NO301576B1 - Process for the preparation of a pharmaceutical composition having immunosuppressive activity - Google Patents

Description

The present invention relates to a method for producing a pharmaceutical preparation with immunosuppressive activity and which can be used to treat autoimmune diseases, comprising a) a cyclosporine as active ingredient, b) a C6_18 fatty acid sucrose monoester and/or fatty acid raffinose monoester, and c) a diluent or a carrier,

and if desired, one or more excipients and/or excipients that are commonly used in the pharmaceutical industry.

These and other features of the invention appear in the patent claims.

The cyclosporins comprise a group of structurally distinctive, cyclic, poly-N-methylated end decapeptides, which usually have pharmacological, particularly immunosuppressive, anti-inflammatory and/or anti-parasitic activity. The first of the cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyklosporine, also known as cyclosporin A and which is commercially available under the trade name Sandimmun or Sandimmune. Cyclosporine is the cyclosporine of formula A: wherein -MeBmt- represents the N-methyl-(4R)-4-but-2E-en-l-yl-4-methyl-(L)threonyl residue of formula B

As the first in the group, Ciclosporin has so far received the most attention. The most important area of clinical investigation for Ciclosporin has been as an immunosuppressive agent, particularly with regard to its use in organ transplant recipients, e.g. heart, lung, combined heart-lung, liver, kidney, pancreas, bone marrow, skin and cornea transplants and especially allogeneic organ transplants. In this area Ciclosporin has been very successful and has gained a great reputation.

At the same time, the applicability of Ciclosporin in various autoimmune diseases and inflammatory conditions, especially inflammatory conditions with an etiology including an autoimmune component such as arthritis (e.g. rheumatoid arthritis, arthritis chronica progrediente 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 where Ciclosporin therapy is proposed or used include autoimmune hematologic disease (including, for example, hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis , dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic psilosis, autoimmune inflammatory bowel disease (including, for example, ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis , primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. extensive idiopathic nephrotic syndrome or minimal change nephropathy).

Further areas that have been investigated have been potential applicability as an anti-parasitic - particularly anti-protozoal - agent, with proposed possible applications including the treatment of malaria, coccidioidomycosis and schistosomiasis and, more recently, use in cancer therapy, e.g. as a means of reversing or counteracting resistance to other anti-neoplastic or cytostatic therapy.

Since the original discovery of ciclosporin, a number of different naturally occurring cyclosporins have been isolated and identified and many non-naturally occurring cyclosporins have been prepared by fully or semi-synthetic methods or using modified cultivation techniques. The group that includes the cyclosporins is thus now significant and includes e.g. the naturally occurring cyclosporins A to Z [cf. Traber et al 1, Heiv. Chim. Acta. 60, 1247-1255

(1977), Traber et al, 2, Heiv. 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, Progress in Allergy, 38, 28-45 (1986)], as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins including those so-called dihydrocyclosporins [in which the residue -x-y- in the -MeBmt- residue (formula B above) is saturated to give -x-y- = -CH2-CH2-], derivatized cyclosporins (e.g. in which a further substituent is introduced on the cc carbon atom in the sarkosyl residue in the 3-position of the cyclosporin molecule), cyclosporins in which the -MeBmt- residue is present in isomeric form (e.g. in which the configuration opposite positions 6' and 7' of the -MeBmt- residue is cis rather than trans ), and cyclosporins in which varying amino acids are incorporated in specific positions within the peptide sequence, using e.g. the total synthesis method for the preparation of cyclosporins developed by R. Wenger - see e.g. Traber 1, Traber 2 and Kobel loe. eit., US-PS 4,108,985, 4,210,581 and 4,220,641, EP Patent Publication 0 034,567, 0 056,782 and 0 296,122, International Patent Publication No. WO 86/02080, Wenger 1, Transp. Pro. 15, Suppl. 1:2230 (1983), Wenger 2, Angew. Chem. Int. Ed., 24, 77 (1985), and Wenger 3, Progress in the Chemistry of Organic Natural Products 50, 123 (1986).

The group comprising the cyclosporins now thus includes

e.g. [Thr]<2->, [Val]<2->, [Nva]<2->and [Nva]<2->[Nva]<5->Cyclosporin (also known as cyclosporins C, D, G respectively and M) [3'-O-acyl-MeBmt]-"--Cyclosporin (also known as cyclosporin A acetate), [dihydro-MeBmt] 1-[Val]2-Cyclosporin (also known as dihydrocyclosporin D), [31 -desoxy-31-oxo-MeBmt]1 [Val] 2- and -[Nva]<2->Cyclosporin, [(D)fluoromethyl-Sar]<3->Cyclosporin, [(D)Ser]<8-> Cyclosporin, [Melle] n-Cyclosporin, [(I)MeVal] 11-Cyclosporin (also known as Cyclosporin H), [MeAla]^Cyclosporin, [(D)Pro]<3->Cyclosporin and so on.

In accordance with the now conventional nomenclature for cyclosporins, these are defined according to the structure of Ciclosporin (ie Cyclosporin A). This is done by first indicating the amino acid residues present which are different from those present in Ciclosporin (e.g. "[(D)Pro]<3>" to indicate that the cyclosporin in question has rather a -(D )Pro- than a -Sar- residue in the 3-position) and then use the term "Ciklosporin" to characterize

sere the remaining residues identical to those present in Ciclosporin. Individual residues are numbered starting from the residue -MeBmt-, -dihydro-MeBmt- or the equivalent in position 1.

Very many of these additional cyclosporins have comparable pharmaceutical utility to Ciclosporin or a more specific utility, e.g. particular activity with regard to the reversal of tumor resistance to cytostatic therapy, and proposals for their use as therapeutic agents are found in the literature.

Despite the important contribution that Ciclosporin has made, particularly in the areas of organ transplantation and therapy of autoimmune diseases, difficulties encountered in providing more effective and appropriate delivery methods as well as the reported incidence of adverse side effects, particularly nephrotoxic reaction, have been obvious serious obstacles to its more widespread use. The cyclosporins are characteristically very hydrophobic. Suggested liquid preparations, e.g. for the oral administration of cyclosporins, has so far largely been based on the use of ethanol and oils or similar excipients as a carrier medium. Thus, the commercially available drinkable Ciclosporin solution uses ethanol and olive oil as a carrier medium together with labrafil as a surfactant - see e.g. US-PS 4,388,307. Use of the drinkable solution and similar preparations as proposed in the art is, however, accompanied by a number of difficulties.

Firstly, the necessity of using oils or oil-based carriers can give the preparations an unpleasant taste or otherwise reduce the appealing taste, especially in long-term therapy. These effects can be hidden by using the preparation in the form of a gelatin capsule. However, to keep the ciclosporin in solution, the ethanol content must be kept high. Evaporation of ethanol, e.g. from capsules or other forms, e.g. when opened, results in the development of a cyclosporine precipitate. Where such preparations are in the form of e.g. gelatin capsules, this particular problem makes it necessary to pack the encapsulated product in an airtight package, e.g. an airtight ampoule or a packet of aluminum foil. This consequently makes the product both bulky and more expensive to produce. The storage properties of the preparations mentioned above are far from ideal.

They achieved bioavailability levels using de

current dosing regimens for oral delivery of cyclosporine are also low and vary greatly between individuals, individual patient types, and even within a single individual at different times during the course of therapy. Reports

within the literature thus indicates that current' available therapy using the commercially available drinkable solution of Ciclosporin provides an average

absolute bioavailability of only approx. 30%, with marked variation between individual groups, e.g. recipients of liver transplants (relatively low bioavailability) and bone marrow transplants (relatively high bioavailability). Reported variability in bioavailability between individuals has ranged from anywhere between one and five percent in some patients to as much as 90% or more in others. As already noted, marked change over time in bioavailability is observed in individuals.

