KR20060086489A - Cyclosporin-containing soft capsule preparations - Google Patents

Abstract

The present invention is selected from the group consisting of cyclosporine as active ingredient, a mixture of propylene carbonate or propylene carbonate and polyethylene glycol as cosurfactant, esterified compound of fatty acid and monovalent alkanol as oil component, intermediate fatty acid triglyceride and monoglyceride A cyclosporin-containing soft capsule agent containing a composition of a species of oil or a mixture of two or more oils and a surfactant having an HLB value of 8 to 17.

Description

Cyclosporin-containing soft capsule preparations

The present invention relates to soft capsules containing cyclosporin as an active ingredient. More specifically, the present invention relates to cyclosporine as the active ingredient, propylene carbonate or a mixture of propylene carbonate and polyethylene glycol as the cosurfactant, esterified compounds of fatty acids and monovalent alkanols as oil components, intermediate fatty acid triglycerides and fatty acid monoglycerides. A soft capsule agent containing one oil or a mixture of two or more oils selected from the group consisting of, and a surfactant having a HLB (Hydrophilic Lipophilic Balance) value of 8 to 17 as a surfactant.

Cyclosporin is a macromolecule (molecular weight 1202.64) in which 11 amino acids are composed of cyclic peptide bonds with each other, and is a unique peptide activator with useful pharmacological action. Cyclosporine is used to suppress the innate immune response that results from tissue and organ transplants, such as heart, lung, liver, kidney, pancreas, bone marrow, skin and corneal transplants, especially exogenous tissues and organs, It is a compound useful for suppressing various autoimmune diseases such as hematological lesions such as anemia, systemic lupus erythematosus and idiopathic malabsorption and arthritis and rheumatic diseases. In addition, cyclosporin is also useful for protozoan diseases such as malaria, schistosomiasis, and more recently, it has a wide range of pharmacological effects, such as being used in some chemotherapy.

While cyclosporine exhibits high lipophilicity and very high hydrophobicity, solubility in water is very low, and it is well soluble in organic solvents such as methanol, ethanol, acetone, ether and chloroform. Cyclosporine having such physical properties has low bioavailability during oral administration due to low water solubility and shows a large individual difference in bioavailability depending on the individual patient's condition, making it difficult to maintain effective therapeutic concentrations and side effects such as kidney toxicity. Also indicates. Due to this low water solubility, there are considerable difficulties in formulating cyclosporin for oral administration, and thus, there is extensive research into an effective oral formulation for providing an appropriate dosage and bioavailability of cyclosporin.

As a method of formulating a poorly water-soluble cyclosporin as an oral preparation, a method of preparing cyclosporin in an emulsion form by combining cyclosporin with a surfactant, an oil, and a cosurfactant has been mainly used.

As a representative of these methods, US Pat. No. 4,388,307 (June 14, 1983) describes a liquid formulation of cyclosporine using ethanol as cosurfactant. According to this US patent, there is provided a liquid composition formed by combining cyclosporin with a carrier consisting of a cosurfactant ethanol, a vegetable oil olive oil and a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol as a surfactant. . However, this liquid composition has a disadvantage in that it is difficult to control a constant dosage when taking the medication because it is required to be diluted with water. Therefore, in order to alleviate the inconvenience of taking the liquid composition by diluting it with water, the liquid composition in the form of an emulsion concentrate is formulated as a soft capsule, and commercially available (trade name: SANDIMMUN ™). However, in the case of cyclosporin soft capsules containing ethanol as co-surfactant, the low boiling point ethanol should be included in consideration of the solubility of cyclosporin. However, since ethanol volatilizes through the gelatin film of capsules at room temperature, The result is a significant change in the composition of the contents resulting in precipitation of cyclosporine and a significant difference in bioavailability, which significantly affects the dose setting for proper treatment maintenance. Therefore, in order to prevent volatilization of low-boiling ethanol from the soft capsule during the distribution period, this preparation is not only inconvenient to carry out special packaging such as aluminum foil foaming and packaging, but also does not maintain a completely constant composition even with such packaging. As a result, the bioavailability is also severely different, and such a special packaging may be a big factor in the rise in drug prices.

