DE4003844A1 - NEW GALENIC FORMULATIONS CONTAINING CYCLOSPORINE - Google Patents

Abstract

Pharmaceutical compositions comprising (a) a cyclosporin as active ingredient (b) a fatty acid saccharide monoester and (c) a diluent or carrier. Components (c) are typically ethanol, an alkylene glycol (e.g. 1,2-propylene glycol), an alkylene polyol (e.g. glycerol), a polyalkylene glycol (e.g. PEG, RTM), an alkylene polyol ether or ester paraffin, or an organosilicon oxide polymer. Component (b) may be raffinose monolaurate or sucrose monolaurate. The compositions increase the in vivo availability of the cyclosporin.

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 is usually a pharmacological, in particular an immunosuppressive anti-inflammatory and / or anti-parasitic Have effect. Of the cyclosporins was called first the naturally occurring fungal metabolite ciclosporin or cyclosporin isolated, also known as cyclosporin A. and under the brand name SANDIMMUN® or SANDIMMUNE® in Trade is available. Ciclosporin is that Cyclosporin of formula A.

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

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

As the parent compound of the class, ciclosporin has so far most attention. The primary clinical examinations at ciclosporin dealt with the immunosuppressive Effect, particularly in relation to its application Organ transplant recipients, e.g. B. of heart, lung, combined cardiopulmonary, liver, kidney, pancreas, bone marrow, Skin and corneal grafts and especially of allogeneic organ transplants. Has in this area Ciclosporin achieved considerable success and recognition.

At the same time, ciclosporin was used intensively for various autoimmune diseases and inflammatory conditions, especially inflammatory conditions with an etiology including an autoimmune component such as arthritis, (such as rheumatoid arthritis, progressive arthritis chronica and arthritis deformans) and rheumatic diseases. Numerous reports and results can be found in the literature on in vitro tests, animal models and clinical Investigations. To the special autoimmune diseases,  for which therapy with cyclosporine is proposed or applied autoimmune haematological disorders (including, for example, hemolytic anemia, aplastic Anemia, pure erythrocyte anemia and idiopathic Thrombocytopenia), systemic lupus erythrematosus, polychondritis, Sclerodoma, Wegener's granular disease, dermatomyositis, chronic active hepatitis, severe myasthenia, psoriasis, Steven Johnson syndrome, idiopathic sprue, autoimmune inflammatory Bowel diseases (including, for example, ulcerative Colitis and Crohn's disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary Biliary cirrhosis, juvenile diabetes (type I diabetes mellitus), Uveitis (anterior and posterior), keratoconjunctivitis sicca and spring keratocunjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, including for example idiopathic nephrotic syndrome or nephropathy with minimal change).

Further areas of investigation with potential applicability are as an antiparasitic, in particular antiprotozoal agent, the treatment of Malaria, coccidiomycosis and schistosomiasis have been suggested and recently also the use in cancer therapy, e.g. B. as a means of reversion or removal of resistance to other antineoplastic or cytostatic therapies.

Since the original discovery of ciclosporin, a variety of naturally occurring cyclosporins have been isolated and identified, and numerous other non-natural cyclosporins have been 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 radical (formula B above) to form -xy = -CH₂-CH₂- is saturated]; derivatized cyclosporins, in which, for example, another substituent on the α- carbon atom of the sarcosyl radical in the 3-position of the cyclosporin molecule is introduced); Cyclosporins in which the -MeBmt residue is present in isomeric form (in which, for example, the configuration at positions 6 ′ and 7 ′ of the MeBmt residue is cis instead of trans); and cyclosporins, in which different amino acids are introduced at specific positions within the peptide sequence, using, for example, the total synthesis process developed by R. Wenger for the production of cyclosporins (see, for example, Traber 1, Traber 2 and Kobel loc. cit., US Pat 41 08 985, 42 10 581 and 42 20 641, European patent publications 00 34 567, 00 56 782 and 02 96 122; 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), [3′-O-acyl-MeBmt] ¹- Ciclosporin (also known as cyclosporin A acetate), [dihydro- MeBmt] ¹- [Val] ²-ciclosporin (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- Cyclosporin, [MeIle] ¹¹-ciclosporin, [(D) MeVal] ¹¹-ciclosporin (also known as Cyclosporin H), [MeAla] ⁶-ciclosporin, [(D) Pro] ³-ciclosporin and the like  

(In accordance with the nomenclature now agreed for cyclosporins, the designation is given with reference to the structure of cyclosporin (i.e. cyclosporin A). this will carried out by first of all the existing amino acid residues, that differ from those in ciclosporin (e.g. "[(D) Pro] ³" to indicate that this is in question cyclosporin represents a - (D) pro residue instead of the -Sar- Rest in the 3 position and then the expression "Ciclosporin" applies to express that the other residues are identical to those of ciclosporin. The individual residues are numbered, with the rest - MeBmt-, -Dihydro-MeBmt- or the equivalent thereof in position 1 begins.)

Many of these additional cyclosporins have one Comparable pharmacological usability or cyclosporine a more specific usability, for example a special one Reverse tumor resistance activity a cytostatic therapy. Can be found in the literature numerous suggestions for the use of these compounds as a therapeutic agent.

Despite the very important contribution, the ciclosporin in particular in the field of organ transplantation and therapy of autoimmune diseases, difficulties arise in providing more effective and appropriate means for administration. Furthermore, the reports on the occurrence of undesirable side reactions, in particular of nephrotoxic reactions, a serious obstacle the extended application of these compounds. Characteristic for the cyclosporins is their highly hydrophobic nature. Proposed liquid formulations, e.g. B. for oral The administration of cyclosporins has so far been predominantly based on the use of ethanol and oils or the like Vehicles as carrier media. Thus, the commercially available Ciclosporin drinking solution methanol and olive oil as a carrier medium  in conjunction with labrafil as a surfactant; see. e.g. B. US-PS 43 88 307. The use of the drinking solution and similar compositions as suggested in the prior art are, however, of numerous difficulties accompanied.

First of all, the need to use oils or from oil-based carriers to unpleasant preparations Lead taste or other taste impairments bring about, especially in long-term therapy. These Effects can be achieved through a presentation in the form of gelatin capsules mask. However, the cyclosporin in solution to keep the ethanol content high. The evaporation of ethanol, e.g. B. from capsules or other dosage forms, if they are open, for example, leads to Development of a cyclosporin precipitate. Become such Compositions in the form of so-called soft gelatin capsules presents, this particular difficulty makes the packaging of the encapsulated product in an airtight container, e.g. B. an airtight blister pack or an aluminum foil Blister pack, required. This in turn leads to a voluminous nature of the product and to a Manufacturing costs. The storage properties of the aforementioned Formulations are therefore far from ideal.

Those with existing oral cyclosporin dosing systems achieved bioavailability levels are also low and point between individuals, individual patient types and also different for the same individuals Large fluctuations in the course of therapy. So Reports in the literature show that currently available standing therapy using the commercially available Ciclosporin drinking solution an average absolute bioavailability results in only 30%, with considerable fluctuations exist between individual groups, e.g. B. between recipients of liver transplants (relatively low bioavailability) and bone marrow transplants (relatively high bioavailability).  The reported fluctuations in bioavailability between patients vary from 1 or a few% for certain Patients up to 90% or more for other patients. As mentioned earlier, individuals often have a pronounced one Change in bioavailability depending on of time watched.

In order to achieve effective immunosuppressive therapy, in the blood or serum cyclosporin levels in a special Area to be maintained. The required area For its part, depending on the particular condition to be treated, for example depending on whether the therapy to prevent graft rejection or to fight an autoimmune disease, and ever after whether another with cyclosporin therapy at the same time immunosuppressive therapy is used or not, vary. Due to the strong fluctuations in those with conventional ones Dosage forms achieved bioavailability levels, also vary to achieve the required Blood serum levels required daily doses from one person to another other and also with one and the same person considerably. Out Because of this, it is necessary to check blood / blood serum levels of patients undergoing cyclosporin therapy on a regular basis and monitor frequent intervals. The supervision the blood / blood serum level, generally determined by RIA or an equivalent immunoassay technique, e.g. B. using the technology based on monoclonal antibodies must be carried out regularly. It is necessary time consuming and annoying and adds to the total cost of therapy. To all of these clearly recognizable practical difficulties comes the appearance of undesirable side reactions already mentioned, which in all available oral dosage forms are observed.