To achieve effective immunosuppressive therapy, blood or blood serum levels of cyclosporine must be maintained within a specified range. However, the required area may vary depending on the particular condition being treated, e.g. whether therapy is to prevent transplant rejection or to control an autoimmune disease, and whether any alternative immunosuppressive therapy is used at the same time as cyclosporine therapy. Due to the large variations in bioavailability levels achieved with commonly used dosage forms, daily dosages necessary to achieve the required blood serum levels will also vary considerably from individual to individual and even within each individual. Because of this, it is necessary to measure blood/blood serum levels regularly and frequently in patients receiving cyclosporine therapy. Measurement of blood/blood serum levels, which is generally carried out by RIA or equivalent immunoassay technique, e.g. when using technology based on monoclonal antibodies, must be carried out regularly. This is inevitably time-consuming and cumbersome and makes the whole therapy significantly more expensive.

Along with all these very obvious practical problems, there is the occurrence of undesirable side-reactions as alluded to above, which have been observed when using available dosage forms for oral administration.

A number of proposals to address such problems have been proposed in the prior art, including both solid and liquid dosage forms for oral administration. Thus, it is proposed in Japanese patent application 71682/1985 by Takada et al., the use of methods to increase the lymphatic delivery of cyclosporins, particularly when administered together with surfactants. Among a general list of surfactants that can be used, there are included agents such as sucrose (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. As the use of both mono- and polyesters is indicated, a general preference for mono- or diesters is suggested. Other stated 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 are clearly indicated to be preferred, e.g. to the above-mentioned sucrose ester surfactants.

Example 3 in the above-mentioned Japanese application describes obtaining an aqueous preparation comprising a sucrose fatty acid ester, identified as F160, as surfactant. The preparation comprises 3.5 mg Ciclosporin and 2 mg sucrose ester in 1 ml H20. To achieve dispersion of Ciclosporin, treatment with ultrasound for 5 min. at 100 W required. A preparation has been obtained, which is described as "a transparent solution" and is used directly in animal models to investigate relative lymphatic resorption. Due to the very low solubility of Ciclosporin in H20 and the small amount of surfactant used, it is clear that the claimed solution is not a suitable product from this procedure. Not only is the achieved Ciclosporin concentration inappropriately low, e.g. for dosing by oral administration, but the preparation is naturally unstable and it is a fact that the preparation is thus excluded as a practical or commercial galenic form regardless of type. It is essentially an experimental system that enables laboratory investigations and nothing more. There is no proposal to use surface active agents in any context other than in connection with lymphatic delivery.

Japanese Patent Application 193129/1987 (Publication No. 038029/- 1989), also by Takada et al, relates to powdered preparations comprising a cyclosporine dispersed in a solid, non-surfactant, carrier phase, e.g. comprising sucrose, sorbitol, tartaric acid, urea, cellulose acetate phthalate, methacrylic acid/methyl methacrylate or hydroxypropyl methyl cellulose phthalate, together with minor amounts of a surfactant. Again, the surfactant is added for the purpose of increasing lymphatic delivery and, in this context, the application is clearly directed to the provision of an intended practical method for applying the teachings of the above-mentioned Japanese application 71682/1985. Reference to sucrose esters as possible surfactants is omitted in this case. Reference to sorbitan esters among listed possible surfactants has been retained. However, Nikkol HCO 60 type products are again indicated to be the preferred surfactant, and Nikkol HCO 60 is the only surfactant used in the examples. There is no indication that the claimed increase in lymphatic delivery provides any practical benefit or alleviates any of the difficulties in cyclosporine therapy hitherto encountered in the art, e.g. as discussed above.

The present invention has provided a method for the production of new ciclosporin galenic preparations comprising fatty acid saccharide monoesters as primary carrier components, which remedy or substantially reduce the difficulties in ciclosporin, e.g. Cyclosporine therapy that has been encountered in the prior art. It has been found in particular that the preparations produced in accordance with the invention allow the production of solid, semi-solid and liquid preparations containing a cyclosporine in a sufficiently high concentration to allow, e.g. suitable oral administration, while at the same time achieving improved effect, e.g. expressed by the bioavailability properties.

More particularly, it has been found that the preparations prepared in accordance with the present invention enable effective cyclosporine dosing with a simultaneous increase in resorption/bioavailability levels, as well as reduced variability in resorption/bioavailability levels obtained for both individual patients receiving cyclosporine therapy and likewise between different individuals. By applying the teachings in accordance with the invention, ciclosporin dosage forms are obtained with reduced variability with regard to achieved ciclosporin blood/blood serum levels between dosages to individual patients as well as between individual patients and individual patient groups. Thus, the preparations produced according to the invention enable the reduction of cyclosporine dosage levels required to achieve effective therapy. In addition, the preparations produced according to the invention allow closer standardization as well as optimization of conditions for the ongoing daily dosage to individual patients receiving cyclosporine therapy as well as to patient groups undergoing equivalent therapy.

By closer standardization of dosage amount and blood/blood serum level response in the individual patient, as well as dosage and response parameters for patient groups, the requirements for measurement can be reduced and thus the costs of the therapy can be significantly reduced.

By reducing the required cyclosporine dosage/standardization for achieving bioavailability properties, the preparations produced according to the present invention also allow a reduction of unwanted side effects, especially nephrotoxic reaction in patients undergoing cyclosporine therapy.

In addition, the present invention enables the preparation of preparations that are not alkanol-based, e.g. which is without or essentially without ethanol. Such preparations avoid difficulties in connection with stability and related processing as described above, which are included in connection with known alkanol preparations. The method according to the invention thus provides, among other things, preparations which are better adapted to e.g. to be in the form of capsules, e.g. capsules of hard or soft gelatin and/or which eliminate or substantially reduce problems in connection with packaging as discussed above, e.g. in connection with encapsulation in soft gelatin.

The present invention thus relates to a method for producing a pharmaceutical preparation with immunosuppressive activity and which can be used to treat autoimmune diseases, comprising a) a cyclosporine as active ingredient, b) a C6_18 fatty acid sucrose monoester and/or fatty acid raffinose monoester, and c) a diluent or a carrier, and if desired, one or more auxiliary substances and/or excipients that are commonly used in the pharmaceutical industry, which are characterized in that component a) is used in a mass ratio of from 1:3 to 1:200 in relative to component b), is dissolved together with component b) in component c) by heating to 50-150°C, or a melt or a solution of component a) and component b), used in the above mass ratio, is brought into solid form with obtaining a solid solution of component a) in component b) which is then mixed or processed with component c), obtaining a pharmaceutical preparation in which: i) both components r a) and b) are, independently of each other,

soluble in component c) in a concentration of at least

10% at ambient temperature, and/or

ii) components a) and c) are present in said preparation in a

mass ratio from 1:0.5 to 1:50, and/or

iii) component c) comprises a poly-(C2_4-alkylene) glycol with an average molecular weight of no more than 7,000 or a viscosity at 50°C of no more than 15,000 mPa.s, or component c) comprises a (C3_5-alkylene) polyol ether or ester ,

and or

iv) component c) comprises a solid polymer carrier, an organosilicon polymer or per- or sub-liquid paraffin, and component a) is present in said preparation which

a solid solution in component b), and/or

v) the preparation is non-aqueous, and/or

vi) the preparation is formulated in fixed unit dose form, e.g.

capsule form, which is suitable for oral administration.

The preparation as presented above is new and particularly advantageous variants of those generically stated in French patent application 8,811,953 and corresponding applications in other countries, including USSN 07/243 577, DOS 38 304945, Japanese patent application 231,396/88 and GB patent application 8,821. 443.9 (first publication in France, March 17, 1989 with 2,620,336).

