KR19990062826A - Cyclosporine-containing pharmaceutical composition - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing cyclosporin as an active ingredient. The composition according to the invention comprises, as its components, cyclosporine, triacetin or triethyl citrate as a cosurfactant alone or a mixture of both and a mixture of propylene carbonate, an oil component, and a surfactant. According to the present invention, an O / W type microemulsion having a particle diameter of 100 nm or less can be obtained when dissolved in water by appropriately adjusting the composition ratio of components. The composition of the present invention can be formulated as a soft capsule, a hard capsule with the junction sealed with gelatin bending, or an oral solution. In particular, when the composition of the present invention is formulated with a soft capsule, it provides an excellent advantage in changing the appearance of the capsule caused by gelatin membrane permeation of the solvent, suppressing the precipitation formation of the drug due to volatilization of the solvent, and economic effects by reducing the manufacturing cost. It is characterized by.

Description

Cyclosporine-containing pharmaceutical composition

The present invention relates to a pharmaceutical composition containing cyclosporin as an active ingredient. More specifically, the composition according to the present invention comprises cyclosporine, triacetin or triethyl citrate as a cosurfactant alone or a mixture of both and a mixture of propylene carbonate, an oil component, and a surfactant.

Cyclosporine is a polymer peptide drug consisting of eleven amino acids, which suppresses immunorejection after transplantation of organs and tissues. There are cyclosporin A, B, C, D, G, etc. according to the structure of the constituent amino acid residues, but cyclosporin A, in which pharmacological activity and clinical applications are most widely used, is most preferably used. Cyclosporin is a poorly soluble drug that is hardly soluble in water. It is difficult to use in clinical practice because of low bioavailability, severe variation among patients, and high toxicity. In particular, the low bioavailability is very difficult to control the dosage of the drug.

Although many studies have been conducted to improve the bioavailability of cyclosporin, commercially available formulations include soft capsules or solutions in which cyclosporin is dissolved in a mixture of vegetable oils, surfactants, and solvents. Soft-encapsulated formulations are only commercially available.

The microemulsion has a high absorption or penetration ability because the particles of the inner phase is less than 100nm, particularly useful for solubilizing poorly soluble drugs and improving bioavailability. However, the single dose of microemulsion was large and practical clinical application was impossible.

Recently, formulations in the form of concentrates of microemulsions have been developed to enable the application of microemulsions to poorly soluble drugs such as cyclosporin. Indeed, microemulsion concentrates can be used for cyclosporin to increase bioavailability up to twofold. Microemulsion concentrate consists of co-surfactant, oil, and surfactant and is a preparation that dissolves in the gastrointestinal tract and becomes a microemulsion by itself. In order for the microemulsion concentrate to be dissolved in the gastrointestinal tract and become a microemulsion, four components including the main medicine should be composed in an appropriate ratio. The composition ratio is obtained through extensive experiments such as 3-Phase plot study.

In order to formulate cyclosporin into a microemulsion concentrate, the choice of co-surfactant that acts as a solvent is very important. This is because poorly soluble cyclosporin precipitates as crystals if the co-surfactant is not appropriate. According to the existing technology, ethanol is essentially used as a cosurfactant. However, ethanol volatilizes over time, and cyclosporine eventually precipitates as crystals. In addition, due to volatilization, the initial composition ratio is also changed, resulting in an emulsion having an average particle size of about 5000 nm without forming a microemulsion in the gastrointestinal tract during administration. As a result, the bioavailability drops and the expected clinical effect cannot be obtained.

In order to alleviate this drawback, methods using non-ethanol components instead of ethanol as hydrophilic cosurfactants have also been proposed. U.S. Patent No. 5,342,625 discloses a microemulsion preconcentrate composition using 1,2-propylene glycol, Transcutol, Glycofurol as hydrophilic solvents and ethanol as a co-solvent. However, these hydrophilic solvents are glycols containing an alcohol group (-OH) in their structure, and have high hygroscopicity, high reactivity and volatility with a gelatin coating, and thus have problems in formulating into soft capsules. In particular, these solvents absorb moisture into the capsule film inside during the manufacturing process of the soft capsule, and the composition ratio of the contents changes up to 20% by voluntarily dispersing the film itself, and volatilizes through the skin during distribution. As a result, the initial composition ratio is greatly changed, which causes the crystals of cyclosporin to precipitate or cause problems in microemulsion formation. In addition, these hydrophilic solvents are reactive with gelatinous coatings, so that the hydrophilic solvents dissolve the capsules.

