, e.g. Estasan GT 8-60 and GT 8-65. Estasan GT 8-60 is a vegetable oil fatty acid triglyceride in which the fatty acid components consist mainly of saturated G8-io fatty acids, especially caprylic acid and capric acid. Fatty acid composition: Caproic acid (Ce) max. about 3%, caprylic acid (Cs) max. about 50-65%, capric acid (C10) max. about 35-45%, lauric acid (C12) max. about 3%. Estasan GT 8-60 has the following additional physical properties: saponification number = about 325-345, iodine number = max. about 1, acid number = max. about 0.1, a20d = about 1.448-1.451. Estasan GT 8-65 is also a vegetable oil fatty acid triglyceride, which mainly consists of saturated Cs-io fatty acids, especially caprylic acid and capric acid. Fatty acid composition: Caproic acid max. about 1%, caprylic acid min. about 65%, capric acid about 25-35%, lauric acid max. about 1%.

Other components of this class are the known products available under the Myritol trade name, e.g. Myritol 318 (see Fiedler, op. Cit., Vol. 2, pages 635-636). Myritol 318 is a Ca-prylic acid / capric acid triglyceride with a saponification number of about 340-350, an iodine number of about 0.5 and an nD20 value of about 1.448-1.450.

Other ingredients that are suitable as components (b) include, for example, vegetable oils, such as corn oils, almond oils, core oils (for example apricot kernel oils), avocado oils, babassu oils, higher fatty acid coconut oils, evening primrose oils (primrose oils), grape seed oils, menhaden oils, olive oils, Orange oils, peanut oils, safflower oils, sesame oils, soy oils and wheat germ oils, as well as animal oils such as fish oils, for example Fish liver oils, such as shark oils, and mink oils. Refined oils of any of the above types are of particular interest for the use according to the invention, in particular vegetable oils which, for example, have the following approximate content of oleic acid / linoleic acid / linolenic acid constituents:

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Oleic acid

Linoleic acid

Linolenic acid

Example about 9% about 27% about 4% about 5% about 25% about 14%

about 68% about 64% about 13% about 40% about 54% about 58%

about 76% about 47% about 6% about 8%

about 15%

Evening primrose grape seeds safflor sesame

Soybean wheat germ

Component (c) suitably contains a partial glycerin fatty acid, i.e. a fatty acid mono- or diglyceride or an acetylated derivative thereof. Ingredients suitable as component (c) are preferably free or substantially free of any fatty acid triglyceride components and contain, for example, less than 25%, preferably less than 10% and especially less than 5, e.g. less than 1 or 2%, fatty acid triglycerides.

Components (c) which are suitable for use in the compositions according to the invention include both symmetrical mono- and diglycerides (ie β-monoglycerides and aa1-diglycerides) and asymmetrical mono- and diglycerides (ie a-monoglycerides and oc, ß-diglycerides and acetylated derivatives thereof, including uniform glycerides (ie products in which the fatty acid component consists predominantly of a single fatty acid) and mixed glycerides (ie products in which the fatty acid component is composed of different fatty acids), and acetylated derivatives thereof.

The fatty acid component of component (c) can comprise both saturated and unsaturated fatty acids with a chain length of 6 to 22 carbon atoms. Preferably the fatty acid component contains predominantly saturated or unsaturated fatty acids with a chain length of 8 to 18 carbon atoms, in particular 8, 10 or 14 to 18 carbon atoms, e.g. 16 or 18 carbon atoms. Mono- and diglycerides in which the fatty acid component consists predominantly of one or more components from the group consisting of caprylic acid, capric acid, linolenic acid, palmitic acid, stearic acid and oleic acid are particularly suitable.

Particularly preferred for use as components (c) are constituents containing mono- and diglycerides in which the proportion of mono- / diglyceride is at least 50% by weight, preferably at least 60% by weight and in particular at least 75% by weight. %, and acetylated derivatives thereof. Examples of components suitable for use as components (c) are:

c.1 fatty acid mono- and diglycerides as are commercially available under the trade name Imwitor (cf. Fiedler, loc. cit., vol. 1, p. 491), in particular: caprylic acid and capric acid mono- and diglycerides, such as Imwitor 742, which contains at least 45% of the monoglycerides mentioned above and has the following further characteristic properties: acid number = max. about 2%, iodine number = max. about 1.0, saponification number = about 250-280, free glycerol content = max. about 2%; and stearic acid monoglycerides, such as Imwitor 191, which contains at least 90% of the abovementioned monoglycerides and has the following further characteristic properties: F. = about 63-66 ° C., acid number = max. about 3, saponification number = about 160-170, iodine number = max. about 3, free glycerol content = max. about 2%; and Imwitor 960K, which contains 30 to 40% of the aforementioned monoglycerides and has the following further characteristic properties: rise from about 56 to about 60 ° C., saponification number = about 155-170, acid number = max. about 3, iodine number = max. about 3, free glycerol content = max. about 4%.