Definitions (i) to (vi) as stated above shall not be understood to be mutually exclusive. The preparations produced in accordance with the invention thus include those indicated above which fulfill one or more of the defined limitations (i) to (vi). Preferred preparations produced in accordance with the invention will thus e.g. be such that fulfill two or more of the constraints (i) to (vi) .

The term "pharmaceutical preparation" as used herein shall be understood to define preparations where the individual components or constituents are in themselves pharmaceutically acceptable, e.g. tolerable for oral application where oral administration is anticipated or are topically tolerable where topical administration is anticipated.

The preferred ciclosporin as component (a) is Ciclosporin. A further preferred component (a) is [Nva]^Cyclosporin, also known as cyclosporin G.

Preferred components (b) for use in the preparations prepared in accordance with the invention are water-soluble fatty acid saccharide monoesters, e.g. 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 part in components (b) can comprise saturated or unsaturated fatty acids or mixtures thereof. Particularly suitable components (b) are C6-18 fatty acid saccharide monoesters, especially water-soluble C6-18 fatty acid saccharide monoesters. Particularly suitable components (b) are caproic acid (C6), caprylic acid (C8), capric acid (C10), lauric acid (C12), myristic acid (C14), palmitic acid (C16), oleic acid (C18), >castor oleic acid (C18) and 12-hydroxystearic acid (<C>18) saccharide monoesters, especially lauric acid saccharide monoesters.

The saccharide moiety in component (b) may comprise any suitable sugar residue, e.g. a mono-, di- or trisaccharide residue. The saccharide moiety will suitably comprise a di- or trisaccharide residue. Preferred components (b) include C6_14 fatty acid disaccharide monoesters and C8_18 fatty acid trisaccharide monoesters.

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

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

Components (b) suitably have an ester residue purity of at least

80%, more preferably at least 90% and most preferably at least 95%. Components (b) suitably have a melting point of from 15°C to 60°C, more preferably from 25°C to 50°C.

The above-mentioned components (c) are materials in which both components (a) and (b) exhibit high solubility at ambient temperature, e.g. at temperatures of approx. 20°C. Preferred components (c) are materials in which (a) and (b) independently of each other have a solubility of at least 10%

[as required by definition (i)], preferably at least 25% and most preferably at least 50% (e.g. in which components (a) or (b) independently have a solubility in the order of at least 100 mg, preferably 250 mg and most preferably at least 500 mg/ml) at ambient temperature. Particularly preferred are materials in which component (a) has a solubility of at least 10%, preferably at least 25% and most preferably at least 50% and/or in which component (b) has a solubility of at least 100%, more preferably at least 200% and most preferably at least 300% (e.g. in which component (b) has a solubility in the order of at least 1000, more preferably 2000 and most preferably at least 3000 mg/ml).

The components (c) which are suitable for use in the preparations prepared in accordance with the invention include:

c<1>) ethanol,

c<2>)<C>2_4-alkylene glycols,

c<3>) C3-5-alkylene polyols,

c<4>) poly-(C2_4-alkylene) glycols, and

c<5>) C3-5-alkylene polyol ethers or esters,

as well as any mixture thereof.

It is preferred to use c<2>, c3 and c4 as component c).

In accordance with the present invention, however, the use of ethanol, either alone or in admixture with any other component (c), will generally be less preferred.

When component (c) comprises a C2-4-alkylene glycol (c<2>), this is preferably a propylene glycol, most preferably 1,2-propylene glycol. When component (c) comprises a C3-5-alkylene polyol (c<3>), this is preferably a C3-5-alkylenetriol, most preferably glycerol.

When component (c) comprises a poly-(C2-4-alkylene) glycol (c<4>), this is suitably a polyethylene glycol. For use in the preparations prepared in accordance with the invention, such components have preferred an average molecular weight of no more than 7000 [see definition (iii)], e.g. up to 6600, more preferably no more than 2000, e.g. up to 1600, and most preferably no more than 500. Such components preferably have a viscosity of no more than 15,000 mPa.s., more preferably no more than 1,000 mPa.s., most preferably no more than 200 mPa.s. at 50°C or, more suitably, at ambient temperatures. Suitable polyethylene glycols for use as components (c) are e.g. described in Fiedler, Lexikon der Hilfstoffe, 2nd revised and expanded edition, [1981] vol. 2, pages 726 to 731, in particular the products PEG (polyethylene glycol) 200, 300, 400 and 600, as well as PEG 1000, 2000, 4000 or 6000, but especially 200, 300 and 400, e.g. in accordance with the following approximate physical properties:

When component (c) comprises a C3-5-alkylene polyol ether or ester (c<5>), this is suitably a C3-5-alkylene triol, in particular glycerol, ether or ester. Suitable components (c<5>) include mixed ethers or esters, i.e. components comprising other ether or ester constituents, e.g. transesterification products of C3-5-alkylene triolesters with other mono-, di- or polyols.

Particularly suitable components (c<5>) 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<5>) for use in accordance with the invention include products which can be obtained by transesterification of glycerides, e.g. triglycerides, with poly-(C2-4-alkylene) glycols, e.g. polyethylene glycols and possibly glycerol. Such transesterification products are generally obtained by alcoholysis of glycerides, e.g. triglycerides, in the presence of poly-(C2-4-alkylene) glycol, e.g. polyethylene glycol and possibly glycerol (ie to effect transesterification from the glyceride to the polyalkylene glycol/glycerol component, ie via polyalkylene glycololysis/glycerolysis). In general, such a reaction is carried out by reacting the indicated components (glyceride, polyalkylene glycol and possibly glycerol) at an increased temperature, under an inert atmosphere and with continuous stirring.

Preferred glycerides are fatty acid triglycerides, e.g.

(C10_22-fatty acid) triglycerides, including natural and hydrogenated oils, especially vegetable oils. Suitable vegetable oils include e.g. olive oil, almond oil, peanut oil, coconut oil, palm oil, soybean oil and wheat germ oil and, in particular, natural or hydrogenated oils rich in (C12_16-fatty acid) ester residues.

Preferred polyalkylene glycol materials are polyethylene glycols, particularly polyethylene glycols with a molecular weight of from 500 to 4000, e.g. from 1000 to 2000.

Suitable components (c<5>) thus include mixtures of C3-5 alkylene triolesters, e.g. mono-, di- and triesters in variable relative amounts, and poly-(C2_4-alkylene) glycol mono- and diesters, together with smaller amounts of free C3-5-alkylene triol and free poly-(C2-5-alkylene) glycol. As indicated above, the preferred alkylene triol moiety is glyceryl, preferred polyalkylene glycol moieties will be polyethylene glycyl, particularly with a molecular weight of from 500 to 4000, and preferred fatty acid moieties will be C10_22 fatty acid ester residues, particularly saturated C10_22<-> fatty acid ester residues.

Particularly suitable components (c<5>) can thus alternatively be defined as: transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and possibly glycerol, or mixtures comprising or consisting of glyceryl mono-, di- and tri-C10_22~ fatty acid esters and polyethyleneglycyl mono- and di-C10_22 fatty acid esters (possibly together with, for example, smaller amounts of free glycerol and free polyethylene glycol).

