FI97524C - Process for the preparation of a pharmaceutical composition containing cyclosporin - Google Patents

Description

97524

METHOD FOR PREPARING A PHYCLOSPORIN-CONTAINING PHARMACEUTICAL COMPOSITION

The invention relates to a process for the preparation of a pharmaceutical composition containing cyclosporin as an active ingredient.

Cyclosporins are a group of structurally distinct, cyclic, poly-N-methylated undecapeptides that usually have pharmacological, especially immunosuppressive, anti-inflammatory and / or antiparasitic effects. The first isolated cyclosporin was the naturally occurring fungal meta-bolite Ciclosporin or cyclosporin, also known as cyclosporin A and is commercially available as SANDIMMUNR or SANDIMMUNER, which are registered trademarks. Ciclosporin is a cyclosporin of formula A, ~ MeBmt-aAbu-Sar-MeLeu-Val-MeLeuj / Ala- (D) .Ala-MeLeu ~ MeLeu-MeVal- 20 1 2.3 4 5 6-7 8-9 10. 11 wherein -MeBmt represents an N-methyl- (4R) -4-but-2E-en-1-yl-4-methyl- (L) threonyl residue of formula B CH3 25 x y 30

HO (R) ^ ^, CH

;; CH (R) ^ "" CH3 (B) -N-CH-CO- 35 (S) CH3 wherein -x-y- is -CH = CH- (trans).

2 97524

As the oldest in the group, Ciclosporin has received the most attention to date. Clinical trials of ciclosporin have focused on its use as an immunosuppressive agent, especially in transplant recipients such as heart, lung, combined heart-lung, liver, kidney, pancreas, bone marrow, skin, cornea transplants. , especially in the case of allogeneic transplants. In this area, Ciclosporin has gained considerable success and reputation.

10 At the same time, the trial of Ciclosporin in various autoimmune diseases and inflammatory conditions, in particular in inflammatory conditions with an autoimmune component etiology, such as joint disease (eg rheumatoid arthritis, chronic progressive joint disease and wear and tear) and rheumatic diseases, in vitro animal models and clinical trials have been commonly reported in the literature. Specific autoimmune diseases for which ciclosporin therapy has been proposed or applied include autoimmune haematological diseases (including e.g. haemolytic anemia, apastatic anemia, pure erythrocyte anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, scleroderma, multiple myelitis, dermatomyositis, chronically active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic fatty diarrhea, autoimmune intestinal inflammation (including e.g. ulcerative colitis and Crohn's disease) endocrine ophthalmosis biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), mucositis (anterior and posterior), dry corneal and conjunctivitis and spring corneal and conjunctivitis, inters-35 titus pulmonary fibrosis, psoriatic arthritis and glo-merulonephritis Oh syndrome, e.g., idiopathic nephrotic syndrome 3 97524 or minimal change nephropathy).

In addition, the potential suitability of the substance as an antiparasitic agent, in particular as an antiprotozoal agent, e.g. for use in the treatment of malaria-5, coccidioidosis and schistosomiasis, and more recently for use in the treatment of cancer has been investigated.

Since the discovery of the original Ciclosporin, a large number of naturally occurring cyclosporins have been isolated and identified, and many non-naturally occurring cyclosporins have been prepared fully or semi-synthetically or using modified culture methods. The group containing cyclosporins is thus considerable today and includes, for example, naturally occurring cyclosporins A to Z [cf. Traber et al. 1, Helv. Chim. Acta. 60, 1247-1255 (1977); Traber et al. 2, Helv. Chim. Acta. 65 no. 162, 1655-1667 (1982); Kobel et al., Europ. J. Applied Microbiology 20 and Biotechnology 14, 273-240 (1982); and von Wartburg et al., Progress in Allergy, 38, 28-45 (1986)] as well as a variety of non-naturally occurring cyclosporin derivatives and artificial or synthetic cyclosporins, including so-called dihydrocyclo-25 porins [in which -xy - a part of the -MeBmt residue (formula B above) is saturated to give -xy- = -CH 2 -CH 2 -]; derived cyclosporins (e.g., an additional substituent is introduced on the α-carbon atom in the sarcosyl residue at the 3-position of the cyclosporin molecule); cyclosporins in which the -MeBmt residue is present in isomeric form (e.g., the configuration of the MeBmt residue at the 6 'and 7' positions is in the cis form rather than the trans form); and cyclosporins in which different amino acids are placed at specific positions in the peptide sequence, e.g., using the fully synthetic synthetic method developed by R. Wenger for the preparation of cyclosporins - see, e.g., Traber 1, Traber 2, and Kobel; U.S. Pat. No. 4,108,985, U.S. Pat. EP 0 034 567 and EP 0 056 782; EP 0 296 122, WO 86/02080; Wenger 1. Transp. Proc.

15, Suppl. 1: 2230 (1983); Wenger 2, Angew. Chem. Int.

Ed., 24, 77 (1 985) and Wenger 3, Progress in the Chemistry of Organic Natural Products 50, 123 (1986).

The group for cyclosporins now comprises, for example, [Thr] 2, [Val] 2, [Nva] 2 and [Nva] 2 - [Nva] 5-cyclosporins (also known as cyclosporins C, D, G and .M), [3'-O-acyl-MeBmt] 1-Cyclosporin (also known as cyclosporin A acetate), [dihydro-

MeBmt] - [Val] -Cyclosporin (also known as dihydrocyclosporin D), [3'-deoxy-3'-oxo-MeBmt] 1 [Val] 2-and - [Nva] 2-Cyclosporin, [(D) fluoromethyl-Sar] 3-Cyclosporin, [(D) Ser] 8-Ciclosporin, [Melle] 11-Ciclosporin, 15 [(D) MeVal] 11-Ciclosporin (also known as cyclosporin H), [MeAla] ^ -Ciclosporin, [(D) Pro] ^ -Ciclosporin and so on.

[According to the current common nomenclature of cyclosporins, these are defined by reference to the structure of Ciclosporin 20 (i.e. cyclosporin A). This is done by first determining the amino acid residues present that differ from those in Ciclosporin (e.g., "[(D) Pro] 3" means that the cyclosporin in question has a - (D) Pro residue at the 3-position of the -Sar residue). pa-25), and then the term "Cyclosporin" is used to describe the remaining residues that are the same as those in Ciclosporin. Individual residues are numbered starting at the residue in position 1 with -MeBmt- or -dihydroMeBmt- or its equivalent in position 1.] 35 a wealth of suggestions for their use as therapeutic agents.

Despite the very important contribution that Ciclosporin has had, especially in the field of transplantation and in the therapy of autoimmune diseases, a major obstacle to its widespread use or introduction has been the difficulty of developing more effective and appropriate dosing regimens, including the occurrence of undesirable side effects, especially the occurrence of nephrotoxic reactions. Cyclosporins are known to be very hydrophobic. The proposed liquid compositions, e.g. oral forms of cyclosporins, have hitherto been based primarily on the use of ethanol and oils or similar excipients as carriers. Thus, the commercially available liquid beverage solution Ciclosporin 15 uses ethanol and olive oil as the carrier together with the surfactant Labrafil - see, e.g., U.S. Pat. No. 4,388,307. However, there are many difficulties in using the liquid beverage solution and the proposed similar compositions.

20 First, the need to use oils or oil-based carriers may impart an unpleasant taste to the compositions or otherwise reduce palatability, especially in long-term therapy. These effects can be masked by using gelatin capsules. However, in order for cyclosporine to remain in solution, the ethanol content must be kept high. When ethanol evaporates, e.g. from capsules or other forms, e.g. when opened, precipitation of cyclosporin occurs. When such compositions are made, for example, in the form of a soft gel-30 capsule, this particular problem requires that the encapsulated product be packaged in an airtight space, for example an airtight film or an aluminum foil film package. This in turn makes the product clumsy and expensive to manufacture. The storage properties of the above-mentioned compositions are also poor.