c.2 fatty acid mono- and diglycerides, as are commercially available under the Cutina name (see Fiedler, loc. cit., vol. 1, pages 263 and 264): in particular palmitic acid and stearic acid mono- and diglycerides, as Cutina MD-A, which contains the aforementioned mono- and diglycerides and has the following further characteristic properties: acid number = max. about 8, saponification number = about 160-170; and stearic acid monoglycerides, such as Cutina GMS, which contains the aforementioned monoglycerides and has the following characteristic properties: F. = about 54-60 ° C, acid number = max. about 2, saponification number = about 162-173, iodine number = max. about 2.

c.3 fatty acid monoglycerides, such as are available under the trade name Myverol (cf. Fiedler, loc. cit., vol. 2, page 637), in particular cis fatty acid, (eg linolenic acid) - monoglycerides, such as Myverol 18-92, that contains at least 90% of the aforementioned monoglycerides and has the following additional characteristic properties: acid number = max. about 3.0, diglyceride content = max. about 5%, free glycerol content = max. about 1.2%.

c.4 fatty acid monoglycerides as they are available under the trade name Myvaplex (see Fiedler, op. cit., vol. 2, page 637), in particular stearic acid monoglycerides, e.g. the products of the Myvaplex 600 series, such as Myvaplex 600P, which contains about 94-90% of the aforementioned monoglycerides and has the following additional characteristic properties: F. = about 73 ° C, density = about 0.92 g / cm3 at 80 ° C.

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c.5 fatty acid monoglycerides as available under the trade name Estagel, e.g. Es-tagel G-18, which mainly consists of Ci6-i8 fatty acid monoglycerides, especially palmitic acid and stearic acid monoglycerides. The content of <x-monoglyceride in Estagel G-18 is min. about 40%. Other characteristic properties: acid number = max. about 2, saponification number = 162-173, iodine number = max. about 3, free glycerol content = max. about 6%.

c.6 Acetylated fatty acid mono- and diglycerides, such as are available under the trade name Myvacet (see Fiedler, op. cit., vol. 2, pages 636-637), in particular mono- and diacetylated fatty acid monoglycerides, e.g. mono- and diacetylated stearic acid monoglycerides, such as Myvacet 9-40 with the following characteristic properties: o © 50 = about 1.4468-1.4476, F. = about 5 ° C, acid number = max. about 1.5, saponification number = about 375-385; and Myvacet 9-45, which has the following characteristics: o © 50 = about 1.4465-1.4475, mp = 8-12.4 ° C; Acid number = 1.5, saponification number = about 375-385.

Other particularly valuable components (c) are glycerol fatty acid partial esters and complete and partial esters of propylene glycol, e.g. Products containing fatty acid mono- and diglycerides and propylene glycol fatty acid mono- and diesters. Examples of such components (c) are:

c.7 fatty acid mono- and diglycerides / propylene glycol fatty acid mono- and diesters, as are available under the trade name Atmos (cf. Fiedler, loc. cit., vol. 1, page 156), in particular Atmos 300, in which the fatty acid residues consist predominantly of oleic acid residues, and Atmos 150, in which the fatty acid residues predominantly consist of stearic acid residues.

c.8 fatty acid mono- and diglycerides / propylene glycol fatty acid mono- and diesters, as are available under the trade name Arlacel (cf. Fiedler, loc. cit., vol. 1, pages 143-144), in particular Arlacel 186, where the fatty acid residues mainly consist of oleic acid residues.

Components (b) and (c) are preferably present in the compositions according to the invention in a ratio of about 1: 0.02 to 3.0 parts by weight. In particular, the ratio of components (b) :( c) is in the range from 1: 0.1 to 2.5 parts by weight and very particularly from 1: 0.25 to 1.25 parts by weight. If components (b) and (c) in the compositions according to the invention contain separate components, e.g. the components described above, these components are suitably used in the same relative proportions. The amount of components (b) in the compositions according to the invention is thus suitably in the order of 10-50% by weight, preferably 20-40% by weight, based on the total weight of components (a) up to and including (d) . The amount of components (c) in the compositions according to the invention is suitably in the order of 1-30% by weight, preferably 10-25% by weight, based on the total weight of the compositions (a) up to and including (d).