The present invention is to provide a cyclosporin-containing pharmaceutical composition that can improve the problems of conventional formulations and can be formulated into soft capsules, the co-surfactant of triacetin or triethyl citrate alone or a mixture of both and propylene carbonate It is an object of the present invention to provide a stable, cyclosporine-containing pharmaceutical composition which does not change its initial composition into a microemulsion concentrate using a mixture and does not react with the coating when prepared as a soft capsule.

1 is a graph comparing the concentrations of cyclosporin in whole blood after administration of a commercially available cyclosporin preparation (Sandimmun, control) and a cyclosporin-containing pharmaceutical composition (test preparation) prepared according to the present invention ( ●, control agent; ▽, test agent of Example 1-D; ■, test agent of Example 2-B; ◇, test agent of Example 3-D; and ▲, test agent of Example 4-C) .

The present invention relates to (1) cyclosporine as active ingredient, (2) triacetin or triethyl citrate alone or a mixture of both and propylene carbonate as a cosurfactant, (3) oil component, and (4) surfactant It relates to a pharmaceutical composition comprising a.

In the cyclosporine-containing pharmaceutical composition according to the present invention, the first essential ingredient is a cyclosporin. Cyclosporins include cyclosporin A, B, C, D and G, but cyclosporin A is most preferably used.

The second essential ingredient of the composition of the present invention is a cosurfactant. The cosurfactant used in the cyclosporine-containing pharmaceutical composition of the present invention is triacetin or triethyl citrate alone or a mixture of both and a mixture of propylene carbonate.

Propylene carbonate, one of the co-surfactant components used in the present invention, is a colorless transparent liquid, which has been used pharmaceutically as a solvent for oral and topical preparations and has a boiling point of 242 ° C., which does not volatilize during distribution. In addition, it is a solvent that is not hygroscopic, such as glycols, but has no reactivity and volatility with gelatinous coatings. In addition, it is a solvent that is easy to apply to cyclosporine because it has excellent solubility in poorly soluble drugs.

In the composition of the present invention, triethyl citrate and triacetin may be used as a hydrophilic cosurfactant in a form mixed with propylene carbonate. Triethyl citrate is a colorless, transparent liquid, widely used as a plasticizer and widely applicable to foods and cosmetics. It is a component that can ensure the stability of the formulation because the boiling point does not volatilize at room temperature or high temperature at 288 ℃. In addition, it is a solvent that can be applied as an effective solvent of cyclosporine due to the amphiphilic soluble very well in the oil phase and water phase according to the properties of the present agent. Triacetin is a reaction product of glycerin and acetic anhydride. It is a colorless transparent liquid widely used as a solvent, humectant, and plasticizer. It has a boiling point of 258 ° C and does not volatilize even under high temperature conditions when stored at room temperature or during the manufacture of soft capsules.It is not only stable in formulations during storage and manufacturing, but also has no reactivity and volatility with gelatinous coatings. to be. It is also an amphiphilic solvent that dissolves well in oils such as soybean oil, water and ethanol, and can be applied as an effective solvent of cyclosporine.

In the present invention, as the co-surfactant, a triacetin or triethyl citrate alone or a mixture of both and a mixture of propylene carbonate is used. It can be used as an optimal solvent of cyclosporine by using a mixture of hydrophilic propylene carbonate, lipophilic triethyl citrate and triacetin.