The bioavailability levels obtained using the 6,97524 existing oral dosing systems are also low and vary widely between individuals, different patient types, and even within individuals at different times during drug treatment. Reports in the literature show that continuous therapy with a commercially available Ciclosporin drinking solution results in an average absolute bioavailability of only about 30% and clearly varies between different groups, e.g., liver (moderately low bioavailability) and bone marrow. - (moderately high bioavailability) between transplant recipients. The reported variability in bioavailability between subjects has ranged from one to a few percent, in others up to 90% in 15 and more patients. And, as already noted, a clear variation in the bioavailability of individuals over time is often noticeable.

In order to achieve effective immunosuppressive therapy, blood and serum cyclosporin-20 levels should be kept within a certain range. The desired range, in turn, may vary depending on the condition being treated, e.g., if the therapy is to prevent transplant rejection or if an autoimmune disease is being treated, and whether alternative immunosuppressive therapies are being used concomitantly with cyclosporine therapy. Because conventional dosage forms produce large variations in bioavailability levels, the daily doses required to achieve the required serum levels vary considerably from individual to individual and even within an individual. Therefore, it is necessary to monitor blood / blood serum levels regularly and at frequent intervals in patients receiving cyclosporine therapy. Monitoring of blood / serum levels, usually by 35 RIA or similar immunoassay techniques, e.g., using a monoclonal antibody technique, should be performed on a regular basis. This is 7,97524 time consuming and cumbersome and significantly increases the total cost of therapy.

Behind all these clearly practical difficulties are the undesirable side effects 5 which have already been referred to and which have been observed with the use of the available oral forms.

Many applications have been made in the field to avoid these difficulties, e.g. various oral applications, both solid and in solution form 10. Thus, in the publication. JP 71682/1985, Takada et al., Has proposed a method for increasing the lymphatic delivery of cyclosporin, in particular by administering cyclosporin with a surfactant. Surfactants that can be used include sucrose fatty acid esters such as sucrose oleate, palmitate or stearate, as well as other fatty acid esters, especially sorbitan fatty acid esters such as sorbitan oleate, palmitate or stearate. Although the use of both mono- and polyesters has been proposed, mono- or diesters are more preferred. Other proposed surfactants are polyoxyethylated hydrogenated vegetable oils, such as those known and commercially available under the trade names Cremophore RH and Nikkol HCO 60, 25, which are considered to be clearly superior to the sucrose ester surfactants disclosed, e.g.

Example 3 in said Japanese application describes a water-soluble preparation containing 30 sucrose fatty acid esters F160 as a surfactant. It contains 3.5 mg of Ciclosporin and 2 mg of sucrose ester in 1 ml of H 2 O. In order to obtain a Ciclos (porinide dispersion, sonication of 5 min / 100 W is required.

The resulting preparation, which has been described as a clear solution, is used directly in animal models to study relative lymphatic resorption. In view of the very low solubility of Ciclosporin Veteem, 8 97524 and the small amount of surfactant used, it is clear that the so-called solution is the product of the sonication process. The resulting Ciclosporin content is not only inappropriately low, e.g. for oral administration, but also the preparation is inherently unstable and is therefore virtually disregarded as a practical or commercial galenic form in any form. It is primarily an experimental system suitable for laboratory studies 10 and nothing else. The publication does not suggest the use of surfactants in any context other than lymphatic delivery.

In JP 193129/1987 (JP 0380-29 / 1989), Takada et al. powdered preparations containing Ciclosporin dispersed in a solid, non-surfactant, carrier and phase, e.g. sucrose, sorbitol, tartaric acid, urea, cellulose acetate acetate phthalate, meta-acrylic acid / methylacinate or methyl methacrylate methacrylate amounts of surfactant. The surfactant is added to provide increased lymphatic delivery, and in this regard the publication is clearly intended to demonstrate the practical application of the method disclosed in JP 71682/1985. In this case, the reference to sucrose esters as possible surfactants has been omitted. The reference to sorbitan esters as possible surfactants has been retained. However, Nikkol HCO 60 type 30 materials are referred to as the primary surfactant, and Nikkol HCO 60 is the only surfactant used in the examples. There is no indication in the publication that the increased lymphatic donation shown would provide any practical benefits or eliminate some of the difficulties encountered in cyclosporine therapy to date, e.g., as described above.

9,97524 The present invention provides a process for the preparation of novel galenic forms of cyclosporin containing fatty acid saccharide monoesters as primary carriers which eliminate or substantially reduce the difficulties encountered heretofore in cyclosporin therapy, e.g. Ciclosporin therapy. In particular, it has been found that the compositions prepared by the process of the invention allow the preparation of solid, semi-solid and solution compositions containing sufficiently large amounts of cyclosporin and allowing e.g. conventional oral administration while providing an improved effect, e.g. in terms of bioavailability.

More particularly, it has been found that the compositions of the method of the invention allow for effective cyclosporine dosing with increased resorption / bioavailability levels, as well as reduced variability in the resulting resorption / bioavailability levels, both in individual patients and among individuals receiving cyclosporine therapy. The invention provides cyclosporin dosage forms that reduce the variability in cyclosporine blood / serum levels between dosages for individual patients as well as between individuals / groups of patients. The invention thus makes it possible to reduce the dosage levels of cyclosporine which are necessary for effective treatment. In addition, it allows for more accurate standardization and optimization of continuous daily dosing, taking into account the needs of individuals receiving cyclosporine treatment and groups receiving similar treatment.

By further standardizing individual patient dose levels and blood / serum response, 35 as well as dose and response parameters in patient groups, the need for monitoring can be reduced, resulting in a significant reduction in treatment costs.

1 O

97524 By reducing the required dose of cyclosporine / standardizing the characteristics of bioavailability achieved, the present invention also provides a means of reducing unwanted side effects, especially a nephrotoxic reaction, in patients receiving cyclosporine therapy.

In addition, the present invention makes it possible to prepare non-alkanol-based compositions, e.g. compositions which are free or substantially free of ethanol. Such compositions avoid the above-mentioned stability and associated manufacturing difficulties inherent in known alkanol compositions. Thus, the invention discloses e.g. a process for the preparation of compositions which are more suitable, e.g. for capsule formulation, e.g. hard or soft gelatin capsule form, and / or which eliminate or substantially reduce packaging problems, e.g. as described above, e.g. for soft gelatine capsules.

Reference is made to the claims for features which characterize the invention.

In particular, the present invention relates to: a process for the preparation of a pharmaceutical composition comprising cyclosporin as an active ingredient, wherein (a) the cyclosporin is mixed or combined with (b) a fatty acid saccharide monoester and (c) a diluent or carrier, wherein component (c) is used as a solvent for components (a) and (b), and components (a) and (b) each independently have at least 10% solubility in component (c) at ambient temperature; and / or (ii) component (c) is used as a solvent for components (a) and (b), and the mixing ratio of components (a) and (c) is 1: 0.5 to 50 parts by weight [(a): (c)]; and / or (iii) component (c) is used as a solvent for components (a) and (b), and the composition thus obtained is formulated in a solid unit dosage form suitable for oral administration; and / or (iv) component (c) contains a poly- (C 2-4 alkylene) -gly-5 coli having an average molecular weight of up to 7,000 or a viscosity at 50 ° C of up to 15,000 mPa.s. or it contains a C 1-6 alkylene polyol ether or ester; and / or (v) the resulting composition is anhydrous or substantially anhydrous; and / or (vi) component (c) contains a solid polymeric carrier, organosilicon oxide polymer or liquid paraffin, and in the resulting composition, component (a) is in solid solution in (b).

The well-defined compositions thus obtained by the process are new and particularly useful modifications of the general compositions disclosed in the claims of FR 88 11953 and corresponding applications in other countries, e.g. US 07/243 577, 20 DE 38 304945, JP 231 396/88 and GB 88 21443.9 (published in France March 17, 1989 No. 2,620,336).

Definitions (i) to (vi) above are to be construed as non-exclusive. Compositions prepared by the method of the invention thus include compositions defined in accordance with one or more of the defined limits (i) to (vi). Thus, of the compositions prepared by the process of the invention, for example, those which are prepared using two or more steps (i) to (v) are preferred.

