Pharmaceutical compositions comprising cyclosporins

(42) Date of commencement of the patent: 15. 7.1997 (45) Date of issue: 25. 2.1998 (30) Priority:

(73) Patent owner:

16th 9.1988 GB 8821754 claims.

9th 2.1989 GB 8902903 claims.

9th 2.1989 GB 8902900 claims.

(56) Citations: DE 3742473A1

NOVARTIS INVENTIONS ADMINISTRATIVE COMPANY A-1235 VIENNA (AT).

cq (54) CYCLOSPORINE-CONTAINING PHARMACEUTICAL COMPOSITION (57) Disclosed are pharmaceutical compositions containing a cyclosporin such as cyclosporin or [Nva]²Ciclosporin, in the form of a so-called microemulsion pre-concentrate or a microemulsion. These compositions usually contain as component 1.1. a C_rC₅Alkyl- or tetrahydrofurfurethanethanether or partial ethers of a low molecular weight mono- or polyoxyalkanediol, such as transcutol or glycofurol, as a hydrophilic component. Also included herein are compositions containing a cyclosporin and a component 1.1. and expediently also a saccharide monoester, such as raffinose monolaurate or sucrose monoarylate. Suitable dosage forms are topical formulations and especially oral dosage forms.

SC17 ίον IV ns e & sas

AT 403 435 B

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

The cyclosporins comprise a class of structurally distinct cyclic poly-N-methylated undecapeptides which usually have pharmacological properties, in particular immunosuppressive properties, anti-inflammatory properties and / or antiparasitic properties. The first cyclosporin to be isolated was the naturally occurring fungal metabolite ciclosporin or cyclosporin, also known as cyclosporin A, and commercially available under the registered trademarks SANDIMMUN® or SANDIMMUNE®. Ciclosporin represents the cyclosporin of the following Formula A.

-EffenEmt- * Äbu-Sar-MeLeu-Val-MeLeu-Ala- (D) Ala-MeLeu-MeLeu-MeVal1 234567 8 9 10 11 (A) wherein -MeBmt- for the N-methyl- (4R) -4- but-2E-en-1-yl-4-methyl- (L) threonyl of the following formula B.

<img file="AT403435B_D0001.tif" />

(B)

Herein, -xy- is -CH = CH- (trans).

As the strain of the class, the ciclosporin has received the most attention so far. Ciclosporin clinical trials have focused primarily on its use as an immunosuppressive agent, in particular its use in the treatment of transplant recipients such as heart transplants, lung transplants, heart-lung transplants, liver transplants, kidney transplants, pancreas transplants, bone marrow transplants, skin grafts or Corneal transplants, and in particular of ailogenic organ transplants. Ciclosporin has been very successful in this field of application.

At the same time, ciclosporin was tested for its suitability for the treatment of various autoimmune diseases and inflammatory conditions, in particular inflammatory conditions with an autoimmune component as the cause of the disease, as of arthritis (for example arthritis rheumatica, Arthritis chronica progressive and arthritis deformans) and rheumatic diseases, and the literature reports in detail on the results obtained in these studies in vitro on animal models and in clinical trials. Autoimmune diseases, for whose treatment ciclosporin has been proposed or used, For example, autoimmune hematologic disorders (such as hemolytic anemia, aplastic anemia, Anemia with pure erythrocyte waste and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener Granuiomatose, dermatomyositis, chronic acute hepatitis, Myasthenia gravis, Psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory diseases of the intestine (such as ulcerative colitis and Crohn2

AT 403 435 Β

Disease), endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (type 1 diabetes mellitus), uveitis (anterior and posterior), vernal conjunctivitis, sicca keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephrosis (with and without nephrosis syndrome, including idiopathic nephrosis syndrome or minimal-damage nephropathy).

Ciclosporin has also been tested for its potential utility in other fields, such as antiparasitic agents, especially antiprotozoal agents, as well as its potential for use in the treatment of malaria, coccidiomycosis and schistosomiasis, and more recently for use as a reversal or reversal agent Resistance of tumors to antineoplastic agents and the like have been proposed.

Since the original discovery of ciclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified, with many other unnatural cyclosporins also being produced by total synthesis or semisynthesis or by use of modified breeding techniques. The cyclosporins thus represent an important class of compounds, and these include, for example, the naturally occurring cyclosporins A to Z (Helv. Chim. Acta. 60, pages 1247 to 1255 (1977) (Traber et al), Helv. Chim. Acta. 65, pages 1655 to 1667 (1982) (Traber et al), Europ. J. Applied Microbiology and Biotechnology 14, Pages 273-240 (1982) (Kobel et al) and Progress in Allergy 38, Pages 28 to 45 (1986) (Wartburg et al.)) And also various unnatural cyclosporin derivatives as well as artificial or synthetic cyclosporins including the so-called dihydrocyclosporins, in which the bridge -xy- of the radical -MeBmt- (above formula B) is saturated, such that -xy-stands for -CH 2 -CH 2 - derivatized cyclosporins, in which a further substituent is introduced at the α-carbon atom of the sarcosyl residue in position 3 of the cyclosporin molecule, cyclosporine, in which the remainder -MeBmt- is present in an isomeric form, where, for example, the configuration of the positions 6 'and 7 * of the remainder -MeBmt- is a cis configuration and not a trans configuration, and cyclosporins, where different amino acids are incorporated at specific positions in the peptide sequence, which, for example, by R. Wenger developed process for the preparation of cyclosporins can be done by total synthesis, and for this purpose, for example, Helv. Chim. Acta. 60, pages 1247 to 1255 (1977) (Traber et al), Helv. Chim. Acta. 65, pages 1655 to 1667 (1982) (Traber et al), Europ. J. Applied Microbiology and Biotechnology 14, pp. 273-240 (1982) (Kobel et al), US-A-4,108,985, US-A-4,210,581, US-A-4,220,641, EU-A-0 034 567, EU-A 0 056 782, WO-A 86/02080, Transp. Proc. 15, Supplement 1, page 2230 (1983) (Wenger), Angew. Chem. Int. Ed. 24, page 77 (1985) (Wenger) and Progress in the Chemistry of Organic Natural Products 50, page 123 (1986) (Wenger).

The cyclosporins are thus indeed a very broad compound class, and these include, for example, [Thr]²-, [Val]²-, [Nva]²- and [Nva]²- [Nvaj⁵Ciclosporin, also known as cyclosporins C, D, G and M, [3-O-acyl MeBmt]¹Ciclosporin, also known as the acetate of cyclosporin A, [Dihydro-MeBmtj¹- [Val]²Ciclosporin, also known as dihydrocyclosporin D, [(D) fluoromethyl-sar]³-Ciclosporin, [(D) Serj^8th-Ciclosporin, [Melle] '¹-Ciclosporin, [(D) MeValj¹¹-Ciclosporin, also known as Cyclosporin H, [MeAla]⁶-Ciclosporin, [(DjProp-Ciclosporin and the like.

According to the nomenclature now recognized for cyclosporins, these compounds are defined by reference to the structure of cyclosporin, namely cyclosporin A. This is done first by stating the amino acid residues present that are different from the residues present in the cyclosporin so that, for example, the term [( D) Proj³ indicates that the cyclosporin in question 3 has a residue - (D) Pro and no residue -Sar-, in which case the term ciclosporin is used to characterize the remaining residues which are identical to the residues present in the cyclosporin. Individual radicals are numbered starting from the radical -MeBmt- or from the radical -DihydroMeBmt- in position 1.

Many of these other cyclosporins have ciclosporin comparable or more specific utility, for example, efficacy, in particular, to reverse the resistance of tumors to therapeutic treatment with cytostatic agents, and there is a wealth of suggestion in the literature for the use of such cyclosporins as therapeutic Medium.

Despite the very significant contribution, has provided ciclosporin, in particular in the field of organ transplantation and the therapeutic treatment of autoimmune diseases, are the difficulties which preclude the creation of more effective and convenient galenic forms, and also the previously known undesirable side reactions, especially nephrotoxic reactions, So far, it appears that there have been serious obstacles to wider use and application of these agents. The cyclosporins are strongly hydrophobic substances. Corresponding liquid formulations of cyclosporins, such as formulations for oral administration, have hitherto mainly been based on the use of ethanol and oils or similar excipients as carrier media. The commercial

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Drinking solution of ciclosporin contains as a carrier medium, for example, ethanol and olive oil in conjunction with Labrafil as a surface-active agent, for which reference is made, for example, to US Pat. No. 4,388,307. However, the use of such a drink solution or similar known compositions is associated with a number of difficulties.

The need to use oil-based oils or vehicles can give the preparations an unpleasant taste or otherwise reduce their acceptability, especially with long-term therapy. In the form of gelatine capsules, however, these effects can be masked. However, in order to keep the cyclosporin in solution, it is necessary to keep the content of ethanol high. By evaporation of the ethanol, for example, from capsules or other forms after opening, however, it comes to the precipitation of cyclosporin. Therefore, if such compositions are, for example, in soft gelatin capsules, then the particular difficulty involved requires packaging the encapsulated product into an airtight container, namely, for example, a package in the form of an airtight bladder or a corresponding aluminum foil. However, this makes the product both voluminous and more expensive in its production. Also, the storage characteristics of such formulations are far from ideal.

Further, the bioavailability data achievable using the known oral dosage systems of cyclosporin are also low and vary fairly widely between the respective recipients, the types of patients and even the individual recipients at different times during the course of the therapeutic treatment. It is therefore reported in the literature that the currently available therapeutic treatment using the commercially available ciclosporin drink solutions gives an absolute bioavailability of only about 30 percent on average, with pronounced discrepancies between the individual patient groups, as between recipients of liver transplants (relatively low bioavailability) or bone marrow transplants (relatively high bioavailability). The reported deviations in bioavailability between the respective recipients vary between one percent or a few percent in certain patients and up to 90 percent or even more in other patients. Furthermore, as already mentioned, a pronounced change in the bioavailability of the respective patients can be observed over time.

In order to obtain an effective immunosuppressive therapeutic regimen, the blood levels or blood serum levels of cyclosporin must be kept within a certain range. The particular range required may vary depending on the particular condition to be treated, such as whether the particular treatment is intended to prevent rejection of the graft or to control autoimmune disease, and whether or not at the same time as therapeutic treatment by cyclosporin therapeutic treatment with another immunosuppressive agent is applied or not. Due to the wide variability of bioavailability values ​​associated with the conventional dosage forms of cyclosporin, the daily doses necessary to achieve the required blood serum levels also vary widely from recipient to recipient and even to a single recipient. The blood levels or blood serum levels of patients undergoing therapeutic treatment with cyclosporin should therefore be monitored at regular and frequent intervals. Such monitoring is generally carried out by the use of radioimmunoassay or comparable immunoassays, for example by the use of monoclonal antibody-based methods, and must, as already mentioned, be carried out on a regular basis. This is inevitably time consuming and cumbersome, thereby significantly increasing the overall cost of therapeutic treatment.

These very significant practical difficulties are the already mentioned occurrence of undesirable side reactions, which are observed in the use of the previously available oral dosage forms.

To solve these various problems, several proposals have already been made in the art including both solid and liquid oral dosage forms. However, the prevailing difficulty has always been that the cyclosporins, such as cyclosporin, are inherently insoluble in aqueous media. There are therefore no dosage forms that contain cyclosporins in such high concentration that they can be used pleasantly and still have the required criteria for bioavailability, namely allow effective absorption in the stomach or intestinal lumen, and stable and sufficiently high blood levels or Blood serum levels.

The particular difficulties encountered with oral administration of cyclosporins have inevitably led to limitations in the use of cyclosporin as a therapeutic agent for the treatment of diseases that are relatively less serious or dangerous. A special area where

There are difficulties of this kind, the use of cyclosporin as a therapeutic for the treatment of autoimmune diseases and other conditions affecting the skin, for example for the treatment of atopic dermatitis and psoriasis and for the stimulation of the growth of hair, which also already has been proposed many times, such as for the treatment of alopecia, what it comes in the course of aging or as a result of illness.

Although oral therapeutic treatment with ciclosporin has shown that this drug can be used to advantage in patients suffering from, for example, psoriasis, the risk of side reactions associated with oral therapeutic treatment has hitherto prevented the general use of this drug , Various proposals have also been made for the use of cyclosporins, such as cyclosporin, in topical forms, and a number of topical delivery systems have also been described. In experiments with a topical application, however, no therapeutic effect could be shown. An agent for topical application, which effectively nourishes the skin and is useful, for example, in the treatment of psoriasis, would therefore make therapeutic treatment with cyclosporin available to a clinical picture in which many patients suffer.