Various proposals are available from the prior art Overcoming these difficulties is known, including inclusion of both solid and liquid oral dosage forms.  

For example, JP-A-71 682/1985 (Takada et al.) Suggests the use of Agents that prevent the lymphatic supply of cyclosporins, especially by administration in conjunction with surfactants, increase. Under a general List of surfactants that are used can, there are sucrose fatty acid esters, such as Sucrose oleate, palmitate or stearate, and other fatty acid esters, especially sorbitan fatty acid esters, such as sorbitan oleate, palmitate or stearate. Although the use of The proposal goes both mono- and polyesters towards a general preference for mono- or diesters. Other surfactants listed are polyoxyethylated, hydrogenated vegetable oils as well as under the trade names Cremophore RH and Nikkol HCO 60 known and commercially available products. Is for these products clearly stated that, for example, compared to the above Sucrose ester based surfactants are preferred.

Example 3 of the aforementioned Japanese patent application describes the provision of an aqueous preparation with a Content of a sucrose fatty acid ester with the designation F160 as a surface active component. The preparation contains 3.5 mg ciclosporin and 2 mg sucrose ester in 1 ml H₂O. Around to achieve a dispersion of the ciclosporin is a 5 Minute ultrasound treatment with 100 W required. That as "Transparent solution" described preparation is directly in Animal testing used the relative lymphatic absorption to investigate. Because of the very low solubility of ciclosporin in H₂O and the minor amount of used surfactants it is clear that the claimed Solution an artificial result of the ultrasound treatment represents. It's not just the ciclosporin scored For example, insufficient concentration for an oral dosage form low, but the preparation is also inherently unstable, so for this reason the use as any practical or commercial galenic form excluded  is. It is essentially just an experimental one System that enables laboratory examinations and is also not applicable. There is no Proposal to use surfactants in any different connection than in relation to the lymphatic Provision.

Japanese Patent Application No. 1 93 129/1987 (publication No. 0 38 029/1989) (also Takada et al.) powdered preparations containing ciclosporin, the in a solid, non-surface-active carrier phase, e.g. B. Containing sucrose, sorbitol, tartaric acid, urea, Cellulose acetophthalate, methacrylic acid / methyl methacrylate or Hydroxypropylmethylcellulose phthalate, along with minor Amounts of a surfactant dispersed is. Again, the surfactant is aimed at added to increase lymphatic delivery. In this Context, the application is clearly geared towards practical means of applying the teaching of the aforementioned Japanese To provide application No. 71 682/1985. A note on sucrose esters as possible surface-active components is missing in this case. The reference to sorbitan esters at the enumeration of possible surface-active components is retained. However, products from the Nikkol HCO 60 type indicated as preferred surfactants. Nikkol HCO 60 is the only surface active in the examples Funds used. There is no evidence that the alleged increase in lymphatic supply brings a practical benefit or to the solution one of the difficulties discussed so far that have occurred during cyclosporin therapy.

According to the invention new galenic cyclosporin formulations provided the fatty acid saccharide monoesters as contain primary carrier components. With these phrases become the difficulties encountered in the prior art in therapy with cyclosporin, e.g. B. with cyclosporine,  overcome or significantly reduced. In particular, was found that the compositions of the invention Manufacture of solid, semi-solid and liquid compositions with a sufficiently high content of cyclosporin Allow concentration, so that for example a comfortable Oral administration is possible while improving Effectiveness, e.g. B. in terms of bioavailability properties, is achieved.

In particular, it has been found that the compositions according to the invention effective cyclosporin dosage simultaneous increase in absorption / bioavailability Levels as well as a reduced fluctuation in absorption / Bioavailability levels in both individuals who receive cyclosporin therapy, as well as between different ones Lessen individuals. By applying the Teachings of the present invention are cyclosporin dosage forms available that have a reduced variation in the achieved Cyclosporin / blood / blood serum levels at doses for single patients as well as single patients / Ensure individual patient groups in comparison with each other. The invention thus enables the reduction of necessary to achieve effective therapy Cyclosporin dosage levels. Furthermore, it enables a closer Standardization and optimization of requirements for continuous daily dosing for individual patients, who are receiving cyclosporin therapy, as well as for groups of patients who have undergone appropriate therapy will.

Due to the closer standardization of the dosage amounts for individual patients and the blood / blood serum level response as well the dosage and response parameters for patient groups the monitoring requirements can be reduced, which significantly lowers the cost of therapy.  

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

Furthermore, the present invention enables manufacture non-alkanol based compositions, i.e. H. the free or are essentially free of ethanol. With such compositions are the stability problems discussed above and the associated processing difficulties, which in known alkanolic compositions of Are avoided by nature. Thus the invention among other things, compositions that are better for administration in the form of capsules, d. H. hard or soft gelatin capsules are suitable and where the packaging difficulties, for example those above for soft gelatin capsules problems described, eliminated or significantly reduced are.

In particular, according to the invention, a pharmaceutical composition provided that contains the following components:

• a) a cyclosporin as active ingredient,
• b) a fatty acid saccharide monoester and
• c) a diluent or carrier,

in which

• i) component (c) is a solvent for the two components (a) and (b), the Components (a) and (b) each independently a solubility in component (c) of at least 10% possess at ambient temperature; or
• ii) component (c) is a solvent for the two components (a) and (b) and the components  (a) and (c) in the composition in a ratio from 1: 0.5 to 50 parts by weight [(a): (c)] is present are; or
• iii) component (c) is a solvent for the two components (a) and (b) and the composition in a fixed unit dosage form that is suitable for oral administration, is formulated; or
• iv) component (c) a poly (C _2-4 alkylene) glycol with an average molecular weight of at most 7000 or a viscosity at 50 ° C of at most 15000 mPa · s or a C _3-5 alkylene polyol ether or -ester contains; or
• v) the composition is non-aqueous or substantially is non-aqueous; or
• vi) composition (c) a solid polymeric carrier, an organosilicon polymer or paraffin per or Sub-liquidum contains and component (a) in the composition is in solid solution (b).

The compositions thus defined represent new and special advantageous variants of the general in the French Patent application No. 88 11 953 and the corresponding patent applications in other countries (including USSN 07/2 43 577, DE-OS 38 304 945, Japanese patent application 2 31 396/88 and GB application 88 21 443.9 [first publication in France, March 17, 1989 under number 26 20 336]) Products.

The above definitions (i) to (vi) are to be understood as that they are not mutually exclusive. The compositions the invention thus comprise compositions which are defined to be one or more of the sub (i) to (vi) correspond to defined conditions. Preferred  Compositions of the invention are those which, for example any two or more of conditions (i) to (v) correspond.

The one used here and in the claims The expression "pharmaceutical composition" is to be understood as that it defines compositions, their individual components or ingredients themselves pharmaceutically acceptable are, for example, in the case of intended oral administration for oral use or for topical purposes Administration tolerated for topical use are.

The preferred cyclosporin in the context of component (a) is Ciclosporin. Another preferred component (a) is [Nva] ²-cyclosporin, also known as cyclosporin G.

Preferred components (b) for use in the invention Compositions are water soluble fatty acid saccharide monoesters, e.g. B. fatty acid monoesters of saccharides with a Solubility in water of at least 3.3% at ambient temperature, d. H. which in water at ambient temperature in a Amount of at least 1 g monoester per 30 ml water can be dissolved are.

