MXPA00008735A

MXPA00008735A - Emulsion preconcentrates containing cyclosporin or a macrolide

Info

Publication number: MXPA00008735A
Application number: MXPA/A/2000/008735A
Authority: MX
Inventors: Michael Ambuhl; Barbara Luckel; Friedrich Richter; Barbara Haberlin; Armin Meinzer
Original assignee: Novartis Ag
Priority date: 1998-03-06
Filing date: 2000-09-06
Publication date: 2001-07-09

Abstract

This invention provides an emulsion, e.g. microemulsion, pre-concentrate comprising a difficultly soluble active agent and a carrier medium. The active agent may e.g. be a cyclosporin or a macrolide.

Description

PRECONCENTRATES IN EMULSION CONTAINING CYCLOSPORINE OR A MACROLIDE The present invention relates to novel galenic compositions, in particular to novel galenic compositions wherein the active ingredient is a difficultly soluble active agent, for example, a macrolide, or in particular an undecapeptide cyclic poly-N-methylated, or a cyclosporin. Cyclosporins also include peptide variants. See, for example, the Patent Publications of Great Britain Nos. 2,222,770 and 2,257,359 A, and their equivalents throughout the world. As discussed in such British Patent publications, cyclosporins present highly specific difficulties in relation to their administration in general, and to their galenic composition in particular, including in particular problems of stability, bioavailability of the drug, and variability in the response at the intra- and intra-patient doses. In order to solve these and other related difficulties, in Patent Publications of Great Britain Nos. 2,222,770 and 2,257,359 A, galenic compositions comprising a cyclosporin as an active ingredient, and taking the form of, inter alia, an emulsion, for example a microemulsion, or an emulsion preconcentrate, for example in microbemulsion. These compositions typically comprise: 1) a hydrophilic component, 2) a lipophilic component, and 3) a surfactant. In accordance with the present invention, it has now been surprisingly found that galenic compositions particularly stable in emulsion, for example in microemulsion, or in emulsion preconcentrate, for example in microemulsion, can be obtained with hardly soluble active agents having bioavailability characteristics particularly interesting and a reduced variability in the inter- and intra-subject bioavailability parameters, using at least one component selected from the group consisting of: (i) triethyl citrate or acetyltriethyl citrate, (ii) glyceryl ester of the fatty acid of polyethylene glycol, (iii) fatty acid glyceryl ester, (iv) glyceryl monoester of the fatty acid, (v) a mixture of mono- and di-glycerides of the fatty acids, (vi) monoester of the propylene glycol fatty acid, (vii) fatty acids and alcohols,. { viii) N-methylpyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) ether or ester of alkylene polyol, for example polyglycolized glycerides, hereinafter referred to as the "secondary component". In accordance with the present invention, it has surprisingly been found that these systems in emulsion, for example in microemulsion, in contrast to the teaching of the art, in practice can actually be prepared from any of the components specified above. as a second component. The present invention provides in one aspect, a pharmaceutical composition that is a preconcentrate in emulsion, for example in microemulsion, comprising: 1) a hardly soluble active agent, and a carrier medium, which comprises: 2) a second component, ) a lipophilic component, and 4) a surfactant. The second component is, for example: i) triethyl citrate or acetyltriethyl citrate, and / or ii) glyceryl ester of the polyethylene glycol fatty acid, for example mono- and / or di- and / or fatty acid tri-ester, example, from 6 to 10 carbon atoms, for example from 8 to 10 carbon atoms, for example from 5 to 10 units [CH2-CH2-0], for example 7 units, for example Cetiol® HE, or Labrasol® , and / or iii) glyceryl diester of the fatty acid, for example from 6 to 16 carbon atoms, for example from 8 to 10 carbon atoms, for example from 8 carbon atoms, for example Sunfat® GDC-N, and / or iv) glyceryl monoester of the fatty acid, for example from 6 to 14 carbon atoms, for example from 8 to 10 carbon atoms, for example Imwitor® 308, or Imitor® 310, and / or v) a mixture of mono- and di-glycerides of the fatty acids, for example from 6 to 16 carbon atoms, for example from 8 to 10 carbon atoms, for example Imwitor® 742, or Capmul® MCM, and / or vi) monoester of the propylene glycol fatty acid, for example from 6 to 12 carbon atoms, for example from 8 to 12 carbon atoms, for example Lauroglycol® 90, Sefsol® 218, or Capryol® 90, and / or vii) fatty acids or alcohols, for example from 6 to 20 carbon atoms, saturated or mono- or di-unsaturated, for example oleic acid, oleyl alcohol, linoleic acid, capric acid, caprylic acid, caproic acid, tetradecanol, dodecay nol, decanol, and / or viii) N-alkylpyrrolidone, for example N-methylpyrrolidone, for example Pharmasolve®, and / or ix) glycerol triacetate, for example Triacetin, and / or x) benzyl alcohol, and / or xi ) ether or ester of alkylene polyol, for example polyglycolized glycerides, for example Gelucire® 44/14.

According to the foregoing, the present invention provides, in one aspect, a composition in the form of an emulsion or microemulsion preconcentrate for oral administration, which comprises: 1) a cyclosporin or a macrolide, and a carrier medium, which comprises: 2) a second component selected from the group consisting of: (i) triethyl citrate or acetyltriethyl citrate, (ii) glyceryl ester of the fatty acid of 6 to 10 carbon atoms of polyethylene glycol, (iii) glyceryl diester of the fatty acid of 6 to 16 carbon atoms, (iv) glyceryl monoester of the fatty acid of 6 to 14 carbon atoms, (v) a mixture of mono- and di-glycerides of the fatty acids of 6 to 16 carbon atoms, ( vi) monoester of the fatty acid of 6 to 12 carbon atoms propylene glycol, (vii) fatty acids and alcohols, (viii) N-methylpyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) ether or ester of alkylene polyol, 3) a lip component ofilic, and 4) a surfactant, with the proviso that, when component 2): (a) consists of triethyl citrate, the composition is free or substantially free of ethanol, and / or (b) consists of a mixture of mono- and diglycerides of the fatty acids of 8 to 10 carbon atoms, the composition is free or substantially free of a triglyceride of the fatty acid of 6 to 12 carbon atoms.

In accordance with the present invention, it has surprisingly been found that a cyclosporin or a macrolide has a high solubility, for exe a solubility of about 20 to about 50 percent, in the second component of the present invention. For exe, the solubility of a cyclosporin or of a macrolide in triethyl citrate is about 35 percent, in Sunfat® GDC-N it is about 33 percent, in Lauroglycol® 90 it is about 40 percent, in oleic acid is approximately 40 percent, in N-methylpyrrolidone it is approximately 50 percent, in Labrasol it is approximately 20 percent, in Dodecanol it is approximately 37.5 percent, in Tetradecanol it is approximately 37.5 percent, in Sefsol® 218 is approximately 50 percent, in Cetiol® HE it is approximately 32.5 percent, and in oleyl alcohol it is greater than 20 percent.

According to the above, the present invention provides, in one aspect, a composition in the form of an emulsion or microemulsion preconcentrate for oral administration, which comprises: 1) a cyclosporin, or a macrolide, and a carrier medium, which comprises: 2) a second component, wherein component 1) has a solubility of from about 20 to about 50 percent, 3) a lipophilic component, and 4) a surfactant.

Preferably, the composition is in the form of a "preconcentrate emulsion, for exe in microemulsion", of the type that provides emulsions, for exe microemulsions of ac / a (oil in water). However, the composition may be in the form of an emulsion, for exe a microemulsion, which additionally contains an aqueous component; preferably water. A "preconcentrate in emulsion, for exe in microemulsion" is defined herein as a composition that spontaneously forms an emulsion, for exe a microemulsion, in an aqueous medium, for exe in water, for exe when diluted from 1: 1 to 1:10, for exe at 1:10, or in gastric juices after oral application.