In addition to the stability of the cyclosporin preparation, there is an increasing demand for a cyclosporin preparation that can be maintained in the biological efficacy and the biological efficacy parameters between subjects and subjects, that is, the biological effect can be kept constant. . One of the methods developed for this purpose is disclosed in Korean Patent Publication No. 93-113 and is marketed under the trademark Sandimmun Neoral ™, but this formulation also uses ethanol as cosurfactant. As in the conventional ethanol-containing preparations known in the prior art, not only are there problems in storage stability, but also there are problems such as precipitation of cyclosporin and a decrease in bioavailability due to ethanol content change.

Accordingly, the present inventors have provided various surfactants and oil components, and particularly non-specifically, to provide a cyclosporine composition which is not only pharmaceutically stable but also provides high bioavailability compared to existing commercially available products from a pharmacokinetic point of view and reduces individual differences in blood concentration. As a result of studying and examining a combination of volatile co-surfactants, the present invention has been completed by confirming that the above-described objects can be achieved by using a combination of specific components as defined below.

According to the present invention there is provided a composition suitable for formulation into soft capsules containing the active ingredient cyclosporin, a propylene carbonate or a mixture of propylene carbonate and polyethylene glycol as cosurfactant, and an oil component and a surfactant as defined below. Is provided.

More specifically, the present invention

(1) cyclosporin as active ingredient;                     

(2) propylene carbonate or a mixture of propylene carbonate and polyethylene glycol as cosurfactant;

(3) an oil or a mixture of two or more oils selected from the group consisting of esterified compounds of fatty acids and monovalent alkanols, intermediate fatty acid triglycerides and fatty acid monoglycerides as oil components; And

(4) A cyclosporin soft capsule comprising a composition containing a surfactant having a HLB (Hydrophilic Lipophilic Balance) value of 8 to 17 as a surfactant.

Cyclosporin used as an active ingredient in the composition according to the present invention is a cyclic peptide compound having immunosuppression and anti-inflammatory action as described above. Cyclosporins that can be used in the present invention include cyclosporin A, B, C, D and G, and the most preferred of these is, but not necessarily limited to, cyclosporin A, the best demonstrated clinical usefulness and pharmacological properties thereof. .

Cosurfactant, which is the second essential ingredient in the composition according to the present invention, may be used propylene carbonate or a mixture of propylene carbonate and polyethylene glycol.

Propylene carbonate, which is used as an essential cosurfactant in the composition of the present invention, is a nonvolatile non-hydrophilic component having a boiling point of about 242 ° C. It is a component which can ensure the stability of a soft capsule agent. In addition, propylene carbonate is a non-alcoholic component that does not contain a hydroxy group, and thus has low hygroscopicity and low permeability to gelatinous coatings, as well as high solubility in poorly water-soluble drugs such as cyclosporine. It is a particularly suitable component for the formulation of cyclosporin soft capsules.

In the composition of the present invention, propylene carbonate may be used alone as a co-surfactant, but a mixture of propylene carbonate, which is a non-hydrophilic component, and polyethylene glycol, which is a hydrophilic component, is preferably used in consideration of the stability of the soft capsule and the solubility of cyclosporine. It may be. Polyethylene glycol, a hydrophilic component used as a cosurfactant, is also a high boiling nonvolatile component having a boiling point of about 330 ° C. Polyethylene glycol as a hydrophilic component can be used as long as it can be liquefied, but preferred is polyethylene glycol (PEG) having a molecular weight of 200 to 600. Especially preferably, PEG 200 is used.

When using a mixture of polyethyleneglycol and propylene carbonate as cosurfactant in the compositions of the invention they are generally 1: 1 to 5, preferably 1: 1 to 3, most preferably 1: by weight. It can mix | blend and use in the mixing ratio of 1-2.

In the present invention, by selecting propylene carbonate and polyethylene glycol as the co-surfactant, the storage stability of the composition containing cyclosporin can be improved to ensure uniformity of the content composition. In particular, by using a non-hydrophilic propylene carbonate as a co-surfactant can not only increase the solubility of cyclosporine as a main component, but also provide a more stable composition by inhibiting water inflow from the gelatin coating to the contents.

Cosurfactant in the composition of the present invention is preferably used in a ratio of 0.1 to 10 parts by weight per 1 part by weight of cyclosporin, more preferably 0.5 to 8 parts by weight per 1 part by weight of cyclosporin, most preferably 1 to 5 parts by weight of cyclosporin It is used as the ratio by weight.