The term pharmaceutical composition, as used herein and in the following claims, means compositions in which the various components or constituents are themselves pharmaceutically acceptable, e.g., oral means means approved for oral use or topical administration means approved for topical use.

12 97524

The primary cyclosporin component (a) is Ciclosporin. Another primary component (a) is [Nva] 2-Cyclosporin, also known as cyclosporin G.

The preferred components (b) for use in the process of the invention are water-soluble fatty acid saccharide monoesters, e.g. fatty acid monoesters of saccharides having a water solubility of at least 3.3% at room temperature, i.e. they are soluble in water at 10 room temperature in an amount of at least 1 g for.

The fatty acid portion of component (b) may contain saturated or unsaturated fatty acids or mixtures thereof. Particularly suitable components (c) are C6-18 fatty acid saccharide monoesters, especially water-soluble C8-18 fatty acid saccharide monoesters. Particularly suitable components (c) are capron (C6), caprylic (C8), caprin (C10), lauric (Ci2), myristic (C1-4), palmitite (C1-g), oil - (C 1-8), castor oil-20 (C18) and 12-hydroxystearin (C18) acid saccharide monoesters, especially lauric acid saccharide monoesters.

The saccharide moiety of component (b) may contain any suitable sugar residue, e.g. mono-, di-25 or trisaccharide residue. Preferably, the saccharide moiety contains a di- or trisaccharide residue. The most preferred components (b) are C8-4 fatty acid disaccharide monoesters and 08-18 fatty acid trisaccharide monoesters.

Particularly suitable saccharide moieties are the rose and raffinose residues of sediment-30. Particularly suitable components (b) are thus: sucrose monocaproate, sucrose monolaurate, sucrose monomyristate, sucrose monooleate, sucrose monoricinoleate, raffinose monocaproate, raffinose monolaurate, raffinose monolaurate, 35 raffino The most preferred components (b) are raffinose monolaurate and in particular sucrose monourate.

Component (b) preferably has a hydrophilic-lipophilic balance (HLB) of at least 10.

Suitably in components (b) the ester residue purity is at least 80%, preferably 90%, most preferably at least 95%. The melting points of components (b) are suitably in the range of about 15 to 60 ° C, more preferably about 25 to 50 ° C.

According to definitions (ii) and (iii) used as in the process of the invention above, components (c) are defined as substances in which both components (a) and (b) have substantial solubility at room temperature, e.g. about 20 ° C. Preferred components (c) are those in which the solubility of components (a) and 15 (b) independently has at least 10% [as required by definition (i)], preferably 25%, most preferably at least 50% (e.g. ) or (b), independently, have a solubility of the order of at least 100 mg, preferably 250 mg, most preferably at least 500 mg / ml) at room temperature. Particularly preferred are substances in which the solubility of component (a) is at least 10%, suitably at least 25%, most preferably at least 50% and / or in which the solubility of component (b) is at least 100%, more preferably at least 200%, most preferably at least 300% (e.g. component (b) has a solubility of the order of at least 1000, more preferably 2000 most preferably at least 3000 mg / ml).

Components (c) suitable for use in the process of the invention are, for example: (c1) ethanol; (c2) C 2-4 alkylene glycols; (c3) C3-5 alkylene polyols; (c4) poly- (C 2-4 alkylene) glycols; and 35 (c5) C3-5 alkylene polyol ethers or esters, as well as mixtures thereof.

However, according to the general objects of the invention, the use of ethanol 1 4 97524, either alone or mixed with another component (c), is less preferred.

When component (c) contains C 2-4 alkylene glycol (C 1-4), this is preferably propylene glycol, most preferably 1,2-propylene glycol. When component (c) contains a C7-5 alkylene polyol (cJ), this is suitably a C3-5 alkylene triol, most preferably glycerol.

When component (c) contains poly- (C 2-4 alkylene) glycol (c4), this is preferably polyethylene glycol-10. In the process of the invention, the average molecular weight of such components is preferably less than about 7,000 [see definition (iv)], e.g. up to about 6600, more preferably less than 2000, e.g. up to about 1600, most preferably less than 500. Preferably, such components have a viscosity of up to about 15000 mPa.s., more preferably up to about 1000 mPa.s. , most preferably up to about 200 mPa.s., at 50 ° C, or more preferably at room temperature [see definition (iv)]. Suitable polyethylene glycols for use as component (c) are, e.g., as described in Fiedler, Lexikon der Hilfstoffe, 2nd. revised and expanded edition, [1981] Vol. 2, page 726-731, in particular the products PEG (polyethylene glycol) 200, 300, 400 and 600, as well as PEG 1000, 2000, 4000 or 25 6000, but in particular 200, 300 and 400, eg answering ·. the following approximate physical characteristics: PEG 200 PEG 300 PEG 400 PEG 600

Mol. Weight n.190-210 n.285-215 n.380-420 n.570-630 viscose. n.46-53 n.66-74 n.85-95 n.130-150 mPa.s.

jäätymisp. n.-50 ° C n.-16- -12 ° C n.-3-8 ° C n.15-25 C

ni 'n. 1.459 n. 1.463 n. 1.465 n. 1.467 1 5 97524

When component (c) contains a C 3-5 alkylene polyol ether or ester (c5), this is suitably a C 3-5 alkylene triol, preferably glycerol, ether or ester. Suitable components (c5) contain mixed ethers or esters, i. components containing other ether or ester substances, e.g. transesterification products of C3-5 alkylene triol esters with other mono-, di- or polyols.

Particularly suitable components (c5) are various 10-5 alkylene triol / poly (C 2-4 alkylene) glycolic fatty acid esters, in particular various glycerol / polyethylene or polypropylene glycol fatty acid esters.

Particularly suitable components (c5) for use in accordance with the present invention are products obtained by transesterifying glycerides, e.g. with triglyceride and poly- (C 2-4 alkylene) glycols, e.g. polyethylene glycols and optionally glycerol. Such transesterification products are usually obtained by alcoholization of glycerides, e.g., triglycerides, in the presence of poly- (C 2-4 alkylene) glycol, e.g., polyethylene glycol, and optionally glycerol (i.e., to enhance transesterification from glycerol to polyalkylene glycol / alkylene component). through glycerolysis). Usually, such a reaction is carried out by reacting the indicated components (glyceride, polyalkylene glycol and optionally glycerol) at an elevated temperature and under an inert atmosphere with constant stirring.

Preferred glycerides are fatty acid triglycerides, e.g. (C 0-22 fatty acid) triglycerides, including natural and hydrogenated oils, especially vegetable oils. Suitable vegetable oils are, for example, olive, almond, peanut, coconut, palm, soybean and wheat germ oil, and in particular natural or hydrogenated oils rich in (C12-5) fatty acid residues.

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

Suitable components (c5) are thus mixtures of C3-5alkylene triol ester esters, e.g. containing varying relative amounts of mono-, di- and 5-triesters, and poly (C2-4alkylene) glycol mono- and diesters together with a small amount of free C3-5alkylene triol and free poly (C2-4alkylene triol). with. As disclosed herein, the preferred alkylene triol moiety is glyceryl; preferably the polyalkylene glycol moiety is polyethylene glycyl, especially one having a molecular weight of about 500 to 4000; and preferably the fatty acid moiety is a C 10-22 fatty wax PP ° ester residue, especially a saturated C 10-22 fatty acid ester residue.

Particularly preferred components (c5) can thus optionally be defined as follows: transesterification products of natural or hydrogenated vegetable oil and polyethylene glycol and optionally glycerol; or compositions containing or consisting of: Gly-20 seryl mono-, di- and tri-C10-fatty esters and polyethylene glycyl mono- and di-O-fatty acid esters (optionally together with e.g. a small amount of free glycerol and free polyethylene glycol).