A microemulsion is thermodynamically stable and contains dispersed particles of an average size of less than about 200 nanometers. In general, microemulsions comprise droplets or particles having an average diameter of less than about 150 nanometers; usually less than 100 nanometers, generally greater than 10 nanometers, and are stable for periods longer than 24 hours. A "microemulsion" can be a non-opaque or substantially non-opaque colloidal dispersion, and alternatively it may be translucent, which forms spontaneously or in a substantially spontaneous manner when its components come into contact. Additional features can be found in the aforementioned British Patent Application Number 2,222,770, the disclosure of which is incorporated herein by reference. In one aspect, the present invention provides a composition according to the present invention, the proportion relative to cyclosporin or macrolide, the second component, the lipophilic component, and the surfactant in this composition, such that, when diluted with water up to a proportion of 1 part by weight of this composition to 1 to 10 parts by weight of water, an oil-in-water microemulsion is spontaneously formed having particles of an average size of less than 200 nanometers. In a further alternative aspect, the lipophilic component can comprise from 5 to 85 weight percent of the carrier medium, for example from 10 to 85 percent; preferably from 15 to 70 weight percent, more preferably from 20 to 60 weight percent, and still more preferably from about 25 weight percent. In a further alternative aspect, the surfactant may comprise from 5 to 80 weight percent of the carrier medium; preferably from 10 to 70 weight percent, more preferably from 20 to 60 weight percent, and still more preferably from about 40 weight percent. In a further alternative aspect, the second component may comprise from 5 to 50 weight percent of the carrier medium, for example from 10 to 50 percent; preferably from 15 to 40 percent by weight, more preferably from 20 to 35 percent by weight. In one aspect, the present invention provides a composition according to the present invention, comprising the second component in an amount of 5 to 50 percent, the lipophilic component in an amount of 5 to 85 percent, and the surfactant in a amount from 5 to 80 weight percent of the carrier medium. The active agent may be present in a weight amount of up to about 20 weight percent of the composition. The active agent is preferably present in an amount of from 1 to 15 weight percent of the composition, for example from about 2 to 10 percent. In one aspect, the present invention provides a composition according to the present invention, which comprises cyclosporin or macrolide in an amount of 1 to 15 weight percent of the composition. The difficultly soluble active agent is preferably a lipophilic drug, for example a cyclosporin or a macrolide. The term "sparingly soluble", as used herein, is understood as a solubility in water at 20 ° C less than 1, for example 0.01 weight percent / volume. The cyclosporins to which the present invention is applied are any of those having pharmaceutical utility, for example, as immunosuppressive agents, antiparasitic agents, and agents for reversing multidrug resistance, as known and described in the art, particular Cyclosporin A (also known as, and later referred to herein as, Cyclosporin), Cyclosporin G, [0- (2-hydroxyethyl) - (D) Ser] 8-Ciclosporin, and [3'-dehydroxy-3 '- keto-MeBmt] 1- [Val] -Cyclosporin. Cyclosporin is preferred. In one aspect, the present invention provides a composition according to the present invention, wherein the cyclosporin is Cyclosporin A. The term "macrolide", as used herein, refers to a macrocyclic lactone, for example a compound that has a lactone ring of 12 members or greater. Of particular interest are "lactam macrolides", ie, macrocyclic compounds having a lactam (amide) bond in the macrocycle in addition to a lactone (ester) bond, for example lactam macrolides produced by microorganisms. of the genus Streptomyces, such as rapamycin, ascomycin, and FK-506, and their numerous derivatives and analogues. It has been demonstrated that these lactam macrolides have interesting pharmaceutical properties, particularly immunosuppressive and anti-inflammatory properties. Rapamycin is an immunosuppressive lactam macrolide that is produced by Streptoipyces hygroscopicus. The structure of rapamycin is given in Kesseler, H., et al .; 1993; Helv., Chim. Minutes: 76: 117. See, for example, McAlpine, J.B. and collaborators, J. Antibiotics (1991) 44: 688; Schreiber, S.L., et al., J. Am. Chem. Soc. (1991) 113: 7433; the United States Patent of North America Number 3,929,992. Rapamycin is an extremely potent immunosuppressant, and has also been shown to have antitumor and antifungal activity. However, its usefulness as a pharmaceutical product is restricted by its very low and variable bioavailability, as well as by its high toxicity. Moreover, rapamycin is highly insoluble, making it difficult to formulate stable galenic compositions. Numerous rapamycin derivatives are known. Certain 16-0-substituted rapamicines are disclosed in International Publication Number WO 94/02136, the content of which is incorporated herein by reference. 40-O-substituted rapa icines are described, for example, in U.S. Patent No. US 5,258,389, and in International Publication Number WO 94/09010 (0-aryl- and 0-alkyl-rapamycins); in International Publication Number WO 92/05179 (carboxylic acid esters), US Pat. No. 5,118,677 (amide esters), US Pat. No. US 5,118,678 (carbamates), in U.S. Patent Number 5,100,883 (Fluorinated Esters), in U.S. Patent Number US 5,151,413 (Acétal), U.S. Patent Number 5,120,842 (Silyl Ether), in US Pat. Publication International Number WO 93/11130 (methylene-rapamycin and its derivatives), in International Publication Number WO 94/02136 (methoxyl derivatives), in International Publication Number WO 94/02385 and in International Publication Number WO 95/14023 (alkenyl derivatives), all of which are incorporated herein by reference. 32-O-dihydro-substituted rapamycins are described, for example, in U.S. Patent No. 5,256,790, incorporated herein by reference. Rapamycin and its structurally similar analogs and their derivatives are collectively referred to as "rapamycins". Ascomycins, of which FK-506 and ascomycin are the best known, comprise another class of lactam macrolides, many of which have immunosuppressive and anti-inflammatory activity. FK-506 is an immunosuppressant of lactam macrolide that is produced by Streptomyces tsukubaensis No. 9993. The structure of FK-506 is given in the appendix of the Merck Index, 11th edition (1989) as article A5. Ascomycin is described, for example, in U.S. Patent No. 3,244,592. Many derivatives of ascomycin and FK-506 have been synthesized, including halogenated derivatives, such as 33-epi-chloro-33-deoxy-ascomycin described in European Patent Number EP-427,680. Ascomycin, FK-506, and its structurally similar analogs and their derivatives are collectively referred to as "ascomycins". Accordingly, the macrolide can be rapamycin or an O-substituted derivative, wherein the hydroxyl group on the cyclohexyl ring of rapamycin is replaced by -ORi, wherein R is hydroxyalkyl, hydroalkoxyalkyl, acylaminoalkyl, and aminoalkyl; for example, 40-0- (2-hydroxy) ethyl-rapamycin, 40-O- (3-hydroxy) propyl-rapamycin, 40-O- [2- (2-hydroxy) ethoxy] ethyl-rapamycin, and 40-O- (2-acetaminoethyl) -rapamycin. A preferred compound is 40-O- (2-hydroxy) ethyl-rapamycin, as disclosed in International Publication. Examples of the compounds of class FK-506 are those mentioned above. These include, for example, FK-506, ascomycin, and other naturally occurring compounds. They also include synthetic analogs. A preferred compound of class FK-506 is disclosed in European Patent Number EP-427,680, for example in Example 66a, also known as 33-epi-chloro-33-deoxy-ascomycin. Other preferred compounds are disclosed in European Patent Numbers EP 465, 426, and in EP 569,337, for example the compound of Example 71 of European Patent Number EP 569,337. The second component can be any of the components i) to xi), individually or in combination with one, two, or more of the other components i) to xi). Examples of the second components suitable for use in this invention are: i) triethyl citrate or acetyltriethyl citrate. They can be obtained by the esterification of citric acid and ethanol, or the esterification of citric acid and ethanol, followed by acetylation with acetic anhydride, respectively. Triethyl citrate or acetyltriethyl citrate are commercially available, for example under the trade names Citroflex® 2 or Citroflex® A-2, or triethyl citrate in a pharmaceutical grade under the name TEC-PG / N, for example , Morflex Inc. Particularly 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 (25 ° C) of 35.2 mPa s, test ( anhydrous base) from 99.0 to 100.5 percent, maximum water 0.25 percent (Fiedler, HP, "Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete", Editio Cantor Verlag Aulendorf, Aulendorf, 4th edition revised and expanded (1996) , volume 1, page 371; "Handbook of Pharmaceutical Excipients", 2nd edition, editors A. Wade and P.J. Weller (1994), joint publication of the American Pharmaceutical Association, Washington, USA, and The Pharmaceutical Press, London, England, page 540). ii) glyceryl ester of the fatty acid of 6 to 10 carbon atoms of polyethylene glycol. The fatty acid ester can include mono- and / or di- and / or tri-ester fatty acid. The fatty acid constituent can include both saturated and unsaturated fatty acids having a chain length, for example, from 8 to 10 carbon atoms. The polyethylene glycols can have, for example, from 5 to 10 units [CH2-CH2-0], for example 7 units. Particularly suitable is polyethylene glycol glyceryl monocoat (7), which is commercially available, for example, under the tradename Cetiol® HE, for example from Henkel KGaA. Cetiol® HE has a D. (20 °) of 1.05, an acid value of less than 5, a saponification value of about 95, a hydroxyl value of about 180, and an iodine value less than 5 (H. Fiedler , loe cit, volume 1, page 337). A transesterified polyethoxyethylated caprylic-capric acid glyceride, commercially available under the tradename Labrasol® from, for example Gattefossé, is also suitable. Labrasol® has a maximum acid value of 1, a saponification value of 90-110, and a maximum iodine value of 1 (H. Fiedler, loe cit, volume 2, page 880). iii) glyceryl diester of the fatty acid of 6 to 16 carbon atoms. Suitable diglycerides for use in the compositions of the invention include both symmetric (ie, a, o1-diglyceride) and asymmetric diglycerides (ie, a, β-diglycerides), and acetylated derivatives thereof. They also include both uniform glycerides (wherein the fatty acid constituent is primarily composed of a single fatty acid), and mixed glycerides (ie, wherein the fatty acid constituent is composed of different fatty acids), and the derivatives acetylated thereof. The fatty acid constituent can include both saturated and unsaturated fatty acids having a chain length, for example, from 6 to 16 carbon atoms, for example from 8 to 10 carbon atoms, for example from 8 carbon atoms. Particularly suitable is the caprylic diglyceride which is commercially available, for example under the trade name Sunfat® GDC-N, for example from Taiyo Kagaku Co., Ltd. Sunfat® GDC-N has an acid value of about 0.3, a diglyceride content of about 78.8 percent, and a monoester content of about 8.9 percent. iv) glyceryl monoester of the fatty acid of 6 to 14 carbon atoms. These can be obtained by esterification of glycerol with vegetable oil, followed by molecular distillation. Suitable monoglycerides for use in the compositions of the invention include both symmetric (i.e., β-monoglycoxides), and asymmetric monoglycerides (α-monoglycerides), and acetylated derivatives thereof. They also include both uniform glycerides (wherein the fatty acid constituent is composed primarily of a single fatty acid), and mixed glycerides (ie, wherein the fatty acid constituent is composed of different fatty acids), and acetylated derivatives of the fatty acids. same. The fatty acid constituent can include both saturated and unsaturated fatty acids having a chain length, for example, from 8 to 10 carbon atoms. Particularly suitable are the monoglycerides of caprylic or capric acid which are commercially available, for example under the trade names Imwitor® 308 or Imwitor® 310, respectively, from, for example, Condea. For example, Imwitor® 308 comprises at least 80 percent monoglycerides, and exhibits the following additional characterization data: maximum free glycerol 6 percent, maximum acid value 3, saponification value of 245-265, maximum iodine value of 1, maximum water content of 1 percent. It normally comprises 1 percent free glycerol, 90 percent monoglycerides, 7 percent diglycerides, 1 percent triglycerides (H. Fiedler, loe cit, volume 1, page 798). v) a mixture of mono- and di-glycerides of the fatty acids of 6 to 16 carbon atoms. The mixed mono- and di-glycerides suitable for use in the compositions of the invention include both symmetrical mono- and di-glycerides (ie, β-monoglycerides and, 1-diglycerides) and asymmetric (i.e., α-monoglycerides already, β-diglycerides), and acetylated derivatives thereof. They also include both uniform glycerides (wherein the fatty acid constituent is composed primarily of a single fatty acid), and mixed glycerides (ie, wherein the fatty acid constituent is composed of different fatty acids), and acetylated derivatives of the fatty acids. same. The fatty acid constituent can include both saturated and unsaturated fatty acids having a chain length, for example, from 8 to 10 carbon atoms. Particularly suitable are mono- and di-glycerides of caprylic acid and capric mixed, as are commercially available, for example, under the trade name Imwitor® 742 from, for example, Condea. For example, Imwitor® 742 comprises at least 45 percent monoglycerides, and exhibits the following additional characterization data: maximum free glycerol 2 percent, maximum acid value 2, saponification value 250-280, iodine value maximum of 1, maximum water 2 percent (H. Fiedler, ioc cit, volume 1, page 798). In addition, the ono / diglyceride of caprylic / capric acid in glycerol is suitable, as is known and commercially available, for example, under the tradename Capmul® MCM from, for example, Abitec Corporation. Capmul® MCM exhibits the following additional characterization data: maximum acid value of 2.5, alpha-Mono (as oleate) minimum of 80 percent, maximum free glycerol of 2.5 percent, maximum iodine value of 1, chain length distribution : caproic acid (6 carbon atoms) maximum of 3 percent, caprylic acid (8 carbon atoms) minimum of 75 percent, capric acid (10 carbon atoms) minimum of 10 percent, lauric acid (12 carbon atoms) ) maximum of 1.5 percent, humidity (using Karl Fisher) maximum of 0.5 percent (manufacturer information). vi) monoester of the fatty acid of 6 to 12 carbon atoms of propylene glycol. The fatty acid constituent can include both saturated and unsaturated fatty acids having a chain length, for example, from 8 to 12 carbon atoms. Particularly suitable are the propylene glycol monoester of caprylic and lauric acid, as are commercially available, for example, under the tradenames Sefsol® 218, Capryol® 90, or Lauroglycol® 90, from, for example, Nikko Chemicals Co., Ltd. or Gattefossé. For example, Lauroglycol®90 exhibits the following additional characterization data: maximum acid value of 8, saponification value of 200-220, maximum iodine value of 5, maximum free propylene glycol content of 5 percent, minimum monoester content of the 90 percent; Sefsol® 218 exhibits the following additional characterization data: maximum acid value of 5, hydroxyl value of 220-280 (H. Fiedler, loe cit, volume 2, page 906, manufacturer's information). vii) fatty acids and / or alcohols. Fatty acids can be obtained by the hydrolysis of different animal and vegetable fats or oils, such as olive oil, followed by the separation of liquid acids. The fatty acid / alcohol constituent can include both saturated and mono- or di-unsaturated fatty acids / alcohols having a chain length, for example, from 6 to 20 carbon atoms. Particularly suitable, for example, are oleic acid, oleyl alcohol, linoleic acid, capric acid, caprylic acid, caproic acid, tetradecanol, dodecanol or decanol. For example, oleyl alcohol is commercially available under the trademark HD-Eutanol® V from, for example, Henkel KGaA. The oleyl alcohol exhibits the following additional characterization data: maximum acid value of 0.1, hydroxyl value of approximately 210, iodine value of approximately 95, maximum saponification value of 1, D.20 of approximately 0.849, nD20 of 1.462, weight molecular weight of 268, viscosity (20 ° C) of about 35 mPa s (manufacturer information). Oleic acid exhibits the following additional characterization data: Molecular weight of 282.47, D.20 of 0.895, nD20 of 1.45823, acid value of 195-202, iodine value of 85-95, viscosity (25 ° C) of 26 mPa s (H. Fiedler, loe cit, volume 2, page 1112; Handbook of Pharmaceutical Excipients, loe, cit, page 325). viii) -alkylpyrrolidone. Particularly suitable, for example, is N-methyl-2-pyrrolidone, for example as is commercially available under the tradename Pharmasolve "1, from, for example, International Specialty Products (ISP) .N-methylpyrrolidone exhibits the following data of additional characterization: molecular weight of 99.1, D 25 of 1. 