Improvements in/relating to organic compounds

Pharmaceutical compositions containing cyclosporins

Full description

Background of the invention

This invention deals with new pharmaceutical formulations comprising cyclosporin as the active ingredient.

Cyclosporins consist of a group of eleven peptides with a distinctive structure, which are cyclic compounds with multiple methyl groups linked to a nitrogen, and in common they have an abasic effect, particularly in the field of immunosuppression, anti-inflammatory and/or anti-parasitic action. The first isolated cyclosporin was the natural product of fungal metabolism called ciclosporin, also known as cyclosporin A, which is commercially available under the brand name SandimmunR or ciclosporin.

Cyclosporin, formula A.

<img file="SA296B1_D0001.tif" />

Where -N-MeBmt-methyl-(4R)-4-but-2E-en-1-yl-4-methyl-(L)threonyl represents N-methyl-(4R)-4-but-2E-en-1 -yl-4-methyl-(L)threonyl as part of formula B:

<img file="SA296B1_D0002.tif" />

Where -xy- is -trans) -CH=CH).

As the first of its group, cyclosporin has received the most attention so far. The first area of clinical investigation for ciclosporin was an immunosuppressive agent, particularly in the field of its application to patients who had affected organs such as the heart, lung, heart and lung together, liver, kidney, pancreas, bone marrow, skin, or cornea. Especially in the case of transplanting organs transferred from others with a different genetic makeup. Ciclosporin has achieved remarkable success and a good reputation in this regard.

At the same time, ciclosporin was used extensively for various autoimmune diseases and inflammatory conditions, especially those whose causes include an autoimmune component such as arthritis (such as rheumatoid arthritis, chronic progressive arthritis, and deforming arthritis), rheumatic diseases, and reports and results of in vitro experiments (outside in vivo), in animals and in the clinical field are widespread in the literature. The list of autoimmune diseases for which ciclosporin therapy has been suggested or applied includes: Autoimmune blood diseases (including anemia caused by breaking down blood cells, non-hypoplastic anemia, solitary red blood cell anemia, thrombocytopenia of unknown (cause), systemic lupus erythematosus, polychondritis, scleroderma, chronic Wegener's tumors, and dermatomyositis Chronic active hepatitis, severe muscle weakness, psoriasis, Stevens-Johnson syndrome, and swelling of unknown cause

and autoimmune inflammatory bowel disease (including ulcerative colitis and Crohn's disease).

Eye suggested endocrine disorder, hyperthyroidism (Graves' disease), sarcoidosis, multiple sclerosis, primary biliary cirrhosis, diabetic urea of the yolk (type 1 diabetes), inflammation of the uveal layer of the eye (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, and interstitial fibrosis. Lung and arthritis, psoriasis, and glomerulonephritis (with or without renal protein loss syndrome, including renal protein loss syndrome of unknown etiology or kidney disease) specified changes).

Further research has shown that the drug could be useful in treating parasites, particularly as an anti-protozoal parasitic, with possible uses suggested for the treatment of malaria.

Coccidiomycosis and schistosomiasis, and it has recently been suggested to use it to reverse or nullify resistance.

For anti-cancer agent in tumors, etc.

Since the original discovery of naturally occurring cyclosporins, a wide range of ciclosporins have been isolated and identified. Cyclosporins have also been prepared from cyclosporins other than those found naturally by fully or partially synthetic methods by applying culture methods. Cyclosporins are now large in number and include, for example, modified cyclosporins. And the class of cyclosporins

Natural cyclosporins A to Z see: [cf Traber et al. 1, Helv. Chim. Acta. 60, 1247-1255 (1977); Traber et al. 2, Helve Chim. Acta. 65 no. 162,1655-1667 (1982); Kobel et al., Europe. J. Applied Microbiology and Biotechnology (1982) 240-273,14 and von Wartburg et al., Progress in Allergy, 38. 28-45 (1986)].

Cyclosporin derivatives not found in nature, as well as many industrial or synthetic cyclosporin derivatives, including the so-called dihydro-cyclosporins and cyclosporins -MeBmt- from the -xy- moiety in which the moiety is dihydro-cyclosporin - cyclosporins and cyclosporins -CH2-CH2- = - xy- above) is saturated so that B becomes (a formula of the derived a-carbon atom (in which a substituent is introduced at the alpha-carbon atom and cyclosporin at position -3 of the sarcosyl molecule, i.e. which) isonreric form In the isomeric form -MeBtm- in which the moiety is cyclosporins (trans, not cis), -MeBtm- is the form in which it is with respect to the 6' and 7' positions of the amino acids in which variations of the amino acids have been introduced cyclosporins and cyclosporins using - for example - the total synthetic method to produce peptide at specific positions in the peptide chain Traber 2 and Traber 1 See - Wenger - developed by cyclosporins Cyclosporins References previously mentioned and US Patent Nos. 4108985, and Kobel; WO 86/02080 581. 421, 4220641, and International Published Patent Nos. Wenger 1, TRansp. Proc. 15, Suppl. 1:2230 (1983); Wenger 2, Angew. Chem. Int. Ed., 24, 77 (1985); and Wenger 3, Progress in the Chemistry of Organic Natural Products 50, 123 (1986).

Cyclosporins now have a very large variety and include, for example, 2[Thif]-,

[Nva]2,-[val]2, [Nva]2- and [Nva]5 cyclosporin (also known as cyclosporins G, D, C and M respectively), [3-zero-acyl-MeBmt]1- Cyclosporin [3-0-acyl-MeBmt]1-Ciclosporin (also known as Cyclosporin A

ciclosporin A acetate), [dihydro-MeBmt]1-[val]2 cyclosporin

[Dihydro-MeBtm]1-[Val]2-Ciclosporin (also known as dihydro-cyclosporin D), [(d)fluoromethylsarcosine)3- Cyclosporin

D)Ser]8 [(D)Fluoromethyl-Sar]3-ciyclosporin)]- cyclosporin D)Ser)8-ciclosporin)]; 11[Melle]-Cyclosporin [(D)Meval]11,[Melle]11-ciyclosporin-Cyclosporin

[(D)MeVal]11-ciclosporin (also known as cyclosporin H),

6(MeAla]- ciclosporin [(D)Pro]3, [MeAla]6-ciclosporin

- Cyclosporin D)Pro]3-ciclosporin] and so on.

[According to the now conventional name for cyclosporins, they are known in reference to the structure of cyclosporin (i.e., cyclosporin A). This is done first by clarifying the existing amino acids that differ from those found in cyclosporin (for example, &amp;3[D)Pro)]&amp; to clarify that the cyclosporin in question contains -D)Pro)- instead of -Sar- at position 3, then by using the term ' 'Ciclosporin' to describe all moieties identical to those found in Ciclosporin. The individual moieties are numbered starting with -MeBmt- or -dihydro-MeBmt- (in position 1).

Many of these cyclosporins have a pharmaceutical benefit comparable to or even better than ciclosporin, for example in reversing the resistance of tumors to anti-cell proliferation therapy, and there are many suggestions in reference materials regarding their use as therapeutic means.

Despite the very great contribution made by ciclosporin, especially in the field of organ transplantation and the treatment of autoimmune diseases, one of the obstacles to its widespread use was the difficulties in providing more effective and appropriate methods of administering it, as well as the occurrence of some undesirable side effects, especially the toxic effect on the kidneys. Cyclosporins are characterized

Cyclosporins are highly hydrophobic. Until now, liquid formulations proposed for oral administration of cyclosporins, for example, have been based primarily on the use of ethanol, oils, etc., and excipients as carriers. Thus, the commercially available syrup of cyclosporin solution uses ethanol and olive oil as carriers in combination with... Labrafil as a surfactant reducer. See, for example, US Patent No. 4,388,307. However, the use of syrup solutions and similar formulations is accompanied by many difficulties in practice.

First, the necessity of using oils or oil-based carriers may give the preparations an unpleasant taste or otherwise reduce their taste quality, especially for long-term treatment purposes. This effect can be blocked by presenting the drug in the form of gelatin capsules. However, to keep cyclosporin in solution form, the ethanol content must remain high. Evaporation of ethanol, for example from capsules or other forms, such as when opened, results in the formation of a precipitate of cyclosporin. If such formulations are presented, for example, in the form of soft gelatin capsules, this difficulty requires filling the preparation that will be placed inside a capsule inside an air-tight space, for example inside an air-tight container or an aluminum-foil container. This therefore makes the product bulky and more expensive to produce. Also, the storage properties of such formulations are far from ideal.

The levels of bioavailability achieved using current oral dosing regimens for cyclosporin are also low and show significant variation between individuals and types of disease, and even for the individual patient at different times in the course of treatment. Reference reports indicate that currently available treatment using commercially available ciclosporin provides an average absolute bioavailability of about 30%, with significant variation between patient groups, for example bioavailability is relatively low for liver transplant patients and relatively high for bone marrow transplant patients. The reported variation in bioavailability between individuals ranged from one or a few percent for some to 90% or more for others. As previously noted, a significant change is often observed in the bioavailability of individuals over time.

To achieve effective immunosuppressive treatment, the concentration of cyclosporin in the blood or serum must be maintained within a specific range. The required extent may vary depending on the condition to be treated, for example if the treatment is to prevent the expulsion of a transplanted organ or to control the course of an autoimmune disease. It also varies depending on the use or non-use of alternative immunosuppressive therapy at the same time as treatment with cyclosporin. Given the wide variation in levels of bioavailability achieved with conventional drug dosage forms, the daily doses required to reach the required levels in blood serum will also vary greatly from one individual to another, and even for the same individual. For this reason, it is necessary to monitor the blood/serum concentration of patients receiving treatment with cyclosporin at regular and frequent intervals. Monitoring the drug concentration in blood or serum, which is usually done by radioimmunoassay or equivalent immunoassay, such as technical methods based on single-group antibodies, must be done on a regular basis. This therefore consumes time, causes discomfort, and greatly increases the cost of treatment.