The ratio of components (a) :( b) plus (c) in the compositions according to the invention is suitably in the order of 1: 0.5 to 40 parts by weight. The ratio of (a) :( b) plus (c) is preferably about 1: 1 to 35, in particular about 1: 1.5 to 30, and very particularly about 1: 2 to 6 parts by weight.

In accordance with the above, the following is also provided according to the invention:

C) a pharmaceutical composition according to definition A above, containing at least one constituent which consists wholly or essentially entirely of one or more of the components defined under (b) above;

D) a pharmaceutical composition according to definition A above, containing at least one constituent which consists entirely or essentially entirely of one or more of the components defined under (c) above;

E) a pharmaceutical composition according to definition A above, in which components (a) and (b) contain separate constituents.

The compositions of the invention may further contain other components as needed, e.g. Thickeners, granulating agents, dispersing agents, flavoring agents and / or coloring agents or antimicrobial agents and the like. They can also contain polymeric thickening agents to enable processing into a solid or semi-solid mass, as is suitable for tableting or granulation.

The compositions of the invention also suitably contain antioxidants to improve durability, e.g. Butylhydroxytoluene (or BHT), butylhydroxyanisole (or BHA), as-corbyl palmitate, ascorbic acid, citric acid or a-tocopheroiacetate.

In particular, the compositions according to the invention suitably also contain one or more stabilizers or buffer substances, in particular in order to prevent the degradation of component (a) during processing or during storage. Such stabilizers can include acidic stabilizers, such as citric acid, acetic acid, tartaric acid or fumaric acid, and basi12

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see stabilizers, such as potassium hydrogen phosphate, glycine, lysine, arginine or tris (hydroxymethyl) aminomethane.

Suitable stabilizers or buffering agents are expediently added in an amount sufficient to achieve or maintain a pH in the range from 5 to 7 and in particular between 6 and 7.

If the components (b) and (c) in the compositions according to the invention consist of a single constituent, which is the transesterification product of a vegetable oil with glycerol, the condition (i) above preferably applies to the compositions according to the invention (i ), ie they are free or essentially free of ethanol. In particular, they are also free or essentially free of any other components which serve as diluents or as a solvent medium for component (a).

While condition (i) above has been applied to a specific case, compositions according to the invention which are free or substantially free of ethanol are generally preferred. Compositions according to the invention which are free or substantially free of any other components which serve as diluents or as solvent medium for (a) are also generally preferred. According to a further series of embodiments, the following is provided according to the invention:

F. a pharmaceutical composition according to one of the above definitions (A) to (E) which is free or essentially free of ethanol; and

G. a pharmaceutical composition according to one of the above definitions (A) to (E) which is free or essentially free of any further components which serve as diluents or as a solvent medium for component (a).

As mentioned, the compositions suitably contain less than 2% by weight and in particular 0 to 0.5 or 1% by weight of ethanol, based on the total weight of the component components. The above-mentioned compositions suitably contain less than 20% by weight, preferably less than 10% by weight and, for example, 0 to 2.5 or 5% by weight of further components which serve as diluents or solvent media for component (a) . Special compositions according to the present invention are pharmaceutical compositions according to one of the above definitions (A) to (G), which are wholly or essentially entirely composed of components (b), (c) and (d) as carrier medium for ( a) exist, ie except for thickeners, granulating agents, dispersing agents, flavoring agents, coloring agents, stabilizers and similar vehicles, which may also be present and which are present as additives in the carrier medium.

Components which serve as diluents are to be understood in particular as components which reduce the viscosity of the compositions according to the invention or increase their fluidity. Components which serve as the solvent medium for (a) are to be understood in particular as cosolvents or other materials which increase the solubility of components (a) in the compositions according to the invention. Examples of such components are, in particular, solvent or diluent components with an HLB value of less than 10, for example the transesterification products of natural vegetable oil triglycerides and polyalkylene polyols, as are known under the trade name Labrafil (cf. Fiedler, loc. Cit., Vol. 2, Page 539) and ethanol.

The compositions of the invention can be provided in any dosage form suitable for administration, e.g. in the form of creams, gels or the like for topical or ocular administration, in the form of granules, tablets, capsules or the like for oral administration or in a form suitable for intralesional use, e.g. in the treatment of psoriasis. However, the compositions of the invention are preferably administered orally. According to a preferred embodiment, a composition according to the given definition is provided in a form suitable for oral administration, in particular in an oral unit dosage form. Particularly suitable unit dosage forms for oral administration are encapsulated forms, e.g. in the form of soft or hard gelatin capsules.

