DK176209B1 - Cyclospore formulation - Google Patents

Description

and DK 176209 B1

The present invention relates to novel galenic formulations comprising a cyclosporin as active ingredient.

The cyclosporins comprise a class of structurally characteristic, cyclic, poly-N-methylated endecapeptides which normally have pharmacological, in particular immunosuppressive, anti-inflammatory and / or anti-parasitic activity. The first cyclosporin to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclo-10 sporine, also known as cyclosporin A and commercially available under the registered trademark SANDIMMUN® or SANDIMMUNE®. Ciclosporin is the cyclosporin red formula A

-MeBmt-ccAbu-Sar-MeLeu-Val-MeLeu-Ala- (D) Ala-MeLeu-MeLeu-MeVal- 1 2 3 A 5 6 7 8 9 10 11

wherein -MeBmt- represents N-methyl- (4R) -4-but-2E-en-1-yl-4-15 methyl- (L) threonyl residue of formula B

CH3 x y \ XCH2 (B)

H0 (R) ^^ CH

-N-CH-CO- (S) ch 3 where -x-y- is -CH = CH- (trans).

2 DK 176209 B1

As the parent compound of the class, Ciclosporin has so far received the most attention. The primary areas of clinical study of Ciclosporin have been as an immunosuppressive agent, especially in relation to its use in recipients of 5 organ transplants, eg heart, lung, combined heart-lung, liver, kidney, pancreas, bone marrow, , skin and corneal transplants, and especially allogeneic organ transplants. In this field, Ciclosporin has achieved a remarkable success and a remarkable reputation.

At the same time, the applicability of Ciclosporin to various autoimmune diseases and to inflammatory conditions, in particular inflammatory conditions with an etiology comprising an autoimmune component, eg arthritis (eg rheumatoid arthritis, chronic progressive arthritis and arthritis deformans) and rheumatic diseases, has been intensive, and reports and results in vitro, in animal models and in clinical trials are widespread in the literature. Specific autoimmune diseases for which Ciclosporin therapy has been proposed or used include autoimmune haematological disorders (including, for example, haemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondositis, granchondritis, , chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel syndrome (including ulcerative colitis and Chrohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), kerato-30 conjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, eg including idiopathic nephrotic syndrome or minimal ti).

DK 176209 B1 3

Additional areas of study have been possible suitability as an antiparasitic, especially antiprotozoal agent, with possible proposed uses including treatment of malaria, coccidiomycosis and schistosomiasis and, more recently, use in cancer therapy, eg as a means of reversing or abolishing resistance to other antineoplastic or cytostatic therapy.

Since the initial discovery of Ciclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified, and many other non-naturally occurring cyclosporins have been prepared by total synthetic or semi-synthetic means or using modified culture techniques. The class constituted by cyclosporins is now significant and includes, for example, the naturally occurring cyclosporins A-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 and Biotechnology 14, 273-340 (1982); and von Wartburg et al., 20 Progress in Allergy, 38, 28-45 (1986)] as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins, including the so-called dihydro-cyclosporins [wherein -MeBmt- residue group -xy- ( formula B above) is saturated to form -xy- = -CH 2 -CH 2 -]; 25 derived cyclosporins (e.g. where an additional substituent is introduced at the α-carbon atom of the sarcosyl residue at the 3-position of the cyclosporin molecule); cyclosporins where the -MeBmt residue is present in isomeric form (eg where the configuration over positions 6 'and 7' of the -MeBmt- residue is cis instead of trans); and cyclosporins, wherein varying amino acids are incorporated at specific positions within the peptide sequence, e.g., using the total synthetic method for producing cyclosporins developed by R.

Wenger - see eg Traber 1, Traber 2 and Kobel loc. cit .; OS 4,108,985, US 4,210,581 and US 4,220,641; EP 0.034,567, EP 0.056,782 and EP 0,296,122; WO 86/02080; Wenger 1,

Transp. Proc. 15, Suppl. 1: 2230 (1983): Wenger 2, Angew.

4 DK 176209 B1

Chem. Int. Ed., 24., 77 (1985); and Wenger 3, Progress in the Chemistry of Organic Natural Products 50, 123 (1986).

Thus, the class constituted by the cyclosporins now includes, for example, [Thr] 2-, [Val] 2-, [Nva] 2- and [Nva] 2- [Nva] 5- 5 Cyclosporin (also known as cyclosporins and C, respectively) D, G and M) [3'-O-acyl-MeBmt] ^ Cyclosporin (also known as cyclosporin A-acetate), [dihydro-MeBmt] [Val] 2-Cyclosporin (also known as dihydro-cyclosporin D), [ 3'-deoxy-3'-oxo-MeBmt] · * [Val] 2- and - [Nva] 2-Cyclosporin, [(D) fluoromethyl-Sar] 4 -Ciclosporin, [(D) Ser] 8-Cyclosporin , [Melle]-'-'-- Ciclosporin [(I) MeVal] -'-'-- Ciclosporin (also known as cyclosporin H), [MeAla] ^ - Ciclosporin, [(D) Pro] 3-Cyclosporin etc.

[In accordance with the applicable conventional nomenclature for cyclosporins, these are defined with reference to the structure of Ciclosporin (ie Cyclosporin A). This is done by first indicating the amino acid residues present that differ from those present in Ciclosporin (eg "[(D) Pro] 3" to indicate that the cyclosporin in question has a - (D) Pro- residue instead of -Sar- residue 20 in the 3-position) and then to use the term "Ciclosporin" to characterize the other residues identical to the residues present in Ciclosporin. Individual residues are numbered beginning with the residue -MeBmt-, -dihydro-MeBmt- or the equivalent thereof in position 1.]

Many of these additional cyclosporins exhibit pharmaceutical utility similar to Ciclosporin or more specifically utility, e.g., activity specifically in reversing tumor resistance to cytostatic therapy, and the literature is replete with suggestions for their use as therapeutic agents.

Despite the very large contribution that Ciclosporin has made, especially in the areas of organ transplantation and therapy of autoimmune diseases, the difficulties encountered in providing more effective and appropriate modes of administration as well as the reported occurrence of undesirable side effects , especially nephrotoxic reaction, has been a serious impediment to its more widespread use or application. The cyclosporins are characteristically highly hydrophobic. Proposed liquid formulations, e.g. for oral administration of cyclosporins, have so far been primarily based on the use of ethanol or oils or similar excipients as carrier substrates. Thus, the commercially available Ciclosporin drinking solution uses ethanol and olive oil as a carrier substrate together with labrafil as a surfactant - see, for example, US 4,388,307. However, the use of the beverage solution and similar compositions proposed in the art has been accompanied by various difficulties.

First, the need to use oils or oil-based carriers can give the compositions an unpleasant taste or otherwise reduce good taste, especially with respect to long-term therapy. These effects can be masked by presentation in the form of gelatin capsules. However, in order to maintain the cyclosporin in the solution, the ethanol content must be kept at a high level. Evaporation of the ethanol, eg from capsules or from other forms, eg when opened, results in the development of a cyclosporin precipitate. When such compositions are presented in the form of, for example, soft gelatin capsules, this particular difficulty necessitates packaging the encapsulated product in an airtight space, for example in an airtight bladder or an aluminum foil bladder package. Consequently, this makes the product both bulky and more expensive to produce. The storage properties of the above formulations are far from ideal.

Bioavailability levels obtained using existing oral cyclosporine dosing systems are also low and show great variation between individuals, individual patient types and even for individual individuals at different times during the course of therapy. Thus, reports in the DK 176209 B1 6 literature suggest that currently available therapy using the commercially available Ciclosporin drinking solution provides an average absolute bioavailability of only approx. 30% with clear variation between individual groups, eg between recipients of liver transplants (relatively low bioavailability) and bone marrow transplants (relatively high bioavailability).