In addition to all these very obvious practical difficulties, there is also the occurrence of the previously mentioned unwanted side effects that are seen when using oral dosage forms.

Specialists presented many suggestions to address these problems, including both solid and liquid forms for oral use. However, the insurmountable difficulty that has remained is the inability of cyclosporins - for example, cyclosporin - to dissolve in aqueous media, and thus the inability to provide a pharmaceutical form containing cyclosporin in a sufficiently high concentration that allows for appropriate use and at the same time fulfills the required requirements for bioavailability, i.e. It allows effective absorption from the stomach or intestine, achieving a stable and appropriately elevated concentration in blood or serum.

The particular difficulties encountered in association with the oral administration of cyclosporins have inevitably led to a limitation in the use of cyclosporin for the treatment of relatively less severe or less serious medical conditions. One of the difficulties in this area is the use of cyclosporin treatment to treat autoimmune diseases and other conditions that affect the skin, such as dermatitis.

Allergies and psoriasis, as well as - as suggested in scientific articles to stimulate hair growth - for example, to treat hair loss due to age or disease.

Thus, although the use of oral cyclosporin for treatment has proven that the drug is of great potential benefit for treating psoriasis patients, for example, the risk of side effects occurring as a result of oral treatment has prevented its widespread use. Many specialists have suggested the use of cyclosporins - such as ciclosporin - topically, and many topical regimens have been described. However, topical applications have failed to show significant therapeutic efficacy. The availability of a method for effective topical application within the skin that is suitable for treating psoriasis, for example, will make treatment with cyclosporin available to a large number of patients who need it.

General description of the invention

This invention provides new pharmaceutical formulations of cyclosporin in the form of a pre-concentrated microemulsion and/or based on the use of certain solvent media as specified below, which counteract or greatly reduce the difficulties of using cyclosporin - for example - in treatment. Currently practicing. In particular, it has been found that the compositions of this invention allow the preparation of solid, semi-solid and liquid compositions containing cyclosporin at a sufficiently high concentration to allow, for example, its convenient oral administration, while at the same time achieving an improvement in effectiveness, for example, in the area of bioavailability properties.

Detailed description of the invention

In particular, it has been found that the compositions according to this invention allow the administration of cyclosporins in effective doses with a concomitant activation of the levels of absorption/bioavailability, as well as reducing the variation in the levels of absorption/bioavailability achieved, whether for an individual patient receiving treatment with cyclosporin or between individuals - and by applying what is recommended. The present invention enables cyclosporin dosage forms to be obtained that reduce the variation in cyclosporin concentration achieved in blood/or serum between Dosing for individual patients as well as between individuals and groups of patients. Thus, the invention allows reducing the amount of cyclosporin dose required to obtain effective treatment. In addition, it allows for better calibration as well as optimal adjustment of individuals' continuous daily dose requirements

Those receiving treatment with cyclosporin, as well as for groups of patients receiving liquid therapy.

With more precise calibration of dose rates for an individual patient and concentration response in blood/or blood solution, as well as dose-response parameters in patient groups, the requirement for follow-up is reduced and the cost of treatment is effectively reduced.

Reducing the requirements for dose adjustment/titration to achieve bioavailability properties, the present invention provides a means of reducing the incidence of unwanted side effects, particularly toxic effects on the kidneys, in patients receiving treatment with cyclosporin.

In addition, the invention allows the preparation of formulations that are not based on alkanolics, that is, they may be free or almost free of ethanol. Such compositions allow avoiding the mechanical problems and associated processing difficulties mentioned above that usually accompany well-known alkanolic compositions. The invention thus provides, among other things, better adaptable compositions such as presentation in the form of capsules, such as hard or soft gelatin capsules, and/or eliminates or significantly reduces packaging difficulties such as those referred to above, such as those associated with soft gelatin capsule forms.

As for topical use, the present invention allows the preparation of new pharmaceutical preparations containing cyclosporin (such as ciclosporin) as an active ingredient, which allows for better treatment of autoimmune diseases affecting the skin, especially skin diseases characterized by cell division and/or pathological formation of keratin in the epithelial layer. Epithelial diseases of the skin, in particular psoriasis and allergic skin diseases, and topically applicable compositions according to the invention are also useful for treating alopecia, i.e. for preparing hair growth.

As a first aspect, the present invention specifically provides pharmaceutical compositions comprising cyclosporin as an active ingredient, which compositions are in the form of an oil-in-water microemulsion pre-concentrate.

The term "oil-in-water microemulsion pre-concentrate" as used herein means a system that, upon contact with water - for example, when water is added to it - can form an oil-in-water microemulsion and the term

Microemulsion as used herein is used in the conventional sense as a colloidal dispersion that is essentially opaque or opaque comprising water and organic components, including organic components that are not hydrophilic (lipophilic). Microemulsions can be recognized as those that It is characterized by one or more of the following features: They are formed spontaneously, or largely spontaneously, when their components are given the opportunity to come into contact, that is, without substantial energy supply, that is, without heating and without the use of financial cutting devices or any significant agitation. It is also thermodynamically stable and is single-phase. It is also not essentially opaque, that is, it is transparent or sparkling when viewed with optical microscopic means. In its undisturbed state, it has uniform optical properties, although non-isotropic structures may be observed, for example, with the use of x-ray methods.

Microemulsions contain a dispersed or particulate (droplet) phase, with a particle size of less than 2000 angstroms, which explains their optical transparency. Microemulsion particles may be spherical, although other shapes are possible, such as liquid crystals with lamellar, hexagonal, or symmetrical symmetries. In general, microemulsions include droplets or particles whose maximum dimensions (diameter) are less than 1500 angstroms, and they are usually between 100 and 1000 angstroms [For further discussion of the properties of microemulsions see, e.g., Rosof, Advances in the Science of Surfaces and Membranes, 12, 405 et seq., Academic Press (1975), Freiberg, Dispersion Science and Technology 6 (3), 317 et seq. (1985) and Müller et al., Pharmaceutical Investigation 50 (3), 370 et seq. (1988)].

It is clear from the above that “oil-in-water microemulsion pre-concentrate” and the related invention are pharmaceutical systems containing cyclosporin as an active ingredient that can form an oil-in-water microemulsion automatically or semi-automatically. Automatically upon contact with water.

Pharmaceutical compositions “oil-in-water microemulsions pre-concentrate” containing cyclosporins

Cyclosporines - as an active ingredient - new formulations. Accordingly, the present invention, in one of its aspects, provides the following:

(a) Pharmaceutical composition based on cyclosporin as the active ingredient.

1- Water-loving phase,

2- Phase Alof of fats, and

3- Reducer of surface tension,

This composition is a preconcentrated oil-in-water microemulsion

oil-in-water microemulsion pre-concentrate&amp;.

(The term "pharmaceutical composition" as used herein and in the attached items sought to be protected should be understood to specify formulations of their components or individual elements that are pharmaceutically acceptable in their own right. That is, when they are intended for oral use, they are acceptable for oral use, and when they are intended for topical use, they are It is acceptable for topical use.

Cyclosporin is carried in the affinity phase of fats. Conveniently, both the hydrophilic and lipophilic phases can act as a carrier medium.

Definition: The “microemulsion pre-concentrate” of the invention is of a type that provides oil-water (also, oil/water) microemulsions. However, it must be taken into account that the formulations according to (a) may contain small amounts of water and otherwise are characterized by microstructural features specific to microemulsions, i.e. those of the oil-in-water or water-in-water type. -in-oil&amp;. The term oil-in-water microemulsion pre-concentrate as used herein should be understood accordingly to include these possibilities.

The microemulsions obtained by contacting the “microemulsion pre-concentrate” formulations derived by the invention to water or another aqueous medium are characterized by thermodynamic stability, meaning that they remain stable at usual temperatures, meaning that they do not darken or form emulsifying droplets of an apparent size or Deposition over a long period of time. It is of course understood that to obtain a precise emulsion an appropriate amount of water must be added. Although the upper limit of mitigation is not one of the fundamental determining factors,

A dilution of 1:1 or higher (eg 5:1 from microemulsion pre-concentrate to water) will usually be appropriate. In preferred cases, the compositions of the invention “pre-concentrated microemulsions” upon contact with water can form microemulsions that remain stable at room temperature, meaning that they do not exhibit opacity or precipitation that can be seen with the eye for at least two hours, and in better cases for at least 4 hours. At least and at best for at least 12 to 24 hours. The microemulsions obtained from the “pre-concentrate microemulsions” of the invention, for example, at the above dilution degrees, have an average particle size in favorable cases of less than about 150 angstroms and in favorable cases of less than 1000 or 1100. Angstroms down to about 150 or 200 angstroms.

Particularly preferable - in accordance with this invention - are the compositions as known under (a) in which the hydrophilic phase includes:

1-1: Pharmaceutically acceptable C1-5alkyl or tetrahydroforfiiryl di or partial-ether of mono- or poly-oxy-alkanediol of low molecular weight; or

1-2: 1,2-propylene glycol 1,2-propyleneglycol.

Suitable components (1-1) are, for example, di- or partial, and in particular, partial ethers of mono or poly-particularly mono- or di-, oxy-alkanediols included On the number from 2 to 12, especially 4 carbon atoms. It is preferable for the part to be a single or poly-oxy-alkanediol straight-chain diode. Compounds particularly suitable for use according to this invention, whether in themselves or in part, are ethers with the formula (I).

R1 -[O-(CH2)2]x-OR2 (I)

Where, R is the alkyl C1-5alkyl C1-5 or tetrahydrofurfuryl, R2 is the hydrogen, alkyl C1-5alkyl C1-5 or tetrahydrofurfuryl.

tetrahydrofurfuryl, and

X is an integer from 1 to 6, especially from 1 to 4, and especially about 2.

Particularly preferable for use according to this invention are partial ethers as defined above, i.e. products of the formula (I) where R2 is hydrogen.

The alkyl moiety C1-5lkyl C1-5 in the ethers specified above may be branched or straight-chain, that is, they include methyl, ethyl, n-propyl, and i-propyl groups. n-butyl and t-butyl groups for example.