The present invention provides novel galenic formulations of cyclosporin which are in the form of a microemulsion pre-concentrate and / or are based on the use of certain solvent media of the type defined in more detail below, thereby resulting in the difficulties encountered in the known therapeutic application of cyclosporin, such as cyclosporine eliminate or significantly reduce. It has been found, in particular, that the compositions of the invention allow the preparation of solid, semisolid or liquid compositions containing a cyclosporin in such a high concentration that thereby, for example, a convenient oral administration is possible, while at the same time an improved efficiency, for example with respect on the bioavailability behavior.

In particular, it has been found that the compositions of the present invention allow effective dosing of cyclosporin with concomitant enhancement of absorption levels / bioavailability levels, and thus also reduce the range of variation in absorption levels / bioavailability levels seen in the past therapeutic use of cyclosporin in the individual patient as well occurs between the different patients. The use of the teaching of the present invention enables the preparation of dosage forms of cyclosporin which can reduce the variability in the blood levels and blood serum levels of cyclosporin achieved between doses for individual patients and also between individual patients and individual patient groups. The invention thus enables a lowering of the dosage levels of cyclosporin which are necessary to achieve an effective therapeutic treatment. Further, this will allow for closer standardization and also optimization of the daily daily dosage requirement for individual patients being treated with cyclosporin therapeutically and also for patient groups that are under comparable therapeutic treatment.

Closer standardization of the dose rate for each patient and the associated response or blood serum level, as well as the dosing parameters and response parameters in the respective patient groups may reduce the level of otherwise required monitoring, thereby significantly reducing the cost of the particular therapeutic agent Treatment results.

By reducing the dosage or standardization of cyclosporin necessary to achieve the required bioavailability characteristics, the present invention also provides for a reduction in the incidence of undesirable side effects, particularly nephrotic responses, in patients undergoing therapeutic treatment with cyclosporin.

Furthermore, the present invention enables the preparation of compositions which are not based on an alkanol and thus, for example, contain no or virtually no ethanol. Such compositions avoid the aforementioned difficulties of lack of stability and associated special processing methods which adhere to the known alkanolic compositions. The invention thus provides, among other things, compositions which are more suitable, for example, for presentation in the form of capsules, such as hard gelatin capsules or soft gelatin capsules, and / or which avoid or greatly reduce the difficulties arising from the otherwise necessary packaging, as they do have been mentioned above, for example, in connection with soft gelatin capsules.

With regard to topical application, the present invention further enables the preparation of novel galenic formulations containing a cyclosporin, such as cyclosporine, as an active ingredient and permits an improved treatment of autoimmune diseases affecting the skin, and in particular

AT 403 435 of dermatological diseases which are based on a morbid proliferation and / or keratinization of the epidermis, in particular of psoriasis and atopic dermatosis. Topically applicable compositions based on the invention can also be used to treat alopecia, such as to increase the growth of hair.

A first embodiment of the present invention are pharmaceutical compositions containing a cyclosporin as active ingredient and having the form of a microemulsion preconcentrate.

A microemulsion preconconcentrate is understood here to mean a system which gives a microemulsion on contact with water, as when added to water. Such a microemulsion is conventionally recognized as a non-opaque or substantially non-opaque colloidal dispersion containing water and organic components including hydrophobic (lipophilic) organic components. Microemulsions can be recognized by having one or more of the following properties. They are formed spontaneously or practically spontaneously when their components are brought into contact with each other. Thus, there is virtually no supply of energy necessary for this, and the formation of such microemulsions therefore proceeds, for example, without heating or application of high shear or other substantial mixing. Such microemulsions are thermodynamically stable and single-phase.

They are virtually non-opaque, namely transparent or opalescent, when viewed under an optical microscope. They are optically isotropic in their undisturbed state, although an anisotropic structure can be observed by observation using, for example, an X-ray technique.

The microemulsions contain a disperse or lumpy (droplet) phase whose particles are less than 200 nm in size, giving rise to their optical transparency. The particles of a microemulsion may be spherical, but may also have other structures, for example liquid crystals with lamellar, hexagonal or isotropic symmetries. In general, the microemulsions contain droplets or particles having a maximum dimension, for example a diameter, of less than 150 nm, for example usually of 10 to 100 nm.

For further discussion of the properties of microemulsions, reference is made, for example, to Progress in Surface and Membrane Science 12, pp. 405 et seq., Academic Press (1975) (Rosof), Dispersion Science and Technology 6, (3), pp. 317 et seq ) (Friberg) and Pharm. Ind. 50, (3), pp. 370 et seq. (1988) (Müller et al).

From the above, it is apparent that the microemulsion preconcentrates according to the invention are galenical systems which contain a cyclosporin as the active ingredient and are capable of forming a microemulsion spontaneously or practically spontaneously when combined with water alone.

Pharmaceutical compositions in the form of such microemulsion preconcentrates containing cyclosporins as active ingredient are new. An embodiment of the present invention is therefore (A) a pharmaceutical composition having a cyclosporin as an active ingredient which is characterized by being a so-called microemulsion pre-concentrate.

By a pharmaceutical composition is meant herein compositions whose individual components or ingredients are themselves pharmaceutically acceptable, such that they are acceptable for oral administration, for example, in the case of an intended oral administration, and acceptable for topical application in the event of an intended topical administration.

In addition to the cyclosporin serving as the active ingredient, the microemulsion pre-concentrate which forms the compositions according to the invention expediently also contains (1) a hydrophilic phase, (2) a lipophilic phase, and (3) a surface-active agent.

The cyclosporin is carried in the lipophilic phase. Conveniently, both the hydrophilic phase and the lipophilic phase serves as a carrier medium.

The microemulsion preconcentrates according to the invention are what are known as oil-in-water emulsions (O / W emulsions). However, compositions according to the composition mentioned above under (A) may, of course, also contain minor amounts of water or otherwise have fine structural features characteristic of microemulsions, such that they may, for example, be O / W or W / O microemulsions (water-in Oil emulsions). From a Mikroemulsionsvorkonzentrat therefore such possibilities are included in the present case.

Microemulsions resulting from contact of the inventive microemulsion preconcentrate with water or other aqueous medium are thermodynamically stable, meaning that they remain stable at ambient temperature for a long time, so that

AT 403 435 Β, for example, they do not become cloudy or form droplets of a regular size for emulsions or give rise to precipitation. Of course, a sufficient amount of water is necessary to form a microemulsion. Although the upper limit for dilution is not critical, a dilution of 1: 1 parts by weight (ppw), for example, of 1: 5 parts by weight (ppw) (microemulsion preconcentrate: H₂0) or above. Preferably, when in contact with water, the microemulsion preconcentrates representing the compositions of the present invention should be capable of producing microemulsions which remain stable at ambient temperatures, as evidenced by the absence of any optically observable clouding or precipitation, for a period of at least 2 hours, preferably at least 4 Hours, and in particular of at least 12 to 24 hours. Microemulsions obtainable from the microemulsion preconcentrates according to the invention preferably have, for example at the dilutions given above, an average particle size of about 150 nm, in particular less than about 100 to 110 nm, and for example down to about 15 or 20 nm.

Particular preference is given according to the invention to compositions of the type defined above under (A), which are characterized in that they

1.1. a pharmaceutically acceptable C 1 -C 8 alkyl or tetrahydrofurfuryl diether or part ether of a low molecular weight mono- or polyoxyalkanediol or

1.2. Contain 1,2-propylene glycol as the hydrophilic component.

Suitable components 1.1. For example, diethers or part ethers, especially partial ethers, are mono- or polyoxyalkanediols, especially mono- or dioxyalkanediols, having 2 to 12 carbon atoms, and most preferably 4 carbon atoms. Preferably, the monooxyalkanediol radical or the polyoxyalkanediol radical is straight-chain. Particularly suitable according to the invention are the diethers or partial ethers of the general formula (I)

Ri - [O- (CH₂)₂] X-OR₂ (I) wherein

Ri is Ci-Cs-alkyl or tetrahydrofurfuryl,

R₂ Is hydrogen, Ci-Cs-alkyl or tetrahydrofurfuryl, and x is a number from 1 to 6, in particular from 1 to 4 and especially of about 2, means. Particularly preferred according to the invention are the part ethers of the type defined above, for example

Products of the indicated general formula (I), wherein R₂ Is hydrogen.

The Ci-Cs-alkyl radicals in the ethers defined above may be branched or straight-chain, and

Examples of these are methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl.

Such ethers are known and commercially available products or may be analogous to known ones

Products are produced. Particularly preferred products of the formula (I) which can be used according to the invention are the products which are commercially available under the trade names Transcutol and Glycofurol.

Transcutol is the compound diethylene glycol monoethyl ether of the formula (I) where R i = C₂Hs, R₂ = H and x = 2.

Glycofurol, which is also known as Tetrahydrofurfurylalkoholpolyethylenglykolether or a- (tetrahydrofurfuryl) - jhydroxypoly (oxy-1,2-ethanediyl), has the formula I with

<img file="AT403435B_D0002.tif" />

R₂ = H and x = an average of 1 to 2. This compound has an average molecular weight of about 190, a boiling point of about 80 to 100 ° C (at 40 N / m²), a density of about 1.070 to 1.090 g / cm³ (at 20 'C), a hydroxyl value of about 300 to 400, a refractive index of about 1.4545 (D-line of sodium, 589 mm) (at 40'C) and a viscosity of about 8 to 18 mN s / m² (at 20'C). For further information on this, reference is made, for example, to Handbook of Pharmaceutical Excipients, publisher American Pharmaceutical Association / The Pharmaceutical Society of Great Britain, page 127 (1986) and to Lexikon der Hilfsstoffe, 3rd edition, page 577 (1989) by Fiedler.

The exact properties of glycofurol vary depending on its relative purity.

Poor quality grades contain a considerable amount of tetrahydrofurfuryl alcohol and other impurities7

AT 403 435 Β cleaning. For the purposes of the present invention, therefore, it is preferable to use glycofurol 75, which is a product having the above-mentioned properties and in which the proportion corresponding to the above formula (I) wherein x is 1 to 2 in th e Minimum 95 percent.

It has been found, in particular, that the use of components of the above under 1.1. and 1.2. defined type compositions according to (A), whose hydrophilic phase is particularly well suited as a carrier medium for cyclosporin, since such a hydrophilic phase allows a loading of the composition with cyclosporin, which is sufficient for a convenient therapeutic dosage, for example, for oral administration.

Compositions of the type mentioned above under (A), which as hydrophilic phase components of the above 1.1. and / or 1.2. Naturally, in addition, one or more further constituents may also be contained as a component of the hydrophilic phase. However, such further components are preferably materials in which the active substance cyclosporin is sufficiently soluble, so that thereby the effectiveness of serving as a carrier medium for the cyclosporin hydrophilic phase is not significantly deteriorated. Examples of such possible further components of the hydrophilic phase are lower alkanols, for example C 1 -C 8 -alkanols, in particular ethanol.

Although the use of alkanoates, such as ethanol, as a component of the hydrophilic phase is possible according to the invention, it is generally less preferred for the reasons already discussed above. The compositions of the type defined above under (A) are therefore preferably not based on alkanols, which means that they contain no alkanol as the predominant component of the hydrophilic phase. The hydrophilic phase desirably contains less than 50 weight percent, preferably less than 25 weight percent, and most preferably less than 10 weight percent of alkanolic components. Most preferably, the hydrophilic phase is free or substantially free of alkanolic components so that it generally contains less than 5 weight percent, and preferably less than 2 weight percent, for example, only 0 weight percent to 1 weight percent of alkanolic components. Under an alkanol are understood in particular Ci -Cs alkanols, and especially ethanol understood.

A particularly preferred embodiment of the hydrophilic phase of the compositions defined above under (A) consists at all or essentially of components of the above in 1.1. or

1.2. defined type, and especially from transcutol, glycofurol and / or 1,2-propylene glycol. Most conveniently, this total hydrophilic phase, or virtually all, consists of either components 1.1. or from component 1.2.

Compositions according to the above definition (A) which contain a component 1.1., And in particular glycofurol, are of particular interest, since they are particularly suitable for inclusion in soft gelatin capsules. It has also been found, according to the invention, of such compositions that they are surprisingly particularly stable, as could be demonstrated, for example, in long-term stability tests at normal and elevated temperatures. Such compositions, therefore, are particularly sensitive to the difficulties associated with transporting and storing medicinal products, including end-user storage, such as in hospitals, clinics, and the like.

Compositions of the type defined above under (A) also contain a lipophilic phase (2).