The third component used in the composition of the present invention is an oil component.

As the oil component used in the present invention, one or a mixture of two or more oils selected from the group consisting of esterified compounds of fatty acids and monohydric alkanols, intermediate fatty acid triglycerides and fatty acid monoglycerides can be used. The esterified compounds of fatty acids and monovalent alkanols are preferably esterified compounds of fatty acids having 8 to 20 carbon atoms and monovalent alkanols having 2 to 3 carbon atoms, for example, isopropyl myristate, isopropyl palmitate, and ethyl. Linoleate, ethyl oleate and the like can be used, and esterified compounds of linoleic acid and ethanol are particularly preferably used. In addition, as the intermediate fatty acid triglyceride, triglycerides of saturated fatty acids having 8 to 10 carbon atoms are preferably used, and particularly preferably caprylic / capric acid triglycerides which are vegetable oil triglycerides of saturated fatty acids are used. On the other hand, the fatty acid monoglycerides that can be used as an oil component in the composition of the present invention include monoglycerides of 18 to 20 carbon atoms of fatty acids, and particularly preferably monoglycerides of oleic acid may be used.

The oil component of the present invention is preferably a ratio of 1 to 10 parts by weight per 1 part by weight of cyclosporine, more preferably used in a ratio of 2 to 6 parts by weight. In the case where an oil mixture is used as an oil component in the present invention, the mixing ratio of fatty acid monoglyceride in the oil mixture: esterified compound of fatty acid and monovalent alkanol: intermediate fatty acid triglyceride is generally 1: 0.1 by weight. -5: 0.1-10, Preferably it is set as 1: 0.1-3.0: 0.1-3.0.

The fourth essential ingredient contained in the composition according to the invention is a surfactant. Surfactant that can be used in the present invention is a pharmaceutically acceptable surfactant that can form a stable emulsion by stable emulsification in water of the hydrophilic component consisting of the oil component containing the lipophilic cyclosporin and co-surfactant Any one may be used as long as HLB (hydrophilic-lipophilic balance) is 8 to 17. Preferably, polyoxyethylene product of hydrogenated vegetable oil, polyoxyethylene-sorbitan-fatty acid ester, and the like are used, for example, Nicole HCO -50, Nicole HCO-40, Nicole HCO-60, Twin 20, Twin 21, Twin 40, Twin 60, Twin 80, Twin 81 and the like are preferable. Particularly preferred surfactants which may be used in the compositions of the present invention are those of Nicole HCO-50 having an acid value of 1 or less, saponification value of about 48 to 56, hydroxyl value of about 45 to 55, and pH (5%) of 4.5 to 7.0. NIKKOL HCO-50: Polyoxyethylene (50) hydrogenated castor oil sold by NIKKO Chemical Co., Ltd., and polyoxyethylene (20) sorbitan mono sold by Tween 20 (ICI Chemicals) Laurate is preferred.

These surfactants may be used alone, respectively, but preferably two or more surfactants may be mixed and used. In the composition of the present invention, the surfactant is present in a ratio of 1 to 10 parts by weight per 1 part by weight of cyclosporin, and preferably used in a ratio of 2 to 8 parts by weight per 1 part by weight of cyclosporin. In addition, when two kinds of surfactants, polyoxyethylene (50) hydrogenated castor oil and polyoxyethylene (20) sorbitan monolaurate, are mixed, these two surfactants are polyoxyethylene (50) hydrogenated castor by weight. It is preferable to use the composition ratio of free: polyoxyethylene (20) sorbitan monolaurate as 1: 0.1-5, More preferably, it mixes and uses in ratio of 1: 0.5-4.

In the composition according to the present invention, each component is preferably present in a ratio of cyclosporin: cosurfactant: oil component: surfactant = 1: 0.1-10: 1-10: 1-10 by weight, preferably cyclosporin : Cosurfactant: Oil component: Surfactant = 1: It exists in ratio of 0.5-8: 2-6: 2-8. In addition, the compositions according to the invention illustrated in the following examples may also be mentioned as preferred further composition examples.

Compositions according to the invention having the composition as described above are used in the form of soft capsules for the purpose of oral administration.