The fatty acid residue of components (b) can contain saturated or unsaturated fatty acids or mixtures thereof. Particularly suitable components (c) are C _6-18 fatty acid saccharide monoesters, in particular water-soluble C _6-18 fatty acid saccharide monoesters. Particularly suitable components (c) are caproic acid (C₆) -, caprylic acid (C₈) -, capric acid (C₁₀) -, lauric acid (C₁₂) -, myristic acid (C₁₄) -, palmitic acid (C₁₆) -, oleic acid (C₁₈) -, ricinoleic acid (C₁₈) - and 12-hydroxystearic acid (C₁₈) - saccharide monoesters, especially lauric acid saccharide monoesters.

The saccharide residue of component (b) can comprise any suitable sugar residues, e.g. B. mono-, di- or trisaccharide residues. The saccharide residue preferably comprises di- or trisaccharide residues. Preferred components (b) include C _6-14 fatty acid disaccharide monoesters and C _8-18 fatty acid trisaccharide monoesters.

Particularly suitable saccharide residues are sucrose and raffinose residues. Components (b) are therefore particularly suitable Sucrose monocaproat, sucrose monolaurate, sucrose monomyristate, Sucrose monooleate, sucrose monoricinoleate, raffinosemonocaproat, Raffinosemonolaurat, Raffinosonomonomistat, Raffinosemonopalmitat and Raffinosemonooleat. Particularly preferred Components (b) are raffinose monolaurate and in particular Sucrose monolaurate.

Components (b) preferably have a hydrophilic-lipophilic Balance (HLB) of at least 10.

Components (b) preferably have a purity of Ester residue of at least 80%, in particular at least 90% and especially from at least 95%. The components (b) preferably have a melting point of about 15 to about 60 ° C and especially from about 25 to about 50 ° C.

According to the above definitions for the compositions of the invention (ii) and (iii) are components (c) as materials defined in which both components (a) and (b) at ambient temperature, e.g. B. at temperatures of about 20 ° C, have substantial solubility. Preferred components (c) are materials in which (a) and (b) are independent of each other a solubility of at least 10% (as required of definition (i)), preferably of at least 25% and in particular at least 50% (in which, for example the components (a) or (b) independently of one another a solubility on the order of at least 100 mg, preferably 250 mg and in particular at least 500 mg / ml) have at room temperature. Materials are particularly preferred,  where component (a) has a solubility of at least 10%, preferably at least 25% and in particular has at least 50%, and / or in which component (b) a solubility of at least 100%, preferably at least 200% and in particular at least 300% (in which for example component (b) has a solubility in The order of magnitude of at least 1000, preferably 2000 and in particular has at least 3000 mg / ml).

Components (c) suitable for use in the compositions of the invention include
c¹) ethanol;
c²) C _2-4 alkylene glycols;
c³) C _3-5 alkylene polyols;
c⁴) poly (C _2-4 alkylene) glycols; and
c⁵) C _3-5 alkylene polyether or ester,
as well as any mixtures thereof.

According to the general objectives of the invention is the use of ethanol either alone or in admixture with any other However, components (c) are generally less preferred.

If component (c) contains a C _2-4 alkylene glycol (c²), it is preferably a propylene glycol, in particular 1,2-propylene glycol. If component (c) comprises a C _3-5 alkylene polyol (c³), it is preferably a C _3-5 alkylene triol, in particular glycerol.

If component (c) comprises a poly (C _2-4 alkylene) glycol (c⁴), it is suitably a polyethylene glycol. For use in the compositions of the invention, these components preferably have an average molecular weight of no more than about 7000 (see definition (iv)), e.g. B. up to 6600, especially not more than about 2000, e.g. B. up to 1600 and especially not more than about 500. Such components preferably have a viscosity of at most about 15,000 mPa · s, in particular of at least about 1000 mPa · s and very particularly of at least about 200 mPa · s at 50 ° C. or in particular at ambient temperatures (cf. definition (iv)) . Suitable polyethylene glycols for use as components (c) are described, for example, in Fiedler, Lexikon der Hilfsstoffe, 2nd revised and extended edition (1981), vol. 2, pages 726 to 731, in particular the products PEG (polyethylene glycol) 200, 300, 400 and 600, and PEG 1000, 2000, 4000 or 6000, and in particular 200, 300 and 400, which have, for example, approximately the following physical properties:

If component (c) comprises a C _3-5 alkylene pololyether or ester (c⁵), it is suitably a C _3-5 alkylene triol, in particular glycerol, ether or ester. Suitable components (c⁵) include mixed ethers or esters, ie components including other ether or ester constituents, for example the transesterification products of C _3-5 -alkylene triolesters with other mono-, di- or polyols.

Particularly suitable components (c⁵) are mixed C _3-5 -alkylene triol / poly- (C _2-4 -alkylene) -glycol fatty acid esters, in particular mixed glycerol / polyethylene or polypropylene glycol fatty acid esters.

The particularly suitable components (c⁵) for the use according to the invention include products which are obtained by transesterification of glycerides, for. B. triglycerides, with poly (C _2-4 alkylene) glycols, e.g. B. polyethylene glycols, and optionally glycerol are available. Such transesterification products are generally by alcoholysis of glycerides, e.g. B. triglycerides, in the presence of a poly (C _2-4 alkylene) glycol, e.g. B. polyethylene glycol, and optionally obtained from glycerol (ie to carry out the transesterification from the glyceride to the polyalkylene glycol / glycerol component, ie via a polyalkylene glycolysis / glycerolysis). In general, such a reaction is carried out by reacting the specified components (glyceride, polyalkylene glycol and optionally glycerin) at elevated temperatures under an inert atmosphere with constant agitation.

Preferred glycerides are fatty acid triglycerides, e.g. B. (C _10-22 - fatty acid) triglycerides, including natural and hydrogenated oils, especially vegetable oils. Suitable vegetable oils include, for example, olive oil, almond oil, peanut oil, coconut oil, palm oil, soybean oil and wheat germ oil and in particular natural or hydrogenated oils which are rich in (C _12-16 fatty acid) ester residues.

Preferred polyalkylene glycol materials are polyethylene glycols, in particular polyethylene glycols with a molecular weight from about 500 to about 4000, e.g. B. from about 1000 to about 2000.

Suitable components (c⁵) thus comprise mixtures of C _3-5 alkylene triol esters, for. B. mono-, di- and triesters in variable relative amounts; and poly (C _2-4 alkylene) glycol mono- and diesters, along with minor amounts of free C _3-5 alkylene triol and free poly (C _2-5 alkylene) glycol. As mentioned above, the preferred alkylene triol residue is glyceryl. Preferred polyalkylene glycol residues are polyethylene glycol residues, in particular with a molecular weight of about 500 to about 4000. Preferred fatty acid residues are C _10-22 fatty acid ester residues, in particular saturated C _10-22 fatty acid ester residues.

Particularly suitable components (c) can thus alternatively be defined as follows: transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and, if appropriate, glycerol; or compositions containing or consisting of the following constituents: glyceryl mono-, di and tri-C _10-22 fatty acid esters and polyethylene glycyl mono- and di-C _10-22 fatty acid esters (optionally together with, for example minor proportions of free glycerin and free polyethylene glycol).

With regard to the above definitions apply to the preferred ones vegetable oils, polyethylene glycols or polyethylene glycol residues the above statements. Particularly suitable Components (c⁵), as described above for the invention Use have been known and commercially available under the trade name Gelucir, especially the following products:

• i) Gelucir 33/01, F: = about 33-38 ° C, Saponification number = about 240/260;
• ii) Gelucir 35/10, mp = about 29-34 ° C; Saponification number = about 120-140;
• iii) Gelucir 37/02, F. = about 34-40 ° C, Degree of saponification = about 200-220;
• iv) Gelucir 42/12, F. = about 41-46 ° C, Saponification number = 95-115;
• v) Gelucir 44/14, F. = about 42-46 ° C, Saponification number = 75-95;
• vi) Gelucir 46/07, F. = about 47-52 ° C, Saponification number = about 125-145 ° C;
• vii) Gelucir 48/09, F. = about 47-52 ° C, Saponification number = about 105-125;
• viii) Gelucir 50/02, F. = about 48-52 ° C, Saponification number = about 180-200;  
• ix) Gelucir 50/13; F. = about 46-41 ° C, Saponification number = about 65-85;
• x) Gelucir 53/10, mp = 48-53 ° C, Saponification number = about 95-115;
• xi) Gelucir 62/05, F: = about 60-65 ° C, Saponification number = about 70-90.

