LU87675A1 - NEW PHARMACEUTICAL COMPOSITIONS BASED ON CYCLOSPORINS - Google Patents

Description

The present invention relates to new galenical formulations comprising a cyclosporine as active substance.

Cyclosporins constitute a class of cyclic poly-N-methylated decapeptides with a characteristic structure, having pharmacological activity, in particular immunosuppressive, anti-inflammatory and / or anti-parasitic activity. The first descyclosporins to be isolated is a fungal metabolite of natural origin Ciclosporin or Cyclos¬porine, also known as cyclosporine A and available commercially under the brand SANDIMMUN R or SANDIMMUNE R. Ciclosporin is cyclosporine of formula A

in which -MeBmt- signifies an N-methyl- (4R) -4-but-2E-en-l-yl-4-methyl- (L) threonyl residue of formula B

in which -x-y- means -CH »CH- (trans).

As the parent molecule of the class, the

Ciclosporin has so far received the greatest attention. The main area of clinical investigation for Ciclosporin has been as an immunosuppressive agent, in particular in relation to its use in organ transplant recipients, e.g. heart, lung, heart-lung, liver transplants, kidneys, pancreas, bone marrow, skin and cornea, especially allogeneic organ transplants. In this sector, Ciclosporin has achieved remarkable success and acquired an excellent reputation.

At the same time, intensive research has been carried out into the possibilities of applying Ciclos¬porine to various autoimmune diseases and inflammatory states, in particular to inflammatory states having an etiology comprising an autoimmune component, such as arthritis (for example, polyarthritis rheumatoid arthritis, deforming arthritis) and rheumatic diseases, and reports of the results of these in vitro, animal and clinical trials are widely reported in the literature. As specific autoimmune diseases for which Ciclosporin has been proposed or used, mention may be made of autoimmune haematological disorders (comprising for example haemolytic anemia, aplastic anemia, purely erythrocytic anemia and idiopathic thrombocytopenia), lupus systemic erythematosus, polychondritis, scleroderma, Weqener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson disease, idiopathic sprue, autoimmune intestinal inflammations immune systems (including ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (type I diabetes mellitus), uveitis (anterior and posterior), spring conjunctivitis, dry keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without syndromenephrotic, for example including idiopathic nephrotic syndrome or nephropathy with low changes).

As other areas of research we can cite the possibilities of using Ciclosporin as an anti-parasitic agent, in particular as an anti-protozoan agent, in particular for the possible use in the treatment of malaria, lacoccidiomycosis and schistosomiasis, and more recently to suppress resistance of tumors to anti-neoplastic agents etc ...

Since the discovery of Ciclosporin, a large variety of cyclosporins of natural origin have been isolated and identified and numerous other non-natural cyclosporins have been prepared by total synthesis or chemical modification or by application of modified culture techniques. This class constituted by cyclosporins is now important and includes, for example cyclosporins A to Z of natural origin [see Traber et al. 1, Helv. Chira. Acta. 60,1247-1255 (1977); Traber et al. 2, Helv. Chim. Acta65, 1655-1667 (1982); Kobel et al., Europ. J. AppliedMicrobiology and Biotechnology 14, 273-340 (1982); etvon Wartburg et al., Progress in Allergy, _38 '28-45 (1986)] as well as various unnatural derivatives of cyclosporins and artificial and synthetic cyclosporins, including dihydro-cyclosporins [in which the remainder -xy- of the remainder -MeBrat- (formula B above) is saturated to give -xy- => -CH2-CHj-], the derivative cyclosporins (for example in which another substituent is introduced on the carbon atom a of the sarcosyle residue in position 3 of the molecule cyclosporin), cyclosporins in which the residue -MeBrat- is present in isomeric form (for example in which the configuration at positions 6 'and 7' of the remainder -MeBmt-is cis instead of trans), and cyclosporins in which various amino acids are incorporated at specific positions in the peptide sequence, using for example the total synthesis method for the preparation of cyclosporins, developed by R. Wenger - see for example Traber 1, Traber 2 and Kobel Loc. cit .; U.S. Patents 4,108,985, 4,210,581 and 4,220,641; European patent applications 34 567 and 56 782; international application No. 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 5_0, 123 (1986).

The class constituted by cyclosporins is thus very vast and includes, for example, [Thr] 2-. [Val] 2-, [Nva] 2- and [Nva] 2- [Nva] 5-Ciclosporin (also known respectively as cyclosporins C, D, G and M), [3-0-acyl- MeBmt] 1-Ciclosporin (also known as cyclosporin A acetate), [Dihydro-MeBmt] 1- (Val] 2-Ciclosporin (also known as dihydrocyclosporin D), [(D) Fluoromethyl-Sar] 3-Ciclosporin, [ (D) Ser] 8-Ciclosporin, [Mellej ^ -Cielosporine, [(D) MeVal] "^ - Ciclosporin (also known as cyclosporine H), [MeAlal ^ -Ciclosporin, [(D) Pro] 3- Ciclosporin, [3'-dexy-3'-oxo-MeBmt] ^ [Val] 2- and - [Nva] 2-Ciclosporin, etc ...

[In accordance with the nomenclature adopted for cyclos¬porines, the latter are defined by reference to the structure of

Your Ciclosporin (i.e. Cyclosporin A). According to this nomenclature, the amino acid residues present which are different from those present in Ciclosporin are indicated (for example "[(D) Pro] 3n to indicate that the cyclosporine in question has a residue- (D) Pro- instead of a residue -San- in position 3) and the name "Ciclosporin" is added to characterize the other residues which are identical to those present in Ciclosporin. The individual remains are numbered starting from the remainder -Meßmt-, -dihydro- MeBmt- or its equivalents in position 1].

Many of these other cyclosporins are those which exert a pharmacological activity comparable to that of cyclosporine or a more specific activity, in particular for the treatment of tumors resistant to cytostatic treatment, and the temperature presents various proposals for their application in therapy.

Despite the very important entherapeutic contribution of Ciclosporin, in particular in the field of organ transplants and the treatment of autoimmune diseases, the difficulties encountered in finding a more effective and practical method of administration as well as the existence of undesirable side effects, in particular in particular nephrotoxic reactions, have seriously limited wider application of the product. Cyclosporines are strongly hydrophobic. The liquid formulations proposed, intended for example for administration of cyclos¬porins by the oral route, are therefore essentially based on ethanol and similar oils or excipients used as vehicles. Thus, the commercially available cyclosporine oral solution includes ethanol and olive oil as excipients in combination with Labrafil as a surfactant (see U.S. Patent No. 4,388,307). The use of oral solution and similar compositions as proposed in the literature, however, is not without difficulties.

First of all, the need to use oils or oil-based excipients can give the preparations an unpleasant taste on the palate, which is troublesome in particular for a long-term treatment. These effects can be masked by a presentation in the form of capsules or capsules. However, to maintain cyclosporine in solution, the ethanol content must remain high. The evaporation of ethanol, for example capsules or other forms, for example during T1 opening of 11 packages · containing the capsules causes the tone format of a cyclosporine precipitate. When such compositions are presented for example in the form of soft gelatin capsules, this particular difficulty requires packaging the encapsulated product in an airtight compartment, for example in a single-celled packaging. ^ airtight or in a meno-cellular packaging with aluminum foil . This in turn makes the product both bulky and its preparation expensive. The storage characteristics of the formulations indicated above are therefore far from ideal.

The bioavailability values obtained by using the existing dosage forms for the oral administration of cyclosporine are also low and show great variations between patients, categories of patients and in the patient himself at various periods of treatment. The reports presented in the literature indicate that current treatments with the commercially available oral solution of cyclosporine give an absolute average bioavailability of approximately 30%, the variations being strongly marked between categories of patients, for example between recipients of liver transplants (bioavailability relatively low) and bone marrow transplant (relatively high bioavailability). The variations observed in the bioavailability between patients being from 1 to a few percent in some patients and 90% or more in others. As indicated above, significant variations in bioavailability were frequently observed for each patient. during treatment.

