RU2235554C2 - Preliminary prepared emulsion concentrates containing cyclosporine or macrolide - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a composition in the form of preliminary prepared emulsion or microemulsion concentrate designated for oral administration and comprising cyclosporine or macrolide and a carrier and also to soft or solid gelatin capsule containing the indicated composition and to a method for reducing variability of bioavailability levels of cyclosporine or macrolide using the indicated composition. Composition elicits improved indices of bioavailability and reduced variability of bioavailability parameters.

EFFECT: improved and valuable properties of composition.

18 cl, 1 tbl, 1 ex

Description

The present invention relates to new galenic compositions, in particular to new galenic compositions in which the active substance is a hardly soluble active substance, for example, macrolide, or, in particular, a cyclic poly-N-methylated undecapeptide, or cyclosporin. The concept of cyclosporins also includes peptolid variants (see, for example, published patent applications GB 2222770 and 2257359 A and well-known equivalents).

As described in the aforementioned patent applications of Great Britain, the use of cyclosporins is associated with highly specific difficulties associated both with their introduction as a whole and with the preparation of a galenic composition, in particular, including, first of all, problems of stability, bioavailability of the drug and variability of the reaction to the administered dose both between different patients and for an individual patient.

To overcome these and other related difficulties, published patent applications GB 2222770 and 2257359 A provide galenical compositions comprising cyclosporin as the active substance, which, inter alia, are in the form of an emulsion, for example a microemulsion, or in the form of a pre-prepared emulsion, for example pre-prepared microemulsion concentrate. Such compositions typically include 1) a hydrophilic component, 2) a lipophilic component, and 3) a surfactant.

When creating the present invention, it was unexpectedly found that the most stable galenical compositions in the form of an emulsion, for example, a microemulsion, or a pre-prepared emulsion, for example, a microemulsion concentrate, based on a sparingly soluble active substance, having the most preferred bioavailability characteristics and reduced variability of bioavailability parameters both between different patients and for an individual patient, can be obtained with and using at least one component selected from the group consisting of (I) triethyl citrate or acetyl triethyl citrate, (II) a mixed ester of a fatty acid, polyethylene glycol and glycerol, (III) a diester of glycerol and a fatty acid, (IV) a monoester of glycerol and a fatty acid, ( V) a mixture of mono- and diglycerides of fatty acids, (VI) a propylene glycol monoester of a fatty acid, (VII) fatty acids and alcohols, (VIII) N-methylpyrrolidone, (IX) glycerol triacetate, (X) benzyl alcohol and (XI) simple or an alkylene polyol ester, for example polyglycolized glycerides, called hereinafter referred to as the "secondary (second) component".

When creating the present invention, it was unexpectedly found that such emulsion, for example microemulsion systems, in contrast to the prior art, can actually be obtained using any of the components listed above as the second component.

One of the objects of the present invention is a pharmaceutical composition, which is a pre-prepared emulsion, for example microemulsion, a concentrate comprising

1) a sparingly soluble active substance and a carrier, including

2) the second component,

3) lipophilic component and

4) surfactant.

The second component is, for example:

(I) triethyl citrate or acetyl triethyl citrate, and / or

(II) a mixed ester of a fatty acid, polyethylene glycol and glycerol, for example, a mono- and / or di- and / or triester of a fatty acid, for example, C ₆ -C ₁₀ , for example, C ₈ -C ₁₀ , for example, having from 5 to 10 units [CH ₂ -CH ₂ -O], e.g., 7 units, such as, e.g., Cetiol ^® HE, or Labrasol ^®, and / or

(III) a diester of glycerol and a fatty acid, for example, C ₆ -C ₁₆ , for example, C ₈ -C ₁₀ , for example, C ₈ , such as, for example, Sunfat ^® GDC-N, and / or

(IV) a monoester of glycerol and fatty acids, e.g., C ₆ -C _14, eg C ₈ -C _10, such as, e.g., Imwitor ^® 308 or Imwitor ^® 310, and / or (V) a mixture of mono- and diglycerides of fatty acids, for example, C ₆ -C ₁₆ , for example, C ₈ -C ₁₀ , such as, for example, Imwitor ^® 742 or Capmul ^® MCM, and / or

(VI) a monoester of propylene glycol and fatty acids, e.g., C ₆ -C _12, eg C ₈ -C _12, such as, e.g., Lauroglycol ^® 90, Sefsol ^® Capriol ^® 218 or 90, and / or

(VII) fatty acids and alcohols, for example, C ₆ -C ₂₀ saturated or mono- or di-unsaturated, such as, for example, oleic acid, oleic alcohol, linoleic acid, capric acid, caprylic acid, caproic acid, tetradecanol, dodecanol, decanol and / or (VIII) N-alkylpyrrolidone, for example, N-methylpyrrolidone, such as, for example, Pharmasolve ^® , and / or

(IX) glycerol triacetate, e.g. triacetin, and / or

(X) benzyl alcohol, and / or

(XI) or a simple ester of alkylene polyols, such as polyglycolized glycerides such as, e.g., Gelucire ^® 44/14.

Therefore, one of the objects of the present invention is a composition in the form of a pre-prepared emulsion or microemulsion concentrate, intended for oral administration, which includes

1) cyclosporine or macrolide and a carrier, including

2) a second component selected from the group comprising (I) triethyl citrate or acetyl triethyl citrate,

(II) a mixed ester of C ₆ -C ₁₀ fatty acid, polyethylene glycol and glycerol,

(III) diester of glycerol and C ₆ -C ₁₆ fatty acids,

(IV) a monoester of glycerol and a C ₆ -C ₁₄ fatty acid,

(V) a mixture of mono- and diglycerides of C ₆ -C ₁₆ fatty acids,

(VI) a propylene glycol monoester and a C ₆ -C ₁₂ fatty acid,

(Vii) fatty acids and alcohols,

(VIII) N-methylpyrrolidone,

(Ix) glycerol triacetate,

(X) benzyl alcohol, and

(XI) alkylene polyol ether or ester,

3) a lipophilic component, and

4) a surfactant, provided that if component 2)

(a) is triethyl citrate, the composition does not contain or practically does not contain ethanol, and / or

(b) is a mixture of mono- and diglycerides of C ₈ -C ₁₀ fatty acids, the composition does not contain or practically does not contain triglyceride C ₆ -C ₁₂ fatty acids.

When creating the invention, it was unexpectedly found that cyclosporine or macrolide has high solubility, for example, solubility, comprising from about 20 to about 50%, in the second component of the present invention. For example, the solubility of a cyclosporin or a macrolide in triethyl citrate is about 35%, in Sunfat ^® GDC-N - about 33%, in Lauroglycol ^® 90 - about 40%, in oleic acid - about 40%, in N-methylpyrrolidone-approximately 50% in Labrasol ^® approximately 20%, in dodecanol approximately 37.5%, in tetradecanol approximately 37.5%, in Sefsol ^® 218 approximately 50%, in Cetiol ^® HE approximately 32.5%, in oleyl alcohol more than 20%.

Therefore, another object of the invention is a composition in the form of a pre-prepared emulsion or microemulsion concentrate, intended for oral administration, which includes

1) cyclosporine or macrolide and a carrier, including

2) a second component, in which component 1) has a solubility of from about 20 to about 50%,

3) a lipophilic component, and

4) surfactant.

Preferably, the composition is in the form of a “pre-prepared emulsion, for example, microemulsion concentrate”, which makes it possible to obtain emulsions, for example, microemulsions, such as oil / water (oil in water). However, the composition may be in the form of an emulsion, for example a microemulsion, which further comprises an aqueous component, preferably water.

The term "pre-prepared emulsion, for example, microemulsion concentrate" in the context of the present description refers to a composition that spontaneously forms an emulsion, for example a microemulsion, in an aqueous medium, for example, in water, for example, when diluted in a ratio of from 1: 1 to 1:10 for example, in a ratio of 1:10, or in gastric juices after oral administration.

The microemulsion is thermodynamically stable and contains dispersed particles with an average size of less than about 200 nm. Typically, microemulsions contain droplets or particles having an average diameter of less than about 150 nm; normally less than 100 nm, usually more than 10 nm, and they remain stable for periods longer than 24 hours. The microemulsion may not be opaque or practically opaque, in the alternative, it may be a translucent colloidal dispersion that forms spontaneously or almost spontaneously when its components come into contact with each other. Other characteristics can be found in the aforementioned patent application GB 2222770, which is incorporated into this description by reference.

Another object of the present invention is a composition of the present invention, characterized in that the relative content of cyclosporin or macrolide, the second component, lipophilic component and surfactant in this composition is such that after dilution with water in a ratio of 1 parts by weight composition for 1-10 parts by weight water spontaneously forms an oil / water microemulsion having an average particle size of less than 200 nm.

In yet another alternative embodiment, the lipophilic component may include from 5 to 85 wt.% Media, for example, from 10 to 85 wt.%, Preferably from 15 to 70 wt.%, More preferably from 20 to 60 wt.%, And even more preferably about 25 wt.%.

In yet another alternative embodiment of the invention, the surfactant may include from 5 to 80 wt.% Media, preferably from 10 to 70 wt.%, More preferably from 20 to 60 wt.%, And even more preferably about 40 wt.% .

In yet another alternative embodiment of the invention, the second component may include from 5 to 50 wt.% Media, for example, from 10 to 50 wt.%, Preferably from 15 to 40 wt.%, More preferably from 20 to 35 wt.%.

The next object of the present invention is a composition of the present invention, comprising a second component in an amount of from 5 to 50%, a lipophilic component in an amount of from 5 to 85% and a surfactant in an amount of from 5 to 80%, based on the weight of the carrier.

The active substance may be present in an amount up to 20 wt.% In terms of the weight of the composition. Preferably, the active substance is present in an amount of from 1 to 15%, based on the weight of the composition, for example, from about 2 to 10%.

Another object of the present invention is a composition of the present invention, comprising cyclosporine or macrolide in an amount of from 1 to 15%, based on the weight of the composition.

The sparingly soluble active ingredient is a lipophilic drug, for example cyclosporine or macrolide. The term "hardly soluble" in the context of the present description means that the solubility of the substance in water is less than 1 wt.% / Vol. for example, 0.01 wt.% / vol.