Preferred vegetable oils, polyethylene glycols or polyethylene glycol moieties and fatty acid moieties with respect to the above definitions have been previously disclosed. Particularly suitable components (C5), as described above, for use in the present invention are the known products available under the trade name Gelucir, in particular products 1

Gelucir 33/01, m.p. about 33-38 ° C, saponification number about 240/260; (ii) Gelucir 35/10, m.p. about 29-34 ° C, saponification number about 12-20-140; (iii) Gelucir 37/02, m.p. about 34-40 ° C, saponification number about 200-220; 1 7 97524 (iv) Gelucir 42/12, sp. about 41-46 ° C, saponification number about 95-115; (v) Gelucir 44/14, sp. about 42-46 ° C, saponification number about 75-95; 5 (vi) Gelucir 46/07, sp. about 47-52 ° C, saponification number = about 125-145; (vii) Gelucir 48/09, sp. about 47-52 ° C, saponification number about 105-125; (viii) Gelucir 50/02, m.p. about 48-52 ° C, saponification number about 180-200; (ix) Gelucir 50/13, m.p. about 46-41 ° C, saponification number about 65-85; (x) Gelucir 53/10, m.p. about 48-53 ° C, saponification number about 95-115; 15 (xi) Gelucir 62/05, m.p. about 60-65 ° C, saponification number about 70-90.

Acid number of products (i) - (x) = <2. Acid number of product (xi) = <5. Iodine value of products (ii), (iii) and (vi) - (x) = <3. Iodine value of product (i) = < 8. Iodine value of products 20 (iv) and (v) = <5. Iodine value of product (xi) = <10. Components (c5) with iodine value = <1 are generally preferred. It will be appreciated that mixtures of components (c5) as defined above may also be used in the process of the invention.

25 When component (c), which is • specifically described above [i.e. component according to any of the definitions (i) to (iv) or (c1) to (c5)], the compositions prepared by the process of the invention generally contain component (a) in a carrier containing components (b) and ( c). Usually, components (a) and (b) are present in the composition prepared by the process of the invention as a dispersion or solution, e.g. as a molecular or micellar dispersion or solution, (if necessary as a solid solution). Thus, component (a) is usually present as a dispersion or solution in both components (b) and (c) and component (b) is in turn present as a solution in 97524 18 (c). Component (b) usually acts as a carrier or diluent (either pre- and / or post-dosed) for component (a) in the compositions prepared by the process of the invention, and component (c) acts as a carrier or liquefier. (The invention is, of course, not to be construed as limited to any functional relationship between components (a), (b) and (c), unless otherwise specified.)

It is preferred that when component (c) is used, the compositions prepared by the method of the invention are formulated in a solid unit dosage form for oral administration, e.g. as a hard or soft gelatin capsule suitable for oral administration. [See. definition (iii)]. Such unit dosage forms, as described below, preferably contain from 2 to 200 mg of component (a) per unit dose.

When component (c) is used, components (a) and (c) are preferably present in the composition prepared by the process of the invention in a ratio of 1: 0.5 to 20 to 50 parts by weight [(a): (c)] [cf. definition (ii)]. Components (a) and (b) are suitably in a ratio of 1: 3 to 200 parts by weight [(a): (b)].

When component (c) is used, it is preferred that the compositions prepared by the process of the invention are anhydrous or substantially anhydrous [see definition (v)], e.g. they contain less than 20%, preferably less than 10%, most preferably less than 5%, 2% or 1% water, based on the total weight of the composition.

As stated above, the invention also discloses a series of different applications prepared by the process according to the invention: - A pharmaceutical composition comprising component (a) and component (b) as defined above and a solvent selected from (c1) to (c4), such as as defined above, or a mixture thereof, and corresponding to definitions (ii) to (v) above; - A pharmaceutical composition comprising component (a), 19 97524 (b) and (c2) as defined above and corresponding to definitions (ii), (iii) or (v) above; and - A pharmaceutical composition comprising components (a), (b) and (c5) as defined above.

5 When component (c), as described above, [i.e. a component which complies with one of the definitions (i) to (iv) or one of the components (c1) to (c5)] is used in the process according to the invention, components (a) and (c) are preferably present in the composition in a ratio of about 10: 1: 0.5- 50 parts by weight. Preferably, components (a) and (c) are present in a ratio of about 1: 1 to 10, more preferably 1: 1 to 5, most preferably about 1: 1.5 to 2.5, e.g. about 1: 1.6 or 1: 2 parts by weight [(a): (c)]. Components (a) and (b) are suitably present in the composition in a ratio of about 1: 3 to 15,200, more preferably about 1: 3 to 100, more preferably about 1: 3 to 50 parts by weight. Suitably, components (a) and (b) are present in a ratio of 1: 5 to 20, preferably about 1: 5 to 10, most preferably about 1: 6.0 to 6.5, e.g. about 1: 6.25 by weight. parts.

[(a): (b)].

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

; [(a): (c)].

The method of the invention may provide compositions comprising component (c) as described above in any dosage form, e.g. for oral, parenteral or topical use, e.g. for dermal or ophthalmic use, e.g. for administration to the surface of the eye, e.g. autoimmune conditions of the eye, as described above, or for intralesional injection, e.g., in the treatment of pso-35 riasis.

Suitably such compositions are prepared in unit dosage form for either oral or other administration.

The amount of component (a) in such unit dosage form will, of course, vary with e.g. the condition being treated, the mode of administration considered and the effect desired. Generally, such a unit dosage form will contain from about 2 to about 200 mg of component (a), e.g., Ciclosporin per unit dose.

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

Compositions prepared by the process of the invention containing component (c) as set out above have the further advantage of providing a basis for compositions with modified release properties, e.g. delayed release of component (a) or component (a). release over a relatively long period of time, e.g. after oral administration. Such compositions further comprise component (d) which allows the release properties of the composition to be modified with respect to component (a). Such components (d) contain e.g. polymeric fillers, in particular thickeners, e.g. polymeric or colloidal thickeners, as well as substances which swell in water, e.g. water-swellable polymers or colloids.

Suitable components (d) known in the art are: (d1) polyacrylate and polyacrylate copolymer resins, e.g. polyacrylic acid and polyacrylic acid methacrylic acid resins, known under the trade name Carbopol (see Fiedler, 1, pages 206-207), in particular the products Carbo-97524 , 940 and 941 and Eudragit (see Fiedler, 1, pages 372 - 373), in particular the products Eudragit E, L, S, RL and RS and in particular the products Eudragit E, L and S; (d2) cellulose and cellulose derivatives: alkylcellulose, e.g. methyl, ethyl and propylcellulose; hydroxyalkylcellulose, e.g. hydroxypropylcellulose and hydroxypropylalkylcellulose such as hydroxypropylmethylcellulose; acylated celluloses, e.g. cellulose acetates, cellulose acetate-10 phthalates, cellulose acetate succinates and hydroxypropylmethylcellulose phthalates; and salts thereof such as sodium carboxymethylcelluloses. Examples of such products suitable for use in accordance with the invention are known and commercially available products, such as those under the trade names Klucel and Methocel (see Fiedler, page 1, 521 and 2, page 601), in particular the products Klucel LF, MF, GF and HF and Methocel K 100, K 15M, K 100M, E 5M, E 15M and E 100M; (d3) polyvinylpyrrolidones, e.g. poly-N-vinylpyrrolidones and copolymers of vinylpyrrolidone, such as vinylpyrrolidone-vinyl acetate copolymers. Examples of such compounds suitable for use in accordance with the invention are known and e.g. pages 526 and 527), in particular the products Kollidon 30 and 90; (d4) polyvinyl resins, e.g., polyvinyl acetates and polyvinyl alcohols, and other polymeric materials, e.g., gum tragacanth, acacia, alginates, e.g., alginic acid 30, and salts thereof, e.g., sodium alginates;

(d5) silicones, hydrophilic silicon dioxide products, e.g. alkylated (e.g. methylated) silica gels, in particular colloidal silicon dioxide products, such as those known and available under the trade name Aerosil 35 [see Handbook of Pharmaceutical Excipients, Pharmaceutical Society of Great Britain, pp. 253-256], in particular Aerosil 130, 200, 300, 380, 0, OX 50, TT

97524 22 600, ΜΟΧ 80, ΜΟΧ 170, LK 84 and methylated Aerasil R 972.

When component (d) is present, it is preferably about 0.5 to 50% by weight, more preferably about 1 to 20% by weight, most preferably about 2 to 10% by weight, based on the components (a) + 5 ( b) + (c) + (d) of the total weight.