The reported variation in bioavailability between patients has ranged from anywhere from one or a few 10 percent for some patients to up to 90% or more for others. As already mentioned, a clear change in bioavailability is often observed over time for individuals.

To achieve effective immunosuppressive therapy, cyclosporin blood or blood serum levels must be maintained within a specified range. The required range may again vary depending on the particular condition being treated, eg whether therapy should prevent transplant rejection or control an autoimmune disease, and whether or not alternative immunosuppressive therapy is used concurrently with cyclosporine therapy. Due to the large variations in bioavailability levels obtained with conventional dosage forms, the daily doses required to achieve required blood serum levels also vary considerably from individual to individual and even for a single individual. Therefore, it is necessary to monitor blood / blood serum levels in patients receiving cyclosporine therapy at regular and frequent intervals. Monitoring of blood / blood serum levels normally performed by RIA or similar immunoassay technique, eg using monoclonal antibody-based technology, should be performed regularly. This control is necessarily time consuming and inappropriate and contributes significantly to the overall cost of the therapy.

In addition to all these very clear practical difficulties, there are undesirable side effects, as already indicated, which side effects are observed using available oral dosage forms.

DK 176209 B1 7

Various suggestions for solving such problems have been mentioned in the art, including both solid and liquid oral dosage forms. Japanese Patent Application No. 71682/1985 by Takada et al. thus proposes the use of agents for increasing the release of cyclosporins to the lymphatic system, specifically by administration in conjunction with surfactants. A general list of surfactants that can be used includes sucrose, fatty acid esters, eg sucrose oleate, palmitate or stearate, as well as other fatty acid esters, especially sorbitan fatty acid esters such as sorbitanolate, palmitate or stearate. While the use of both mono- and polyesters is mentioned, it is suggested that mono- or diesters be preferred. Other said surfactants include polyoxyethylated hydrogenated vegetable oils such as the products known and commercially available under the trade names Cremophore RH and Nikkol HCO 60, and these products are clearly stated to be preferred, for example over the said sucrose ester surfactants.

Example 3 of the above Japanese application describes obtaining an aqueous composition comprising a sucrose fatty acid ester identified as F160 as a surfactant component. The preparation comprises 3.5 mg Ciclosporin and 2 mg sucrose ester in 1 ml H2O. To obtain dispersion of the Ciclosporin, sonication for 5 minutes at 100 W is required.

The obtained preparation, described as "a transparent solution", is used directly in animal models for the study of relative lymphatic resorption. Given the very low solubility of Ciclosporin in H 2 O and the small amount of surfactant used, it is clear that the claimed solution is an artifact of the sonication process. The concentration of Ciclosporin obtained is not only inappropriately low, for example for an oral dosage form, but the preparation is itself unstable and therefore de facto excluded as a practical or commercially galenic form of any type. It is essentially an experimental DK 176209 B1 8 system that enables laboratory investigations and nothing else. There is no suggestion of using surfactants in any context other than in relation to charge to the lymphatic system.

Japanese Patent Application 193129/1987 (Publication No.

038029/1989), also by Takada et al., Discloses powdered compositions comprising a Ciclosporin dispersed in a solid, non-surfactant carrier phase, for example comprising sucrose, sorbitol, tartaric acid, urea, cellulose acetate phthallate, methacrylic acid / methylmethacrylic acid thyl hydroxyl , together with minor amounts of surfactant. The surfactant is added again for the purpose of increasing charge to the lymphatic system, and in this context the application is clearly directed to the provision of a deliberate practical means for applying the teachings of the above-mentioned Japanese patent application 71682/1985. Reference to sucrose esters as possible surfactant components is omitted in this case. Reference to sorbitan esters among a list of possible surfactant components is retained. Products of

However, the Nikkol HCO 60 type is again indicated as being preferred as a surfactant, and Nikkol HCO 60 is the only surfactant used in the examples. There is no evidence that the alleged increase in charge to the lymphatic system provides any practical benefit or solves any of the difficulties hitherto encountered in the field of cyclosporin therapy, e.g., as discussed above.

The present invention provides novel galenic cyclosporin formulations comprising fatty acid saccharide monoesters as primary carrier components, which solve or substantially reduce the difficulties hitherto encountered in the field of cyclosporin, eg Ciclosporin, therapy. In particular, it has been found that the compositions of the invention enable the preparation of solid, semi-solid and liquid compositions containing a cyclo-sporin in a sufficiently high concentration to enable, for example, convenient oral administration, while at the same time improving effect, eg with respect to bioavailability characteristics.

In particular, it has been found that compositions of the present invention enable effective cyclosporine dosing while increasing resorption / bioavailability levels as well as reduced variability in achieved resorption / bi-inaccessibility levels both for individual patients receiving cyclosporin therapy and between individuals. . Using the teachings of the present invention, cyclosporin dosage forms can be obtained that reduce the variability in achieved cyclosporin blood / blood serum levels between doses for individual patients as well as between individuals / individual patient groups. The invention thus enables the reduction of the cyclosporine dose levels required to achieve effective therapy. In addition, the invention enables closer standardization as well as optimization of ongoing daily dosing requirements for individual patients receiving cyclosporine therapy, as well as for groups of patients undergoing similar therapy.

By closer standardization of individual patients' dose level and blood / blood serum level response as well as dosage and response parameters for patient groups, control requirements can be reduced, thereby significantly reducing therapy costs.

In reducing required cyclosporin dosing / standardization of bioavailability characteristics obtained, the present invention also provides an agent that enables reduction in the incidence of undesirable side effects, particularly nephrotoxic reaction, in patients undergoing cyclosporin therapy.

In addition, the present invention enables the preparation of compositions which are not alkanol-based, for example which may be free or substantially free of ethanol. Such compositions avoid stability difficulties and related process difficulties as described above, which difficulties naturally belong to known alkanolic compositions. The invention thus relates, inter alia, to compositions which are more suitable for, for example, presentation in capsule form, for example in the form of hard or soft gelatin capsules, and / or which remove or substantially reduce packaging difficulties, for example as described above, for example for soft gelatin capsules.

In particular, the present invention relates to:

A pharmaceutical composition comprising a) a cyclosporin as active ingredient, b) a fatty acid saccharide monoester and c) a diluent or carrier, wherein i) component (c) is a solvent with respect to both component (a) and (b) , components (a) and (b) each independently having a solubility in component (c) of at least 10% at ambient temperature; Or ii) component (c) is a solvent with respect to both components (a) and (b), and components (a) and (c) are present in the composition in a weight ratio of 1: 0.5 to 50 [(a) ) :( c)]; or iii) component (c) is a solvent with respect to both components (a) and (b), and the composition is formulated in solid unit dosage form suitable for oral administration; or iv) component (c) is a poly- (C 2-4 alkylene) glycol having an average molecular weight of at least 7000 or a viscosity at 50 ° C of not more than 15,000 mPa.s or comprises a C 3-5 alkylene polyol ether or ester or DK 176209 B1 11 v) the composition is non-aqueous or is substantially non-aqueous; or vi) component (c) comprises a solid polymer support, an organo-silica polymer or paraffin per- or subliquidum, and component (a) is present in the preparation in solid solution in (b).

The compositions thus defined are novel and particularly advantageous variants of those generically described in French Patent Application No. 88 11953 and similar applications in other countries worldwide, including USSN 07/243 577, DOS 38 304945, Japanese Application No 231 396/88 and GB Application No 88 21443.9 (first publication in France, 17 March 1989 under No 2,620,336).