Suitable components which can be used as the lipophilic phase include all pharmaceutically acceptable solvents which react with the particular hydrophilic phase selected, such as a hydrophilic phase of the above 1.1. or 1.2. defined type, do not mix. Such solvents expediently have no or virtually no surface-active function. Particularly suitable components which can be used as components (2) for the lipophilic phase are, for example, the following:

Fatty acid triglycerides, preferably medium chain fatty acid triglycerides. Particularly suitable are neutral oils, such as neutral vegetable oils, and in particular fractionated coconut oils, as known for example under the trade name Miglyol and commercially available, including again on Lexicon of excipients, 3rd edition, pages 808-809, (1989) by Fiedler is pointed out. These include, for example, the following products:

Miglyol 810

This is a fractionated coconut oil, the triglycerides of caprylic acid and

Capric acid contains and has a molecular weight of about 520. It has a fatty acid composition with Cb not more than 2 percent, Ce about 65 to 75 percent, C10 about 25 to 35 percent and C12 not more than 2 percent, has an acid value of about 0.1, has a saponification number of about 340 to 360 and has over a maximum iodine value of 1.

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Miglyol 812

This is a fractionated coconut oil containing triglycerides of caprylic acid and capric acid and having a molecular weight of about 520. It has a fatty acid composition with Οβ maximum 3 percent, Cs about 50 to 65 percent, C10 about 30 to 45 percent and Ci 2 at most 5 percent, has an acid value of about 0.1, has a saponification number of about 330 to 345 and has a maximum iodine value of 1.

Miglyol 818

It has a fatty acid composition with Cs maximum 3, Cs about 45-60, C10 about 25-40, C12 about 2-5 and Ci_{8: 2} about 4 to 6, has an acid number of not more than 0.2, has a saponification number of about 315 to 335 and has a maximum iodine value of 10.

Captex 355 (¹)

Triglyceride of caprylic acid and capric acid. This triglyceride has a fatty acid content of caproic acid of about 2 percent, caprylic acid of about 55 percent and capric acid of about 42 percent. It has an acid number of at most 0.1, has a saponification number of at most about 325 to 340 and has an iodine value of not more than 0.5.

Furthermore, triglycerides of caprylic acid and capric acid are also suitable, such as those under

Trade name Myritol known and commercially available products, for which reference is made, for example, to Lexikon der Hilfsstoffe, 3rd edition, page 834 (1989) by Fiedler. The associated product Myritol 813 has an acid number of at most 1, has a saponification number of about 340 to 350 and has an iodine value of about 0.5.

Other suitable products in this class are Capmul MCT (¹), Captex 300 (¹), Captex 800 (¹)

Neobee M5 (²) and Mazol 1400 (³).

(¹) = Capital City Products, PO Box 569, Columbus, OH, V.St.A.

(²) = Stepan, PVO Dept., 100 West Hunter Ave., Maywood, NJ 07607, V.St.A.

(³) = Mazer Chemicals, 3938 Porett Drive, Gurnee, IL, V.St.A.

Particularly preferred as a component of the lipophilic phase is the product Miglyol 812.

The compositions according to the invention of the type defined above under (A) also contain a pharmaceutically acceptable surfactant (3). This surface-active component may be a hydrophilic surfactant 3.1. or a lipophilic surfactant

3.2. or to be mixtures of these. Particularly preferred are the nonionic hydrophilic surfactants and the nonionic lipophilic surfactants. Examples of suitable hydrophilic surfactants that can be used as surface-active components are as follows:

3.1.1. Reaction products of natural or hydrogenated vegetable oils and ethylene glycol, namely polyoxyethylene glycolated natural or hydrogenated vegetable oils, such as polyoxyethylene glycolated natural or hydrogenated castor oils. Such products can be obtained in a known manner, for example by reacting a natural or hydrogenated castor oil or fractions thereof with ethylene oxide at a molar ratio of, for example, about 1:35 to about 1:60 and optionally removing the free polyethylene glycol components from the product, as described in U.S. Pat DE-B 1 182 388 and DE-B 1 518 819 will be described. Particularly suitable are the various surfactants available under the trade name Cremophor. Of these, especially the products with the names Cremophor RH 40 with a saponification number of about 50 to 60, an acid number of less than 1, an iodine value of less than 1, a water content (according to Fischer) of less than 2 percent, a refractive index n are suitable_D® ° of about 1.453 to 1.457 and an HLB value of about 14 to 16, Cremophor RH 60 having a saponification number of about 40 to 50, an acid number of less than 1, an iodine value of less than 1, a Fischer water content of about 4.5 to 5.5 percent, a refractive index n_D²⁵from about 1.453 to 1.457 and an HLB of about 15 to 17; and Cremophor EL having a molecular weight (as determined by vapor osmometry) of about 1630, a saponification number of about 65 to 70, an acid number of about 2, an iodine number of about 28 to 32 and a refractive index n_D²⁵ of about 1.471, including, for example, again on Lexikon the excipients, 3. Edition, pages 326 to 327 (1989) by Fiedler. Also suitable as such products are the various surfactants available under the trade name Nikkol, for example Nikkol HCO-60. The product Nikkol HCO-60 is a reaction product of hydrogenated castor oil and ethylene oxide having the following properties: acid value = about 0.3, saponification number = about 47.4, hydroxyl value = about 42.5, pH value (5 percent) = about 4, 6, APHA color = about 40, melting point = about 36.0 C,

AT 403 435 Β

Freezing point = about 32.4 · C, water content (percent, according to Karl Fischer) = about 0.03.

3.1.2. Polyoxyethylene sorbitan fatty acid esters, for example the mono- and trilauryl esters, mono- and Tripalmitylester, mono- and Tristearylester and mono- and Trioleylester, as they are known under the trade name Tween and commercially available, including on Lexicon of excipients, 3rd edition, pages 1300 bis 1304 (1989) by Fiedler. These include, for example, the following products:

Tween 20 = polyoxyethylene (20) sorbitan monolaurate,

Tween 40 = polyoxyethylene (20) sorbitan monopalmitate,

Tween 60 = polyoxyethylene (20) sorbitan monostearate,

Tween 80 = polyoxyethylene (20) sorbitan monooleate,

Tween 65 = polyoxyethylene (20) sorbitan tristearate,

Tween 85 = polyoxyethylene (20) sorbitan trioleate,

Tween 21 = polyoxyethylene (4) sorbitan monolaurate,

Tween 61 = polyoxyethylene (4) sorbitan monostearate and Tween 81 = polyoxyethylene (5) sorbitan monooleate.

Particularly favored products of this class for use in the compositions according to the invention are the above-mentioned products Tween 40 and Tween 80.

3.1.3. Polyoxyethylene fatty acid esters, for example the known types of polyoxyethylene stearic acid esters, which are commercially available under the trade name Myrj, including Lexikon der Hilfsstoffe, 3. Edition, page 834 (1989) by Fiedler, and also the known polyoxyethylene fatty acid esters, which are commercially available under the trade name Cetiol HE, for which reference is made to Lexikon der Hilfsstoffe, 3. Edition, page 284 (1989) by Fiedler, and a particularly preferred product of this class for use in the compositions according to the invention is the product Myrj 52, which has a refractive index n²⁵D of about 1.1, has a melting point of about 40 to 44 · C, has an HLB of about 16.9, has an acid value of about 0 to 1, and has a saponification number of about 25 to 35.

3.1.4. Copolymers of polyoxyethylene and polyoxypropylene, as known, for example, under the trade names Pluronic and Emkalyx and are commercially available, which is referred to Encyclopedia of adjuvants, 3rd edition, pages 956 to 958 (1989) by Fiedler. A particularly preferred product of this class for use in the compositions of the invention is the product Pluronic F68.

3.1.5. Block copolymers of polyoxyethylene and polyoxypropylene, as known, for example, under the trade name Poloxamer and are commercially available, for which reference is made to Lexikon der Hilfsstoffe, 3rd edition, page 959 (1989) by Fiedler. A particularly suitable product of this class for use in the compositions according to the invention is the product poloxamer 188.

3.1.6. Dioctyl succinate, dioctyl sodium sulfosuccinate, di- [2-ethylhexyl] succinate or sodium lauryl sulfate.

3.1.7. Phospholipids, in particular lecithins, for which reference is made to Lexikon der Hilfsstoffe, 3rd edition, pages 731 to 733 (1989) by Fiedler. Lecithins suitable for use in the compositions of the invention include, in particular, soybean lecithins.

3.1.8. Mono- and difatty acid esters of propylene glycol, such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and the like, to which reference is made to Lexikon der Hilfsstoffe, 3. Edition, pages 1013 ff. (1989) by Fiedler. Particularly preferred is Propylengylkolcaprylsäurecaprinsäurediester, which is known under the trade name Miglyol 840 and commercially available, including on Lexikon the excipients, 3. Edition, page 809 (1989) by Fiedler. Miglyol 840 has a maximum fatty acid content of Ce of about 3 percent, Cs about 65 to 80 percent, C10 about 15 to 30 percent, and C12 a maximum of 3 percent, and has an acid value of not more than 0.1, a saponification number of about 320 to 340, and a iodine number of maximum 1 on.

3.1.9. Bile salts, for example, alkali salts such as sodium taurocholate.

Examples of suitable lipophilic surfactants for use as a surface active component are as follows:

3.2.1. Transesterification products of natural vegetable oil glycerides and polyalkylene polyols. Such

Transesterification products are known in the art and can be, for example, under

Use of the method generally described in US-A 3,288,824. These include transesterification products of various natural, for example non-hydrogenated,

AT 403 435 Β

Vegetable oils, such as corn oil, seed oil, almond oil, peanut oil, olive oil and palm oil and mixtures thereof with polyethylene glycols, in particular with polyethylene glycols having an average molecular weight of 200 to 800. Preferred products are obtained by transesterification of 2 moles of a natural vegetable oil triglyceride with 1 mole of polyethylene glycol having, for example, an average molecular weight of 200 to 800. Var ious forms of this class of transesterification products are known and commercially available under the trade name Labrafil, for which reference is made to Lexikon der Hilfsstoffe, 3. Edition, page 707 (1989) by Fiedler. Particularly suitable as components in the compositions according to the invention are the products Labrafil M 1944 CS, which is a transesterification product of seed oil and polyethylene glycol, which has an acid number of about 2, has a saponification number of about 145 to 175 and has an iodine value of about 60 to 90, and Labrafil M 2130 CS, which is a transesterification product of C 12-Cie glyceride and polyethylene glycol, which has a melting point of about 35 to 40'C, has an acid number of less than 2, has a saponification number of about 185 to 200 and has an iodine value of less than 3.

3.2.2. Monoglycerides, diglycerides and mono / di-glycerides, in particular esterification products of caprylic acid or capric acid with cly cerol. Preferred products of this class are, for example, the products containing or consisting essentially or practically of monoglycerides and diglycerides of caprylic acid / capric acid, and such products are commercially available under the trade name Imwitor, for which reference is made to Lexikon der Hilfsstoffe, 3. Edition, page 645 (1989) by Fiedler. A particularly suitable product of this class for use in the compositions of the invention is the product Imwitor 742, which is an esterification product of a mixture of about 60 parts by weight (ppw) of caprylic acid and about 40 parts by weight (ppw) of capric acid with glycerin. Imwitor 742 is usually a yellowish crystalline mass which is liquid at about 26 ° C. It has an acid number of not more than 2, has a maximum iodine value of 1, has a saponification number of about 235 to 275, contains about 40 to 50 percent monoglycerides, has a maximum free glycerol content of 2 percent, has a melting point of about 24 to 26'C , contains non-saponifiable components of maximum 0.3 percent and has a maximum peroxide value of 1.

3.2.3. Sorbitan fatty acid esters of various known types, such as those commercially available under the trade name Span, and these include, for example sorbitan monolauryl, sorbitan monopalmitylester, sorbitan monostearyl, sorbitan tristearyl, sorbitan and the sorbitan trioleylester, and this is, for example, on Lexikon the excipients, 3rd edition, pages 1139 bis 1140 (1989) by Fiedler.

3.2.4. Pentaerythritol fatty acid esters and polyalkylene glycol ethers such as pentaerythritol dioleate, pentaerythritol distearate, pentaerythritol monolaurate, pentaerythritol polyglycol ether and pentaerythritol monostearate and also pentaerythritol fatty acid esters, reference being made to Lexikon der Hilfsstoffe, 3rd edition, pages 923 to 924 (1989) by Fiedler.

3.2.5. Monoglycerides, such as glycerol monooleate, glycerol monopalmitate and glycerol monostea rate, as known, for example, under the trade names Myvatex, Myvaplex and Myverol, and commercially available, for which reference is made to Encyclopaedia der Hilfsstoffe, 3. Edition, page 836 (1989) by Fiedler, and acetylated, for example, monoacetyated and diacetylated, monoglycerides, as known, for example, under the trade name Myvacet and commercially available, to which Lexikon der Hilfsstoffe, 3. Edition, page 835 (1989) by Fiedler.