027-1.028, purity (as percentage of area by gas chromatography) (including methyl isomers) of minimum 99.85 percent (H. Fiedler, loe cit, volume 2, page 1004, manufacturer's information). ix) glycerol triacetate or (1, 2, 3) -triacetin. It can be obtained by esterification of glycerin with acetic anhydride. Glycerol triacetate is commercially available as, for example, Priacetin® 1580 from Unichema International, or as Eastman Triacetin from Eastman, or from Courtaulds Chemicals Ltd. Glycerol triacetate exhibits the following additional characterization data: molecular weight of 218.03, D .20.3 of 1,159-1,163, nD20 of 1,430-1,434, maximum water content of 0.2 percent, viscosity (25 ° C) of 17.4 mPa s, maximum acid value of 0.1, saponification value of approximately 766-774, minimum triacetin content of 97 percent (H. Fiedler, loe cit, volume 2, page 1580; Handbook of Pharmaceutical Excipients, loc cit, page 534, manufacturer information). x) benzyl alcohol. It can be obtained by distillation of benzyl chloride with potassium or sodium carbonate. Benzyl alcohol is commercially available, for example, from Merck. Benzyl alcohol exhibits the following additional characterization data: molecular weight of 108.14, D. 1.043-1.049, nD 1.538-1.541 (H. Fiedler, loe cit, volume 1, page 238; Handbook of Pharmaceutical Excipients, loe cit, page 35 ). xi) ether or ester of alkylene polyol. It can suitably be an ether or alkylene-triol ester of 3 to 5 carbon atoms, in particular glycerol. Suitable ether or alkylene-triol ester of 3 to 5 carbon atoms includes mixed ethers or esters, ie, components that include other ether or ester ingredients, for example the transesterification products of alkylene-triol esters of 3 to 5 carbon atoms with other mono-, di-, or poly-oles. Particularly suitable alkylenepolyol ethers or esters are fatty acid alkylene-triol esters of 3 to 5 carbon atoms / mixed poly (alkylene-2 to 4 carbon) glycol, especially the fatty acid esters of glycerol / mixed polyethylene or polypropylene glycol. Alkylene polyol ethers or esters especially suitable for use in accordance with the present invention include products obtainable by the transesterification of glycerides, for example triglycerides, with poly (alkylene of 2 to 4 carbon atoms) glycols, for example polyethylene glycols, and optionally glycerol. These transesterification products are generally obtained by alcoholysis of glycerides, for example triglycerides, in the presence of a poly (alkylene of 2 to 4 carbon atoms) glycol, for example polyethylene glycol, and optionally glycerol (ie, to effect transesterification). from the glyceride to the polyalkylene glycol / glycerol component, ie, by glycolysis / glycerolysis of polyalkylene). In general, this reaction is carried out by reaction of the indicated components (glyceride, polyalkylene glycol, and optionally glycerol) at elevated temperature under an inert atmosphere with continuous stirring. Preferred glycerides are triglycerides of the fatty acid, for example triglycerides of (fatty acid of 10 to 22 carbon atoms), including natural and hydrogenated oils, in particular vegetable oils. Suitable vegetable oils include, for example, olive, almond, peanut, coconut, palm, soybeans, and wheat germ oils, and in particular natural or hydrogenated oils rich in ester residues (12 to 18 fatty acid). carbon atoms). Preferred polyalkylene glycol materials are polyethylene glycols, in particular polyethylene glycols having a molecular weight of from about 500 to about 4,000, for example from about 1,000 to about 2,000. In this way, suitable ethers or alkylene polyol esters comprise mixtures of alkylene-triol esters of 3 to 5 carbon atoms, for example mono-, di-, or tri-esters in a variable relative amount, and mono- and di-esters of poly (C 2 -C 4 -alkylene) glycol, together with minor amounts of alkylene-triol of 3 to 5 free carbon atoms and free poly (alkylene-2-C 5 -glycol) glycol. As stated hereinbefore, the preferred alkylene-triol fraction is glyceryl; the preferred polyalkylene glycol moieties will be polyethylene glycol, in particular with a molecular weight of from about 500 to about 4,000; and the preferred fatty acid moieties will be the fatty acid ester residues of 10 to 22 carbon atoms, in particular the saturated fatty acid ester residues of 10 to 22 carbon atoms. Accordingly, the particularly suitable alkylenepolyol ethers or esters can alternatively be defined as: the transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol, and optionally glycerol; or compositions comprising or consisting of glyceryl-mono-, di-, and tri-esters of the fatty acid of 10 to 22 carbon atoms, and mono- and di-fatty esters of 10 to 22 carbon atoms of polyethylene glycol (optionally together with, for example, minor amounts of free glycerol and free polyethylene glycol). Preferred vegetable oils, polyethylene glycols, or polyethylene glycol fractions, and fatty acid moieties in relation to the above definitions are as described hereinabove. Particularly suitable alkylene polyol ethers or esters as described above for use in the present invention are those known and commercially available under the tradename Gelucire® from, for example, Gattefossé, in particular the products: a) Gelucire® 33/01 , that has a pf = approximately 33-38 ° C and a saponification value = approximately 240/260; b) Gelucire® 35/10, p.f. = approximately 29-34 ° C, saponification value = approximately 120-140; c) Gelucire® 37/02, p.f. = approximately 34-40 ° C, saponification value = approximately 200-220; d) Gelucire® 42/12, p.f. = approximately 41-46 ° C, saponification value = approximately 95-115; e) Gelucire® 44/14, p.f. = approximately 42-46 ° C, saponification value = approximately 75-95; f) Gelucire® 46/07, p.f. = approximately 47-52 ° C, saponification value = approximately 125-145; g) Gelucire® 48/09, p.f. = approximately 47-52 ° C, saponification value = approximately 105-125; h) Gelucire® 50/02, p.f. = approximately 48-52 ° C, saponification value = approximately 180-200; i) Gelucire® 50/13, p.f. = approximately 46-41 ° C, saponification value = approximately 65-85; j) Gelucire® 53/10, p.f. = approximately 48-53 ° C, saponification value = approximately 95-115; k) Gelucire® 62/05, p.f. = approximately 60-65 ° C, saponification value = approximately 70-90. Products (a) to (j) above all have a maximum acid value of 2. The product (k) has a maximum acid value of 5. Products (b), (c) and (f) to (j) above, they all have a maximum iodine value of 3. The product (a) has a maximum iodine value of 8. The products (d) and (e) have a maximum iodine value of 5 or 2. The product (k ) has a maximum iodine value of 10. The ether or alkylene polyol ester having a maximum iodine value of 2 will generally be preferred. As will be appreciated, mixtures of ether or alkylene polyol ester can also be used as defined in the compositions of the invention. Gelucire® products are inert semisolid waxy materials with an amphiphilic character. They are identified by their melting point and their hydrophilic-lipophilic equilibrium value. Most grades of Gelucire® are saturated polyglycolized glycerides that can be obtained by polyglycolysis of natural vegetable oils hydrogenated with polyethylene glycols. They consist of a mixture of mono-, di-, and tri-glycerides, and mono- and di-esters of the polyethylene glycol fatty acid. Gelucire® 44/14 having a nominal melting point of 44 ° C and a hydrophilic-lipophilic equilibrium of 14 is particularly suitable. It is derived from the reaction of hydrogenated palm seed and / or hydrogenated palm kernel oils. polyethylene glycol 1,500. It consists of approximately 20 percent mono-, di-, and triglycerides, 72 percent of mono- and di-esters of polyethylene glycol fatty acid 1,500, and 8 percent of free polyethylene glycol 1,500. The distribution of the fatty acid for Gelucire® 44/14 is as follows: 4-10 C8, 3-9 C? 0, 40-50 Ci2, 14-24 C? 4, 4-14 C16, 5-15 C18. Gelucire® 44/14 exhibits the following additional characterization data: maximum acid value of 2, maximum iodine value of 2, saponification value of 79-93, hydroxyl value of 36-56, maximum peroxide value of 6, impurities alkaline maximum 80, maximum water content of 0.50, maximum free glycerol content of 3, monoglyceride content of 3.0-8.0. (H. Fiedler, loe cit, volume 1, page 676; manufacturer information). Although any pharmaceutically-acetable components selected from the group specified above may be used, in the composition of the invention, certain components are preferred. These include triethyl citrate, acetyltriethyl citrate, N-methylpyrrolidone, glycerol triacetate, benzyl alcohol, Cetiol® HE, oleic acid, or alkylene polyol ether or ester, for example polyglycolized glycerides. More preferred are triethyl citrate, acetyltriethyl citrate, N-methylpyrrolidone, benzyl alcohol, Cetiol® HE, or oleic acid. Accordingly, the present invention provides, in one aspect, a composition according to the present invention, wherein the second component is selected from the group consisting of: (i) triethyl citrate or acetyltriethyl citrate, (ii) glyceryl ester of the fatty acid of 6 to 10 carbon atoms of polyethylene glycol, (iii) fatty acids and alcohols, (iv) N-methylpyrrolidone, (v) glycerol triacetate, (vi) benzyl alcohol, and (vii) ether or alkylene polyol ester, In one aspect, the present invention provides a composition according to the present invention, wherein the second component is triethyl citrate or N-methylpyrrolidone. The second component may also comprise a co-component, which may be hydrophilic, for example selected from Transcutol (having the formula C2H5- [0- (CH2) 2] 2-0H), Glycofurol (also known as polyethylene glycol ether of tetrahydrofurfuryl alcohol), and 1,2-propylene glycol. The second component may include other hydrophilic co-components, for example lower alkanols such as ethanol. These co-components will generally be present in a partial replacement of other components of the second component. Although the use of ethanol in the compositions is not essential, it has been found to be of particular advantage when the compositions are to be manufactured in a soft gelatin encapsulated form. This is because the storage characteristics are improved, in particular the risk of precipitation of the active agent is reduced immediately following the encapsulation procedures. Accordingly, the stability of the shelf life can be extended by using ethanol or some other co-component, such as an additional ingredient of the second component. In a further alternative aspect, the ethanol may comprise from 0 to 60 weight percent of the second component; preferably from 20 to about 55 weight percent, and more preferably from about 40 to 50 weight percent. Small amounts of liquid polyethylene glycols can also be included in the second component. British Patent Number GB 2,222,770 A discloses a wide variety of lipophilic components suitable for use in the present invention. Typical examples for the lipophilic components are: (i) triglycerides of the medium chain fatty acid, for example from 6 to 12 carbon atoms, for example Miglyol® 812, and / or (ii) mono-, di-, and tri mixed glycerides, for example from 6 to 20 carbon atoms, for example from 16 to 18 carbon atoms, for example Maisine®, and / or (iii) transesterified ethoxylated vegetable oils, for example Labrafil®, and / or (iv ) monoesters of the propylene glycol fatty acid, for example from 14 to 18 carbon atoms, for example propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol ricinoleate, propylene glycol stearate, and / or (v) propylene glycol fatty acid diesters, example of 6 to 20 carbon atoms, for example 8 to 12 carbon atoms, for example propylene glycol dicaprylate, for example Miglyol® 840, or propylene glycol dilaurate, and / or (vi) esterified compounds of the fatty acid and primary alcohol , for example acids fatty acids of 8 to 20 carbon atoms, and alcohols of 2 to 3 carbon atoms, for example ethyl linoleate, and / or (vii) mono- and / or di-glyceride, for example a mixture of mono- and di- glycerides with, for example, a monoglyceride of the fatty acid of 18 carbon atoms as its main component, for example GMOrphic®-80 or Tegin® O. Preferred lipophilic components are triglycerides of medium chain fatty acid, mono-, di-, and mixed tri-glycerides, and the transesterified ethoxylated vegetable oils. Accordingly, in one aspect, the present invention provides a composition according to the present invention, wherein the lipophilic component is selected from the group consisting of: (i) triglycerides of the medium chain fatty acid, ( ii) mixed mono-, di-, and tri-glycerides; and (iii) transesterified ethoxylated vegetable oils. In another aspect, the lipophilic component may comprise a medium chain triglyceride and / or a mono- and diglyceride, or a mixture thereof. As the triglyceride of the medium chain fatty acid in the lipophilic component, a triglyceride of the saturated fatty acid having from 6 to 12, for example from 8 to 10, carbon atoms can be used. Suitable medium chain fatty acid triglycerides are those known and commercially available under the tradenames Acomed®, Myritol®, Captex®, Neobee® M 5 F, Miglyol® 810, Miglyol® 812, Miglyol® 818, Mazol®, Sefsol ® 860, Sefsol® 870; Miglyol® 812 being the most preferred. Miglyol® 812 is fractionated coconut oil comprising triglycerides of caprylic-capric acid, and having a molecular weight of approximately 520 Daltons. Fatty acid composition = maximum Ce approximately 3 percent, C8 approximately 50 to 65 percent, C? 0 approximately 30 to 45 percent, Ci2 maximum 5 percent; acid value of approximately 0.1; saponification value from about 330 to 345; maximum iodine value of 1. Miglyol® 812 is available in Condea. Neobee® M 5 F is a triglyceride of fractionated caprylic-capric acid available from coconut oil; maximum acid value of 0.2; saponification value from about 335 to 360; maximum iodine value of 0.5, maximum water content of 0.15 percent, D.20 0.930-0.960, nD20 1.448-1.451 (manufacturer information). Neobee® is available in Stepan Europe. These triglycerides are described in Fiedler, H.P. loe cit, whose content is incorporated herein by reference. In a further alternative aspect, preferably the monoglycerides comprise from about 25 to about 50 percent, based on the total weight of the lipophilic components. More preferably, from about 30 to about 40 percent (e.g., 35 to 40 percent) of monoglycerides are present. In a further alternative aspect, diglycerides preferably comprise from about 30 to about 60 