For effective immunosuppressive therapy, it is important to maintain the levels of cyclosporine in the blood and serum within a specific interval. The required interval may vary depending on the particular conditions to be treated, for example if it is a treatment intended to avoid rejection of a transplant or to treat an autoimmune disease, and if another immuno treatment ¬ suppressor is used or not at the same time as the treatment with cyclosporine. Due to the significant variations in the bioavailability values obtained with the usual dosage forms, the daily doses necessary to obtain the required levels in the blood serum will also vary considerably from one individual to another and even for a single individual. This therefore requires regular monitoring of the blood or serum levels of patients undergoing treatment with cyclosporine. This check, which is generally carried out by RIA or according to an equivalent radioimmunoassay technique, for example using monoclonal antibodies, must be carried out regularly, which inevitably takes time, is not practical and greatly increases the total cost of treatment.

In addition to these obvious practical difficulties, there remains the appearance of undesirable side effects already mentioned / which are observed when using the forms to be administered orally.

To overcome these difficulties, various proposals have been made in the art concerning the solid and liquid forms to be administered orally. Japanese patent application No. 71682/1985 by Takada et al. Suggests the application of means intended to increase the lymphatic resorption of cyclosporins, especially by administration in combination with surfactants. Among the so-called active ingredients which can be used, the document citers of fatty acid esters of sucrose such as oleate, palmitate or sucrose stearate, as well as other fatty acid esters, in particular fatty acid esters of sorbitan, such as oleate, palmitate or sorbitan stearate.

Although it is stated that mono and polyesters can be used, mono- or diesters are generally preferred. Other surfactants mentioned in this document include polyoxyethylated hydrogenated vegetable oils, such as the products known and marketed under the brands Cremophore RH and Nikkol HCO 60, which are clearly preferred, for example in relation to the sucrose esters mentioned therein.

Example 3 of said Japanese patent application describes the production of an aqueous preparation comprising a fatty acid ester of sucrose, designated F160, used as surfactant component. The preparation contains 3.5 mg of Ciclosporin and 2 mg of sucrose ester in 1 ml of H2O. To obtain the dispersion of Ciclosporin, it is necessary to carry out a treatment with ultrasound for 5 minutes at 100 W. The preparation obtained, described as "transparent solution", is used directly on animals in order to determine the lymphatic resorption relative. Due to the very low solubility of Ciclosporin in water and the minor amount of surfactant used, it is evident that the so-called solution is an artifact of the ultrasound treatment. Not only is the concentration of Ciclosporin obtained extremely low and therefore unsuitable, for example for an oral form, but the preparation is also unstable and therefore of no practical use for obtaining a galenical commercial form. It essentially represents only an experimental system allowing laboratory tests and nothing more. There is no proposal to use surfactants in a context other than that concerning lymphatic resorption.

Japanese patent application No. 193129/1987 (publication No. 038029/1989) also from Takada etcoll., Describes pulverulent preparations comprising a Ciclosporin in dispersion in a solidenon surfactant vehicle, comprising for example sucrose, lesorbitol, l tartaric acid, urea, cellulose acetate phosphate, a methacrylic acid / methyl methacrylate system or hydroxypropyl methyl cellulose phtallate, in combination with small amounts of a surfactant. Here also, the surfactant is added for the purpose of increasing lympha¬tic resorption and, in this context, the patent application clearly aims to provide an allegedly practical means for the implementation of the above-mentioned Japanese patent application. No. 71682/1985. The document does not mention the esters of sucrose as possible surfactants. On the other hand, the sorbitan esters are cited among many possible surfactants. However, products of the Nikkol HCO60 type are indicated as being the preferred surfactants and Nikkol HCO 60 is the only surfactant used in the examples. It is not mentioned in this document that the increase in lymphatic resorption gives practical advantages or makes it possible to overcome the difficulties due to a treatment based on cyclosporine of the type mentioned above.

The object of the present invention is to provide new galenical forms of cyclosporin comprising monoesters of fatty acids of a saccharide as essential vehicles, which make it possible to overcome the difficulties encountered during treatment with a cyclosporine, for example Ciclosporin, or to reduce them substantially. It has been found in particular that the compositions of the invention allow the preparation of solid, semi-solid and liquid compositions containing a cyclosporine in a sufficiently high concentration to allow for example a convenient administration by oral route, while improving the effectiveness, for example in terms of bioavailability.

It has been found more particularly that the compositions of the invention allow an effective treatment with a cyclosporine and a concomitant improvement in the resorption or bioavailability rates as well as a reduction in the variations in the desorption or bioavailability rates both in each patient and between patients receiving cyclosporin. According to the invention, galenic forms based on a cyclosporin are obtained, giving only slight variations in the levels of cyclosporin in the blood and / or in the blood serum between doses administered to each patient as well as between patients and categories. of patients. The invention therefore allows a reduction in the dosage of cyclosporine necessary for obtaining an effective treatment. It also allows for a more exact standardization and optimization of the permanent daily doses necessary for the various patients subjected to a cyclosporin treatment as well as those necessary for the categories of patients subjected to equivalent treatment.

By a more exact normalization of the frequency of the doses administered to each patient and the response obtained in the patient with regard to the levels in the blood and in the blood serum, as well as the parameters of frequency of administration and response for the groups of patients, can reduce controls and thus greatly reduce treatment costs.

By reducing the required encyclosporin dosage and / or normalizing the characteristics affected by bioavailability, the invention also allows a reduction in the appearance of undesirable secondary effects, in particular of nephrotoxic effect, in patients subjected to a cyclosporin treatment. .

Furthermore, the present invention allows the preparation of compositions which are not based on alkanol, for example which may be free or essentially free of ethanol. Such compositions do not pose the stability and processing difficulties mentioned above, which are inherent in known alkanolic compositions. The invention therefore makes it possible to obtain, among other things, compositions which are better suited, for example for presentation in capsules, for example in soft or hard gelatin capsules, and / or which eliminate or reduce strongly packaging problems, of the type mentioned above, for example for soft gelatin capsules.

The present invention relates more particularly to a pharmaceutical composition comprising a) a cyclosporine as active substance, b) a monoester of a fatty acid with a saccharide and c) a diluent or vehicle, i) the component (c) being a solvent for the two components (a) and (b), the components (a) and (b) each having, independently, a solubility in the component (c) of at least 10% at ambient temperature; or ii) component (c) being a solvent for the two components (a) and (b), and components (a) and (c) being present in said composition in a weight ratio of from 1: 0.5 to -50 Γ [(a) :( c)]; or iii) component (c) being a solvent for the two components (a) and (b) and said composition being formulated in the form of solid unit doses suitable for administration by the oral route; or iv) component (c) comprising a poly (C 2 -C 4 alkylene) glycol having a maximum average molecular weight of 7,000 or a maximum viscosity at 50 eC of 15,000 mPa.s, or comprising an ether or an ester of a ( C3-C5 alkylene) polyol; or v) said composition being nonaqueous or essentially nonaqueous; or vi) the component (c) comprising a solid polymer vehicle, a silicone or a liquid paraffin or a light liquid paraffin and the component (a) being present in said composition in the form of a solid solution in (b).

The compositions as defined are new and represent particularly advantageous variants of those claimed in a general manner in French patent application No. 2,620,336.

Conditions (i) to (vi) above should be understood as not being mutually exclusive.

The compositions of the invention therefore comprise the compositions as defined which satisfy one or more of the conditions mentioned above under (i) to (vi). The preferred compositions of the invention are therefore, for example, those fulfilling two or more of the conditions (i) to (v).

By the term "pharmaceutical composition" is meant compositions in which the individual components or ingredients are themselves pharmaceutically acceptable, for example when oral administration is envisaged, that they are acceptable for such administration, and when topical administration is envisaged, they are acceptable for such administration.