The above products (i) to (x) all have an acid number from <2 to. The product (xi) has an acid number of <5 on. Products (ii), (iii) and (vi) to (x) have one Iodine number of <3. The product (i) has an iodine number of 8 on. Products (iv) and (v) have an iodine number of <5. The product (xi) has an iodine number of <10. Components (c⁵) with an iodine number of <1 are generally preferred. It should be noted that mixtures of components (c⁵) according to the above definition also in the invention Compositions can be used.

If a component (c) according to the specific description above (i.e. a component, any of the foregoing Definitions (i) to (iv) suffice or any components is used according to the definition (c¹) to (c⁵)), generally contain the compositions of the invention component (a) in a carrier medium containing components (b) and (c). The components are usually (a) and (b) each in the compositions of the invention present in dispersion or solution, e.g. B. as molecular or microcellular dispersion or solution (if necessary including inclusion a solid solution). Thus component (a) is in the generally in dispersion or solution in the two components (b) and (c) are present and component (b) is in turn in solution in (c). Component (b) is used in the Compositions according to the invention generally as carriers or solubilizer (before and / or after administration) for component (a) and component (c) serves as Carrier or fluidizing agent (the present invention is of course in no way special  functional relationship between components (a), (b) and (c) limited unless expressly stated otherwise is specified).

It is further preferred that when using a component (c) the compositions as described above of the invention in solid unit dosage forms for oral administration be formulated, d. H. that, for example, in encapsulated form in hard or soft gelatin that are suitable for oral administration (see Definition (iii)). These unit dosage forms contain such explained in more detail below, preferably for. B. 2 to 200 mg of component (a) per unit dose.

When using component (c) according to the above Components (a) and (c) are in the embodiments according to the invention Compositions preferably in a ratio from 1: 0.5 to 50 parts by weight [(a): (c)] (see definition (ii)) before. Components (a) and (b) are preferably in a ratio of 1: 3 to 200 parts by weight of [(a): (b)].

If a component (c) according to the above statements used, it is further preferred that the inventive Compositions non-aqueous or essentially non-aqueous are (see definition (v)), d. H. they point for example a water content of less than 20%, in particular less than 10% and especially less than 5, 2 or 1% based on the total weight of the composition, on.

In accordance with the foregoing according to the invention also a number of special embodiments provided:

• - a pharmaceutical composition containing a component (a) and a component (b) according to the above definitions, and a diluent, the  among any components (c¹) to (c⁴) according to the above Definitions or under any mixture is selected, any of the foregoing Definitions (ii) to (v) are met;
• - a pharmaceutical composition containing a component (a), (b) and (c²) according to the above Definitions, where the above definitions (ii), (iii) or (v) are satisfied; and a pharmaceutical composition containing a component (a), (b) and (c⁵) as defined above.

If a component (c) according to the above special Executions (i.e. a component, any of the definitions (i) to (iv) corresponds, or any components (c¹) to (c⁵)) used in the compositions according to the invention, components (a) and (c) are suitably in the compositions in a ratio of 1: 0.5 to 50 Parts by weight. Components (a) and are preferably located (c) in a ratio of about 1: 1 to 10, especially from 1: 1 to 5 and especially from about 1: 1.5 to 2.5 before, i.e. H. approximately in the ratio of 1: 1.6 or 1: 2 parts by weight [(a): (c)]. Components (a) and (b) are preferably in the compositions in a ratio of about 1: 3 to 200, preferably from about 1: 3 to 100 and especially from about 1: 3 up to 50 parts by weight. In particular, the components (a) and (b) in a ratio of about 1: 5 to 20, preferably from about 1: 5 to 10 and in particular from about 1: 6.0 to 6.5 before, for example in a ratio of 1: 6.25 parts by weight [(a): (b)].

When the compositions of the invention sucrose monolaurate as component (b) and 1,2-propylene glycol as component (c) contain, the components (a) and (b) are preferably in a ratio of about 1: 6 to 7 parts by weight [(a): (b)] and components (a) and (c) preferably in  a ratio of about 1: 1.5 to 2.5, e.g. B. of about 1: 2 Parts by weight [(a): (c)].

Compositions according to the invention containing one Component (c) according to the above statements can in any suitable dosage forms are prepared, e.g. B. for oral, parenteral or topical use as for one dermal or ophthalmic application, e.g. B. for application on the surface of the eye, for example for the treatment of autoimmune diseases of the eye as set out above, or for intralesional injections, e.g. B. in the treatment of psoriasis.

Preferably such compositions are in unit dosage forms both for oral administration and for others Routes of administration provided.

The amount of those present in such a unit dosage form Component (a) can of course, depending on the treating condition, the intended route of administration and the desired effect vary. Generally included however, such unit dosage forms are from about 2 to about 200 mg component (a), e.g. B. Ciclosporin, per unit dose.

Suitable dosage forms for oral administration include for example liquids, granules and the like. Preferred but are fixed unit dosage forms, e.g. B. tablets or capsules, especially hard or soft gelatin capsules. Such oral unit dosage forms preferably contain about 5 to about 200 mg, in particular about 10 or 20 to about 100 mg, e.g. 15, 20, 25, 50, 75 or 100 mg of component (a), e.g. B. Cyclosporine, per unit dose.

Compositions according to the invention which have a component (c) contained according to the above, own the further advantage that they are the basis for compositions with modified release properties,  e.g. B. for a delayed release of component (a) or a release of component (a) over longer periods away, for example following oral administration. Such compositions additionally contain one Component (d) capable of releasing properties the composition with respect to component (a) to modify. Such components (d) include, for example polymeric vehicles, especially thickeners, e.g. B. polymeric or colloidal thickeners, and agents which can swell in water, e.g. B. Water-swellable polymers or colloids.

Suitable components (d) are known from the prior art. These include:

• d¹) polyacrylate and polyacrylate copolymer resins, e.g. B. polyacrylic acid and polyacrylic acid-methacrylic acid resins such as the known and commercially available products with the Name Carbopol (see Fiedler, op. Cit., Vol. 1, p. 206 to 207), especially the products Carbopol 934, 940 and 941, and Eudragit (Fiedler, op. Cit., Vol. 1, pp. 372-373), in particular the products Eudragit E, L, S, RL and RS and in particular the products Eudragit E, L and S;
• d²) celluloses and cellulose derivatives including: alkyl celluloses, such as methyl, ethyl and propyl celluloses; Hydroxyalkyl celluloses, such as hydroxypropyl celluloses and Hydroxypropylalkyl celluloses, e.g. B. hydroxypropylmethyl celluloses; acylated celluloses, such as cellulose acetates, cellulose acetophthalates, Cellulose acetosuccinates and hydroxypropylmethyl cellulose phthalates; and salts thereof, such as sodium carboxymethyl celluloses. Examples of such products which are suitable according to the invention are known and commercially available, e.g. B. under the designation Klucel and Methocel (see Fiedler, op. cit., vol. 1, p. 521 and Vol. 2, p. 601), in particular the products Klucel LF, MF,  GF and HF as well as Methocel K 100, K 15M, K 100M, E 5M, E 15, E 15M and E 100M.
• d³) polyvinyl pyrrolidones, including for example poly N-vinyl pyrrolidones and vinyl pyrrolidone copolymers, such as vinyl pyrrolidone Vinyl acetate copolymers. Examples of such Compounds which are suitable according to the invention known and commercially available, e.g. B. under the name Kollidon (see Fiedler, op. Cit., Vol. 1, p. 526 and 527), especially the products Kollidon 30 and 90.
• d⁴) polyvinyl resins, for example including polyvinyl acetates and polyvinyl alcohols, as well as other polymers Materials including gum tragacanth, rubber arabic, alginates, e.g. B. alginic acid and salts thereof, e.g. B. Sodium alginates.
• d⁵) silicon dioxide, including hydrophilic silicon oxide products, such as alkylated (e.g. methylated) silica gels, especially colloidal silica products such as they are known and commercially available, e.g. B. Aerosil (see Handbook of Pharmaceutical Excipients, published by Pharmaceutical Society of Great Britain, S. 253 to 256) in particular the products Aerosil 130, 200, 300, 380, O, OX 50, TT 600, MOX 80, MOX 170, LK 84 and that methylated Aerosil R 972.