3.2.6. Glycerol triacetate or (1,2,3) -Triacetin, for which reference is made, for example, to Lexikon der Hilfsstoffe, 3rd edition, page 952 (1989) by Fiedler.

3.2.7. Sterols and derivatives thereof, for example cholesterols and derivatives thereof, in particular phytosterols, such as products containing sitosterol, campesterol or stigmasterol, and ethylene oxide adducts thereof, for example soybeanols and derivatives thereof, as known and commercially available under the trade name Generol, including Lexicon of excipi ents, 3. Edition, pages 554 and 555 (1989) by Fiedler, in particular the products Generol 122, 122 E5, 122 E10 and 122 E25.

Compositions of the type defined above under (A) include systems containing either a single surfactant or a mixture of surfactants, for example systems of a first surfactant and one or more co-surfactants

Means. Surface-active and co-surface-active combinations can, for example, be known from the well-known 11

AT 403 435 Arten types of surfactants are selected, the above in 3.1.1. to 3.2.7. have been specified.

If the hydrophilic phase contains a diether or partial ether of the above 1.1. defined type, especially transcutol or glycofurol, then the use of a single surfactant is generally sufficient, although if desired co-surfactants may be added to further improve, for example, stability behavior. When 1,2-propylene glycol is used as the sole or principal component of the hydrophilic phase, it is generally necessary to use at least two surfactants, namely a surfactant and a co-surfactant. Thus, compositions of the type defined above under (A), in which 1,2-propylene glycol is present as the hydrophilic phase, desirably contain both a surfactant and a co-surfactant.

Surfactants used in 3.1.1., 3.1.3., 3.1.7., 3.2.2. and 3.2.5. of the type defined are of particular interest for use in compositions of the type mentioned above under (A). Particularly suitable combinations of surfactants and co-surface active agents are hydrophilic / lipophilic surface-active combinations, such as combinations of surfactants of the type mentioned above under 3.1.1. described type with surfactants of the above 3.2.5. described type.

If the surfactant contains a solvent suitable for the active ingredient cyclosporin, as described, for example, in the surfactants or mixtures of surfactants described in 3.1.1. to 3.2.7. mentioned type, then this agent can be incorporated into the compositions of the type defined above under (A) not only as a surfactant, but also in excess as another carrier phase or cosolvent phase, as part of the hydrophilic or lipophilic phase.

The compositions of the type mentioned above under (A) may also be used as further component

4th contain a thickener.

As such thickening agents are those known in the art and used thickening agents, and these include, for example, pharmaceutically acceptable polymeric materials and inorganic thickening agents, such as thickeners of the following types:

4.1. Polyacrylate resins and copolymers Polyacrylatharze, such as resins of polyacrylic acid and of polyacrylic acid and polymethacrylic acid, as known, for example, under the trade name Carbopol and are commercially available, including on Lexikon the excipients, 3. Edition, pages 254 to 256 (1989) by Fiedler, in particular the products Carbopol 934, 940 and 941, and Eudragit, including on Lexikon the excipients, 3. Edition, pages 486 to 487 (1989) by Fiedler, in particular the products Eudragit E, L, S, RL and RS, and especially the products Eudragit E, L and S.

4.2. Celluloses and cellulose derivatives including alkylcelluloses such as methylcellulose, ethylcellulose and propylcellulose, hydroxyalkylcelluloses such as hydroxypropylcelluloses and hydroxypropylalkylcelluloses such as hydroxypropylmethylcelluloses, acylated celluloses such as cellulose acetates, cellulose acetate phthalates, cellulose acetate succinates and hydroxypropylmethylcellulose phthalates, and salts thereof such as sodium carboxymethylcelluloses. Examples of such products which are suitable for use in the present invention are the various known and commercially available products, such as the products with the trade names Klucel and Methocel, reference being made to Lexikon der Hilfsstoffe, 3. Edition, pages 688 and 790 (1989) by Fiedler, in particular the products with the names Klucel LF, MF, GF and HF and Methocel K 100, K 15M, K 100M, E 5M, E 15, E 15M and E 100M ,

4.3. Polyvinylpyrrolidones including, for example, poly-N-vinylpyrrolidones and Vinylpyrrolidoncopolymerisaten, such as vinylpyrrolidone-vinyl acetate copolymers. Examples of such compounds which are suitable for use in the present invention are the known and commercially available products, such as the product with the trade name Kollidon, which is also referred to in the United States of America as Povidone, to which encyclopedia of Excipients, 3. Edition, pages 694 to 696 (1989) by Fiedler, and in particular Kollidon 30 and 90.

4.4. Polyvinyl resins including, for example, polyvinyl acetates and polyvinyl alcohols, and also other polymeric materials including gum tragacanth, gum arabic, alginates such as alginic acid, and salts thereof, such as sodium alginates.

4.5. Inorganic thickening agents, such as attapulgite, bentonite and silicates, including hydrophobic silicas, such as alkylated, for example, methylated, silica gels, in particular

AT 403 435 colloidal silicas known and commercially available under the trade name Aerosil, including, for example, Handbook of Pharmaceutical Excipients, Ed

American Pharmaceutical Association / The Pharmaceutical Society of Great Britain, pages 253 to 256 (1986), 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.

In the case of compositions of the type mentioned above under (A), which are to be administered orally, thickening agents may be used which, for example, provide the effect of sustained release of the active ingredient. When oral administration is contemplated, the use of such thickening agents is generally unnecessary, and generally less preferred. The use of thickening agents, on the other hand, is however indicated where, for example, topical application is contemplated.

Compositions of the type indicated above under (A) may also contain one or more further additives, especially diluents, antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT) and tocopherols such as a-tocopherol (vitamin E), flavoring agents and the like , The use of an antioxidant, in particular a tocopherol, is particularly favorable.

If it is envisaged, particularly in the case of an intended oral administration, that the compositions according to the invention of the type defined under (A) should be suitable for direct administration, then pharmaceutical compositions containing a cyclosporin as active ingredient can also be provided by the present invention and which themselves are microemulsions. For oral administration, microemulsions obtained, for example, by dilution of a microemulsion pre-concentrate of the type defined under (A) with water or other aqueous medium may be used directly as drinking formulations. If a topical application is intended, then contain compositions in which a hydrocolloidal thickener, for example, the above 4.2. or 4.4. given type, expediently also water, so that an aqueous microemulsion in the form of a gel, a paste, a cream or the like results. Such compositions are also new. For a further embodiment of the invention therefore belongs:

(B) a pharmaceutical composition which is a microemulsion and contains a cyclosporin as an active ingredient.

Compositions according to this definition (B) may contain any components (1) to (3) of the type defined above in connection with the compositions (A) and water. The compositions (B) are microemulsions of oil-in-water (O / W emulsions). They preferably have stability properties as described above in connection with microemulsions which can be obtained from the compositions defined under (A).

According to the invention has further been recognized that the use of diethers or part-ethers of the above 1.1. defined manner as carrier media is quite generally advantageous for the preparation of cyclosporin-containing pharmaceutical compositions, and not only in connection with the preparation of microemulsion preconcentrates and microemulsion formulations of the type described above. By using such ethers as components in other oral and, above all, topical systems for the delivery of active ingredients, there is thus the direct advantage that the difficulties of the type described hitherto in the prior art do not occur. Such compositions are also new. Another embodiment of the present invention therefore also includes:

(C) a pharmaceutical composition containing a cyclosporin as an active ingredient together with a pharmaceutically acceptable C 1 -C 8 -alkyl or tetrahydrofurfuryl diether or partial ether of a low molecular weight mono- or polyoxyalkanediol.

Preferred ether components for use in compositions of the type defined above under (C) are those mentioned above under 1.1. described components, wherein the products Transcutol and glycofurol are particularly preferred. The compositions (C) suitably comprise one or more further additives, such as surfactants, co-solvents or thickeners.

The compositions according to the above definition (C) expediently contain, above all, a pharmaceutically acceptable hydrophilic surfactant, in particular a nonionic hydrophilic surfactant. Suitable hydrophilic surface-active components are those mentioned above

3.1.1. to 3.1.9. described means.

The compositions as defined above (C) also conveniently contain a pharmaceutically acceptable lipophilic surfactant, either as a surface-active agent

Agent or as a cosolvent, or a pharmaceutically acceptable cosolvent. For this purpose as

Cosolvent / lipophilic surfactant suitable agents are the agents mentioned above

AT 403 435 B (2) and 3.2.1. to 3.2.7. have been described.

Compositions according to (C) also include forms which are other than the compositions described above under (A) and (B), such as solutions, suspensions, dispersions, regular emulsions and the like. In particular, compositions according to (C) which additionally contain a surfactant or both a surfactant and a cosolvent, such as emulsion preconcentrates, namely compositions, when blended with water provide, in contrast to microemulsions, regular emulsions of the oil-water or water-in type And also give regular emulsions of both hydrophilic / lipophilic type and lipophilic / hydrophilic type. In the case of formulations which are used, for example, by drinking or topical, this includes above all aqueous emulsions of the oil-in-water (O / W) or water in oil (W / O) type. In general, emulsion preconcentrates which yield oil-in-water emulsions are preferred, with (ii) oil-in-water (O / W) emulsions being preferred as such, especially in the case of an intended oral administration.

Compositions as defined above (C) may further comprise a pharmaceutically acceptable thickener, and as such thickening agents, for example, those described above

4.1. to 4.5. described means.

Compositions according to definition (C) may also contain other additives, for example preservatives, flavorings and the like, as described above in connection with the compositions (A). They also preferably contain an antioxidant, for example any of the antioxidants described above in connection with the compositions (A).

Of particular interest according to the invention are also:

(D) Compositions as defined above (C) containing as further component (5) a fatty acid saccharide monoester.

Such compositions (D) generally contain the cyclosporin in a carrier medium, which is one of components 1.1., Such as glycofurol or transcutol, and a component (5). The cyclosporin and component (5) are usually present in compositions (D) in molecular dispersion or solution, including, if appropriate, a solid solution. Component (5) in the compositions (D) generally acts as a solubilizer for the cyclosporin. The compositions according to definition (D) have the particular advantage that they are stable and do not have the difficulties which otherwise occur with the components (5), since these have highly hygroscopic properties.

Preferred components (5) for use in compositions (D) are water-soluble fatty acid saccharide monoesters, for example fatty acid monoesters of saccharides, which have a water solubility of at least 3.3 percent in water at ambient temperature, such as 20'C, and those in water of Ambient temperature in an amount of at least 1 g of monoester are soluble in 30 ml of water.

The fatty acid residue of components (5) may be derived from a saturated or unsaturated fatty acid or mixtures thereof. Particularly suitable components (5) are C6-C18 fatty acid saccharide monoesters, and especially water-soluble C6-C18 fatty acid saccharide monoesters. Particularly suitable components (5) are saccharide monoesters of caproic acid (Cs), caprylic acid (Cg), capric acid (C10), lauric acid (Ci2), myristic acid (Ci₄), Palmitic acid (C16), oleic acid (Cis), rizinoic acid (Cis) and 12-hydroxystearic acid (Cig), and especially lauric acid monoester.

The saccharide residue of component (5) may be any suitable sugar residue, such as a monosaccharide residue, disaccharide residue or trisaccharide residue. Conveniently, the saccharide residue is a disaccharide residue or a trisaccharide residue.

Preferred components (5) include Ce-Ci₄Fatty acid disaccharide monoesters and Cg-Cis fatty acid trisaccharide monoesters. Particularly suitable saccharide residues are the sucrose residues and the raffinose residues.

Particularly suitable components (5) are thus sucrose monocaproate, sucrose monolaurate, sucrose monomyristate, sucrose monooleate, sucrose monorizinoleate, raffinose monocaproate, raffinose monolaurate, raffinose monomyristate, raffinose monopalmitate and raffinose monooleate. The most preferred components (5) are raffinose monolaurate and especially sucrose monolaurate.

The components (5) suitably have a hydrophilic-lipophilic balance value (HLB value) of at least 10.

The components (5) suitably contain an ester radical having a purity of at least

Percent, preferably of at least 90 percent, and in particular of at least 95 percent. Conveniently, components (5) have a melting point of from about 15 ° C to about

AT 403 435 B • C, and preferably from about 25 C to about 50 'C.

The compositions (D) may also contain other additives such as those described above in connection with the compositions (C).