percent, based on the total weight of the lipophilic component. More preferably, from about 40 to about 55 percent (e.g., 48 to 50 percent) of diglycerides are present. In a further alternative aspect, the triglycerides suitably comprise at least 5 percent, but less than about 25 percent, based on the total weight of the lipophilic component. More preferably, from about 7.5 to about 20 percent (e.g., about 9 to 12 percent) of triglycerides are present. Suitable mixed mono-, di-, and tri-glycerides are those known and commercially available under the trade name Maisine® from Gattefossé. These are transesterification products of corn oil and glycerol. These products are comprised predominantly of mono-, di-, and triglycerides of linoleic and oleic acid, together with minor amounts of mono-, di-, and tri-glycerides of palmitic and stearic acid (corn oil itself being comprised of approximately 56 percent by weight of linoleic acid, 30 percent by oleic acid, approximately 10 percent by palmitic acid constituents, and approximately 3 percent by stearic acid). The physical characteristics are: maximum free glycerol 10 percent, monoglycerides of about 40 percent, diglycerides of about 40 percent, triglycerides of about 10 percent, free oleic acid content of about 1 percent. Other physical characteristics are: maximum acid value of 2, iodine value of 85-105, saponification value of 150-175, mineral acid content = 0. The content of fatty acid for Maisine® is typically: palmitic acid approximately 11 percent, stearic acid about 2.5 percent, oleic acid about 29 percent, linoleic acid about 56 percent, others about 1.5 percent (H. Fiedler, loe cit, volume 2, page 958, manufacturer information ). In a further alternative aspect, the lipophilic component may alternatively comprise, for example, a pharmaceutically acceptable oil, preferably with an unsaturated component, such as vegetable oil or fish oil. The lipophilic component may alternatively comprise suitable transesterified ethoxylated vegetable oils, such as those obtained by the reaction of different natural vegetable oils (e.g., corn oil, palm kernel oil, almond oil, peanut oil, olive oil, soy bean oil, sunflower oil, oil of saffron, and palm oil, or mixtures thereof) with polyethylene glycols having an average molecular weight of 200 to 800, in the presence of an appropriate catalyst. These methods are known, and one example is described in U.S. Patent No. 3,288,824. Transesterified ethoxylated corn oil is particularly preferred. The transesterified ethoxylated vegetable oils are known and commercially available under the tradename Labrafil® (H. Fiedler, loe cit, volume 2, page 880). Examples are Labrafil® M 2125 CS (obtained from corn oil, and having an acid value less than about 2, a saponification value from 155 to 175, a hydrophilic-lipophilic equilibrium value from 3 to 4, and an iodine value of 90 to 110), and Labrafil® M 1944 CS (obtained from palm kernel oil, and having an acid value of approximately 2, a saponification value of 145 to 175, and a value of iodine from 60 to 90). Labrafil® M 2130 CS (which is a transesterification product of a glyceride of 12 to 18 carbon atoms and polyethylene glycol, and having a melting point of about 35 ° C to 40 ° C, an acid value less than about 2, a saponification value of 185 to 200, and an iodine value less than about 3), can also be used. The preferred transesterified ethoxylated vegetable oil is Labrafil® M 2125 CS, which can be obtained, for example, from Gattefossé, Saint-Priest Cedex, France. Other lipophilic components suitable for use in this invention are, for example, mono- and diesters of the propylene glycol fatty acid, such as propylene glycol dicaprylate (also known and commercially available under the tradename Miglyol® 840 from, for example, Condea; H. Fiedler, loe cit, volume 2, page 1008), or propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate, and the like (Fiedler, loe cit, 2, page 1277 And next) . As another lipophilic component, esterified fatty acid and primary alcohol compounds can be used. These may include esterified fatty acid compounds having 8 to 20 carbon atoms, and primary alcohol having 2 to 3 carbon atoms, for example, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, etc., an esterified compound of linoleic acid and ethanol being particularly preferable. In a further aspect, such as the lipophilic component, mono- and / or di-glyceride can be used. A mono- and / or di-glyceride is, for example, a mixture of glycerol mono- and di-esters of a fatty acid, wherein the content of monoglyceride is, for example, at least 40 percent. It is preferable that the mono- and di-glycerides contain a monoglyceride of the fatty acid of 18 carbon atoms as its main component. This compound has been marketed under the tradename GM0®AV1 (Croda Co.), ATMOS®300 (ICI Co.), GMOrphic®-80 (Eastman Co.), Tegin®0 (Goldschmidt Co.), and so on. For example, GMOrphic®-80 (glyceryl mono-oleate) exhibits the following additional characterization data: minimum monoglyceride content of 94 percent, C18 content: minimum 75 percent, maximum peroxide value 2.5, C18 : 2 + C18: 3 maximum of 15 percent, C16: 0 + C18: 0 + C20: 0 maximum of 10 percent, maximum water of 2 percent, maximum acid value of 3, iodine value of 65-75, saponification value of 155-165, free glycerin maximum 1 percent, hydroxyl number 300-330 (manufacturer information). Tegin® O (glyceryl oleate) exhibits the following additional characterization data: monoglyceride content of 55 to 65 percent, maximum peroxide value of 10, maximum water content of 1 percent, maximum acid value of 2, iodine value of 70 -76, saponification value of 158-175, free glycerol maximum of 2 percent (manufacturer information). Typically, the mono / diglyceride is present in a concentration of 5 to 10 weight percent, for example, of the composition, carrier medium, or lipophilic component. In a further alternative aspect in the composition of the present invention, any of the above lipophilic components, for example oils, alone or in combination, can be used as the lipophilic component. When a mixture of either the medium chain triglyceride and the mono- and di-glyceride is used in the lipophilic component, it may be present in the mixing ratio of 1: 0.1-1, preferably 1: 0.1-0.5, with base in weight. In the pharmaceutical composition of the present invention, in a further alternative aspect, the constitution rate of the lipophilic component to the cyclosporin is preferably 1-10: 1, and more preferably 2-6: 1, based on the weight . Examples of the surfactants suitable for use in this invention are: i) the reaction products of a natural or hydrogenated castor oil and ethylene oxide. The natural or hydrogenated castor oil can be reacted with ethylene oxide in a molar ratio of about 1:35 to about 1:60, with optional removal of the polyethylene glycol component from the products. Several of these surfactants are commercially available. Hydrogenated polyethylene glycol castor oils available under the tradename Cremophor® are especially suitable. Particularly suitable are Cremophor® RH 40, which has a saponification value of about 50 to 60, an acid value of less than about 1, a water content (Fischer) of less than about 2 percent, an nD60 of about 1,453 to 1,457. , and a hydrophilic-lipophilic balance of approximately 14 to 16; and Cremophor® RH 60, which has a saponification value of about 40 to 50, an acid value less than about 1, an iodine value less than about 1, a water content (Fischer) of about 4.5 to 5.5 percent , an nD60 of about 1453 to 1457, and a hydrophilic-lipophilic balance of about 15 to 17. An especially preferred product of this class is Cremophor® RH 40. Also suitable are polyethylene glycol castor oils, such as those available under the trade name Cremophor® EL, which has a molecular weight (by vapor osmometry) of about 1,630, a saponification value of about 65 to 70, an acid value of about 2, an iodine value of about 28 to 32, and a nD25 of approximately 1,471. Similar or identical products that can also be used are available under the trade names Nikkol® (for example, Nikkol® HCO-40 and HCO-60), Mapeg® (for example, Mapeg® CO-40h), Incrocas® (for example, Example Incrocas® 40), Tagat® (for example, glycerol esters of polyoxyethylene fatty acid, for example Tagat® RH 40, and Tagat® TO, a polyoxyethylene glycerol trioleate having a hydrophilic-lipophilic equilibrium value of 11.3; ® RH 40 is preferred), and Simulsol OL-50 (PEG-40 castor oil, having a saponification value of about 55 to 65, a maximum acid value of 2, an iodine value of 25 to 35, a maximum water content of 8 percent, and a hydrophilic-lipophilic balance of approximately 13, available in Seppic). These surfactants are further described in Fiedler loe, cit. ii) Polyoxyethylene sorbitan fatty acid esters, for example mono- and tri-lauryl-, palmityl-, stearyl-, and oleyl-esters of the type known and commercially available under the trade name Tween® (Fiedler, loe. pages 1615 et seq.), including the Tween® products: 20 [polyoxyethylene sorbitan monolaurate (20)], 21 [polyoxyethylene sorbitan monolaurate (4)], 40 [polyoxyethylene sorbitan monopalmitate (20)], 60 [ polyoxyethylene sorbitan monostearate (20)], ^ 5 [polyoxyethylene sorbitan tristearate (20)], 80 [polyoxyethylene sorbitan mono-oleate (20)], 81 [polyoxyethylene sorbitan mono-oleate (5)] , 85 [polyoxyethylene sorbitan trioleate (20)], The most preferred products of this class are Tween® 40 and Tween® 80. iii) Polyoxyethylene fatty acid esters, for example esters of polyoxyethylene stearic acid of the type known and commercially available under the trade name Myrj® (Fiedler, loe, ci t., 2, page 1042). A particularly preferred product of this class is Myrj® 52 having a D25 of about 1.1, a melting point of about 40 ° C to 44 ° C, a hydrophilic-lipophilic equilibrium value of about 16.9, an acidic value of about 0 to 1, and a saponification number of about 25 to 35. iv) Copolymers and polyoxyethylene-polyoxypropylene block polymers, poloxamers, for example of the type known and commercially available under the tradenames Pluronic®, Emkalyx® (Fiedler, loe, cit., 2, page 1203). An especially preferred product of this class is Pluronic® F68 (poloxamer 188), which has a melting point of about 52 ° C, and a molecular weight of about 6,800 to 8,975. An additional preferred product of this class is Synperonic® PE L44 (poloxamer 124). v) Sodium dioctylsulfosuccinate, as is known and commercially available under the trademark Aerosol OT® in, for example, American Cyanamid Co. (Fiedler loe, cit, 1, page 118), or di- [2-ethylhexyl succinate] ] (Fiedler, loe. Ci t., JL, page 487). vi) Phospholipids, in particular lecithins (Fiedler, loe, cit., 2, pages 910, 1184). Suitable lecithins include, in particular, soybean lecithins. vii) Sorbitan fatty acid esters, for example sorbitan 12 to 18 carbon fatty acid monoesters, or sorbitan 12 to 18 carbon fatty acid triesters, as are known and commercially available under the trademark Span® in, for example, ICI. An especially preferred product of this class is, for example, Span® 20 (sorbitan monolaurate), or Span® 80 (sorbitan monooleate) (Fiedler, loe, cit., 2, page 1430; Handbook of Pharmaceutical Excipients, loe, cit., page 473). viii) Polyoxyethylene monoesters of a saturated fatty acid substituted with 10 to 22 carbon atoms, for example with 18 carbon atoms, for example fatty hydroxy acid; for example, polyethylene glycol ester of 12-hydroxystearic acid, for example of polyethylene glycol of about, for example, 600 to 900, for example 660 Daltons of molecular weight, for example Solutol® HS 15 of BASF, Ludwigshafen, Germany. ix) Polyoxyethylene alkyl esters, for example polyoxyethylene glycol ethers of alcohols having 12 to 18 carbon atoms, for example Polyoxyl-2-, 10-, or 20-cetylether or Polyoxyl-4- or 23-lauryl ether, or polyoxyl-2-, -, or 20-oleyl ether, or Polyoxyl-2-, 10-, 20-, or 100-stearyl ether, as are known and commercially available under the trademark Brij® in, for example, ICI. An especially preferred product of this class is, for example, Brij® 35 (Polyoxyl-23-lauryl ether), or Brij® 98 (Polyoxyl-20-oleyl ether) (Fiedler, loe, cit., 1, page 259; Handbook of Pharmaceutical Excipients, loc, cit., Page 367). Similar products which may also be used are polyoxyethylene polyoxypropylene alkyl ethers, for example polyoxyethylene polyoxypropylene ethers of the alcohols of 12 to 18 carbon atoms, for example polyoxyethylene-20-polyoxypropylene-4-cetylether which is known and commercially available available under the trademark Nikkol PBC® 34, in, for example, Nikko Chemical Col, Ltd. (Fiedler loe, volume 2, page 1239). x) Water-soluble tocopheryl-polyether-glycol succinic acid esters (TPGS), for example with a polymerization number of about 1,000, for example available from Eastman Fine Chemicals Kingsport, Texas, USA. xi) Polyglycerol esters of the fatty acid, with, for example, from 2 to 20, for example 10 units of glycerol. The fatty acid constituent can include both saturated and unsaturated fatty acids having a chain length, for example, from 8 to 18 carbon atoms. Particularly suitable, for example, are decaglyceryl monolaurate, or decaglyceryl monomyristate, as are known and commercially available under the trademark Decaglyn® 1-L or Decaglyn® 1-M, respectively, in, for example, Nikko Chemicals C, Ltd (Fiedler, loe, ci t., Volume 2, page 1228). xii) Glyceryl ester of polyethylene glycol fatty acid. The fatty acid ester may include mono- and / or di- and / or fatty acid tri-ester. The fatty acid constituent can include both saturated and unsaturated fatty acids having a chain length, for example, from 12 to 18 carbon atoms. The polyethylene glycols can have, for example, from 10 to 40 units [CH2-CH2-0], for example 15 or 30 units. Particularly suitable is polyethylene glycol glyceryl stearate (15), or polyethylene glycol glyceryl monoleate (15), which is commercially available, for example, under the tradename TGMS®-15 or TGMO®-15, respectively, for example in Nikko Furthermore, glyceryl mono-oleate of polyethylene glycol (30), which is commercially available, for example, under the tradename Tagat® O, for example in Goldschmidt (H. Fiedler, loe, cit., volume 2, pages 1502-1503). xiii) Sterols and their derivatives, for example cholesterols and their derivatives, in particular phytosterols, for example products comprising sitoesterol, campesterol, or stigmasterol, and their ethylene oxide adducts, for example soy sterols and their derivatives, for example polyethylene glycol sterol, for example polyethylene glycol phytosterol or polyethylene glycol soy sterols. The polyethylene glycols can have, for example, from 10 to 40 units [CH2-CH2-0], for example 25 or 30 units. Particularly suitable is polyethylene glycol- (30) -fitoesterol which is commercially available, for example, under the tradename Nikkol BPS®-30, for example from Nikko Chemicals Co., Ltd. Polyethylene glycol soy sterol (25) is also suitable. ) which is commercially available, for example, under the trade name Generol® 122 E 25, for example in Henkel (H. Fiedler, loe, cit., volume 1, page 680). It should be noted that the surfactants may be complex mixtures containing by-products or unreacted starting materials involved in their preparation, for example the surfactants made by polyoxyethylation may contain another secondary product, for example polyethylene glycol. A surfactant having a hydrophilic-lipophilic equilibrium (HLB) value of 8 to 17 is preferred. The hydrophilic-lipophilic equilibrium value is preferably the average hydrophilic-lipophilic equilibrium value. The surfactant selected preferably has a hydrophilic-lipophilic balance (HLB) of at least 10, for example Cremophor. In one aspect, the present invention provides a composition according to the present invention, wherein the surfactant is selected from the group consisting of: (i) the reaction products of natural or hydrogenated vegetable oil and ethylene oxide, and (ii) esters of the polyoxyethylene sorbitan fatty acid.