Such ethers are known and commercially available compounds or can be produced in a manner similar to known products. Particularly preferred compounds of Formula I for use in connection with the present invention are those known and commercially available under the trade names Transcutol and Glycofurol.

Transcutol is the compound diethyleheglycol monoethyl ether of formula (I) where H = R2, C2H5 = R1 and X = 2. Glycofurol, also known as tetrahydrofurfryl alcohol polyethylene glycol ether or alpha -(tetrahydrofuranyl)-omega-hydroxy poly(oxy-2,1-diallyl)

α-(tetrahydrofuranyl)-ɷ-hydroxypoly(oxy-1,2-ethanediyl) of the formula (I) where R1 =

<img file="SA296B1_D0003.tif" />

H = R2 and X average their value from 1 to 2. The average molecular weight is about

190. The boiling point is about 80-100 C (at 40 N/m2), the density is about 1.07-1.09 g/cm3 (at 20 C), the hydroxy value is about 300-400, and the refractive index is about 1.4545 (sodium D line). , 589 mm) (at 40 C) and a viscosity of about 8-18 mS/m2 (at 20 C).

[cf &amp;Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association/The Pharmaceutical Society of Great Britain (1986), p. 127 and Fiedler, ''Lexikon der Hilfetoffe&amp;, 3rd edition (1989), p. 577.)

According to its degree of relative purity. Grades of Glycofiirol The exact characteristics of lower quality glycofiirol contain significant amounts of tetrahydrofurfuryl alcohol and other impurities. For the purposes of this invention, glycofuranol 75 tetrahydrofiirfiiryl alcohol is preferred

75 glycofurol; Which means a product that fulfills the Phoenician data referred to above and in which the part whose formula is the formula (I) shown above, in which X is - 1-2, reaches a minimum of 95%.

It has been found that the use of the known components under (1-1) and (1-2) above provides, in particular, compositions identical to (a) in which the water-friendly phase is particularly suitable as a carrier medium for cyclosporin, meaning that the water-friendly phase in it makes the loaded cyclosporin The composition is suitable for therapeutic doses suitable for oral administration, for example.

Compositions according to (a) comprising components as defined under (1.1) and/or (1.2) as a hydrophilic phase may, of course, include one or more components of those described as components of the hydrophilic phase. However, it is preferable that any additional ingredients include substances in which the active ingredient of cyclosporin can be sufficiently dissolved so that its effectiveness is not appreciably affected. The hydrophilic phase as a carrier medium for cyclosporin. Possible examples of additional components of the hydrophilic phase include lower alkanols (eg C1-5) and in particular ethanol.

Although the use of alkanols, such as ethanol, as a component of the hydrophilic phase is contemplated in this invention, for reasons previously discussed, this would generally be less desirable. It is preferable that the compositions specified under (a) are not based on alkanol, that is, they do not include alkanol as a basic component of the water-friendly phase. It is appropriate for the hydrophilic phase to contain a percentage of cannolic components less than 50% by weight, better than that, less than 25%, and preferably less than 10%. It is most appropriate for the water-friendly phase to be devoid of or almost devoid of alkanolic components, i.e. containing less than 5%, and preferably less than 2%, i.e. 0 to 1%, of alkanolic components. By “alkanol” we mean in particular, C1-alkanols. 5alkanols C1-5, especially ethanol.

In a particularly preferable way, the hydrophilic phase of the compositions known under (a) will or will consist primarily of components as defined under (1.1) or (1.2) above, in particular transcutol, glycofiirol and/or 1,2-Propylene

Glycol 1,2-propylene glycol. It is most appropriate that it consists or consists primarily of any of the components

(1-1) or component (1-2).

Compositions according to (a) containing a component (1.1), particularly glycofirrol, are of particular interest in that they are well suited for provision in the form of soft gelatin capsules. According to the invention, these compositions are found to have surprisingly excellent stability, for example as shown by long-term stability tests at normal and elevated temperatures. These formulations are therefore particularly suitable for overcoming the difficulties that usually occur in transporting and storing pharmaceutical preparations, including long-term storage at the consumer, i.e. in hospitals, clinics and similar places.

The known structures under (a) include, in addition to, the aloof phase of fats (2). Components suitable for use as a fat affinity phase include any pharmaceutically acceptable solvent that is immiscible with the chosen water affinity phase, i.e. as defined under (1-1) or (1-2). These solvents should preferably be free or almost free of the property of reducing surface tension. Components particularly suitable for use as components of the affinity phase of lipids (2) include, for example:

Triglycerides are fatty acid triglycerides, the best of which are triglycerides of medium-chain fatty acids. Particularly suitable are neutral oils, for example neutral vegetable oils and in particular fractionated coconut oils such as those well-known and commercially available under the trade name (808-809 Miglyol (cf. Fiedler, loc. cit. pp), including the following products:

Miglyol 810 810 Miglyol: Fractionated coconut oil containing caprylic and capric acid triglycerides with a molecular weight of about 520. Fatty acid composition: C6 = fatty acid maximum 2%, C8 about 65-75%, C10 about 25-35 %, C12 max. 2%, acid number = about 0.1, saponification number = about 340-360, iodine number = max. 1;

Miglyol 812 812 Miglyol: Fractionated coconut oil contains triglycerides of caprylic and capric acid triglycerides, with a molecular weight of about 520.

Composition of fatty acids C6 = fatty acid max. about 3%, C8, about 50-65%, C10 about 30-45%, C12 max. 5%, acid number = about 0.1, saponification number = about 345-330, Iodine number = max 1;

Miglyol 818 818 Miglyol: a triglyceride of capric acids, capric and linoleic acids, and its molecular weight = about 510. Composition of fatty acids C6 = fatty acid maximum 3, C8 maximum 45-65, C10 approximately 25-

40, C12 about 2-5, C18-2 about 4-6, acid number = max. 0.2, saponification number = about 315-335, iodine number = max. 10; And

Captex 355 355 Captex(1) Caprylic acid triglyceride containing fatty acids = caproic about 2%, caprylic about 55%, capric about 42%, acid number = maximum 0 ,1, saponification number is about 325-340, iodine number = max. 0.5.

Also suitable are caprylic-capric acid triglycerides such as those known and commercially available under the trade name CF Fiedler Loe. cit., P. 834) Myritol) and includes the product Myritol 3 81 813 Myritol, which has an acid number = 1 maximum, a saponification number = about 340-350, and an iodine number = about 0.5. Other suitable products in this group include: Capmul MCT(1), Captex

300(1) (1)300 Captex, Captex 800(1) (1)800 Captex, Neobee M5(2) M5 and Mazol 1400(3) (3)1400 Mazol.

1) = Capital City Products, PO. Box 569, Columbus, OH, USA. (2) = Stepan,)]

PVO Dept., 100 West Hunter Ave., Maywood, NJ 07607, USA. (3) = Mazer

[.(Chemicals, 3938 Porrett Drive, Gurnee, IL, USA

The compositions according to the invention and knowledge under (a) also include a pharmaceutically acceptable surfactant (3). The surfactant component may include (3-1) a surfactant that is affinity for water, (3-2) that is affinity for fats, or a mixture of both. Non-ionic surfactants that are friendly to water and non-ionic surfactants that are friendly to fats are particularly preferred. Examples are

Suitable surfactants that are affinity for water for use as surfactant components

the following:

3-1-1: Products of the reaction of vegetable or hydrogenated oils with ethylene glycol, i.e. polyoxyethylene glycolate. Natural or hydrogenated vegetable oils, for example polyoxyethylene glycolate, natural or hydrogenated castor oils. Such preparations can be obtained by a known method, such as the reaction of natural castor oil or Hydrogenated or parts thereof with ethylene oxide, for example in molecular ratios ranging from 35:1 to about 60:1, with the possibility of eliminating the free polyethylene components. Polyethyleneglycol of the product, for example, according to the methods described in German Patents 1,182,388 and 1,518,819. Particularly relevant are the various surfactants available under the trade name Cremophor. from

Particularly suitable preparations are Cremophor RH 40, which has a saponification number of about 60-50, an acid number of less than 1, an iodine number of less than 0.1, a water content (Fischer) of less than 2%, and an optical refractive index at 25 of about 1.453-1.457.

Water/fat affinity balance = about 14-16, 60 Cremophor RH, its saponification number = about 40-50, the acid number is less than 1, the iodine number is less than 1, the water content (Fischer) = about 4.5-5.5%, and the coefficient Optical refraction at 25 = about 1.453-1.457 and the balance of water and fat = about 15-17, and EL Cremophor. And its molecular weight (by measure

Steam osmosis) = about 1630, the saponification number 5 is about 65-70, the acid number = about 2, the iodine number = about 28-32, and nD25 = about 1,471 (326-327. CF Fiedler loc. cit. pp). It is also convenient to use in this group the various interpretations available under the brand name Nikkol, for example 60-Nikkol HCO. This compound 60-HCO is the product of the reaction of hydrogenated castor oil with ethylene oxide and has the following properties: acid number = about 0.3, saponification number = about 47.4, and hydroxy value =

About 42.5, pH (5%) = about 4.6, APHA color - about 40,

Melting point = about 36 Celsius,; Freezing point - about 32.4 C, water content (KF,%) = about 0.03;

3-1-2: Polyoxyethylene-sorbitan-fatty acid esters, for example, mono- and trilauryl esters, palmityl, stearyl, and oleyl. For example, the well-known type is commercially available under the trade name Twin CF Fiedler, loc. cit. pp. 1300-1304 (Tween) including Tween preparations.