In particular, these compositions may contain a component which can be used to modify the release characteristics of the composition for the cyclosporin, for example thickeners, as described above under 4.1. to 4.5. have been described.

The compositions (D) advantageously also comprise, alone, one or more antioxidants, such as those mentioned above in connection with the compositions (A).

The compositions (D) expediently also contain one or more stabilizers or buffers, which in particular prevent hydrolysis of the component (5) during processing or storage. Such stabilizers include acidic stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid, and also basic stabilizers such as potassium hydrogen phosphate.

Such stabilizers or buffers are conveniently added in an amount sufficient to achieve or maintain a pH within the range of about 3 to 8, preferably about 5 to 6, compositions (D) having a pH within the range of The above ranges are generally preferred.

The compositions (D) preferably also contain, above all, a polyoxyalkylene-free hydrophilic surface-active agent, for example an agent as described above under 3.1.6. or 3.1.7. described type.

The compositions of the invention may be applied for administration in any suitable manner, for example orally in a unit dosage form, as in the form of a hard gelatin capsule or a soft gelatin capsule, parenteral or topical, for example for application to the skin, as a cream, Paste, Lotion, Gel, Ointment, Poultice, cataplasm Plaster, Skin pad and the like, or for an ophthalmic application, for example in the form of eye drops, Eye lotions or eye gels. Easily flowable forms, such as solutions and microemulsions, may also be applied or rectally administered, for example, for intralesional injection for the treatment of psoriasis, for example as an enema for the treatment of inflammatory bowel diseases or Crohn's disease. However, the compositions of the invention are intended primarily for oral or topical application, and more particularly for application to the skin.

Of course, the relative proportion of ingredients in the compositions of the invention will vary widely depending on the particular type of composition, such as whether it is a microemulsion preconcentrate, a microemulsion, a regular emulsion, a solution and the like. The relative proportions also vary depending on the particular function of the additives contained in the composition, as in the case of a surfactant component in a microemulsion pre-concentrate thereof, whether this component is used only as a surfactant or as a surfactant as well as a cosolvent , The relative proportions also vary depending on the particular additives used and the physical properties desired for the particular composition, for example in the case of a composition for topical application thereof, whether it is a free-flowing liquid or a paste. The determination of the quantities that can be processed in each case is generally within the skill of the art. All of the proportions and relative weight ranges given below are therefore to be considered as preferred or individual teachings of the invention and not as a limitation of the invention in its broadest aspects.

The amount of cyclosporin present in the compositions of the invention will, of course, vary depending on, for example, the intended route of administration and the extent to which the other components, and in particular the components (2) to (5) described above, are present. In general, however, the cyclosporin is present in an amount that is within the range of 0.05, more preferably from about 0.1 to about 35, weight percent, based on the total weight of the composition.

The components (1) are conveniently present in the compositions of the present invention in an amount of from about 0.5 to about 90 percent by weight, based on the total weight of the composition. In the case of compositions according to the invention which contain a component 1.1., Such as glycofurol or transcutol, this component is 1.1. generally in an amount of from about 1 to about 90 weight percent, and usually in an amount of from about 5 or 10 to about 70 weight percent, based on the total weight of the composition. In the case of compositions of the type defined above under (A) or (B), which is a component 1.2. contain, is the component 1.2. generally present in an amount of from about 2 to about 50 percent by weight, based on the total weight of the composition. In the case of inventive compositions, the

AT 403 435 Β contain a component (2) or (3), each of these components is generally present in an amount of from about 0.5 to about 90 percent by weight, based on the total weight of the composition. A particularly preferred embodiment of the invention therefore relates to (E) compositions according to the above definition (A) or (C) for oral administration, for example in a form suitable or usable for oral administration.

For compositions according to definitions (A) to (C) above, which are intended for non-topical administration and in particular for oral dosage forms (E), the following also applies:

(a) The cyclosporin is generally present in an amount of from about 1 or 2 to about 30 weight percent, and conveniently in an amount of from about 4 to about 25 weight percent, based on the total weight of the composition. Preferably, the cyclosporin is present in an amount of about 5 to about 25 weight percent, more preferably about 20 weight percent, for example, in an amount of about 5 to 15 weight percent, based on the total weight of the composition.

(b) Component 1.1. when present, is generally present in an amount of from about 15 to about 85 percent by weight, suitably from about 20 to about 80 percent by weight, and most preferably from about 25 to about 70 percent by weight, for example, from about 30 to about 50 or 60 percent by weight based on the total weight of the composition.

(c) Cyclosporin and component 1.1. when present, are generally in a ratio of about 1: 0.75 to 20, preferably about 1: 1 to 15, and more preferably about 1: 1 to 5, for example about 1: 1 or 1: 1.5 to 4 Parts by weight (ppw) (cyclosporin to component 1.1.) Present.

(d) Component 1.2. If present, it is generally present in an amount of from about 3 to about 45 weight percent, suitably from about 5 to about 30 weight percent, based on the total weight of the composition.

(e) Cyclosporin and Component 1.2. if present, are generally present in a ratio of 1: 0.1 to 20, suitably about 1: 0.2 to 10 parts by weight (ppw). In particular, these components are present in a ratio of about 1: 0.3 to 6, for example a ratio of 1: 0.5 to 3 parts by weight (ppw) (cyclosporin to component 1.1.).

(f) Component (2), if present, is generally present in an amount of up to about 45% by weight, and more preferably up to about 40% by weight, based on the total weight of the composition. Component (2) is preferably in an amount of about 2 to about 45 weight percent, more preferably in an amount of about 3 to about 35 weight percent, and most preferably in an amount of about 5 or 10 weight percent to about 30 weight percent based on the total weight of the composition, present.

(g) Components (2) and 1.1. when present, are generally present in a ratio of about 1: 0.5 to 40, suitably about 1: 0.5 to 20, and more preferably about 1: 0.75 to 10, for example, from about 1: 0.75 to 4, parts by weight (ppw) (component 2 to component 1), present.

(h) Components (2) and 1.2. when present, usually in a ratio of about 1: 0.075 to 22, preferably about 1: 0.1 to 15, and more preferably about 1: 0.15 to 6, for example about 1:05 to 3, parts by weight (ppw) Component 2 to Component 1.2.

(i) Components (3), if present (including both components of type 3.1. and also of type 3.2.), generally in an amount of up to about 90% by weight, for example from about 20 to about 90% by weight, based on the total weight of the composition. The components (3) are preferably present in an amount of from about 20 or 25 to about 80 or 90 percent by weight based on the total weight of the composition, for example in an amount of from about 25 to about 55 percent by weight, if one component is 1.1. is used, or in an amount of about 40 to 75 weight percent, when a component 1.2. is applied.

(j) The cyclosporin and component (3) (including both components of the type 3.1

3.2. ) are present, if present, generally in a ratio of about 1: 0.5 to 20, suitably up to 12, parts by weight (ppw). By way of example, these components are present in a ratio of about 1: 1 to 10 parts by weight (ppw), this weight ratio being about 1: 1 to 5 if one component is 1.1. is present, or is about 1: 3 to 8, if a component

1.2. is present. (Cyclosporin to Component (3).)

In the case of compositions of the type defined above under (A) and (B) (microemulsion preconcentrates and

Microemulsions) are the relative proportions of the components of (1) the hydrophilic phase, (2) the lipophilic phase, and (3) the surfactant of the concentration of the existing one

Cyclosporin dependent. They also vary depending on the relative proportion of each other.

AT 403 435 Β

The compositions (A) can therefore be defined as comprising a cyclosporin together with (1) a hydrophilic phase, for example those mentioned above under 1.1. or 1.2. defined type, (2) a lipophilic phase, for example, the above 2.1. or 2.2. defined type, and (3) a surfactant, for example, the above under 3.1. or 3.2. The relative proportions of cyclosporin to (1) to (2) to (3) are chosen such that upon contact with water, such as the relative proportions of 1: 1 parts by weight (ppw) (ppw.) ( Cyclosporin + (1) + (2) + (3): H₂O) or above, a microemulsion, for example of the oil-in-water type (O / W), can be obtained.

Similarly, the compositions (B) may be defined by containing a cyclosporin together with the above-mentioned components (1), (2) and (3), and water in relative proportions as mentioned above, for example to form a microemulsion, for example, an oil-in-water type emulsion (O / W).

Compositions according to definitions (A) and (B) above preferably contain from about 2 to about 30, more preferably from about 5 to about 20, and most preferably from about 10 to about 15, weight percent of cyclosporin, based on the total weight of cyclosporin and the components (1 ) + (2) + (3).

Does the component (1) of the compositions (A) or (B) of the above 1.1. defined type, so that it is for example Transcutol or glycofurol, then the components 1.1., (2) and (3) are present so that the component 1.1. preferably from about 15 to about 85 percent by weight, in particular from about 25 to about 65 weight percent, accounts, component (2) preferably in an amount of about 2 to 40, in particular from about 3 to about 35, and especially from about 3 to about 30, Weight percent is present, and the amount of component (3) is about 15 to about 85 weight percent, and preferably about 25 to about 55 or 60 weight percent, accounts, where all percentages are based on the weight of the total 1.1. + (2) + (3). The use of glycofurol is of particular interest.

If the component (1) in the compositions (A) or (B) 1,2-propylene glycol, namely the above-mentioned component 1.2., Then the components 1.2., (2) and (3) are expediently present in amounts which from about 3 to about 35 weight percent, preferably from about 3 to about 25 weight percent, of component 1.2. from about 2 to about 35 weight percent, preferably from about 3 to about 30 weight percent of component (2), and from about 45 to about 90 weight percent, preferably from about 50 to about 90 weight percent, for example from about 55 to about 80 weight percent, of the K component (3), all percentages being based on the total weight of components 1.2 + (2) + (3). When component (1) is 1,2-propylene glycol, component (3) will generally contain both a surfactant and a co-surfactant. When a co-surfactant is used, the surfactant and co-surfactant are suitably in a ratio of up to about 50: 1, preferably up to 20: 1, and more preferably up to 15: 1, for example from 2 to 15: 1, Parts by weight (ppw) (mid surface active agent).

Figure I of the drawing shows a three-way plot for the relative concentrations of components 1.1., For example of glycofurol, (2), for example from Migiyol 812, and (3), for example from Cremophor RH 40, in compositions according to (A) which are approximately 10% by weight of cyclosporin, for example ciclosporin. The relative concentration of component 1.1. increases from 0 percent along the left boundary of the plot to 100 percent at the lower right corner, as indicated by arrow 1.1. The concentration of component (2) increases from 0 percent at the right boundary of the plot to 100 percent at the lower left corner, as indicated by arrow 2. A composition containing only 50 percent of component 1.1. and 50 percent of component (2) is therefore determined by the midpoint of the baseline of the plot. The relative concentration of component (3) increases from 0 percent at the baseline of the application to 100 percent at the apex, as indicated by arrow 3. The lines within the plot correspond to proportions of 10 percent each, ranging from 0 percent at each boundary to 100 percent at the opposite apex.

For compositions of the types defined under (A) and (B), the relative ratio of components 1.1, (2) and (3) is conveniently within the area A defined by line a of FIG. Preferably, the relative ratio of components 1.1, (2) and (3) lies within area B defined by line b of Figure I, with microemulsions based on these ratios being characterized as having the best stability for example, have a stability of over 24 hours with an average particle size of less than 100 nm (1000 Å). Compositions according to the invention containing components 1.1, (2) and (3) in a relative ratio, as defined above in connection with FIG. 1, are therefore particularly preferred embodiments.

AT 403 435 Β

Figure II of the drawing shows a three-way order for the relative concentrations of components 1.2., (2), for example Miglyol 812, and (3) in compositions according to (A) containing about 10% by weight of cyclosporin, for example cyclosporin. In this case, component (3) is a suitable surface-active agent-co-surface-active agent mixture, for example, in a ratio of 11: 1 parts by weight (ppw) containing, for example, 11 parts by weight of Cremophor RH 40 and 1 part by weight of glycerol monooleate. The relative amounts of the components 1.2., (2) and (3) are also here, as in the figure I, in turn determined by the arrows 1.2, 2 and 3.

For compositions of the type defined under (A) and (B), the relative proportions of the components 1.2, (2) and (3) are conveniently within the area X defined by the line x of Figure II. Preferably, the relative ratios of the components 1.2, (2) and (3) are within the area Y defined by the line y of FIG. In particular, the relative ratios of components 1.2., (2) and (3) are within the area Z of FIG. 1 defined by line z, with microemulsions based on ratios within the areas Y and Z over an average particle size in FIG of the order of 110 nm (1100 Å) and under 20 nm (under 200 Å) and have a stability of, for example, over 24 hours.

