WO1999029335A1

WO1999029335A1 - Pharmaceutical composition containing cyclosporin

Info

Publication number: WO1999029335A1
Application number: PCT/KR1998/000407
Authority: WO
Inventors: Chung Il Hong; Jung Woo Kim; Nam Hee Choi; Hee Jong Shin; Su Geun Yang
Original assignee: Chong Kun Dang Corp.
Priority date: 1997-12-05
Filing date: 1998-12-05
Publication date: 1999-06-17
Also published as: KR100300251B1; AU1509799A; KR19990062826A

Abstract

The present invention is related to a pharmaceutical composition comprising cyclosporin as an active component. The compositions according to the present invention comprise (1) cyclosporin; (2) a mixture of triacetin, thriethyl citrate or a mixture thereof, and propylene carbonate as a cosurfactant; (3) an oil; and (4) a surfactant. The pharmaceutical composition containing cyclosporin according to the present invention is characterized in that it dissolves in water by controlling the mixing ratio of the components, thereby getting the o/w microemulsion form of inner phase diameter of 100 nm or below.

Description

PHARMACEUTICAL COMPOSITION CONTAINING

CYCLOSPORIN

TECHNICAL FIELD

The present invention is related to a pharmaceutical composition containing cyclosporin as an active component. More specifically, the composition according to the present invention comprises cyclosporin; a mixture of triacetin, triethyl citrate or a mixture thereof, and propylene carbonate as a cosurfactant; an oil; and a surfactant.

BACKGROUND ART

Cyclosporin is a high molecular peptide compound consisting of 1 1 amino acids that achieves its potent immunosuppressive activity against allograft rejection, which appears after transplantation of tissue or organ. There are many cyclosporins such as cyclosporin A, B, C, D, G, etc., depending on the structure of constituent amino acids, but cyclosporin A is preferably used in the clinical field. The reason for the preference for cyclosporin A is because its pharmacological activity, clinical indication, and effectiveness are well established in the art. Cyclosporin, which is relatively insoluble in water, has low bioavailability and its individual difference is large. Furthermore, cyclosporin shows severe adverse effects occasionally. The clinical usage of cyclosporin, therefore, is very difficult, and especially, the control of dose needs careful attention. There has been many studies for the development of cyclosporin preparation that can show improved bioavailability of cyclosporin. However, the only commercially available preparations of cyclosporin are in soft capsule form or solution form, comprising cyclosporin dissolved in the mixture of vegetable oil, surfactant and solvent, and, recently, microemulsion preconcentrate encapsulated in soft capsule.

Microemulsion has a small inner phase with a diameter of less than 100 nm, which results in high absorption and permeation properties of drug delivered by microemulsion. The microemulsion is, especially, very useful in solubilization and bioavailability improvement of insoluble drugs. However, since the microemulsion preparation has a large dosage volume, it was impossible for microemulsion, as a dosage form to be used in clinical field.

Recently, the form of microemulsion preconcentrate has come to be developed as a dosage form, and so the microemulsion can now be applied to such water-insoluble drugs as cyclosporin, etc. Microemulsion preconcentrate that is applied to cyclosporin can increase its bioavailability as much as two times. Microemulsion preconcentrate, which is composed of cosurfactant, oil and surfactant, is a pharmaceutical preparation that can form microemulsion spontaneously after being dissolved in gastrointestinal tract. In order to be able to form microemulsion spontaneously after being dissolved in gastro-intestinal tract, the microemulsion must be composed of the said four components, comprising a drug with proper composition. The composition ratio can be determined through wide scope studies such as 3-phase plot study (preparation of phase equilibrium diagram).