20 [polyoxyethylene (20) sorbitanmonolaurate],

40 and polyoxyethylene (20) sorbitan monopalmitate],

60 [polyoxyethylene (20) sorbitanmonostearate],

80 [polyoxyethylene (20) sorbitan monooleate],

65 [polyoxyethylene (20) sorbitan tristearate],

85 [polyoxyethylene (20) sorbitan trioleate sorbitantrioleate],

21 and polyoxyethylene (4) sorbitanmonolaurate],

61 [polyoxyethylene(4) sorbitanmonostearate],

81 [polyoxyethylene (5) sorbitan monooleate],

Particularly preferred products from this group for use in the compounds of the invention are

The above-mentioned preparations Tween 40 and Tween 80,

3-1-3: Polyoxyethylene fatty acid esters, for example, polyoxyethylene stearic acid esters of the well-known type that are commercially available under the trade name CF Fiedler, loc. cit., p. 834) Myrj

As well as polyoxyethylene fatty acid esters, which are known and commercially available under the trade name .cf Fiedler, loc. cit., p. 284) Cetiol HE; A particularly preferred preparation for use in the compositions of this invention is Myrj 52, for which the optical refractive index at D25 = about 1.1, the melting point = about 40-44 C, the water-fat affinity balance = about 16.9, and the acid number = about 0-1. The saponification number = about 25-35.

3-1-4: Polyoxyehylene-polyoxypropylene copolymers, for example, are of the well-known type and commercially available under the trade names Pluronic and Emkalyx (956-958 cf. Fiedler, loc. cit., pp). A particularly preferred preparation from this group for use in the compositions of the invention is Pluronic F68;

5-1-3: Polyoxyethylene-polyoxypropylene copolymers

polyoxyethylene- polyoxypropylene, for example the type known and commercially available under the trade name Poloxamer (c.f. Fiedler, lor. cit., pp. 959). A particularly suitable compound of this group for use in the compositions of the invention is Poloxamer (c.f. Fiedler, lor. cit., pp. 959);

3-1-6: Sodium dioctylsuccinate

dioctylsodiumsulfosuccinate, di-[2-ethylhexyl]-

di-[2-ethylhexyl]-succinate or sodium lauryl sulfate;

3-1-7: Phospholipids (phosphorylated fats), especially lecithins.

(731-733 .cf. Fiedler, loc. cit., pp.). Lecithins suitable for use in the compositions of the invention include in particular soybean lecithins;

3-1-8: Propylene glycol esters, monoprotective fatty acids such as propylene glycol dicaprylate,

Propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate earate etc. (.cf Fiedler , loc. cit., pp. 1013 et seq. Particularly preferred is the propylene glycol diester of caprylic and capric acids, propylene glycol caprylic-capric acid diester, known and traded commercially under the trade name 840 cf Fiedler, loc. cit., p. 809) Miglyol). And 840 Miglyol has fatty acid content = C6 max. About 43, Cb about 65-80%, C10 about 15-30%, C12 max. 3%. Acid number = max. 0.1, saponification number = about 320-340, iodine number = max. 1; And 3-1-9: bile salts, for example, alkaline mineral salts such as sodium taurocholate.

Examples of lipophilic surfactants suitable for use as a surfactant ingredient are:

3-2-1: Trans esterification compounds for triglycerides of polyalkylene natural vegetable oils. These trans-esterification compounds are technically known and can be obtained, e.g

According to the general method described in US Patent No. 4 3,288.82.

It includes trans-esterification preparations of various natural (i.e. non-hydrogenated) vegetable oils such as corn oil, kernel oil, almond oil, peanut oil, olive oil, palm oil and their mixtures with polyethylene glycols, in particular polyethylene glycols of The average molecular size ranges from 200 to 800. We prefer preparations that are obtained by trans-esterification of two molecular parts of a natural vegetable oil triglyceride with one molecular part of polyethylene glycol. glycol (such as those whose average molecular weight varies from 200 to 800). There are various forms of trans-esterification preparations from the well-known group that are commercially available under the trade name Tsee Fiedler, loc. cit., 707] Labrafil. Particularly useful preparations as components of the compositions of the invention are: Labrafil Ml944 CS, which is a transesterification preparation of polyethylene glycol core oil with acid number = about 2, saponification number about 145-175 and iodine number = about 60-90, and Labrafil M2130 CS, which is a transesterification preparation of C12- glyceride to C18 and polyethylene glycol. Its melting point = about 35-40 Celsius, acid number = less than 2, saponification number = about 185-200, and iodine number = less than 3;

3-2-2: Mono-, di- and mono/di-glycerides, especially the esterification products of caprylic or capric acid with glycerol. Preferred preparations from this class are those containing or consisting primarily or mainly of mono- and diglycerides of caprylic/capric acid such as those commercially available under the trade name CF LOC. cit., pp. 645) Imwitor. One preparation of this class that is particularly suitable for use in the compositions of the invention is preparation 742 Imwitor, which is the esterification product of a mixture of about 60 percent by weight of acid.

Caprylic acid and about 40 percent by weight of capric acid with glycerol. The 742 Imwitor is typically a yellow crystalline mass,

Liquid at about 26 C, acid number = max. 2, iodine number = max. 1, saponification number = about 235-275, % monoglycerides. About 40-50%, free glycerol maximum 2%, melting point = about 24-26 C, unsaponifiable fraction = 0.3% maximum,

Peroxide number = max 1;

3-2-3: sorbitan fatty acid esters, for example of the type known and commercially available under the trade name Span, including, for example, sorbitan-monolauryl esters,

monopalmityl, monostearyl, tristearyl, monooleyl and trioleyl (1139-1140 cf. Fiedler, loc. cit., pp.);

3.2.4: Pentaerythritol fatty acid esters and polyalkylene glycol ethers, for example pentaerythrite, dioleate, distearate, monolaurate, polyglycol ether and monolaurate. Monostearate- as well as pentaerythrite esters of fatty acids cf Fiedler, loc. cit. pp. 923-924) pentaerythrite-fatty acid esters);

3-2-5: Monoglycerides, for example - glycerol monooleate, glycerol monopalmitate and glycerol monostearate, for example what is known and commercially available under the trade names Myvatex, CF Fiedler, loc. cit., pp. 836) Myverol (Myvaplex), and any of them are acetylated, i.e. mono- and di-acetylated monoglycerides, for example what is known and is commercially available under the trade name CF Fiedler, loc. cit., pp. 835) Myvacet);

3-2-6: glycerol triacetate or (3,2,1)-triacetin cf Fiedler, loc. cit., pp. 952) (l,2,3)-triacetin); And 3.2.7: sterols and their derivatives, for example cholesterol and their derivatives, especially phytosterols, such as compounds that include sitosterol, campesterol, or stigmasterol, and their ethylene oxide derivatives, for example soya sterols and their derivatives, such as It is known under the trade name cf Fiedler loc. cit., PP 554 and 555) Generol) and in particular preparations 122E10, 122E25, Generol 122 and 122E5.

The compositions as defined under (a) above include systems comprising either a single surfactant or a combination of surfactants, such as those comprising a first surfactant plus one or more auxiliary surfactants. Combinations of surfactants and surfactants may be selected from any of the types of surfactants as described under (3.1.1) to (3.2.7) above.

If the water-friendly phase includes a binary or partial ether as known under (1-1) above, especially transcutol or glycofirrol, then the use of a single surface tension reducer will be sufficient, although auxiliary surface tension reducers can be added if there is a desire to So, to further improve the stability properties for example. If 1,2-propylene glycol is used as the sole or major component of the hydrophilic phase, the use of at least two surfactants, i.e. a surfactant and a co-surfactant, will generally be required - the compositions as defined below ( A) It includes 1,2-propylene glycol as a water-friendly phase and thus includes both a reducer and a surfactant.

Surfactants as they are known under (3.1.1), (3.1), (3.1.7), (3.2.2) and (3.2.5) above are particularly interesting to use. In the compositions as they are known under (a). Particularly suitable surfactant/surfactant adjuvant groups are hydrophilic/lipophilic surfactant groups.

For example, combinations of surfactants according to formula (3-1-1) with reducers, according to formula (3-2-5).

If the surfactant includes an active solvent for the active cyclosporin component,

As is the case, for example, with surfactants or combinations thereof (3.1.1) to (3.2.7) above, they may be introduced into compositions as defined under (A) not only as a surfactant but in excess. As an additional carrier phase or co-solvent, i.e. as part of the water-friendly or fat-loving phase.

The compositions according to (a) above may also include:

4- Thickening agent.

Suitable thickening agents may be those known and used in extensive applications, including, for example, pharmaceutically accepted polymeric materials and inorganic thickeners, for example the following types:

4-1: Polyacrylate resins and polyacrylate copolymers

polyacrylate and polyacrylate co-polymer resins, for example poly-acrylic acid and poly-acrylic acid/methacrylic resins, such as those known and available

Commercially under the trade name CF Fiedler, loc. cit., pp. 254-256) Carbopol),

In particular, preparations 941 and Eudragit, Carbopol 934, 940 and (486-487 .cf Fiedler, loc. cit., pp), in particular preparations Eudragit E, L, S, RL and RS, and, in particular, preparations Eudragit E, L andS;

4-2: Celluloses and cellulose derivatives, including: celluloses

alkyl celluloses, such as methyl, ethyl and propyl-celluloses; hydroxypropyl-celluloses such as hydroxyalkyl-celluloses and hydroxy

Hydroxypropylalkyl-celluloses such as hydroxypropyl-methyl-celluloses, and acylates

acylated-celluloses, such as acetateseelluloses,

cellulose-acetatephthallates, cellulose-acetatesuccinates and hydroxypropylmethyl-cellulose phthalates; And salts each, such as sodium-carboxymethyl-cellulose. Examples of such preparations suitable for use pursuant to this invention are those known and traded commercially under the trade names Klucel and Methocel (790 cf. Fiedler, loc. eit., pp. 688 and), in particular the preparations GF, MF, LF Klucel, HF, 100 E 5M, K 100M, K 15M, Methocel KE 15M, E 15 and E 100M;

4-3: Polyvinylpyrrolidones, which include, for example, poly-N-

Poly-N-vinylpyrrolidones and vinylpyrrolidone are co-polymers such as vinylpyrrolidone-vinylacetate. Examples of such compounds suitable for use according to the present invention are those known and commercially available under the trade name Kollidon (or in the United States, c.f. Fiedler, loc. cit., pp. 694-696) (Povidone), in particular preparations Kollidon 90 and 30;

4-4: Polyvinyl resins, such as those containing alcohols and polyvinyl

Polyvinylacetates and alcohols, as well as other resinous materials such as tragacanth gum, gum arabic, and alginates such as alginic acid and its salts, sodium alginates;

4-5; Inorganic thickening agents such as atapulgite, bentonite and silicates, including water-friendly silicon dioxide preparations such as alkylated (eg methylated) silica gels and in particular colloidal silicon dioxide preparations such as those known and commercially available under the name Commercial

[cf Hand book of Pharmaceutical Excipients, loc. cit., pp. 253-256] Aerosil

In particular, preparations 130 OX 50, 0, 380, 300, 200, Aerosil,

600 LK 84, MOX 170, MOX 80, TT and 972 Aerosil R have a methylated methyl group.

In the case of formulations according to (a) intended for oral use, such thickening agents may be used to obtain a long-lasting drug release effect. However, in cases where the drug is intended to be used orally, the use of the aforementioned thickening agents is usually not required and is usually not Preferable, but on the other hand the use of thickening agents is required if the drug is intended for topical use.