The preferred cyclosporine as component (a) is Ciclosporin. Another preferred component (a) is [Nva] 2-Ciclosporin or cyclosporin G.

The preferred components (b) for use in the compositions of the invention are water-soluble monoesters of a fatty acid with an unsaccharide, for example those having a solubility in water of at least 3.3 % at room temperature, that is to say which are soluble in water at room temperature in an amount of at least 1 g of monoester per 30 ml of water.

The fatty acid residue of components (b) can be a saturated or unsaturated fatty acid residue or a mixture of these residues. As particularly preferred components (c), there may be mentioned the monoesters of C6-C18 fatty acids with a saccharide, in particular the water-soluble monoesters of C6-C18 fatty acids with a saccharide. As specially suitable components (c), there may be mentioned the monoesters of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, acidicoleoleic acid and 12-hydroxystearic acid with unsaccharide, especially monoesters of acidelauric with a saccharide.

The saccharide residue of component (b) can be any suitable carbohydrate residue, for example the residue of a mono-, di- or tri-saccharide. Advantageously, the saccharide residue is that of undi- or tri-saccharide . Preferred components (b) include monoesters of C6-Cx4 fatty acids with a di-saccharide and monoesters of C8-C18 fatty acids with a tri-saccharide.

The remnants of specially suitable saccharides are the remnants of sucrose and raffiose. As particularly suitable components (b), the following can therefore be cited: monocaproate, lemonolaurate, sucrose monomyristate, mono-oleate and lemonoricinoleate, and monocaproate, lemonolaurate, monomyristate, monopalmitate and lemon-oleate raffinose. The particularly preferred components (b) are raffinose monolaurate and especially sucrose monolaurate.

The value of the hydrophilic-lipophilic balance (HLB) of the components (b) is advantageously at least 10.

The components (b) preferably have an ester residue of a purity of at least 80%, more preferably at least 90%, especially at least 95%. Their melting point is advantageously between approximately 15 and about 60 ° C, more preferably between about 25 and about 50 ° C.

Referring to the conditions (ii) and (iii) above applied to the compositions of the invention, the components (c) defined are materials in which the components (a) and (b) have a. substantial solubility at room temperature, for example at a temperature of about 20 ° C. The preferred components (c) are materials in which the components (a) and (b) have, independently, a solubility of at least 10% [as required by condition (i)], preferably at least at least 25%, especially at least 50% (for example in which the components (a) or (b) have, independently, a solubility of at least 100 mg, preferably at least 250 mg, especially at least 500 mg / ml) at room temperature. Especially preferred materials are those in which component (a) has a solubility of at least 10%, preferably at least 25%, especially at least 50% and / or in which component (b) has a solubility of at least 100%, more preferably at least 200%, especially at least 300% (for example in which component (b) has a solubility of the order of at least 1000, more preferably at least 2000 , especially at least 3000 mg / ml).

Components (c) suitable for use in the compositions of the invention include: c1) ethanol, c2) (C2-C4 alkylene) glycols; c3) (C3-C5 alkylene) polyols, c4) poly- (C2-C4 alkylene) glycols, and c5) ethers or esters of (C3-C5 alkylene) polyols, and mixtures thereof.

According to the invention, the use of ethanol, alone or in mixture with any of the components (c) is however generally less preferred.

When the component (c) comprises a (C2-C4 alkylene) glycol (c2), it is preferably a propylene glycol, especially 1,2-propylene glycol. When the component (c) comprises a (alkylene en- c3-C5) polyol (c3), it is preferably a (C3-C5 alky¬lene) triol, especially glycerol.

When the component (c) comprises a poly (C2-C4 alkylene) glycol (c4), it is advantageously a polyethylene glycol. For use in the compositions of the invention, such components preferably have an average molecular weight not exceeding about 7000 [see definition under (iv)], for example up to 6600, more preferably not exceeding about 2000, for example up to 'at 1600, especially up to around 500. Such components preferably have a maximum viscosity of around 15,000 mPa.s., more preferably at least 1000 mPa.s, especially around 200 mPa.s., at 50 ° Neck, advantageously, at room temperature [see condition (iv)]. As polyethylene glycols suitable for use as components (c), mention may be made, for example, of those described by Fiedler, in Lexikon der Hilfstoffe, 2nd revised and augmented edition, [1981], vol. 2, pages 726 to 731, in particular the PEG (polyethylene glycol) 200, 300,400 and 600 products as well as PEG 1000, 2000, 4000 or 6000, but especially 200, 300 and 400, for example having the following physical characteristics:

When component (c) comprises an ether or ester of a (C3-C5 alkylene) polyol (c5), it is advantageously a (C3-C5 alkylene) triol, in particular an ether or ester of glycerol. Suitable components (c5) include ethers or mixed esters, i.e. components comprising other ethers or esters, for example transesterification products of (C3-C5 alkylene) triols with other mono-, di- or polyols.

The particularly suitable components (c5) are the mixed esters of fatty acids with a (C3-C5 alkylene) triol / poly (C2-C4 alkylene) -glycol, especially the mixed esters of fatty acids of glycerol and polyethylene- or polypropylene-glycol.

The components (c5) specially suitable for use according to the invention include the products obtained by transesterification of glycerides, for example triglycerides, with poly- (C2-C4 alkylene) glycols, for example polyethylene glycols and, possibly glycerol. Such transesterification products are generally obtained by alcoholysis of glycerides, for example destriglycerides, in the presence of a poly- (C 2 -C 4 alkylene) glycol, for example polyethylene glycol and, optionally, glycerol (that is to say to carry out the transesterification on the poly-alkylene glycol / glycerol component from the glyceride, i.e. by poly-alkylene glycolysis / glycerolysis).

In general, such a reaction is carried out by reacting the indicated components (glyceride, polyalkylene glycol and, optionally, glycerol) at a high temperature, under an inert atmosphere and with continuous stirring.

The preferred glycerides are the triglycerides of fatty acids, for example the triglycerides of C 10 -C 22 fatty acids / comprising natural and hydrogenated oils, in particular vegetable oils. Suitable vegetable oils include, for example, olive oil, almond oil, peanut oil, coconut oil, palm oil, soybean oil and the like. wheat germ oil and, in particular, natural or hydrogenated oils enriched in fatty acid esters of Ci2-Ci6 ·

The preferred polyalkylene glycols are polyethylene glycols, in particular polyethylene glycols having a molecular weight of between approximately 500 and approximately 4000, for example between approximately 1000 and approximately 2000.

Suitable components (c5) therefore include mixtures of (C 3 -C 5 alkylene) esters triols, e.g. mono-, di- and tri-esters in varying relative amounts, with mono- and di-esters of poly { C2-C4 alkylene) glycols, in combination with small amounts of free (C3-C5 alkylene) triol and free poly (C2-Cs alkylene) glycol. As indicated above, the preferred alkylenetriol residue is the remainder of the glycerol; the preferred polyalkylene glycol residues are the polyethylene glycol residues, in particular those having a molecular weight of between approximately 500 and approximately 4000? and the preferred fatty acid residues are the C10-C22 fatty acid residues / in particular the saturated C10-C22 fatty acid residues.

The particularly suitable components (c5) can therefore be defined as being products of transesterification of a natural or hydrogenated vegetable oil and of a polyethylene glycol and, optionally, of glycerol; or as being compositions made up, in whole or in part, of demono-, di- and tri-esters of C10-C22 fatty acids with glycerol and of mono- and di-esters of Cio-C22 fatty acids with polyethylene glycols (possibly with, for example, small amounts of free glycerol and free polyethylene glycol).

