SK123299A3 - Pharmaceutical compositions containing cyclosporin - Google Patents

Abstract

The present invention relates to a cyclosporin-containing soft capsule preparation which comprises a composition containing cyclosporin as an active ingredient; a hydrophilic component polyethylene glycol or a non-hydrophilic component propylene carbonate or their mixture, one or a mixture of two or more selected from the group consisting of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component; and a surfactant having an HLB (Hydrophilic Lipophilic Balance) value of 8 to 17.

Description

The soft capsule contains a composition in which cyclosporin is the active ingredient. The composition further comprises a hydrophilic component of polyethylene glycol or a non-hydrophilic component of propylene carbonate or a mixture thereof, one or a mixture of two or more of an esterified fatty acid compound and a primary alcohol, a medium chain fatty acid triglyceride and a fatty acid monoglyceride as an oily component; and a surfactant having an HLB (hydrophilic-lipophilic balance) value of 8 to 17.

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Pharmaceutical compositions containing cyclosporin

Technical field

The present invention relates to compositions containing cyclosporin as an active ingredient, for example, soft capsules. More specifically, the present invention relates to soft gelatin capsules containing cyclosporin as an active ingredient; propylene carbonate or polyethylene glycol or a mixture thereof; one or a mixture of two or more substances selected from the group consisting of an esterified fatty acid compound and a primary alcohol, a medium chain fatty acid triglyceride and a fatty acid monoglyceride as an oily component; and a surfactant having an HLB (hydrophilic lipophilic balance) value of 8 to 17.

BACKGROUND OF THE INVENTION

Cyclosporin is a specific macromolecular (molar mass 1202,64) cyclic peptide compound of 11 amino acids having a wide range of pharmacologically useful activities, particularly immunosuppressive activity and anti-inflammatory activity. Cyclosporin is therefore used to suppress the innate immunological reactions of animals that result from tissue or organ transplants, for example, transplants of the heart, lung, liver, kidney, pancreas, bone marrow, skin, cornea, and particularly in transplants of foreign tissues and organs. Furthermore, cyclosporin is useful for the suppression of hematological disorders such as anemia, various autoimmune diseases such as systemic lupus erythematosus, idiopathic malabsorption syndrome, and so on, and inflammatory diseases such as arthritis, rheumatoid disorders, and so on. Cyclosporin is useful in the treatment of protozoal diseases such as malaria, schistosomiasis, and so on, and more recently in chemotherapy.

Cyclosporin is very lipophilic and hydrophobic. Therefore, cyclosporin is poorly soluble in water and dissolves in organic solvents such as methanol, ethanol, acetone, ether, chloroform and the like. Because ciclosporin is poorly water soluble and has the aforementioned properties, it has a very low bioavailability which can be strongly influenced by the condition of each individual patient when administered orally. Thus, it is very difficult to maintain an effective therapeutic concentration. Furthermore, cyclosporin can have significant side effects, such as nephrotoxicity. Because ciclosporin is poorly soluble in water, it is therefore very difficult to formulate it into compositions for oral administration. Extensive studies are underway to provide a composition suitable for the effective oral administration of cyclosporin, which can provide appropriate unit doses and appropriate bioavailability.

Prior art compositions suitable for oral administration of poorly water-soluble cyclosporin contain cyclosporin usually in the form of a concentrated emulsion.

One typical way of using this combination is described in U.S. Pat. No. 4,388,307, issued Jul. 14, 1983. This patent discloses a liquid composition comprising cyclosporin using ethanol. According to the method described in the US patent application, cyclosporin is admixed with a carrier comprising ethanol as an additional surfactant; olive oil as a vegetable oil and the transesterification product of the natural vegetable oil triglyceride and polyalkylene polyol as a surfactant to form a liquid composition.

However, the resulting liquid composition is administered as an aqueous solution, which makes it difficult to accept upon administration and makes it difficult to obtain a uniform dosage by oral administration.