If component (d) is present, it is preferably in an amount of about 0.5 to 50%, especially about 1 up to 20% and very particularly from about 2 to 10% by weight on the total weight of the components (a) + (b) + (c) + (d) in front.

If component (c) in the compositions according to the invention as component (c⁶) according to a solid polymeric carrier contains the above definition (vi)  preferably by a water-insoluble or in Water essentially insoluble polymeric carrier.

Polyvinylpyrrolidones are particularly preferred as components (c⁶) (see Fiedler, op. cit., vol. 2, pp. 748 to 750), including in particular cross-linked polyvinyl pyrrolidones. examples for materials of this type which are suitable according to the invention, are known and commercially available, for example at the designation Kollidon (see Fiedler, loc. cit., vol. 1, p. 527), Kollisept (see Fiedler, op. Cit., Vol. 2, pp. 719 to 720), Povidone and Crospovidone (see Fiedler, op. Cit., Vol. 2, p. 751).

Particularly suitable components (c⁶) are polyvinyl pyrrolidones with a molecular weight of at least about 10,000 and whole especially at least about 20,000 or about 25,000, so for example products with a molecular weight of about 40,000 or more.

Crosslinked polyvinylpyrrolidones are of particular interest. Examples of special products according to the invention as a component (c⁶) are suitable are Plasdone XL, Plasdone XL 10 and cropovidones.

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

Other examples of such materials of particular interest for the compositions of the invention containing on component (c⁶) are known and commercially available Products, e.g. B. under the name Avicel (cf. Fiedler, op. Cit., Vol. 1, pp. 160 to 161), Elcema (cf. Fiedler, loc. cit., vol. 1, p. 326) and Pharmacoat (see Fiedler, loc. cit., vol. 2, p. 707), e.g. B. the products Avicel PH 101 and PH 102, Elcema and Pharmacoat 603.  

In the case of compositions according to the invention with a content on component (c⁶) component (a) is in the Component (b) in solid solution including a solid, precarious solution, d. H. completely or essentially completely in molecular or multicellular dispersion. (In In practice, components (b) often have at least one certain fluidity, e.g. B. at ambient temperature or slightly elevated temperatures, and are therefore not strictly speaking "firmly". The term "fixed solution" as used in the present Description and claims used is accordingly interpret, e.g. B. including viscous or highly viscous systems.) The solid solution containing (a) and (b) is suitably dispersed, for example in particle form, e.g. B. in the form of fine particles within the entire component (c⁶). The components (c⁶) serve thus generally in the compositions according to the invention as a decay accessible matrix for [(a) + (b)]. The component (d) usually serves as a means of decay supports, e.g. B. on contact with the contents of the gastrointestinal Tracts.

Compositions of the invention containing a component (c⁶) further suitably contain as a component (e) a binder and / or lubricant. Materials suitable for use as binders / lubricants are, in particular, fatty acids and alkyl sulfonate salts, such as metal salts, e.g. B. those with 10 or more carbon atoms in the fatty acid / alkyl radical, such as C _10-22 fatty acid and C _10-22 alkyl sulfonate alkali metal or alkaline earth metal salts, such as sodium, calcium or magnesium salts. Examples of such materials which are suitable for use in the present invention are sodium lauryl sulfate and magnesium stearate (cf. Fiedler, loc. Cit., Vol. 2, p. 584).

When the compositions of the invention have a component (c⁶) contain, the components (a) and (b) are more suitable  Manner in a ratio of about 1: 2 to 20, preferably from about 1: 2.5 to 10 and in particular from 1: 3 to 8, [(a): (b)].

The components (c⁶) are suitably in the invention Compositions in an amount of at least 10%, preferably at least 15% and in particular at least 20%, based on the total weight of the composition. Suitable components (c⁶) are in the compositions according to the invention in an amount of 10 to 60%, preferably from 15 to 50% by weight, e.g. B. from about 20 to 40 wt .-%, such as 25, 30 or 35% by weight, based on the total weight of the composition, available.

If a component (d) is present, the components lie (d) and (c⁶) suitably in a ratio of 1: 0.5 to 4, preferably from about 1: 1 to 3 and in particular from about 1: 1.5 to 2.5, e.g. B. about 1: 2 or about 1: 2.5 parts by weight before, [(d): (c⁶)].

If a component (s) is present, the components are located (e) and (c⁶) suitably in a ratio of about 1: 5 to 25, preferably from about 1: 5 to 20 and in particular from 1: 7 to 15 parts by weight before, [(e): (c⁶)].

The compositions of the invention all contain three components (c⁶), (d) and (e), these are suitable together in an amount of about 25 to 75%, preferably about 30 to 65% and in particular 40 to 65% on the total weight of the composition present. The relationship of components [(a) + (b)]: [(c) + (d) + (e)] suitably lies on the order of 1: 0.25 to 7.5 and preferably from 1: 0.5 to 5 and in particular from 1: 0.5 to 2, e.g. B. about 1: 0.8, 1: 1.2 or 1: 1.3 parts by weight.

The compositions of the invention containing a component (c⁶) in any suitable dosage form,  e.g. B. for oral, parenteral or topical use, to be provided. Such are according to the invention suitably Compositions provided in unit dosage form, either for oral or other administration.

The amount of those present in such unit dosage forms Component (a) naturally varies, for example, depending on the Condition of the patient to be treated, the intended route of administration and the desired effect. In general This amount is suitably in the range of about 2 to about 200 mg of component (a), e.g. B. Ciclosporin, per unit dose.

To suitable dosage forms for oral administration belong to granules and the like. However, solid unit dosage forms are preferred, e.g. B. tableted or encapsulated forms. Such oral unit dosage forms suitably contain about 5 to about 200 mg, preferably 10 or 20 to about 100 mg, e.g. B. 15, 20, 25, 50, 75 or 100 mg, component (a), e.g. B. Ciclosporin, per unit dose.

If component (c) in the compositions according to the invention as component (c⁷) an organosilicon polymer or Paraffinum per- or subliquidum as defined above (vi) contains, component (c⁷) is preferably at Temperatures up to 150 ° C, preferably at 100 ° C and in particular easily flowable up to 50 ° C. Suitable components (c⁷) have a maximum viscosity of 15,000 mPa · s and preferably of 1000 mPa · s at the temperatures indicated.

Paraffinic hydrocarbons suitable for use as component (c⁷) are liquid and semi-solid paraffins and mixtures of which, e.g. B. Paraffinum subliquidum and Paraffinum perliquidum (see Fiedler, op. cit., vol. 2, pp. 690 to 691). Around The component is made to ensure easy formulation (c⁷) suitably entirely or essentially  fluid or semi-solid paraffins, d. H. Paraffinum perliquidum or Paraffinum subliquidum or mixtures thereof. Is it however, desirable compositions with, for example Produce slower drug release, this can can be achieved by adding a solid paraffin, d. H. Paraffinum durum, adds.

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

If the compositions according to the invention are additionally a contain solid paraffin as component (c⁷), that is Ratio of liquid / semi-solid paraffin components: solid Paraffin components suitably about 1: 0.06 to 0.1 Parts by weight. In this case, components (a) and (c⁷) suitably in a ratio of 1: 6 to 200, preferably from 1: 6 to 100 and in particular from 1: 8 to 20, e.g. B. about 1:10 parts by weight, before, [(a): (c⁷)].