Vegetable oils, polyethylene glycols or residues of polyethylene glycols and preferred fatty acid residues in relation to the above definitions are indicated above. The components (c5) which are particularly suitable for use according to the invention are those known and marketed under the brand name Gelucir, in particular the following products: i) Gelucir 33/01: Melting point - approximately 33- 38 ° C and saponification index " about 240/260; ii) Gelucir 35/10: Melting point - approximately 29-34 ° C and saponification index - approximately 120-140; iii) Gelucir 37/02: Melting point "approximately 34-40 ° C and saponification index approximately 200-220; iv) Gelucir 42/12: Melting point = approximately 41-46 ° C and saponification index - approximately 95-115; v) Gelucir 44/14: Melting point = * approximately 42-46 ° C and saponification index - approximately 75-95; vi) Gelucir 46/07: Melting point * about 47-52 ° C and saponification index ”about 125-145; vii) Gelucir 48/09: Melting point = approximately 47-52 ° C and saponification index = approximately 105-125; viii) Gelucir 50/02 Melting point * approximately 48-52 ° C and saponification index - approximately 180-200; ix) Gelucir 50/13: Melting point * approximately 46-41 ° C and saponification index "approximately 65-85; x) Gelucir 53/10: Melting point = approximately 48-53 ° C and saponification index = approximately 95-115; xi) Gelucir 62/05: Melting point = approximately 60-65 ° C and saponification index "approximately 70-90.

The products (i) to (x) above, all have an acid number <2. The product (xi) has an acid number <5. The products (ii), (iii) and (vi) to ( x) all have an iodine index <3. The product (i) has an iodine index £ 8. Products (iv) and (v) have an iodine index <5. The product (xi) has an iodine index 'iodine <10.

Components (c5) having an iodine value <1 are generally preferred. It will be noted that the mixtures of components (c5) as defined can also be used in the compositions of the invention.

When using a component (c) as described above [i.e. a component fulfilling any of the conditions (i) to (iv) above or any of the components defined under (c1) to (c5)], the compositions of the invention generally comprise component (a) in a vehicle comprising components (b) and (c). Components (a) and (b) are each usually present in the compositions of the invention in the form of a dispersion or a solution, for example a molecular or miscellar dispersion or solution (including, if necessary, solid solutions ). Thus, component (a) is generally present in the form of a dispersion or a solution in the two components (b) and (c) and components (b) are in turn present in the form of a solution in component (c). In the compositions of the invention, component (b) generally serves as a vehicle or solubilizer (before and / or after administration) for component (a) and component (c) serves as a vehicle or fluidizer.

(The present invention is in no way limited to any functional relationship between components (a), (fa) and (c), unless otherwise indicated).

When component (c) as defined above is used, the compositions of the invention are preferably formulated in the form of solid single doses intended for oral administration, for example in the form of soft or hard gelatin capsules intended for oral administration [see condition under (iii)]. Such forms of unit doses are described in detail below and advantageously comprise for example from 2 to 200 mg of component (a) per unit dose.

When using a component (c) as described above, the components (a) and (c) are present in the compositions of the invention preferably in a weight ratio of 1: 0.5 to 50 [(a) :( c)] [see condition under (ii)]. Components (a) and (b) are advantageously present in a weight ratio of 1: 3 to 200 [(a) :( b)].

When using a component (c) as defined above, the compositions of the invention are preferably nonaqueous or substantially nonaqueous [see condition under (v) J, their water content should for example be less than 20%, more preferably less than 10%, especially less than 5%, 2% or 1% relative to the total weight of the composition.

The present invention therefore also relates to:

A pharmaceutical composition comprising a component (a) and a component (b) as defined above and a diluent chosen from any of the components (c1) to (c4) as defined above or their mixtures, and filling the one of the conditions (ii) to (v) above; - A pharmaceutical composition comprising a component (a), (b) and (c2) as defined above and fulfilling the conditions (ii) / {iii) or (v) above; and

A pharmaceutical composition comprising a component (a), (b) and (C5) as defined above.

When using in the compositions of the invention a component (c) as defined above [that is to say a component fulfilling any of the conditions (i) to (iv) or any of the compo ¬sants (c1) to (c5)], the components (a) and (c) are advantageously present in the said compositions in a weight ratio of approximately 1: 0.5 to 50. The components (a) and (c) are preferably present in a weight ratio of about 1: 1 to 10, more preferably about 1: 1 to 5, especially about 1: 1.5 to 2.5, for example about 1: 1.6 or 1: 2 [(a) :( c)]. Components (a) and (b) are advantageously present in said compositions in a weight ratio of approximately 1: 3 to 200, preferably of approximately 1: 3 to 100, especially of approximately 1: 3 to 50. components (a) and (b) are more preferably present in a weight ratio of about 1: 5-20, preferably about 1: 5-10, especially about 1: 6.0-6.5, for example about 1: 6.25 [(a) :( b) 3.

When the compositions of the invention comprise sucrose monolaurate as component (b) and 1,2-propylene glycol as component (c), components (a) and (b) are preferably present in a weight ratio about 1: 6 to 7 [(a) :( b)] and components (a) and (c) are preferably present in a ratio of about 1: 1.5 to 2.5, for example about 1: 2 [(a) :( c)].

The compositions of the invention comprising a component (c) as described above, can be put into any suitable form, for example intended for oral, parenteral or topical administration, for example for application by the dermal or ophthalmic route. , for example for application to the surface of the eye, for example for the treatment of autoimmune conditions of the eye as indicated above, or for injection into the lesion, for example for the treatment of psoriasis.

Such compositions are advantageously presented in the form of unit doses, either for oral administration or for any other mode of administration.

The amount of component (a) present in such unit doses depends for example on the conditions to be treated, the mode of administration and the desired effect. In general, however, the unit doses advantageously comprise from about 2 to about 200 mg of component (a), for example deCllosporin.

Forms suitable for oral administration include, for example liquids, granules, etc. The preferred forms are, however, solid unit doses, for example in the form of tablets or capsules, in particular hard gelatin capsules (capsules) or soft. Such unit doses for oral administration advantageously comprise from about 5 to about 200 mg, more preferably 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.

The compositions of the invention comprising 'a component (c) as defined above, has the additional advantage of being able to serve as a basis for compositions having modified release properties, for example delayed release of the component ( a) or a release of component (a) over prolonged periods, for example after oral administration. Such compositions also comprise a component (d) capable of modifying the release properties of the composition with regard to component (a). Such components (d) comprise for example polymeric excipients, in particular thickeners, for example polymeric or colloidal thickeners, as well as swelling agents in water, for example polymers or colloids swelling in water.

As suitable components (d), the following can be cited: d1) Polyacrylic resins and polyacrylic co-polymers, for example acrylic acid polymers and acrylic / methacrylic acid copolymers, for example those known and marketed under the trade name Carbopol (see Fiedler, loc. cit., 1, pages 206-207), in particular the Carbopol 934, 940 and 941, and the Eudragit (see Fiedler, loc. cit., 1, pages 372-373), in particular Eudragit E, L, S, RL and RS and especially Eudragit E, L and S; d2) Celluloses and its derivatives, including alkyl-celluloses, for example methyl-, ethyl- and propyl-celluloses; hydroxyalkyl-celluloses, for example hydroxypropyl-celluloses and hydroxypropyl-alkyl-celluloses such as hydroxypropyl-methyl-celluloses; acylated celluloses, for example cellulose acetates, cellulose acetoterephthalates, cellulose aceto-succinates and hydro-xypropylmethyl-cellulose phatalates and their salts such as the sodium salts of carboxymethylcellulose. As examples of such products suitable for use according to the invention, mention may be made of those known and marketed under the brands Klucel and

Methocel (see Fiedler, loc. Cit., 1, page 521 and 2, page 601), in particular the Klucel LF, MF, GFet HF and Methocel K 100, K 15M, K 100M, E 5M, E 15, E 15M and E 100M; d3) Polyvinylpyrrolidones, comprising for example • poly-N-vinylpyrrolidones and co-polymers of vinylpyrrolidone such as co-polymers vinylpyrrolidone / vinyl acetate. As examples of such compounds suitable for use according to the present invention, mention may be made of those known and marketed under the brand Kollidon (see Fiedler, loc. Cit., Pages 526 and 527), in particular Kollidon 30 and 90; d4) Polyvinyl resins, including acetates and polyvinyl alcohols, as well as other polymeric materials such as gum tragacanth, arabic gum, alginates, for example alginate acid and its salts, for example sodium alginates; ds) Silicas, comprising hydrophilic silicas, for example alkylated silica gels (for example methylated), in particular anhydrous colloidal silica known and marketed under the brand Aerosil [see Handbook of PharmaceuticalExcipients, published by the Pharmaceutical Society of Great Britain, pages 253 a 256], in particular 1 Aerosil 130, 200, 300, 380, 0, OX 50, TT 600, MOX 80, MOX 170, LK 84 and Aerosil R 972 methylated.