To alleviate the difficulty of diluting the liquid cyclosporin composition with water prior to oral administration, the liquid composition in the form of an emulsified concentrate is formulated into soft capsules, which are currently commercially available as Sandimmune (registered trademark). In this case, the soft cyclosporin capsule contains ethanol because of the solubility of the cyclosporin. However, since ethanol can penetrate the gelatin shell of the capsule as a volatile substance even at normal temperature, soft capsules must be packaged in special packaging material, such as aluminum-aluminum blister packs, to prevent evaporation of ethanol from the soft capsule during storage and distribution.

More recently, storage-stable cyclosporin compositions may be prepared, and there is almost no change in bioavailability between patients so that the biological effect of cyclosporin can be maintained uniform. One of the means developed for this purpose is described in Korean Patent Application no. 93-113. This composition is commercially available under the registered trademark Sandimmun Neoral. Since this composition contains ethanol, it may have some disadvantages than previously used ethanol-containing compositions, such as storage stability and changes in ethanol content.

Thus, the present inventors study many combinations of different surfactants, oil components, surfactant additives, and so on to find a cyclosporin-containing composition that is stable and provides high bioavailability, a small difference in blood levels between patients, compared to with earlier cyclosporin formulations, based on their pharmacokinetic properties. As a result, we have found that a particular cyclosporin composition comprising the components defined below may meet the above requirements, and that composition is an object of the present invention.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a formulation suitable for formulation into soft capsules comprising cyclosporin as the active ingredient; a hydrophilic substance polyethylene glycol or a non-hydrophilic substance propylene carbonate or a mixture thereof; an oil component as defined above and a surfactant.

It is another object of the present invention to provide a soft capsule containing a composition comprising cyclosporin as an active ingredient; a hydrophilic polyethylene glycol or a non-hydrophobic propylene carbonate or a mixture thereof; one or a mixture of two or more substances selected from the group consisting of an esterified medium chain fatty acid compound (if appropriate) and a fatty acid monoglyceride as an oily component; and a surfactant having an HLB (hydrophilic lipophilic balance) value of 8 to 17.

It is a further object of the present invention to provide a process for preparing soft capsules as defined above.

While the present invention is particularly described with respect to soft gelatin capsules, it should be noted that the invention encompasses compositions themselves that can be used by themselves, for example, as drinking solutions, such as Sandimmun Neoral, or may be in the form of other uniform ingredients. dosage forms.

In one embodiment, the present invention relates to cyclosporin-containing capsules having high storage stability, such as compositions that are only a small variation of the foregoing compositions and have increased bioavailability, and which contain cyclosporin as an active ingredient; a hydrophilic polyethylene glycol substance or a non-hydrophobic propylene carbonate substance or a mixture thereof as a second component; an oil component as defined above and a surfactant.

A gelatin shell is required to formulate such cyclosporin-containing compositions in a soft capsule. However, when the soft capsule is formulated with the usual capsule shell containing glycerin as a plasticizer, the soft capsule has some disadvantages in that the emulsified state of the concentrated emulsion may change due to the penetration of glycerin into the emulsion and thereby significantly reduce the solubility of cyclosporin and cyclosporin from the emulsion. starts to precipitate.

Accordingly, according to the present invention, a mixture of propylene glycol and polyethylene glycol is preferably used as the plasticizer of the gelatin shell of the capsule, which solves the problem associated with the penetration of glycerin.

However, if the strip of capsule shell containing propylene glycol and polyethylene glycol of the present invention is prepared by a water cooling method common in the art of cooling a drum, it is poorly removed from the drum. This removability of the capsule shell strip from the cooling drum can be improved by cooling the cooling drum with continuously circulating cooling water to a lower strip temperature of about 17 ° C. However, a capsule shell strip that is cooled to a lower temperature may provide a low degree of sticking during the encapsulation process and may result in a decrease in productivity.

Therefore, the method for preparing a gelatin sheath strip not containing glycerin as plasticizer according to the present invention is carried out according to the air cooling method, instead of the previously used water cooling method, when the capsule strip sheath can be cooled to optimum temperature by blowing air from the fan. and further maintained at an optimum temperature of about 21 ° C, thereby increasing the bonding rate in the encapsulation process and ensuring high productivity.