When component (c) in the process of the invention contains (c6) a solid polymeric carrier as defined in (vi), this is preferably a water-insoluble or substantially water-insoluble polymeric carrier.

Particularly preferred components (c 2) are polyvinylpyrrolidones [see Fiedler, 2, pp. 748-750], especially cross-linked polyvinylpyrrolidones. Examples of such known and commercially available substances useful in the invention are under the trade names Kollidon [cf. Fiedler, 1, p. 527], Col-lisept [cf. Fiedler, 2, pp. 719-720], Povidone and Crospovidone [cf. Fiedler, 2, page 751].

Particularly suitable components (c6) are polyvinylpyrrolidones having a molecular weight of at least about 10,000, preferably at least about 20,000 or 25,000, e.g. about 40,000 or more. Cross-linked polyvinylpyrrolidones are of particular interest. Examples of 25 specific products that can be used in the invention. components (c6) are: Plasdone XL, Plasdone XL 10 and Crospovidone.

When the compositions prepared by the process of the invention contain component (c1), they preferably also contain component (d), water-swellable or water-soluble, e.g. cellulose or a cellulose derivative as defined in (d2) above.

Further examples of such substances of particular interest in the compositions prepared by the process of the invention and containing component (c6) are those known under the trade names Avicel [cf. Fiedler, 1, p. 326] and Pharmacoat 97524 [cf. Fiedler, 2, p. 707] products, e.g., Avicel PH 101 and PH 102, Elcema and Pharmacoat 603.

If the compositions prepared by the process of the invention contain component (c6), component (a) is present in component (b) as a solid solution, e.g. as a solid micellar solution, e.g. as a completely or substantially completely molecular or micellar dispersion, [In practice, component (b) ) is often at least somewhat liquid, e.g., at room temperature or at a slightly elevated temperature, and is therefore not "solid" in the narrow sense. The term "solid solution", as used in this application and claims, is to be construed to include, e.g., viscose or a high viscosity system for 15 minutes.] A solid solution consisting of components (a) and (b) is preferably dispersed, e.g. in particulate form, e.g. in particular in the form of fine particles, e.g. entirely in component (c6). Component (c) thus acts as a degradable matrix [(a) + (b)] in the compositions prepared according to the invention. Components (d) usually function as substances that contribute to degradation, e.g. by contact with the contents of the gastrointestinal tract.

Compositions prepared by the process of the invention containing component (c6), incl. also preferably use component (e) as a binder and / or lubricant. Substances suitable for use as binders / lubricants include, in particular, fatty acids and alkyl sulfonate salts, e.g., metal salts, e.g., those having 10 or more carbon atoms in the fatty acid / alkyl moiety, e.g., C 1-22 fatty acid and C 10-22 alkylsulfonate; an alkali metal salt, e.g. sodium, calcium or magnesium salts. Examples of such substances suitable for use in the present invention include sodium lauryl sulfate and magnesium stearate [cf. Fiedler, 2 page 584].

97524 24

When the compositions prepared by the process of the invention contain component (c6), components (a) and (b) are suitably present in a ratio of about 1: 2 to 20, preferably about 1: 2.5 to 10, most preferably about 1: 3 to 5 8 [(a): (b)].

Components (c6) are suitably present in the compositions prepared by the process of the invention in an amount of at least 10% by weight, more preferably at least 15% by weight, even more preferably at least 20% by weight based on the total weight of the composition. Component (c6) is preferably present in the compositions according to the invention in an amount of from 10 to 60% by weight, more preferably from 15 to 50% by weight, e.g. about 20 to 40% by weight, e.g. about 25, 30 or 35% by weight. the total weight of the composition.

When component (d) is present, components (d) and (c6) are suitably present in a ratio of about 1: 0.5-4, more preferably about 1. 3, most preferably 1. 1.5-2.5, e.g. 1: 2 or about 1: 2.5 parts by weight [(d): (c®)].

When component (e) is present, components (e) 20 and (c6) are suitably in a ratio of about 1: 5-25, more preferably about 1: 5-20, most preferably Γ: 7-15 parts by weight [(e) : (c6)].

When the compositions prepared by the process of the invention contain all three components 25 (c), (d) and (e), these are suitably present together in an amount of about 25 to 75%, more preferably about 30 to 65%, most preferably about 40 to 65% based on the total weight of the composition. The ratios of the components [(a) + (b)]: [(c) + (d) + (e)] are preferably of the order of 1: 0.25 to 7.5, more preferably 1: 0.5-5, most preferably 1 : 0.5-2, e.g. about 1: 0.8, 1: 1.2 or 1: 1.3 parts by weight.

; Compositions prepared by the method of the invention containing component (c5) may be in any suitable dosage form, e.g. for oral, parenteral or topical use. Preferably, the compositions prepared by the method of the invention are in unit dosage form, either for oral or other administration.

The amount of component (a) present in such unit dosage form will, of course, vary with e.g.

5 conditions to be treated, the desired dosage form and the desired efficacy. Generally, however, they will contain from about 2 to about 200 mg of component (a), e.g., Ciclosporin per unit dose.

Suitable dosage forms for oral administration include granules and the like. However, solid unit dosage forms, e.g., tablets or capsules, are preferred. Such oral unit dosage forms suitably contain about 5 to 200 mg, more preferably about 10 or 20 to 100 mg, e.g. 15, 20, 25, 50, 75 or 100 15 mg, of component (a), e.g. Ciclosporin per unit dose. .

When component (c) in the compositions prepared by the process of the invention comprises: (c7) an organosilicon oxide polymer or liquid paraffin as defined in (vi), component (c) is preferably readily flowable at 150 ° C, preferably 100 ° C, more preferably 50 ° C. Suitable components (c7) have a maximum viscosity of 15,000 mPa.s., more preferably 1,000 mPa.s. at said temperatures.

Paraffinic hydrocarbons suitable for use as components (c7) are liquid and semi-solid paraffins or mixtures thereof, i. liquid paraffin [see Fiedler, 2, pp. 690 - 691]. To allow easy preparation, component (c7) 30 suitably consists entirely or substantially of liquid or semi-solid paraffin, i. liquid paraffin or mixtures thereof. However, if it is desired to prepare compositions having properties which affect the inhibition of the release of the active substance, this can be achieved by the addition of solid paraffin, i. Paraffin durum.

When the compositions prepared by the process of the invention contain liquid or semi-solid paraffins only as component (c), these are preferably present in a ratio of about 1: 0.5 to 1.0 [liquid: semi-solid]. In this case, components (a) and 5 (c7) are preferably present in a ratio of about 1: 6 to 200, more preferably about 1: 6 to 100, most preferably 1: 6 to 20, e.g. about 1: 8 parts by weight [( a): (c)].

When the compositions prepared by the process of the invention further comprise solid paraffin as component (c7), the ratio of liquid / semi-solid paraffin to solid paraffin components is preferably about 1: 0.06 to 0.1 parts by weight.

In this case, component (a) and (c7) are preferably present in a ratio of 1: 6 to 200, more preferably 1: 6 to 15,100, most preferably 1: 8 to 20, e.g. about 1:10 parts by weight. [(a): (c7)].

Organosilicon oxide polymers suitable for use as component (c7) contain in particular a liquid, i. liquid and semi-solid polymeric substances having a structural unit of the formula -R 2 Si-O-, in which each R is a monovalent organic radical, e.g. C 2-4 alkyl, in particular methyl or phenyl. Particularly preferred are organosiloxane polymers having a viscosity of about 25 to 0.65 to 10 cP, especially about 10 or 50 to 500 or 1,000 CP.

To allow easy preparation, component (c7) preferably contains liquid organosiloxane polymers, e.g. polymethylsiloxane polymers, e.g. any known silicone oil, such as silicone oil 550, DC 200, SF-1066 and SF-1091 [see

; Fiedler, 2, page 826]. When the compositions prepared by the process of the invention contain only organosiloxane polymers, components (a) and (c7) are suitably present in a ratio of about 1: 6 to 200, more preferably about 1: 6 to 100, most preferably 1: 6 to 20, e.g., about 1: 8 parts by weight [(a): (c7)].