According to the present invention, when a mixed component of propylene carbonate and triethyl citrate or triacetin is used as a hydrophilic cosurfactant, it is used by mixing in a ratio of 1: 0.1-5, more preferably 1: 0.1-2. Can be. In addition, when using a mixture of propylene carbonate, triethyl citrate and triacetin as the hydrophilic cosurfactant according to the present invention, the ratio of each component is 1: 0.1 to 5: 0.1 to 5, more preferably 1: 0.1 to 2: 0.1. It can mix and use in the ratio of -2.

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

The third essential ingredient contained in the composition of the present invention is an oil component. Oil components in the composition of the present invention include vegetable oils; Esterification products of vegetable oils; Animal oils and derivatives thereof; And a single component or a mixture of two or more selected from the group consisting of higher unsaturated fatty acids can be used. As a matter of course, in addition, when using two or more kinds of mixed ingredients, one or more kinds may be selected and used in each of the subgroups of the above classification, or two or more kinds may be taken in any one of the subgroups of the above classification.

In the present invention, for example, vegetable oils such as corn oil, borage oil, sesame oil, primrose oil, peanut oil, olive oil, and the like may be used.

Purified vegetable oils have high purity and low impurity content, and because they can regulate the content of higher unsaturated fatty acids according to the purification process, intravenous injection used in consumable diseases such as diabetic neuropathy and rheumatoid arthritis in the pharmaceutical field. It has been mainly used in nutritional fluids, that is, high purity lipid fluids, and has been used as a stable base against various intravenous solvents and unstable drugs. Purified vegetable oil has been purified by chromatographic method. It has more transparent properties than general oil, and it removes oxidizing substances such as aldehydes, alcohols, ketones, etc. in oil and enhances stability against oxidation. By greatly reducing the content, the solubilization ability for drugs is superior to that of ordinary oils. Purified and commercially available vegetable oils generally have a peroxide value of 0.5 or less, an anisidine value of 0.2 to 0.5, and an acid value of 0.1 to 1.0 or less. Oil can be selected and used.

Examples of purified vegetable oils that are preferred vegetable oils that can be used in the compositions of the present invention include, but are not limited to, super-refined oils (superfine corn oils, commercially available from Croda Co.), Western Bored oil, sesame oil, primrose oil, peanut oil and olive oil. A more preferred vegetable oil which can be used in the composition of the present invention is a form in which the content of gamma linolenic acid (gamma linolenic acid (C _{18: 3} )) is increased to 50% or more, and as an example, Crosential [Crodada Products] There is a concentrated borage oil under the trade name.

Other oil component esterification products of vegetable oils that can be used in the composition of the present invention include, but are not limited to: i) esterification products of vegetable oils with glycerin; Ii) esterification products of vegetable oils with monohydric alcohols; V) esterification products of vegetable oils with polyglycerols. At this time, the esterification reaction is to react the fatty acids present in the vegetable oil, and this reaction product, which is mixed with various substances, can be separated and purified and used as a pure oil state. In addition, the fatty acid in the vegetable oil may be separated and purified, followed by esterification to be used as the product.

Among the esterification products of vegetable oils, among the esterification products of vegetable oils with glycerin, triglycerides of fatty acids; Or mono- and di-glycerides of fatty acids.

Preferred as triglycerides of fatty acids, one of the esterification products of vegetable oils, are triglycerides of intermediate fatty acids having 8 to 12 carbon atoms, namely medium chain triglycieride (MCT) oils. Emcity oil is produced by esterification of fatty acids in palm oil with glycerin and is the triglyceride of intermediate fatty acids whose main constituent fatty acids are caprylic acid (50-80%) and capric acid (20-50%). Commercially available products such as C-City oil include SEPOL 860, SEPOL 870, SEPOL 880, MIGOLOL 810, MIGOLOL 812, and MIGOLOL 818.