In the formulation of cyclosporin as a dosage form of microemulsion preconcentrate, the selection of cosurfactant acting as a solvent is very important. This is because the selections of an inappropriate cosurfactant result in the crystallization of cyclosporin, which is insoluble. According to prior arts, ethanol is essentially used as a cosurfactant. However, ethanol is given time to evaporate, and cyclosporin is crystallized thereafter. Furthermore, a preparation of such a microemulsion preconcentrate form, after administration, can not produce "microemulsion" in the GI tract but does produce an "emulsion" which has inner phase diameter of about 5000 nm. The reason for this emulsion production is that the initial composition ratio is changed by ethanol evaporation. The subsequent result is that bioavailability of cyclosporin decreases and clinical effects objected can not be achieved. To improve the said disadvantages, the methods using non-ethanol material instead of ethanol as a hydrophilic cosurfactant were proposed. U. S. Patent No. 5,342,625 discloses microemulsion preconcentrate composition in which 1 ,2-propylene glycol, Transcutol and Glycofurol are used as a hydrophilic solvent, and ethanol is used as a hydrophilic co- solvent. However, all the hydrophilic solvents used in this patent are glycols having the alcoholic group (-OH) in their structure. Such hydrophilic solvents, which are glycols containing -OH group, are very hygroscopic, highly reactive with gelatin shell, and very volatile. Therefore, There are many problems in the formulating of a composition containing such a glycolic cosurfactant into a soft capsule preparation. Of the drying steps in the preparation of soft capsules, it should be noted that the said solvents absorb water of the capsule shell into the capsule content, then are distributed in the capsule shell to cause the change in composition ratio to an amount corresponding to 20% of the capsule content. And the said solvents can evaporate through the capsule shell during the storage and distribution. Consequently, the composition ratio is greatly changed from its initial value, and it results in problems of cyclosporin crystallization and of difficulties in the microemulsion formation. The reactivity of said hydrophilic solvents with capsule shell also cause serious problems in the stability of the preparation appearance.

The present inventors have worked in developing the pharmaceutical composition containing cyclosporin that could compensate for the disadvantages involved in the various pharmaceutical preparations of the prior art, and be suitable for the formulation into the soft capsule. It was identified that the usage of a mixture of triacetin, triethyl citrate or a mixture thereof, and propylene carbonate, as a cosurfactant, can provide a stable pharmaceutical composition containing cyclosporin, as a microemulsion preconcentrate form, of which composition is not changed from initial state and of which components does not react with soft capsule shell. Hence, the present invention was completed.

DESCLOSURE OF INVENTION

The present invention relates to a pharmaceutical composition that comprises (1 ) cyclosporin as an active ingredient; (2) a mixture of triacetin, triethyl citrate or a mixture thereof, and propylene carbonate as a cosurfactant; (3) oil; and (4) surfactant.

The first essential component of the pharmaceutical composition according to the present invention is cyclosporin as an active ingredient. There are cyclosporin A, B, C, D, G, etc., and cyclosporin A is preferred.

The second essential component of the composition according to the present invention is a cosurfactant. The cosurfactant used in the composition according to the present invention is a mixture of triacetin, triethyl citrate or a mixture thereof, and propylene carbonate. - 3 -

Propylene carbonate, which is a component used in the composition of the present invention, is colorless and a transparent liquid. It has been used as a solvent in oral and topical preparations in medicinal fields. Propylene carbonate, of which boiling point is 242°C, is not evaporated during the storage and distribution. And it is a solvent, unlike glycols, that is neither hydroscopic nor reactive with gelatin shell. Furthermore, because it has excellent dissolving ability of cyclosporin, it is a solvent that is appropriate for application to cyclosporin.

Components used in the mixed form with propylene carbonate as a hydrophilic cosurfactant in the composition of the present invention, are triethyl citrate and/or triacetin. Triethyl citrate is colorless and transparent liquid. It is widely used as a plasticizer, and the scope of its application is very broad in food and cosmetics. Triethyl citrate, of which boiling point is 288°C, is not evaporated at room temperature or higher temperatures. Therefore, this material makes it possible for the stability of pharmaceutical preparation to be maintained during the preparation process and the storage. The stability of pharmaceutical preparation can be maintained also prior to the expiration date because triethyl citrate is neither reactive with gelatin shell nor volatile. Furthermore, it is an ambiphilic solvent capable of dissolving in such oil as soybean oil, water or ethanol, and can be appropriated as a successful solvent for cyclosporin.

As a cosurfactant in the composition according to the present invention, a mixture of triacetin, triethyl citrate or a mixture thereof, and propylene carbonate can be used. This is because they can act as the most suitable solvent for cyclosporin by being used in a mixed form of propylene carbonate, which is more hydrophilic, and with triacetin and triethyl citrate, which are more lipophilic. In the case of using a mixture of triacetin or triethyl citrate, and propylene carbonate, the ratio of propylene carbonate to triacetin or triethyl citrate is preferably in the range of 1 :0.1-5, or more preferably 1 :0.1-2 by weight. And in the case of using a mixture of triacetin, triethyl citrate, and propylene carbonate, propylene carbonate : triethyl citrate : triacetin is preferably in the range of 1 :0.1-5:0.1-5, or more preferably 1 :0.1-2:0.1-2 by weight.