Preferred vegetable oils, polyethylene glycols or polyethylene glycol moieties and fatty acid moieties in connection with the above definitions are as indicated previously. Particularly suitable components (c<5>) as described above for use in the present invention are those that are known and commercially available under the trade name Gelucir, in particular the products:

i) Gelucir 33/01, with a melting point of 33-38°C and

a saponification number of 240-260,

ii) Gelucir 35/10, with a melting point of 29-34°C and

a saponification number of 120-140,

iii) Gelucir 37/02, with a melting point of 34-40°C and

a saponification figure of approx. 200-220, iv) Gelucir 42/12, with a melting point of 41-46°C and a

saponification number of 95-115,

v) Gelucir 44/14, with a melting point of 42-46°C and a saponification number of 75-95,

vi) Gelucir 46/07, with a melting point of 47-52°C and

a saponification number of 125-145,

vii) Gelucir 48/09, with a melting point of 47-52°C and et

saponification number of 105-125,

viii) Gelucir 50/02, with a melting point of 48-52°C and a

saponification number of 180-200,

ix) Gelucir 50/13, with a melting point of 46-41°C and et

saponification number of 65-85,

x) Gelucir 53/10, with a melting point of 48-53°C and a

saponification number of 95-115,

xi) Gelucir 62/05, with a melting point of 60-65°C and a

saponification figure of 70-90.

The products (i) to (x) mentioned above all have an acid value

<2. Product (xi) has an acid value <5. The products (ii), (iii) and (vi) to (x) as indicated above all have an iodine number <3. Product (i) has an iodine number^8. The products (iv) and (v) have an iodine number <5. Product (xi) has an iodine number <10. The components (c<5>) with an iodine number <1 will generally be preferred. Mixtures of the components (c<5>) as indicated can also be used in the preparations prepared in accordance with the invention.

When a component (c) as particularly described above is used, the preparations produced according to the invention will generally comprise component (a) in a carrier medium comprising the components (b) and (c). Commonly used components (a) and (b) will each be present in the preparations produced according to the invention in dispersion or solution, e.g. molecular or miscellar 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 component (b) will again be present in solution in (c). Component (b) will generally act as a carrier or a solubilizer (either pre- and/or post-supply) for component (a), and component (c) will act as a carrier or a fluidizing agent It is further preferred that when a component (c) as mentioned above is used, the preparations produced in accordance with the invention should be in fixed unit dose form which is suitable for oral administration, e.g. in the form of a capsule of hard or soft gelatin suitable for oral administration [see definition vi)]. Such unit dosage forms will, as described in detail later, suitably include e.g. from 2 to 200 mg of component (a) per unit dose.

When a component (c) as mentioned above is used, components (a) and (c) will preferably be present in the preparations produced according to the invention in a ratio of 1:0.5 to 50 parts by weight [(a):(c)] [see definition (ii)]. Components (a) and (b) will suitably be present in a ratio of from 1:3 to 200 parts by weight [(a):(b)].

When a component (c) as mentioned above is used, it is further preferred that the preparations produced in accordance with the invention are non-aqueous [see definition (v)]. The preparations may have a water content of less than 20%, more preferably less than 10% and even more preferably less than 5%, 2% or 1%, based on the total weight of the preparation.

In accordance with what has been mentioned above, the method according to the present invention also provides in a number of special embodiments: a pharmaceutical preparation comprising a component (a) and a component (b) as defined above and a diluent selected from any of components (c<1>.) to (c<4>) as defined above, or any mixture thereof, and meeting any of the definitions ( (ii)

(iii) , (v) and (vi) as set forth above,

a pharmaceutical preparation comprising a component (a), (b)

and (c<2>) as set out above and which meets definitions (ii), (v) or (vi) as set out above, and

a pharmaceutical preparation comprising a component (a), (b)

and (c<5>) as indicated above.

When a component (c) as specified above [ie component meeting any of the definitions (i) to (iii) or any of the components (c<1>) to (c<5>)] is used in said preparations prepared according to the invention, components (a) and (c) are suitably present in said preparations in a ratio of from 1:0.5 to 1:50 parts by weight. More suitably, components (a) and (c) are present in a ratio of from 1:1 to 1:10, more preferably from 1:1 to 1:5 and most preferably from 1:1.5 to 1:2.5, e.g. 1:1.6 or 1:2 parts by weight [(a):(c)]. Components (a) and (b) are suitably present in the above preparations in a ratio of from 1:3 to 1:200, preferably from 1:3 to 1:100 and more preferably from 1:3 to 1:50 parts by weight. More suitably, components (a) and (b) are present in a ratio of from 1:5 to 1:20, preferably 1:5 to 1:10 and most preferably from 1:6.0 to 1:6.5, e.g. e.g. 1:6.25 parts by weight [(a):(b)].

When the preparations produced in accordance with 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 ratio of 1:6 to 1:7 parts by weight [ (a):(b)] and components (a) and (c) are preferably present in a ratio of from 1:1.5 to 1:2.5, e.g. about 1:2 parts by weight [(a) : (c) ] .

Preparations prepared in accordance with the invention comprising a component (c) as indicated above can be prepared in any suitable dosage form, e.g. for oral, parenteral or topical administration, e.g. for dermal or ophthalmic administration, e.g. for delivery to the surface of the eye, e.g. for the treatment of autoimmune conditions in the eye as indicated above, or for intralesional injection, e.g. in the treatment of psoriasis.

Such preparations will conveniently be in unit dose form, either for oral administration or otherwise.

The amount of component (a) present in such unit dosage forms will of course vary depending on e.g. the condition being treated, the intended method of delivery and the desired effect. In general, however, such unit dosage forms will suitably comprise from 2 to 200 mg of component (a), e.g. Cyclosporine, per unit dosage form.

Suitable dosage forms for oral administration include e.g. liquid forms, granules and the like. However, solid unit dosage forms are preferred, e.g. in the form of tablets or capsules, especially hard or soft gelatin capsules. Such unit dosage forms for oral administration will suitably comprise from 5 to 200 mg, more suitably from 10 or 20 to 100 mg, e.g. 15, 20, 25, 50, 75 or 100 mg of component (a), e.g. Cyclosporine, per unit dose.

Preparations produced in accordance with the invention comprising a component (c) as indicated above have the further advantage that they are able to form a basis for preparations with modified release properties, e.g. delayed release of component (a) or release of component (a) over an extended period of time, e.g. after oral administration. Such preparations additionally comprise (d), a component capable of modifying the release properties of the preparation with respect to component (a). Such components (d) include e.g. polymeric auxiliaries, especially thickeners, e.g. polymeric or colloidal thickeners, as well as agents which are swellable in water, e.g. polymers or colloids which are swellable in water.

Suitable components (d) are known from the art and include: d<1>) Polyacrylate and polyacrylate copolymer resins, for for example polyacrylic acid and polyacrylic acid-methacrylic acid resins, which are known and commercially available under the trade name Carbopol (see Fiedler, loe. eit., 1,

pp. 206-207), in particular the products Carbopol 934, 940 and 941, and "Eudragit" (see Fiedler, loe. eit., 1, p. 372-373), in particular the products Eudragit E, L, S, RL and RS and especially the products Eudragit E, L and S.

d<2>) Celluloses and cellulose derivatives including: alkyl cellulose, e.g. methyl, ethyl and propyl celluloses, hydroxyalkyl celluloses, e.g. hydroxypropylcelluloses and hydroxypropylalkylcelluloses such as hydroxypropylmethylcelluloses, acylated celluloses, e.g. cellulose acetates, cellulose acetate phthalates, cellulose acetate succinates and hydroxypropylmethyl cellulose phthalates, and salts thereof such as sodium carboxymethyl celluloses. Examples of such products which are suitable for use in accordance with the invention are those which are known and commercially available, e.g. under the trade names Klucel and Methocel (see Fiedler, loe. eit., 1, p. 521 and 2, p. 601), especially the products Klucel LF, MF, GF and HF and Methocel K 100, K 15M, K 100M, E 5M , E 15, E 15M and E 100M.

d<3>) Polyvinylpyrrolidones, comprising e.g. poly-N-vinylpyrrolidones and vinylpyrrolidone copolymers such as vinylpyrrolidone vinylacetate copolymers. Examples of such compounds which are suitable for use in accordance with the invention are those which are known and commercially available, e.g. under the trade name Kollidon (see Fiedler, loe. eit., 1, pp. 526 and 527), especially the products Kollidon 30 and 90.

d<4>) Polyvinyl resins, e.g. including polyvinyl acetates and polyvinyl alcohols, as well as other polymeric materials including gum tragacanth, gum arabic, alginates, e.g. alginic acid and salts thereof, e.g. sodium alginates.

d<5>) Silicon dioxides, including hydrophilic silicon dioxide products, e.g. alkylated (eg methylated) silica gels, in particular colloidal silica products known and available under the trade name Aerosil [see Handbook of Pharmaceutical Excipients, published by the Pharmaceutical Society of Great Britain, pp. 253 to 256], and in particular the products Aerosil 130, 200, 300, 380, 0, OX 50, TT 600, MOX 80, MOX 170, LK 84 and the methylated Aerosil R 972.