The cyclosporins to which the present invention relates are any cyclosporins used in pharmaceuticals, for example immunosuppressants, antiparasitic agents and agents for eliminating multiple drug resistance, known and described in this field, especially cyclosporin A (also known and referred to in the present description under the name cyclosporine), cyclosporin G, [0- (2-hydroxyethyl) - (D) Ser] ⁸ -cyclosporin and [3'-dehydroxy-3'-keto-MeBmt] [Val] ² -cyclosporin. Cyclosporin is preferred.

One of the objects of the present invention is the composition of the present invention, where cyclosporin is cyclosporin A.

The term "macrolide" in the context of the present description refers to a macrocyclic lactone, for example, a compound having a lactone ring comprising 12 or more members. Of particular interest are lactam macrolides, i.e. macrolides having in the macrolide, in addition to the lactone (ether) bond, a lactam (amide) bond, for example, lactam macrolides produced by Streptomyces microorganisms, such as rapamycin, ascomycin and FK-506, as well as their numerous derivatives and analogues. It has been established that such lactam macrolides possess valuable pharmaceutical properties, in particular immunosuppressive and anti-inflammatory properties.

Rapamycin is an immunosuppressive lactam macrolide produced by Streptomyces hygroscopicus. The structure of rapamycin is described by Kesseler H. et al., Helv. Chim. Acta: 76: 117 (1993) (see also McAlpine JB et al., J. Antibiotics 44: 688 (1991); Schreiber SL et al., J. Am. Chem. Soc. 113: 7433 (1991); US patent 3929992).

Rapamycin is a very strong immunosuppressant, it is found that it also has antitumor and antifungal activity. However, its applicability as a pharmaceutical is limited by its very low and variable bioavailability, as well as its high toxicity. In addition, rapamycin is poorly soluble, which makes it difficult to prepare stable galenic compositions. Numerous rapamycin derivatives are known. Some 16-O-substituted rapamycins are described in WO 94/02136, the contents of which are incorporated herein by reference. 40-O-substituted rapamycins are described, for example, in US 5,258,389 and WO 94/09010 (O-aryl and O-alkylrapamycins); in WO 92/05179 (carboxylic acid esters), in US 5118677 (amide esters), in US 5118678 (carbamates), in US 5100883 (fluorinated esters), in US 5151413 (acetals), in US 5120842 (silyl ethers ), in WO 93/11130 (methylene rapamycin and its derivatives), in WO 94/02136 (methoxy derivatives), in WO 94/02385 and WO 95/14023 (alkenyl derivatives), the contents of which are incorporated herein by reference. 32-O-dihydro- or substituted rapamycins are described, for example, in US Pat. No. 5,256,790, incorporated herein by reference.

Rapamycin and its structurally similar analogs and derivatives are herein denoted by the generic term “rapamycin”.

Ascomycins, among which the most famous are FK-506 and ascomycin, are another class of lactam macrolides, many of which have strong immunosuppressive and anti-inflammatory activity. FK-506 is an immunosuppressant produced by strain Streptomyces tsukubaensis No. 9993. The structure of the FK-506 is presented in the appendix to the Merck Index, 11th ed. (1989), in paragraph A5. Ascomycin is described, for example, in US 3244592. Numerous derivatives of ascomycin and FK-506 have been synthesized, including halogenated derivatives such as 33-epichloro-33-deoxycoscomycin described in EP 427680. Ascomycin, FK-506 and their structurally similar analogues and derivatives are denoted by the general concept of "ascomycin."

The macrolides can, for example, be rapamycin or an O-substituted derivative, wherein the hydroxyl group on the cyclohexyl ring of rapamycin is substituted with the radical —OR ₁ , where R ₁ is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl and aminoalkyl; for example, 40-O- (2-hydroxy) ethylrapamycin, 40-O- (3-hydroxy) propylrapamycin, 40-O- [2- (2-hydroxy) ethoxy] ethylrapamycin and 40-O- (2-acetaminoethyl) rapamycin .

A preferred compound is 40-O- (2-hydroxy) ethylrapamycin as described in WO 94/09010.

Examples of compounds from the class FK-506 are the compounds indicated above. These include, for example, FK-506, ascomycin, and other naturally occurring compounds. They also include synthetic analogues.

A preferred compound of class FK-506 is described in EP 427680, for example, in Example 66a, it is also known as 33-epichloro-33-deoxy-hescomycin. Other preferred compounds are described in EP 465426 and in EP 569337, for example, the compound from example 71 EP 569337.

The second component may be any of the components I) -XI) individually or in combination with one, two or more other components I) -XI). Examples of compounds suitable for use according to the invention as second components are:

I) Triethyl citrate or acetyl triethyl citrate. They can be obtained by esterification of citric acid and ethanol or by esterification of citric acid and ethanol followed by acetylation with acetic anhydride, respectively. Triethyl citrate or acetyl triethyl citrate is commercially available, for example, under the trademarks Citroflex ^® 2 or Citroflex ^® A-2, or triethyl citrate with pharmaceutical grade is supplied by Morflex Inc. under the trademark TEC-PG / N. The most suitable is triethyl citrate, having a molecular weight of 276.3, a specific gravity of 1.135-1.139, a refractive index of 1.439-1.441, a viscosity coefficient (at 25 ° C) of 35.2 mP, and a content (anhydrous base) of 99.0-100.5% , maximum water content 0.25% (Fiedler HP, Lexicon der Hilfstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Cantor Verlag Aulendorf, Aulendorf, 4th revised and supplemented edition, Volume 1, p. 371 (1996 ); "Handbook of Pharmaceutical Excipients", 2nd ed., A. Wade and PJ Weller (eds.), Joint publication of American Pharmaceutical Association, Washington, USA and The Pharmaceutical Press, London, UK, p. 540 ( 1994)).

(II) Mixed ester of C ₆ -C ₁₀ fatty acid, polyethylene glycol and glycerol. The fatty acid ester may include a mono-, di- and / or triester of a fatty acid. A fatty acid moiety may include both saturated and unsaturated fatty acids having a chain length of, for example, C ₈ -C ₁₀ . Polyethylene glycols may have, for example, from 5 to 10 units of [CH ₂ —CH ₂ —O], for example, 7 units. Particularly preferred is polyethylene glycol (7) glyceryl monococoate sold, for example, under the trademark Cetiol ^® HE, for example, from Henkel KGaA. Cetiol ^® HE has a density (D) at 20 ° C of 1.05, an acid number of less than 5, a saponification number of approximately 95, a hydroxyl number of approximately 180, and an iodine number of less than 5 (H. Fiedler, loc. Cit (at the indicated location) Volume 1, p. 337).

Another suitable product is polyoxyethylene glyceride caprylic acid, sold under the trademark Labrasol ^® , for example, from the company Gattefosse. Labrasol ^® has an acid number equal to a maximum of 1, a saponification number of 90-110 and an iodine number equal to a maximum of 1 (H. Fiedler, loc. Cit., Vol. 2, p. 880).

(III) Diester of glycerol and C ₆ -C ₁₆ fatty acids. Diglycerides suitable for use in the compositions of the present invention include both symmetric (i.e., α, α ¹ -diglycerides) and asymmetric diglycerides (i.e., α, β-diglycerides) and their acetylated derivatives. They also include both homogeneous glycerides (in which the acid component is primarily a single fatty acid) and mixed glycerides (i.e., glycerides in which the acid component consists of several fatty acids) and their acetylated derivatives. A fatty acid moiety may include both saturated and unsaturated fatty acids having a chain length of, for example, C ₆ -C ₁₆ , for example C ₈ -C ₁₀ , for example C ₈ . Most preferred is a diglyceride of caprylic acid, commercially available, e.g., under the trademark Sunfat ^® GDC-N, for example, from Taiyo Kagaku Co., Ltd. Sunfat ^® GDC-N has an acid value of approximately 0.3, diglycerides approximately 78.8%, monoester approximately 8.9%.

(IV) Monoester of glycerol and C ₆ -C ₁₄ fatty acid. These esters can be obtained by esterification of glycerol with vegetable oil followed by molecular distillation. Monoglycerides suitable for use in the compositions of the invention include both symmetric (i.e., β-monoglycerides) and asymmetric monoglycerides (i.e., α-monoglycerides) and their acetylated derivatives. They also include both homogeneous glycerides (in which the acid component is primarily a single fatty acid) and mixed glycerides (i.e., glycerides in which the acid component consists of several fatty acids) and any acetylated derivatives thereof. A fatty acid moiety may include both saturated and unsaturated fatty acids having a chain length of, for example, C ₈ -C ₁₀ . Most preferred are monoglycerides of caprylic or capric acid, commercially available, for example under the trademarks Imwitor ^® 308 or Imwitor ^® 310, respectively, for example, from Condea company. For example, Imwitor ^® 308 contains at least 80% monoglycerides and has the following additional characteristics: free glycerol content maximum 6%, acid 20 number maximum 3, saponification number 245-265, iodine number maximum 1, water content maximum 1%. Typically, this product contains 1% free glycerol, 90% monoglycerides, 7% diglycerides, 1% triglycerides (H. Fiedler, loc. Cit., Vol. 1, p. 798).

(V) A mixture of mono- and diglycerides of C ₆ -C ₁₆ fatty acids. Mixed mono- and diglycerides suitable for use in the compositions of the invention include both symmetric (i.e., β-monoglycerides and α, α ¹ -diglycerides) and asymmetric mono- and diglycerides (i.e., α-monoglycerides and α, β-diglycerides) and their acetylated derivatives. They also include both homogeneous glycerides (in which the acid component is primarily a single fatty acid) and mixed glycerides (i.e., glycerides in which the acid component consists of several fatty acids) and any acetylated derivatives thereof.