The compositions in accordance with (a) above may also include one or more of the following components, in particular diluents and antioxidants [such as ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT). ) and tocopherols, such as alpha-tocopherol (vitamin E) I, flavoring substances, etc., and the use of an antioxidant, especially tocopherol, is particularly beneficial.

Although it has been taken into account, particularly if oral administration is considered, that the compositions according to this invention as defined under (a) must include finished pharmaceutical dosage forms for administration in this form, this invention also provides pharmaceutical compositions comprising cyclosporin as an ingredient The same are effective oil-in-water microemulsions. If oral administration is required, microemulsions obtained by diluting “microemulsion pre-concentrate” as defined under (a) with water or another aqueous medium can be used as combinations to use the drug as a syrup. Also, if topical use is being considered, formulations containing a hydrocolloidal thickening agent, such as those shown under (4.2) or (4.4) above, will appropriately contain water and thus provide an aqueous microemulsion in gel form. ) or paste, cream, or similar forms. Such combinations are also new. Accordingly, the present invention provides, in a new field, the following:

(b) A drug composition that includes cyclosporin as an active ingredient (1) a hydrophilic state, (2) a lipophilic state, (3) a surfactant and water, where this composition is an oil-in-water microemulsion.

The compositions as known under (b) may include any of the components (1) to (3) as previously described above in connection with the compounds known under (a) and water. As for formulations (B), they are oil-water microemulsions. It is best to have the previously described stability properties in association with microemulsions obtained from the known formulations under (a).

The compositions according to the present invention can be used for administration in any suitable form, for example orally or in the form of standardized medicinal doses, in the form of hard or soft gelatin capsules, or for use by injection or topically such as application to the skin or in the form of a cream, paste, lotion, gel (gel). ointment, spray, compress, plaster, skin patch or the like, or for use in the eye in the form of an eye drop, lotion or gel. Easy-flowing forms, for example microemulsions, can also be used, for example for injection into the lesion. itself for treatment Psoriasis Or it can be used rectally, for example by enema to treat inflammatory bowel disease or Crohn's disease. However, the compositions according to this invention are primarily intended for oral use or topical use, especially topical use on the skin.

It is natural that the ratios between the amounts of ingredients in the compositions of the invention vary greatly according to the specific type of the intended composition, for example, whether this composition is an “oil-in-water microemulsion pre-concentrate” or an oil-in-water microemulsion. in-water microemulsion. The ratios between the amounts will also vary according to the specific function of each of the components in the composition. For example, in the case of the surfactant component in the oil-in-water microemulsion pre-concentrate, the ratios depend on whether it is used. As a surfactant only or as a surfactant and co-solvent at the same time. Relative amounts will also vary depending on the ingredients used and the desired natural properties of the formulation. For example, in the case of formulations for topical use, the matter differs if the formulation is an easy-flowing liquid than if it is a paste. Determining practical ratios for any particular case is usually possible for a person

Experienced in this technical field. Therefore, all areas of ratios and relative weights described below should be understood as illustrative of personal preferences or efforts and not as limits to the invention in its broad sense.

Of course, the amount of cyclosporin in the compositions of the invention will vary, for example according to the intended method of administration and the degree of availability of the other components, especially components (2) to (4) as described above. In general, though, cyclosporin will range

Its percentage ranges from 0.05, especially about 0.1 to 35% by weight in relation to the total weight of the composition.

It is appropriate for the percentage of components (1) in the compositions of the invention to be in the amount ranging from 0.5 to 90% by weight relative to the total weight of the composition. In the case of compositions according to the invention containing a component (1-1) (for example, glycofurol or transcutol), (1-1) its percentage will generally be from 1 to 90% by weight, and usually from 5 or 10 to 70% by weight. to the total installation weight. In the case of compositions according to (a) or (b) above that include component (1-2), the percentage (1-2) will generally be from 2 to 50% by weight relative to the total weight of the composition. In the case of compositions according to the invention containing component (2) or (3), each of these will typically be present in quantities ranging from 0.5 to 90% by weight attributable to the total weight of the composition. In particular, the present invention relates to:

(c) Compositions as known under (a) above for oral administration, i.e. in a form suitable or suitable for oral use.

For formulations as known under (a) to (c) intended for use other than topical use, and in particular, drug dosage forms for oral use (c): (a) The percentage of cyclosporin generally ranges from 1 or 2 to 30%, and preferably from 4 to 25% by weight attributable to the total weight of the composition. It is most appropriate for the percentage of cyclosporin to range from 5 to 25, that is, 20% or from 5 to 15% by weight attributable to the total weight of the composition;

(b) Component (1-1) in quality condition will range from 15 to 85, preferably from 20 to 80, and even better from 25 to 70, for example from 30 to 50 or 60% by weight

Based on total installation weight;

(c) Cyclosporin and the component (1-1). If they are present, the ratio between them will range from 0.75:1 to 20. The most appropriate is 1:1 to 15, and the best is 1:1 to 5, that is, for example, 1:1 or 1. 5:1 to 4 by weight [cyclosporin:

(١-١)]؛

(d) Component (1-2) in quality condition will range from 3 to 45%, preferably from 5 to 30% by weight relative to the total weight of the composition.

(e) Cyclosporin and component (1-2). If they are present, the ratio between them will range from 0.1:1 to 20, and it is appropriate for it to be 0.2:1 to 10 by weight. It is better that

It is in a ratio of 0.3:1 to 6, for example 0.5:1 to 3 by weight [cyclosporin: (1-1)].

(f) Component 2, if present, shall be amounted to 45%, and it is appropriate to reach 40% by weight based on the total weight of the composition. It is best for the quantity of ingredient (2) to be between 2 and 45, and even better, between 3 and 35. The best option is from 5 or 10 to 30% by weight, based on the total weight of the composition.

(g) Components (2), (1-1) if present will usually be in ratios of 0.5:1 to 40, and the best

To be 0.5:1 to 20 and the most appropriate 0.75:1 to 10, for example 0.75:1

To 4 by weight ratios. [(2): (1)].

(h) Components (2), (1-2) if their occurrences are in the ratio of 0.075:1 to 22, and the best is 0.1:1.

to 15, and the most suitable is 0.15:1 to 6 by weight, for example 0.5:1 to 3 by weight.

[(2): (2-1)].

(i) Components (3), if present [including components of types (3-1) and (3-2)] are usually in proportions up to 90, for example from 20 to 90% by weight based on the total weight of the composition.

It is best for the components (3) to be in quantities ranging from 20 or 25 to 80 or 90% by weight based on the total weight of the composition, for example from 25 to 55% when using a component (1-1) or from 40 to 75% when using a component. (1-2).

(j) Cyclosporin and component (3) [including both components of type (3-1) and type (3-2)] If they are present, the ratio between them will generally be 0.5:1 to 20, and the best is to

2 1 weight. It is appropriate for the ratio to be 1:1 to 10 by weight, for example 1:1 to 5 by weight in the case of a component (1-2). [Cyclosporin: (3)].

Compositions as known under (a), (b) [&amp; oil-in-water microemulsions pre-concentrates&amp; and foil-in-water microemulsions with varying relative quantities of components including (1) phase Water affinity, (2) fat affinity phase, (3) surfactant depending on the concentration of cyclosporin. They will also vary depending on the ratios between each other.

Compositions according to (a) may be defined as including cyclosporin in addition to:

(1) Aloof phase of water [for example as defined under (1-1) or (1-2) above].

(2) Aloof phase of fats [for example as defined under (2-1) or (2-2) above].

And a surfactant [for example, as defined under (3-1) or (3-2) above], and the ratios between cyclosporin: (1): (2): (3) are such that upon contact with water - on For example, as indicated above in ratios of 1:1 by weight or more [cyclosporin + (1) + (2) + (3): H2O] consisting of an oil-in-water microemulsion [e.g. Oil/water type.

Likewise, the compositions according to (b) can be defined as including cyclosporin with components (1), (2), and (3) as previously mentioned, with water in proportions - as previously indicated - that allow the formation of an oil-in-water microemulsion. water microemulsion [eg from

Type of oil/water].

The compositions according to (a) and (b) preferably include 2 to 30, preferably 5 to 20, and most appropriately 10 to 15% by weight of cyclosporin based on the total weight of cyclosporin plus components (1) + (2) + (3).

When (1) is one of the compositions (A) or (B) as defined under (1-1) above - that is, it includes, for example, transcutol or glycofurol - then the components (1-1), (2), ( 3) It is preferable that it be in amounts from 15 to 85%, and it is preferable that it be from 25 to 65% from (1-1) and from 2 to 40, and preferably from 3 to 35, and most preferably from 3 to 30% of

(2) and from 15 to 85, and better from 25 to 55 or 60% of (3), where all percentages are based on weight and based on the total of (1-1) + (2) + (3). The use of Glycofurol is of particular interest.