97524 27

Compositions in which the active substance is slowly released can be obtained by using semi-solid organosiloxane polymers, e.g. any known silicone paste, e.g. silicone paste A [cf. Fiedler, 52, page 826] as a component (c7) or by adding them, e.g. to other organosilicon oxide polymers, as described above. In the latter case, the ratio of liquid: semi-solid organosilicone polymers present is suitably of the order of about 1: 0.5 to 10 1. In this case, the ratio between components (a): (c7) is preferably of the order of about 1: 6 to 100, preferably n. 1: 6 to 20 parts by weight [(a): (c7)].

It can be seen that mixtures of the defined components (c7) can also be used in the process according to the invention.

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

In case the compositions prepared by the process of the invention contain component (c7), component (a) is present in component (b) wholly or substantially entirely as a molecular or micellar dispersion, e.g. in the form of a solid solution or a solid micellar solution [where the term "solid solution" "is used in the same broad sense as for compositions such as component (c6)]. The solid solution consisting of (a) and (b) is preferably dispersed in a particulate form, e.g. in the form of fine particles with component (c7), e.g. throughout component (c7).

The method of the invention can be used to prepare compositions comprising component (c7) in any suitable dosage form, e.g. for oral, parenteral or topical use, e.g. for dermal or ophthalmic use, e.g. for application to the surface of the eye, e.g. for autoimmune conditions of the eye. for treatment as described above or for intralesional injections, e.g. for the treatment of psoriasis. Preferably, they are prepared in unit dosage form, either for oral administration or otherwise.

The amount of component (a) in such unit dosage forms will, of course, vary with the condition being treated, the intended dosage form and the desired potency. In general, however, unit doses will preferably contain from about 2 to about 200 mg of component (a), e.g., Ciclosporin per unit dose.

Suitable dosage forms for oral administration include solutions, granules and the like. More preferred are solid unit dosage forms, e.g. tablets or capsules, especially hard or soft gelatin capsules. Such oral unit dosage forms preferably contain about 5 to 200 mg, more preferably about 10 or 20 to 100 mg, e.g. 15, 20, 25, 50, 75 or 100 mg of component (a), e.g. Ciclosporin per unit dose.

Compositions of component (c7) prepared by the process of the invention have the additional advantage that they can form the basis of compositions with modified release properties, e.g., delayed release of component (a) or release of component 25 (a) over an extended period of time, e.g. after oral administration. Such compositions can be obtained, as described above, using appropriate amounts of solid or semi-solid components (c7). Alternatively, they can be obtained using additional component (d); a component that can modify the release properties of the composition relative to component (a). Such components (d) contain, for example, polymeric fillers, in particular thickeners, e.g. polymeric or colloidal thickeners, and substances which may swell in water, e.g. water-swellable polymers or colloids, e.g. one of (d1) to (above). d5) of the specified 29,97524 substances.

When component (d) is present, it is preferably about 0.5 to 30%, more preferably about 1 to 20%, most preferably about 1 to 10%, based on the components (a) + (b) + 5 (c7) + (d) of total weight.

Components (d5) are particularly indicated for use in compositions prepared by the process of the invention which contain an organosilicone oxide polymer as component (c7).

Compositions prepared by the process of the invention which contain component (c6) or (c7) should be, or are preferably anhydrous or substantially anhydrous, e.g. as described above, relative to other compositions consisting of the other components (c).

Compositions prepared by the process of the invention may, with the exception of selected component (c) [e.g. either component (c) comprises any of components (c1) to (c7) as described above or a mixture thereof] contains each additive, e.g. which is known and commonly used in the art, e.g. an antioxidant [e.g. ascorbyl palmitate, tocopherols, butylhydroxyanisole (BHA) or butylhydroxytoluene (BHT)] flavoring agent and so on.

In particular by the method according to the invention. the compositions prepared also preferably contain one or more stabilizers or buffers, in particular to prevent the hydrolysis of component (b) or the degradation of component (a) during preparation and storage. Such stabilizers may include acid stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid, as well as basic stabilizers such as potassium hydrogen phosphate, glycine, lysine, arginine or tris (hydroxymethyl) α-35 minomethane.

Such stabilizers or buffers are preferably added in amounts sufficient to effect or maintain the pH in the range of about 3 to 8, more preferably about 5 to 7, e.g., 6 to 7. Such stabilizers are generally present in amounts up to 5% by weight, based on the total weight of the composition, or 10% by weight, e.g. when citric or acetic acid is used. Preference is given to compositions prepared by the process according to the invention, in particular compositions in which component (a) is Ciclosporin and whose pH is in the above-mentioned range.

The compositions prepared by the process of the invention also preferably contain a polyoxyalkylene-free surfactant, such as, for example, dioctyl succinate, dioctyl sulfosuccinate, di [2-ethylhexyl] succinate, sodium lauryl sulphate or phospholipids, e.g. lecithins. When a surfactant is present, this is suitably 5 to 50, more preferably 10 to 50, e.g. 10-25% by weight of component (b).

In the case that the compositions prepared by the process of the invention contain component (a) as a solid solution in component (b), e.g. when component (c) is component (c6) or (c7) as described above, any stabilizer, buffer and / or a surfactant, as described above, may be included in the solid solution phase. Such substances can be included in component (c), etc.

The compositions prepared by the process of the invention, with the exception of selected component (c), are free or substantially free of ethanol, e.g. containing less than 5.0%, more preferably less than 30%, e.g. 0-1% ethanol based on the total weight of the composition.

The present invention thus provides a process for preparing a pharmaceutical preparation as defined above, which process comprises intimately mixing or blending components 35 (a), (b) and (c), as defined above, together with component (d) and / or another component, if desired. , e.g., a stabilizer, buffer, or surfactant, as described above, and, if necessary, formulating the resulting composition into a unit dosage form, e.g., a unit dosage form for oral administration, e.g., by tableting, filling into gelatin capsules, or other suitable methods.

When component (c) is a solvent for components (a) and (b) or contains component (c1), (c1), (c1), (c4) or (c5) as defined above, components 10 (a), ( b) and (c) are suitably combined by the above-mentioned method by dissolving components (a) and (b) together in component (c), e.g. by heating to 50 or 150 ° C, preferably not more than 70 or 75 ° C. The mixture thus obtained can be further mixed with the components (d), etc.

15, e.g. by thorough mixing according to methods known in the art. Filling, e.g., hard or soft gelatin capsules, is preferably performed at an elevated temperature, e.g. 50 ° C, whereby the composition is obtained, e.g. by heating.

When the compositions of matter according to the invention contain component (a) as a solid solution in component (b), e.g. when the compositions of composition contain component (c6) or (c7) as defined above, said process preferably first prepares a solid solution (a) and (b) followed by mixing or blending the resulting solid solution with the remaining components (c), and optionally (d), etc.

Solid solutions containing components (a) and (b) may be prepared according to methods known in the art, e.g., by solidifying a melt containing (a) dissolved in (b) or by removing the solvent from components (a) and (b). ) solution. In view of the purpose of the present invention, the latter alternative is generally preferred.

Suitable solvents for components (a) and (b) are lower alkanols, e.g. ethanol. Stabilizers, buffers and / or surfactants are preferably added in the solution step.

The solid solution thus obtained is then preferably mixed, e.g. in fine form, with component 5 (c), and optionally with components (d) and (e), etc., e.g. by mixing with component (c).

Although ethanol can be used in the process of the invention, e.g. in the preparation of solid solutions as described above, this is preferably removed, e.g. by evaporation, before the final dosage form is prepared to give an ethanol-free or substantially ethanol-free product as described above.

The following examples illustrate the present invention.

The sucrose monolaurate product L-1969 used in the examples is commercially available from Mitsubishi-Kasei Food Corp., Tokyo 104, Japan: HLB value is at least 12.3: lauryl ester residue is at least 95% pure: M.p. is about 35 ° C: decomposes at about 235 ° C: surface tension with 0.1 wt% aqueous solution is about 72.0 dynes / cm at 25 ° C.