Oral unit dosage forms according to the invention suitably contain 5 to 200 mg, preferably 20 to 100 mg and, for example, about 25.50 or 100 mg of component (a), for example for administration twice or twice a day.

In addition to the above statements, the invention also provides a method for producing pharmaceutical compositions according to the above definition and description, which comprises the intimate mixing of components (a), (b), (c) and (d).

According to a preferred aspect of the invention, there is provided a method of the aforementioned type which comprises the intimate mixing of a component (a) with a first component (b), which consists wholly or essentially entirely of one or more fatty acid triglycerides, and a second component (c) which contains a glycerol fatty acid partial ester or a complete or partial ester of propylene glycol or sorbitol, or with a first component (b) which contains a fatty acid triglyceride and a second component (c) which wholly or essentially entirely of one or more glycerol fatty acid partial esters and complete or partial esters of propylene glycol

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and / or sorbitol, and comprises with (d) a surfactant with a hydrophile-lipophile balance of at least 10.

According to a particularly preferred aspect of the invention, there is provided a method of the type mentioned above which involves the intimate mixing of a component (a) with a first component (b) which consists wholly or essentially entirely of one or more fatty acid triglycerides, a second Constituent (c) which consists wholly or substantially entirely of one or more glycerol-fatty acid re-partial esters and / or complete or partial esters of propylene glycol and / or sorbitol, and (d) a surfactant with a hydrophilic-lipophilic balance of at least 10.

The following examples illustrate the preparation of the compositions according to the invention.

example 1

component

Amount (mg)

a) Cyclosporin (e.g. ciclosporin)

50.00

b) Miglyol 812

100.00

c) Myverol 18-92

100.00

d) Cremophore RH 40

50.00

(a) - (d) are intimately mixed in the specified proportions in a conventional manner. The mixture obtained is filled into soft or hard gelatin capsules, each containing 50 mg of cyclosporin.

Example 2

Soft or hard gelatin capsules containing the constituents listed below in the amounts listed are produced in a manner analogous to that in Example 1.

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Component quantity (mg)

2a a)

Cyclosporin (e.g. ciclosporin)

50.00

b)

Miglyol 812

100.00

c)

Imwitor 742

100.00

d)

Cromophore RH40

100.00

2b a)

Cyclosporin (e.g. ciclosporin)

50.00

b) + c)

Maisine

300.00

d)

Cremophore RH40

100.00

2c a)

Cyclosporin (e.g. ciclosporin)

50.00

b)

Soybean oil

150.00

c)

Myverol 18-92

50.00

d)

Emuìgin R040 *

250.00

2d a)

Cyclosporin (e.g. ciclosporin)

50.00

b)

sesame oil

150.00

c)

Imwitor 900K

125.00

d)

Emulphor EL-719 *

150.00

2e a)

Cyclosporin (e.g. ciclosporin)

50.00

b)

Myritol 318

75.00

c)

Estagel G-18

100.00

d)

Pluronic F 68

175.00

2f a)

Cyclosporin (e.g. ciclosporin)

50.00

b)

Estasan GT 8-60

130.00

c)

Arlacel 186

75.00

d)

Tween 80

125.00

2g a)

Cyclosporin (e.g. ciclosporin)

50.00

b) + c)

Maisine

100.00

c)

Myverol 18-92

200.00

d)

Cremophore RH40

100.00

2h a)

Cyclosporin (e.g. ciclosporin)

50.00

b)

Miglyol 812

100.00

c)

Myverol 18-92

200.00

d)

Cremophore RH40

100.00

(* see Hedler, op. cit., vol. 1, page 344.)

The compositions obtained according to Examples 1 and 2 are suitable for administration with the aim of preventing graft rejection or in the treatment of autoimmune diseases, for example 1 to 5 capsules being administered daily. An equivalent composition can be made by substituting any other cyclosporin, e.g. [Nva] 2-ciclosporin used in equal or equivalent amounts.

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

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

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

Blood samples of 2 ml (or 5 ml for the blank value) are taken from the saphenous vein and placed in 5 ml plastic tubes containing EDTA at the time point -15 min (blank value), 30 min and 1, 1,5, 2, 3,

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4, 6, 8, 12 and 24 hours after administration. The blood samples are stored at -18 ° C before the determination.

The blood samples are analyzed by RIA. The areas under the curves where the blood drug concentration is plotted against time are calculated according to the trapezoidal rule. The analysis of variance is performed with respect to AUC (area under the curve), Cmax (maximum concentration) and Tmax (maximum time).