If (1) of the compositions (A) or (B) is 1,2-propylene glycol [(2,1) above, then components (1-2), (2), and (3) are preferred. It should be in quantities from 3 to 35%, and preferably from 3 to 25% of (1-2), and from 2 to 435, and preferably from 3 to 30% of (2), and from 45 to 90%, and preferably from 50 to 90%. , for example from 55 to 80% of (3), where all percentages are weight-based and based on the sum of (1-2) + (2) + (3). As previously noted, if (1) is 1,2-propylene glycol then component (3) will typically include a surfactant and a co-surfactant. When using an auxiliary surface tension reducer, the ratio between the reducer and the auxiliary reducer is preferably 50-1, and it is preferable for it to be 2:1, and the most appropriate is for it to be 1:15, for example from 2 to 1:15 by weight (surface tension reducer: auxiliary reducer to surface tension).

The attached Figure 1 shows a three-track plot of the relative concentrations of the components (1-1) Glycofurol (for example), (2) (812 Miglyol for example), and (3) (Cremophore RH40 RH40 for example) in the compositions according to (a) containing about 10% cyclosporin (Ciclosporin, for example) by weight. The relative concentration of component (1-1) increases from 0% at the left edge of the diagram to 100% at the bottom right corner, as shown by the arrow &amp;1-1&amp;. The concentration of component (2) increases from 0% at the right edge of the drawing to 100% at the bottom iso-corner, as shown by the arrow &amp;2&amp;. Thus, for combinations containing 50% of (1-1), only 50% of (2), represented at the midpoint of the base line of the drawing. The relative concentration of component (3) increases from 0% at the baseline of the diagram to 100% at the peak, as shown by the arrow &amp;3&amp;. The lines within the drawing represent 10% increments from 0% at each edge to 100% at the corresponding peak.

For the compositions as defined under (a) and (b), the ratios between the components (1-1), (2), and (3) are preferably within the space (a) defined by line (c) in Figure (1). It is more appropriate for the ratios between the components (1-1), (2), and (3) to be within the area B defined by line B in Figure (2), if

Microemulsions formed based on these ratios have been found to have higher stability, for example for periods of more than 24 hours and an average particle size of less than 1000 angstroms. Therefore, the compositions according to the invention comprising components (1-1), (2) and (3) in the proportions specified above by reference to a figure represent particularly preferred patterns.

The attached Figure 2 represents a three-track diagram of the relative concentrations of the components (1-2), (2), for example 812 Miglyol, and (3) in the formulations according to (A), which include about 10% cyclosporin (Ciclosporin, for example) by weight. In this case (3) includes an appropriate mixture of surfactants and auxiliary surfactants, for example in a ratio of 1:11 by weight, for example 11 parts by weight of Cremophor RH40 and one part by weight of Glycerinmonooleate, and the relative amounts of the components (1- 2),

(2), (3) are shown as in Figure (1) by arrows (1-2), (2), (3) respectively.

For the compositions as known under (a), (b), the ratios between the components (1-2), (2), and (3) are appropriate to be within the area (r) defined by the line (m) in Figure 2. It is best for the ratios between the components (1-2), (2), and (3) to be within the area (j) defined by line (l) in Figure 2. It is most appropriate for the ratios between the components (1-2), (2), and (3) within the space (x) to be in the form of (1) defined by the line (k), and in microemulsions formed on the basis of the proportions within the spaces (j) and (x). ) Its average particle size is in the range of 1100 angstroms and less than 200 angstroms, respectively, and its stability - for example - exceeds 24 hours.

Formulations in accordance with (c) above may additionally include a thickening agent, although, as previously explained, this is less desirable. Suitable thickening factors include any of those described above under (4). The amount of thickening agent used may vary - for example, depending on the degree of cohesion required in the final product - whether what is required is a thick form capable of flowing onto capsules or the like, or a form flexible enough to be shaped or synthesized for use, for example, in the manufacture of tablets or the like. The quantity will of course depend on the nature of the thickening agent chosen. In general, the components (4), if present, are at a ratio of up to 25% by weight relative to the total weight of the composition, and it is preferable that they be at a ratio of 15 to 20% by weight, for example, at a ratio of 0.5 or 5 to 15 or 20% by weight attributed to the total Installation weight.

Compositions pursuant to (c) may also include additives or ingredients, for example - as described above in connection with compositions (a). In particular, antioxidants may include:

For example, an amount up to 0.5 to 1% by weight, attributed to the total weight of the composition, and sweetening or flavoring materials, for example, in an amount up to 2.5 or 5%, by weight, attributed to the total weight of the composition.

Compositions (C) have been found to have some properties that are particularly advantageous for oral administration, for example with respect to consistency and the high degree of bioavailability achieved. In particular, in comparison with other pharmaceutical systems - as is known from recent literature - it has been found that these formulations are compatible with surfactants such as bile salts present in the digestive tract. That is, they are fully dispersible in aqueous systems containing surfactants, and thus they can provide localized microemulsion systems that are stable and do not show sedimentation or any other disturbance to the fine particle system. The performance of these systems when administered orally remains independent and/or unaffected by the relative presence or absence of bile salts at a given time or for a given individual. Such compositions therefore represent a form of special preference.

The compositions in accordance with (C) above are preferably synthesized in “unit dosage” forms, i.e., for example, by filling capsule shells for oral administration, capsule shells for oral administration, soft or hard gelatin capsule shells, or by forming them in the form of tablets or other formulation methods, even if the compositions are (C). ) In the form of “unit doses”, each dose unit is appropriate to contain from 5 or 10 to 200 mg cyclosporin, and it is preferable between 15 or 25 to 150 mg, i.e., for example, 25, 50 or 100 mg cyclosporin. Therefore, the dosage forms according to the invention are suitable for administration once, twice, three to five times daily (depending on the specific purpose of the treatment, the reference of the treatment itself, etc.). It is appropriate to contain, for example, 50 mg or 100 mg of cyclosporin per dose unit.

Compositions in accordance with (b) above may be prepared for oral administration, by adding the compositions as described in connection with (a) or (c) above to water or another aqueous system in proportional amounts (composition: water) as noted above, e.g. preparing Sweetened or flavored for use as a drink. Such combinations could include any known system

above or described in conjunction with formulations (A) or (C) plus sufficient water to form a microemulsion.

Compositions as defined under (d) above are administered particularly orally, but also include use in a form suitable for topical use, whether on the skin or eye, or administration.

Injection or rectally.

The compositions, as defined under (a) to (b) above, are also of particular interest for topical use. Therefore the present invention also provides as a new aspect:

(d) Compositions as defined under any of (a) to (b) above for topical use. If topical use is intended, cyclosporin is appropriate in an amount of 0.05 and preferably 0.1 to 15% by weight relative to the total. Installation weight. It is most preferable that it be in an amount from 0.1 to 10% by weight.

In the case of compositions (D), the ratios between components (1), (2), and (3) will be as previously described above for these compositions, for example, by referring to Figures (1) and (2).

(d) Compositions may appropriately include one or more carriers, diluents and/or other components that provide a carrier system such as thickening agents, emulsifying agents, preservatives, humectants, coloring agents, etc.

Compositions (D) may be in any form suitable for topical use, i.e. application on the surface of the skin. They may be streamable - in liquid or semi-liquid form, for example, and they may be in powder form or in the form of a spray solution for topical use. Examples of suitable flowable forms are gels, including emulsions or microemulsions, oil-in-water or water-in-oil, creams, primers, paints and the like, lotions, dyes, etc. These formulations also include patches and sprays as well as skin-penetrating patch systems.

The choice of excipients for preparing such formulations will, of course, be determined by the type of formulation desired, as well as the disease condition to be treated, the degree of evaluation of the condition, the area to be treated, the condition of the skin, and the desired effect. Thus, chronic plaque psoriasis is best treated with compositions that are not waterproof, for example, oil-based compositions, such as the compositions according to the invention.

Apply a petroleum jelly-based ointment or cream (such as Vaseline) as a carrier medium. On the other hand,

The compositions used in the treatment of symptomatic cases involving acute inflammatory processes are best treated with compositions that are more affinity for water, for example, compositions according to the invention in the form of an oil-in-water emulsion or gel, although the compositions (D) may include short cannulae. Such as ethanol, as a diluent or component of a diluent, for example. It is preferable to avoid such, for example, when treating affected skin, as in cases of psoriasis. Preferred compositions (D) are thus declared free or nearly free of alkanols, i.e. containing less than 5%, or preferably less than 2%, for example 0 to 1% by weight, of alkanol components, especially ethanol.

ethanol.

Particularly preferred combinations (d) include combinations according to (a) or (b) additionally including:

(5) On a pharmaceutically acceptable (additional) diluent or carrier medium that is immiscible with the component (1-1). The compositions, according to what was mentioned above, preferably should be in the form of a water-free or almost water-free emulsion, that is, containing less than 10% of water, preferably less than 5%, and most preferably less than 1%. Such emulsions include emulsions containing the component (1-1) in (5) as well as emulsions containing (5) in (1-1). It is better to contain an emulsion than

(1-1) in (5).

Suitable components (5) include, for example: 1-5: Solid hydrocarbons, for example petroleum gels such as vaseline, ceresin and solid paraffins.

As well as waxy materials such as animal, plant and synthetic waxes such as amber wax, carnauba wax and beeswax.

2-5: Liquid hydrocarbons, such as liquid paraffins and esters

fatty acid esters such as isopropylmyristate and cetyl pahnitate;

3-5: Non-volatile silicones, including oils and pastes

Silicones and silicon-polyalkylene oxide copolymers

[cf Fiedler, loc. cit., pp. 1109 and 1110] silicone-polyalkyleneoxide

For example, it is known and commercially available under the trade name Piroethicon.

Components (5) It is appropriate to be in compositions (D) in an amount of up to 80% to, for example, 5 to 70%, and preferably 25 to 60% by weight attributed to the total weight of the composition.

By using single components (5) or mixtures thereof, emulsions can be obtained in liquid or semi-liquid form depending, for example, on the desired requirements for topical use.