In addition, compositions as defined above (E) may additionally contain a thickening agent although, as noted above, this is generally less preferred. Suitable thickening agents include any thickening agents of the type described in (4) above. The amount of such thickening agent may vary and depends, for example, on the required consistency of the final product, namely whether this product should be a thickened flowable form, for example for filling into capsules and the like, or sufficiently flexible for it to knead or form and so forth for example, to use for the production of tablets or the like. The amount of thickener, of course, depends on the nature of the particular thickener. The components (4), if present, are generally in an amount of up to about 25% by weight, based on the total weight of the composition, and in particular in an amount of up to about 15 or 20 weight percent, for example in an amount of 0, 5 or 5 to 15 or 20 percent by weight, based on the total weight of the composition.

Compositions as defined above (E) also include additives or additives such as those described in connection with compositions (A) and (C). In particular, they may comprise antioxidants, for example in an amount of up to about 0.5 or 1% by weight, based on the total weight of the composition, and sweetening agents or flavoring agents, for example in an amount of up to about 2.5 or 5% by weight on the total weight of the composition.

The compositions (E), which correspond to the definition (A), have particularly favorable properties when administered orally, for example as regards both the stability and the high level of bioavailability obtainable therewith. In particular, unlike other galenical systems known in the art, it has been found that such compositions are compatible with surfactant materials such as bile salts present in the gastrointestinal tract. This means, that such compositions are completely dispersible in aqueous systems, which contain natural surfactants, so that they can form microemulsion systems in situ, which are stable and show no precipitation or other disturbance of the finely divided structure The function of such systems after oral administration remains independent of and / or unaffected by the relative presence or absence of bile salts (bitter salts) at any particular time or in the particular patient. Such compositions therefore form a particularly preferred embodiment of the invention.

The compositions (E) are preferably compounded in unit dosage form by, for example, being filled into capsule casings which can be administered orally, such as in soft gelatin capsules or hard gelatin capsules, or by tableting or other shaping. When compositions (E) are in unit dosage form, each dosage unit contains between about 5 or 10 and about 200 mg cyclosporin, and conveniently between about 15 or 25 and about 150 mg cyclosporin, for example 25, 50 or 100 mg cyclosporin. Thus, unit dosage forms of the present invention suitable for once, twice, three times and up to five times daily administration depending, for example, on the particular purpose of the therapeutic treatment, the therapeutic treatment phase and the like, conveniently contain, for example, about 50 mg or about 100 mg of cyclosporin per dosage unit.

Compositions as defined above (B) for oral administration may be prepared by subjecting compositions such as those described above with respect to composition (A) or (E) to water or other aqueous system in, for example, the above

AT 403 435 Β specified relative proportions (composition:) ^ 0) are given, so that, for example, sweet or flavored drinking preparations are formed. Such compositions may therefore contain any system as defined or described above in connection with compositions (A) or (E) plus an amount of water sufficient to form a microemulsion.

The compositions according to the above definition (D) are intended in particular for oral administration, although they may also be administered in a form which can be administered topically, including dermal and topically ophthalmically, parenterally or rectally or else by intralesional injection is included.

In the case of compositions as defined above (D), the cyclosporin and the required component 1.1. in a ratio of about 1: 0.5 to 200, preferably about 1: 0.5 to 100, and especially about 1: 0.5 to 50, parts by weight (ppw) may be present. More suitably, these components are in a ratio of from about 1: 1 to 10, more preferably from 1: 1 to 5, and most preferably from about 1: 1.5 to 2.5, for example from about 1: 1.6 or 1: 2 Parts by weight (ppw) (cyclosporin for component 1.1.) Present. The cyclosporin and required component (5) are suitably present in a ratio of about 1: 3 to 200, preferably about 1: 3 to 100, and more preferably about 1: 3 to 50, parts by weight (ppw). More suitably, these components are present in a ratio of about 1: 5 to 20, preferably about 1: 5 to 10, and more preferably about 1: 6.0 to 6.5, for example about 1: 6.25, parts by weight (ppw) ( Cyclosporin to component 1.1.).

Compositions according to (D) are conveniently processed into unit dosage forms, whether or not administered orally or otherwise.

Of course, the amount of cyclosporin present in such unit dosage forms will vary depending on, for example, the condition being treated, the intended mode of administration, and the effect desired. Generally, however, unit dosage forms according to definition (D) will conveniently contain from about 2 to about 200 mg of cyclosporin per unit dosage.

Suitable dosage forms for oral administration include, for example, liquids, granules, and the like. However, preferred dosage forms are unit dosage forms, for example in the form of tablets or capsules, especially hard gelatin capsules or soft gelatin capsules.

Unit dosage forms for oral administration as defined above (D) conveniently contain about 5 or 10 to about 200 mg, preferably about 15 or 20 to about 100 mg, for example 25, 50 or 100 mg, of cyclosporin per unit dosage.

The compositions (D) have the further advantage of being able to form the basis for modified release composition compositions for the active ingredient, such as sustained release of cyclosporin or release of cyclosporin for a prolonged period of time, for example after oral administration. Such compositions also contain a component which can alter the release characteristics of the composition for the cyclosporin. Such compositions include, for example, a thickener (4), such as any of those listed at 4.1 above. to 4.5. indicated means.

If the compositions (D) contain a component (4), then this is suitably in an amount of about 0.5 to 50 weight percent, preferably from about 1 to 20 weight percent, and in particular from about 2 to 10 weight percent, based on the total weight of Cyclosporin plus the components 1.1. + (4) + (5), available.

As already mentioned, the compositions as defined above (D) may also contain one or more stabilizers or buffers or polyoxyalkylene-free surfactants. Such stabilizers and / or buffers are usually present in an amount of up to about 5% by weight or, if citric acid or acetic acid is used, in an amount of up to 10% by weight based on the weight of cyclosporin plus components 1.1. + (5), available. If a surfactant is also present, it is conveniently present in an amount of from about 5 to about 50 weight percent, preferably in an amount of from about 10 to about 25 weight percent, based on the weight of component (5).

The compositions according to definition (D) may expediently also comprise further additives, in particular flavorings or, in particular, antioxidants. The antioxidants suitable for this purpose and the amounts to be used correspond to what has already been said above in connection with the compositions (E).

The compositions according to definition (D) are preferably free or practically free of lower ones

Alkanols, especially of ethanol, and they contain, for example, less than 5 percent, preferably less than 2 percent, for example 0 percent to 1 percent, of lower alkanolic components,

AT 403 435 Β based on the total weight of the composition.

The compositions according to definitions (A) to (C) above are also of particular interest for topical administration. Another embodiment of the present invention therefore includes (F) compositions according to the above definitions (A) to (C) for topical application, in particular dermal application, for example in a form suitable or suitable for topical application.

In the case of intended topical administration, the cyclosporin is usually present in an amount of about 0.05% by weight, and preferably in an amount of about 0.1 to about 15% by weight, based on the total weight of the composition. In particular, the amount of cyclosporin present is from about 0.1 to about 10 weight percent.

In the case of compositions (F) which are compositions according to (A) or (B), the relative proportions of components (1), (2) and (3) are as described above for such compositions by way of example with reference to Figures I and II described relationship.

On the other hand, compositions (F) in accordance with (C) may take any suitable form and be in the form of, for example, solutions, suspensions, dispersions and regular emulsions. The amount of component 1.1. in such compositions is suitably about 1 to about 70 weight percent, preferably about 5 to about 50 weight percent, and more preferably about 7 to about 25 weight percent, based on the total weight of the composition.

The compositions (F) suitably comprise one or more carriers or diluents and / or other additives which provide a carrier system, such as thickeners, emulsifiers, preservatives, humectants, dyes and the like.

The compositions (F) may each be of suitable form for topical application, such as application to the surface of the skin, and therefore, for example, have a fluid form, be in the form of a powder or be a topically applicable spray as a liquid or semi-liquid. Examples of suitable flowable forms include gels, including oil-in-water emulsions and water-in-oil emulsions, or microemulsions, creams, pastes and ointments, and the like, as well as lotions and tinctures and the like. Such compositions therefore include, for example, cataplasms and slip packs as well as transdermal patch systems.

The choice of excipients for the preparation of such formulations will of course be determined by the nature of the formulation desired and also by the particular condition to be treated, the condition of the area to be treated, the condition of the skin and the effect desired. Chronic psoriatic stains are therefore more conveniently treated with hydrophobic, fat-based compositions, namely compositions of the invention containing an ointment or cream based on petrolatum as a carrier medium. In contrast, for the treatment of disease states including acute-phase inflammatory processes, more favorable hydrophilic compositions are used, for example compositions according to the invention in the form of an oil-in-water emulsion or a gel. While the compositions (F) may contain, for example, lower alkanols, such as ethanol, as a diluent or diluent component, the use of such alkanols should preferably be avoided, for example when dealing with damaged skin, as in psoriasis the case is. Thus, preferred compositions (F) are free or substantially free of alkanol so as to contain, for example, less than 5 weight percent, preferably less than 2 weight percent, for example about 0 to 1 weight percent of alkanolic components, and especially ethanol.

Particularly preferred compositions (F) are compositions according to (Α), (B) or (C) which additionally contain a component (6) as (further) pharmaceutically acceptable diluent or carrier which is combined with the component 1.1. is immiscible. Such compositions are preferably in the form of an anhydrous or substantially anhydrous emulsion such that they contain less than 10 percent, preferably less than 5 percent, and most preferably less than 1 percent water. Such emulsions include both emulsions containing component 1.1. in the component (6), as well as emulsions containing the component (6) in the component 1.1. contain. These are preferably emulsions of component 1.1. in component (6).

Suitable components (6) include, for example:

6.1. Solid hydrocarbons, for example petroleum gels: such as white petrolatum or Vaseline®, ceresin and solid paraffins, and also waxes including animal, vegetable and synthetic waxes, such as spermaceti wax, carnauba wax and beeswax.

6.2. Liquid hydrocarbons, for example liquid paraffins, and fatty acid esters, such as isopropyl myristate and cetyl palmitate.

AT 403 435 Β

6.3. Non-volatile silicones including silicone oils and silicone pastes and copolymers of silicone and polyalkylene oxide, as described, for example, in Lexikon der Hilfsstoffe, 3rd edition, pages 1109 and 1110 (1989) by Fiedler, for example those known under the trade name piroethicone and commercially available products.

The components (6) are suitably in the compositions (F) in an amount of up to about 80 weight percent, for example in an amount of about 5 to about 70 weight percent, and preferably in an amount of about 25 to about 60 weight percent, based on the total weight of the composition, present.

By using individual additives (6) or mixtures thereof, emulsions in liquid or semi-solid form can be obtained, depending, for example, on the needs desired for topical application.

The compositions (F) also contain a surfactant. Suitable surfactants include, in p articular, lipophilic surfactants including those listed above

3.2.1. to 3.2.7. surfactants with HLB values ​​of about 5 to 7. Examples of surfactants which are particularly suitable for compositions (F) include those mentioned above under 3.1.2. and 3.2.3. and also glycerol monostearate, propylene glycol monostearate, diethylene glycol monostearate and glycerol ricinoleate.

The surfactants in compositions (F) are desirably present in an amount up to about 60 weight percent, for example from about 2 to about 50 weight percent, and preferably from about 10 to about 40 weight percent, based on the total weight of the composition.

The compositions (F) may also contain one or more consistency promoting agents, for example, microcrystalline waxes, Vegetable oils, like olive oil, Corn oil and seed oil, and vegetable oil derivatives including hydrogenated vegetable oils and vegetable oil partial glycerides, for example, in an amount of from about 0.1 to about 10 weight percent, and preferably in an amount of about 1 to about 5 weight percent, based on the total weight of the composition, available.

The compositions (F) expediently also include:

an antioxidant, such as any antioxidant of the type described above in connection with compositions (A), which is present, for example, in an amount of about 0.01 to about 0.5 percent by weight, based on the total weight of the composition:

an antibacterial agent such as benzyl alcohol, methylparaben, propylparaben, benzalkonium chloride, benzoic acid, sorbic acid or chlorobutanol, present in, for example, an amount of from about 0.05 to about 2 percent by weight based on the total weight of the composition:

a stabilizer, such as microcrystalline starch, sodium EDTA or magnesium sulfate, present, for example, in an amount of from about 0.1 to about 10 percent by weight based on the total weight of the composition;

and / or an agent for improving skin penetration, such as a mono- or polyunsaturated C 12-24 fatty acid or a corresponding alcohol, for example vaccenic acid, cis-vaccenic acid, linoleic acid, linolenic acid, elaidic acid, oleic acid, petroselinic acid, erucic acid or nervonic acid, or corresponding alcohols thereof, in particular Oleic acid or oleyl alcohol, or l-dodecylazacycloheptan-2-one, which is also known as azone, including, for example, Lexikon der Hilfestoffe, 3. Edition, page 190 (1989) by Fiedler, and such agent is present, for example, in an amount of about 1 to about 20 percent by weight, suitably about 3 to about 15 percent by weight, based on the total weight of the composition.