Preferably, the relative proportion of the second components, the lipophilic component, and the surfactant, is within the "microemulsion" region in a standard three-way graph. The compositions thus obtained are preconcentrated in microemulsion of a high stability which are capable, when added to water, of providing microemulsions having an average particle size < 200 nanometers The standard three-way graphs, for example phase diagrams, can be generated in a conventional manner, as described, for example, in British Patent Publication Number 2,222,770, or in International Publication Number WO 96/13273. In a further alternative aspect, the present invention relates to the preparation of a cyclosporin or a macrolide, comprising: 1) a cyclosporin or a macrolide as an active ingredient; 2) a second component as specified above; 3) one or a mixture of two or more selected from the group consisting of an esterified compound of the fatty acid and primary alcohol, triglyceride of the medium chain fatty acid, and monoglyceride of the fatty acid, as an oil component, and ) a surfactant with an HLB value (hydrophilic-lipophilic balance) of 8 to 17, for example, in a gelatin shell containing polyethylene glycol and propylene glycol as a plasticizer.

In another aspect, the present invention provides a preparation of cyclosporin or macrolide, which comprises a composition containing: 1) cyclosporin or macrolide as an active ingredient, and 2) the second component as described above. Although any pharmaceutically acceptable components selected from the group specified above may be used as the minor components in this composition, certain components are preferred. These include Sunfat® GDC-N, Lauroglycol®90, oleyl alcohol, oleic acid, ether or alkylene polyol ester, for example polyglycolized glycerides. According to the foregoing, in another aspect, the present invention provides a preparation of cyclosporin or macrolide, which comprises a composition containing: 1) cyclosporin or macrolide as an active ingredient, and 2) a second component selected from the group which consists of: (i) glyceryl di-ester of the fatty acid of 6 to 16 carbon atoms, 4 (ii) monoester of the fatty acid of 6 to 12 carbon atoms of propylene glycol, (iii) fatty acids and alcohols, and (iv) ether or ester of alkylene polyol. This composition, which is also a composition of the invention, optionally may further comprise any other component as described herein, if desired in the amounts described herein. The compositions can be formulated in a conventional manner using the recipes disclosed in International Publication Number WO 97/36610 (PCT / KR / 98), the content of which is incorporated herein by reference, replacing propylene carbonate with the component secondary. If desired, polyethylene glycol, which has a high boiling point, which is non-volatile, and which is a solvent for cyclosporin may also be present. In the composition according to the present invention, although any polyethylene glycol which can be liquefied can be used, preferably polyethylene glycol (PEG) having a molecular weight of 200 to 600, particularly PEG 200 can be used. In the present invention, in a further alternative aspect, a mixture of polyethylene glycol and the second component can be used, as the component in the present invention, and in general it can be combined in the ratio of 1: 0.1-5, preferably 1: 0.1-3, more preferably 1: 0.2-2, based on weight. In the composition of the present invention, in a further alternative aspect, the second component can be used preferably in the proportion of 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 of cyclosporin. The third component that can be used in the emulsion preconcentrate, for example in microemulsion, according to the present invention, is a lipophilic component, for example oil. As the lipophilic component, for example oil, in the present invention, one or a mixture of two or more selected from the group consisting of esterified fatty acid and primary alcohol, medium chain fatty acid triglycerides can be used. (when present), and monoglycerides of the fatty acid. The esterified fatty acid and primary alcohol compound that can be used in the present invention can include an esterified fatty acid compound having 8 to 20 carbon atoms, and primary alcohol having 2 to 3 carbon atoms, for example isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, etc., with an esterified compound of linoleic acid and ethanol being particularly preferable. In addition, as the triglyceride of the medium chain fatty acid (when present), a triglyceride of the saturated fatty acid having 8 to 10 carbon atoms may be used, with the triglyceride of caprylic / capric acid being more preferred as a triglyceride of saturated fatty acid vegetable oil. The monoglyceride of the fatty acid which can also be used as the lipophilic component, for example oil, in the present invention, includes a monoglyceride of the fatty acid having from 18 to 20 carbon atoms, particularly monoglyceride of oleic acid. In a microemulsion preconcentrate according to the present invention, the lipophilic component, for example oil, can be used in the proportion of 1 to 10 parts by weight, preferably 2 to 6 parts by weight, per 1 part by weight of cyclosporin. In a further alternative aspect, preferably the monoglyceride of the fatty acid and the fatty acid ester are present as the lipophilic component, for example oil, for example in the ratio of 1: 1 to 1: 2, for example 1: 1. to 1: 1.2. In a further alternative aspect, optionally caprylic / capric acid triglyceride is also present, for example, in a ratio to ethyl linoleate of 1: 0.05 to 1, for example 1: 0.1 to 0.2. In the oil mixture used as the lipophilic component, for example oil, according to the present invention, the mixing ratio of the monoglyceride of the fatty acid: an esterified compound of the fatty acid and primary alcohol: medium chain fatty acid triglyceride ( when present), it can be in general in the scale of 1: 0.1-5: 0.1-10, preferably in the scale of 1: 0.1-3.0: 0.1-3.0, based on weight. The fourth component that can be used in the composition according to the present invention is a surfactant. Suitable surfactants for use in the present invention include any of the pharmaceutically acceptable surfactants having an HLB (Hydrophilic-Lipophilic Balance) value of 8 to 17, which are capable of stably emulsifying the lipophilic portion of the composition comprising the lipophilic component, for example, oil, which contains cyclosporin, and the portion comprising the second component and the co-surfactant in water to form a stable microemulsion. Examples of the preferred surfactant according to the present invention include polyoxyethylene products of natural or hydrogenated vegetable oils, esters of polyoxyethylene sorbitan fatty acid, 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, and so on. For example, polyoxyethylene (50) or polyoxyethylene (40) hydrogenated castor oil, which is marketed under the trademark Nikkol® HCO-50 or Nikkol® HCO-40, respectively, can be used (NIKKO Chemical Co., Ltd.) and a polyoxyethylene sorbitan monolaurate (20) which is marketed under the trademark Tween® 20 (ICI Chemicals), which has an acid value of less than 1, a saponification value of about 48-56, a hydroxyl value of about 45-55, and a pH value (5 percent) of 4.5-7.0. In a further alternative aspect, the surfactant may include any of the above-mentioned surfactants alone, or preferably, in a combination of two or more surfactants selected from the above surfactants. In the composition according to the present invention, the surfactants can be used in the proportion of 1 to 10 parts by weight, preferably in the proportion of 2 to 8 parts by weight, per 1 part by weight of cyclosporin. In addition, when the mixture of two surfactants, ie hydrogenated polyoxyethylene castor oil (50) and polyoxyethylene sorbitan monolaurate (20) is used in the composition of the present invention, the constitution ratio of the hydrogenated castor oil of polyoxyethylene (50): polyoxyethylene sorbitan monolaurate (20) is preferably in the scale of 1: 0.1-5, more preferably in the scale of 1: 0.5-4, most preferably in the scale of 1: 0.1-0.25, based on weight.