Definitions (i) - (vi) above shall be understood as meaning that the 15 are not mutually exclusive. The compositions of the invention thus comprise compositions as defined according to any one or more of the defined constraints (i) - (vi). Thus, for example, preferred compositions in accordance with the invention will comply with two or more of the definitions (i) - (v).

The term "pharmaceutical composition" as used in the present specification and claims is to be understood as defining compositions in which the individual components or constituents are themselves pharmaceutically acceptable, for example, in which oral administration is to be used, acceptable for oral use or, where topical administration is to be used, topically acceptable.

The preferred cyclosporin as component (a) is Ciclosporin. A further preferred component (a) is [Nva] 2-30 Ciclosporin, also known as cyclosporin G.

DK 176209 B1 12

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

The fatty acid group of components (b) may comprise saturated or unsaturated fatty acids or mixtures thereof. Particularly suitable components (c) are C8_18 fatty acid saccharide monoesters, in particular water-soluble C8_18 fatty acid saccharide monoesters. Particularly suitable components (c) are capron (C6) -, capryl (C8) -, caprin (C10) laurin (C12) - myristin (C14) -, palmitin (C16) oil (C18) -, castor oil (C18) - and 12-hydroxy-stearin (C18) -acid saccharide monoesters, especially lauric acid saccharide monoesters.

The saccharide group of component (b) may comprise any sugar residue, for example mono-, di- or tri-saccharide residue. The saccharide group suitably comprises a partial trisaccharide residue. Preferred components (b) comprise 20 C8-14 fatty acid disaccharide monoesters and C8-18 fatty acid trisaccharide monoesters.

Particularly preferred saccharide groups are sucrose and raffinose residues. Particularly suitable components (b) are thus: sucrose monocaproate, sucrose monolaurate, sucrose semonomyristate, sucrose monooleate, sucrose monoricinoleate, raffinose monocaproate, raffinose monolaurate, raffinose semonomyristate, raffinose monopalmitate and raffinose monoaleate. The most preferred components (b) are raffinose monolaurate and especially sucrose monolaurate.

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

Components (b) suitably have an ester ester purity of at least 80%, in particular at least 90%, most preferably at least 95%.

DK 176209 B1 13

Components (b) suitably have a melting point of from approx. 15 ° C to approx. 60 ° C, especially from approx. 25 ° C to approx. 50 ° C.

According to definitions (ii) and (iii) above as used in the compositions according to the invention, components (c) 5 are defined as materials in which both components (a) and (b) exhibit significant solubility at ambient temperature, eg at temperatures of approx. 20 ° C. Preferred components (c) are materials in which (a) and (b) independently have a solubility of at least 10% [as required by definition 10 (i)], preferably at least 25%, especially at least 50% (e.g. where components (a) or (b) independently have a solubility of the order of at least 100 mg, preferably 250 mg, especially at least 500 mg / ml) at ambient temperature.

Particularly preferred are materials in which component (a) has a solubility of at least 10%, especially at least 25%, most preferably at least 50%, and / or in which component (b) has a solubility of at least 100%, in particular at least 200%. most preferably at least 300% (e.g. where component (b) has a solubility of the order of at least 1000, especially 2000, most preferably at least 3000 mg / ml).

Components (c) suitable for use in compositions of the invention include: c1) ethanol; c2) 2-4 alkylene glycols; C3) C3-5 alkylene polyols; c4) poly- (C 2-4 alkylene) glycols and c5) C 3-5 alkylene polyol ethers or esters, and any mixture thereof.

However, in accordance with the general object of the invention, the use of ethanol either alone or in admixture with any other component (c) is generally less preferred.

When component (c) comprises a C 2-4 alkylene glycol (c2), this is preferably a propylene glycol, especially 1,2-propylene glycol. When component (c) comprises a C 3-5 alkylene polyol (c3), this is preferably a C 3-5 alkylene triol, especially glycerol.

When component (c) comprises a poly- (C 2-4 alkylene) glycol (c4), this is suitably a polyethylene glycol. For use in the compositions of the invention, such components preferably have an average molecular weight of at most about 7000 [sml. definition (iv)], eg up to 6600, especially 10 not more than approx. 2000, eg up to 1600, most preferably no more than approx.

500. Such components preferably have a viscosity of at most approx. 15000 mPa.s, especially not more than approx. 1000 mPa.s, most preferably approx. 200 mPa.s, at 50 ° C or more conveniently at ambient temperature [m.p. definition (iv)].

Suitable polyethylene glycols for use as components (c) are, for example, those described in Fiedler, Lexikon der Hilfstoffe, 2nd revised and expanded edition, [1981] vol.

2, pages 726-731, in particular the products PEG (polyethylene glycol) 200, 300, 400 and 600 as well as PEG 1000, 2000, 4000 or 6000, 20 but especially 200, 300 and 400, eg PEG which suits the following approximate physical properties: PEG 200 PEG 300 PEG 400 PEG 600

Molecular weight approx. 190-210 ca. 285-215 ca. 380-420 ca. 570-630

Viscosity mPa.s approx. 46-53 ca. 66-74 ca. 85-95 ca. 130-150

Freezing point about -50 ° C about -16 to -12 ° C about -3 to 8aC about 15-25 ° C

30 nf} 5 ca. 1,459 ca. 1,463 ca. 1,465 ca. When component (c) comprises a C3-5 alkylene polyol ether or ester (c5), it is suitably a C3-5 alkylene tri ester, in particular glycerol, ether or ester. Suitable components (c5) include mixed ethers or esters, i.e. components comprising other ether or ester components, for example transesterification products of C 3-5 alkylene triol esters with other mono-, di- or polyols.

Particularly suitable components (c5) are mixed C3-5 alkylene triol / poly (C2-4 alkylene) glycol fatty acid esters, especially mixed glycerol / polyethylene or polypropylene glycol fatty acid esters.

Particularly suitable components (c 2) for use in accordance with the present invention include products obtainable by transesterification of glycerides, eg triglycerides, with poly- (C 2-4 alkylene) glycols, eg polyethylene glycols, and optionally glycerol. Such transesterification products are generally obtained by alcoholysis of glycerides, eg triglycerides, in the presence of a poly (C 2-4 alkylene) glycol, eg polyethylene glycol, and optionally glycerol (i.e. for carrying out transesterification from the glyceride to the polyalkylene glycol / glycerol component, i.e. via polyalkylene glycolysis / glycerolysis). In general, such a reaction is carried out by reacting the indicated components (glyceride / polyalkylene glycol and optionally glycerol at elevated temperature under an inert atmosphere of constant agitation.

Preferred glycerides are fatty acid triglycerides, eg (C10_22-25 fatty acid) triglycerides, including natural and hydrogenated oils, especially vegetable oils. Suitable vegetable oils include, for example, olive, almond, peanut, coconut, palm, soybean and wheat germ oils and in particular natural or hydrogenated oils rich in (C12_16 fatty acid) ester residues.

Preferred polyalkylene glycol materials are polyethylene glycols, especially polyethylene glycols with a molecular weight of from about

500 to approx. 4000, eg from approx. 1000 to approx. 2000.

DK 176209 B1 16

Thus suitable components (c - ') comprise mixtures of C3-5 alkylene triol esters, for example mono-, di- and triesters in different amounts relative to each other, and poly (C2-4-alkylene) glycol mono- and diesters, together with minor amounts of 5 free C 3-5 alkylene triol and free poly (C 2-5 alkylene) glycol. As indicated above, the preferred alkylene triol group is glycerol; preferred polyalkylene glycol groups are polyethylene glycol, especially with a molecular weight of from about 500 to approx.