When a component (d) is present, it advantageously represents from about 0.5 to 50%, more preferably from about 1 to 20%, especially from about 2 to 10% by weight, relative to the total weight of the components (a) + (b) + (c) + (d).

When in the compositions of the invention the component (c) comprises: (c6) a solid polymer vehicle as indicated in condition (vi) above, it is preferably a polymer vehicle insoluble in water or essential insoluble in water.

As components (c6), special preference is given to polyvinylpyrrolidones [see Fiedler, loc. Cit., 2, pages 748-750], especially comprising crosslinked polyvinylpyrrolidones. As examples of such compounds suitable for use according to the present invention, mention may be made of those known and marketed under the brand Kollidon [see Fiedler, loc. cit., 1, page 527], Kollisept [see Fiedler, loc. cit., 2, pages 719-720], Povidone and Crospovidone [see Fiedler, loc. cit., 2, page 751].

As specially suitable components (ce), there may be mentioned polyvinylpyrrolidones having a molecular weight of at least about 10,000, more preferably at least about 20,000 or 25,000, for example having a molecular weight of about 40,000 or more. Crosslinked polyvinylpyrrolidones are of particular interest. As examples of specific products suitable for use according to the present invention as components (c6), mention may be made of: Plasdone XL, Plasdone XL 10 and Crospovidone.

When the compositions of the invention comprise a component (c6), they also preferably comprise a swelling component (d) soluble in water, for example cellulose or one of its derivatives as defined above under (d2) .

As other examples of such compounds which are of particular interest for the compositions of the invention comprising a component (c6), there may be mentioned known and marketed under the brands Avicel [see Fiedler, loc. cit., 1, pages 160-161], Elcema [see Fiedler, loc. cit., page 326] and Pharmacoat [see Fiedler, loc. cit., 2, page 707], for example the products Avicel PH 101 and PH 102, Elcema and Pharmacoat603.

In the case of the compositions of the invention comprising a component (cfi), the component (a) is present in the component (b) in the form of a solid solution, comprising the solid miscellar solutions, for example in the form of a dispersion entirely or substantially entirely molecular or miscel-laire. [In practice, the components (b) frequently have at least one degree of fluidity, for example at room temperature or at a slightly higher temperature, and therefore cannot be considered as really "solid". The expression "solid solutions", as used in the present application, must therefore be considered, for example as comprising viscous or highly viscous systems]. The solid solutions comprising components (a) and (b) are advantageously dispersed, for example in the form of particles, for example of fine particles, in the component (cfi), for example fully dispersed. The components (c6) therefore generally serve as a disintegrable matrix in the compositions of the invention for the components (a) + (b). The components (d) generally serve as auxiliary disintegrating agents, for example in contact with the contents of the gastrointestinal tract.

Advantageously, the compositions of the invention comprising a component (cs) also comprise a component (e), namely a binder and / or lubricant. As compounds suitable for use as a binder / lubricant, mention may be made in particular of the salts of fatty acids and of alkyl sulfonates, for example the salts of metals, for example having at least 10 carbon atoms in the fatty acid / alkyl residue , such as the alkali or alkaline earth metal salts of C 10 -C 22 fatty acids and (C 10 -C 22 alkyl) sulfonates, for example calcium, sodium or magnesium salts. As examples of such compounds suitable for use according to the invention, mention may be made of sodium lauryl sulfate and magnesium stearate [see Fiedler, loc. cit., 2 page 584].

When the compositions of the invention comprise a component (c6), the components (a) and (b) are advantageously present in a weight ratio of about 1: 2 to 20, preferably about 1: 2.5 to 10, especially from approximately 1: 3 to 8 [(a) :( b)].

The components (c6) are advantageously present in the compositions of the invention in an amount of at least 10%, more preferably at least 15%, especially at least 20% by weight, relative to the total weight of the composition. The components (cÂ) are suitably present in the compositions of the invention in an amount between 10 and 60%, more preferably between 15 and 50%, for example from about 20 to 40%, for example from about 25, 30 or 35% by weight, relative to the total weight of the composition.

When a component (d) is present, the components (d) and {c6) are advantageously present in a weight ratio of about 1: 0.5 to 4, more preferably about 1: 1 to 3, especially about 1: 1.5 to 2.5, for example about 1: 2 or about 1: 2.5 [(d) :( c6)].

When a component (e) is present, the components (e) and (c6) are advantageously present in a weight ratio of about 1: 5 to 25, more preferably about 1: 5 to 20, especially from about 1: 7 to 15 [(e) :( c6)].

When the compositions of the invention comprise the three components (c6), (d) and (e), these are advantageously present in an overall amount of between approximately 25 and 75%, more preferably between approximately 30 and 65%, especially between about 40 and 65%, based on the total weight of the composition. The weight ratio of the components [(a) + (b)]: [(c) + (d) + (e)] is advantageously from approximately 1: 0.25 to 7.5, more preferably from approximately 1: 0 , 5 to 5, especially about 1: 0.5 to 2, for example about 1: 0.8, 1: 1.2 or 1: 1.3.

The compositions of the invention comprising a component (c6) can be put under any suitable uniform, for example intended for an oral, parenteral or topical administration. Such compositions of the invention advantageously come in the form of unit doses, intended for oral or other administration.

The amount of component (a) present in such unit doses naturally depends, for example, on the condition to be treated, on the mode of administration and on the desired effect. In general, however, they advantageously contain from about 2 to about 200 mg of component (a), for example Ciclospo¬rine.

Forms suitable for oral administration include granules and the like. The preferred forms, however, are solid unit doses, for example tablets and capsules. Such unit doses for oral administration advantageously comprise from approximately 5 to approximately 200 mg, more preferably from approximately 10 or 20 to approximately 100 mg, for example 15, 20, 25, 50, 75 or 100 mg of component (a), for example Ciclosporin,

When the component (c) in the compositions of the invention comprises (c7) a silicone or a liquid or light paraffin as indicated by condition (vi) above, the component (c7) is preferably easily pourable at temperatures which can go up to 150 ° C, preferably up to 100 ° C, especially up to 50 ° C. The components (c7) advantageously have a maximum viscosity of 15,000 mPa.s., More preferably 1000 mPa.s. at the temperatures indicated.

The paraffin hydrocarbons suitable for use as a component (c7) are liquid and semi-solid paraffins and their mixtures, i.e. liquid paraffin (Faraffinum liquidum from the European Pharmacopoeia and previously designated thick vaseline oil) and light liquid paraffin (Paraffinum perliquidum from the European Pharmacopoeia and previously designated fluid petroleum jelly oil [see paraffins called paraffinum perliquidumet paraffinum subliquidum in Fiedler loc.cit., 2, pages 690-691]. For component formulation (c7) , in whole or in part, fluid or semi-solid paraffins, that is to say liquid paraffin or light liquid paraffin or mixtures thereof, preferably mixtures thereof. When however it is desired to prepare compositions having properties of slower release of the active substance, solid paraffin (paraffinumsolidum from the European Pharmacopoeia) is added.