In the pharmaceutical composition according to the present invention, the ratio of cyclosporin to hydrophilic cosurfactant is preferably in the range of 1 :0.5~5, or more preferably 1 : 1-3 by weight.

The third essential component of the composition according to the present invention is oil. Oil that can be used in the composition of the present invention comprises vegetable oils; esterification products of vegetable oils; animal oils and derivatives thereof; and unsaturated long chain fatty acids. They may be used alone or as the mixture of two kinds or more. In the case of a mixture, the selection may be performed only in one small group of the said classification; or in two or more small groups of the said classification. Examples of vegetable oils that can be used in the composition of the present invention are corn oil, borage oil, sesame oil, primrose oil, peanut oil, olive oil, etc. Refined vegetable oils are preferred.

The refined vegetable oils have high purity and low inpurity content, and the refining process can control the contents of unsaturated long chain fatty acids. Therefore, they have been used mainly in the total parenteral nutrition, for wasting diseases such as diabetic nervous disease, rheumatic arthritis, etc. And they have been used as a solvent for venous injection, and a vehicle for stabilization of unstable drug. The refined vegetable oils, which passed through refining procedure by chromatography, are more transparent than general oils. Because oxidants such as aldehydes, alcohols, ketones, etc. are removed from them, they are more resistant to oxidation than general oils. And because the polar materials and water contents of them are reduced highly, they have more excellent solubilization effect of drug than general oils. The commercial refined vegetable oils generally have peroxide value of 0.5 or less, anisidine value of 0.2-0.5, and acid value of 0.1-1.0 or less. The commercial refined vegetable oils have various contents of unsaturated fatty acids depending on the kind of vegetable oil. The oil having the proper content of unsaturated fatty acids for the requirement, therefore, may be selected and used.

Examples of the refined vegetable oils, which are preferable oils of the composition according to the present invention, are super-refined corn oil, borage oil, sesame oil, primrose oil, peanut oil and olive oil, which are on the market, known by the trade name, "Super-refined oil (Croda Co.)". The more preferable oil that can be used in the composition according to the present invention is the kind where the high gamma linolenic acid content in the oil is increased in more than 50 %. Example of such an oil is concentrated borage oil, known by the trade name, "Crossential (Croda Co.)".

As another oil component that can be used in the composition according to the present invention, esterification products of vegetable oils are i) the product from esterification of vegetable oil with glycerin, ii) the product from esterification of vegetable oil with monohydric alcohol, iii) the product from esterification of vegetable oil with polyglycerol, etc. The said esterification of vegetable oil means that fatty acids contained in vegetable oils undergo the esterification reaction. The esterification products, a mixture of various components, may be separated and refined to form a pure objective material. And then, this pure material may be used as an oil component in the composition of the present invention. Moreover, the fatty acids contained in vegetable oils may be separated and refined, and then may be esterification-reacted to form the said products separately.

Regarding the first example of esterification products of vegetable oils, the product from esterification of vegetable oil with glycerin may be used. The product comprises fatty acid triglycerides; mono-glycerides; mono- and di- glycerides; or a mixture thereof.

As a class of the product from esterification of vegetable oil with glycerin, fatty acid triglycerides may be used. C₈~C₁₂ fatty acid medium chain triglyceride (MCT) is the preferable fatty acid triglycerides. MCT is prepared by esterification of glycerin and fatty acids extracted from palm oil, and is triglyceride of medium chain fatty acids of which main fatty acids are capric acid (50-80 %) and caprylic acid (20-50 %). MCT has been commercialized under the trade names Sefol 860, Sefol 870, Sefol 880, Miglyol 810, Miglyol 812, Miglyol 818, etc.