In a further alternative aspect, in the composition according to the present invention, there are up to four components present preferably in the proportion of cyclosporin or macrolide: second component: lipophilic component, for example oil: surfactant = 1: 0.1-10: 1 -10: 1-10, and more preferably in the proportion of cyclosporin or macrolide: second component: lipophilic component, for example oil: surfactant = 1: 0.5-8: 2-6: 2-8, by weight. Another substance that can be used, for example, is a hydrophilic co-surfactant, for example a polyoxyethylene-polyoxypropylene block copolymer, a poloxamer, which is liquid at room temperature. This block copolymer has been marketed under the trade name Pluronic® LlO, L31, L35, L43, L44 (poloxamer 124), Llol, 31R1, preferably using poloxamer 124 which is pharmaceutically acceptable as the mixture with the secondary component specified above. . Poloxamer 124 is also available under the tradename Lutrol® or Synperonic® PE L44. The poloxamer is a high molecular weight hydrophilic surfactant, having a molecular weight of 2,000 to 18,000, which can be used as a solvent for medicinal components, lipid emulsions, ointment base, binders or coating agents for tablets, gelling agents , etc. Although the properties of poloxamers depend on their series, they are thermally stable with a flash point of 260 ° C. 4 Poloxamer 124 readily dissolves in organic solvents, such as propylene glycol or xylene, in contrast to other poloxamers. In addition, in comparison with all other solvents used in the cyclosporin formulations of the prior art, the poloxamer is not hygroscopic. Therefore, the constitutive proportion does not change by dissolving the gelatin shell, permeation or evaporation. In one aspect, the present invention provides a composition according to the present invention, wherein a hydrophilic co-surfactant is additionally present, for example. a polyoxyethylene-polyoxypropylene block copolymer. In a further alternative aspect, when a mixture of the second component and the polyoxyethylene-polyoxypropylene block copolymer is used in a liquid state at room temperature in the second component of the present invention, they can be combined in the ratio of 1: 0.1- 5, preferably 1: 0.1-3, more preferably 1: 0.1-1, based on weight. Normally, it is present in a concentration of 5 to 10 percent. In one aspect, the present invention provides a composition according to the present invention, wherein the second component and the hydrophilic co-surfactant, for example a polyoxyethylene-polyoxypropylene block copolymer, are combined in the ratio of 1: 0.1 to 5 based on weight. In the pharmaceutical composition according to the present invention, in a further alternative aspect, the proportion of cyclosporin to the hydrophilic co-surfactant is preferably in the scale of 1: 0.1-1, more preferably 1: 0.5-0.8, based on weight. The compositions of the emulsion preconcentrate, for example in microemulsion, for example those of the examples which are found hereinafter, can show good stability characteristics, as indicated by conventional stability tests, for example with a life stability of shelf up to one, two, or three years, and even more. The microemulsion preconcentrate compositions of this invention produce stable microemulsions, for example for up to a day or more, for example a day. The pharmaceutical composition may also include additives or additional ingredients, for example antioxidants. (such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and tocopherols), and / or preservatives. In a further alternative aspect, these additives or ingredients may comprise from about 0.05 to 1 weight percent of the total weight of the composition. The pharmaceutical composition may also include sweetening or flavoring agents in an amount of up to about 2.5 or 5 percent by weight, based on the total weight of the composition. Preferably, the antioxidant is α-tocopherol (vitamin E). The details of the excipients of the invention are described in Fiedler, H.P., loe. cit. ,; "Handbook of Pharmaceutical Excipients", loe cit; or can be obtained from the relevant manufacturers, whose content is incorporated herein by reference. Any carbon chain not otherwise specified herein, conveniently contains from 1 to 18 carbon atoms, for example from 10 to 18 carbon atoms when it is a terminal group, or from 2 or 3 carbon atoms when it is a fraction of polymer. It will be appreciated that the present invention encompasses: a) with respect to component 2), any of components i) to xi) individually or in combination with one, two, or more of the other components i) to xi), b) with with respect to component 3), any of the lipophilic components specified above, individually or in combination, c) with respect to component 4), any of the surfactants specified above, for example the surfactants i) to xiii), individually or in combination. The pharmaceutical compositions exhibit particularly convenient properties when administered orally; for example, in terms of consistency and high level of bioavailability obtained in standard bioavailability tests, for example 2 to 4 times higher than emulsions. These assays are performed on animals, for example rats or dogs, or healthy volunteers, using high pressure liquid chromatography, or a specific or nonspecific monoclonal kit, to determine the level of drug substance, for example the macrolide, in the blood. For example, the composition of Example 1 administered orally to dogs, can give surprisingly high values of Cmax, as detected by ELISA, using a specific monoclonal antibody. In one aspect, the present invention provides a method for orally administering a pharmaceutical composition, this method comprising orally administering to a patient in need of therapy with cyclosporin or macrolide, a composition according to the present invention. Pharmacokinetic parameters, for example absorption and blood levels, also become surprisingly more predictable, and problems in administration with erratic absorption can be eliminated or reduced. Additionally, the pharmaceutical compositions are effective with tensile materials, for example bile salts, which are present in the gastrointestinal tract. That is, the pharmaceutical compositions are absolutely dispersible in aqueous systems comprising these natural tensides, and therefore, can provide microemulsion systems in themselves that are stable and do not exhibit precipitation of the active agent or other alteration of the fine particulate structure. . The function of the pharmaceutical compositions after oral administration remains substantially independent of, and / or without being impaired by, the relative presence or absence of bile salts at any particular time or for any given individual. The compositions of this invention reduce the variability in the response to the intra- and intra-patient dose. In one aspect, the present invention provides a method for reducing the variability of the bioavailability levels of a cyclosporin or a macrolide for patients during therapy with cyclosporin or macrolide, this method comprising orally administering an oral pharmaceutical composition according to the present invention. invention. In a further alternative aspect, the invention also provides a process for the production of a pharmaceutical composition as defined above, which process comprises intimately mixing (1) the second component; (2) the lipophilic component; and (3) the surfactant, and adding the active agent, for example cyclosporin or the compound of the macrolide class. When required, the composition can be compounded into a unit dosage form, for example the composition can be filled into gelatin capsules. Optionally, other components or additives can be mixed, in particular a hydrophilic co-component, for example ethanol, with the components (1), (2), and (3), or with, or after, the addition of the active agent . The composition may be combined with water or with an aqueous solvent medium, such that an emulsion, for example a microemulsion, is obtained. The present applicants also contemplate emulsion preconcentrate compositions, for example in microemulsion, which may be free of refined fish oil and / or ethanol and / or transesterified ethoxylated vegetable oil. It has also been found that stable compositions containing macrolides can be obtained by formulating the macrolide in an acid environment. Herein, the compositions are understood to be stable when the macrolide drug substance remains substantially intact after a period of days or weeks at room temperature (25 ° C). The acid can be soluble in lipid and / or soluble in ethanol. The acid can be, for example, a fatty acid, for example oleic acid. The acid can be a carboxylic acid, for example a mono-, di-, or tri-carboxylic acid, and preferably a mono- or di-carboxylic acid. The acid may comprise one or more hydrophilic groups, for example hydroxyl groups, and preferably one or two hydrophilic groups. Suitable acids for use in this invention include malonic acid, fumaric acid, maleic acid, D-malic acid, L-malic acid, citric acid, ascorbic acid, succinic acid, oxalic acid, benzoic acid, or lactic acid, or an acid with a similar pKa, for example from 2 to 7. Preferred acids include malonic acid, oxalic acid, citric acid, and lactic acid. Malonic acid is more preferred. The preferred amount of the acid can be determined by routine experimentation. The weight ratio of the macrolide to the acid in the compositions of this invention can be up to 20: 1, for example from 1: 5 to 5: 1, for example 1: 1. In a further alternative aspect, the acid may be present in an amount of between 0.05 percent and 5 percent by weight of the composition. In a further alternative aspect, the macrolide may be present in an amount of 1 to 15 weight percent of the composition. The type of pharmaceutical composition is not critical. It can be solid, but preferably it is liquid. The macrolide, for example, can be formulated in an emulsion preconcentrate, for example in a microemulsion, or in an emulsion preconcentrate as defined above, and can be combined with an amount of acid. The acid-stabilized composition can be administered enterally, for example orally, for example as a capsule or solution for drinking, or parenterally, for example as a concentrate for infusion. Oral administration is preferred. The utility of all pharmaceutical compositions of the present invention can be observed in conventional clinical tests, for example, in known indications of dosages of active agent, giving equivalent blood levels of the active agent; for example, using dosages in the range of 2.5 milligrams to 1,000 milligrams of active agent per day for a 75 kilogram mammal, for example an adult, and in conventional animal models. The increased bioavailability of the active agent provided by the compositions can be observed in conventional animal tests and in clinical trials, for example, as described above. The optimal dosage of the active agent to be administered to a particular patient, should be carefully considered, because the individual response to, and the metabolism of, the macrolide compound, for example rapamycin, can vary. It may be advisable to monitor blood serum levels of the active agent by radioimmunoassay, monoclonal antibody assay, or other appropriate conventional means. Dosages of a macrolide will generally be from 1 to 1,000 milligrams per day, for example from 2.5 milligrams to 1,000 milligrams per day for an adult of 75 kilograms, preferably from 25 milligrams to 500 milligrams, with the optimum dosage being approximately 50 to 100 milligrams per day. 100 milligrams a day. Satisfactory results are obtained by administering approximately 75 milligrams per day, for example in the form of two capsules, one containing 50 milligrams, and one containing 25 milligrams.; or three capsules, each containing 25 milligrams. Cyclosporin dosages may be from 25 to 1,000 milligrams per day (preferably 50 milligrams to 500 milligrams), and the dosage of FK-506 may be from 2.5 milligrams to 1,000 milligrams per day (preferably from 10 milligrams to 250 milligrams). ). A daily dosage of between 0.5 and 5 milligrams / kilogram of body weight / day is indicated for the administration of 40-O- (2-hydroxy) ethyl-rapamycin. The pharmaceutical compositions are preferably compounded in a unit dosage form, for example by filling them into orally administrable capsule shells. The capsule covers can be covered with soft or hard gelatin capsules. When the pharmaceutical composition is in a unit dosage form, each unit dosage suitably will contain between 10 and 100 milligrams of the active agent, more preferably between 10 and 50 milligrams; for example, 15, 20, 25, or 50 milligrams. These unit dosage forms are suitable to be administered from 1 to 5 times a day, depending on the particular purpose of the therapy, the therapy phase, and the like. However, if desired, the pharmaceutical compositions may be in a drinking solution form, and may include water or any other aqueous system, to provide emulsion systems, for example in microemulsion, suitable for drinking. The pharmaceutical compositions are particularly useful for the treatment and prevention of the conditions disclosed on pages 40 and 41 of the European Patent Number EP-427,680 and on pages 5 and 6 of the Patent Number PCT / EP93 / 02604, incorporating The content of these applications is hereby referenced. The pharmaceutical compositions are particularly useful for: a) the treatment and prevention of rejection of organ or tissue transplantation, for example for the treatment of heart, lung, heart-lung transplant recipients, liver, kidney, pancreas, skin, or cornea. The pharmaceutical compositions are also indicated for the prevention of graft-versus-host disease, such as occurs sometimes following bone marrow transplantation; b) the treatment and prevention of autoimmune disease and inflammatory conditions, in particular inflammatory conditions with an etiology including an autoimmune component such as arthritis (eg, rheumatoid arthritis, chronic arthritis progrediente, and arthritis deformans), and diseases rheumatic and c) the treatment of multidrug resistance (MDR). In a further aspect, the present invention provides the use of a composition according to the present invention, in the manufacture of a medicament for the treatment and prevention of an autoimmune or inflammatory condition, or for the treatment and prevention of rejection of transplant, or for the treatment of multidrug resistance. The macrolide active agents also exhibit antitumor and antifungal activity, and accordingly, the pharmaceutical compositions can be used as antitumor and antifungal agents. The content of all the references referred to above, especially the exemplified compounds, are incorporated herein by reference, and each of the exemplified compounds can be used as a macrolide in the examples listed below.