When the compositions of the invention comprise liquid and semi-solid paraffins as a single component (c7), their weight ratio is preferably between approximately 1: 0.5 and 1.0 [liquid: semi-solid]. In this case, the components (a) and (c7) are advantageously present in a weight ratio of about 1: 6 to 200, more preferably about 1: 6 to 100, especially about 1: 6 to 20, per example of about 1: 8 [(a) :( c7) J.

When the compositions of the invention additionally comprise a solid paraffin as component (c7), the weight ratio liquid paraffin / semi-solid to solid paraffin is advantageously about 1: 0.06 to 0.1. In this case, the components (a) and (c7) are advantageously present in a weight ratio of 1: 6 to 200, more preferably from 1: 6 to 100, especially from 1: 8 to 20, for example of approximately 1:10 [ (a) :( c7)].

The silicones suitable for use as a component (c7) include, in particular, fluid polymers, that is to say liquids and semi-solids having a structure of formula - (R) 2Si-o-in which R signifies a mono-valent organic group, for example a Ci-Ci alkyl group, especially a methyl or phenyl group. The especially preferred polymers are organopolysilo-xanes having a viscosity of between about 0.65 and 105 cP, especially between about 10 or 50 to 500 or 1000 cP.

To facilitate the formulation, component (c7) advantageously comprises liquid organopolysiloxanes, for example poly-methylsiloxanes, for example any of the known silicone oils, such as silicone oil 550, DC 200, SF-1066 and SF- 1091 [see Fiedler, loc. cit ,, 2, page 826]. When the compositions of the invention contain only liquid organopolysiloxanes, the components (a) and (c7) are advantageously present in a weight ratio of about 1: 6 to 200, more preferably about 1: 6 to 100, especially about 1 : 6 to 20, for example about 1: 8 [(a): (c7)].

The compositions having slower release properties of the active substance can be obtained by using, as component (c7), semi-solid organopolysiloxanes, for example any of the known silicone pastes, for example silicone paste A [see Fiedler, loc. cit., 2, page 826] or by adding them for example to other si¬ licones as described above. In the latter case, the weight ratio of the liquid: semi-liquid silicones present in the compositions of the invention is advantageously about 1: 0.5 to 1. In this case, the ratio of the components (a) :( c7) is preferably from about 1: 6 to 100, preferably from about 1: 6 to 20 [(a): (c7)].

It will be noted that mixtures of components (c7) as defined above, can also be used in the compositions of the invention.

When the compositions of the invention comprise a component (c7), the components (a) and (b) are advantageously present in a weight ratio of about 1: 6 to 20, preferably about 1: 6 to 10, especially of about 1: 6.0 to 6.5, for example about 1: 6.25 [(a) :( b)].

In the case of the compositions of the invention comprising a component (c7), the component (a) is present in the component (b), in whole or in part, in the form of a molecular or miscellar dispersion, for example in the form of a solid solution or a solid miscellular solution [the expression "solid solutions" having the same broad meaning as for the compositions comprising a component (c6)]. The solid solution comprising the components (a) and (b) is advantageously dispersed in the form of particles, for example fine particles, with the component (c7), for example throughout the component (c7).

The compositions of the invention comprising a component (c7) can be put in any suitable form, for example intended for oral, parenteral or topical administration, for example for application by dermal or ophthalmic route, for example for application on the surface of the eye, for example for the treatment of autoimmune conditions of the eye, as described above, or for an injection into the lesion, for example for the treatment of psoriasis. The compositions are advantageously presented in the form of unit doses, intended for administration by the oral or other route.

The amount of component (a) present in such unit doses naturally depends, for example, on the condition to be treated, on the mode of administration and on the desired effect. In general, however, each unit dose contains from about 2 to about 200 mg of component (a), for example Ciclosporin.

Forms suitable for oral administration include liquids, granules and the like. The preferred forms are, however, solid unit doses, for example in the form of tablets or capsules, in particular capsules, in particular capsules or soft capsules. Each unit dose advantageously comprises from approximately 5 to approximately 200 mg, more preferably from approximately 10 or 20 at about 100 mg, for example 15, 20, 25, 50, 75 or 100 mg of component (a), for example Ciclosporin.

The compositions of the invention comprising a component (c7) can also serve as a basis for the compositions having modified liberating properties, for example the delayed release of the component (a) or the release of the component (a) over an extended period of time, for example after oral administration. Such compositions can be obtained as described above, by introduction of appropriate quantities of solid or semi-solid components (c7). They can also be obtained by introducing an additional component (d) capable of modifying the release properties of the composition in relation to the component (a). Such components (d) include for example polymeric excipients, in particular thickeners, for example polymeric or colloidal thickeners as well as water-blowing agents, for example colloids or water-blowing polymers, for example one any of the compounds defined above under (d1) to (d5).

When a component (d) is present, it preferably represents an amount of between approximately 0.5 and 30%, more preferably between approximately 1 and 20%, especially between approximately 1 and 10% by weight, relative to the total weight of the components ( a) + (b) + (c7) + (d).

The components (d5) are particularly indicated for use in the compositions of the invention comprising a silicone as component (c7).

The compositions of the invention comprising a component (c6) or (c7) are preferably nonaqueous or essentially nonaqueous, for example as described above for the compositions comprising other components (c).

The compositions according to the invention can, whatever the component (c) chosen [for example that the component (c) comprises any one of the components (c1) to (c7) indicated above or any mixture of these compounds], include any additional additives, for example those known and usually used in the art, for example anti-oxidants [for example ascorbyl palmitate, tocopherols, butyl-hydroxy-anisole (bha) or butyl-hydroxy-toluene (BHT)], flavorings etc ...

Advantageously, the compositions of the invention also advantageously include one or more stabilizers or buffering agents, in particular to prevent the hydrolysis of the component (b) or the degradation of the component (a) during processing or storage. Such stabilizers can be acid stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid, or basic stabilizers such as potassium hydrogen phosphate, glycine, lysine, argi¬nine or tris (hydroxymethyl) aminomethane.

Such stabilizers or buffering agents are suitably added in an amount sufficient to obtain or maintain a pH of between about 3 and 8, more preferably about 5 to 7, for example between 6 and 7. Such stabilizers are generally present in a maximum amount of 5% by weight relative to the total weight of the composition, or up to 10% by weight, for example when citric acid or acetic acid is used. The compositions of the invention, in particular the compositions in which component (a) is cyclosporine, having a pH corresponding to the values indicated above, are preferred.

Advantageously, the compositions of the invention also comprise a surfactant free from polyoxyalkylene residues such as for example dioctyl-succinate, dioctyl-sulfo-succinate, di [2-ethyl-hexy] -succinate, laurylsulfate sodium or phospholipids, for example lecithins. When such a surfactant is present, it is advantageously present in an amount between 5 and 50, preferably between 10 and 50, for example from 10 to 25%, relative to the weight of component (b).

In the case of the compositions of the invention comprising a component (a) in solid solution in the component (b), for example when the component (c) is- a component (ce) or (c7) as described above, stabilizing it, The buffering agent and / or the surfactant as described above are advantageously incorporated into the solid solution. Such compounds can also be included in component (c) etc ...

The compositions of the invention, regardless of the component (c) chosen, are preferably free or substantially free of ethanol and contain, for example, less than 5.0%, more preferably less than 1.5%, for example 0 at 1.0% ethanol, relative to the total weight of the composition.

The present invention therefore also comprises a process for the preparation of a pharmaceutical composition as described above, a process in which the components (a), (b) and (c) are intimately combined as defined above, optionally with a component (d) and / or other components, for example a stabilizer, a buffering agent or a surfactant as described above and, if necessary, the composition obtained is presented in the form of a unit dose, intended for example for a oral administration, for example in the form of tablets, capsules, capsules or in another suitable form.