As noted above, the products of the present invention can be prepared using a glycerin-free gelatin capsule shell and air cooling method to produce compositions that do not contain ethanol as a low boiling volatile solvent and therefore have a high storage stability when time only occurs small changes and the means have increased bioavailability.

More specifically, the present invention relates to cyclosporin compositions comprising:

1. cyclosporin as an active ingredient;

2. polyethylene glycol or propylene carbonate or a mixture thereof;

3. one or a mixture of two or more compounds selected from the group consisting of an esterified fatty acid compound and a primary alcohol, a medium chain fatty acid triglyceride and a fatty acid monoglyceride as an oily component; and

4. a surfactant having an HLB (hydrophilic lipophilic balance) value of 8 to 17, for example in a gelatin shell comprising polyethylene glycol and propylene glycol as a plasticizer. In another aspect, the present invention provides a cyclosporin composition comprising

1. cyclosporin as an active ingredient; and

2. propylene carbonate

In another embodiment, the composition of the present invention does not comprise polyethylene glycol.

This composition, which also forms part of the present invention, may optionally further comprise any suitable components described herein, in an amount described herein. Cyclosporin, which is used as a pharmaceutical active ingredient in the composition of the present invention, is a cyclic peptide compound having preferred immunosuppressive activity and anti-inflammatory activity as described above. Cyclosporin A, B, D, C, G and the like can be used as the cyclosporin component of the present invention. Cyclosporin A is most preferred because its clinical efficacy and pharmacological properties are well established.

Propylene carbonate or polyethylene glycol or mixtures thereof may be used as the second component in the compositions of the present invention, which may serve as a further surfactant.

Propylene carbonate, which has a high boiling point (about 242 ° C), is non-volatile, has poor hygroscopic properties and

Nosť envelope permeability and has a high solubility with respect to cyclosporin, can be used as a non-hydrophilic substance. Alternatively, the high boiling polyethylene glycol is non-volatile, does not pass through the soft capsule gelatin shell, and has a high solubility with respect to cyclosporin, can also be used as a hydrophilic substance. Although any polyethylene glycol can be used in the composition of the present invention, it is preferred to use polyethylene glycol (PEG) having a molecular weight of 200 to 600.

A mixture of a non-hydrophilic substance and a hydrophilic substance as defined above may also be used according to the present invention. When a mixture of polyethylene glycol and propylene carbonate is used as a component of the invention, the components may be mixed in a weight ratio of 1: 0.1-5, preferably 1: 0.1-3, most preferably 1: 0.2-2.

According to the present invention, the use of polyethylene glycol and propylene carbonate provides certain advantages. That is, the stability of the cyclosporin-containing composition during storage is increased and therefore the content of the ingredients in the composition is kept almost unchanged. Further, the use of propylene carbonate may increase the solubility of the active ingredient cyclosporine and inhibit the penetration of water from the gelatin capsule shell into the composition, thereby achieving greater stability of the composition.

In the composition of the present invention, the second component is preferably used in a ratio of 0.1 to 10 parts by weight, more preferably 0.8 to 8 parts by weight, and most preferably 1 to 5 parts by weight, not one part by weight of cyclosporin.

The third component used in the emulsified concentrate of the present invention is an oil component. As the oil component of the present invention, one or a mixture of two or more substances selected from the group consisting of an esterified fatty acid compound and a primary alcohol, a medium chain fatty acid triglyceride (if present) and a fatty acid monoglyceride may be used. The esterified fatty acid and primary alcohol compound to be used according to the present invention may comprise an esterified fatty acid compound having 8 to 20 carbon atoms, for example isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate and so on, with the esterified linoleic acid compound being particularly preferred. and ethanol. Further, a C 8 -C 10 saturated fatty acid triglyceride (if present) may be used, preferably caprylic / capric triglyceride as vegetable oil of the fatty acid triglyceride. The fatty acid monoglyceride which may be used as the oily component of the present invention includes a C 18 -C 20 fatty acid monoglyceride, especially oleic acid monoglyceride.