It is also appropriate for compositions (d) to contain a surfactant. Suitable surfactants are those that are affinity for fats, including any of those mentioned under (3.2.1) to (3.2.7) above, and in particular surfactants that The balance value between affinity for water and affinity for fat is about 5-7. Examples of surfactants that are particularly useful for formulations (D) include those described under (3.1.2) and (3.2.3) above, as well as glycerol monostearate, propyleneglycol jnonostearate, and ethylene monostearate. Glycol diethyleneglycol monostearate and glycerol ricinoleate.

Surfactants, as referred to above, are appropriate to have their percentage in formulations (D) of up to 60% - for example, from 2 to 50%, and preferably from 10 to 40% by weight relative to the total weight of the formulation.

Compositions (d) may also include one or more consistency improving agents, for example microcrystalline waxes, vegetable oils, olive oils, corn oils, kernel oils, vegetable oil derivatives including hydrogenated vegetable oils and vegetable oils partially combined with glycerides, for example, In amounts from 0.1 to 10%, the best formulations (D) are also appropriate to include:

An antioxidant like any of the antioxidants previously described above in association with formulations (A),

For example from 0.01 to 0.5% by weight attributed to the total weight of the composition,

Antibacterial, eg benzyl alcohol, methyl or propyl paraben, benzalkonium chloride, benzoic acid

benzoic acid, sorbic acid or chlorobutanol, for example in an amount of 0.05 to 2% by weight relative to the total weight of the composition.

Stabilizer such as microcrystalline starch, sodium EDTA or magnesium sulfate, for example in an amount of 0.1 to

10 % by weight attributable to the total weight of the composition; wow

Skin penetration stimulant, e.g., C12-24 mono- or poly-unsaturated fatty acid or alcohol (e.g. cis-vaccenic, cis-vaccenic, linoleic acids) linoleic, linolenic, elaidic oleic, petroselinic, erucic or nervonic acid or any of their corresponding alcohols, particularly oleic acid or oleyl alcohol), or

1- The well-known 1-dodecylazacycloheptan-2-one

Also known as CF Fiedler, loc. (cit., P. 190) Azone), for example in the amount of 1 to 20 ml, and most appropriately from 3 to 15% by weight relative to the total weight of the composition.

In addition to the above, the present invention also provides a method for producing a pharmaceutical composition as specified above - that is, as specified under any of (a) to (d) above - and this method includes combining the aforementioned individual components in a controlled mixture, and if necessary, compounding Obtained from a composition in unit dosage form - e.g. mL of said composition enclosed in gelatin, e.g. hard or soft gelatin capsules.

More specifically, the invention also provides a method for preparing a composition as defined under either (a) to (d) above, and this method includes tightly mixing a cyclosporin, such as “Ciclosporin” with component (1-1) or (1-2). As specified above with component (2) and component (3) as specified before, the ratios between the amounts of components (1-1) or (1-2), (2) and (3) are chosen such that the combination is as follows Defined under (A) As needed, this composition (A) may be brought into contact with water so that a composition as defined under (B) can be obtained. If necessary, the obtained composition (A) can be packaged in unit dosage forms such as hard gelatin capsules or tablets.

In particular, the present invention provides a method for preparing a composition as defined under (a) above, which method includes controlled mixing of Ciclosporin (e.g.

Ciclosporin&amp;) with component (1-1) or (1-2) as previously defined and component (2) and component (3) as previously defined, with choosing the ratios between the amounts for components (1-1), (1-2) or (2). ) or (3) for the amount of cyclosporin used such that an “oil-in-water microemulsion pre-concentrate” can be obtained, i.e. a composition capable of forming a system containing a dispersed or particulate phase, the particle size of which is less than 2000 angstroms, and preferably from about 100 to about 1000 angstroms when added to water.

The preferred cyclosporin in association with the compositions of the invention is “ciclosporin.” Another preferred cyclosporin to which this invention may be applied is [Nva]2-ciclosporin, also known as

cyclosporin G.

The following examples illustrate compositions according to the present invention. Examples 2.1 illustrate the preparation of compositions in oral unit dosage forms and are suitable for use, for example, to prevent expulsion of transplanted organs or to treat autoimmune diseases such as any of the autoimmune diseases or conditions described above when administered from 1 to 5 dosage units per day. Example 3 shows the preparation of formulations for topical use, which are suitable, for example, for treating allergic or contact dermatitis, psoriasis, or hair loss. They are applied to the site to be treated, such as an inflammatory skin reaction or scalp psoriasis, at regular intervals, for example, once, twice, or three times daily.

Examples are described with special reference to ciclosporin. However, equivalent formulations can be obtained with the use of another suitable cyclosporin. In particular, equivalent formulations can always be obtained by substituting &amp;2[Nva]- ciclosporin for &amp;ciclosporin in the same amounts as shown for ciclosporin.

Example 1

Preparation of oral dosage forms of preconcentrated oil-in-water microemulsion type

:&amp;oil-in-water microemulsion pre-concentrate

1-1 Ingredients Quantity (mg/capsule).

Cyclosporin (&amp; Cyclosporin 50

eg) &amp; Ciclosporin

180 Glycofurol 75 (1-1) Glycofurol 75

90 Miglyol 812 (1-2) Miglyol 812

180 Cremophor RH 40 RH 40 (1-3) Cremophor

The total is 500 in (1-1) while stirring at room temperature and adding cyclosporin. Dissolve cyclosporin 2-1) and (3-1-1) to the solution obtained while stirring again. The resulting mixture is packed into a size 1 hard gelatin capsule and sealed using the Quali-Seal method. The following compositions can also be prepared to fill size 1 or size 2 gelatin capsules.

Solid:

1-2 Ingredients Quantity (mg/capsule) Cyclosporin 50. Cyclosporin

eg) &amp; Ciclosporin

180 Glycofurol l75 (1-1) Glycofurol 75

78 Miglyol 812 (2-1) Miglyol 812

192 Cremophor RH 40 RH 40 (3-1-1) Cremophor

Total 500

1-3 Ingredients Quantity (mg/capsule) For example, cyclosporin 50

(&amp;ciclosporin

200 Glycofurol 75 (1-1) Glycofurol 75

60 Miglyol 812 (2-1) Miglyol 812

120 Nikkol HCO-40 HCO-40 (3-1-1) Nikkol

19 Ethanol* *Ethanol

1 Ascorbyl palmitate** **Ascorbyl palmitate

Total 450

* Co-solvent (water-affinity phase)

Antioxidant**

1-4 Ingredients Quantity (mg/capsule).

For example &amp; cyclosporin 50) cyclosporin

(&amp;ciclosporin

100 glycofurol 75 (1) Glycofurol 75

75 Miglyol 812 (2-1) Miglyol 812

75 Lecithin Lecithin ((3-1-7

Total 300

5-1 Ingredient Quantity (mg/capsule)

For example &amp; cyclosporin 100) Cyclosporin

(&amp;ciclosporin

260 glycofurol 75 (1-1) Glycofurol 75

50 propyleneglycol (1-2) Propylene glycol

100 Myritol 318 (2-1) Myritol 318

340 Cremophor RH 40 RH 40 (3-1-1) Cremophor

5 BHA*

Total 855

*Anti-oxidant

1-6 Ingredient Quantity (mg/capsule) Cyclosporin 50. Cyclosporin

For example) &amp;ciclosporin

68 l,2-propyleneglycol (1-2) 1,2-propylene glycol

68 Miglyol 812 (2-1) Miglyol 812

250 Cremophor RH 40 RH 40 (3-1-1) Cremophor

3-2-5) Glycerol monooleate 24)

Glycerol monooleate.

Total 460

1-7 Ingredients Quantity (mg/capsule) Cyclosporin (Ciclosporin 50 for example)

(1-2) 1,2-propylene glycol l,2-propyleneglycol 68 (2-1) Miglyol 812 Miglyol 812 24 (3-1-1) Cremophor RH 40 RH 40 250 (3-2-5) Monoglycerol Primitives 68

Glycerol monooleate.

Total 460

1-8 Ingredients Quantity (mg/capsule)

Cyclosporin (eg Cyclosporin 100

ciclosporin&amp;)

(1-2) 1,2-propylene glycol 1,2-propyleneglycol 75

(2-1) Miglyol 812 812 Miglyol 25

(3-1-1) Cremophor RH 40 RH 40 150

(3-2-5) Glycerol monooleate 150

Glycerol monooleate*

Total 500

1-9 Ingredients Quantity (mg/capsule)

Cyclosporin (eg Cyclosporin 50

ciclosporin&amp;)

(1-2) 1,2-propylene glycol 1,2-prop yleneglycol 200

(2-1) Miglyol 812 50

(3-1-1) Cremophor RH 40 RH 40 150

(3-2-7) Generol 122 *Generol 122 E16* E16 50

Total 500

1-10 Ingredient Quantity (mg/capsule)

Cyclosporin (eg 50

&amp;ciclosporin&amp;)

(1-2)2,1-Propylene glycol 75

1,2-propyleneglycol

(2-1) Miglyol 812 75

(3-1-1) Cremophor RH 40 RH 40 250

(3-2-7) Generol 122 *Generol 122 E25* E25 50

Total 500

* Auxiliary surface tension reducer.

Combinations 1-1, 1-2, 1-6 and 1-7 are particularly preferred.

In all cases, formulations equivalent to formulations 1-1 to 1-5 can be prepared by replacing component 5, glycofurol, with transcutol in the same or equivalent quantity.

Compositions equivalent to formulations 1-1 to 1-5 can be prepared by replacing the amount of 50 mg cyclosporin with 15, 20, or 100 mg cyclosporin (for example, “ciclosporin”) while the amounts of the other components of each formulation remain as shown.

Example 2

Preparation of dosage forms for oral administration: oil-in-water microemulsion pre-concentrate type and thickener:

2-1 Ingredients Quantity (mg/capsule)

Cyclosporin (eg Cyclosporin 50

ciclosporin&amp;)

(1-1) glycofurol 75 glycofurol l75 180

(2-1) Miglyol 812 812 Miglyol 90

(3-1-1) Cremophor RH 40 RH 40 180

(4-2) Methocel K100 K100 100

Total *60

“Ciclosporin” is combined with (1-1) to (3-1-1) as in Example 1, and the resulting mixture is mixed homogeneously with (4-2). The product is packed in hard gelatin capsules size 2.