In order to formulate the cyclosporin-containing compositions according to the invention with soft capsules, gelatinous coatings can be used according to conventional methods. In this regard, Korean Patent Application No. 96-22617 discloses an example of formulating a cyclosporin soft capsule using a mixture of polyethylene glycol and propylene carbonate as a cosurfactant. In the detailed description of the present invention, cyclosporine When polyethylene glycol is mainly used as a co-surfactant in consideration of the solubility of propylene, a small amount of propylene carbonate may cause manufacturing problems such as crystal formation. Therefore, a stable soft capsule agent may be prepared by adding a specific plasticizer to the gelatin coating. It is written. However, unlike the prior art, in the present invention, propylene carbonate is used alone or as a co-surfactant, or propylene carbonate is used as a main component and only a small amount of polyethylene glycol is used, so that the solubility to cyclosporin or the stability of a soft capsule agent is improved. In view of the above, it has been found to be advantageous to formulate long-term stable cyclosporin-containing soft capsules without the use of specific plasticizers in the gelatin coating.

Such gelatin coatings include glycerin, sorbitol, hexanetriol, propylene carbonate, hexane glycol, sorbitan, tetrahydrofuryl alcohol ether, diethylene glycol monoethyl ether, 1,3-dimethyl-2-imidazolidone, diethyl One or more plasticizers selected from conventional plasticizers such as isosorbide and the like can be used without particular limitation. In particular, since the composition of the present invention uses propylene carbonate, which is a non-hydrophilic component, as the co-surfactant as mentioned above, it is possible to effectively suppress the inflow of other components such as water or plasticizer from the gelatin coating into the contents of the capsule. Therefore, there is an advantage that there is no restriction on the use of plasticizer.                     

In the case of formulating the composition of the present invention with a soft capsule, the capsule may further contain, in addition to the above-mentioned composition, additives which are usually used for the preparation of the soft capsule. Such additives may include, for example, lecithin, viscosity modifiers, fragrances (such as peppermint oil), antioxidants (such as tocopherol), preservatives (such as parabens), pigments, amino acids, and the like.

The soft capsule according to the present invention firstly uniformly mixes the co-surfactant, oil component and surfactant, and then dissolves by adding cyclosporin while gently warming to a temperature of about 60 ℃ and the resulting concentrate as it is or if necessary It is prepared by formulating according to a conventional method in a soft capsule preparation machine by adding a pharmaceutically acceptable additive commonly used in the preparation of the soft capsule preparation as mentioned above.

The present invention is explained in more detail by the following examples, but the present invention is not limited in any way by these examples.

Example 1

                 ingredient Content (mg / capsule) Cyclosporin 25 Propylene carbonate 50 Polyoxyethylene (50) hydrogenated castor oil 90 Polyoxyethylene (20) sorbitan monolaurate 80 Ethyl linoleate 40 Caprylic / Capric Acid Triglycerides 5 Oleic acid monoglycerides 35                      gun 325 mg

Example 2

                 ingredient Content (mg / capsule) Cyclosporin 25 Propylene carbonate 100 Polyoxyethylene (50) hydrogenated castor oil 80 Polyoxyethylene (20) sorbitan monolaurate 80 Ethyl linoleate 30 Caprylic / Capric Acid Triglycerides 10 Oleic acid monoglycerides 50                      gun 375 mg

Example 3

                 ingredient Content (mg / capsule) Cyclosporin 100 Propylene carbonate 200 Polyoxyethylene (50) hydrogenated castor oil 300 Polyoxyethylene (20) sorbitan monolaurate 280 Ethyl linoleate 150 Caprylic / Capric Acid Triglycerides 20 Oleic acid monoglycerides 120 Labrafil 50                        gun 1220 mg

Example 4

                 ingredient Content (mg / capsule) Cyclosporin 25 Propylene carbonate 50 Polyoxyethylene (50) hydrogenated castor oil 90 Polyoxyethylene (20) sorbitan monolaurate 80 Caprylic / Capric Acid Triglycerides 5 Oleic acid monoglycerides 35                       gun 285 mg

Example 5

                 ingredient Content (mg / capsule) Cyclosporin 25 Propylene carbonate 100 Polyoxyethylene (50) hydrogenated castor oil 90 Polyoxyethylene (20) sorbitan monolaurate 80 Ethyl linoleate 40 Caprylic / Capric Acid Triglycerides 5 Oleic acid monoglycerides 35                        gun 375 mg