In the microemulsion concentrate of the present invention, the oil component may be used in a ratio of 1 to 10 parts by weight, preferably 2 to 6 parts by weight, per 1 part by weight of cyclosporin.

Preferably, the fatty acid monoglyceride and the fatty acid ester are present as an oily component, for example in a ratio of 1: 1 to 1: 2, for example 1: 1 to 1: 1.2.

Optionally, a caprylic / capric acid triglyceride is also present, for example in a ratio of 1: 0.1 to 0.2 to ethyl linoleate.

In the oil composition used as the oil component of the present invention, the weight mixing ratio of the fatty acid monoglyceride: esterified fatty acid compound and primary alcohol: medium chain fatty acid triglyceride (if present) may preferably be 1: 0.1-5: 0.1 -10, preferably 1: 0.1-3.0: 0.1-3.0.

The fourth component used in the present invention is a surfactant. Surfactants suitable for use in the present invention include pharmaceutically acceptable surfactants having an HLB (hydrophilic-lipophilic balance) value of 8 to 17 and capable of stably emulsifying the lipophilic portion of the composition comprising the cyclosporin-containing oil component and the hydrophilic portion comprising the other surface-active agent. active ingredient in water to form a stable emulsion. Examples of preferred surfactants of the present invention are the polyoxyethylene products of hydrogenated vegetable oils, polyoxyethylene sorbitan fatty acid esters and the like, for example, NIKKOL HCO-50, NIKKOL HCO40, NIKKOL HCO-60, TWEEN 20, TWEEN 21, TWEEN 40, TWEEN 60, TWEEN 60, TWEEN 60 TWEEN 81 and so on. Especially preferably, hydrogenated castor oil containing 50 polyoxyethylene units (polyoxyethylene (50) hydrogenated castor oil), which is commercially available under the trademark NIKKOL HCO-50 (NIKKO Chemicals Co., Ltd.) and polyoxyethylene sorbitan monolauric acid ester containing 20 polyoxyethylene units (polyoxyethylene (20) sorbitan monolaurate), which is commercially available under the trademark TWEEN 20 (ICI Chemicals) having an acid number of less than 1, a saponification value of 48-56, a hydroxyl value of 45-55 and a pH value of 5%, 5 to 7.0.

The surfactant may be any of said surfactants alone or preferably in a combination of two or more surfactants selected from said surfactants. In the composition of the present invention, the surfactant may be used in a ratio of 1 to 40 parts by weight, preferably 2 to 8 parts by weight, per 1 part by weight of cyclosporin.

Further, when a mixture of two surfactants is used, i. hydrogenated castor oil containing 50 polyoxyethylene units and polyoxyethylene sorbitan ester of monolauric acid containing 20 polyoxyethylene units in the composition of the present invention, the weight ratio of hydrogenated castor oil containing 50 polyoxyethylene units: polyoxyethylene sorbitan ester of monolauric acid containing 1 to 20 polyoxyethylene units; more preferably 1: 0.5-4.

Preferably, four components are present in the composition of the present invention in a weight ratio of cyclosporine: second component: oil component: surfactant = 1: 0.1-10: 1-10: 110, and more preferably in a ratio of cyclosporine: second component: oil component: surfactant = 1: 0.5-8: 2-6: 2-8.

In addition to this composition, the compositions illustrated in the following examples may be considered as a further preferred composition of the present invention.

For oral administration, the composition of the present invention containing said ingredients may be formulated as a soft capsule. Since the soft capsules of the present invention do not contain ethanol as a low boiling volatile solvent, they are pharmaceutically stable and the desired improvements, including enhancement in bioavailability, can be determined.

However, it may be difficult to prepare conventional soft capsule shells by using the usual soft capsule method. When the soft capsule is formulated in conventional capsules containing glycerin as a plasticizer, the soft capsule thus prepared may have some disadvantages that the emulsified state of the emulsified concentrate may change due to the penetration of glycerin into the emulsion, thereby significantly reducing the solubility of cyclosporin and cyclosporin. it starts to precipitate from the emulsion.