As another class of the product from esterification of vegetable oil with glycerin, mono- and di- glycerides may be used. Mono- and di- glycerides is an oil which is obtained through esterification of fatty acids contained in vegetable oil with glycerin followed by separation and refining, and has many kinds depending on the kind of fatty acid and the extent of esterification. Mono- and di- glycerides that have the ratio of monoglyceride to total glycerides of at least 40 %, more preferably at least 90 % and of which fatty acid is that is the high chain of C₁₆~C₁₈ may be preferably used. It is even more preferable that mono- and di- glycerides contain a monoglyceride of C₁₈ fatty acid as its main component. Such a compound has been commercialized under the trade name, "GMO AVI" (Croda Co.), "ATMOS 300" (ICI Co.), "GMOrphic-80" (Eastman Co.), "Mivacet", etc. Of these, GMOrphic-80 is, particularly, a pure monoglyceride that does not have diglyceride, because it is prepared through isolation of only monoglyceride using molecular distillation following after esterification. Accordingly, GMOrphic-80 is an example of the most preferable oil component in the composition according to the present invention.

Regarding the second example of esterification products of vegetable oils, the product from esterification of vegetable oils with monohydric alcohol may be used. There are many kinds of the said product according to the kinds of vegetable oil reacted. The representative example comprises "Crossential GLO E50" (concentrated borage oil ethyl ester; Croda Co.), which is the product from esterification of borage oil with ethanol, and Nikkol E00 (ethyl olive oleate; Nikkol Co.), which is the product from esterification of olive oil with ethanol. The said product may be also prepared using only fatty acid component isolated from vegetable oil instead of using total 'vegetable oil' components. Examples of this product include ethyl oleate, ethyl linoleate, isopropyl palmitate, isopropyl myristate, etc.

Regarding the third example of esterification products of vegetable oils, the product from esterification of fatty acid with polyglycerol, that is, polyglyceryl fatty acid ester, may be used. Examples of polyglycerol used in esterification include diglycerol, tetraglycerol, hexaglycerol, decaglycerol, etc. Examples of fatty acid reacted with those polyglycerol include oleic acid, linoleic acid, stearic acid, etc. Examples of polyglyceryl fatty acid ester include Plurol Oleique CC 497 (polyglyceryl oleate; Gattefosse Co.), Plurol Stearique (polyglyceryl palmitostearate; Gattefosse Co.), DGMO-C (diglyceryl monooleate; Nikkol Co.), Tetraglyn 1-0 (tetraglyceryl monooleate; Nikkol Co.), Hexaglyn 1-0 (hexaglyceryl monooleate; Nikkol Co.), Decaglyn 5-0 (Decaglyceryl pentaoleate; Nikkol Co.), etc.

Moreover, animal oils and derivatives thereof may be used as an oil component in the composition according to the present invention. The first example of animal oils and derivatives thereof is squalenes. Squalene, which is obtained from the liver oil of shark, is colorless and a transparent oil, with its chemical name being hexamethyltetracosa-hexaene. Compared to general animal oils, squalene is more excellent in the stability against oxidation, and has a lower melting point. Therefore, it could dissolve cyclosporin effectively. Hydrogenated squalene may be also used as oil component in the pharmaceutical composition according to the present invention. Examples of squalenes commercial products include "Squalene EX" (Nikkol Co.), "Squalene" (Nikkol Co.), etc.

The second example of animal oils and derivatives thereof comprises omega-3 essential fatty acids (EFAs), an oil of ethyl esterificated form of the said fatty acids and an oil of triglyceride form of the said fatty acids. 'Omega-3 essential fatty acids' is an animal oil of which fatty acid component is eicosapentaenoic acid and docosahexaenoic acid. Examples of commercial product of 'omega-3 essential fatty acids' include Incromega F2250 (Croda Co.) and Incromega F2628 (Croda Co.). Examples of commercial product of ethyl esterificated form of the said fatty acids include Incromega E2251 (Croda Co.), Incromega F2573 (Croda Co.), etc. Examples of commercial product of triglyceride form of the said fatty acids include Incromega TG2162 (Croda Co.), Incromega TG2779 (Croda Co.), Incromega TG2928 (Croda Co.), etc.

Moreover, unsaturated long chain fatty acids may be used as an oil component in the composition according to the present invention. Examples of such fatty acids include oleic acid, linoleic acid, linolenic acid, etc. There are examples of their commercial products such as

Crossential 094 (Croda Co.), which is the commercial product of oleic acid;

Crossential L99 (Croda Co.), which is the commercial product of linoleic acid; and Crossential LN80 (Croda Co.), which is the commercial product of linolenic acid.

The said various oils may be used with combinations of proper ratio to control cyclosporin absorption.

In the pharmaceutical composition according to the present invention, oil component is present preferably in the ratio of cyclosporin : oil component = 1 :0.1 ~5, or more preferably 1 : 1-3 by weight.