4000; and preferred fatty acid groups are Cio-22 "f an * acid-10 ester residues, especially saturated Cio-22-fe (^ acid ester residues.

Thus, particularly suitable components (c5) may alternatively be defined as: transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and optionally glycerol; or preparations comprising or consisting of glycerol mono-, -di- and -tri-C10-22 "fatty acid esters and polyethylene glycol mono- and -di-C10-22" fatty acid esters (optionally together with eg minor amounts of free glycerol and free polyethylene glycol).

Preferred vegetable oils, polyethylene glycols or polyethylene glycol groups and fatty acid groups in relation to the definitions above are as indicated above. Particularly suitable components (c5) as described above for use in the present invention are those which are known and commercially available under the trade name Gelucir, in particular the products

i) Gelucir 33/01, which has a melting point = approx. 33-38 ° C

and a saponification number = approx. 240-260; ii) Gelucir 35/10, melting point = approx. 29-34 ° C, saponification number = approx. 120-140; Iii) Gelucir 37/02, melting point = approx. 34-40 ° C, saponification number = approx. 200-220; iv) Gelucir 42/12, melting point = approx. 41-46 ° C, DK 176209 B1 17 saponification number = ca- 95-115; v) Gelucir 44/14, melting point = approx. 42-46 ° C, saponification number = approx. 75-95; vi) Gelucir 46/07, melting point = approx. 47-52 ° C, 5 saponification numbers = approx. 125-145; vii) Gelucir 48/09, melting point = approx. 47-52 ° C, saponification number = approx. 105-125; viii) Gelucir 50/02, melting point = approx. 48-52 ° C, saponification number = approx. 180-200; 10 ix) Gelucir 50/13, melting point = approx. 46-41 ° C, saponification number = approx. 65-85; x) Gelucir 53/10, melting point = approx. 48-53 ° C, saponification number = approx. 95-115; xi) Gelucir 62/05, melting point = approx. 60-65 ° C, 15 saponification numbers = approx. 70-90.

Products (i) - (x) above all have an acid value of <2.

Product (xi) has an acid value of <5. The products (ii), (iii) and (vi) - (x) above all have an iodine value of <3. Product (i) has an iodine value of <8. Products (iv) and (v) have an iodine value of <5. Product (xi) has an iodine value of <10. Components (c5) with an iodine value of <1 are generally preferred. It is clear that mixtures of components (c5) as defined above can also be used in the compositions according to the invention.

When a component (c) as specifically described above [i.e. a component suitable for any of the definitions (i) - (iv) above or any component as defined in (c1) - (c5)] is used, the compositions of the invention will generally comprise component (a) i DK 176209 B1 18 a carrier substrate comprising components (b) and (c). Normally, components (a) and (b) will each be present in the compositions of the invention in dispersion or in solution, for example molecular dispersion or solution or micellar dispersion or solution (including, where appropriate, solid solution). Thus, component (a) will generally be present in dispersion or solution in both components (b) and (c), and components (b) will again be present in solution in (c). Component (b) will generally act in the compositions of the invention as a carrier or solubilizing agent (pre- and / or post-administration) for component (a), and component (c) will act as a carrier or liquid. (Of course, the present invention is not to be construed as being limited in any way to a particular functional relationship between components (a), (b) and (c), unless otherwise indicated.)

It is further preferred that when a component (c) as indicated above is used, the compositions of the invention should be formulated in solid unit dosage form suitable for oral administration, for example presented in the form of hard or soft gelatin capsules suitable for oral administration [ sml. definition (iii)]. Such unit dosage forms will, as described below in greater detail, conveniently comprise, for example, from 2 to 200 mg of component (a) per unit dose.

25 unit dose.

When a component (c) as indicated above is used, components (a) and (c) are preferably present in the compositions according to the invention in a weight ratio of from 1: 0.5 to 50 [(a) :( c)] [m.p. . definition (ii)]. Components (a) and (b) are suitably present in a weight ratio of from 1: 3 to 300 [(a) :( b)].

When a component (c) as indicated above is used, it is further preferred that the compositions of the invention are non-aqueous or substantially non-aqueous [m.p.

35 definition (v)], for example, a water content of less than 20% by weight, in particular less than 10% by weight, in particular less than 5% by weight, 2% by weight or 1% by weight, based on the total weight of the preparation.

In accordance with the foregoing, the present invention also relates to a series of particular embodiments: A pharmaceutical composition comprising a component (a) and a component (b) as defined above and a diluent selected from any any of the components (c1) - (c4) as defined above or any mixture thereof, which composition meets any of the definitions (ii) - (v) above; - a pharmaceutical composition comprising a component (a), (b) and (c ^) as defined above and which meets definition (ii), (iii) or (v) above; and - a pharmaceutical composition comprising a component (a), (b) and (c 2) as defined above.

When a component (c) as specifically described above [i.e. a component that meets any of the definitions (i) - (iv), or any of the components (c1) - (c5)] used in the compositions of the invention, components (a) and ( c) suitably present in the preparations in a weight ratio of approx. 1: 0.5-50. More suitably, components (a) and (c) are present in a weight ratio of approx. 1: 1-10, especially 1: 1-5, most preferably 25 approx. 1: 1.5-2.5, e.g. approx. 1: 1.6 or 1: 2 [(a): (c)]. Components (a) and (b) are suitably present in the compositions in a weight ratio of approx. 1: 3-200, especially approx. 1: 3-100, especially approx. 1: 3-50. More suitably, components (a) and (b) are present in a weight ratio of approx. 1: 5-20, especially approx. 1: 5-10, 30 most preferably approx. 1: 6.0-6.5, e.g. ca. 1: 6.25 [(a): (c)].

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

Compositions of the present invention comprising a component (c) as set forth above may be prepared in any suitable dosage form, for example for oral, parenteral or topical administration, for example for dermal or ophthalmic administration, for example for administration to the surface of the eye, e.g. for the treatment of autoimmune eye disorders as described above or for intralesional injection, e.g. for the treatment of psoriasis.

Such compositions are conveniently prepared in unit dosage form, whether administered orally or otherwise.

The amount of component (a) present in such unit dosage forms will, of course, vary depending upon, inter alia, the condition to be treated, the intended mode of administration and the desired effect. In general, however, such unit dosage forms will comprise from about 2 to approx.

200 mg component (a), e.g. Ciclosporin, pr. unit dose.

Suitable dosage forms for oral administration include, for example, liquids, granules and the like. However, solid unit dosage forms are preferred, for example tablets or capsules, especially hard or soft gelatin capsules. Such oral unit dosage forms will conveniently comprise from about 5 to approx.

200 mg, more conveniently from approx. 10 or 20 to approx.

100 mg, e.g., 15, 20, 25, 50, 75 or 100 mg, component (a), e.g. Ciclosporin, per unit dose.

Compositions in accordance with the present invention comprising a component (c) as set forth above have the additional advantage of being able to provide a basis for compositions exhibiting modified release properties, e.g., delayed release of component (a) or release of component (a) over extended periods of time, eg after oral administration. Such compositions further comprise (d), a component capable of modifying the release properties of the composition with respect to component (a).

Such components (d) comprise, for example, polymeric excipients, in particular thickeners, for example polymeric or colloidal thickeners, as well as agents which swell in water, for example water-swellable polymers or colloids.