Example 6

                 ingredient Content (mg / capsule) Cyclosporin 25 Polyethylene Glycol 200 35 Propylene carbonate 45 Polyoxyethylene (50) hydrogenated castor oil 30 Polyoxyethylene (20) sorbitan monolaurate 80 Ethyl linoleate 35 Caprylic / Capric Acid Triglycerides 5 Oleic acid monoglycerides 35                        gun 290 mg

Example 7

                 ingredient Content (mg / capsule) Cyclosporin 25 Polyethylene Glycol 200 50 Propylene carbonate 100 Polyoxyethylene (50) hydrogenated castor oil 35 Polyoxyethylene (20) sorbitan monolaurate 90 Ethyl linoleate 40 Caprylic / Capric Acid Triglycerides 5 Oleic acid monoglycerides 30                      gun 375 mg

Example 8

                 ingredient Content (mg / capsule) Cyclosporin 25 Polyethylene Glycol 200 25 Propylene carbonate 45 Polyoxyethylene (50) hydrogenated castor oil 50 Polyoxyethylene (20) sorbitan monolaurate 75 Ethyl linoleate 40 Caprylic / Capric Acid Triglycerides 5 Oleic acid monoglycerides 35                       gun 300mg

Example 9

                 ingredient Content (mg / capsule) Cyclosporin 25 Polyethylene Glycol 200 20 Propylene carbonate 80 Polyoxyethylene (50) hydrogenated castor oil 35 Polyoxyethylene (20) sorbitan monolaurate 85 Ethyl linoleate 80 Caprylic / Capric Acid Triglycerides 10 Oleic acid monoglycerides 85                      gun 420mg

Example 10

From the contents prepared according to Example 1 of the present invention, a soft capsule prepared according to a conventional method was used as a test preparation, and Sandimun capsule (SANDIMMUN ™ CAPSULE), a commercial ethanol-containing commercial preparation, was used as a control preparation. The bioavailability was compared to evaluate the effect on the bioavailability and individual difference of the cyclosporin preparation according to the present invention.

In this experiment, the control and test formulations were all administered in the same amount as 300 mg as the cyclosporine per kg rabbit.

Rabbits were given a solid feed for regular rabbits for more than four days under the same conditions in a mesh box. When oral preparations were administered, they were fasted for 48 hours or more in an iron box to prevent dietary symptoms. A Levin's tube of 5 mm in diameter is inserted up to 30 cm in esophagus length, and the contents of the test and control formulations are emulsified in 50 ml of water, and placed in a syringe. At this time, petroleum jelly was applied to the surface of the levin tube to reduce friction, and test and control agents were pushed through a connected syringe. Using xylene to expand the rabbit's ear veins, heparinized disposable syringes were used for pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 10 Hourly, 24 hour intervals were taken. 0.5 ml of saturated aqueous sodium chloride solution and 2 ml of ether were added to 1 ml of blood, followed by shaking for 5 minutes. The solution was centrifuged at 5000 rpm for 10 minutes to take 1 ml of the supernatant (ether layer) and run on activated silica sep-pak ™ (Waters). The developed Sep-Pak was washed with 5 ml of n-hexane and eluted with 2 ml of methanol, and the liquid was evaporated to dryness under reduced pressure in nitrogen gas, and the residue was analyzed by HPLC (high-performance liquid chromatography). [HPLC conditions: column u-Bondapak ™ C ₁₈ (Waters), mobile phase CH ₃ CN: methanol: H ₂ O = 55: 15: 30, detector 210 nm, flow rate 1.0 ml / min, column temperature 70 ° C., sensitivity 0.01 Aufs, Injection volume 100 μl].

Test results of the test and control formulations are shown in Table 1 below.

Bioavailability of Test and Commercial Agents of the Invention (SANDIMMUN ™)    Parameter      Preparation (A)   Test agent (B)   P (B / A)   M ± S.D. (n = 6)    C V% (S.D./M)   M ± S.D. (n = 6)   C V% (S.D./M)  AUC (μghr / ml)  13.5 ± 10.0    74.0%  60.1 ± 18.0    30.0%    4.4   Cmax (μg / ml)   0.8 ± 0.3    37.5%   6.2 ± 1.5    24.2%    7.7

AUC (Area under the curve): Area under the blood concentration curve

Cmax: highest blood concentration of cyclosporine

 M ± S.D. : Mean ± Standard Deviation

 CV: ratio of standard deviation to mean

P (B / A): ratio of the mean value of the test product to the mean value of the control product

As can be seen from the results of the above table, the test agent showed a significant increase in bioavailability, with the ratio of AUC increased by about 4 times or more and the ratio of Cmax about 7 times or more. In addition, the variation among individuals (CV%) also decreased by about 2 times in AUC and about 1.5 times in Cmax.