The organosilicon oxide polymers which are suitable as component (c⁷) include in particular fluid, ie liquid and semi-solid, polymer materials with structural units of the formula (-R) ₂Si-O, in which each of the radicals R is a monovalent organic radical, such as C _{1 -4} alkyl, especially methyl, or phenyl. Organosiloxane polymers with a viscosity of approximately 0.65 to 10⁵ cP and in particular of 10 or 50 to 500 or 1000 cP are particularly preferred.

To enable easy formulation, the component contains (c⁷) suitably liquid organosiloxane polymers, e.g. B. Polymethylsiloxane polymers, such as any of the various known silicone oils, such as silicone oil 550, DC 200, SF-1066  and SF-1091 (see Fiedler, op. cit., vol. 2, p. 826). If the compositions according to the invention only liquid organosiloxane Containing polymers, components (a) and (c⁷) suitably in a ratio of about 1: 6 to 200, preferably from 1: 6 to 100 and in particular from 1: 6 to 20, e.g. B. from about 1: 8 parts by weight, [(a): (c⁷)].

Compositions in which, for example, a slower one Drug release can be given using semi-solid organosiloxane polymers, e.g. B. from any of the various known silicone pastes, such as silicone paste A (see Fiedler, op. cit., vol. 2, p. 826), as component (c⁷) or by adding these ingredients, e.g. B. to other organosilicon Polymers according to the above statements, be preserved. In the latter case, the ratio is of liquid: semi-solid organosilicon polymers in the invention Composition suitably in the order of magnitude from about 1: 0.5 to 1. In this case the ratio is of components (a): (c⁷) suitably of the order of magnitude from about 1: 6 to 100 and preferably from 1: 6 to 20 parts by weight [(a): (c⁷)].

It should be noted that mixtures of components (c⁷) according to the given definition also in the invention Compositions can be used.

When the compositions of the invention are a component (c⁷) contain, the components (a) and (b) are suitably in a ratio of about 1: 6 to 20 and preferably from about 1: 6 to 10 and in particular from about 1: 6.0 to 6.5, e.g. B. about 1: 6.25 parts by weight, [(a): (b)].

In the case of the compositions according to the invention with a content on a component (c⁷) is the component (a) in the Component (b) completely or essentially completely in molecular or miscellular dispersion, e.g. B. in the form a solid solution or a solid multicellular solution (where  the expression "fixed solution" in the broad sense as in the Compositions with a component (c⁶) is used). The solid solution containing (a) and (b) is suitably in the form of particles, e.g. B. of fine particles with component (c⁷), e.g. B. in the entire component (c⁷), dispersed.

Compositions according to the invention containing one Component (c⁷) can be in any suitable dosage form, e.g. B. for oral, parenteral or topical use, for example for dermal or ophthalmic use, e.g. B. for application to the surface of the eye, e.g. B. for treatment of autoimmune conditions of the eye as above set out, or for intralesional injections, e.g. B. for treatment from psoriasis. Suitably they are in unit dosage forms for either oral administration or provided for other routes of administration.

The amount of those present in such unit dosage forms Component (a) naturally depends on, for example treating condition, the intended route of administration and the desired effect. Generally these amounts are suitably in the range of about 2 to about 200 mg of Components (a), e.g. B. Ciclosporin, per unit dose.

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

Compositions according to the invention containing one Component (c⁷) also have the advantage that they are used as a basis for compositions with modified release properties  can be used, for example for delayed Release of component (a) or to release the Component (a) over extended periods of time, e.g. B. in the connection to an oral administration. Such compositions can be obtained in the manner described above by solid or semi-solid components (c⁷) in suitable Amounts incorporated. Another way of making of these compositions is as additional Component (d) to incorporate a component which is described in capable of releasing properties of the compositions to be modified with respect to component (a). To such components (d) include, for example, polymers Vehicles, especially thickeners, e.g. B. polymeric or colloidal thickeners, as well as agents in water are swellable, e.g. B. water-swellable polymers or Colloids, e.g. B. those defined above under (d¹) to (d⁵) Materials.

If component (d) is present, it suitably lies in an amount of about 0.5 to 30%, preferably of 1 to 20% and in particular from about 1 to 10%, based on the Total weight of components (a) + (b) + (c⁷) + (d).

The components (d⁵) are particularly indicated for use in compounds according to the invention containing one Organosilicon polymer as component (c⁷).

Compositions according to the invention containing one Component (c⁶) or (c⁷) are preferably non-aqueous or procured substantially non-aqueous, d. H. the apply the above statements regarding the compositions Containing other components (c).

The compositions according to the invention can be used independently of the selected component (c) (for example, regardless of whether component (c) one of components (c¹) to (c⁷) according to the foregoing, or any mixture thereof  contains) any additional additives as they are known from the prior art and conventionally are used, e.g. B. antioxidants (e.g. ascorbyl palmitate, Tocopherols, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT)), flavorings and the like.

In particular, the compositions according to the invention contain suitably also one or more stabilizers or Buffer substances, especially for the hydrolysis of the component (b) or degradation of component (a) during processing or to prevent during storage. To such Stabilizers can include acidic stabilizers, such as citric acid, Acetic acid, tartaric acid or fumaric acid, as well as basic Stabilizers, such as potassium hydrogen phosphate, glycine, lysine, Arginine or tris (hydroxymethyl) aminomethane.

Suitable stabilizers or buffering agents are expedient added in an amount sufficient to maintain a pH Value in the range of about 3-8, preferably about 5-7, e.g. B. between 6 and 7, to achieve or maintain. Such Stabilizers are generally in an amount up to 5% by weight, based on the total weight of the composition, before or up to 10% by weight, for example when used of citric acid or acetic acid. The compositions according to the invention, especially compositions in which the Component (a) is ciclosporin, with a pH within the above ranges are preferred.

Compositions of the invention suitably contain also a polyoxyalkylene-free surfactant, e.g. B. dioctyl succinate, Dioctyl sulfosuccinate, di- [2-ethylhexyl] succinate, sodium lauryl sulfate or phospholipids such as lecithins. There is a surfactant according to the above, this is suitable in an amount of 50, preferably 5-50, e.g. B. of 10-25%, based on the weight of component (b).  

In the case of compositions according to the invention with a content on a component (a) in solid solution in the component (b), e.g. B. if component (c) is a Component (c⁶) or (c⁷) according to the above acts, any of the aforementioned stabilizers, Buffers and / or surfactants suitably the solid Solution phase to be incorporated. Such materials can component (c) and the like are also incorporated.

The compositions according to the invention are again independent free or essentially of the selected component (c) free of ethanol and contain, for example, less than 5.0%, preferably less than 2.5%, e.g. B. 0-1.0% ethanol on the total weight of the composition.

In addition to the foregoing, the present invention also a method of making a pharmaceutical Composition provided as defined above, the method being intimate mixing or compounding of components (a), (b) and (c) according to the above Definition together with a component (d) if necessary and / or other components, e.g. B. stabilizers, buffers and Surfactants according to the foregoing, comprising optionally the composition obtained in unit dose form, e.g. B. in a unit dosage form for oral administration, e.g. B. by tableting, filling in gelatin capsules or others appropriate measures.

If component (c) is a solvent for components (a) and (b) or contains a component (c¹), (c²), (c³), (c⁴) or (c⁵) according to the above Definition, components (a), (b) and (c) are suitably brought together in the above procedure by components (a) and (b) together in the component (c) triggers e.g. B. with heating to temperatures up to 50 or 150 ° C, preferably not above 70 or 75 ° C. That on this The mixture obtained in this way can then continue with the components  (d) and the like can be compounded by making an intimate mixture according to known techniques. The filling, for example in hard or soft gelatin capsules Way carried out at elevated temperatures, e.g. B. at temperatures up to 50 ° C to ensure fluidity of the composition, e.g. B. to achieve in the heat.