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

When component (c) in the preparations produced according to the invention comprises: (c<6>) a solid polymer carrier as required by definition (iv) as mentioned above, this is preferably a polymer carrier which is soluble in water or in all essentially soluble in water.

Particularly preferred as components (c<6>) are polyvinylpyrrolidones [see Fiedler, loe. eit., 2, pp. 748-750], comprising especially cross-linked polyvinyl pyrrolidones. Examples of such materials which can be suitably used in the present invention are those which are known and commercially available under the trade name Kollidon [see Fiedler, loe. own., 1,

p. 527], Collisept [see Fiedler, loe. eit., 2, pp. 719-720],

Povidone and Crospovidone [see Fiedler, loe. eit., 2, p. 751].

Particularly suitable components (c<6>) are polyvinylpyrrolidones with a molecular weight of at least 10,000, and more suitably at least 20,000 or 25,000, e.g. with a molecular weight of about 40,000 or more. Crosslinked polyvinylpyrrolidones are of particular interest. Examples of specific products that can be suitably used in the present invention as (c<6>) are Plasdone XL, Plasdone XL 10 and Crospovidone.

When the preparations produced in accordance with the invention comprise a component (c<6>), they preferably also comprise (d), a component which is swellable in water or soluble in water, e.g. a cellulose or a cellulose derivative as stated under (d<2>) above.

Further examples of such materials which are of particular interest in connection with the preparations produced in accordance with the invention comprising a component (c<6>) are those which are known and commercially available under the trade name Avicel [see Fiedler, loe. eit., 1, pp. 160-161], Elcema [see Fiedler, loe. eit., 1, p. 326] and Pharmacoat [see Fiedler, loe. eit., 2, p. 707], e.g. the products Avicel PH 101 and PH 102, Elcema and Pharmacoat 603.

In the case where preparations produced according to the invention comprise a component (c6), component (a) is present in component (b) in solid solution, comprising solid micellar solution, e.g. wholly or substantially wholly, in molecular or miscellar dispersion. [In practice, components (b) will often exhibit at least a degree of fluidity, e.g. at ambient temperature or slightly increased temperature, and will thus not be "solid" in the truest sense. The term "solid solution" as used in the present description and patent claims shall be understood accordingly, e.g. to include viscous or highly viscous systems.] The solid solution covered by (a) and (b) is suitably dispersed, e.g. in particulate form, e.g. in the form of fine particles in, e.g. through, component (c<6>). Components (c<6>) will thus generally, in preparations prepared according to the invention, serve as a disintegrating matrix for [(a)+(b)]. Components (d) will generally serve as agents supporting the disintegration, e.g. by contact with the contents of the gastrointestinal tract.

Preparations produced according to the invention comprising a component (c<6>) will also suitably comprise (e), a binder and/or lubricant. Materials that can be suitably used as a binder/lubricant are particularly fatty acids and alkyl sulphonate salts, e.g. metal salts, e.g. with 10 or more carbon atoms in the fatty acid/alkyl part, e.g. C10_22 fatty acids and <C>10_22 alkylsulfonate alkali metal or alkaline earth metal salts, e.g. sodium, calcium or magnesium salts. Examples of such materials suitable for use in the present invention are sodium lauryl sulfate and magnesium stearate [see Fiedler, loe. eit., 2, p. 584].

When the preparations prepared in accordance with the invention comprise a component (c<6>), the components (a) and (b) are suitably present in a ratio of from 1:2 to 1:20, preferably from 1:2.5 to 10 and most preferably from 1:3 to 1:8 [ (a) : (b) ] .

The components (c<6>) are suitably present in the preparations prepared according to the invention in an amount of at least 10% by weight, more preferably at least 15% by weight and even more preferably at least 20% by weight based on the total weight of the preparation. Appropriate components (c<6>) are present in the preparations prepared according to the invention in an amount from 10 to 60% by weight, more preferably from 15 to 50% by weight, e.g. from 20 to 40% by weight, e.g. about 25, 30 or 35% by weight, based on the total weight of the preparation.

When a component (d) is present, the components (d) and (c<6>) are suitably present in a ratio of from 1:0.5 to 1:4, more preferably from 1:1 to 1:3 and most preferably from 1:1.5 to 1:2.5, e.g. 1:2 or about 1:2.5 parts by weight [(d):(c<6>)].

When a component (e) is present, the components (e) and (c<6>) are suitably present in a ratio of from 1:5 to 1:25, more preferably from 1:5 to 1:20 and most preferably from 1 :7 to 1:15 parts by weight [ (e):(c6)].

When the preparations produced in accordance with the invention comprise all three components (c<6>), (d) and (e) these are suitably present together in an amount from 25 to 75% by weight, more preferably from 30 to 65% by weight and most preferably from 40 to 65% by weight based on the total weight of the preparation. The ratio of the components [(a)+(b)]:[(c)+(d)+(e)] is suitably in the order of magnitude from 1:0.25 to 1:7.5, more preferably from 1:0, 5 to 1:5 and most preferably from 1:0.5 to 1:2, e.g. about 1:0.8, 1:1.2 or 1:1.3 parts by weight.

Preparations prepared in accordance with the invention comprising a component (c<6>) can be prepared in any suitable dosage form, e.g. for oral, parenteral or topical administration. Such preparations prepared in accordance with the invention will suitably be prepared in unit dose forms, either for oral administration or other administration.

The amount of component (a) present in such unit dosage forms will of course vary depending on e.g. the condition being treated, method of administration and desired effect. However, they will generally suitably comprise from 2 to 200 mg of component (a), e.g. Cyclosporine, per unit dose.

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

When component (c) in the preparations manufactured according to the invention comprises: (c<7>) an organosilicon oxide polymer or paraffinum per- or sub-flowable according to definition (iv) as stated above, component (c<7>) is preferably flowable at temperatures up to 150°C, preferably up to 100°C and more preferably up to 50°C. Matching components (c<7>) have a

maximum viscosity of 15,000 mPa.s., more preferably 1,000

mPa.s at the indicated temperatures.

Paraffin hydrocarbons suitable for use as component (c<7>) are liquid and semi-solid paraffins and mixtures thereof, e.g. paraffinum subliquidum and paraffinum perliquidum [see Fiedler loe. eit., 2, pp. 690-691]. To provide a ready-to-use preparation, component (c<7>) suitably consists of or essentially consists of liquid or semi-solid paraffins, i.e. "paraffinum perliquidum" or "paraffinum subliquidum", or mixtures thereof. However, when it is desired to form preparations with e.g. slower release of active ingredient, this can be achieved by further adding a solid paraffin, i.e. "paraffinum durum".