When component (c) is a solvent for components (a) and (b), or comprises a component (c1), (c2), (c3), (c4) or (c5) as defined above, the components ( a), (b) and (c) are advantageously mixed in the process described above by dissolving the components (a) and (b) in the component (c), for example by heating to temperatures ranging up to 50 or 150 ° C, preferably not exceeding 70 or 75 ° C. The mixture thus obtained can then be combined with the components (d), etc., for example by an intimate mixture according to techniques known to specialists. The filling, for example in capsules or soft capsules, is carried out advantageously at a high temperature, for example up to 50 ° C., to make the composition fluid, for example hot.

In the case of compositions of the invention comprising a component (a) in solid solution in the component (b), for example the compositions comprising a component (c6) or (c7) as described above, said method advantageously comprises first the preparation of a solid solution of (a) in (b) and then the intimate mixing or combination of the solid solution obtained, with the remaining components (c) and, optionally with (d) etc ...

The solid solutions comprising the components (a) in (b) can be prepared according to techniques known to specialists, for example by solidifying a melt comprising (a) ensolution in (b), or by removing the solvent from the solution comprising components (a) and (b). In accordance with the objective of the invention, the latter alternative is generally preferred.

Suitable solvents for components (a) and (b) include lower alkanols, for example ethanol. Stabilizers, buffering agents and / or surfactants are advantageously incorporated at the solution stage.

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

Although it is possible to use ethanol for the preparation of the compositions of the invention, for example for the preparation of solid solutions as described above, it is preferred to eliminate it, for example by evaporation, before complete the preparation of the final form, in order to obtain an ethanol-free or substantially ethanol-free product as mentioned above.

The following examples illustrate the present invention without in any way limiting its scope.

The sucrose monolaurate L-1969 used in the examples is commercially available from Mitsubishi-Kasei Food Corp., Tokyo 104,

Japan: HLB value “at least 12.3; purity of the lauryl ester residue "at least 95%; F * about 35 ° C; decomposes at about 235 ° C; surface tension of an aqueous solution at 0.1% by weight about 72.0 dyn / cm at 25 ° C.

EXAMPLES

INGREDIENTS QUANTITY (mg) 1. a) Cycloporine (e.g.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) 1,2-propylene glycol 100.0 TOTAL 462.5 2. a) Cyclosporine (eg.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Glycerol 100.0 TOTAL 462.5 3. a) Cyclosporine e.g.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) PEG 200 100.0 TOTAL 462.5 4. a) Cyclosporine (e.g.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) PEG 400 100.0 TOTAL 462.5 5. a) Cyclosporine (e.g.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) 1,2-propyleneglycol 100.0 d) Eudragit E 50.0 TOTAL 550.0 6. a) Cyclosporine (e.g.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) 1,2-propyleneglycol 100.0 d) Methocel K100 110.0 TOTAL 610.0 7. a) Cyclosporine (eg.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) 1,2-propyleneglycol 100.0 d) Aerosil 200 15.0 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 2.5 TOTAL 602.5 9. a) Cyclosporine (e.g.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelucir (eg Gelucir 42/12, 44/14 or 35/10 100.0 TOTAL 462.5 / 10. a) Cyclosporine (by ex.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelucir 100.0 d) Klucel LP 50.0 TOTAL 512.5

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

Under heating, the compositions obtained are poured into capsules, size 1 (examples 1 to 4 and 9), or size 0 (examples 5 to 7 and 10), to give a final encapsulated product, each capsule containing 50 mg of cyclosporine (for example Ciclosporin ). These capsules are suitable for the prevention of transplant rejection or for the treatment of auto¬immune diseases, for example by administration of 1 to 5 capsules per day.

EXAMPLES

INGREDIENTS QUANTITY (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 25.0 TOTAL 925.0 12. a) Cyclosporine (by ex.

Ciclosporin) 50.0 b1) Sucrose monolaurate L-1695 350.0 b2) Sucrose monostearate 50.0 c) Crospovidone 250.0 d) Elcema 150.0 e) Magnesium stearate 30.0 TOTAL 880.0 13. a) Cyclosporine (e.g.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 160.0 c) Plasdone XL 10 200.0 d1) Pharmacoate 603 25.0 d2) Avicel PH 101 75.0 e) Magnesium stearate 20.0 TOTAL 530, 0

The compositions 11 to 13 above also each comprise (f) 25 mg of tartaric acid and / or (g) 50 mg of dioctylsuccinate, preferably both, to give a final weight of 1000 mg for composition 11, of 955 mg for the composition 12 and 605 mg for composition 13.

The compositions 11 to 13 are prepared as follows: The components (a) and (b) are dissolved in absolute ethanol and the ethanol is completely evaporated at 50 ° C. under reduced pressure. The components (c) to (e) are mixed thoroughly (by adding components (f) and (g) when used) using the usual mixing techniques. The solid solution comprising [(a) + (b)] is transformed into a fine powder, it is mixed uniformly in [(c) - (g)] and the resulting uniform mass is compressed, which gives tablets each containing 100, 50 or 25 mg of component (a) and suitable for use in the prevention of transplant rejection or in the treatment of autoimmune diseases, for example by administration of 1 to 5 tablets per day.

EXAMPLES

INGREDIENTS QUANTITY (mg) 14. a) Cyclosporine (e.g.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Light liquid paraffin 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 completely evaporated at 50 ° C. under reduced pressure. The solid solution obtained is transformed into a fine powder which is uniformly suspended in the component (c). The liquid suspension obtained is poured into size 0 capsules to obtain an encapsulated final product, each capsule containing 50 mg of cyclosporine (for example Ciclos¬porine). These capsules are suitable for the prevention of transplant rejection or for the treatment of autoimmune diseases, for example by administration of 1 to 5 capsules per day.

EXAMPLES

INGREDIENTS QUANTITY (mg) 16. a) Cyclosporine (e.g.

Ciclosporin 50.0 b) Sucrose monolaurate L-1695 312.5 c) Liquid paraffin 372.5 d) Solid paraffin 25.0 TOTAL 760.0 17. a) Cyclosporine (e.g.

Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Light liquid paraffin 397.5 d) Aerosil 10.0 TOTAL 770.0

Compositions 16 and 17 are prepared analogously to compositions 14 and 15 above. In composition 16, the components (c) and (d) are first combined by fusion and intimate agitation. The solid solution comprising [(a) + (b)] is then suspended in E (c) + (d)]. In composition 17, component (d) is suspended, together with [(a) + (b)], in component (c).

Compositions equivalent to those of Examples 1 to 17 can be prepared by replacing Ciclosporin as component (a) with any other cyclosporine, for example [Nva] 2-Ciclosporin, or by replacing sucrose monolaurate as component (b ) by any fatty acid monoester with a saccharide, for example as indicated above, for example deraffinose monolaurate, in each case in identical or equivalent amounts or in relative proportions.

The advantageous properties of the compositions of the invention can be demonstrated in the following tests:

BIOAVAILABILITY STUDY OF THE COMPOSITIONS OF THE INVENTION

a) Test compositions COMPOSITION I as for Example 1 COMPOSITION II as for Example 14 b) Test method

Groups of 8 beagle dogs (males, 11-13 kg) are used. 18 hours before the administration of the test composition, the animals are deprived of food but have free access to water until administration. The compositions to be tested are administered by gavage, then 20 ml of a 0.9% NaCl solution. Three hours after the administration of the test composition, the animals have free access to food and water.

Samples of 2 ml of blood (or 5 ml for the control test) are taken from the veinsaphene which are collected in 5 ml plastic tubes containing EDTA at -15 min. (Control test) , 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after administration. Store blood samples at -18 ° C during the test.

The blood samples are analyzed by RIA. The areas under the curve are calculated according to the trapezoid method from the plasma concentration / time curves. The analysis of the variations is carried out from the area under the curve (AUC), from Cmax (maximum concentration) and from Tmax (maximum time).

c) Results

The following table gives the average values of the area under the curve (in ng hr./ml-1) and of the Cmax (in ng / ml_1) calculated from the standard tests, as well as the variations of responses calculated among the animals subjected to the test before the same composition (CV)

It will be noted that the compositions of the invention exhibit a high bioavailability (AUC and Cmax) associated with a relatively small variation in the response of the subjects both for AUC and for LaCmax.