Furthermore, the present invention also relates to a process for the preparation of a pharmaceutical composition of the type defined above, for example, for the preparation of compositions of the type defined above under (A) to (F), that consists in that the individual components are intimately mixed with each other and the resulting composition is compounded, if necessary, into unit dosage forms, for example, by adding the respective composition to gelatine capsules, like soft gelatin capsules or hard gelatine capsules, is bottled.

A further embodiment of the invention consists in a process for the preparation of a composition of the type defined above under (A) to (D), and this process is characterized in that a cyclosporin, such as cyclosporin, is intimately mixed with a component 1.1. according to the above definition, with the formation of a composition as defined above (C) and optionally with a component (5) to form a composition as defined above (D) or with a component 1.2. as defined above, these components optionally, if a component 1.1.

AT 403 435 Β, or necessarily, if a component 1.2. is further combined with a component (2) and with a component (3) of the definition given above and wherein the relative proportions of the components 1.1. or 1.2., (2) and (3) are selected to give a composition as defined above (A), and the resulting composition (A) is further contacted with water if necessary to form a composition as defined above (A) B), and the resulting compositions (A), (C) or (D) are compounded, if necessary, into unit dosage forms such as soft gelatin capsules or hard gelatin capsules.

A particular embodiment of the present invention is to provide a process for preparing a composition having the above definition (A), and this process is characterized in that a cyclosporin, such as cyclosporin, is intimately mixed with a component 1.1. or 1.2. of the type defined above and having a component (2) and a component (3) of the type defined above, wherein the relative proportions of the components 1.1. or 1.2., (2) and (3) are selected depending on the quality of the cyclosporin used, to give a microemulsion pre-concentrate, namely a composition, by adding to water, for example in a ratio of at least 1: 1 parts by weight (ppw) (composition: H2O), gives a system which contains a disperse or particulate phase, in which the individual particles have a size of less than 200 nm, preferably about 10 nm to about 100 nm, to have.

The preferred cyclosporin for the compositions of the invention is cyclosporin. Another preferred cyclosporin to which the teaching of the present invention can be applied is [Nva]²Cyclosporin, also known as cyclosporin G.

The following examples further illustrate the compositions according to the invention. Examples 1, 2, 4, 5 and 7 show the preparation of compositions in unitized oral dosage forms suitable, for example, for the prevention of graft rejection or for the treatment of autoimmune diseases, such as autoimmune diseases or conditions of the type described above, when incorporated in US Pat 1 to 5 unit doses per day are administered. Examples 3 and 6 show the preparation of compositions for topical application, For example, for the treatment of atopic dermatitis or contact dermatitis, Psoriasis or hair loss, these compositions at regular intervals, for example once, twice or three times a day, at the desired site to be treated therapeutically, for example, a site with a dermatitic reaction or psoriatic lesion or on the scalp, be applied.

The examples are described with particular reference to cyclosporin. By using other suitable cyclosporins, however, comparable compositions can be prepared. In particular, comparable compositions can be obtained in all cases by using [Nvaf-cyclosporin instead of cyclosporin in the same amount as indicated for cyclosporin.

example 1

Preparation of microemulsion pre-concentrate type oral dosage forms

<td>1.1. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. Glycofurol 75</td><td>180.0</td>

<td>2.1. Miglyol 812</td><td>90.0</td>

<td>3.1.1. Cremophor RH 40</td><td>180.0</td>

<td>total quantity</td><td>500.0</td>

The cyclosporin is stirred at room temperature in component 1.1. dissolved, and the resulting solution with further stirring with the components 2.1. and 3.1.1. added. The resulting mixture is filled into a size 1 hard gelatin capsule and the capsule is sealed using the Quali-Seal technique.

In an analogous manner, the following compositions can also be prepared and filled into hard gelatine capsules of sizes 1 or 2.

AT 403 435 Β

<td>1.2. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine 1.1. Glycofurol 75 2.1. Miglyol 812 3.1.1. Cremophor RH 40 total</td><td>50.0 180.0 78.0 192.0 500.0</td>

<td>1.3. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine 1.1. Glycofurol 75 2.1. Miglyol 812 3.1.1. Nikkol HCO-40 ethanol ' Ascorbyl palmitate ** total</td><td>50.0 200.0 60.0 120.0 19.0 1.0 450.0</td>

'Cosolvent (hydrophilic phase)' Antioxidant

<td>1.4. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine 1. Glycofurol 75 2.1. Miglyol 812 3.1.7. lecithin total quantity</td><td>50.0 100.0 75.0 75.0 300.0</td>

<td>1.5. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine 1.1. Glycofurol 75 1.2. propylene glycol 2.1. Myritol 318 3.1.1. Cremophor RH 40 BHA * total quantity</td><td>100.0 260.0 50.0 100.0 340.0 5.0 855.0</td>

* Antioxidant

<td>1.6. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine 1.2. 1,2-propylene glycol 2.1. Miglyol 812 3.1.1. Cremophor RH 40 3.2.5. Glycerol monooleate total</td><td>50.0 68.0 68.0 250.0 24.0 460.0</td>

'Cosolvent

AT 403 435 B

<td>1.7. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.2. 1,2-propylene glycol</td><td>68.0</td>

<td>2.1. Miglyol 812</td><td>24.0</td>

<td>3.1.1. Cremophor RH 40</td><td>250.0</td>

<td>3.2.5. Glycerol monooleate '</td><td>68.0</td>

<td>total quantity</td><td>460.0</td>

'Cosolvent

<td>1.8. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>100.0</td>

<td>1.2. 1,2-propylene glycol</td><td>75.0</td>

<td>2.1. Miglyol 812</td><td>25.0</td>

<td>3.1.1. Cremophor RH 40</td><td>150.0</td>

<td>3.2.5. Glycerol monooleate *</td><td>150.0</td>

<td>total quantity</td><td>500.0</td>

<td colspan="2">* Cosolvent</td>

<td colspan="2"></td>

<td>1.9. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.2. 1,2-propylene glycol</td><td>200.0</td>

<td>2.1. Miglyol 812</td><td>50.0</td>

<td>3.1.1. Cremophor RH 40</td><td>150.0</td>

<td>3.2.7. Generol 122 E16 *</td><td>50.0</td>

<td>total quantity</td><td>500.0</td>

* Cosolvent

<td>1.10. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.2. 1,2-propylene glycol</td><td>75.0</td>

<td>2.1. Miglyol 812</td><td>75.0</td>

<td>3.1.1. Cremophor RH 40</td><td>250.0</td>

<td>3.2.7. Generol 122 E25 *</td><td>50.0</td>

<td>total quantity</td><td>500.0</td>

* Cosolvent

The compositions 1.1., 1.2., 1.6. and 1.7. are particularly preferred

Comparable compositions to 1.1. to 1.5. In all cases, it is also possible to produce it by replacing glycofurol with an equal or comparable amount of transcutol.

Comparable compositions to 1.1. to 1.5. may also be prepared by using 15, 20 or 100 mg of cyclosporin, such as cyclosporin, in place of 50 mg of cyclosporin and leaving the amounts of the remaining ingredients for each composition as indicated.

AT 403 435 Β

Example 2

Preparation of Thickened Microemulsion Pre-Concentrate Type Oral Dosage Forms

<td>2.1. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. Glycofurol 75</td><td>180.0</td>

<td>2.1. Miglyol 812</td><td>90.0</td>

<td>3.1.1. Cremophor RH 40</td><td>180.0</td>

<td>4.2. Methocel K100</td><td>100.0</td>

<td>total quantity</td><td>600.0</td>

Ciclosporin and components 1.1. to 3.1.1. are combined together as in Example 1, and the resulting mixture is until homogeneous with the component 4.2. mixed. The resulting product is then filled into size 2 hard gelatin capsules.

In an analogous manner, the following compositions are prepared:

<td>2.2. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. Glycofurol 75</td><td>180.0</td>

<td>2.1. Miglyol 812</td><td>90.0</td>

<td>3.1.1. Cremophor RH 40</td><td>180.0</td>

<td>4.6. Aerosil 200</td><td>9.0</td>

<td>4.2. Methocel K100</td><td>100.0</td>

<td>total quantity</td><td>609.0</td>

<td>2.3. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>100.0</td>

<td>1.1. glycofurol</td><td>210.0</td>

<td>2.1. Myritol 318</td><td>90.0</td>

<td>3.1.1. Nikkol HCO-60</td><td>170.0</td>

<td>4.2. Klucel EF</td><td>30.0</td>

<td>total quantity</td><td>600.0</td>

Comparable compositions to 2.1. to 2.3. are prepared by using transcutol in an equal or comparable amount instead of glycofurol.

Example 3

Preparation of Topically Applicable Microemulsion Preconcentrate Forms

<td>component</td><td>weight</td>

<td>Cyclosporin, such as cyclosporine</td><td>0.1</td>

<td>1.1. glycofurol</td><td>50.0</td>

<td>2.1. Miglyol 812</td><td>16.6</td>

<td>3.1.1. Cremophor RH 40</td><td>33.3</td>

The above composition is prepared analogously to Example 1. A comparable composition is made by using Transcutol instead of glycofurol. The composition

AT 403 435 Β may serve as a base for a cream, gel and the like by combining with other additives such as hydrocolloidal thickeners, paraffins and the like of the type described above.

Example 4

Preparation of oral dosage forms, front type of regular emulsion pre-concentrate

<td>4.1. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>100.0</td>

<td>1.1. Transcutol</td><td>154.0</td>

<td>3.1.1. Cremophor RH 40</td><td>146.0</td>

<td>3.2.1. Labrafil M 1944 CS</td><td>50.0</td>

<td>total quantity</td><td>450.0</td>

The cyclosporin is stirred at room temperature in component 1.1. dissolved, and the resulting solution is added with further stirring with the components 3.1.1. and 3.2.1. added. The resulting mixture is filled into size 1 hard gelatin capsules, and the capsules are sealed using the Quali-Seal technique.

In an analogous manner, the following compositions are prepared and optionally filled into hard gelatin capsules sizes 1 or 2.

<td>4.2. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. Transcutol</td><td>80.0</td>

<td>3.1.1. Cremophor RH 40</td><td>75.0</td>

<td>3.2.1. Labrafil M 2130 CS</td><td>25.0</td>

<td>total quantity</td><td>230.0</td>

<td>4.3. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>100.0</td>

<td>1.1. Glycofurol 75</td><td>150.0</td>

<td>3.1.1. Nikkol HCO-40</td><td>200.0</td>

<td>total quantity</td><td>450.0</td>

<td>4.4. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. Transcutol</td><td>100.0</td>

<td>3.1.1. Cremophor RH 40</td><td>94.0</td>

<td>3.2.1. Labrafil M 1944</td><td>31.0</td>

<td>total quantity</td><td>275.0</td>

Substituting Transcutol in Compositions 4.1., 4.2. or 4.4. by an equal or comparable amount of glycofurol or by replacement of glycofurol in the composition 4.3. By an equal or comparable amount of transcutol, comparable compositions can be made.

AT 403 435 Β

Example 5

Preparation of Thickened Emulsion Precast Concentrate Type Oral Dosage Forms

<td>5.1. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. Transcutol</td><td>80.0</td>

<td>3.1.1. Cremophor RH 40</td><td>75.0</td>

<td>3.2.1. Labrafil M 1944 CS</td><td>25.0</td>

<td>4.1. Eudragit E</td><td>50.0</td>

<td>total quantity</td><td>280.0</td>

The components 3.1.1., 3.2.1. and 4.1. with stirring and gentle heating with the component 1.1. united and dissolved in it. Cyclosporin is then added with gentle warming and further stirring, whereupon the resulting product is filled into size 2 hard gelatin capsules and sealed therein.

In an analogous manner, the following compositions are also prepared and optionally filled into hard gelatin capsules of sizes 1 or 2.

<td>5.2. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>100.0</td>

<td>1.1. Transcutol</td><td>180.0</td>

<td>3.1.4. Pluronic F68</td><td>140.0</td>

<td>3.1.6. sodium lauryl sulfate</td><td>5.0</td>

<td>4.2. sodium</td><td>25.0</td>

<td>total quantity</td><td>350.0</td>

<td>5.3. component</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. Transcutol</td><td>163.0</td>

<td>3.1.1. Cremophor RH 40</td><td>100.0</td>

<td>3.2.1. Labrafil M 1944 CS</td><td>35.0</td>

<td>4.3. Kollidon 30</td><td>72.0</td>

<td>total quantity</td><td>420.0</td>

Comparable compositions may also be made by using glycofurol in an equal or comparable amount instead of transcutol.