When the preparations produced in accordance with the invention only comprise liquid or semi-solid paraffins as component (c<7>), these are preferably present in a ratio of from 1:0.5 to 1:1.0 [liquid:semi-solid]. In this case, components (a) and (c<7>) are suitably present in a ratio of from 1:6 to 1:200, more preferably from 1:6 to 1:100 and most preferably from 1:6 to 1:20 , e.g. about 1:8 parts by weight [ (a) : (c) ] .

When the preparations produced in accordance with the invention further comprise a solid paraffin as component (c<7>), the ratio between liquid/semi-solid paraffin: solid paraffin is suitably from 1:0.06 to 1:0.1 parts by weight. In this case, components (a) and (c<7>) are suitably present in a ratio of from 1:6 to 1:200, more preferably from 1:6 to 1:100 and most preferably from 1:8 to 1:20 , e.g. about 1:10 parts by weight [ (a) : (c7) ] .

Organosilicon polymers suitable for use as component (c<7>) include in particular fluid, i.e. liquid and semi-solid polymer materials with a structural unit of the formula

-R2Si-0- in which each R is a monovalent organic radical, e.g. C1-4-alkyl, especially methyl, or phenyl. Especially for

drawn are organosiloxane polymers with a viscosity from 0.65 to 10<5>cP, in particular from 10 or 50 to 500 or 1,000 cP.

To provide ready-to-use preparations, component (c<7>) comprises suitable liquid organosiloxane polymers, e.g. polymethylsiloxane polymers, e.g. any of the known silicon oils, such as Silicon Oil 550, DC 200, SF-1066 and SF-1091 [see Fiedler, loe. eit., 2, p. 826]. When the preparations prepared in accordance with the invention comprise only liquid organosiloxane polymers, components (a) and (c<7>) are suitably present in a ratio of from 1:6 to 1:200, more preferably from 1:6 to 1:100 and most preferably from 1:6 to 1:20, e.g. about 1:8 parts by weight [ (a) : (c7) ] .

Preparations with e.g. slow release of the active ingredient can be achieved by using semi-solid organosiloxane polymers, e.g. any of the known silicon pastes, e.g. silicon paste A [see Fiedler, loe. own., 2,

p. 826] as a component (c<7>) or by adding these, e.g. to other organosilicon polymers as described above. In the latter case, the ratio of liquid:semi-solid organosilicon polymers present in the preparation prepared according to the invention is suitably in the order of magnitude from 1:0.5 to 1:1. In this case, the ratio of the components (a):(c<7>) is suitably in the order of magnitude from 1:6 to 1:100, preferably from 1:6 to 1:20 parts by weight [ (a) : (c7)] .

Mixtures of components (c<7>) as indicated can also be used in the preparations produced according to the invention.

When the preparations produced according to the invention comprise a component (c7), the components (a) and (b) are suitably present in a ratio of from 1:6 to 1:20, preferably from 1:6 to 1:10 and most preferably from 1:6.0 to 1:6.5, e.g. about 1:6.25 parts by weight [ (a): (b)].

In the case where the preparations produced according to the invention comprise a component (c<7>), component (a) is completely or substantially completely present in component (b) in molecular or miscellular dispersion, e.g. in the form of a solid solution or solid micellar solution [where the term "solid solution" is used here in the same broad way as in connection with preparations with component (c<6>)]. The solid solution comprising (a) and (b) is suitably dispersed with component (c<7>) in the form of particles, e.g. in the form of fine particles, e.g. throughout component (c7) .

Preparations prepared in accordance with the invention comprising a component (c<7>) can be prepared in any suitable dosage form, e.g. for oral, parenteral or topical administration, e.g. for dermal or ophthalmic administration, e.g. for delivery to the surface of the eye, e.g. for the treatment of autoimmune conditions in the eye as indicated above, or for intralesional injection, e.g. in the treatment of psoriasis. The preparations will suitably be prepared in unit dose form, either for oral administration or other administration.

The amount of component (a) present in such unit dosage forms will of course vary depending on e.g. the condition being treated, the intended method of administration and the desired effect. However, they will generally suitably comprise from 2 to 200 mg of component (a), e.g. Cyclosporine, per unit dose.

Suitable dosage forms for oral administration include liquids, granules and the like. However, solid unit dosage forms are preferred, e.g. in the form of tablets or capsules, especially in the form of hard or soft gelatin capsules. Such unit dosage forms for oral administration will suitably comprise from 5 to 200 mg, more suitably from 10 or 20 to 100 mg, e.g. 15, 20, 25, 50, 75 or 100 mg, component (a), e.g. Cyclosporine, per unit dose.

Preparations produced in accordance with the invention comprising a component (c<7>) have the further advantage that they can form the basis for preparations with modified release properties, e.g. delayed release of component (a), or release of component (a) over extended periods of time, e.g. after oral administration. Such preparations can be obtained as described above by incorporating solid or semi-solid components (c<7>) in appropriate amounts.

Alternatively, they can be obtained by incorporating a further component (d), i.e. a component capable of modifying the release properties of the mixture with respect to component (a). Such components (d) include e.g. polymeric auxiliaries, especially thickeners, e.g. polymeric or colloidal thickeners, as well as agents which are swellable in water, e.g. polymers or colloids which are swellable in water, e.g. any of the materials defined in the foregoing under (d<1>) to (d5) .

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

The components (d<5>) are particularly indicated for use in preparations prepared in accordance with the invention comprising an organosilicon polymer as component (c7).

Preparations produced in accordance with the invention comprising a component (c<6>) or (c<7>) will be, or preferably be non-aqueous, e.g. as described above in connection with preparations comprising other components - (c).

Preparations produced in accordance with the present invention can, regardless of the selected component (c)

[e.g. if component (c) comprises any of the components (c<1>) to (c<7>) as stated above or

any mixture thereof] include any additional additive, e.g. additives which are known and suitably used in the art, e.g. antioxidants [e.g. ascorbyl palmitate, tocopherols, butylhydroxyanisole (BHA) or butylhydroxytoluene (BHT)], flavorings, etc.

The preparations produced in accordance with the invention will particularly suitably comprise one or more stabilizers or buffers, in particular to prevent hydrolysis of component (b) or breakdown of component (a) during processing or storage. Such stabilizers may include acidic stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid, as well as basic stabilizers such as potassium hydrogen phosphate, glycine, lysine, arginine or tris(hydroxymethyl)aminomethane.

Such stabilizers or buffers will suitably be added in an amount sufficient to achieve or maintain a pH within the range from 3 to 8, more preferably from 5 to 7, e.g. between 6 and 7. Such stabilizers will generally be present in an amount of up to 5% by weight based on the total weight of the preparation, or up to 10% by weight, e.g. where citric acid or acetic acid is used. Preparations produced in accordance with the invention, in particular preparations where component (a) is Cyclosporine, and with a pH within the above-mentioned ranges, are preferred.

Preparations produced in accordance with the invention will also suitably comprise a polyoxyalkylene-free surfactant, such as e.g. dioctyl succinate, dioctyl sulfosuccinate, di[2-ethylhexyl] succinate, sodium lauryl sulfate or phospholipids, e.g. lecithins. When a surfactant as mentioned is present, this is suitably present in an amount of from 5 to 50, more preferably from 10 to 50, e.g. 10 to 25 by weight based on the weight of component (b).

When preparations produced according to the invention comprise component (a) in solid solution in component (b), e.g. when component (c) is a component (c<6>) or (c<7>) as set forth above, any stabilizer, buffer and/or surfactant is suitably incorporated into the solid solution. Such materials may also be included in component (c) etc.