The fourth essential component of the composition according to the present invention is a surfactant. Surfactants which may be used for this purpose preferably have a HLB value of 1-20, and there are examples of them such as the following: i) Reaction products of natural or hydrogenated vegetable oils and ethylene glycol; i. e., polyoxyethylene glycolated natural or hydrogenated vegetable oils: for example, polyoxyethylene glycolated natural or hydrogenated castor oils. Surfactants commercialized under the trade names "Cremophor RH40", "Cremophor RH60", "Cremophor

EL", "Nikkol HCO-40" and "Nikkol HCO-60" may be used in the composition according to the present invention. Cremophor RH40 and

Cremophor EL are preferred. ii) Polyoxyethylene sorbitan fatty acid esters: e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters; e.g. products of the trade name

"Tween", which includes polyoxyethylene (20) sorbitan mono-laurate (Tween 20), polyoxyethylene (20) sorbitan mono-palmitate (Tween 40), polyoxyethylene (20) sorbitan mono-oleate (Tween 80), etc. depending on the kind of fatty acid. Tween 20 and Tween 40 can be used preferably in the composition according to the present invention, iii) Polyoxyethylene-polyoxypropylene block co-polymers: e.g. of the type known and commercially available under the trade name "Poloxamer". iv) Trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols; e.g. of the type known and commercially available under the trade name "Labrafil". Specially, "Labrafil M 1944

CS", "Labrafil WL 2609 BS", "Labrasol", etc. can be used preferably in the composition according to the present invention.

The said surfactants can be used alone or in the mixture of two kinds or more. In the pharmaceutical composition according to the present invention, The said surfactants is present preferably in the ratio of cyclosporin : surfactant = 1 :2~10, or more preferably 1 :3~8 by weight. In the pharmaceutical composition according to the present invention, the said four essential components should preferably be present in the mixing ratio of cyclosporin: cosurfactant: surfactant: oil =1 : 0.1-5 : 2-10 : 0.1-5, and more preferably in the mixing ratio of cyclosporin: cosurfactant: surfactant: oil =1 : 1-3 : 3-8 : 1-3, on the basis of weight.

The cyclosporin-containing composition according to the present invention may further comprise any pharmaceutically acceptable additives as needed. Examples of the said additives include antioxidant (e.g., tocopherol, butylated hydroxyanisole (BHA), etc.), viscosity control agent, dissolution control agent, flavor (e.g., peppermint oil, etc.), flavors, preservatives (e.g., benzyl alcohol, parabens, etc.), coloring agents, etc.

For clinical use, the composition according to the present invention can be formulated into such oral dosage forms as a soft capsule, a hard capsule sealed with a gelatin banding at the conjugated portion, or an oral liquid preparation by conventional method, and if necessary, by adding pharmaceutically acceptable additives.

BRIEF DESCRIPTION OF THE DRAWINGS For a thorough understanding of the nature and objects of the invention, reference should be had to the following detailed description taken in connection with the accompanying drawings in which:

Figure 1 shows blood concentration-time profiles of cyclosporin following the oral administration of cyclosporin commercial product (Sandimmun^®: comparative preparation) and pharmaceutical compositions according to the present invention (test preparations) to dogs (#, comparative preparation; v, test preparation of Example 1-D; |, test preparation of Example 2-B; O, test preparation of Example 3-D; A, test preparation of Example 4-C).

MODES FOR CARRING OUT THE INVENTION

The present invention is described in more detail by Examples and Experiment as shown below but is not confined to the said scopes.

Example 1. Cyclosporin soft capsule for oral administration The soft capsule containing the composition of 1-A in Table 1 according to the present invention was prepared according to the following procedure:

50 g of cyclosporin A, as an active ingredient, was dissolved in 80 g of propylene carbonate and 80 g of triacetin as a cosurfactant component, with stirring and heating. To the resulting solution, 150 g of Miglyol 812 as an oil component and 225 g of Cremophor RH 40 as a surfactant component were added to obtain the mixture, which was stirred until a homogeneous solution was formed. The resulting composition was poured to a machine for preparing soft capsules and then encapsulated according to conventional methods for producing soft capsules. Each capsule contained 50 mg of cyclosporin A.