Suitable components (d) are known in the art and include: d1) Polyacrylate and polyacrylate copolymer resins, for example polyacrylic acid and polyacrylic acid-methacrylic acid resins, for example those known and commercially available under the trade name Carbopol (cf. Fied-15 ler, loc. . cit., 1, pp. 206-207), especially the products

Carbopol 934, 940 and 941, and Eudragit (cf. Fiedler, loc. Cit., 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 cellulose, for example methyl, ethyl and propyl celluloses; hydroxyalkylcellulose, for example hydroxypropylcelluloses and hydroxypropylalkylcelluloses such as hydroxypropylmethylcelluloses; acylated celluloses, for example cellulose acetates, cellulose acetate phthalates, cellulose acetate succinates and hydroxypropyl methylcellulose phthalates; and salts thereof such as sodium carboxymethylcelluloses. Examples of such products suitable for use according to the present invention are those which are known and commercially available, for example under the trade names Klucel and Methocel (cf. Fiedler, loc. Cit., 1. p.

521 and 2, p. 601), in particular the products Klucel LF, MF, GF and HF and Methocel K 100, K 15M, K 100M, E 5M, E 35 15, E 15M and E 100M.

DK 176209 B1 22 d3) Polyvinylpyrrolidones, including for example poly-N-vinylpyrrolidones and vinylpyrrolidone copolymers such as vinylpyrrolidone-vinyl acetate copolymers. Examples of such compounds suitable for use in the present invention are those which are known and commercially available, for example under the trade name Kollidon ((cf. Fiedler, loc. Cit., 1, pp. 526 and 527), in particular the products Kollidon 30 and 90.

D4) Polyvinyl resins, for example including polyvinyl acetates and polyvinyl alcohols, as well as other polymeric materials, including tragacanth, gum arabic, alginates, eg alginic acid, and salts thereof, eg sodium alginates.

D5) Silica dioxides, including hydrophilic silica products, eg alkylated (eg methylated) silica gels, in particular colloidal silica products, known and commercially available under the trade name Aerosil [sml. Handbook of 20 Pharmaceutical Excipients, published by the Pharmaceutical Society of Great Britain, pp. 253-256], in particular the products Aerosil 130, 200, 300, 380, O, OX 50, TT 600, MOX 80, MOX 170, LK 84 and the methylated Aerosil R 972.

When a component (d) is present, it is suitably present in an amount of from about 0.5 to 50% by weight, especially from approx. 1 to 20% by weight, most preferably from approx. 2 to 10% by weight, based on the total weight of the components (a) + (b) + (c) + (d).

When component (c) in the compositions of the invention comprises (c6) a solid polymeric carrier as required by definition (vi) above, it is preferably a water-soluble or substantially water-soluble polymeric carrier.

DK 176209 B1 23

As components (c6), polyvinylpyrrolidones are especially preferred [m.p. Fiedler, loc. cit., 2, pp. 748-750], including in particular cross-linked polyvinylpyrrolidones. Examples of such materials suitable for use in the present invention are those known and commercially available under the trade name Kollidon [m.p. Fiedler, loc. cit., 1. p. 527], Kollisept [sml. Fiedler, loc. cit., 2, pp. 719-720], Povidone and Crospovidone [sml. Fiedler, loc. cit., 2, p. 751], 10 Particularly suitable components (c6) are polyvinylpyrrolidones with a molecular weight of at least approx. 10000, more suitably at least approx. 20,000 or 25,000, eg with a molecular weight of approx. 40,000 or more. Crosslinked polyvinylpyrrolidones are of particular interest. Examples of specific products suitable for use as (c6) in the present invention are: Plasdone XL, Plasdone XL 10 and Crospovidone.

When the compositions of the invention comprise a component (c6), they also preferably comprise (d), a water-swellable or water-soluble component, for example a cellulose or a cellulose derivative as defined under (d2) above.

Further examples of such materials of particular interest to the compositions of the invention comprising a component (c6) are those known and commercially available under the tradenames Avicel [sml. Fiedler, loc. cit., 1. pp. 160-161], Elcema [sml. Fiedler, loc. cit., l. p. 326] and Pharmacoat [sml. Fiedler, loc. cit., 2, p. 707], eg the products Avicel PH 101 and PH 102,

Elcema and Pharmacoat 603.

When compositions of the invention comprise a component (c6), component (a) is present in component (b) in solid solution, including solid micellar solution, for example wholly or substantially wholly in molecular or micellar dispersion.

DK In 176209 B1 24 [In practice, components (b) will often exhibit at least some degree of fluidity, eg at ambient temperature or slightly elevated temperature, and thus will not be strictly "solid". The term "solid solution" as used in the present description and claims is to be construed accordingly, e.g., as comprising viscous or highly viscous systems.] The solid solution consisting of (a) and (b) is suitably dispersed, e.g. particulate form, eg fine particle form, within, eg throughout component 10 (c6). Thus, components (c6) will generally function in compositions of the invention as a disintegratable matrix for [(a) + (b)]. Components (d) will generally function as agents that contribute to disintegration, eg after contact with the contents of the gastrointestinal tract.

Compositions according to the invention comprising a component (c6) will suitably also comprise (e), a binder and / or a lubricant. Materials suitable for use as a binder / lubricant are in particular fatty acid and alkyl sulfonate salts, eg metal salts, eg with 10 or more 20 carbon atoms in the fatty acid / alkyl moiety, eg C10-22 fatty acid- 9 C sodium, calcium or magnesium salts. Examples of such materials suitable for use in the present invention are sodium lauryl sulfate and magnesium stearate [m.p. Fiedler, loc. cit., 2, p. 584].

When compositions of the invention comprise a component (c6), components (a) and (b) are suitably present in ratios of approx. 1: 2-20, especially approx. 1: 2.5-10, most preferably approx. 1: 3-8 [(a) :( b)].

Components (c6) are suitably present in compositions according to the invention in an amount of at least 10% by weight, preferably at least 15% by weight, in particular at least 20% by weight, based on the total weight of the composition. Components (c6) are suitably present in compositions according to the invention in an amount of from 10 to 60% by weight, in particular from 15 to 50% by weight, for example from about 20 to 40% by weight, for example approx. 25, 30 or 35% by weight, based on the total weight of the preparation.

When a component (d) is present, components (d) and 5 (c6) are suitably present in a weight ratio of approx.

1: 0.5-4, preferably approx. 1: 1-3, especially approx. 1: 1.5-2.5, e.g. approx.

1: 2 or approx. 1: 2.5 [(d) :( c6)].

When a component (s) is present, components (e) and (c6) are suitably present in a weight ratio of approx.

1: 5-25, preferably approx. 1: 5-20, especially approx. 1: 7-15 [(e) :( c6)].

When the compositions of the invention comprise all three components (c6), (d) and (e), these are suitably present together in an amount of from about 25-75% by weight, preferably approx. 30-65% by weight, especially approx. 40-65% by weight based on the total weight of the preparation. The weight ratio of components [(a) + (b)]: [(c) + (d) + (e)] is suitably of the order of 1: 0.25-7.5, preferably 1: 0.5-5, in particular 1: 0.5-2, e.g. ca.

1: 0.8, 1: 1.2 or 1: 1.3.

Compositions of the invention comprising a component (c6) may be prepared in any suitable dosage form, for example for oral, parenteral or topical administration. Such compositions of the invention are conveniently prepared in unit dosage form, whether administered orally or otherwise.

The amount of component (a) present in such unit dosage forms will, of course, vary depending upon, inter alia, the condition to be treated, the intended mode of administration and the desired effect. In general, however, they comprise from approx. 2 to approx. 200 mg component (a), e.g. Ciclosporin, pr. unit dose.