Therefore, the soft capsule according to the present invention prepared in this manner increases bioavailability by about four times as compared with SANDIMMUN ™ CAPSULE, a commercially available ethanol-containing formulation according to the prior art, as a control agent during oral administration. In addition, the variation is also reduced, and at the same time, there is little change over time during long-term storage, which represents a remarkable progress in the field of manufacturing cyclosporine soft capsules.

Claims (15)

 (1) cyclosporin as the active ingredient; (2) propylene carbonate or a mixture of propylene carbonate and polyethylene glycol as cosurfactant; (3) an oil or a mixture of two or more oils selected from the group consisting of esterified compounds of fatty acids and monovalent alkanols, intermediate fatty acid triglycerides and fatty acid monoglycerides as oil components; And (4) a composition comprising a surfactant containing a surfactant having a HLB (Hydrophilic-lipophilic balance) value of 8 to 17, Cyclosporine-containing soft capsules. The cyclosporin-containing soft capsule according to claim 1, wherein the cyclosporin is cyclosporin A. The cyclosporin-containing soft capsule according to claim 1, wherein the co-surfactant polyethylene glycol is polyethylene glycol having a molecular weight of 200 to 600. The cyclosporin-containing soft capsule according to claim 3, wherein the polyethylene glycol as co-surfactant is polyethylene glycol having a molecular weight of 200. The cyclosporine-containing soft capsule according to claim 1, wherein the cosurfactant is a mixture of polyethylene glycol and propylene carbonate in a mixing ratio of 1: 1 to 5. 6. The cyclosporin-containing soft capsule according to claim 5, wherein the cosurfactant is a mixture of polyethylene glycol and propylene carbonate in a mixing ratio of 1: 1 to 2. The cyclosporine-containing soft capsule according to claim 1, wherein the esterified compound of the fatty acid and the monohydric alkanol in the oil component is ethyl linoleate. The cyclosporin-containing soft capsule according to claim 1, wherein the triglyceride of the intermediate fatty acid in the oil component is caprylic / capric acid triglyceride. The cyclosporine-containing soft capsule according to claim 1, wherein the fatty acid monoglyceride in the oil component is a monoglyceride of oleic acid. 2. A mixture according to claim 1, wherein a mixture of fatty acid monoglycerides: esterified compounds of fatty acids and monoalkanols: intermediate fatty acid triglycerides in a weight ratio of 1: 0.1 to 5: 0.1 to 10 is used. Cyclosporine-containing soft capsule made from. The cyclosporin-containing soft capsule according to claim 1, wherein the surfactant is a polyoxyethylene product or a polyoxyethylene-sorbitan-fatty acid ester of a hydrogenated vegetable oil. 12. The cyclosporin-containing cyclohydrochlorin of claim 11, wherein the surfactant is a mixed surfactant composed of a polyoxyethylene (50) hydrogenated castor oil: polyoxyethylene (20) sorbitan monolaurate = 1: 0.1 to 5 ratio. Containing soft capsules. The cyclosporine-containing soft capsule according to claim 1, wherein the composition contains a cyclosporin, a cosurfactant, an oil component, and a surfactant in a ratio of 1: 0.1 to 10: 1 to 10: 1 to 10 by weight. The cyclosporin-containing soft capsule according to claim 13, wherein the composition contains a cyclosporin, a cosurfactant, an oil component and a surfactant in a ratio of 1: 0.5 to 8: 2 to 6: 2 to 8 by weight. The composition according to claim 1, wherein the composition is glycerin, sorbitol, hexanetriol, propylene carbonate, hexane glycol, sorbitan, tetrahydrofuryl alcohol ether, diethylene glycol monoethyl ether, 1,3-dimethyl-2-imidazoli A cyclosporin-containing soft capsule agent encapsulated in a gelatinous film containing one or more plasticizers selected from the group consisting of don and diethylisosorbide.