The soft capsule preparations of Examples 1 -B to 1-E, having the compositions given in the following Table 1 , were also prepared according to the said method. Table 1

Example 2. Cyclosporin soft capsule for oral administration

The soft capsule preparations of Examples 2-A to 2-E, having the compositions given in the following Table 2, were prepared according to the method of Example 1.

Table 2

Example 3. Cyclosporin soft capsule for oral administration

The soft capsule preparations of Examples 3-A to 3-E, having the compositions given in the following Table 3, were prepared according to the method of Example 1.

Table 3

Example 4. Cyclosporin soft capsule for oral administration

The soft capsule preparations of Examples 4-A to 4-E, having the compositions given in the following Table 4, were prepared according to the method of Example 1.

Table 4

Example 5. Cyclosporin soft capsule for oral administration

The soft capsule preparations of Examples 5-A to 5-E, having the compositions given in the following Table 5, were prepared according to the method of Example 1.

Table 5

Example 6~10. Cyclosporin hard capsule for oral administration

The pharmaceutical compositions were prepared in the same compositions and methods as Examples 1 to 5, and then were filled in hard gelatin capsules. The conjugated portion of the hard capsules was sealed with gelatin banding to produce hard capsules.

Experimental example 1.

To compare the pharmacological effect of the pharmaceutical composition according to the present invention with that of commercial products prepared according to prior art, the bioavailability comparison experiment was performed using dogs, as follows. The soft capsules of Examples 1-D, 2-B, 3-D and 4-C were used as test preparations according to the present invention, and Sandimmun^® 100-mg soft capsules, which are commercial product, were used as a comparative preparation. In this bioavailability study, fifteen male dogs, weighing 1 1.0-15.0 kg, were used, and each groups consisted of three dogs. No food except water was supplied to dogs for 18 h prior to drug administration. The dogs were given each soft capsule preparations with the dose of cyclosporin A at 100 mg per a dog, and followed immediately the administering of 50 ml of water. After 4 h from drug administration, food was provided. Venous blood samples of 2 ml was withdrawn from the cephalic vein prior to drug administration for baseline cyclosporin A levels, and at scheduled intervals after dosing. Blood samples were frozen under -18 C until assay. Blood concentrations of cyclosporin A were analyzed by a RIA (radioimmunoassay) method.

Whole blood cyclosporin A concentration of the dog v.s. time curves of each preparations are presented in Fig. 1 , and the pharmacokinetic parameters calculated from the experimental data are given in the following Table 6.

Table 6. Bioavailability of the test preparation of the present invention and the comparative preparation

As can be shown from Fig. 1 and Table 6, the pharmaceutical compositions using cosurfactant according to the present invention showed very larger AUC (area under the curve of cyclosporin A blood concentration) as well as higher C_max (maximum blood concentration of cyclosporin A) than comparative preparation did. Compared with a comparative preparation, the AUC of cyclosporin A after the oral administration of test preparation 1-D, 2-B, 3-D and 4-C were 2.23, 1.86, 2.10 and 2.36 times, respectively, or in sum, the test preparations showed a high absorption pattern.

From the results of the Experimental example as mentioned above, it was certified that the composition of the present invention has high bioavailability of two or more times, compared with preparation of prior art, and may show the excellent effect of cyclosporin.

Particularly, in such a case where the composition according to the present invention is formulated in a soft capsule, the resultant capsule does not show the disadvantages of the prior arts such as the reactivity of hydrophilic solvent with gelatin shell of soft capsule and the volatility of hydrophilic solvent. In addition, the pharmaceutical composition according to the present invention provides an excellent cyclosporin preparation which can overcome the various disadvantages, that is, forming of cyclosporin precipitation due to solvent evaporation, non-expectable changing of cyclosporin bioavailability induced by drug precipitating, undesirable changing of external appearance of pharmaceutical preparation, increasing of production cost due to use of special package, etc.

Claims

1. A pharmaceutical composition containing cyclosporin which comprises: 1) a cyclosporin as an active ingredient; 2) a mixture of triacetin, triethyl citrate or a mixture thereof, and propylene carbonate as a cosurfactant;

3) an oil; and

4) a surfactant.

2. A pharmaceutical composition containing cyclosporin according to claim 1 , wherein the said cyclosporin is cyclosporin A.

3. A pharmaceutical composition containing cyclosporin according to claim 1 , wherein the said cosurfactant is a mixture of propylene carbonate and triethyl citrate with the mixing ratio of 1 : 0.1-5 by weight.