Comparable advantageous results can be obtained by using the other compositions of Examples 1 to 17, in particular the compositions of Examples 1 to 10.

CLINICAL TEST

The advantageous properties of the compositions of the invention intended for oral administration can also be demonstrated in the following clinical trials:

The tests are carried out on voluntary adults, for example men with a high level of training and aged 30 to 55 years. Each group includes 12 people.

The following inclusion / exclusion criteria are applied:

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

Exclusion:

Intercurrent disease likely to interfere with absorption, distribution, metabolism, excretion or safety of the drug; symptoms of a clinically significant disease during the 2 weeks preceding the trial; abnormal EKG or ECG results; need for concomitant medication for the duration of the study; administration of any drug known for its well-defined potential toxicity to a vital organ, during the previous 3 months; administration of any test medication 6 weeks before the start of the trial; history of drug or alcohol abuse; loss of 500 ml or more of blood in the past 3 months; adverse reaction or hypersensitivity to the drug; history of allergy requiring treatment, medical; hepatitis -B / HIV-positive.

A full physical exam and an ECG are performed before and after the test. The following parameters are analyzed 1 month before and after the test: Hematology:

Red blood cell count, hemoglobin, hematocrit, sedimentation rate, white blood cell count, blood platelet count, leukocyte formula, fasting blood sugar.

Serum / plasma:

Total proteins and electrophoresis, choles¬terol, triglycerides, Na +, K +, Fe ++, Ca ++, Cl-, creatinine, urea, uric acid, SGOT, SGPT, -GT, alkalinephosphatase, total bilirubin, a-amylase; urine pH, microalbumin, glucose, erythrocytes, ketones, sediments.

Creatinine clearance is also determined 1 month before the start of the trial.

Each patient receives the test compositions randomly. The compositions are administered orally at one time, namely a dose of 150 mg of cyclosporine, for example Ciclosporine, and an interval of 14 days is left between each administration.

The administration takes place in the morning after a 10 hour fast during the previous night when only water absorption is authorized. During the next 24 hours, administration only of non-caffeine drinks is permitted. During the 12 hours following administration, patients are not allowed to smoke. They receive a standardized lunch 4 hours after administration.

Blood samples (2 ml) are taken 1 hour before administration and 25 minutes, half an hour, 1 hour, 1 hour and a half, 2 hours, 2 and a half hours, 3 hours, 3 hours and a half, 4 hours, 4 and a half hours, 5 hours, 6 hours, 9 hours, 12 hours, 2 hours, 24 hours, 28 hours and 32 hours after administration. For the determination of creatinine, 2 ml blood samples are taken immediately before administration and 12, 24 and 48 hours after administration. For the determination of cyclosporin, samples are collected in two polystyrene-coated tubes containing EDTA (1 ml each) at each time reference point and they are frozen at −20 ° C. after gentle agitation. The presence of cyclosporine in whole blood is analyzed according to the RIAspecific method using monoclonal and / or specific antibodies, the detection limit in both cases being approximately 10 ng / ml.

In the tests carried out according to the above protocol, for example by comparing the composition of Example 1 in the form of capsules with the oral drinkable solution of Ciclosporin in the form of soft capsules (Ciclosporin "50 mg, Labrafil" 150 mg, ethanol " 50 mg, corn oil = "213 mg, final content weight - 463 mg / dose) serving as a control, substantially high bioavailability rates are recorded for the composition of Example 1 compared with the control composition, as it emerges from AUC (0-32 hours) and LaCmax values. Furthermore, the comparison of the variation in the concentration of Ciclosporin in the blood (as determined according to the specific RIA method using monoclonal antibodies) as a function of the time after a single administration of the compositions to be tested for a dose of Ciclosporin of 150 mg, shows a reduction. significant variation in response between all patients receiving the composition of Example 1 compared to that of all patients receiving the control composition.

Identical or equivalent results are obtained after oral administration of the other compositions of the invention, for example as described in the examples.

Claims (10)

1. A pharmaceutical composition, characterized in that it comprises a) a cyclosporine as active substance, b) a monoester of a fatty acid with a saccharide and c) a diluent or vehicle, i) the component (c) being a solvent for the two components (a) and (b), the components (a) and (b) each having, independently, a solubility in the component (c) of at least 10% at room temperature; or ii) component (c) being a solvent for the two components (a) and (b), and components (a) and (c) being present in said composition in a weight ratio of 1: 0.5 to 50 t ( a) :( c)]; or iii) component (c) being a solvent for the two components (a) and (b) and said composition being formulated in the form of solid unit doses suitable for administration by the oral route; or iv) component (c) comprising a poly (C 2 -C 4 alkylene) glycol having a maximum average molecular weight of 7,000 or a maximum viscosity at 50 ° C of 15,000 mPa.s, or comprising an ether or a ester of a (C3-C5 alkylene) polyol; or v) said composition being nonaqueous or essentially nonaqueous; or vi) the component (c) comprising a solid polymer vehicle, a silicone or a liquid paraffin or a light liquid paraffin and the component (a) being present in said composition in the form of a solid solution in (b). 2. A pharmaceutical composition, characterized in that it comprises a) a cyclosporine as active substance, b) a monoester of a fatty acid with a saccharide and c) a diluent chosen by parmic1) ethanol c2) the ( C2-C4 alkylene glycols, c3) (C3-C5 alkylene) polyols, c4) poly- (C2-C4 alkylene) glycols, and - mixtures of these compounds, ii) components (a) and ( c) being present in said composition in a weight ratio of 1: 0.5 to 50 [(a) :( c)]; or iii) said composition being formulated as solid unit doses suitable for oral administration; or iv). component (c) comprising a component (c4) having a maximum average molecular weight of 7000 or a maximum viscosity at 50 ° of 15,000 mPa.s.; or v) said composition being non-aqueous or substantially non-aqueous. 3. A pharmaceutical composition, characterized in that it comprises a) a cyclosporine as active substance, b) a monoester of a fatty acid with a saccharide etc2) 1,2-propylene glycol, ii) the components (a ) and (c2) being present in said composition in a weight ratio of 1: 0.5 to 50 [(a) :( c2)]; or iii) said composition being formulated as solid unit doses suitable for oral administration; or v) said composition being nonaqueous or substantially nonaqueous. 4. A composition according to any one of claims 1 to 3, characterized in that the components (a) and (b) are present in a weight ratio of 1: 3 to 200 [(a) :( b)]. 5. A pharmaceutical composition, characterized in that it comprises a) a cyclosporine as active substance in the form of a solid solution in b) a monoester of a fatty acid with a saccharide, and c6) a solid polymer vehicle, comprising a polyvinylpyrrolidone. 6. A composition according to claim 5, characterized in that the components (a) and (b) are present in a weight ratio of 1: 2 to 20 [(a) :( b)], and the component (c6) is present in an amount of at least 10% by weight relative to the total weight of the composition. 7. A composition according to any one of claims 1 to 6, characterized in that it is presented in the form of unit doses comprising from 2 to 200 mg of component (a) per unit dose. 8. A pharmaceutical composition, characterized in that it comprises a) a cyclosporine as active substance, b) a monoester of a fatty acid with a saccharide and c2) 1,2-propylene glycol, said composition being in the form of unit doses comprising from about 20 to about 100 mg of component (a) per unit dose, the components (a) and (b) being present in said composition in a weight ratio of 1: 3 to 200 [(a) :( b)] and components (a) and (c) being present in said composition in a weight ratio of 1: 0.5 to 50 [(a) :( c)]. 9. A composition according to any one of claims 1 to 8, characterized in that the component (a) is Ciclosporin or [Nva] 2-Ciclos-porine. 10. A composition according to any one of claims 1 to 9, characterized in that the component (b) comprises sucrose or raffinose monolaurate.