Thus, in another object of the present invention, it has been found that when a capsule shell is prepared using a mixture of polyethylene glycol and propylene glycol and not glycerin as a plasticizer, a soft capsule is obtained which is stable over the long term. Although any polyethylene glycol which can be liquefied can be used as a plasticizer, it is preferable to use polyethylene glycol having a molecular weight of 200 to 600.

Particularly preferred is polyethylene glycol 200. In the soft capsule containers of the present invention, the mixture of polyethylene glycol and propylene glycol is preferably used in a ratio of 0.1 to 0.5 parts by weight, more preferably 0.1 to 0.4 parts by weight, and most preferably 0.2 to 0, 3 parts by weight relative to one part by weight of gelatin used to prepare the capsule shell. In the mixture of polyethylene glycol and propylene glycol as plasticizer, propylene glycol is mixed preferably in a ratio of 1 to 10 parts by weight and most preferably 3 to 6 parts by weight with respect to one part by weight of polyethylene glycol.

In order to facilitate removal of the soft capsule wrapper strip from the cooling drum, the method of preparing the gelatin capsule wrapper strip of the present invention is performed using an air-cooling method instead of a water-cooling method. According to this method of air cooling, since the capsule shell strip does not overheat and can be easily removed from the cooling drum at an optimum temperature of about 21 ° C, the bonding rate in the encapsulation process is high, thereby achieving high productivity and therefore the process can be advantageously performed.

In the preparation of the soft gelatin capsules of the present invention, a suitable cooling air flow rate for cooling the capsule shells is preferably 5 to 15 m ³ / min, most preferably 10 ³ / min.

Since propylene carbonate alone or the main component can be used as the second component of the present invention, cyclosporin-containing soft capsules that are stable over the long term, due to the solubility of the cyclosporin and the soft capsule stability, can be formulated without the use of a special gelatin shell softener.

In the gelatin shell, one or more substances selected from the group consisting of glycerin, sorbitol, hexanetriol, propylene carbonate, hexane glycol, sorbitans, tetrahydrofuryl alcohol ether, diethylene glycol monoethyl ether, 1,3-dimethyl-2-imidazolidide, dimethylisososide, dimethylisososide, dimethylisosolidide, dimethylisosolidide, dimethylisososide can be used. It should be noted, however, that the plasticizer used in the present invention is not limited to the examples given.

When formulating the composition of the present invention into soft capsules, the capsule may further comprise, as appropriate, pharmaceutically acceptable excipients commonly used in the preparation of soft gelatin capsules. Such additives include, for example, lecithin, viscosity modifiers, fragrance (e.g. peppermint oil, etc.), antioxidants such as tocopherol, vitamin E, etc.), preservatives (e.g. paraben, etc.), colorants, amino acids, etc.

The soft capsules of the present invention can be prepared by homogeneously mixing the other surfactant, the oil component and the surfactant, dissolving the cyclosporin in this mixture with stirring and warming to about 60 ° C and then formulating the resulting concentrate with or without said pharmaceutically acceptable. additives commonly used in the preparation of soft capsules by means of an air-cooling method, to suitable soft capsules containing cyclosporin.

The compositions and methods of the present invention are suitable for the same indications and can be administered in the same manner and within the same dosage range as known cyclosporin-containing compositions. If appropriate, the dose is adjusted based on a standard bioavailability test in animals, for example dogs or humans, as described, for example, below.

Since the composition of all ingredients or ingredients is not described herein, these data can be found in the literature, for example, HP Fiedler, Lexicon der Hilfsstoffe, Edito Cantor Verlag, Aulendorf, Germany, fourth edition 1996, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, A Pharmaceutical Society, London, Second Edition, 1994, and Korean Patent Application 94-29208, Nov. 2, 1994.

The present invention will be further illustrated by the following examples. It should be noted, however, that these examples do not limit the scope of the present invention in any respect.