A fatty acid moiety may include both saturated and unsaturated fatty acids having a chain length, for example, C ₈ -C ₁₀ . Most preferred are mono- and diglycerides of caprylic or capric acid, commercially available, e.g., under the trademark Imwitor ^® 742, for example, from Condea company. For example, Imwitor ^® 742 contains at least 45% monoglycerides and has the following additional characteristics: maximum glycerol content 2%, acid maximum 2, saponification 250-280, iodine maximum 1, water maximum 2% (N. Fiedler , loc. cit., volume 1, p. 798). Another suitable mixed glyceride is a mono / diglyceride of caprylic / capric acid in glycerol as known and commercially available, e.g., under the trademark Capmul ^® MCM, e.g., Abitec Corporation company. Capmul ^® MCM has the following additional characteristics: acid value maximum 2.5, alpha monoglycerides (as oleate) minimum 80%, free glycerol maximum 2.5%, iodine maximum 1, acid distribution with different chain lengths: caproic acid (C ₆ ) maximum 3%, caprylic acid (C ₈ ) minimum 75%, capric acid (C ₁₀ ) minimum 10%, lauric acid (C ₁₂ ) maximum 1.5%, moisture content (according to Karl Fischer) maximum 0 , 5% (according to the manufacturer).

(VI) Propylene glycol monoester and C ₆ -C ₁₂ fatty acid. A fatty acid moiety may include both saturated and unsaturated fatty acids having a chain length, for example, C ₈ -C ₁₂ . Most preferred are monoesters of propylene glycol and caprylic and capric acid, commercially available, for example under the trademarks Sefsol ^® 218, Capriol ^® Lauroglycol ^® 90 or 90, for example, from Nikko Chemicals Co., Ltd. or Gattefosse. For example, Lauroglycol ^® 90 has the following additional characteristics: acid number maximum 8, saponification number 200-220, iodine number maximum 5, free propylene glycol content maximum 5%, monoester content minimum 90%; Sefsol ^® 218 has the following additional characteristics: acid number maximum 5, hydroxyl number 220-280 (H. Fiedler, loc. Cit., Volume 2, p. 906, according to the manufacturer).

(Vii) Fatty acids and alcohols. Fatty acids can be obtained by hydrolysis of various animal and vegetable fats and oils, such as olive oil, and subsequent separation of liquid acids. A fatty acid / alcohol moiety may include both saturated and mono- or di-unsaturated fatty acids / alcohols having a chain length of approximately C ₆ -C ₂₀ . Most preferred are, for example, oleic acid, oleyl alcohol, linoleic acid, caprylic acid, capric acid, caproic acid, tetradecanol, dodecanol or decanol. For example, oleyl alcohol is commercially available under the trademark HD-Eutanol ^® V from Henkel KGaA. Oleyl alcohol has the following additional characteristics: acid number maximum 0.1, hydroxyl number approximately 210, iodine number approximately 95, saponification number maximum 1, D ²⁰ (density at 20 ° C) approximately 0.849, n $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ 1,462, molecular weight 268, viscosity coefficient (at 20 ° С) approximately 35 MP (according to the manufacturer). Oleyl acid has the following additional characteristics: molecular weight 282.47, D ²⁰ 0.895, n $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ 1.45823, acid number 195-202, iodine number 85-95, viscosity (at 25 ° C) 26 mP (H. Fiedler, loc. Cit., Volume 2, p. 1112; Handbook of Pharmaceutical Excipients, loc. Cit ., p. 325).

(VIII) N-Alkylpyrrolidone. Most suitable is N-methyl-2-pyrrolidone, for example, as marketed under the trademark Pharmasolve ™, for example, from International Specialty Products (ISP). N-methylpyrrolidone has the following additional characteristics: molecular weight 99.1, D ²⁵ 1.027-1.028, purity (estimated by peak area (in%) obtained by gas chromatography (GC)) (including methyl isomers) at least 99.85% (H. Fiedler, loc. Cit., Volume 2, p. 1004, according to manufacturer information).

(IX) Glycerol triacetate or (1,2,3) -triacetin. It can be obtained by esterification of glycerol with acetic anhydride. Glycerol triacetate is marketed, e.g., in the form Priacetin ^® 1580 from the company Unichema International, or as Eastman Triacetin from Eastman company or firm Courtaulds Chemicals Ltd. Glycerol triacetate has the following additional characteristics: molecular weight 218.03, D ^20.3 1.159-1.163, n $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ 1.430-1.434, water content at most 0.2%, viscosity (at 25 ° C) 17.4 mP, acid number at most 0.1, saponification number at about 766-774, triacetin content at least 97% (N. Fiedler, loc. cit., vol. 2, p. 1580; Handbook of Pharmaceutical Excipients, loc. cit., p. 544, according to the manufacturer).

(X) Benzyl alcohol. It can be obtained by distillation of benzyl chloride with potassium or sodium carbonate. Benzyl alcohol is sold, for example, from Merck. Benzyl alcohol has the following additional characteristics: molecular weight 108, 14, D. 1,043-1,049, n _D 1,538-1,541 (N. Fiedler, loc. Cit., Volume 1, p. 238; Handbook of Pharmaceutical Excipients, loc. Cit. , p. 35).

(XI) An alkylene polyol ether or ester. Suitable may be a simple or complex ester of C ₃ -C ₅ alkylenetriol, in particular glycerol. Suitable C ₃ -C ₅ alkylenetriol ethers or esters include mixed ethers or esters, i.e. compounds comprising fragments of other ethers or esters, for example, transesterification products of C ₃ -C ₅ alkylenetriol esters and other mono-, di- or polyols.

Particularly suitable alkylene polyol ethers or esters are C ₃ -C ₅ alkylenetriol / polyC ₂ -C ₄ alkylene glycol mixed esters, especially mixed glycerol / polyethylene or polypropylene glycol and fatty acid esters.

Most suitable for use in the present invention, alkylene polyol esters or esters include products obtained by transesterification of glycerides, for example triglycerides with polyC ₂ -C ₄ alkylene glycols, for example polyethylene glycols and optionally glycerol.

Such transesterification products are typically obtained by alcoholysis of glycerides, for example triglycerides, in the presence of polyC ₂ -C ₄ alkylene glycol, for example polyethylene glycol, and optionally glycerol (for example, to transesterify the glyceride to obtain a polyalkylene glycol / glycerol component, i.e. by polyalkylene glycolysis / glycerolysis).

In general, such a reaction is carried out by reacting these components (glyceride, polyalkylene glycol and optionally glycerol) at an elevated temperature in an inert gas atmosphere with continuous stirring.

Preferred glycerides are fatty acid triglycerides, for example, C ₁₀ -C ₂₂ fatty acid triglycerides, including natural and hydrogenated oils, in particular vegetable oils. Suitable vegetable oils include, for example, olive, almond, peanut, coconut, palm, soybean and wheat germ oil and, in particular, natural or hydrogenated oils with a high content of C ₁₂ -C ₁₈ fatty acid ester residues.

Preferred polyalkylene glycols are polyethylene glycols, especially polyethylene glycols having a molecular weight of from about 500 to about 4000, for example, from about 1000 to about 2000.

Thus, alkylene polyol ethers or esters include mixtures containing C ₃ -C ₅ alkylenetriol esters, for example mono-, di- or triesters in variable ratios, and mono- and diesters of polyC ₂ -C ₄ alkylene glycol along with minor amounts of free C ₃ -C ₅ alkylenetriol and free polyC ₂ -C ₅ alkylene glycol. As indicated above, the preferred alkylenetriol moiety is glycerol; preferred polyalkylene glycol moieties are polyethylene glycols, in particular having a molecular weight of from about 500 to about 4000; and preferred fatty acid moieties are residues of C ₁₀ -C ₂₂ fatty acid esters, in particular residues of saturated C ₁₀ -C ₂₂ fatty acid esters.

Thus, in an alternative embodiment, the category of the most preferred alkylene polyol ethers or esters can be defined as follows: transesterification products of natural or hydrogenated vegetable oil and polyethylene glycol and optionally glycerol; or compositions comprising or consisting of mono-, di- or triesters of C ₁₀ -C ₂₂ fatty acids and glycerol and mono-, di- or triesters of polyethylene glycol C ₁₀ -C ₂₂ fatty acids (optionally in combination, for example, with small amounts of free glycerol and free polyethylene glycol).

Preferred vegetable oils, polyethylene glycols or fragments of polyethylene glycols and fragments of fatty acids, as defined above, are given above in the present description. Most preferred for use according to the present invention is simple esters or alkylene as defined above are those known and commercially available under the trademark Gelucire ^®, for example from the company Gattefosse, in particular the following products:

a) Gelucire ^® 33/01, having a _{melting point} t of about 33-38 ° C and a saponification value of about 240/260;

b) Gelucire ^® 35/10, _mp approximately 29-34 ° C and a saponification number of approximately 120/140;

c) Gelucire ^® 37/02, _mp approximately 34-40 ° C and a saponification number of approximately 200/220;

g) Gelucire ^® 42/12, _mp approximately 41-46 ° C and a saponification number of approximately 95/115;

d) Gelucire® 44/14, _mp approximately 42-46 ° C and a saponification number of approximately 75/95;

e) Gelucire ^® 46/07, t _mp about 47-52 ° C and a saponification value of about 125/145;

g) Gelucire ^® 48/09, _mp approximately 47-52 ° C and a saponification number of approximately 105/125;

h) Gelucire ^® 50/02, _mp approximately 48-52 ° C and a saponification number of approximately 180/200;

i) Gelucire ^® 50/13, _mp approximately 46-41 ° C and a saponification number of approximately 65/85;

a) Gelucire ^® 53/10, t _mp about 48-53 ° C and a saponification value of about 95/115;

k) Gelucire ^® 62/05, _mp approximately 60-65 ° C and a saponification number of approximately 70/90.

All products listed in paragraphs a) to k) above have an acid number equal to a maximum of 2. The product specified in paragraph k) has an acid number equal to a maximum of 5. All products listed in paragraph b), c) above and f) -k), have an iodine number equal to a maximum of 3. The product specified in paragraph a) has an iodine number equal to a maximum of 8. Products specified in paragraphs d) and e) have an iodine number equal to a maximum of 5 or 2 The product specified in paragraph k) has an iodine number equal to a maximum of 10.

In general, alkylene polyol ethers or esters having an iodine number of maximum 2 are preferred. It should be understood that mixtures of alkylene polyol ethers or esters, as defined above, can also be used in the compositions of the invention.

Products manufactured under the Gelucire ^® trademark are inert semi-solid waxy products with amphiphilic properties. They are characterized by their melting points and HLB values (hydrophilic-lipophilic balance).