The following combination can also be obtained:

2-2 Ingredients Quantity (mg/capsule)

Cyclosporin (eg Cyclosporin 50

ciclosporin&amp;)

(1-1) glycofurol 75 glycofurol 75 180

(2-1) Miglyol 812 90

(3-1-1) Cremophor RH 40 RH 40 180

(4-6) Aerosil 200 200 Aerosil 9

(4-2) Methocel K100 K100 100

Total 609

2-3 Ingredients Quantity (mg/capsule)

Cyclosporin (eg Cyclosporin 100

ciclosporin&amp;)

(1-1) glycofurol 210

(2-1) Miglyol 813 90

(3-1-1) Nikkol 60-Nikkol HCO-60 HCO 170

(4-2) Klucel 30 Klucel EF EF

Total 600

Equivalent formulations of 2-1 to 2-3 can be prepared by replacing the glycofurol component with transcutol in the same or equivalent quantity.

Example 3

Preparation of a form for topical use of the preconcentrated oil-in-water microemulsion type

&amp;oil-in-water microemulsion pre-concentrate

Ingredient Quantity (mg/capsule)

Cyclosporin (eg Cyclosporin 0.1

ciclosporin&amp;)

(1-1) glycofurol 50

(2-1) Miglyol 812 812 Miglyol 16,6

(3-1-1) Cremophor RH 40 RH 40 33.3

The above composition is prepared in a manner similar to Example 1. An equivalent composition can be obtained by replacing the glycofurol component with transcutol. The mixture may be made on the basis of a cream, gel (gel) or the like in combination with other additives, such as hydrocolloidal thickeners, paraffins, etc. As described above.

The usefulness of the compositions prepared according to the invention can be demonstrated in animal experiments or clinical trials, for example, as follows:

Study of the bioavailability of the compositions according to the invention in the dog: (a) Compositions for testing

Structure 1, as in Example 1-1

Combination 2 as in Example 1-2

Combination 3 as in Example 1-6

Combination 4 as in Example 2-1

Combination 5 as in Example 2-2

(b) Test method

Groups of 8 beagles (weight about 11-13 kg) are used. The animals are withheld from food for 18 hours before giving the test formula, but they are allowed to have free intake of water until the time the drug is given. The test formulations are given by tube feeding, followed by 20 milliliters of a 0.9% solution of each. The animals are allowed to freely consume food and water three hours after giving the test formula.

Two milliliters of blood samples (or 5 milliliters of the drug-free control sample) are taken from the saphenous vein and collected in 5 milliliters of plastic tubes containing ethylene diamine tetraacetate.

EDTA at 15 minutes (for drug-free control sample), 30 minutes and 1, 1,5, 2, 3, 4, 6, 8, 2, 1, 4 and 2 hours after administration. Blood samples are kept at -18°C until calibration.

Blood samples are analyzed by radioimmunoassay. The areas under the drug concentration curves in the blood versus time are calculated using the trapezoid rule. Variational analysis of area under the curve, maximum concentration and peak timing are performed.

(c) Results

The following table shows average values of areas under the curve (in ng/ml) and maximum concentration (in ng/ml) from typical experiments. Also shown is the calculated variation in response between tested animals that received the same formulation.

<img file="SA296B1_D0004.tif" />

As can be seen from the table above, the compositions according to the invention are characterized by high bioavailability (AUC and maximum concentration) combined with a relatively low variation in individual response, both in terms of AUC and maximum concentration.

Excellent results can also be obtained using other combinations according to Examples 2.1 above, in particular the combinations of Example 1.

The excellent properties of the compositions of the invention for oral administration in clinical trials can also be demonstrated, for example, as follows:

The subjects of the experiment are volunteer volunteers, for example, vocationally educated males from 30 to 55 years old. It is appropriate for experimental groups to include 12 individuals.

The following criteria for inclusion and exclusion apply:

Damage: normal electrocardiogram, blood pressure and heart rate within normal limits.

Body weight = 50-95 kg.

Exclusion: Occasional medical conditions of clinical importance that could affect the absorption, distribution, metabolism, excretion or safety of the drug, as well as symptoms of any clinical disease of importance in the study.

During the two-week period prior to the experiment and results laboratory or electrocardiogram results that are abnormal and clinically significant, and the need to use other medications throughout the duration of the research, and to give any drug known to have a toxic effect on important organs of the body during the three months preceding the study, and to give Any other elective medication within 6 weeks before entering the trial, previous history of alcohol or drug addiction, blood loss of 500 milliliters or more in the previous 3 months, hypersensitivity or adverse drug reactions, previous Having an allergy that requires treatment with medications, positive for hepatitis B virus or AIDS.

A comprehensive medical examination and electrocardiogram are conducted before and after the experiment. The following variables are evaluated at one-month intervals before and after the experiment.

Blood: red blood cell count, hemoglobin, hematocrit, erythrocyte sedimentation, white blood cell count, smear for blood elements, platelet count and fasting glucose measurement;

Serum/plasma - total protein, protein electrophoresis and cholesterol

Cholesterol, triglycerides, sodium +Na, potassium +K, iron +Fe, calcium +Ca, chloride Cl, creatinine, urea, uric acid, glutamic enzyme or kasaloacetic transaminase, glutamic enzyme peptide transaminase, alkaline phosphatese, total bilirubin, and α-amylase.

Urine: pH, microalbumin, glucose, red blood cells, ketone bodies, sediment.

Creatinine clearance is also determined within a month before joining the study. Each of the subjects receives experimental combinations in a random sequence. The formulations are given orally, once, for a total dose of 150 mg of cyclosporin, for example “ciclosporin”, and at least a period of 14 days is allowed between each administration and the next.

It is given in the morning after fasting during the previous night for 10 hours, during which only water is allowed. Only caffeine-free drinks are permitted during the 24-hour period prior to administration. Individuals are not allowed to smoke within 12 hours after administration. Individuals receive a standardized meal four hours after administration.

Blood samples (2 milliliters) are taken one hour before administration and then after administration at 0.25, 0.5, 1, 1.5,

2, 2.5, 3.5, 4, 4.5, 5, 6, 9, 12, 14, 24, 28 and 32 hours. To determine creatinine, 2 milliliters of blood samples are taken immediately before administration and at 12, 24 and 48 hours after administration. Samples for cyclosporin measurement are collected in two polystyrene tubes lined with ethylenediaminetetraacetate (1 ml each) at each time point and deep frozen at -20 C after gentle agitation. Cyclosporin is titrated in whole blood using radioimmunoassay with specific and/or non-specific MAb titration - the detection in both cases was found to be approximately 10 ng/ml.

In one of these experimental attempts, composition 1 above according to the invention (in the form of hard gelatin capsules) was compared with composition 10.

Combination 10 [Comparative Technical Combination]

Unit dosage form (soft gelatin capsule) contains: Ciclosporin 50 mg

Labrafil 150 mg

Ethanol 50 mg

Maize oil corn oil 213 mg

Total 463 mg/dose

(= Sandimon syrup solution known for oral administration)

In an experiment conducted in this way, a bioavailability of 149% (± 48) was recorded for formulation 1 compared to formulation 10 (for which the bioavailability was considered 100%). The AUC values (0-32 hours, ng.hour/mL) and peak concentration values (ng/mL) determined for formulation 1 are 2992 (± 627) and 882 (± 18) respectively compared to 2137 (± 606) and 515 (±180) for formulation 10.

The attached Figures 3.4 show the results, graphically and by comparison, from one such experiment on the concentration of Ciclosporin in whole blood, as recorded for 12 participants in the experiment after administering a single oral dose of Formula 1 (Figure 3) and Formula 10 (Figure 4), each in an amount Provides a ciclosporin dose of 150 mg as determined by single-group specific radioimmunoassay. The concentration in the blood is recorded vertically (in nanograms/ml) and the time (in hours) is recorded horizontally.

Comparing Figures (3) and (4) clearly shows the clear decrease in the variation in response between individuals with respect to the bioavailability measures recorded when formula 1 was given compared to formula 10. The specific coefficient of variation [(standard deviation/mean value) x 100] for the peak concentration is 35. % for composition 10, compared to a value of only 20 for composition 1.

Similar or equivalent results have been obtained after oral administration of other compositions in accordance with the invention, for example, as described above in the examples and in particular the compositions of Example 1.

Testing of topical forms in vivo

Testing for allergic contact dermatitis in guinea pigs.

A state of hypersensitivity was created in guinea pigs (Hartley, male, 400-500 mg) by using 50 μl of 0.5% DNFB in acetone/olive oil applied to the visible parts of the right and left flanks after shaving them and subjecting them to this treatment (excitatory treatment) once. Again, it leads to allergic inflammation that causes redness and dermatitis (thickening) of the skin. Using a spoon, the composition under test (for example according to Example 3 above) is spread in an amount of 200-250 mg on the parts treated with DNFB on the right flank. The left flank is also treated with placebo to be used as a control case for comparison. The test formulation/placebo was applied 5 times at intervals of 20 minutes, 8 hours, 24 hours, 32 hours, and 48 hours after elicitation treatment. The thickness of the skin is measured at the treatment site before each painting operation and also 8 hours after the last of these operations by bending the skin and measuring the thickness of the fold. We also estimate the degree of redness or inflammation by looking on a scale from 0 to 4. The effectiveness of the preparation under test in preventing the occurrence of an inflammatory response is determined by comparing the results recorded with those recorded for the loin treated with placebo.

By applying the test described above, a significant reduction in the increase in skin thickness was achieved compared to placebo in the case of prior use of the tested composition, for example according to Example 3, and this phenomenon continued throughout the treatment until the completion of the experiment. The following results were recorded for the combination of Example 3.

<img file="SA296B1_D0005.tif" />