Preparations produced in accordance with the invention, again regardless of the selected component (c), will preferably be without or essentially without ethanol. It may optionally contain less than 5.0%, more preferably less than 2.5%, e.g. from 0 to 1.0% ethanol, based on the total weight of the preparation.

The method according to the invention comprises thorough mixing of the components (a), (b) and (c) as defined above, possibly together with a component (d) and/or another component, e.g. stabilizer, buffer or surfactant as described above, and, if desired, the resulting preparation is prepared in the form of unit doses, e.g. unit dose for oral administration by e.g. tablet making, filling gelatin capsules or other suitable means.

When component (c) is a solvent for components (a) and (b), or comprises a component (c1), (c<2>), (c3), (c4) or (c<5>) as indicated above , the components (a), (b) and (c) are suitably brought together as mentioned by the components (a) and (b) being dissolved together in component (c) by heating to 50 - 150°C, preferably no more than 70°C or 75°C. The thus obtained mixture can then be further mixed with components (d) etc., by e.g. thorough mixing in accordance with known techniques. Filling hard or soft gelatin capsules is suitably carried out at an increased temperature, e.g. up to 50°C, to achieve preparation fluidity, e.g. in the heat.

In the case where preparations produced in accordance with the invention comprise component (a) in solid solution in component (b), e.g. preparations comprising a component (c<6>) or (c<7>) as indicated above, the method first comprises the appropriate preparation of a solid solution of (a) in (b) followed by thorough mixing of the obtained solid solution with the remaining components (c) and, optionally, (d), etc.

Solid solutions comprising components (a) in (b) can be prepared in accordance with known techniques, e.g. by solidifying a melt comprising (a) in solution in (b), or removing the solvent from a solution of components (a) and (b). In connection with the present invention, the last alternative is usually preferred.

Suitable solvents for components (a) and (b) include lower alkanols, e.g. ethanol. Stabilizers, buffers and/or surfactants are suitably incorporated in the dissolution step.

The solid solution thus obtained is then mixed appropriately, e.g. in the form of fine particles, with component (c) and possibly components (d) and (e) etc., e.g. by distribution in component (c).

Although ethanol can be used for the preparation of the preparations by e.g. preparation of solid solutions as described above, this will preferably be removed, by e.g. evaporation, before producing the final dosage form to give a product without ethanol or essentially without ethanol as indicated above.

The following examples illustrate preparations prepared according to 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: purity of lauryl ester residue = at least 95%: M.p. = about 35°C: cleavage at about 235°C: surface tension for 0.1% by weight aqueous solution = about 72.0 dyne/cm at 25°C.

EXAMPLES 1-10

The preparation in example 1 is prepared by dissolving components (a) and (b) in component (c) with stirring and heating in an oil bath at 100°C. The preparations in examples 2 to 10 are prepared in the same way. In the case of Examples 5 and 8, component (d) is dissolved in the first obtained mixture of components (a) to (c). In the case of Examples 6, 7 and 10, component (d) is suspended in (a) to (c).

The preparations obtained are filled, with heating, into capsules of hard gelatin, size 1 (Examples 1 to 4 and 9), or size 0 (Examples 5 to 7 and 10), to give an encapsulated final product, each capsule containing 50 mg of cyclosporine (e.g. cyclosporine) and are suitable for administration for the prevention of transplant rejection or for the treatment of autoimmune diseases, e.g. by supplying from 1 to 5 capsules per day.

EXAMPLES 11-13

The above preparations 11 to 13 will each suitably further comprise 25 mg (f) tartaric acid and/or 50 mg (g) dioctyl succinate, preferably both, with the preparations 11, 12 and 13 achieving a final weight of 1000 mg, 1055 mg and 6180 mg respectively .

Preparations 11 to 13 are prepared as follows: Components (a) and (b) are dissolved in absolute ethanol and the ethanol is evaporated at 50°C under reduced pressure. Components (c) through (e) are well mixed [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 into [(c)-(g)] and the obtained homogeneous mass is pressed into tablets each containing 100, 50 or 25 mg (a ) and which are appropriately administered to prevent transplant rejection or in the treatment of autoimmune diseases, e.g. by supplying from one to five tablets daily.

EXAMPLES 14-15

Components (a) and (b) are dissolved in absolute ethanol and the ethanol is evaporated at 50°C under reduced pressure. The resulting solid solution is ground to a fine powder and suspended homogeneously in component (c). The obtained liquid suspension is filled into capsules of hard gelatin, size 0, to give an encapsulated final product where each capsule contains 50 mg of cyclosporine (e.g. Ciclosporin) and which is suitably used to prevent transplant rejection or in the treatment of autoimmune diseases, e.g. .ex. by supplying from one to five capsules daily.

EXAMPLES 16-17

Preparations 16 and 17 are prepared analogously to preparations 14 and 15. In the case of preparation 16, (c) and (d) are first combined by melting them together and stirring thoroughly. The solid solution comprising [(a)+(b)] is then suspended in [(c)+(d)]. In the case of preparation 17, suspend (d) together with [(a)+(b)] in (c).

Equivalent preparations to those indicated in Examples 1 to 17 can be prepared using any other cyclosporin, e.g. [Nva]<2->Cyclosporin instead of Ciclosporin as component (a), or by using any other fatty acid saccharide monoester, e.g. as stated above, e.g. raffinose monolaurate, instead of sucrose monolaurate as component (b) in the same equivalent amount or relative proportion.

Use of the preparations prepared in accordance with the invention can be demonstrated in animal experiments or clinical trials such as e.g. has been carried out as follows: Investigation of bioavailability in dogs for preparations produced in accordance with the invention

a) Test preparations

PREPARATION I as in example 1

PREPARATION II as in example 14

b) Test method

Groups of 8 beagle dogs (males, approx. 11-13 kg)

are used. The animals received no food for 18 hours before administration of the test preparation, but had free access to water until administration. The test preparations are added by forced feeding, followed by 20 ml of 0.9% NaCl solution. The animals had free access to food and water three hours after administration of the test compound.

Blood samples of 2 ml (or 5 ml for the blank) are taken from the saphenous vein and collected in plastic tubes of 5 ml and containing EDTA at -15 min. (blind test), 30 min. and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after administration. The blood samples are stored at -18°C during the experiment. The blood samples are analyzed using RIA. The areas under curves showing the concentration of drug in blood versus time are calculated using the trapezoidal rule. Variance analysis is carried out with regard to AUC (area under the curve), Cmax. (maximum concentration) and Tmax. (maximum time).

c Results

Calculated mean values for AUC (in ng h/ml-<1>) and Cmax. (in ng/ml-<1>) from typical experiments are shown in the following table, together with calculated variation in response between test animals receiving the same preparation (CV).

As will be seen from the table above, the preparations prepared in accordance with the invention exhibit high bioavailability (AUC and Cmax.) together with relatively low variability with respect to response in each animal both for AUC and Cmax.

Comparably beneficial results can be obtained using other preparations in accordance with Examples 1 to 17, especially the preparations in Examples 1 to 10.

Clinical trial

The beneficial properties of the preparations produced according to the invention by oral administration can also be demonstrated in clinical trials, e.g. carried out as follows: The subjects were voluntary adults, e.g. men from 30 to 55 years. The experimental groups comprise a suitable twelve individuals.

The following criteria for inclusion/exclusion are used: Inclusion: Normal screening ECG, normal blood pressure and heart activity, body weight = 50-95 kg.

Exclusion: Clinically significant intercurrent medical

condition that may interfere with drug absorption, distribution, metabolism, excretion or safety, symptoms of significant clinical illness in the two weeks prior to the trial period, clinically relevant abnormal laboratory values or electrocardiogram, need for concomitant medication throughout the trial period, administration of any drug that is known to have a well-defined potential toxicity against an important organ system in the previous 3 months, administration of any investigational drug within 6 weeks before joining the trial, drug or alcohol abuse, loss of 500 ml or more of blood within the last 3 month period, adverse reaction to drug or hypersensitivity, allergy requiring drug therapy, Hep.B/HIV-positive.