Example 6

Preparation of topical dosage forms of the emulsion type

The following formulations are prepared by intimately mixing the specified ingredients analogously to Examples 2 and 5 above, resulting in ointment formulations suitable for topical application.

AT 403 435 Β

<td>6.1. component</td><td>weight</td>

<td>Cyclosporin, such as cyclosporine</td><td>0.1</td>

<td>1.1. Transcutol</td><td>15.0</td>

<td>3.1.1. Cremophor RH 40</td><td>5.0</td>

<td>3.2.1. Labrafil M 213</td><td>15.0</td>

<td>3.2.5. glycerol</td><td>10.0</td>

<td>6.2. Weißpetrolatum</td><td>54.9</td>

<td>6.2. component</td><td>weight</td>

<td>Cyclosporin, such as cyclosporine</td><td>0.1</td>

<td>1.1. glycofurol</td><td>15.0</td>

<td>3.2.5. glycerol</td><td>8.0</td>

<td>6.1. mineral oil</td><td>39.0</td>

<td>6.2. Weißpetrolatum</td><td>37.9</td>

Example 7

Preparation of oral dosage forms of the sugar ester type

<td>7.1. ingredients</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. glycofurol</td><td>100.0</td>

<td>(5) sucrose monolaurate L-1695 *</td><td>312.5</td>

<td>total quantity</td><td>462.0</td>

This is a product available from Mitsubishi-Kasei Food Corporation, Tokyo 104, Japan, with the following physical data: HLB = at least 12.3, lauryl ester = purity at least 95 percent, melting point = about 35'C, Decomposition at about 235'C, surface tension of 0.1 wt% aqueous solution = about 72.0 dynes / cm at 25 xC.

<td>7.2. ingredients</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. Transcutol</td><td>80.0</td>

<td>(5) sucrose monolaurate L-1695 *</td><td>312.5</td>

<td>total quantity</td><td>442.5</td>

This is a product available from Mitsubishi-Kasei Food Corporation, Tokyo 104, Japan, with the following physical data: HLB = at least 12.3, lauryl ester = purity at least 95 percent, melting point = about 35'C, Decomposition at about 235C, surface tension of 0.1 wt% aqueous solution = about 72.0 dynes / cm at 25 xC.

AT 403 435 Β

<td>7.3. ingredients</td><td>Quantity (mg / capsule)</td>

<td>Cyclosporin, such as cyclosporine</td><td>50.0</td>

<td>1.1. glycofurol</td><td>100.0</td>

<td>(5) sucrose monolaurate L-1695 *</td><td>312.5</td>

<td>4.2. Klucel LF</td><td>50.0</td>

<td>total quantity</td><td>512.5</td>

* This product is a product available from Mitsubishi-Kasei Food Corporation, Tokyo 104, Japan, with the following physical data: HLB value = at least 12.3, purity of the lauryl ester residue = at least 95 percent, melting point = about 35 * C, Decomposition at about 235 x C, surface tension of 0.1 wt% aqueous solution = about 72.0 dynes / cm at 25 x C.

The composition of Example 7.1. is prepared by mixing cyclosporin and component (5) with stirring and heating with an oil bath at 100 * C in component 1.1. be solved. The compositions of Examples 7.2. and 7.3. are produced analogously.

The resulting compositions are filled with heating into hard gelatin capsules of size 1 (compositions 7.1 and 7.2.) Or of size 0 (composition 7.3.).

The utility of the compositions of the invention may be demonstrated in animal or clinical trials, for example, performed as follows.

Testing the bioavailability of compositions according to the invention on the dog

a) Compositions to be tested Composition I according to Example 1.1 Composition II according to Example 1.2 Composition III according to Example 1.6 Composition IV according to Example 2.1 Composition V according to Example 2.2 Composition VI according to Example 4.4 Composition VII according to Example 5.3

b) test method

It works with groups of 8 beagle dogs (male, about 11 to 13 kg). The animals do not receive food within 18 hours prior to administration of the composition to be tested, but have free access to water until administration. The compositions to be tested are administered by gavage, followed by administration of 20 ml of a 0.9% solution of NaCl. 3 Hours after administration of the composition to be tested, the animals are allowed free access to food and water. Blood samples of 2 ml each (or 5 ml for the blank) are taken from the saphenous vein and collected in 5 ml plastic tubes containing EDTA, 15 minutes before administration (blank) and 0.5 hours, 1 hour, 1.5 Hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration. The blood samples are stored at -18'C during the test.

The blood samples are analyzed by a radioimmunoassay (RIA). The areas under the curves for drug concentration in the blood versus time are calculated using the trapezoidal method. The range of variation is in terms of the AUC values ​​(area under the curve), the Cmax value (maximum concentration) and the T_MaxValues ​​(maximum time).

c) Test results

The calculated mean values ​​for the AUC values ​​(in ng.h / ml^-1) and the C_MaxValues ​​(in ng / ml^-1) of typical tests are shown in the following table, together with the calculated range of variation of the response between experimental animals receiving the same composition (CV values).

AT 403 435 Β

<td>composition</td><td>AUC values ​​(0 - 24 h)</td><td>CV values ​​(%)</td><td>Cmax</td><td>CV values ​​(%)</td>

<td>I</td><td>2969</td><td>46.1</td><td>655</td><td>42.4</td>

<td>II</td><td>3315</td><td>35.9</td><td>606</td><td>29.0</td>

<td>III</td><td>3392</td><td>33.0</td><td>623</td><td>25.0</td>

<td>IV</td><td>4010</td><td>35.1</td><td>756</td><td>30.0</td>

<td>V</td><td>2769</td><td>27.8</td><td>469</td><td>21.7</td>

<td>VI</td><td>2375</td><td>40.3</td><td>518</td><td>29.2</td>

<td>VII</td><td>2329</td><td>23.1</td><td>470</td><td>36.1</td>

It can be seen from the data in the above table that the compositions according to the invention have a high bioavailability (AUC values ​​and C_MaxValues), which is coupled with a relatively low variability of respondent response for both AUC and Cmax values.

Comparable results can also be obtained using other compositions according to the above Examples 1, 2, 4, 5 and 7, and in particular with the composition of Example 1.

The advantageous properties of the compositions according to the invention when administered orally can also be demonstrated in clinical trials which are carried out, for example, as follows.

Subjects are adult volunteers, such as professionally educated men from 30 to 55 years of age. The groups of probands suitably comprise 12 men.

The following inclusion criteria / exclusion criteria are applied.

Inclusion criteria: normal ECG, normal blood pressure and normal heart rate, body weight 50 to 95 kg.

Exclusion criteria: clinically significant, intermittent medical condition, the absorption, the distribution, the metabolism, may interfere with the secretion or safety of the active substance, Symptoms of significant clinical disease during the two-week pre-trial period, clinically relevant abnormal laboratory values ​​or in the electrocardiogram, The need for concomitant medication throughout the course of the trial, Administration of any active substance, that you know that it has a well-defined potential toxicity for a larger organ system, within the previous 3 months, Administration of any active substance to be tested within 6 weeks prior to the start of the test, History of drug dependence or alcohol dependence, Loss of 500 ml of blood or more within the past 3 months, disturbing reaction or hypersensitivity to the drug, Disease history of an allergy requiring therapeutic treatment with an active agent, positive reaction to Hep-B / HIV.

Before and after the experiment, a complete physical examination is performed and an ECG is made. Within a period of one month before the trial and after the trial, the following parameters are determined.

Blood: count of red blood cells, hemoglobin, hematocrit, erythrocyte sedimentation, white blood cell count, mucus, platelet count and glucose after fasting.

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.

One month before the start of the experiment, the creatinine value is also determined.

Subjects receive the compositions to be tested, each in an arbitrary order. The administration of the compositions is carried out orally once in a total dose of cyclosporin 150 mg, such as cyclosporin, with at least 14 days elapsed between each administration.

The administration is carried out in the morning after a fasting of 10 hours, with only a drink of water is allowed. Within 24 hours of administration, only caffeine-free drinks are allowed. Subjects should not smoke within 12 hours of administration. Subjects receive a standardized meal 4 hours after administration.

Blood samples (2 ml each) are taken 1 hour prior to 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, blood samples of 2 ml each are taken immediately before administration and at 12, 24 and 48 hours after administration. Samples for determination of cyclosporin are collected at any time into two EDTA-coated polystyrene tubes (1 ml each) and deep-frozen after gentle mixing at -20 ° C. The cyclosporin is tested in whole blood using a radioimmunoassay (RIA) with a specific and / or non-specific MAB assay, with a detection limit of about 10 ng / ml in both cases.

AT 403 435 Β

In such an experiment, the above inventive composition I (included in a hard gelatin capsule) is compared to the following composition X.

Composition X *^&gt; Comparative Composition of the Prior Art

A unit dosage form (soft gelatin capsule) contains the following ingredients

<td>cyclosporine</td><td>50 mg</td>

<td>Labrafil</td><td>150 mg</td>

<td>ethanol</td><td>50 mg</td>

<td>corn oil</td><td>213 mg</td>

<td>total quantity</td><td>463 mg per dosage</td>

In an experiment carried out in this way, a bioavailability value of 149.0% (± 48%) results for composition I compared to composition X (which is assigned the bioavailability value 100%). The AUC values ​​(0 to 32 hours ng.h / ml) and the C_MaxValues ​​(ng / ml) for Composition I are 2992 (± 627) and 882 (± 18) compared to 2137 (± 606) and 515 (± 180) for Composition X.

Figures III and IV of the drawing show superimposed plots of such an experiment for the concentration of ciclosporin in whole blood for all 12 subjects after a single oral administration of Composition I (Figure III) and Composition X (Figure IV), each in an amount which gives a dose of cyclosporin of 150 mg, determined after a specific monoclonal radioimmunoassay (RIA). The blood concentration (in ng / ml) is applied vertically, while the time (in h) is applied horizontally.

A comparison of Figures III and IV clearly shows the pronounced reduction in the variability of the response between the subjects with respect to the determined parameters for the bioavailability after administration of the composition I compared to the composition X. The coefficient of variation (variability) [(standard deviation / mean) x 100] with respect to the Cmax values ​​is 35% in the composition X, while that of the composition I is only 20% by comparison.

Similar or comparable results can also be obtained by oral administration of other compositions of the invention, such as the compositions described in the examples, and in particular the compositions of Example I.

Testing topical forms in vivo

Testing allergic contact dermatitis in guinea pigs

Guinea pigs (Hartley, male, 400-500 g) are sensitized by treatment with 50 μl of a 0.5% preparation of DNFB in acetone / olive oil (4: 1) applied to labeled areas of the shaved left and right side of the body. This irritation causes allergic inflammation, resulting in redness and cellular infiltration (swelling) of the skin. The compositions to be tested, such as the compositions of Examples 3, 6.1 or 6.2 above, are applied in a quantity of 200 to 250 mg with a spatula to the DNFB-treated skin area of ​​the right side of the body. Similarly, the left side skin area is treated with placebo as a control. The composition to be tested and the placebo are administered five times at intervals of 20 minutes, 8 hours, 24 hours, 32 hours and 48 hours after the time of induction of allergic inflammation. Before each treatment, the thickness of the skin is determined at the site of application, and again 8 hours after the last application, by lifting the skin to form a fold and measuring the thickness of this fold. Further, by visual determination after a scale ranging from 0 to 4, the degree of redness or inflammation is also determined. The efficacy of the preparation to be tested for the prevention of an inflammatory response is determined by comparison with the results obtained for the placebo-treated skin areas on the lateral body parts.

*&gt; = current drinking solution Sandimmun oral

AT 403 435 Β

In this test method, there is a substantial reduction in the swelling of the skin compared to the placebo after the first application of the composition to be tested, such as a composition according to Examples 3, 6.1 or 6.2, and this reduction in the thickness of the swelling of the skin persists until completion of the experiment.

The results obtained in the above experiment for the composition of Example 3 are shown in the following table.

<td>Time after initiation of an allergic</td><td>8th</td><td>24</td><td>32</td><td>48</td><td>56</td>

<td>Inflammation (hours)</td><td></td><td></td><td></td><td></td><td></td>

<td>Percent inhibition of skin swelling versus placebo as a control</td><td>56</td><td>68</td><td>76</td><td>75</td><td>73</td>