The calculated average AUC values (in ng.h / mM) and Cmax values (in ng / mM) of typical experimental approaches prove in comparison with the results when administering the conventional sand immune drinking solution for the compositions according to the invention, e.g. the composition of Example 1 has high bioavailability (AUC and Cmax) along with a relatively small variation in patient response for both AUC and Cmax.

Clinical examinations

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

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

The following entry / exclusion criteria are applied.

Acquisition: normal screening ECG; normal blood pressure and normal heart rate; Body weight = 50-95 kg.

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

A complete physical examination and an ECG are carried out before and after the test. The following parameters are evaluated 1 month before and after the examination:

Blood: number of red blood cells, hemoglobin, hematocrit, erythrocyte sedimentation, number of white blood cells, smear, number of platelets and glucose when fasted;

Serum / Plasma: total protein and electrophoresis; Cholesterol, triglycerides, Na +, K +, Fe ++, Ca ++, Cl ~, creatinine, urea, uric acid, SGOT, SGPT, gamma-GT, alkaline phosphatase, total bilirubin, a-amylase;

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

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

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

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

In the tests carried out according to the above procedure, for example, when comparing the composition of Example 1 in the form of a hard gelatin capsule with the current ciclosporin drinking solution (ciclosporin = 50 mg, labrafil = 150 mg, ethanol = 50 mg, corn oil = 213 mg, in Form of soft gelatin capsules with a final weight of 463 mg / dose) as standard significantly increased bioavailability concentrations for the composition of Example 1 in comparison with the standard both in terms of AUC values (0-32 h) and in terms of Cmax values

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detected. Furthermore, a comparison of the temporal change in ciclosporin concentrations in whole blood (determined by specific monoclonal RIA) following a single administration of the test compositions with a ciclosporin dose of 150 mg shows a marked reduction in the variability of the response among all subjects who made up the composition of Example 1 compared to all subjects who received the standard composition.

Similar or equivalent results can be obtained following oral administration of other compositions of the invention, e.g. are described in the present example 2, achieve.

Claims (10)

Claims 1. Pharmaceutical composition containing a) a cyclosporin as active ingredient in a carrier medium, containing b) a fatty acid triglyceride, c) a glycerol-fatty acid partial ester or a complete or partial ester of propylene glycol or sorbitol and d) a surfactant with a hydrophile-lipophile balance (HLB value) of at least 10; with the proviso that if components (b) and (c) consist wholly or essentially of the individual components of a transesterification product of a vegetable oil with glycerol, the composition: i) free or substantially free of ethanol; or ii) contains cyclosporin or [Nva] 2-cyclosporin as component (a); or iii) components (a) and (d) in a ratio of 1 contains at least 1 part by weight. 2. Composition according to claim 1, characterized in that (a) in an amount of 2 to 20 wt .-%, based on the total weight of components (a) up to and including (d). 3. Composition according to claim 1 or 2, characterized in that (d) the reaction product of a natural or hydrogenated castor oil and of ethylene oxide, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene-polyoxypropylene copolymer or block copolymer, Contains dioctyl succinate, di- (2-ethylhexyl) succinate, a phospholipid, a propylene glycol mono- or difatty acid ester or sodium lauryl sulfate. 4. Composition according to one of claims 1 to 3, characterized in that (a) and (dt> • - a ratio of 1: 1 to 25 parts by weight (a) :( d) are present. 5. Composition according to one of claims 1 to 4, characterized in that it comprises a component (a) and a component (d) as defined in claim 1 and (b) + (c) a transesterification product of a vegetable oil and Contains glycerin, propylene glycol or sorbitol. 6. Composition according to one of claims 1 to 4, characterized in that (b) and (et consist of the individual components (b) and (c) of a component (b) + (c) defined in claim 5 or essentially therefrom consist. 7. The composition according to claim 6, characterized in that (a) and (b) + (c) are present in a ratio of 1: 0.75 to 35 parts by weight (a): (b) + (c). 8. Composition according to one of claims 1 to 5, characterized in that it contains at least one constituent consisting of one or more of the components (b) as defined in claim 1 or one or more of the components (c) as defined of claim 1 or consists essentially of it. 9. Composition according to one of claims 1 to 6 or 8, characterized in that (c) contains a glycerol fatty acid partial ester or an acetylated derivative thereof. 10. Composition according to one of claims 1 to 5, 8 or 9, characterized in that (b) and (c) are present in a ratio of 1: 0.02 to 3.0 parts by weight (b) :( c). 17th