Most types of Gelucire ^® are saturated polyglycolized glycerides obtained by the polyglycolysis of naturally occurring hydrogenated vegetable oils and polyethylene glycols. They consist of a mixture of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol and fatty acids. Especially preferred is Gelucire ^® 44/14, having a nominal melting point of 44 ° C and HLB value equal to 14. It is obtained by reacting hydrogenated palm kernel oil and / or hydrogenated palm oils with polyethylene glycol 1500. It consists of approximately 20% mono-, di - and triglycerides, 72% of mono- and diesters of fatty acids and polyethylene glycol 1500 and 8% of free polyethylene glycol 1500. Gelucire ^® 44/14 has the following composition of fatty acids: 4-10% C ₈ , 3-9% C ₉ , 40- 50% C ₁₂ , 14-24% C ₁₄ , 4-14% C ₁₆ , 5-15% C ₁₈ . Gelucire ^® 44/14 has the following additional characteristics: acid number maximum 2, iodine number maximum 2, saponification number 79-93, hydroxyl number 36-56, peroxide number maximum 6, alkaline content of impurities maximum 80, water content maximum 0.50, the content of free glycerin is a maximum of 3, the content of monoglycerides is 3.0-8.0 (N. Fiedler, loc. cit., volume 1, p. 676; according to the manufacturer).

Although any pharmaceutically acceptable compound selected from the above group may be used in the composition of the invention, certain compounds are preferred. These include triethyl citrate, acetyl triethyl citrate, N-methylpyrrolidone, glycerol triacetate, benzyl alcohol, Cetiol ^® HE, oleic acid or an alkylene polyol or ester, for example polyglycolized glycerides. More preferred are triethyl citrate, acetyl triethyl citrate, N-methylpyrrolidone, benzyl alcohol, Cetiol ^® HE or oleic acid.

Thus, one of the objects of the present invention is a composition of the present invention, where the second component is selected from the group including:

(I) triethyl citrate or acetyl triethyl citrate,

(II) C ₆ -C ₁₀ fatty acid ester, polyethylene glycol and glycerol,

(Iii) fatty acids and alcohols,

(IV) N-methylpyrrolidone,

(V) glycerol triacetate,

(Vi) benzyl alcohol, and

(Vii) alkylene polyol ether or ester.

The next object of the present invention is a composition of the present invention, where the second component is triethyl citrate or N-methylpyrrolidone.

The second component may also include an auxiliary component, which may have hydrophilic properties, for example, selected from Transcutol (having the formula C ₂ H ₅ - [O- (CH ₂ ) ₂ ] ₂ -OH, Glycofurol (also known as tetrahydrofuryl alcohol ether and polyethylene glycol) and 1,2-propylene glycol. The second component may include other hydrophilic auxiliary components, for example lower alcohols such as ethanol. Typically, these auxiliary components partially replace other components of the second component. the ethanol content in the compositions is not critical, it was found that it should preferably be used if the compositions are to be prepared in the form of a soft gelatin capsule, due to the fact that in this case storage characteristics are improved, in particular, reduced risk of precipitation of the active substance after the encapsulation procedure.Thus, due to the use of ethanol or some other auxiliary component as an additional ingredient of the second composition nta can be improved storage stability. In yet another embodiment, ethanol may be from 0 to 60% based on the weight of the second component; preferably from 20 to about 55 wt.% and more preferably from about 40 to 50 wt.%. Small amounts of liquid polyethylene glycols may also be included in the second component.

GB 2222770 describes a wide variety of lipophilic components suitable for use in accordance with the present invention. Typical examples of lipophilic components are:

(I) fatty acid triglycerides having an average chain length of, e.g., C ₆ -C _12, e.g., Migliol ^® 812 and / or

(II) mixed mono-, di-, triglycerides, for example, C ₆ -C ₂₀ , for example, C ₁₆ -C ₁₈ , for example, Maisine ^® , and / or

(III) transesterified ethoxylated vegetable oils, e.g. Labrafil ^® , and / or

(IV) mono-esters of propylene glycol and a fatty acid, for example, C ₁₄ -C ₁₈ , for example, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol ricinoleate, propylene glycol stearate, and / or

(V) propylene glycol diesters of fatty acids, e.g., C ₆ -C _20, eg C ₈ -C _12, for example, propylene glycol dicaprylate, e.g., Migliol ^® 840, or propylene glycol dilaurate, and / or

(VI) esterified derivatives of a fatty acid and a primary alcohol, for example C ₆ -C ₂₀ fatty acids and C ₂ -C ₃ alcohols, for example ethyl linoleate, and / or

(VII) mono- and / or diglycerides, for example, a mixture of mono- and diglycerides, for example, with monoglyceride C ₁₈ fatty acid as its main component, for example GMOrphic ^® -80 or Tegin ^® O.

Preferred lipophilic components are medium chain triglycerides of fatty acids, mixed mono-, di-, triglycerides and transesterified ethoxylated vegetable oils.

Thus, another object of the present invention is a composition of the present invention, where the lipophilic component is selected from the group consisting of (I) medium chain fatty acid triglycerides, (II) mixed mono-, di-, triglycerides and (III) transesterified ethoxylated vegetable oils.

In another embodiment, the lipophilic component may include a medium chain fatty acid triglyceride and / or a mono- and diglyceride or a mixture thereof.

As a medium chain length fatty acid triglyceride in the lipophilic component, a saturated fatty acid triglyceride having 6-12, for example 8-10 carbon atoms, can be used. Suitable medium chain length fatty acid triglycerides are products known and marketed under the trademarks Acomed ^® , Myritol ^® , Captex ^® , Neobee ^® M 5F, Migliol ^® 810, Migliol ^® 812, Migliol ^® 818, Mazol ^® , Sefsol ^® 860, Sefsol ^® 870; most preferred is Migliol ^® 812. Migliol ^® 812 is a fractionated coconut oil comprising caprylic-capric acid and has a molecular weight of approximately 520 Da. The composition of fatty acids: C _{6 a} maximum of approximately 3%, C ₈ approximately 50-65%, C ₁₀ approximately 30-45%, C _{12 a} maximum of 5%; an acid number of about 0.1; saponification number of approximately 330345; iodine number maximum 1. Migliol ^® 812 is available from Condea. Neobee ^® M 5F is a fractionated caprylic-capric acid triglycerides derived from coconut oil; acid number maximum 0.2; saponification number of approximately 335-360; iodine number maximum 0.5, water content maximum 0.15%, D ²⁰ . equal to 0.930-0.960, n $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ equal to 1,448-1,451 (according to the manufacturer). Neobee ^® M 5F is supplied by Stepan Europe.

These triglycerides are described by Fiedler H.P., loc. cit., the contents of the document are incorporated into this description by reference.

In another alternative embodiment, the monoglycerides preferably comprise from about 25 to about 50%, based on the total weight of the lipophilic components. More preferably, monoglycerides are present in an amount of from about 30 to about 40% (e.g., from 35 to 40%).

In yet another alternative embodiment, the diglycerides preferably comprise from about 30 to about 60%, based on the total weight of the lipophilic component. More preferably, diglycerides are present in an amount of from about 40 to about 55% (for example, from 48 to 50%).

In yet another alternative embodiment, the triglycerides preferably comprise at least 5, but less than about 25%, based on the total weight of the lipophilic component. More preferably, triglycerides are present in an amount of from about 7.5 to about 20% (for example, from about 9 to 12%).

Suitable mixed mono-, di-, triglycerides are products known and marketed under the trademark Maisine ^® from Gattefossе. They are transesterification products of corn oil and glycerol. Such products mainly contain mono-, di-, triglycerides of linoleic and oleic acids, along with small amounts of mono-, di-, triglycerides of palmitic and stearic acids (corn oil itself as constituents includes approximately 56 wt.% Linoleic acid, 30 wt.% oleic acid, about 10 wt.% palmitic acid and about 3 wt.% stearic acid). The products have the following physical characteristics: free glycerol maximum 10%, monoglycerides approximately 40%, diglycerides approximately 40%, triglycerides approximately 10%, free oleic acid approximately 1%. Other physical characteristics have the following meanings: acid number maximum 2, iodine number 85-105, saponification number 150-175, the content of mineral acids is zero. Maisine ^® typically has the following fatty acid composition: palmitic acid — about 11%, stearic acid — about 25%, oleic acid — about 29%, linoleic acid — about 56%, other acids — about 1.5% (N Fiedler, loc. Cit., Volume 2, p. 958; according to manufacturer information).

In yet another alternative embodiment, the lipophilic component may include, for example, a pharmaceutically acceptable oil, for example, preferably containing an unsaturated component, such as vegetable oil or fish oil.

In yet another alternative embodiment, the lipophilic component may include suitable transesterified ethoxylated vegetable oils, such as products obtained by reacting various natural vegetable oils (e.g., corn oil, kernel oil, almond oil, peanut oil, olive oil, soybean oil, sunflower oil , safflower oil and palm oil or mixtures thereof) with polyethylene glycols having an average molecular weight of from about 200 to 800, in the presence of suitable catalyst. These methods are known and are described, for example, in US Pat. No. 3,288,824. Most preferred is transesterified ethoxylated corn oil.

Transesterified ethoxylated vegetable oils are known and are marketed under the trademark Labrafil ^® (H. Fiedler, loc. Cit., Vol. 2, p. 880). Examples are Labrafil ^® M 2125 CS (obtained from corn oil having an acid number less than 2, saponification number 155-175, HLB value 3-4 and iodine number 90-110) and Labrafil ^® M 1944 CS (obtained from kernel oil, having an acid number of about 2, a saponification number of 145-175 and an iodine number of 60-90). Labrafil ^® M 2130 CS (a transesterification product of C ₁₂ -C ₁₈ glyceride and polyethylene glycol having a _{melting point of} about 35-40 ° C, an acid number less than about 2, a saponification number 185-200 and an iodine number less than than about 3). The preferred transesterified ethoxylated vegetable oil is Labrafil ^® M 2125 CS, which can be obtained, for example, from Gattefosse, Saint-Priest Cedex, France.

In other lipophilic components suitable for use in the present invention are, for example, mono- and diesters of propylene glycol fatty acid esters such as propylene glycol dicaprylate (also known and commercially available under the trade name Migliol ^® 840 from the firm Condea; H. Fiedler, loc cit., vol. 2, p. 1008) or propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate, etc. (H. Fiedler, loc. Cit., Vol. 2, p. 1277 ff.).