Examples Below is a description by way of example only, of the compositions of this invention. Unless indicated otherwise, the components are shown in percent by weight, based on each composition. Miglyol® 812 is from Condea Company, Germany. Labrafil® M 2125 CS, Gelucire® 44/14, Maisine®, Lauroglycol® 90 are from the Gattefossé Company, France. Tegin® O is a representative monoglyceride that is about 55 to 65 percent pure, the rest containing diglycerides, which can be obtained from Goldschmitt, Essen, Germany. Neobee® M-5 F is from Stepan Europe, France. GMOrphic® 80 is a representative monoglyceride that is approximately 94 percent pure, the rest containing diglycerides, which can be obtained from Eastman Chemicals Co., Kingsport, CN, USA. Synperonic® PE L44 is a poloxamer representative of ICI, United Kingdom. Simulsol® 01-50 is from Seppic, France. Cremophor® RH 40 is from BASF, Germany, Sunfat® GDC-N is from Taiyo Kagaku Co., Japan. Cetiol® HE is from Henkel KGaA, Germany. Measurements of particle sizes are made to ° C, at a dilution of 1 milliliter of composition in 10 to 100 milliliters of water, by photon correlation spectroscopy using, for example, a Malvern ZetaSizer No. 3 from Malvern Instruments.

Example 1: Preparation of oral solutions for drinking. Compositions are made with the following components. Some compositions are cloudy, but optionally, when heated to 40 ° C, at a 1:10 dilution, they give a non-opaque or translucent liquid, which contains particles whose size is measured by a Zetasizer.

COMPONENT AMOUNT I II III IV%%%% Cyclosporine A 10 10 10 10 Triethyl citrate 10 14 5 5 Cremophor® RH 40 40 43.75 43.11 42.5 Synperonic® PE L44 5.71 6.00 6.07 6.07 GMOrphic® 80 8 2 - 8.5 Tegin® 0 - - 8.5 - Labrafil® M 2125 CS 5.71 6.25 5.10 6.07 Miglyol® 812 20.57 18.0 21.86 21.86 Alpha-tocopherol - - 0.36 - Average drop size (nm) 30 36 32 29 V VI%% Cyclosporin A 10 10 N-methylpyrrolidone 9 9 Simulsol® OL-50 63 54 Neobee® M-5 F 18 27 Average drop size (nm) 28 37 VII VIII IX X%%%% Cyclosporin A 10 5 10 8 Cremophor® RH40 45 22.5 45 36 Sunfat® GDC-N 27 13.5 - -Lauroglycol® 90 - - 36 28.8 Propylene glycol 18 9 9 7.2 Gelucire® 44/14 - 50 - 20 Average droplet size (nm) 33 36 31 21 XI XII XIII XIV%%%% Cyclosporin A 10 8 10 8 Cremophor® RH40 54 43.2 63 50.4 Oleyl alcohol 18 14.4 _ _ Oleic acid 18 14.4 Propylene glycol 18 14.4 7.2 Gelucire® 44/14 20 20 Average drop size (nm) 26 18 39 18 XV XVI XVII XVIII%%%% Cyclosporine A 10 10 10 10 Cremophor® RH40 38.6 38.6 38.6 38.6 Cetiol® HE 9.5 - - - Acetyltriethyl citrate - 9.5 - - N-methylpyrrolidone - - 9.5 - Benzyl alcohol - - - 9.5 Ethanol 9.5 9.5 9.5 9.5 Maisine® 32.4 32.4 32.4 32.4 Average drop size (nm) 34 25 31 30 XIX XX%% Cyclosporin A 10 10 Cremophor® RH40 38.6 38.6 Propylene glycol 9.5 9.5 Ethanol 9.5 9.5 Oleic acid 17.4 17.4 Labrafil® 1944CS 15 Labrafil® 2125 CS 15 Average drop size (mn) 29 31 These compositions can be encapsulated in hard and soft gelatin capsules. Other examples can be made excluding Synperonic® PE L44, GMOrphic® 80, Tegin® O, Labrafil® M 2125 CS, Alpha-tocopherol, ethanol, propylene glycol. Other examples can be made by replacing triethyl citrate, N-methylpyrrolidone, Sunfat® GDC-N, Lauroglycol® 90, oleyl alcohol, Cetiol® HE, acetyltriethyl citrate, benzyl alcohol or oleic acid, by any of the specified second components. previously. The examples illustrate compositions useful, for example, in the prevention of transplant rejection, or for the treatment of autoimmune disease, after administration of 1 to 5 unit doses / day, in a dose of 2 to 5 milligrams / kilogram per day . The examples are described with particular reference to Cyclosporin, but equivalent compositions can be obtained using any macrolide or other active agent. On visual inspection after dilution, each of the compositions forms a transparent and stable microemulsion.