4. A pharmaceutical composition containing cyclosporin according to claim 1 , wherein the said cosurfactant is a mixture of propylene carbonate and triacetin with the mixing ratio of 1 : 0.1-5 by weight.

5. A pharmaceutical composition containing cyclosporin according to claim 1 , wherein the said cosurfactant is a mixture of propylene carbonate, triethyl citrate and triacetin with the mixing ratio of 1 : 0.1-5 : 0.1-5 by weight.

6. A pharmaceutical composition containing cyclosporin according to claim 1 , wherein the said oil is at least one member selected from the group consisting of a vegetable oil; an esterification product of vegetable oil; an animal oil and derivatives thereof; and an unsaturated long chain fatty acid.

7. A pharmaceutical composition containing cyclosporin according to claim 6, wherein the said vegetable oil is a refined vegetable oil.

8. A pharmaceutical composition containing cyclosporin according to claim 7, wherein the said refined vegetable oil are Super-refined forms of corn oil, borage oil, sesame oil, primrose oil, peanut oil and olive oil.

9. A pharmaceutical composition containing cyclosporin according to claim 6, wherein the said esterification products of vegetable oil are i) a product from esterification of vegetable oil with glycerin; ii) a product from esterification of vegetable oil with monohydric alcohol; and iii) a product from esterification of vegetable oil with polyglycerol.

10. A pharmaceutical composition containing cyclosporin according to claim 9, wherein the said product from esterification of vegetable oil with glycerin are fatty acid triglycerides; mono-glycerides; and mono- and di- glycerides.

1 1. A pharmaceutical composition containing cyclosporin according to claim 10, wherein the said fatty acid triglyceride is C₈~C₁₂ fatty acid medium chain triglyceride.

12. A pharmaceutical composition containing cyclosporin according to claim 10, wherein the said mono- and di- glycerides is C₁₆~C_lg fatty acid mono- and di- glycerides

13. A pharmaceutical composition containing cyclosporin according to claim 9, wherein the said product from esterification of vegetable oil with monohydric alcohol are products from esterification of borage oil or/and olive oil with monohydric alcohol.

14. A pharmaceutical composition containing cyclosporin according to claim 9, wherein the said product from esterification of vegetable oil with monohydric alcohol are ethyl oleate, ethyl linoleate, isopropyl palmitate and isopropyl myristate.

15. A pharmaceutical composition containing cyclosporin according to claim 9, wherein the said product from esterification of vegetable oil with polyglycerol are oil formed from esterification of fatty acid with di-, tetra-, hexa- or/and deca-glycerol.

16. A pharmaceutical composition containing cyclosporin according to claim 6, wherein the said animal oil and derivative thereof are squalenes; omega-3 essential fatty acid; oils formed from the esterification of omega- 3 essential fatty acid with monohydric alcohol; and oils of triglyceride form of omega-3 essential fatty acid.

17. A pharmaceutical composition containing cyclosporin according to claim 1 , wherein the said surfactant has HLB value of 1-20.

18. A pharmaceutical composition containing cyclosporin according to claim 17, wherein the said surfactant is/are at least one member selected from the group consisting of polyoxyethylene glycolated natural or hydrogenated vegetable oils; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block co-polymers; and trans- esterification products of natural vegetable oil triglycerides and polyalkylene polyols.

19. A pharmaceutical composition containing cyclosporin according to claim 1 , wherein the said cyclosporin, the said cosurfactant, the said surfactant and the said oil component is present in the mixing ratio of 1 : 0.1-5 : 2-10 : 0.1-5 by weight.

20. A pharmaceutical composition containing cyclosporin according to claim 19, wherein the said cyclosporin, the said cosurfactant, the said surfactant and the said oil component is present in the mixing ratio of 1 : 1-3 : 3-8 : 1-3 on the basis of weight.

21. A pharmaceutical composition containing cyclosporin according to claim 1 , wherein it further comprises at least one species of pharmaceutically acceptable additives selected from the group consisting of antioxidant, viscosity control agent, dissolution control agent, flavor, preservatives and coloring agents.

22. A pharmaceutical formulation comprising the pharmaceutical composition containing cyclosporin according to claims 1 , wherein the dosage form is a soft capsule, a hard capsule sealed with a gelatin banding at the conjugated portion, or an oral liquid preparation.