DK 176209 B1 26

Suitable dosage forms for oral administration include granules and the like. However, solid unit dosage forms are preferred, such as tablets or capsules. Such oral unit dosage forms will conveniently comprise from about 5 to 5 approx. 200 mg, more conveniently from approx. 10 or 20 to approx. 100 mg, eg 15, 20, 25, 50, 75 or 100 mg component (a), eg Ciclosporin, per unit dose.

When component (c) in the compositions of the invention comprises: (c7) an organosilicon oxide polymer or paraffin perper or subliquid as required by definition (vi) above, component (c7) is preferably slightly liquid at temperatures up to 150 ° C, preferably up to 100 ° C, especially up to 50 ° C. Suitable components (c7) have a maximum viscosity of 15000 mPa.s, preferably 1000 mPa.s, at the indicated temperatures.

Paraffinic hydrocarbons suitable for use as component (c7) are liquid and semi-solid paraffins and mixtures thereof, ie. paraffinum subliquidium and paraffi-num perliquidum [see Fiedler, loc. cit., 2, pp. 690-691]. To enable easy formulation, component (c7) consists wholly or essentially of liquid or semi-solid paraffins, i.e. paraffinum perliquidum or paraffinum subliquidium, or mixtures thereof. However, when it is desired to prepare compositions with, for example, slower release properties for the active ingredient, this can be achieved by further addition of a solid paraffin, eg paraffinum durum.

When compositions according to the invention comprise exclusively liquid or semi-solid paraffins as component (c7), these are preferably present in a ratio of from approx. 1: 0.5 to 1.0 [liquid: semi-solid]. In this case, components (a) and (c7) are suitably present in a weight ratio of from about 1: 6 to 200, preferably approx. 1: 6-100, especially 1: 6-20, eg approx. 1: 8 [(a): (c7)].

When compositions according to the invention further comprise a solid paraffin as component (c7), the weight ratio between the liquid / semi-solid paraffin components and the solid paraffin components is suitably approx. 1: 0.06-0.1. In this case, components (a) and (c7) are suitably present in a weight ratio of 1: 6-200, preferably approx. 1: 6-100, especially 1: 8-20, eg approx. 1:10 [(a) :( c7)].

Organosilicon polymers suitable for use as component (c7) include in particular liquid, i.e. liquid 10 and semi-solid polymeric materials having a structural unit of the formula - (R 2 Si-O-, wherein each R is a monovalent organic radical, eg C 1-4 alkyl, especially methyl, or phenyl. Organosiloxane polymers with a viscosity of from approx. 0.65 to 105 cP, especially from about 10 or 50 to 500 or 1000 cP.

To enable ease of formulation, component (c7) suitably comprises liquid organosiloxane polymers, eg polymethylsiloxane polymers, eg any of the well known silicone oils such as silicone oil 550, DC 200, SF-1066 and SF-1091 [see Fiedler, loc. cit., 2, p. 826]. When compositions of the invention comprise only liquid organosiloxane polymers, components (a) and (c7) are suitably present in a weight ratio of from about 1: 6 to 200, preferably approx. 1: 6-100, especially 1: 6-20, eg approx. 1: 8 25 [(a) :( c7)].

Compositions with, for example, slower release properties of the active ingredient can be obtained using semi-solid organosiloxane polymers, for example any of the various known silicon pastes, for example silicon paste A [see Fiedler, loc. cit., 2, p. 826] as component (c7) or by adding them, for example to other organosilicon polymers as described above. In the latter case, the ratio of the liquid and semi-solid organosilicon polymers present in the composition according to the invention 35 is suitably in the order of approx. 1: 0.5 to 1. I

DK 176209 B1 28 in this case the weight ratio between components (a) and (c7) is suitably of the order of approx. 1: 6 to 100, preferably approx. 1: 6-20 [(a) :( c7)].

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

When compositions according to the invention comprise a component (c7), components (a) and (b) are suitably present in a weight ratio of approx. 1: 6-20, preferably approx. 1: 6-10, especially 10 approx. 1: 6.0-6.5, e.g. 1: 6.25 [(a) :( b)].

When compositions of the invention comprise a component (c7), component (a) is present in component (b) wholly or substantially wholly in molecular dispersion or micellar dispersion, for example in the form of a solid solution or solid micellar solution [wherein the term "solid solution" here is used in the same broad sense as in relation to preparations with a component (c6)]. The solid solution consisting of (a) and (b) is suitably dispersed in particulate form, eg fine particulate form, with component (c7), eg all through component (c7).

Compositions according to the invention comprising a component (c7) may be prepared in any dosage form, for example for oral, parenteral or topical administration, for example for dermal or ophthalmic administration, for example for administration to the surface of the eye, for example for treatment of autoimmune eye disorders as described above, or for intralesional injection, for example in the treatment of psoriasis. They are conveniently prepared in unit dosage form, whether administered orally or otherwise.

The amount of component (a) present in such unit dosage forms will, of course, vary depending upon, for example, the condition to be treated, the intended mode of administration and the desired effect. In general, the imid DK 176209 B1 29 clay time will comprise from approx. 2 to approx. 200 mg component (a), e.g. Ciclosporin, pr. unit dose.

Suitable dosage forms for oral administration include liquids, granules and the like. However, solid unit dosage forms are preferred, for example tablets or capsules, especially hard or soft gelatin capsules. Such oral unit dosage forms will conveniently comprise from about 5 to approx. 200 mg, more conveniently from approx. 10 or 20 to approx. 100 mg, eg 15, 20, 25, 50, 75 or 100 mg, component (a), eg Ciclo-10 sporin, pr. unit dose.

Compositions according to the invention comprising a component (c7) have the further advantage that they can provide a basis for compositions which exhibit modified release properties, for example delayed release of component (a) or release of component (a) over extended periods of time, eg after oral administration, such preparations may be obtained as described above using solid or semi-solid components (c7) in appropriate amounts. Alternatively, they can be obtained by using an additional component (d): a component that can modify the release properties of the composition with respect to component (a). Such components (d) comprise, for example, polymeric excipients, in particular thickeners, for example polymeric or colloidal thickeners, as well as agents which swell in water, for example water-swellable polymers or colloids, for example any of the materials defined under ( d1) - () above.

When a component (d) is present, it is suitably present in an amount of from about 0.5 to 30% by weight, preferably from approx. 1 to 20% by weight, especially from approx. 1 3 0 to 10% by weight, based on the total weight of components (a) + (b) + (c7) + (d).

Components (d5) are particularly suitable for use in compositions of the invention comprising an organosilicon polymer as component (c7).

DK 176209 B1 30

Compositions of the invention comprising a component (c6) or (c7) will be or will preferably be non-aqueous or substantially non-aqueous, for example as described above with respect to compositions comprising 5 other components (c) .

Compositions of the present invention may, regardless of the component (c) selected [e.g., whether component (c) comprises any of components (c1) - (c7) listed above or any mixture thereof], comprise one or several additional arbitrary additives, eg additives known and widely used in the field, eg antioxidants [eg ascorbyl palmitate, tocopherols, butylhydroxyanisole (BHA) or butylhydroxy-toluene (BHT)], flavors, etc.

The compositions according to the invention will in particular also suitably comprise one or more stabilizers or one or more buffering agents, in particular in order to prevent hydrolysis of component (b) or degradation of component (a) during manufacture or storage. Such stabilizers may include acid stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid as well as basic stabilizers such as potassium hydrogen phosphate, glycine, lysine, arginine or tris (-hydroxymethyl) aminomethane.