Claims

1. A composition in the form of an emulsion preconcentrate for oral administration, which comprises: 1) a cyclosporin or a macrolide, and a carrier medium, which comprises: 2) a second component selected from the group consisting of: i) triethyl citrate or acetyltriethyl citrate, (ii) glyceryl ester of the fatty acid of 6 to 10 carbon atoms of polyethylene glycol, (iii) fatty acid glyceryl ester of 6 to 16 carbon atoms, (iv) glyceryl onoester of the fatty acid from 6 to 14 carbon atoms, (v) a mixture of mono- and di-glycerides of the fatty acids of 6 to 16 carbon atoms, (vi) monoester of the fatty acid of 6 to 12 carbon atoms of propylene glycol, ( vii) fatty acids and alcohols, (viii) N-methylpyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) ether or ester of alkylene polyol, 3) a lipophilic component, and 4) a surfactant, with the condition that, when component 2): (a) consist In triethyl citrate, the composition is free or substantially free of ethanol, and / or (b) consists of a mixture of mono- and diglycerides of the fatty acids of 8 to 10 carbon atoms, the composition is free or substantially free. of a triglyceride of the fatty acid of 6 to 12 carbon atoms.

2. A composition in the form of an emulsion or microemulsion preconcentrate for oral administration, which comprises: 1) a cyclosporin or a macrolide, and a carrier medium, which comprises: 2) a second component selected from the group consisting of in: (i) triethyl citrate or acetyltriethyl citrate, (ii) glyceryl ester of the fatty acid of 6 to 10 carbon atoms of polyethylene glycol, (iii) glyceryl diester of the fatty acid of 6 to 16 carbon atoms, (iv) glyceryl monoester of the fatty acid of 6 to 14 carbon atoms, (v) a mixture of mono- and di-glycerides of the fatty acids of 6 to 16 carbon atoms, (vi) monoester of the fatty acid of 6 to 12 carbon atoms of propylene glycol , (vii) arrases acids and alcohols, (viii) N-methylpyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) alkylenepolyol ester or alkylenetriol ether of 3 to 5 carbon atoms, 3) a lipophilic component, and 4) a surfactant or, with the proviso that, when component 2): (a) consists of triethyl citrate, the composition is free or substantially free of ethanol, and / or (b) consists of triethyl citrate, acetyltriethyl citrate, or glycerol triacetate, cyclosporin is not present, and / or (c) consists of a mixture of mono- and diglycerides of the fatty acids of 8 to 10 carbon atoms, the composition is free or substantially free of the triglyceride of the fatty acid of 6 to 12 carbon atoms.

3. A composition in the form of an emulsion or microemulsion preconcentrate for oral administration, which comprises: 1) a cyclosporin or a macrolide, and a carrier medium, which comprises: 2) a second component selected from the group consisting of in: (i) triethyl citrate or acetyltriethyl citrate, (ix) glycerol triacetate, 3) a lipophilic component selected from the group consisting of: (i) transesterified ethoxylated vegetable oil, (ii) mono-, di- , and mixed tri-glycerides, (iii) mono- and di-esters of propylene glycol fatty acid, and (iv) esterified compounds of the fatty acid and primary alcohol, 4) a surfactant, with the proviso that, when the component 2) consists of triethyl citrate, the composition is free or substantially free of ethanol.

4. A composition in the form of an emulsion or microemulsion preconcentrate for oral administration, which comprises: 1) a cyclosporin or a macrolide, and a carrier medium, which comprises: 2) a second component selected from the group consisting of in: a) (i) triethyl citrate or acetyltriethyl citrate, (ix) glycerol triacetate, and a second component selected from the group consisting of: b) (ii) glyceryl ester of the fatty acid of 6 to 10 carbon atoms of polyethylene glycol, (iii) fatty acid glyceryl ester of 6 to 16 carbon atoms, (iv) ) glyceryl monoester of the fatty acid of 6 to 14 carbon atoms, (v) a mixture of mono- and diglycerides of the fatty acids of 6 to 16 carbon atoms, (vi) monoester of the fatty acid of 6 to 12 carbon atoms of propylene glycol, (vii) fatty acids and alcohols, (viii) N-methylpyrrolidone, (x) benzyl alcohol, and (xi) ether or ester of alkylene polyol, 3) a lipophilic component, and 4) a surfactant.

5. A composition in the form of an emulsion or microemulsion preconcentrate for oral administration, which comprises: 1) a cyclosporin or a macrolide, and a carrier medium, which comprises: 2) a second component selected from the group consisting of in: (i) triethyl citrate or acetyltriethyl citrate, (ii) glyceryl ester of the fatty acid of 6 to 10 carbon atoms of polyethylene glycol, (iii) glyceryl diester of the fatty acid of 6 to 16 carbon atoms, (iv) glyceryl monoester of the fatty acid of 6 to 14 carbon atoms, (v) a mixture of mono- and diglycerides of the fatty acids of 6 to 16 carbon atoms, (vi) monoester of the fatty acid of 6 to 12 carbon atoms of propylene glycol, ( vii) fatty acids and alcohols, (viii) N-methylpyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) ether or alkylenepolyol ester, 3) a lipophilic component, and 4) a surfactant, ) one or more antioxidants selected at ddeell ggrruuppoo consisting of "ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and tocopherols, in from about 0.05 to 1 weight percent of the total weight of the composition, with the proviso that when the component 2): (a) consists of triethyl citrate, the composition is free or substantially free of ethanol, and / or (b) consists of a mixture of mono- and diglycerides of the fatty acids of 8 to 10 carbon atoms, the composition is free or substantially free of a triglyceride of the fatty acid of 6 to 12 carbon atoms.

6. A composition according to claim 5, wherein the antioxidant present is α-tocopherol.

7. The use of a composition in the form of an emulsion or microemulsion preconcentrate for oral administration in kidney or heart transplantation, which comprises: 1) a cyclosporin or a macrolide, and a carrier medium, which comprises: 2) a second component selected from the group consisting of: (i) triethyl citrate or acetyltriethyl citrate, (ii) glyceryl ester of the fatty acid of 6 to 10 carbon atoms of polyethylene glycol, (iii) fatty acid glyceryl ester of 6 to 16 carbon atoms, (iv) glyceryl monoester of the fatty acid of 6 to 14 carbon atoms, (v) a mixture of mono- and diglycerides of the fatty acids of 6 to 16 carbon atoms, (vi) monoester of the fatty acid of 6 carbon atoms. to 12 carbon atoms of propylene glycol, (vii) fatty acids and alcohols, (viii) N-methylpyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) ether or alkylene polyol ester, 3) a component lipophilic, and 4) a surfactant, with the proviso that, when component 2): (a) consists of triethyl citrate, the composition is free or substantially free of ethanol, and / or (b) consists of a mixture of mono- and diglycerides of the fatty acids of 8 to 10 carbon atoms, the composition is free or substantially free of a triglyceride of the fatty acid of 6 to 12 carbon atoms.

8. A use or composition according to any of the preceding claims, comprising the cyclosporin or the macrolide in an amount of 1 to 15 weight percent of the composition.

9. A use or composition according to any of the preceding claims, comprising the second component in an amount of 5 to 50 percent, the lipophilic component in an amount of 5 to 85 percent, and the surfactant in an amount of 5 to 80 weight percent of the carrier medium.

10. A use or composition according to any of the preceding claims, the relative proportion of the cyclosporin or macrolide, the second component, the lipophilic component, and the surfactant in this composition, such that, after dilution with water to a ratio of 1 part by weight of the composition to 1 to 10 parts by weight of water, an oil-in-water microemulsion is spontaneously formed having particles of an average size of less than 200 nanometers.

11. A use or composition according to any of the preceding claims, wherein the cyclosporin is Cyclosporin A.

12. A use or composition according to any of the preceding claims, wherein the second component is N-methylpyrrolidone.

13. A use or composition according to any of the preceding claims, wherein the surfactant is selected from the group consisting of: (i) reaction products of natural or hydrogenated vegetable oil and ethylene oxide, and (ii) esters of polyoxyethylene sorbitan fatty acid.

14. A use or composition according to any of the preceding claims, wherein the proportion of cyclosporin or macrolide: second component: lipophilic component: surfactant, is from 1: 0.1 to 10: 1 to 10: 1 to 10 with base in weight.

15. A use or composition according to any of the preceding claims, wherein a hydrophilic co-surfactant is additionally present.

16. A use or composition according to claim 15, wherein the hydrophilic co-surfactant is a polyoxyethylene-polyoxypropylene block copolymer.

17. A use or composition according to claim 15 or 16, wherein the second component and the hydrophilic co-surfactant are combined in the ratio of 1: 0.1 to 5 based on weight.

18. A use or composition according to any of the preceding claims, wherein a mixture of polyethylene glycol and the second component is used.

19. A use or composition of any of the preceding claims, in a unit dosage form.

20. A method for reducing the variability of the bioavailability levels of a cyclosporin or a macrolide for patients during therapy with cyclosporin or macrolide, this method comprising orally administering an oral pharmaceutical composition according to any of claims 2 to 19.

21. A method for orally administering a pharmaceutical composition, this method comprising orally administering to a patient in need of therapy with cyclosporin or macrolide, a composition according to any of the preceding claims.

22. The use of a composition according to any of claims 2 to 20 in the manufacture of a medicament for oral administration to a patient in need of therapy with cyclosporin or macrolide.

23. The use of a composition according to any of claims 2 to 20, in the manufacture of a medicament for the treatment and prevention of an autoimmune or inflammatory condition, or for the treatment and prevention of transplant rejection, or for the treatment of multidrug resistance.