As another lipophilic component, esterification products of a fatty acid and a primary alcohol can be used. These may include, for example, esterified derivatives of a fatty acid having 8 to 20 carbon atoms and a primary alcohol having 2 to 3 carbon atoms, such as, for example, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, etc., with particular preference being given. is an esterified derivative of linoleic acid and ethanol.

In another embodiment, mono- and / or diglyceride can be used as the lipophilic component. Mono- and / or diglyceride is, for example, a mixture of mono- and diesters of glycerol and fatty acids, in which the content of monoglyceride is, for example, at least 40%. Preferably, mono- and diglycerides contain C ₁₈ fatty acid monoglyceride as the main component. Such compounds are commercially available under the trademarks GMO ^® AV1 (Croda Co.), ATMOS ^® 300 (ICI Co.), GMOphph ^® -80 (Eastman Co.), Tegin ^® O (Goldschmidt Co.), etc. .d. For example, GMOrphic ^® -80 (glycerol monooleate) has the following additional characteristics: monoglyceride content minimum 94%, C18: 1 minimum 75%, peroxide maximum 2.5, C18: 2 + C18: 3 maximum 15%, C16: 0 + C18: 0 + C20: 0 maximum 10%, water content maximum 2%, acid number maximum 3, iodine number 65-75, saponification number 155-165, free glycerin content maximum 1%, hydroxyl number 300-330 (according to manufacturer information). Tegin ^® O (glycerol oleate) has the following additional characteristics: monoglyceride content 55-65%, peroxide number maximum 10, water content maximum 1%, acid number maximum 2, iodine number 70-76, saponification number 158-175, free glycerol content maximum 2% (according to the manufacturer).

Typically, mono / diglyceride is present at a concentration of 5-10%, for example, based on the weight of the composition, carrier or lipophilic component.

In another alternative embodiment, any of the above lipophilic components, for example, oils, individually or in combination with each other, can be used as the lipophilic component in the composition of the present invention. If mixtures of any medium chain triglycerides and mono- and diglycerides are used in the lipophilic component, they may be present in the mixture in a weight ratio of 1: 0.1-1, preferably 1: 0.1-0.5.

In yet another embodiment, in the composition of the present invention, the mass ratio of the lipophilic component and cyclosporin is preferably 1-10: 1, and more preferably 2-6: 1.

Examples of surfactants suitable for use in accordance with the present invention are:

I) Products of the interaction of natural or hydrogenated castor oil and ethylene oxide. Natural or hydrogenated castor oil can be reacted with ethylene oxide in a molar ratio of from about 1:35 to about 1:60 with optional removal of the polyethylene glycol component from the product. Especially preferred are polyethylene glycol-type hydrogenated castor oils available under the trademark Cremophor ^®. Most preferred are Cremophor ^® RH 40 having a saponification value of about 50-60, an acid number less than about 1, a water content (Fischer) less than about 2%, n $\genfrac{}{}{0ex}{}{\text{60}}{\text{D}}$ approximately 1.453-1.457 and an HLB value of approximately 14-16; and Cremophor ^® RH 60 having a saponification value of about 40-50, an acid number less than about 1, an iodine number less than about 1, a water content (Fischer) less than about 4,5-5,5%, n $\genfrac{}{}{0ex}{}{\text{60}}{\text{D}}$ approximately 1.453-1.457 and the HLB value of approximately 15-17. The most preferred product of this class is Cremophor ^® RH 40. Also suitable are products such as polyethylene glycol castor oils, sold under the trademarks Cremophor ^® EL, having a molecular weight (determined by steam osmometry) of about 1630, a saponification number of about 65-70, an acid number about 2, iodine number about 28-32 and n $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ approximately 1,471.

Similar or identical products that can also be used according to the invention are commercially available under the trademarks Nikkol ^® (e.g. Nikkol ^® НСО-40 and НСО-60), Mapeg ^® (e.g. Mapeg ^® СО-40h), Incrocas ^® (e.g. , Incrocas ^® 40), Tagat ^® (e.g., mixed fatty alcohol ethers, polyoxyethylene glycerol such as Tagat ^® RH 40, and Tagat ^® TO, polyoxyethylene sorbitan trioleate having a HLB value of 11.3; preferred is Tagat ^® RH 40) and Simulsol OL-50 (PEG-40 castor oil having a saponification number of approximately 55-65, an acid number of maximum 2, an iodine number of 25-35, s Erzhanov water up to 8% and an HLB of approximately 13, commercially available from Seppic company). These surfactants are described by Fiedler, loc. cit.

II) Esters of polyoxyethylene sorbitan and fatty acids, for example mono- and trilauryl, palmityl, stearyl and oleyl esters, known and marketed under the trademarks Tween ^® (Fiedler, loc. Cit., P. 1615 ff.), Including the following products Tween ^® :

20 [polyoxyethylene (20) sorbitan monolaurate],

21 [polyoxyethylene (4) sorbitan monolaurate],

40 [polyoxyethylene (20) sorbitan monopalmitate],

60 [polyoxyethylene (20) sorbitan monostearate],

65 [polyoxyethylene (20) sorbitan tristearate],

80 [polyoxyethylene (20) sorbitan monooleate],

81 [polyoxyethylene (5) sorbitan monooleate],

85 [polyoxyethylene (5) sorbitan trioleate].

Especially preferred products of this class are Tween ^® 40 and Tween ^® 80.

III) Esters of polyoxyethylene and fatty acids, for example, esters of polyoxyethylene and stearic acid, known and sold under the trademark Myrj ^® (Fiedler, loc. Cit., Vol. 2, p. 1042). The most preferred product of this class is Myrj ^® 52, having a D ^{25 of} about 1.1, a _{mp of} about 40-44 ° C, an HLB value of about 16.9, an acid number of about 0-1, and a saponification number of about 25-35.

IV) copolymers of polyoxyethylene and polyoxypropylene and block copolymers, poloxamers, such as known and commercially available under the trademarks ^{Pluronic ®, Emkalyx ® (Fiedler,} loc. Cit., Volume 2, str.1203). Nabolee preferred product of this class is Pluronic ^® F68 (poloxamer 188) having a _{melting point} of about 52 t ° C and a molecular weight of about 6800-8975. Another preferred product of this class is Synperonic ^® PE L44 (poloxamer 124).

V) Dioctyl sodium sulfosuccinate, known and marketed under the trademark Aerosol OT ^® from American Cyanamid Co. (Fiedler, loc. Cit., Volume 1, p. 118) or di- [2-ethylhexyl] succinate (Fiedler, loc. Cit., Volume 1, p. 487).

VI) Phospholipids, especially lecithins (Fiedler, loc. Cit., Vol. 2, pp. 910, 1184). Suitable lecithins include, in particular, soya lecithins.

VII) Esters of sorbitan and fatty acids, for example, monooesters of sorbitan and C ₁₂ -C ₁₈ fatty acids or triesters of sorbitan and C ₁₂ -C ₁₈ fatty acids, known and commercially available under the trademark Span ^® from the company ICI. An especially preferred product of this class is the Span ^® 20 (sorbitan monolaurate) or Span ^® 80 (sorbitan monooleate) (Fiedler, loc cit, vol 2, str.1430;.. Handbook of Pharmaceutical Exipients, loc cit, str.473..).

VIII) Monoesters of polyoxyethylene and saturated C ₁₀ -C ₂₂ fatty acids, for example, substituted C ₁₈ , for example, hydroxy-substituted fatty acids; for example, PEG-ester of 12-hydroxystearic acid, for example, where the PEG has a molecular weight of about 600-900, for example, 660 Yes, for example, Solutol ^® HS 15, supplied by BASF, Ludwigshafen, Germany.

IX) Polyoxyethylene alkyl ethers, for example, polyoxyethylene glycol ethers and C ₁₂ -C ₁₈ alcohols, such as polyoxyl 2-, 10- or 20-cetyl ether or polyoxy-4- or 23-lauryl ether, or polyoxy-2-, 10- or 20-oleyl ether, or polyoxy-2-, 10-, 20- or 100-stearyl ether, known and sold under the trademark Brij ^® from ICI. The most preferred product in this class is Brij ^® 35 (polyoxy-23-lauryl ether) or Brij ^® 98 (polyoxy-20-oleyl ether) (Fiedler, loc. Cit., Vol. 1, p. 259; Handbook of Pharmaceutical Exipients, loc. cit., p. 367).

Similar products that can also be used according to the invention are polyoxyethylene-polyoxypropylene alkyl ethers, for example, polyoxyethylene-polyoxypropylene ethers and C ₁₂ -C ₁₈ alcohols, for example, polyoxyethylene-20-polyoxypropylene-4-cetyl ether, known and commercially available under the trademark Nikkol PBC ^® 34 from Nikko Chemicals Co., Ltd. (Fiedler, loc. Cit., Volume 2, p. 1239).

X) Water-soluble esters of tocopheryl polyethylene glycol and succinic acid (TPHN), for example, with a polymerization number of approximately 1000, commercially available from Eastman Fine Chemicals Kingsport, Texas, USA.

XI) Esters of polyglycerol and fatty acids, for example, having from 2 to 20, for example, 10 fragments of glycerol. A fatty acid moiety may include both saturated and unsaturated fatty acids having a chain length of, for example, C ₈ -C ₁₈ . The most suitable is decaglycerol monolaurate or decaglyceryl monomyristate, known and sold under the trademarks Decaglyn ^® 1-L or Decaglyn ^® 1-M, respectively, for example, from the company Nikko Chemicals Co., Ltd. (Fiedler, loc. Cit., Volume 2, p. 1228).

XII) Mixed ester of polyethylene glycol, glycerol and fatty acid. The fatty acid ester may include a mono- and / or di- and / or tri-fatty acid ester. A fatty acid moiety may include both saturated and unsaturated fatty acids having a chain length, for example, C ₁₂ -C ₁₈ . Polyethylene glycols may have, for example, from 10 to 40 units of [CH ₂ —CH ₂ —O], for example, 15 or 30 units. The most suitable is polyethylene glycol (15) glyceryl monostearate or polyethylene glycol (15) glyceryl monooleate, which are sold, for example, under the trademarks TGMS ^® -15 or TGMO ^® -15, respectively, for example, from the company Nikko Chemicals Co., Ltd. Another suitable product is polyethylene glycol (30) glyceryl monooleate, which is commercially available, for example, under the trademark Tagat ^® O, for example, from Goldschmidt (H. Fiedler, loc. Cit., Volume 2, p. 1502-1503).