A complete physical examination and EKG are carried out before and after the experiment. The following parameters are evaluated within one month before and after the experiment: Blood count of red blood cells, hemoglobin, hematocrit, erythrocyte sedimentation rate, white blood cell count, smear, platelet count and measurement of 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, sediment.

Creatinine clearance is also determined 1 month before the experiment starts.

Each individual received the experimental preparations in random order,<p>the preparations are administered orally once to a total dose of 150 mg cyclosporine, e.g. Cyclosporine, and at least 14 days are allowed between each application.

The supply is carried out in the morning after fasting for ten hours overnight, followed only by water. Only caffeine-free beverages are permitted in the 24-hour period after delivery. Individuals may not smoke for twelve hours after administration. The subjects received a standardized lunch four hours after administration.

Blood samples (2 ml) are taken one hour before administration and after administration at 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. For the determination of creatinine, blood samples of 2 ml were taken immediately before administration and 12, 24 and 48 hours after administration. Samples for cyclosporine determination are collected in two EDTA-coated polystyrene tubes (1 ml each) at each time point and deep-frozen at -20°C after careful shaking. Cyclosporine is measured in whole blood using RIA with specific and/or non-specific MAB determination

- detection limit in both cases = approx. 10 ng/ml.

In experiments carried out in accordance with the above, e.g. when comparing the preparation in example 1 encapsulated in hard gelatin with the current drinkable Ciclosporin solution (Ciklosporin = 50 mg, Labrafil =

150 mg, ethanol = 50 mg, corn oil = 213 mg, encapsulated in soft gelatin, final weight = 463 mg/dose) as a standard, significantly increased bioavailability levels are measured for the preparation from example 1 compared to the standard, which is reflected in both the AUC (0 -32 hours) and the Cmax. values. In addition, comparison of variation of cyclosporine concentration in whole blood (as determined by specific monoclonal RIA) with time after single administration of the test compounds to a cyclosporine dose of 150 mg will show a marked reduction in variability with respect to response between all subjects receiving the preparation in accordance with Example 1 compared to all subjects receiving the standard preparation.

Similar or equivalent results can be obtained after oral administration of other preparations prepared in accordance with the invention, e.g. as described in the examples.

Claims (12)

1. Process for the production of a pharmaceutical preparation with immunosuppressive activity and which can be used to treat autoimmune diseases, comprising a) a cyclosporine as active ingredient, b) a C6_18 fatty acid sucrose monoester and/or fatty acid raffinose monoester, and c) a diluent or a carrier, and if desired, one or more auxiliary substances and/or excipients that are commonly used within the pharmaceutical industry, characterized in that component a), used in a mass ratio of 1:3 to 1:200 in relation to component b), dissolves together with component b) in component c) by heating to 50-150°C, or a melt or a solution of component a) and component b), used in the above mass ratio, is brought into solid form with the achievement of a solid solution of component a) in component b) which is then mixed or processed with component c), obtaining a pharmaceutical preparation in which: i) both components a) and b) are, independently of each other, soluble in component c) in a concentration of at least 10% at ambient temperature, and/or ii) components a) and c) are present in said preparation in a mass ratio from 1:0.5 to 1:50, and/or iii) component c) comprises a poly-(C2_4-alkylene) glycol with an average molecular weight of no more than 7,000 or a viscosity at 50°C of at most 15,000 mPa.s, or component c) comprises a (C3-5-alkylene) polyol ether or ester, and/or iv) component c) comprises a solid polymer carrier, an organosilicon polymer or per- or sub-liquid paraffin, and component a) is present in said preparation as a solid solution in component b), and/or v) the preparation is non-aqueous, and/or vi) the preparation is formulated in fixed unit dose form, e.g. capsule form, which is suitable for oral administration. 2. Process as stated in claim 1 for the production of a pharmaceutical preparation comprising a) a cyclosporine as active ingredient and b) a C6_18 fatty acid sucrose monoester and/or fatty acid raffinose monoester and, in a given case, one or more excipients that are generally used within the pharmaceutical industry, and which has immunosuppressive activity and which can be used to treat autoimmune diseases, characterized in that a substance is used as component c) where the active agent a) and component b) can be dissolved independently of each other in a concentration of at least 10% at ambient temperature . 3. Process as stated in claim 1 for the production of a pharmaceutical preparation comprising a) a cyclosporine as active ingredient and b) a C6_18 fatty acid sucrose monoester and/or fatty acid raffinose monoester and, in a given case, one or more excipients that are generally used within the pharmaceutical industry, and which have immunosuppressive activity and which can be used for the treatment of autoimmune diseases, characterized in that component a) is used in the form of a solid solution formed with component b) in a carrier. 4. Process as stated in claim 1 for the production of a pharmaceutical preparation comprising a) a cyclosporine as active ingredient and b) a C6_18 fatty acid sucrose monoester and/or fatty acid raffinose monoester and, in a given case, one or more excipients that are generally used within the pharmaceutical industry, and which have immunosuppressive activity and which can be used for the treatment of autoimmune diseases, characterized in that component a) is used in the form of a solid solution formed with component b), and where a solid carrier, preferably a solid polymer, is used as component c). 5. Procedure as stated in claim 1, characterized by that a C6_18 fatty acid sucrose monoester is used as component b), and c<2>) a<C>2-4-alkylene glycol, c<3>) a<C>3-5-alkylene polyol, or c<4>) a poly-(C2-4-alkylene)glycol, is used as dilution component c), in which i) components a) and c) are present in said preparation in a mass ratio from 1:0.5 to 1:50, ii) said preparation is formulated in fixed unit dose forms, e.g. capsule form, which is suitable for oral administration, and/or iii) component c) is a component with an average molecular weight of not more than 7,000 or a viscosity at 50°C of not more than 15,000 mPa.s. 6. Procedure as stated in claim 1, characterized by that a ciclosporin-active agent is used as component a), a C6_18 fatty acid sucrose monoester is used as comp nent b) , and 1,2-propylene glycol is used as component c), wherein i) components a) and c) are present in a mass ratio from 1:0.5 to 1:50, and/or ii) said preparation is formulated in fixed unit dosage forms, e.g. capsule, suitable for oral administration. 7. Method as stated in claim 1, characterized in that component a) is used in the form of a solid solution formed with component b) and poly(vinylpyrrolidone) is used as component c) as a solid polymer carrier. 8. Method as stated in claim 7, characterized in that the cyclosporin, as active agent, is used in said preparation in a mass ratio of 1:3 to 1:20 in relation to the C6_18 fatty acid sucrose mono-ester, while component c) is used in a mass ratio of at least 10% in relation to the total preparation mass. 9. Procedure as specified in one or more of claims 1 or 5-8, characterized in that the preparation is produced in unit dose form and comprises from 2 to 200 mg of component a) per unit dose. 10. Procedure as stated in claim 1, characterized by a ciclosporin is used as component a), a C6_18 fatty acid sucrose monoester is used as component b), and 1,2-propylene glycol is used as component c), where component a) is used in an amount from 20 to 100 mg, component a) is used in a mass ratio of 1:3 to 1:200 in relation to component c), and component a) is used in relation to component c) in a mass ratio of 1:0.5 to 1:50. 11. Procedure as specified in one or more of claims 1 or 5 - 10, characterized in that cyclosporine A is used as component a). 12. Procedure as specified in one or more of claims 1 or 5-11, characterized in that C6_18-raffinose monolaurate or sucrose monolaurate is used as component b).