In the case of compositions according to the invention with a content on a component (a) in solid solution in the component (b), e.g. B. in the case of compositions with a content on a component (c⁶) or (c⁷) according to the above definitions, suitably initially involves this process followed by the preparation of a solid solution of (a) in (b) of intimate mixing or compounding of the obtained solid solution with the remaining components (c) and possibly (d) and the like. Solid solutions containing the components (a) in (b) can be produced by known techniques, for example by solidifying a melt with a content to (a) in solution in (b) or by removing the Solvent from a solution of components (a) and (b). For the purposes of the invention, the latter is Alternative generally preferred.

Examples of suitable solvents for components (a) and (b) are lower alkanols, e.g. B. ethanol. Stabilizers, Buffers and / or surfactants may suitably be used in the solution step be added.

The solid solution thus obtained is then suitably with component (c) and possibly with the components (d) and (e) and the like. compounded, e.g. B. in the form of fine particles, for example by distribution in the component (c).

Although ethanol for the preparation of the compositions according to the invention can be used, such as in the preparation of the solid solutions is carried out above,  this ethanol is made before the final dosage form is completed removed, for example by evaporation, whereby one is ethanol-free or essentially ethanol-free Product receives as set out above.

The following examples serve to illustrate the invention.

In the product sucrose monolaurate used in the examples L-1969 is the commercial product of Mitsubishi-Kasei Food Corp., Tokyo 104, Japan: HLB value = at least 12.3; Purity of the lauryl ester residue = at least 95%; F. about 35 ° C; Decomposes at about 235 ° C; Surface tension in 0.1% by weight; aqueous solution = 72.0 dynes / cm at 25 ° C.

Examples 1-10

The composition of Example 1 is made by components (a) and (b) with stirring and heating in one Oil bath at 100 ° C in component (c) dissolves. The compositions Examples 2-10 are prepared in an analogous manner. In the case of Examples 5 and 8, component (d) in the mixture of components (a) to (c) originally obtained solved. In the case of Examples 6, 7 and 10, the component (d) suspended in (a) to (c).

The compositions obtained are heated under Size 1 hard gelatin capsules (Examples 1-4 and 9) or Size 0 (Examples 5-7 and 10) filled. You get encapsulated End products, the capsules each containing 50 mg cyclosporin (e.g. Ciclosporin) included and for administration for prevention of graft rejection or in the treatment of Autoimmune diseases are suitable, for example one Administration of 1 to 5 capsules daily.

Examples 11-13

The above compositions 11-13 each additionally contain 25 mg (t) tartaric acid and / or 50 mg (g) Dioctyl succinate and preferably both components, wherein a final weight of 1000 mg for composition 11, of 1055 mg for the composition 12 and of 680 mg for the Composition 13 results.

Compositions 11-13 are made in the following manner: Components (a) and (b) are in absolute ethanol dissolved and the ethanol at 50 ° C under reduced Pressure evaporated thoroughly. Components (c) to (e) are thoroughly mixed (adding (f) and (g) if used), using conventional mixing techniques. The solid solution containing [(a) + (b)] becomes one Grind fine powder and mix evenly into [(c) to (g)]. The uniform mass obtained becomes tablets pressed, each containing 100, 50 or 25 mg (a) and for administration to prevent graft rejection or in the treatment of autoimmune diseases are suitable, for example, 1-5 tablets administered daily will.

Examples 14 and 15

Components (a) and (b) are dissolved in absolute ethanol and the ethanol is then under reduced pressure at 50 ° C evaporated thoroughly. The solid solution obtained becomes one grind fine powder and evenly in component (c) suspended. The liquid suspension obtained is in hard gelatin capsules filled with size 0. You get an encapsulated one Final product, each capsule containing 50 mg cyclosporine (e.g. Ciclosporin) contains and is for administration for prevention of graft rejection or in the treatment of Autoimmune diseases are suitable, for example 1-5 capsules administered daily.

Examples 16 and 17

Compositions 16 and 17 are made in an analogous manner compositions 14 and 15 above. in the In the case of composition 16, (c) and (d) are passed through first Melting and intimate stirring combined. The solid solution containing [(a) + (b)] is then suspended in [(c) + (d)].  In the case of compositions 17, (d) coexists with [(a) + (b)] suspended in (c).

Equivalent compositions to that of Examples 1-17 can be prepared by replacing ciclosporin as Component (a) any other cyclosporins, e.g. B. [Nva] ²- Ciclosporin, or by using any other fatty acid saccharide monoester, as listed above are, for example, raffinosemonolaurate, instead of sucrose monolaurate used as component (b), wherein in the respective Cases equal or equivalent amounts or relative Ratios are applied.

Below is the utility of the compositions of the invention through animal experiments or clinical studies explained, for example, in the following way be performed.

Investigation of the bioavailability of the invention Compositions in dogs (a) Test compositions

Composition I as in Example 1.
Composition II as in Example 14.

(b) Test procedure

Groups of 8 beagle dogs (male, about 11-13 kg) will be used. The animals received 18 hours before administration of the test composition no feed, but have up to Administration free access to water. The test compositions are by a probe with subsequent administration of 20 ml 0.9 NaCl solution administered. 3 hours after administration the animals have free access to the test composition to feed and water.

Blood samples of 2 ml (or 5 ml for the blank value) are taken from the saphenous vein and placed in 5 ml plastic tubes containing EDTA at the time point -15 min (blank value), 30 min and 1, 1.5, 2 , 3, 4, 6, 8, 12 and 24 hours after administration. The blood samples are stored at -18 ° C before the determination. The blood samples are analyzed by RIA. The areas under the curves where the blood drug concentration is plotted against time are calculated according to the trapezoidal rule. The analysis of variance is performed with respect to AUC (area under the curve), Cmax (maximum concentration) and Tmax (maximum time).

(c) results

The calculated average AUC values (in ng · h / ml ^-1 ) and Cmax values (in ng / ml ^-1 ) of typical experimental approaches are shown in the table below together with the calculated variation (CV) in relation to the reaction between test animals that get the same composition.

From the table above it can be seen that the compositions of the invention have high bioavailability (AUC and Cmax) along with a relatively small variation in response for both AUC and Cmax .

Comparable favorable results can be seen when using the other compositions according to Examples 1-17 and obtained in particular according to Examples 1-10.

Clinical examinations

The beneficial properties of the compositions of the invention with oral administration can also be used in clinical Investigations carried out in the following way to prove.  

The subjects are adult volunteers, for example, men with higher education from 30 to 55 years. The experimental groups suitably include 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 is a disturbance of absorption, distribution, metabolism, excretion or safety of the drug could cause; Symptoms of a significant clinical illness in the period of 2 weeks before Investigation; clinically relevant abnormal laboratory values or Electrocardiograms; Need for simultaneous medication during the entire test period; Administration of any drugs that have a well-defined potential Have toxicity to an important organ system, within the previous 3 months; Administration of any investigational drug within 6 weeks before the start of the investigation; Medical history with 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 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⁺, Ka⁺, Fe ⁺⁺ , Ca ⁺⁺ , Cl ^- , creatinine, urea, uric acid, SGOT, SGPT, gamma-GT, alkaline phosphatase, total bilirubin, α- amylase;
Urine: pH, microalbumin, glucose, erythrocytes, keto body, sediment. Furthermore, the creatinine clearance is determined 1 month before the start of the experiment.

The test subjects each receive test compositions in arbitrary order. The compositions are at once in a total dose of 150 mg cyclosporin, e.g. B. cyclosporin, administered, taking at least 14 days between each Administrations are.

Administration is the morning after a fasting period of 10 hours during which only water absorption is allowed is carried out. Only decaffeinated drinks are inside allowed for a period of 24 hours after administration. The subjects are allowed within 12 hours after the Do not smoke. The subjects received 4 hours a standardized midday meal after administration.