XIII) Sterols and their derivatives, for example, cholesterols and their derivatives, especially phytosterols, for example, products including sitosterol, campesterol or stigmasterol and their ethylene oxide adducts, for example, soy sterols and their derivatives, for example, polyethylene glycol sterols, for example, polyethylene glycol phytosterols or polyethylene glycol soy sterols. Polyethylene glycols may have, for example, from 10 to 40 units of [CH ₂ —CH ₂ —O], for example, 25 or 30 units. The most suitable is polyethylene glycol (30) phytosterol, sold under the trademark Nikkol BPS ^® -30, for example, from the company Nikko Chemicals Co., Ltd. Another suitable product is polyethylene glycol (25) soya sterol, commercially available under the trademark Generol ^® E 25 122, for example, from Henkel (H. Fiedler, loc. Cit ., Volume 1, str.680).

It should be understood that surfactants can be complex mixtures, including by-products or unreacted starting materials used to prepare them, for example, surfactants obtained by polyoxyethylation may contain another by-product, for example polyethylene glycol.

A surfactant having a hydrophilic lipophilic balance (HLB) value of from 8 to 17 is preferred. The HLB value is preferably the average HLB value.

The selected surfactant preferably has a hydrophilic-lipophilic balance (HLB) value of at least 10, for example, it is a cremophor.

One of the objects of the present invention is the composition of the present invention, where the surfactant is selected from the group consisting of (I) reaction products of natural or hydrogenated vegetable oil and ethylene oxide and (II) polyoxyethylene sorbitan fatty acid esters.

Preferably, the relative contents of the second component (s), the lipophilic component and the surfactant are in the microemulsion region in a standard three-dimensional diagram. The compositions thus obtained are highly stable pre-prepared microemulsion concentrates, which are capable of forming microemulsions having an average particle size <200 nm after adding water.

Standard three-dimensional graphs, for example, phase diagrams, can be constructed by the conventional method described, for example, in published patent application of Great Britain 2222770 or in WO 96/13273.

Another alternative object of the invention is a composition based on cyclosporine or macrolide, including

1) cyclosporine or macrolide as an active substance;

2) the second component, as described above;

3) one compound or a mixture of two or more compounds selected from the group comprising a fatty acid ester of a primary alcohol, a medium chain fatty acid triglyceride and a fatty acid monoglyceride as a lubricant; and

4) a surfactant having an HLB value (hydrophilic-lipophilic balance) from 8 to 17, for example, enclosed in a gelatin shell containing polyethylene glycol and propylene glycol as a plasticizer.

Another object of the present invention is a preparation based on cyclosporine or macrolide, which contains a composition comprising

1) cyclosporine or macrolide as an active substance; and

2) the second component, as described above.

Although any pharmaceutically acceptable components selected from the group above may be used as second components in such a composition, certain components are preferred. These include Sunfat ^® GDC-N, Lauroglycol ^® 90, oleyl alcohol, oleic acid, alkylene polyol or ester, for example polyglycolized glycerides.

Therefore, another object of the present invention is a preparation based on cyclosporine or macrolide, which contains a composition comprising

1) cyclosporine or macrolide as an active substance; and

2) a second component selected from the group including

(I) a diester of glycerol and a C ₆ -C ₁₆ fatty acid,

(II) a monoester of propylene glycol and a C ₆ -C ₁₂ fatty acid,

(Iii) fatty acids and alcohols,

(Iv) an alkylene polyol ether or ester.

Such a composition, which is also a composition of the invention, optionally optionally may further include any other component from the above described in the above amounts.

Compositions can be prepared by the conventional method using the recipes described in WO 97/36610 (PCT / KR / 98), the contents of which are incorporated herein by reference, with the substitution of propylene carbonate for the second component.

If necessary, polyethylene glycol may also be present, which has a high boiling point and is non-volatile, as well as a cyclosporin solvent. Although any polyethylene glycol that can be liquefied may be used in the composition of the present invention, polyethylene glycol (PEG) having a molecular weight of 200 to 600, especially PEG 200, should preferably be used.

In another alternative embodiment of the present invention, a mixture of polyethylene glycol and a second component can be used as a component of the present invention, which are usually combined in a weight ratio of 1: 0.1-5, preferably 1: 0.1-3, most preferably 1 : 0.2-2.

In another alternative embodiment, the second component in the composition of the present invention can preferably be used in a ratio of from 0.1 to 10 parts by weight, more preferably from 0.5 to 8 parts by weight. and most preferably from 1 to 5 parts by weight per 1 part by weight cyclosporine.

A third component that can be used in a pre-prepared emulsion, for example, microemulsion concentrate, of the present invention, is a lipophilic, for example, oily, component. As the lipophilic, e.g., oil, component of the present invention, one compound or a mixture of two or more compounds selected from the group consisting of a fatty acid ester of a primary alcohol, medium chain fatty acid triglycerides (if present) can be used, and fatty acid monoglycerides. An ester of a fatty acid and a primary alcohol that can be used according to the present invention may include an ester of a fatty acid having from 8 to 20 carbon atoms and a primary alcohol having from 2 to 3 carbon atoms, for example, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, etc. .d., with linoleic acid and ethanol ester being particularly preferred. In addition, as a medium chain length fatty acid triglyceride (if present), a saturated fatty acid triglyceride having from 8 to 10 carbon atoms can be used, most preferably caprylic / capric triglyceride as a saturated fatty acid and vegetable oil triglyceride acids. A fatty acid monoglyceride, which can also be used as a lipophilic, for example, oil component, according to the present invention includes a fatty acid monoglyceride having from 18 to 20 carbon atoms, in particular oleic acid monoglyceride.

In the pre-prepared emulsion concentrate of the present invention, the lipophilic, for example, oily, component can be used in a ratio of from 1 to 10 parts by weight, preferably from 2 to 6 parts by weight. per 1 part by weight cyclosporine.

In another alternative embodiment of the invention, the fatty acid monoglyceride and fatty acid ester used as the lipophilic, for example, oil, component are present, for example, in a ratio of 1: 1 to 1: 2, for example, from 1: 1 to 1: 1.2.

In another alternative embodiment of the invention, caprylic / capric acid triglyceride is also optionally present, for example in a ratio of 1: 0.05-1, for example 1: 0.1-0.2 to ethyl linoleate.

In the oil mixture used as the lipophilic, for example, oil component of the present invention, the weight ratio in the mixture: fatty acid monoglyceride: fatty acid ester of primary alcohol: medium chain fatty acid triglyceride (if present) can usually be in the range 1: 0.1-5: 0.1-10, preferably in the range of 1: 0.1-3.0: 0.1-3.0.

A fourth component that can be used in the composition of the present invention is a surfactant.

Suitable surfactants for use according to the present invention include any pharmaceutically acceptable surfactants having an HLB value (hydrophilic-lipophilic balance) of from 8 to 17, which are capable of stably emulsifying the lipophilic portion of the composition, including the lipophilic containing cyclosporin, for example, oil, a component and a part comprising a second component and an auxiliary surfactant in water to form a stable microemulsion. Examples of preferred surfactants of the present invention include polyoxyethylene products of natural or hydrogenated vegetable oils, polyoxyethylene sorbitan fatty acid esters and the like, for example, Nikkol ^® HCO-50, Nikkol ^® HCO-40, Nikkol ^® HCO-60, Tween ^® 20, Tween ^® 21, Tween ^® 40, Tween ^® 60, Tween ^® 80, Tween ^® 81, etc. For example, hydrogenated castor oils containing 50 or 40 moles of ethylene oxide units sold under the trademark Nikkol ^® HCO-50 or Nikkol ^® HCO-40, respectively (NIKKO Chemical Co., Ltd), and polyoxyethylene (20) can preferably be used. sorbitan monolaurate sold under the trademark Tween 20 (ICI Chemicals), having an acid number less than 1, a saponification number of approximately 48-56, a hydroxyl number of 45-55, and a pH value (5%) of 4.5-7.0.

In yet another alternative embodiment of the invention, the surfactant may include either one of any of the above surfactants, or preferably a combination of two or more surfactants selected from the above surfactants. In the composition of the present invention, surfactants can be used in a ratio of 1 to 10 parts by weight, preferably in a ratio of 2 to 8 parts by weight. per 1 part by weight cyclosporine.

In addition, if a mixture of two surfactants is used in the composition of the present invention, for example, hydrogenated castor oil containing 50 moles of ethylene oxide units and polyoxyethylene (20) sorbitan monolaurate, the accepted weight ratio of hydrogenated castor oil containing 50 moles of ethylene oxide units and polyoxyethylene (20) sorbitan monolaurate, is preferably in the range of 1: 0.1-5, more preferably in the range of 1: 0.5-4, most preferably in the range of 1: 0.1-0.25.

In yet another alternative embodiment of the invention, in the composition of the present invention, four components are preferably present in the following weight ratio: cyclosporin or macrolide: second component: lipophilic, for example, oil component: surfactant = 1: 0.1-10: 1- 10: 1-10, and more preferably in a weight ratio of cyclosporin or macrolide: second component: lipophilic, for example, oil component: surfactant = 1: 0.5-8: 2-6: 2-8.

Another substance that, for example, can be used according to the present invention is a hydrophilic secondary surfactant, for example, a polyoxyethylene-polyoxypropylene block copolymer, a poloxamer, which is in a liquid state at room temperature. Such block copolymers are commercially available under the trademark ^{Pluronic ® L10, L31, L35,} L43, L44 ( poloxamer 124), L101, 31R1, with poloxamer 124 which is pharmaceutically acceptable, is preferably used in admixture with the second component, the above . Poloxamer 124 is also marketed under the trademark Lutrol ^® or Synperonic ^® PE L44. Poloxamer is a hydrophilic high molecular weight surfactant having a molecular weight of from 2000 to 18000, which can be used as a solvent for compounds of medical importance, lipid emulsions, ointment bases, binders or tablet coatings, gelling agent, etc. . Although the characteristics of poloxamers depend on the series number, they are heat resistant and have a flash point of 260 ° C. Unlike other poloxamers, poloxamer 124 is readily soluble in organic solvents such as propylene glycol or xylene. In addition, unlike all other solvents used in cyclosporin compositions according to the prior art, poloxamer is not hygroscopic. It does not change the accepted ratio of components due to dissolution of the shell of the gelatin capsule, leakage or evaporation.