Such stabilizers or buffering agents are conveniently added in an amount sufficient to achieve or maintain a pH in the range of from about 3 to 8, preferably approx. 5-7, eg between 6 and 7. Such stabilizers are generally present in an amount of up to 5% by weight based on the total weight of the composition or up to 30 to 10% by weight, eg when citric acid or acetic acid is used. Compositions according to the invention, in particular compositions in which component (a) is Ciclosporin, with a pH within the above ranges are preferred.

DK 176209 B1 31

Compositions of the invention will also suitably comprise a polyoxyalkylene-free surfactant such as, for example, dioctyl succinate, dioctyl sulfosuccinate, di [2-ethylhexyl] succinate, sodium lauryl sulfate or phospholipids, eg lecithins.

When a surfactant as indicated above is present, it is suitably present in an amount of from 5 to 50, preferably 10 to 50, eg 10 to 25% by weight based on the weight of component (b).

When compositions according to the invention comprise component (a) in solid solution in component (b), for example when component (c) is a component (c6) or (c7) as described above, any stabilizers are suitably incorporated in the solid solution phase. , buffer and / or any surfactant as indicated above. Such materials may also be comprised of component (c), etc.

Compositions according to the invention, again regardless of the selected component (c), are preferably free of or substantially free of ethanol, eg they contain less than 5.0% by weight, preferably less than 2.5% by weight, eg from 20 to 1, 0% by weight of ethanol, based on the total weight of the preparation.

In addition to the foregoing, the present invention also relates to a process for the preparation of a pharmaceutical composition as defined above, which process is characterized in that components (a), (b) and (c) as defined above are intimately mixed or compounded, optionally together. with a component (d) and / or another component, eg a stabilizer, a buffer or a surfactant as described above, and if necessary, that the preparation obtained is formulated in unit dosage form, eg unit dosage form for oral administration, eg by tableting , filling into gelatin capsules or other suitable means.

When component (c) is a solvent for components (a) and (b) or comprises a component (c1), (c2), (c3), DK 176209 B1 32 (c4) or (c5) as defined above, components are brought (a), (b) and (c) conveniently by the above procedure together by dissolving components (a) and (b) together in component (c), for example while heating at temperatures up to 5 to 50 ° C or 150 ° C , preferably not above 70 ° C or 75 ° C. The mixture thus obtained can then be further compounded with components (d), etc., for example by intimate mixing according to techniques known in the art. Filling, eg in hard or soft gelatin capsules, is conveniently carried out at elevated temperature, eg up to 50 ° C, to obtain a liquid preparation, eg during heating.

When compositions according to the invention comprise component (a) in solid solution in component (b), for example compositions comprising a component (c6) or (c?) As indicated above, the process will suitably first comprise preparing a solid solution of ( a) in (b) followed by intimate mixing or compounding of the obtained solid solution with the other components (c) and optionally (d), etc.

Solid solutions comprising components (a) in (b) may be prepared according to techniques known in the art, for example by solidifying a molten mass comprising (a) in solution in (b) or removing the solvent. from a solution of components (a) and (b). For the purposes of the present invention, the latter alternative is generally preferred.

Suitable solvents for components (a) and (b) include lower alkanols, eg ethanol. Stabilizers, buffers and / or surfactants are conveniently incorporated at the dissolution stage.

The solid solution thus obtained is suitably then compounded, for example in fine particulate form, with component (c) and optionally components (d) and (e), etc., for example by distribution in component (c).

33 DK 176209 B1

Although ethanol may be used for the purpose of preparing compositions of the invention, for example in the preparation of solid solutions as described above, it will preferably be removed, for example by evaporation, before completion of the final dosage form to form an ethanol-free or substantially ethanol-free product as indicated above.

The following examples illustrate the present invention.

The product sucrose monolaurate L-1969 used in the examples is commercially available from Mitsubishi-Kasei Food Corp., Tokyo 104, Japan: HLB value = at least 12.3; lauryl ester residue purity = at least 95%; melting point = approx. 35 ° C; decomposition at approx. 235 ° C; surface tension of 0.1% by weight aqueous solution = approx. 72.0 dynes / cm at 25 ° C.

15 EXAMPLES

INGREDIENT RELATIVE AMOUNT (mg) 1. a) Cyclosporine (eg Cyclosporine) 50.0 b) Sucrose monolaurate L-1695 312.5 c) 1,2-propylene glycol 100.0 20 ____

Total 462.5 2. a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Glycerol 100.0

Total 462.5 DK 176209 B1 34 3. a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) PEG 200 100.0 5 Total 462.5 4. a) Cyclosporin (eg Ciclosporin ) 50.0 b) Sucrose monolaurate L-1695 312.5 C) PEG 400 100.0 10 Total 462.5 5. a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) 1, 2-propylene glycol 100.0 d) Eudragit E 50.0 15 _

Total 550.0 6. a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) 1,2-propylene glycol 100.0 d) Methocel K100 110.0

Total 610.0 7. a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 25 c) 1,2-propylene glycol 100.0 d) Aerosil 200 15.0

Total 515.0 DK 176209 B1 35 8. a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 350.0 c) PEG 400 200.0 d) Eudragit L 2.5 5 _

Total 602.5 9. a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelucir (eg Gelucir 42/12, 44/14 10 or 35/10) 100.0

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

Total 512.5

The composition of Example 1 is prepared by dissolving 20 components (a) and (b) with stirring and heating over an oil bath at 100 ° C in component (c). The compositions of Examples 2-10 are prepared similarly. With respect to Examples 5 and 8, component (d) is dissolved in the initially obtained mixture of components (a) to (c). With respect to Examples 6, 7 and 10, component (d) of (a) - (c) is suspended.

The resulting preparations are filled during heating into hard gelatin capsules, size 1 (Examples 1-4 and 9), or size 0 (Examples 5-7 and 10), to form an encapsulated final product, each capsule containing 50 mg of 30 cyclosporin (e.g. Ciclosporin) and is suitable for administration for the prevention of transplant rejection or for the treatment of autoimmune diseases, eg for the administration of from 1 to 5 capsules daily.

DK 176209 B1 36

EXAMPLES

INGREDIENT RELATIVE AMOUNT (mg) 11.a) Cyclosporin (eg Ciclosporin) 100.0 b) Sucrose monolaurate L-1695 300.0 5 c) Plasdone XL 350.0 d) Avicel PH 102 150.0 e) Sodium lauryl sulphate 25.0

Total 925.0 12.a) Cyclosporin (eg Ciclosporin) 50.0 b1) Sucrose monolaurate L-1695 350.0 b2) Sucrose monostearate 50.0 c) Crospovidone 250.0 d) Elcema 150.0 15 e) Magnesium stearate 30, 0

Total 980.0 13.a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 160.0 20 c) Plasdone XL 10 200.0 d1) Pharmacoate 603 25.0 d2) Avicel PH 101 75.0 e ) Magnesium stearate 20.0 25 Total 605.0

The above compositions 11-13 each suitably comprise an additional 25 mg (f) of tartaric acid and / or 50 mg (g) of dioctyl succinate, preferably both, giving a final weight for composition 11 of 1000 mg, for composition 12 of 1055 mg and for preparation 13 of 6180 mg.

DK 176209 B1 37

Preparations 11-13 are prepared as follows: Components (a) and (b) are dissolved in absolute ethanol and the ethanol is thoroughly evaporated at 50 ° C under reduced pressure. Components (c) to (e) are mixed thoroughly [with the addition of (f) and (g) when used] using conventional mixing techniques. The solid solution comprising [(a) + (b)] is ground to a fine powder and mixed evenly in [(c) - (g)] and the resulting uniform mass is compressed into tablets each containing 100, 50 or 25 mg (a) and is suitable for administration for the prevention of transplant rejection or for the treatment of autoimmune diseases, for example by the administration of from 1 to 5 tablets daily.