Blood samples (2 ml) are taken 1 hour before administration as well 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 taken. Blood samples from are used to determine creatinine 2 ml immediately before administration and 12, 24 and 48 hours removed after administration. The samples for the cyclosporin Determination are made in 2 with EDTA-coated polystyrene tubes (1 ml each) at the respective times obtained and frozen after moderate agitation at -20 ° C. Cyclosporin is in the whole blood by RIA with a specific and / or non-specific MAB test, the Detection limit in both cases is about 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 the form of soft gelatin capsules with a final weight of 463 mg / dose) as standard significantly increased bioavailability concentrations for the composition of Example 1 in comparison with the standard both in terms of AUC values (0-32 h) and Cmax values detected. Furthermore, a comparison of the change over time in the 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 found below to oral administration of other compositions of the invention as in the present examples are described.

Claims (38)

1. Pharmaceutical composition containing

• a) a cyclosporin as active ingredient,
• b) a fatty acid saccharide monoester and
• c) a diluent or carrier,

in which

• i) component (c) is a solvent for the two components (a) and (b), components (a) and (b) each independently of one another having a solubility in component (c) of at least 10 % at ambient temperature; or
• ii) component (c) is a solvent for the two components (a) and (b) and components (a) and (c) in the composition in a ratio of 1: 0.5 to 50% by weight . Parts [(a): (c)] are present; or
• iii) component (c) is a solvent for both components (a) and (b) and the composition is formulated in a solid unit dosage form suitable for oral administration; or
• iv) component (c) a poly (C _2-4 alkylene) glycol with an average molecular weight of at most 7000 or a viscosity at 50 ° C of at most 15000 mPa · s or a C _3-5 alkylene polyol ether or -ester contains; or
• v) the composition is non-aqueous or substantially non-aqueous; or
• vi) the composition (c) contains a solid polymeric carrier, an organosilicon oxide polymer or paraffin per- or subliquidum and component (a) is present in the composition in solid solution (b).

2. Pharmaceutical composition containing

• a) a cyclosporin as active ingredient,
• b) a fatty acid saccharide monoester and
• c) a diluent selected from the following group:
  • c¹) ethanol;
  • c²) C _2-4 alkylene glycols;
  • c³) C _3-5 alkylene polyols;
  • c⁴) poly (C _2-4 alkylene) glycols; and mixtures thereof,

in which

• ii) components (a) and (c) are present in the composition in a ratio of 1: 0.5 to 50 parts by weight of [(a): (c)]; or
• iii) the composition is formulated in a solid unit dosage form suitable for oral administration; or
• iv) component (c) contains a component (c⁴) with an average molecular weight of at most 7000 or a viscosity at 50 ° C. of at most 15,000 mPa · s; or
• v) this composition is non-aqueous or substantially non-aqueous.

3. Composition according to claim 2, characterized in that component (c) is selected from the following group:

• c²) 1,2-propylene glycol,
• c³) glycerin and
• c⁴) polyethylene glycols with an average molecular weight of at most 7000 or a viscosity at 50 ° C of at most 15,000 mPa · s.

4. Pharmaceutical composition containing

• a) a cyclosporin as active ingredient,
• b) a fatty acid saccharide monoester and
• c²) 1,2-propylene glycol

in which

• ii) components (a) and (c²) are present in the composition in a ratio of 1: 0.5 to 50 parts by weight of [(a): (c²)]; or
• iii) the composition is formulated in solid unit dosage form suitable for oral administration; or
• v) the composition is non-aqueous or substantially non-aqueous.

5. Pharmaceutical composition containing

• a) a cyclosporin as active ingredient,
• b) a fatty acid saccharide monoester and
• c⁵) a C _3-5 alkylene polyol ether or ester.

6. Composition according to claim 5, characterized characterized in that component (c⁵) is a transesterification product a natural or hydrogenated vegetable oil and one Contains polyethylene glycol. 7. The composition according to claim 6, characterized characterized in that component (c⁵) is a transesterification product a natural or hydrogenated vegetable oil and one Polyethylene glycol with a molecular weight of 500-4000 contains. 8. Composition according to claim 6 or 7, characterized characterized in that component (c⁵) is a transesterification product  a natural or hydrogenated vegetable oil, one Contains polyethylene glycol and glycerin. 9. Composition according to one of claims 5-8, characterized in that the components (a) and (c⁵) in a ratio of 1: 0.5 to 50 parts by weight. 10. Composition according to one of claims 1-9, characterized in that components (a) and (c) or in the case of claim 4 the component (c²) or in the case of Claims 5-9 the component (c⁵) in a ratio of 1: 1 to 10 parts by weight of [(a): (c) / (c²) / (c⁵)] are present. 11. The composition according to claim 10, characterized characterized in that the ratio is 1: 1.5 to 2.5 parts by weight is. 12. The composition according to any one of claims 1-11, characterized in that the components (a) and (b) in a ratio of 1: 3 to 200 parts by weight [(a): (b)] are available. 13. The composition according to claim 12, characterized characterized in that the ratio is 1: 5 to 20 parts by weight is. 14. The composition according to claim 13, characterized characterized in that the ratio is 1: 6 to 6.5 parts by weight is. 15. Pharmaceutical composition containing

• a) a cyclosporin as an active ingredient in solid solution,
• b) a fatty acid saccharide monoester and
• c⁶) a solid polymeric carrier.

16. The composition of claim 15 thereby characterized in that the component (c⁶) polyvinylpyrrolidone contains. 17. The composition according to claim 15 or 16, characterized characterized in that the components (a) and (b) in one Ratio of 1: 2 to 20 parts by weight of [(a): (b)]. 18. The composition according to claim 17, characterized characterized in that the ratio is 1: 3 to 8 parts by weight is. 19. The composition according to any one of claims 15-18, characterized in that component (c⁶) in an amount of at least 10 wt .-%, based on the total weight of the Composition, is present. 20. The composition according to claim 19, characterized characterized in that the component (c⁶) in an amount of 15 up to 50 wt .-%, based on the total weight of the Composition, is present. 21. The composition according to any one of claims 15-20, characterized in that they additionally (d) one in water contains swellable component. 22. The composition according to claim 21, characterized characterized in that the components (d) and (c⁶) in one Ratio of 1: 0.5 to 4 parts by weight [(d): (c⁶)] are present. 23. The composition according to any one of claims 1-23, characterized in that it is in unit dosage form with a Content of 2 to 200 mg of component (a) per Unit dosage is available.   24. The composition according to claim 23, characterized characterized as having about 10 or 20 to 100 mg of component (a) contains per unit dose. 25. Pharmaceutical composition containing

• a) a cyclosporin as active ingredient,
• b) a fatty acid saccharide monoester and
• c²) 1,2-propylene glycol,

the composition being in unit dosage form and about 20 to about 100 mg component (a) per unit dose contains the components (a) and (b) in the composition in a ratio of 1: 3 to 200 parts by weight [(a): (b)] are present and components (a) and (c) in the Composition in a ratio of 1: 0.5 to 50 Parts by weight are present. 26. The composition according to claim 25, characterized characterized in that the components (a) and (b) in one Ratio of 1: 5 to 10 parts by weight and the Components (a) and (c) in a ratio of 1: 1.5 to 2.5 Parts by weight are present. 27. The composition according to any one of claims 1-26, characterized in that it is in an oral dosage form encapsulated in soft or hard gelatin. 28. The composition according to any one of claims 1-27, characterized in that they additionally have a stabilizer or contains a buffering agent. 29. The composition according to claim 28, characterized characterized that they have a pH of 3 to 8 is buffered. 30. The composition according to any one of claims 1-29, characterized in that component (a) is Ciclosporin or [Nva] ²-ciclosporin.   31. Composition according to one of claims 1-30, characterized in that component (b) a contains water-soluble fatty acid saccharide monoester. 32. Composition according to claim 31, characterized in that component (b) contains a C _6-18 fatty acid di- or tri-saccharide monoester. 33. Composition according to claim 32, characterized characterized in that component (b) or raffinose Contains sucrose monolaurate. 34. Composition according to one of the preceding Claims essentially as described above with reference to any of the accompanying examples.