DETAILED DESCRIPTION OF THE INVENTION

Examples 1 to 5

Example component

cyclosporine

Polyethylene glycol 200

propylene carbonate

Polyoxyethylene (50) hydrogenated castor oil

Polyoxyethylene (20) sorbitan monolaurate

ethyl linoleate

Caprylic / capric acid triglyceride

Oleic acid monoglyceride

Total (mg)

1 2 Contents 3 4 (Mg / capsule) 5 25 25 25 25 25 45 70 100 45 45 25 - 50 25 25 35 35 35 50 35 85 85 85 100 85 40 40 40 40 80 5 5 5 5 10 35 35 35 35 70 295 295 375 325 375

Example 6

A soft gelatin capsule is prepared from the composition of Example 1 using the following capsule shell composition and then visually observed change in properties and content state under the influence of glycerin penetration.

6.1. (control group)

Ingredient gelatin purified water glycerin

6.2 (test group)

Gelatin component purified water propylene glycol polyethylene glycol

Weight ratio

Weight ratio

200 1

The results observed are shown in Table 1 below.

Table 1: Stability of the capsule contents by capsule shell

composition Just after 1 day Mon 2 Mon 5 Mon 10 Mon 30 capsules training days days days days inspection 0 + + ++ +++ +++ group test 0 0 0 0 0 0

group

Remarks: 0 = content is stable + = poor emulsification ++ = slight precipitation +++ precipitation

As can be seen from the results in Table 1, capsules prepared using a control group 6.1 formulation containing glycerin as a plasticizer cause some difficulties, including the formation of a precipitate due to glycerin infiltration, while compositions prepared using a test group formulation 6.1 containing polyethylene glycol with propylene glycol as a plasticizer, they remain stable.

Example 7

The soft capsules of the composition of Example 1 were prepared using the capsule shell of Test Group 6.2 used in Example 6 using a water cooling method (water temperature about 12 ° C) and an air cooling method (air flow 10 m ³ / min).

In both cases, the removability of the capsule shell strip from the cooling drum is observed and compared. The observed results are shown in Table 2 below.

Table 2: Removing the gelatin sheath strip from the cooling drum depending on the cooling method (Unit: angle)

Composition of packaging Water cooling method Method of cooling by air Example 6.2 > 100 degrees <50 degrees (bad removability) (good removability)

As can be seen from the results presented in Table 2, the soft gelatin capsules prepared by the air cooling of the present invention have much better removability from the cooling drum compared to the compositions prepared by the water cooling method. In general, if the degree to remove the gelatin sheath strip from the cooling drum 70 or higher is removable, it is considered poor and if the angle to remove the sheath strip is less than 70, the removability is considered good. The soft capsules prepared by the water cooling method are poorly removed from the cooling drum even if the removal angle is 100 degrees or higher.

In contrast, the soft capsules prepared by the air-cooling method of the present invention are readily removed from the cooling drum at an angle of 50 degrees or less and can provide good bonding and productivity.

Example 8

The bioavailability of the composition prepared by encapsulating the composition of Example 1 with a gelatin shell having the composition of Example 6.2 as a test composition was compared to the bioavailability of a commercial composition containing ethanol (SANDIMMUN capsules) as a control and revealed the effect of the cyclosporin-containing composition. The invention for the bioavailability of cyclosporin and the difference in utility between the two agents. In this experiment, the test composition and the control composition were administered in an amount of 300 mg cyclosporin per kg of rabbit.

The rabbits were fed with the same conventional solid feed for 4 days or more under the same conditions in wire cages. When the formulation was orally administered, the rabbits were left for 48 hours without food in steel cages and allowed free access to water.