EXAMPLES

15 COMPONENT RELATIVE AMOUNT (mg) 14. a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Paraffinum perliquidum 397.5 20 Total 760.0 15. a) Cyclosporin (eg Ciclosporin) 50 B) Sucrose monolaurate L-1695 312.5 c) Silicone oil DC 200 397.5 25

Total 760.0

Components (a) and (b) are dissolved in absolute ethanol and the ethanol is evaporated thoroughly at 50 ° C under reduced pressure. The solid solution obtained is ground to a fine powder and suspended evenly in component (c). The resulting liquid suspension is filled into hard gelatin capsules, size 0, to form an encapsulated final product, each capsule containing 50 mg of cyclosporin (eg Ciclosporin) and suitable for administration for the prevention of transplant rejection or for the treatment of autoimmune disorders. diseases, eg by administering from 1 to 5 capsules daily.

EXAMPLES

INGREDIENT RELATIVE AMOUNT (mg) 5 16.a) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Paraffinum subliquidum 372.5 d) Paraffinum durum 25.0 10 Total 760.0 17.a ) Cyclosporin (eg Ciclosporin) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Paraffinum perliquidum 397.5 d) Aerosil 10.0

Total 770.0

Compositions 16 and 17 are prepared analogously to 14 and 15 above. In the case of preparation 16, first combine (c) and (d) by melting and intimate stirring together. The solid solution comprising [(a) + (b)] is then suspended in [(c) + (d)]. In the case of preparation 17, (d) is suspended together with [(a) + (b)] in (c).

Compositions similar to those of Examples 1-17 above may be prepared by replacing Ciclosporin as component (a) with any other cyclosporin, eg [Nva] 1-Ciclosporin, or replacing sucrose monolaurate as component (b) with any preferably other fatty acid saccharide monoester, e.g. as indicated above, e.g. raffinose semonolaurate, in each case in the same or corresponding amount or relative proportion.

DK 176209 B1 39

The utility of compositions according to the invention can be demonstrated in animal experiments or clinical trials, eg performed as follows:

BIO-AVAILABILITY STUDIES IN DOGS FOR PREPARATIONS ACCORDING TO THE INVENTION

5 a) Test preparations

Preparation I according to Example 1 Preparation II according to Example 14 b) Test method

Groups of 8 beagle dogs (males, approx. 11-13 kg) are used. The animals do not receive food for 18 hours before administration of test preparation, but have free access to water until administration. Test preparations are administered by gavage followed by 20 ml of 0.9% NaCl solution.

The animals have free access to food and water 3 hours after ad-15 administration of test substance. 1 ml blood samples (or 5 ml for the control) are taken from the vena saphena and collected in 5 ml plastic tubes containing EDTA, -15 minutes (control), 30 minutes and 1, 1.5, 2, 3, 4, 6, 8 , 12 and 24 hours after administration. Blood-20 samples are stored at -18 ° C before assay. Blood samples are examined by RIA. Areas below curves for blood drug concentration relative to time are calculated according to the trapezoidal rule. Analysis of variance is performed with respect to AUC (area under the curve), Cmax (maximum concentration) and Tmax (time for maximum concentration).

c) Results

Calculated mean AUC (in ng hour / ml) and Cmax (in ng / ml) values from typical sample runs are shown in the following table, along with calculated variation in response 30 between test animals receiving the same specimen (CV).

DK 176209 B1 40

Compound AUC CV (%) Cmax CV% (0-24 hours) I 3058 19.9 583 30.9 5 II 2894 14.91 544 19.7

As can be seen from the table above, compositions of the invention exhibit high bioavailability (AUC and Cmax) along with relatively low variability in patient response for both AUC and Cmax.

Similarly advantageous results can be obtained using other compositions of Examples 1-17 above, especially the compositions of Examples 1-10.

Clinical examination

The beneficial properties of the compositions of the invention after oral administration can also be demonstrated in clinical trials, eg performed as follows:

Experimental patients are adult volunteers, eg professionally trained men aged 30 to 55 years. Experimental groups suitably include 12 patients.

The following inclusion / exclusion criteria are used:

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

Exclusion criteria: Clinically significant intercurrent medical condition that may interfere with drug adsorption, distribution, metabolism, excretion or safety; symptoms of a significant clinical disease in the 2 week period before the trial; clinically relevant abnormal laboratory values or electrocardiogram; need for concomitant drug treatment throughout the study; Administration of any drug known to have a well-defined possible toxicity to a major organ system within the previous 3 months; administration of any study drug within 6 weeks of participating in the trial; previous drug or alcohol abuse; loss of 500 ml of blood or more within the last 3 months period; drug side effect or hypersensitivity; previous allergies requiring drug therapy; hepatitis B / HIV positive.

10 Complete health examination and ECG are performed pre- and post-tests. The following parameters are evaluated within 1 month periods pre- and post-trial:

Blood: Number of red blood cells, hemoglobin, hematocrit, erythrocyte sedimentation, white blood cell count, smears, platelet count and fasting glucose;

Serum / plasma - total protein and electrophoresis, cholesterol, triglycerides, Na +, K +, Fe ++, Ca ++, Cl-, creatinine, urea, uric acid, SGOT, SGPT, -GT, alkaline phosphatase, total bilirubin, α-amylase; Urine - pH, microalbumin, glucose, erythrocytes, ketone bodies, precipitate.

Creatine clearance is also determined 1 month before participating in the trial.

Patients each receive test specimens in randomized order. Preparations are administered orally once in a total dose of 150 mg cyclosporine, eg Ciclosporin, and there is a minimum of 14 days between each administration.

The administration is performed in the morning after a fast overnight of 10 hours, during which only water may be ingested. Only coffee-30 fein-free beverages are allowed for a period of 24 hours after administration. Patients are not allowed to smoke for a period of 12 hours after administration. Patients receive a standardized lunch 4 hours after administration.

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Blood samples (2 ml) are taken 1 hour before administration 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 hours after administration. To determine creatinine, 2 ml blood samples are taken immediately before administration and 12, 24 and 48 hours after administration.

Samples for cyclosporin determination are taken in two EDTA-coated polystyrene tubes (1 ml each) at each time point and kept frozen at -20 ° C after slight agitation. Cyclosporin is analyzed in whole blood using RIA with specific 10 and / or non-specific MAB assay - detection limit in both cases = approx. 10 ng / ml.

In experiments performed according to the protocol above, eg experiments comparing the preparation from Example 1 in hard gelatin capsules with the current Ciclosporin drink solution (Ciclosporin = 50 mg, Labrafil = 150 mg, ethanol = 50 mg, corn oil = 213 mg , in soft gelatin capsules: final weight = 463 mg / dose) as standard, significantly increased bioavailability levels of the preparation from Example 1 were recorded compared to the standard as expressed in both established AUC (0-32 hours) and Cmax values. In addition, a comparison of variation in whole blood Ciclosporin concentration (as determined by specific roonoclonal RIA) with time after a single administration of test preparations to a 150 mg dose of Ciclosporin shows a marked reduction in response variability between all patients receiving the preparation of Example 1, compared to the variability of all patients receiving the standard preparation.

Similar or similar results may be obtained after oral administration of other compositions of the invention, for example as described above in the examples.

Claims (2)

An alcohol-free composition containing cyclosporin in a solid solution of sucrose monolaurate or raffinose monolaurate, in which cyclosporin: sucrose monolaurate or raffinose monolaurate is present in a ratio of 1: 3 to 200 parts by weight. A composition according to claim 1, in which cyclosporin is a solid solution of sucrose monolaurate.