EXAMPLES

Ingredients Relative amount 25 (mg) 1. a) Cyclosporin 50.0 (eg Ciclosporin) b) Sucrose monolaurate L-1695 312.5 c) 1,2-propylene glycol 100.0 30

Total 462.5 1

II

a) Cyclosporin 50.0 (e.g. Ciclosporin) 35 b) Sucrose monolaurate L-1695 321.5 c) Glycerol 100.0

Total 462.5 97524 33 3. a) Cyclosporine 50.0 (e.g. Ciclosporin) b) Sucrose monolaurate L-1695 312.5 c) PEG 200 _100.0 5 Total 462.5 4. a) Cyclosporine 50.0 (e.g. Ciclosporin) b) Sucrose monolaurate L-1695 312.5 c) PEG 400 _100.0 1 0 Total 462.5 5. a) Cyclosporin 50.0 (eg Ciclosporin) b) Sucrose monolaurate L-1695 350.0 c) 1 , 2-propylene glycol 100.0 d) Eudragit E50.0

Total 550.0 6. a) Cyclosporin 50.0 (eg Ciclosporin) b) Sucrose monolaurate L-1695 350.0 20 c) 1,2-propylene glycol 100.0 d) Methocel K1 00 110.0

Total 610.0 7. a) Cyclosporin 50.0 (Eg Ciclosporin) 25 b) Sucrose monolaurate L-1695 350.0 c) 1,2-propylene glycol 100.0 d) Aerosil 200 _15.0

Total 515.0 30 8. a) Cyclosporine 50.0 (eg Ciclosporin) b) Sucrose monolaurate L-1695 350.0 c) PEG 400 200.0 35 d) Eudragit L _2.5

Total 602.5 97524 34 9. a) Cyclosporine 50.0 (e.g. Ciclosporin) b) Sucrose monolaurate L-1695 312.5 c) Gelucir (e.g. Gelucir 42/12, 5 44/1 4 or 35/10 _100. 0

Total 462.5 10. a) Cyclosporin 50.0 (eg Ciclosporin) b) Sucrose monolaurate L-1695 312.5 10 c) Gelucir 100.0 d) Klucel LF _50.0

A total of 512.5

The composition of Example 1 was prepared by dissolving-15 components of components (a) and (b) with stirring and heating in an oil bath, 100 ° C, to component (c). The compositions of Examples 2-10 were prepared analogously. In the cases of Examples 5 and 8, component (d) was dissolved in the initial mixture of components (a) to (c). In the case of pre-20 marks 6, 7 and 10, component (d) was suspended in components (a) to (c).

The resulting compositions were added with heating to hard gelatin capsules, size 1 (Examples 1 to 4 and 9) or size 0 (Examples 5 to 7 and 10) to give an encapsulated final product, and each capsule contained 50 mg of cyclosporin (e.g. Ciclosporin) and was suitable for administration to prevent rejection of transplanted organs or for the treatment of autoimmune diseases, e.g. by administering 1 to 5 capsules per day.

30 35 i <35 97524 EXAMPLES

Ingredients Relative amount (mg) 11. a) Cyclosporine 100.0 5 (eg Ciclosporin) b) Sucrose monolaurate L-1695 300.0 c) Plasdone XL 350.0 d) Avicel PH 102 150.0 e) Sodium lauryl sulfate _25.0 10 Total 925.0 12. a) Cyclosporine 50.0 (eg Ciclosporin) b1) Sucrose monolaurate L-1965 350.0 b2) Sucrose monostearate 50.0 15 c) Crospovidone 250.0 d) Elcema 150.0 e) Magnesium stearate _30 .0

Total 980.0 13. a) Cyclosporine 50.0 20 (e.g. Ciclosporin) b) Sucrose monolaurate L-1965 160.0 c) Plasdone XL 10 200.0 d1) Pharmacoate 603 25.0 d2) Avicel PH 101 75.0 25 e) Magnesium stearate _20.0

A total of 605.0

Each of the above compositions 11 to 13 preferably further contained 25 mg (f) of tartaric acid and / or 50 mg (g) of dioctyl succinate, preferably 30 each, the final weights being: composition 11 1000 mg; composition 12 1.055 mg; and composition 13 6180 mg.

Compositions 11-13 were prepared as follows. Components (a) and (b) were dissolved in absolute ethanol, and the ethanol was completely evaporated at 50 ° C under reduced pressure. Components (c) - (e) were mixed completely [adding (f) and (g) when used] using 97524 36 using conventional mixing methods. A solid solution containing [(a) + (b)] was ground to a fine powder and mixed uniformly with [(c) - (g)], and from the resulting uniform mass, tablets each containing 100, 50 or 25 mg of (a) were compressed. and is suitable for administration to prevent rejection of transplanted organs or for the treatment of autoimmune diseases, e.g. by administering 1 to 5 tablets per day.

10 EXAMPLES

Ingredients Relative amount (mg) 14. a) Cyclosporine 50.0 (eg Ciclosporin) 15 b) Sucrose monolaurate L-1695 312.5 c) Liquid paraffin _397.5

Total 760.0 15. a) Cyclosporin 50.0 (e.g. Ciclosporin) 20 b) Sucrose monolaurate L-1695 312.5 c) Silicone oil DC 200 397.5

A total of 760.0

Components (a) and (b) were dissolved in absolute ethanol, and the ethanol was completely evaporated at 50 ° C under reduced pressure. The resulting solid solution was ground to a fine powder and uniformly suspended in component (c). The resulting liquid suspension was filled into hard gelatin capsules, size 0, to give an encapsulated final product, each capsule containing 50 mg of cyclosporin (e.g. Ciclosporin) and suitable for administration to prevent transplant rejection or in the treatment of autoimmune diseases, e.g. 1-5 capsules per day. 97524 37 EXAMPLES

Ingredients Relative amount (mg) 16. a) Cyclosporine 50.0 5 (eg Ciclosporin) b) Sucrose monolaurate L-1695 312.5 c) Paraffin sub-liquid 372.5 d) Paraffin durum _25.0

Total 760.0 10 17. a) Cyclosporine 50.0 (eg Ciclosporin) b) Sucrose monolaurate L-1695 312.5 c) Liquid paraffin 397.0 d) Aerosil _10.0 15 Total 770.0

Compositions 16 and 17 were prepared analogously to compositions 14 and 15 as described above. In preparing composition 16, first (c) and (d) were combined by melting and mixing together. A solid solution containing [(a) + (b)] was then suspended [(c) + (d)]. In the preparation, composition 17 (d) was suspended together with [(a) + (b)] in (c).

Equivalent compositions with those shown in Examples 1 to 25 17 can be prepared by replacing: as component (a) of Ciclosporin with any cyclosporin, e.g. [Nva] 2-Ciclosporin, or by replacing sucrose monolaurate as component (b) with any fatty acid saccharide monoester, e.g. as described above, e.g. in each case by the same or an equivalent amount or a relative amount.

The utility of the compositions prepared by the method of the invention can be demonstrated in animal or clinical trials, as described, for example, below.

97524 38

BIODAYABILITY STUDIES OF COMPOSITIONS PREPARED BY THE METHOD OF THE INVENTION IN DOGS

a) Test Compositions 5 Composition I as in Example 1

Composition II 14 (b) Test method

8 groups of beagle dogs (males, approx.

11 - 13 kg). The animals were given no food for 18 h 10 prior to administration of the test composition, but all had free access to water until drug administration. The test compositions were administered by gavage, followed by 20 ml of 0.9% NaCl solution. Animals were allowed to eat and drink freely for 3 h after administration of the test dose.

15 2 ml blood samples (or 5 ml for comparison) were taken from the dermal vein of the upper arm and collected in 5 ml plastic tubes containing EDTA for -15 min (comparison), 30 min, and 1, 1.5, 2, 3, 4, 6 , 8, 12 and 24 h after dosing. Blood samples were stored at 20-18 ° C until assay.