The 5 mm diameter Levin tube is greased with petroleum jelly to reduce friction and is inserted through the esophagus to a depth of 30 cm. Each test composition and control composition is emulsified with 50 ml of water and then introduced into a syringe attached to the Levin tube. Rabbit ear vessels are expanded with xylene, and then blood is drawn from each rabbit ear prior to the test and after 0.5, 1, 1.5, 2, 3, 4, 6, 10, and 24 hours using a disposable heparin-treated syringe. 0.5 ml of saturated aqueous sodium chloride solution and 2 ml of ether are added to 1 ml of the blood thus obtained, and the mixture is shaken for 5 minutes and centrifuged at 5000 rpm for 10 minutes to separate the supernatant and apply to activated silica gel sep. then ^R (Waters). The residue is washed with 5 ml of hexane and eluted with 2 ml. The eluate is evaporated to dryness under a nitrogen atmosphere. The residue is analyzed by HPLC (methanol under reduced pressure conditions).

HPLC: p-Bondapak ^R Cie column (Waters), acetonitrile: methanol: water - 55:15:30, detection at 210 nm, flow rate 1.0 mL / min, column temperature 70 ° C, sensitivity 0, 01

Aufs, injection volume 100 μΐ).

The results obtained for the test composition and the control composition are shown in Table 3:

Table 3: Bioavailability of the test composition of the invention and the commercial composition (SANDIMMUN®).

parameter inspection Prostr. (A) tested prostr. (B) B / A M ± S.D.. CV% M ± S.D.. CV% (N = 6) (S.D./M) (N = 6) (S.D./M) AUC 13.5 ± 10.0 4.1 (gg.h / l) 74% 57.0 ± 17.0 29,8% Cmax 0.8 ± 0.3 37,5% 6.0 ± l, 5 25,0%

7.5 (pg.h / l)

Notes: AUC = Area under the blood concentration curve

Cmax = Maximum cyclosporin blood concentration

M ± S.D.. = Mean ± standard deviation

CV = Ratio of standard deviation to mean

P (B / A) = Ratio of the mean of the test agent to the mean of the control agent

As can be seen from the table above, the test composition exhibits increased AUC and C _max values that are about four or more times and seven or more times higher than the control composition. Thus, the test composition by the control means of the present invention will be apparent to those of skill in the art that the bioavailability is significantly higher compared to that of the test composition by reducing the difference in individuals (CV%) by about two or more Cmax / as compared to control.

Thus, it can be determined that when the soft capsule of the present invention is administered orally, it exhibits an increased bioavailability of cyclosporin about four times higher than previous commercial ethanol-containing formulations (SANDIMMUN ^R capsules) and also a lesser difference in bioavailability of cyclosporin in individual subjects. remains stable without any changes during long shelf life. Thus, it will be appreciated that the soft capsule of the present invention provides a significant improvement in the field of cyclosporin-containing soft capsules.

Example 9

Soft capsules are prepared having the following composition:

I II cyclosporine 25 mg 100 mg Polyethylene glycol 200 45 mg 180 mg propylene carbonate 25 mg 100 mg

Polyoxyethylene (50) hydrogenated • I 40 mg II 160 mg castor oil Polysorbate 20 85 mg 340 mg ethyl linoleate 40 mg 160 mg Glycerol monooleate 40 mg 160 mg Vitamin E 1 mg 4 mg Pretty 301 mg 1204 mg

Examples 10 11 12 13 14 Contents (Mg / capsule) cyclosporine 25 25 100 25 25 propylene carbonate 50 100 200 50 100 Polyoxyethylene (50) hydrogenated castor oil 90 80 300 90 90 Polyoxyethylene (20) sorbitan monolaurate 80 80 280 80 80 ethyl linoleate 40 30 150 - 40 Caprylic acid triglyceride vej / capric 5 10 20 5 5 Oleic acid monoglyceride 35 50 120 35 35 Labrafil - - 50 - - Pretty 325 375 1220 285 375

Examples 15 16 17 18 Content (mg / capsule) cyclosporine 25 ' 25 25 25 Polyethylene glycol 200 35 50 25 20 propylene carbonate 45 100 45 80 Polyoxyethylene (50) hydrogenated 30 35 50 35 castor oil Polyoxyethylene (20) sorbitan 80 90 75 85 monolaurate ethyl linoleate 35 40 40 80 Caprylic acid triglyceride 5 5 5 10 vej / capric Oleic acid monoglyceride 35 30 35 85 Pretty 290 375 300 420 Example 19 Bioavailability soft capsules ready

the composition of Example 10 by a conventional method, such as the test preparation, the commercial usability was compared with a biological composition containing ethanol (SANDIMMUN ^R) as the control preparation to reveal the influence of the cyclosporin preparation according to the present invention on the bioavailability of cyclosporin and its difference between individuals.