The next object of the present invention is a composition of the present invention, which additionally contains a hydrophilic auxiliary surfactant, for example, polyoxyethylene-polyoxypropylene block copolymer.

In yet another alternative embodiment of the invention, if a mixture of the second component and a polyoxyethylene-polyoxypropylene block copolymer in a liquid state is used in the second component of the present invention, they can be combined in a mass ratio of 1: 0.1-5, preferably 1 : 0.1-3, more preferably 1: 0.1-1. Usually it is present in a concentration of 5 to 10%.

The next object of the present invention is a composition of the present invention, where the second component and a hydrophilic auxiliary surfactant, for example, polyoxyethylene-polyoxypropylene block copolymer, are combined in a mass ratio of 1: 0.1-5.

In another alternative embodiment, the weight ratio of cyclosporin to hydrophilic auxiliary surfactant in the pharmaceutical composition is preferably in the range of 1: 0.1-1, more preferably 1: 0.5-0.8.

Compositions that are pre-prepared emulsion concentrates, for example, microemulsion concentrates, for example, those described below in the examples, can have very good stability characteristics demonstrated in standard stability studies, for example, they can maintain storage stability for up to one, two or three years, and even over a longer period of time.

Compositions, which are pre-prepared microemulsion concentrates of the present invention, allow to obtain stable microemulsions that remain stable for a period of time up to one day or more, for example, one day.

The pharmaceutical composition may also include other additives or ingredients, for example, antioxidants (such as ascorbyl palmitate, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT) and tocopherols) and / or preservatives. In yet another alternative embodiment of the invention, these additives or ingredients may comprise about 0.05-1 wt.%, Based on the total weight of the composition. The pharmaceutical composition may also include sweeteners or flavoring agents in an amount up to about 2.5 or 5% by weight, based on the total weight of the composition. Preferably, the antioxidant is α-tocopherol (vitamin E).

Excipients of the invention are described in detail by Fiedler, loc. cit .; in "Handbook of Pharmaceutical Exipients", loc. cit .; or the necessary information may be obtained from the respective manufacturers, the contents of these publications and documents are incorporated into this description by reference.

Any carbon chain, unless otherwise indicated, usually contains 1-18 carbon atoms, for example, 10-18 carbon atoms, if it is an end group, or 2 or 3 carbon atoms, if it is a polymer fragment.

It should be understood that the scope of the present invention falls within

a) as component 2) - any of the components listed in subparagraphs I) -XI) individually or in combination with one, two or more other components listed in subparagraphs I) -XI),

b) as a component 3) - any of the above lipophilic components individually or in combination with others,

c) as component 4) - any of the above surfactants, for example, surfactants specified in subparagraphs I) -XIII), individually or in combination.

Pharmaceutical compositions have particularly preferred characteristics when administered orally; for example, with regard to consistency and high bioavailability, demonstrated in standard experiments on the study of bioavailability, for example, exceeding 2-4 times the corresponding characteristics of emulsions. These experiments are performed on animals, for example rats or dogs, or on healthy volunteers using HPLC or a set of specific or non-specific monoclonal antibodies to determine the level of drug in the blood, for example, the level of macrolides in the blood. For example, when administered to dogs po (orally) the compositions of Example 1 were unexpectedly obtained by ELISA using specific monoclonal antibodies with very high C _max values.

One of the objects of the present invention is a method for oral administration of a pharmaceutical composition comprising orally administering to a patient in need of treatment with cyclosporine or macrolide the composition of the present invention.

Pharmacokinetic parameters, such as absorption and blood levels, are also unexpectedly more predictable, and administration problems associated with erroneous absorption can be eliminated or reduced. In addition, pharmaceutical compositions remain effective in environments where surfactants are present, for example, bile salts present in the gastrointestinal tract. This means that the pharmaceutical compositions are completely dispersible in aqueous systems, including such natural surfactants, and therefore are capable of forming in situ microemulsion systems that are stable and in which no precipitation of the active substance or other destruction of the finely dispersed structure occurs. The functional activity of the pharmaceutical compositions upon oral administration remains practically unchanged and / or does not deteriorate in the presence or absence of bile salts at any particular time or for a particular patient.

The compositions of the present invention can reduce the variability of the reaction depending on the dose between different patients and for one patient.

The next object of the present invention is a method of reducing the variability of the levels of bioavailability of cyclosporine or macrolide for patients undergoing treatment with cyclosporine or macrolide, comprising orally administering the oral composition of the pharmaceutical composition of the present invention.

Another alternative object of the invention is also a method of preparing the above pharmaceutical composition, comprising carefully mixing (1) the second component; (2) a lipophilic component; and (3) a surfactant and the addition of an active substance, for example, cyclosporin or a compound from the macrolide class. If necessary, the composition can be prepared in the form of a standard dosage form, for example, the composition can be made in gelatin capsules.

With components (1), (2) and (3) during the addition of the active substance or after it, optionally other components or additives can be mixed, especially a hydrophilic auxiliary component, for example ethanol.

The compositions may be combined with water or with an aqueous solvent system to form an emulsion, for example a microemulsion.

The invention also provides compositions comprising a pre-prepared emulsion, for example microemulsion, concentrate, which may not contain purified fish oil and / or ethanol and / or transesterified ethoxylated vegetable oil.

When creating the invention, it was also found that stable compositions comprising macrolides can be obtained by treating the macrolide under acidic conditions. In the context of the present description, it is believed that the compositions are stable if the active substance of the drug, which is a macrolide, remains practically intact for a period of time from several days to several weeks at room temperature (25 ° C).

The acid may be fat soluble and / or soluble in ethanol. The acid may, for example, be a fatty acid, for example, oleic acid. The acid may, for example, be a carboxylic acid, for example mono-, di- or tricarboxylic acid, preferably mono- or dicarboxylic acid. An acid may have one or more hydrophilic groups, for example hydroxy groups, preferably one or two hydrophilic groups. Acids suitable for use according to the invention include malonic acid, fumaric acid, maleic acid, D-maleic acid, L-malic acid, citric acid, ascorbic acid, succinic acid, oxalic acid, benzoic acid or lactic acid, or an acid having a similar acidity number (pKa), for example, 2-7. Preferred acids include malonic acid, oxalic acid, citric acid and lactic acid. More preferred is malonic acid.

A preferred amount of acid can be determined by routine experimentation. The mass ratio of macrolide and acid in the compositions of the present invention can be up to 20: 1, for example, from 1: 5 to 5: 1, for example, 1: 1. In another alternative embodiment, the acid may be present in an amount of from 0.05% to 5%, based on the weight of the composition.

In yet another alternative embodiment, the acid may be present in an amount of from 1 to 15%, based on the weight of the composition.

The type of pharmaceutical composition is not critical. It may be solid, but preferably liquid. Macrolide, for example, can be included in the formulation in the form of a pre-prepared emulsion, for example microemulsion, concentrate or pre-prepared emulsion concentrate, as defined above, and combined with an appropriate amount of acid. The acid-stabilized composition may be administered by the enteral, for example, oral route, for example, in the form of a capsule or solution for drinking, or parenterally, for example, in the form of a concentrate for infusion. Oral administration is preferred.

The suitability of all pharmaceutical compositions of the present invention can be demonstrated in standard clinical trials, for example, by determining the doses of the active substance, giving equivalent levels of the active substance in the blood; for example, using doses in the range of 2.5 to 1000 mg of active substance per day to a mammal weighing 75 kg, for example, an adult mammal, as well as standard models using animals. The increased bioavailability of the active substance provided by the compositions can be detected in standard animal experiments and in clinical trials, for example according to the methods described above.

The optimal doses of the active substance that should be administered to a particular patient should be carefully determined taking into account the individual reaction and metabolism of macrolide, for example, rapamycin, and they can vary. It is advisable to monitor the levels of the active substance in blood serum using radioimmunoassay analysis, analysis using monoclonal antibodies or other appropriate methods. Typically, macrolide doses range from 1 mg to 1000 mg per day, for example, from 2.5 mg to 1000 mg per day for an adult patient weighing 75 kg, preferably from 25 mg to 500 mg, with an optimal dose of approximately 50-100 mg per day. Satisfactory results are obtained with the administration of approximately 75 mg per day, for example, in the form of two capsules, one of which contains 50 mg and the other contains 25 mg; or three capsules, each containing 25 mg. Dosages of cyclosporin can be from 25 to 1000 mg per day (preferably from 50 mg to 500 mg), and doses of FK 506 can be from 2.5 to 1000 mg per day (preferably from 10 mg to 250 mg). With the introduction of 40-O- (2-hydroxy) ethylrapamycin, daily doses from 0.5 to 5 mg / kg body weight / day are indicated.

The pharmaceutical compositions are preferably prepared in unit dosage form, for example, by filling capsule shells for oral administration. The capsule shells may be hard or soft gelatin capsule shells. If the pharmaceutical composition is in the form of a unit dosage form, it is convenient that each unit dosage form contains from 10 to 100 mg of active ingredient, more preferably from 10 to 50 mg, for example, 15, 20, 25 or 50 mg. Such unit dosage forms are suitable for administration 1-5 times per day depending on the specific purpose of the treatment, phase of treatment, and the like.

However, if necessary, the pharmaceutical compositions may be in the form of a solution for drinking and may include water or any other aqueous system to form an emulsion, for example microemulsion, drinkable system.

The pharmaceutical compositions are most suitable for the treatment and prevention of the conditions described on pages 40 and 41 of EP 427680 and on pages 5 and 6 of PCT / EP93 / 02604, the contents of these applications are incorporated herein by reference.