Blood samples were analyzed by the R1A method. The areas between the blood drug concentration curve and the time curve were calculated using the trapezoidal rule. Analysis of variance was performed for AUC (area under the curve), Cmax 25 (maximum concentration) and Tmax (maximum time).

c) Results

The calculated mean AUC (ng h / ml-1) and Cmax (ng / ml_1) from typical experimental runs are shown in the following table, together with the calculated response variability for the 30 animals receiving the same composition (CV).

Composition AUC CV (%) Cmax CV% (0-24h) 35 I 3058 19.9 583 30.9 II 2894 14.91 544 19.7 97524 39

As can be seen from the table above, the compositions prepared by the method of the invention had a high bioavailability (AUC and Cmax.) Together with a relatively low variability in substance response in terms of AUC and Cmax.

Comparable useful results were obtained using other compositions of Examples 1-17, especially the compositions of Examples 1-10.

10 CLINICAL TRIALS

The beneficial properties of the compositions prepared by the method of the invention, especially for oral administration, can be demonstrated in clinical trials, e.g., as follows: Subjects were adult volunteers, e.g., trained males between 30 and 55 years of age. The experimental groups included 12 people.

The following criteria were applied for inclusion / exclusion in the experiment.

20 Included: normal ECG screening; nor paint blood pressure and heart rate; weight 50 - 95 kg.

Excludes: a clinically significant non-persistent medical condition that could interfere with the absorption, distribution, metabolism, excretion, or safety of a drug; symptoms of significant clinical disease during the two weeks prior to the trial; clinically significant abnormal laboratory values or electrocardiograms; the need for concomitant medication during the experiment; taking a drug during the 3 months prior to the experiment in which the drug is known to have identified potential organ toxicity; taking an investigational drug within 6 weeks before starting the experiment; drug or alcohol abuse; 35 500 ml or more of blood lost in the previous 3 months before the experiment; adverse drug reaction or hypersensitivity; allergies that require medication; 97524 40

Hep, -B / HIV positivity.

A complete physical examination and ECG were performed before and after the experiment. The following parameters were calculated over a 1-month period before and after the experiment: 5 - Blood: red blood cell count, hemoglobin, hematocrit, erythrocyte sedimentation, white blood cell count, smear sample, platelet count, and glucose fasting; - Serum / plasma: total protein and electrophoresis, cholesterol, triglycerides, Na +, K +, Fe ++, Cl-creatine, urea, uric acid, SGOT, SGPT, -GT, alkaline phosphatase, total bilirubin, α-amylase; - Urine: pH, microalbumin, glucose, erythrocytes, 15 ketones, sediment.

Creatinine clearance was also determined 1 month before the start of the experiment.

Subjects received the test composition in random order. The compositions were administered orally, in 20 single doses up to a total dose of 150 mg cyclosporin, e.g. Ciclosporin, and doses were administered at least every 14 days.

The drug was administered in the morning, after an overnight fast of 10 h, with water only. Only 25 decaffeinated beverages were allowed during the next 24 h following drug administration. Bodies were not allowed to smoke for 12 h after drug administration. Subjects received a standardized lunch 4 h after drug dosing.

Blood samples (2 ml) were taken 1 h before dosing and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 9, 12, 14, 24, 28 and 32 h after dosing. To determine creatinine, 2 ml blood samples were taken immediately before dosing and 12, 24 and 35 48 h after dosing. Samples for cyclosporin assays were collected in two EDTA-coated polystyrene tubes (1 mL each) at each time point 97524 41, the tubes were frozen after stirring at -20 ° C. Cyclosporine was determined from a whole blood sample using an RIA-specific and / or non-specific MAB assay. The detection limit in each case was approximately 10 ng / ml.

The experiments were performed as described above, e.g. by comparing the composition of Example 1 in hard gelatin capsule form with the Ciclosporin drinking solution in use (Ciclosporin 50 mg, Labrafil 150 mg, ethanol 50 mg, corn oil 213 mg, soft gelatin-10 capsule form: content and weight 463 mg / dose) as a standard, substantially increased bioavailability levels for the composition of Example 1 were obtained by comparison with the standard, comparing both AUC (0-32 h) and Cmax. In addition, in an experiment to monitor the variation in whole blood Ciclosporin concentration as a function of time (as determined by specific monoclonal RIA), the effect of test composition and 150 mg cyclosporine was monitored, showing a clear decrease in response variability in all subjects receiving Example 20 1. who received a standard composition.

Similar or equivalent results may be obtained with other compositions prepared by the method of the invention when administered orally, as set forth in the Examples above.

Claims (10)

A process for the preparation of a pharmaceutical composition which comprises cyclosporin as an active ingredient, characterized in that (a) cyclosporin is mixed in or joined with (b) fatty acid saccharide monoester and (c) a diluent or carrier substance, wherein (i) component (c) is used as the solvent for components (a) and (b), and components (a) and (b) each independently have a solubility of at least 10% in component (c). ) at rescue temperature; and / or (ii) component (c) is used as a solvent for components (a) and (b), and that the mixing ratio of components (a) and (c) is 1: 0.5-50 parts by weight [(a): ( c)]; and / or (iii) component (c) is used as a solvent for components (a) and (b), and the so obtained composition is formulated into a solid unit dosage form suitable for oral administration; and / or (iv) component (c) contains poly- (C2-4 alkylene) glycol, whose average molecular weight is at most 7000 or viscosity at 50 ° C is at most 15000 mPa.s. or it 1 contains C3-5 alkylene polyol ether or ester; and / or (v) the obtained composition is anhydrous or substantially anhydrous; and / or (vi) component (c) contains a solid polymeric carrier, organosilicon oxy polymer or liquid paraffin and in the obtained composition, component (a) comprises as a solid solution in (b). A process according to claim 1, characterized in that component (c) is selected from a group to which (c1) ethanol (c2) C2_4alkylene glycols 97524 (c2) C3_5 alkylene polyols (c4) poly (C2_4 alkylene) glycols and mixture of them, wherein the (ii) components (a) and (c) mixing ratio are 1: 0.5-50 parts by weight [(a): (c)]; and / or (iii) the resulting composition is formulated into a solid unit dosage form suitable for oral administration; and / or (iv) component (c) contains component (c4), whose average molecular weight is at most 7000 or viscosity at 50 ° C is at most 15000 mPa.s .; and / or (v) the obtained composition is anhydrous or substantially anhydrous. 3. A process according to claim 1 or 2, characterized in that component (c) is (c2) 1,2-propylene glycol, wherein (ii) the mixing ratio of components (a) and (c2) is 1: 0.5: 50 parts by weight [ (a): (c2)]; and / or (iii) the resulting composition is formulated into a solid unit dosage form suitable for oral administration; and / or (v) the obtained composition is anhydrous or substantially anhydrous. Process according to any of claims 1 to 3, characterized in that the mixing ratio of components (a) and (b) is 1: 3 - 200 parts by weight [(a): (b)]. 5. A process according to claim 1, characterized in that a composition is prepared wherein cyclosporin (a) is included as a solid solution in the fatty acid saccharide monoester (b) and component (c) is component (c ) a solid polymeric carrier containing polyvinylpyrrolidone. 6. A process according to claim 5, characterized in that the mixing ratio of components (a) and (b) is 1: 2 - 20 parts by weight [(a): 97524 (b)] and of component (c®) is mixed in at least 10 wt. -% calculated on the total weight of the composition. Process according to any one of claims 1 to 6, characterized in that the composition is brought into a unit dosage form containing 2 -200 mg of component (a) per unit dose. 8. A process according to claim 1, characterized in that component (c) is (c) 1,2-propylene glycol, wherein the blend ratio of components (a) and (b) is 1: 3 to 200 parts by weight [(a): (b)] and the blend ratio of components (a) and (c) is 1: 0.5 - 50 parts by weight [(a): (c)], and the resulting composition is formulated into a unit dosage form which contains ca. 20 - 100 mg of component (a) per unit dose. Method according to any of claims 1-8, characterized in that the component (a) is Cyclosporin or [Nva] 2-Cyclosporin. Process according to any one of claims 1 to 9, characterized in that the component (b) contains raffinose or sucrose monolaurate.