The test procedure is the same as described in Example 8.

The results obtained from the test formulation and the control formulation are shown in Table 4 below:

Table 4: Bioavailability of the test composition of the invention and the commercial composition (SANDIMMUN *)

parameter inspection Prostr. (A) tested prostr. (B) B / A M ± S.D.. CV% M ± S.D.. CV% (N = 6) (S.D./M) (N = 6) (S.D./M) AUC 13.5 ± 10.0 4.1 (gg.h / l) 74% 60, l ± 18.0 30,8% Cmax 0.8 ± 0.3 7.5 (pg.h / l) 37,5% 6.2 ± 1.5 24,2%

Notes: AUC = Area under the blood concentration curve

Cmax = Maximum cyclosporin blood concentration

M ± S.D.. = Mean ± standard deviation

CV = Ratio of standard deviation to mean

P (B / A) = Ratio of the mean of the test agent to the mean of the control agent

As can be seen from the above table, the test composition exhibits elevated AUC and C _max values that are about four or more times and seven or more times higher than the control composition. Thus, it is evident that the bioavailability of the test composition is significantly higher compared to the control composition. Further, the test composition of the present invention has the effect of reducing the difference between the respective test subjects (CV%) by about two or more times according to the AUC and about one and a half times according to the C max value, compared to the control composition.

Thus, it can be determined that when the soft capsule of the present invention is administered orally, it exhibits an increased bioavailability of cyclosporin about four times higher than previous commercial formulations containing ethanol (SANDIMMUN ^R capsules) and also reduced the difference in bioavailability of cyclosporin in different subjects and while maintaining stability without any changes during long-term storage. Thus, it is clear that the soft capsule of the present invention provides a significant improvement in the field of cyclosporin-containing soft capsules.

Claims (10)

A composition comprising cyclosporin, characterized in that it comprises: a) cyclosporin as an active ingredient (b) propylene carbonate c) one or a mixture of two or more substances selected from the group consisting of an esterified fatty acid compound and a primary alcohol, a medium chain fatty acid triglyceride and a fatty acid monoglyceride as an oil component. (d) a surfactant having an HLB (hydrophilic lipophilic balance) value of 8 to 17 The cyclosporin-containing composition of claim 1, wherein the medium chain fatty acid triglyceride is caprylic / capric acid triglyceride. The cyclosporin-containing composition of claim 1 or 2, wherein:. the fatty acid monoglyceride is oleic acid monoglyceride. The cyclosporin-containing composition of any one of claims 1 to 3, wherein the surfactant is a polyoxyethylenated hydrogenated vegetable oil product or a polyoxyethylene sorbitan fatty acid ester. The soft capsule containing the cyclosporin composition of claim 4, wherein the surfactant is a mixed surfactant comprising hydrogenated castor oil containing 50 polyoxyethylene units: polyoxyethylene sorbitan ester of monolauric acid containing 20 polyoxyethylene units in a mixing ratio of 0.1: 5th A soft capsule containing a cyclosporin composition according to any one of claims 1 to 5, wherein the cyclosporin, component b), the oil component and the surfactant are present in a weight ratio of 1: 0.1-10: 1-10: 1. -10. The cyclosporin-containing composition of claim 6, wherein the cyclosporin, component (b), the oil component and the surfactant are present in a weight ratio of 1: 0.5-8: 2-6: 2-8. 8. A cyclosporin-containing composition comprising (a) cyclosporin as active ingredient; and (b) propylene carbonate. Composition according to claim 8, characterized in that it comprises one or more further components as defined in claims 1 to 7. 10. The composition of claim 8, wherein said composition is free of polyethylene glycol.