Pharmaceutical compositions are most suitable for:

a) treating and preventing organ or tissue transplant rejection, for example, for treating recipients of heart, lung, heart-lung, liver, kidney, pancreatic, skin, or corneal transplants. Pharmaceutical compositions are also indicated to prevent graft versus host disease, which sometimes occurs after bone marrow transplantation;

b) treating and preventing autoimmune disease and inflammatory conditions, especially those whose etiology includes an autoimmune component, such as arthritis (for example, rheumatoid arthritis, chronic progressive arthritis and deforming arthritis) and rheumatoid diseases; and

c) treatment of multiple drug resistance (MDR).

Another object of the present invention is the use of the composition of the present invention for the preparation of a medicament for the treatment and prevention of an autoimmune disease or inflammatory condition, or for the treatment and prevention of transplant rejection, or for the treatment of multiple drug resistance.

Macrolides as active substances also have antitumor and antifungal activity and therefore pharmaceutical compositions can be used as antitumor and antifungal agents.

The contents of all the references cited above, especially regarding the compounds cited as examples, are incorporated by reference in the present description, and each of the compounds cited as examples can be used as macrolide in the examples below.

Examples

The following is a description of the compositions of the present invention, given for illustration only. Unless otherwise indicated, the content of the components is indicated in wt.% In terms of the weight of each composition.

Miglyol ^® 812 is supplied by Condea, Germany.

Labrafil ^® M 2125 CS, Gelucire ^® 44/14, Maisine ^® , Lauroglycol ^® 90 is supplied by Gattefosse, France.

Tegin ^® O is a representative monoglyceride with a purity of approximately 55-65%, the remainder includes diglycerides, supplied by Goldschmidt, Essen, Germany.

Neobee ^® M-5 F is supplied by Stepan Europe, France.

GMOrphic ^® 80 is a representative monoglyceride with a purity of about 94%, the remainder includes diglycerides, available from Eastman Chemicals Co., Kingsport, CN, USA.

Synperonic ^® PE L44 is a representative poloxamer, supplied by ICI, UK.

Simulsol ^® O1-50 is available from Seppic, France.

Cremophor ^® RH 40 is supplied by BASF, Germany.

Sunfat ^® GDC-N is supplied by Taijo Kagaku Co., Japan.

Cetiol ^® HE is supplied by Henkel KGaA, Germany.

Particle sizes are measured at 20 ° C. by diluting 1 ml of the composition with 10-100 ml of water using photon correlation spectroscopy using, for example, a Malvern ZetaSizer No. 3 instrument from Malvern Instruments.

Example 1

Obtaining solutions for drinking, intended for oral administration.

Prepare compositions having the following composition of the components. Some compositions are cloudy, but when diluted 1:10, optionally when heated to 40 ° C, they form an incompletely transparent or translucent liquid containing particles, the size of which is measured using ZetaSizer.

These compositions may be enclosed in hard and soft coated gelatin capsules.

Other examples are compositions obtained by excluding Synperonic ^® PE L44, GMOphph ^® 80, Tegin ^® 0, Labrafil ^® M 2125 CS, α-tocopherol, ethanol, propylene glycol.

Still other examples of compositions can be created by replacing triethyl citrate, N-methylpyrrolidone, Sunfat ^® GDC-N, Lauroglycol ^® 90, oleyl alcohol, Cetiol ^® HE, acetyl triethyl citrate, benzyl alcohol or oleic acid with any of the above second components.

The examples illustrate compositions suitable, for example, for preventing transplant rejection or for treating autoimmune disease by administering 1-5 unit dosage forms / day in a dose of 2 to 5 mg / kg / day. The examples described specifically use cyclosporine, however, equivalent compositions can be prepared using any macrolide or other active substance.

According to visual inspection, each composition after dilution forms a transparent and stable microemulsion.

Claims (38)

1. The composition in the form of an emulsion or microemulsion pre-prepared concentrate, intended for oral administration, which includes 1) cyclosporine or macrolide and a carrier comprising 2) a second component selected from the group comprising (I) triethyl citrate or acetyl triethyl citrate, (II) mixed ether C ₆ -C ₁₀ fatty acid, polyethylene glycol and glycerol, (III) a diester of glycerol and C ₆ -C ₁₆ fatty acid, (IV) and glycerol monoester of a C ₆ -C ₁₄ fatty acids, (V) a mixture of mono- and diglycerides C ₆ - C ₁₆ fatty acids, (VI) complex mono-ester of propylene glycol and C ₆ -C ₁₂ fatty acids, (VII) fatty acids and alcohols, (VIII) N-methylpyrrolidone, (IX) glycerol triacetate, (X) benzyl alcohol, and (XI) natural or hydrogenated olive transesterification product, almond, fir, coconut, palm, palm kernel, soy beans or from wheat germ oil and poly (C ₂ -C ₄ alkylene) glycol and optionally glycerol, and 3) a lipophilic component, and 4) a surfactant, provided that if component 2) (a) is triethyl citrate, then the composition free or substantially free of ethanol; (b) is a mixture of mono- and diglycerides of C ₈ -C ₁₀ fatty acids, the composition does not contain a C ₆ -C ₁₂ fatty acid triglyceride; (c) is N-methylpyrrolidone, the composition is in the form of a microemulsion pre-prepared concentrate. 2. The composition according to claim 1, in which the lipophilic component is selected from the group comprising (I) transesterified ethoxylated vegetable oil, (II) mixed mono-, di- and triglycerides, (III) propylene glycol esters of mono- and fatty acids and ( Iv) ester compounds of fatty acid and primary alcohol. 3. The composition according to claim 1 or 2, further comprising one or more antioxidants selected from the group consisting of ascorbyl palmitate, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT) and tocopherols in an amount of from 0.05 to 1 wt.% In terms of total weight of the composition. 4. The composition according to claim 3, where α-tocopherol is present as an antioxidant. 5. The composition according to any one of the preceding paragraphs, comprising cyclosporine or macrolide in an amount of from 1 to 15%, based on the weight of the composition. 6. The composition according to any one of the preceding paragraphs, where the second component is present in an amount of from 5 to 50%, the lipophilic component in an amount of from 5 to 85%, and the surfactant in an amount of from 5 to 80%, based on the weight of the carrier. 7. The composition according to any one of the preceding paragraphs, where the relative ratio of cyclosporine or macrolide, the second component, lipophilic component and surfactant in the composition is such that after dilution with water in a ratio of 1 wt.h. composition for 1-10 parts by weight water spontaneously forms an oil / water microemulsion having an average particle size of less than 200 nm. 8. The composition according to any one of the preceding paragraphs, where cyclosporin is cyclosporin A. 9. The composition according to any one of the preceding paragraphs, where the surfactant is selected from the group comprising (I) products of the interaction of natural or hydrogenated vegetable oil and ethylene oxide and (II) polyoxyethylene sorbitan esters and fatty acids. 10. The composition according to any one of the preceding paragraphs, where the mass ratio of cyclosporine or macrolide: the second component: lipophilic component: surfactant is 1: 0.1-10: 1-10: 1-10. 11. The composition according to any one of the preceding paragraphs, which additionally contains a hydrophilic auxiliary surfactant. 12. The composition according to claim 11, where the hydrophilic auxiliary surfactant is a polyoxyethylene / polyoxypropylene block copolymer. 13. The composition according to claim 11 or 12, where the second component and the hydrophilic auxiliary surfactant are combined in a mass ratio of from 1: 0.1 to 5. 14. The composition according to any one of the preceding paragraphs in the form of a standard dosage form. 15. The composition according to any one of the preceding paragraphs, where the second component comprises the product of transesterification of hydrogenated palm kernel oil and / or hydrogenated palm oil with polyethylene glycol 1500. 16. The composition according to any one of the preceding paragraphs, where the macrolide is rapamycin, 40-O- (2-hydroxyethyl) -rapamycin, FK506 or 33-epichloro-33-deoxycoscomycin. 17. A soft or hard gelatin capsule comprising a composition in the form of an emulsion or microemulsion pre-prepared concentrate comprising 1) cyclosporine or macrolide and a carrier comprising 2) a second component selected from the group consisting of (I) triethyl citrate or acetyl triethyl citrate, (II) mixed C ₆ -C ₁₀ fatty acid, polyethylene glycol and glycerol ester, (III) glycerol diester and C ₆ -C ₁₆ fatty acid, (IV) glycerol mono-ester and C ₆ -C ₁₄ fatty acid, (V) a mixture of mono- and diglycerides of C ₆ -C ₁₆ fatty acids, (VI) mono-ester of propylene glycol and C ₆ -C ₁₂ fatty acids, (VII) fatty acids and alcohols, (VIII) N-methylpyrrolidone, (IX) glycerol triacetate, (X) benzyl alcohol, and (XI) natural or hydrogenated olive transesterification product, almond, fir, coconut, palm, palm kernel, soya beans or wheat germ oil and poly (C ₂ -C ₄ alkylene) glycol and optionally glycerol, and 3) a lipophilic component, and 4) a surfactant, provided that if component 2) (a) is triethyl citrate, then the composition tion is free or substantially free of ethanol; (b) is a mixture of C ₈ -C ₁₀ fatty acid mono- and diglycerides, the composition does not contain C ₆ -C ₁₂ fatty acid triglyceride. 18. A method of reducing the variability of the level of bioavailability of cyclosporine or macrolide in patients during therapy with cyclosporine or macrolide, which includes oral administration of an oral pharmaceutical composition according to any one of claims 1 to 17. 19. A method for oral administration of a pharmaceutical composition comprising orally administering to a patient in need of treatment with cyclosporine or macrolide a composition according to any one of claims 1-17. Priority on points and signs: 1. The second component: (I) triethyl citrate 03/06/1998 or acetyl triethyl citrate 03/04/1999; (II) 03/04/1999; (III) 03/04/1999; (IV) 03/04/1999; (V) 03/04/1999; (VI) 03/04/1999; (VII) 03/11/1998; (VIII) 03/11/1998; (IX) 03/11/1998; (X) 03/04/1999; (XI) 03/04/1999; 02.03.1998; 3.03.03.1998; 4.6.03.1998; 05.03.1998; 06.03.1998; 07.03.1998; 8. March 6, 1998; 9.03.03.1999; 10.03.03.1998; 11.03.03998; 12. March 6, 1998; 13..03.03.1998; 14..03.03.1998; 15.03.03.1999; 16. March 6, 1998; 17. different parts of priorities as for claim 1; 18. March 04, 1999; 19.03.03. 1999.