Mono- and di-glycerides can be used as another kind of esterification reaction of vegetable oils with glycerin. Mono- and di-glycerides are oils obtained through a process of separating and purifying fatty acids in vegetable oils with a glycerin esterification reaction, and there are various kinds according to the type of the fatty acids reacted and the degree of esterification. Preferred mono- and di-glycerides which can be used in the compositions according to the invention contain at least 40% of mono-glycerides and preferably at least 90% and are higher grades having from 16 to 18 carbon atoms in the constituent fatty acids. Mono- and di-glycerides of fatty acids. More preferably, monoglycerides of higher unsaturated fatty acids having 18 carbon atoms are mono- and di-glycerides as main components. Commercially available products such as mono- and diglycerides include GMO AV1 (manufactured by Croda Co.) and ATMOS 300 (ICMOS Co.). Products], GMOrphic 80 (product of EASTMAN Co.), mivaset and the like. In particular, GMmolpick 80 is pure monoglycerides without diglycerides by purely separating and extracting only monoglycerides of oleic acid through molecular distillation after the esterification reaction, and thus can be used as an oil component in the composition of the present invention. Is an even more preferred example.

Second of the esterification products of vegetable oils, esterification products of vegetable oils with monohydric alcohols can be used. Oils obtained by reacting vegetable oils with monohydric alcohols are divided into various types according to the vegetable oils to be reacted, and as a representative example, reaction products of borage oil and ethanol are referred to as CROSSENTIAL GLO E50 (concentrated borage oil ethyl ester). As a reaction product of [Croda Co., Ltd.] and olive oil and ethanol, the brand name Niko EOO (ethyl olive oleate) [product of Nikkol Co.]. There are also oils obtained by separating single fatty acids from vegetable oils and reacting with monohydric alcohols. Examples of such reaction products of fatty acids with monohydric alcohols include ethyl oleate, ethyl linoleate, and isopropyl palmitate. Isopropyl palmitate), isopropyl myristate, etc. are mentioned.

Third among esterification products of vegetable oils are esterification reaction products of fatty acids with polyglycerols, namely polyglyceryl fatty acid esters. Polyglycerols used in the esterification reaction include diglycerol, tetraglycerol, hexaglycerol, decaglycerol, and the like, and the reaction fatty acids include oleic acid, linoleic acid and stearic acid. Polyglyceryl fatty acid esters can be selected as a hydrophilic oil according to its structure and has been applied as a food additive. Such polyglyceryl fatty acid esters include Plurol Oleique CC 497 (ie polyglyceryl oleate) [product of Gattefosse Co.], Plurol Stearique (ie polyglyceryl palmitostearate) [ Product of GATEPOSE, DGMO-C (ie diglyceryl monooleate) [product of Nicole], Tetraglyn 1-O (ie tetraglyceryl monooleate) [product of Nicole], hexagly 1- O (Hexaglyn 1-O; hexaglyceryl monooleate) [product of Nicole Corporation], decaglyn 5-O (ie decaglyceryl pentaoleate) [Product of Nicole Corporation].

In the composition of the present invention, animal oil and derivatives thereof may be used as the oil component, and the first example is squalene. Squalene from shark liver oil is a colorless, transparent oil whose chemical name is Hexamethyltetracosahexaene. Squalene is more resistant to oxidation than common animal oils and has a low freezing point that can effectively solubilize cyclosporine. In addition, hydrogenated squalene obtained by hydrogenation of squalene may also be used as an oil component of the cyclosporine microemulsion concentrate. Commercial products of such squalene include Squalene EX and Squalene of Nicole.

Omega-3 essential fatty acids (EFAs), oils in their ethyl esterified form, triglycerides thereof as second examples of animal oils and derivatives thereof which can be used as oil components in the compositions of the invention Oil in the form, and the like. Omega-3 essential fatty acids are animal oils containing eicosapentaenoic acid and docosahexaenoic acid as fatty acids, and are commercially available from Croda Co. Incromega F2250 and Incromega F2628. The ethyl esterified oils are commercially available products from Croda, Incromega E2251 and Incromega F2573. The triglyceride type oils are commercially available products of Chroda Inc. Ingmega TG2162, Incromega TG2779 and Incromega TG2928.

In addition, higher unsaturated fatty acids may be used as the oil component in the composition of the present invention. Such fatty acids include oleic acid, linoleic acid, linolenic acid, and the like. Oleic acid is commercially available under the trade name Crosensal 094 (manufactured by Croda Co., Ltd.), linoleic acid under the trade name Crocensal L99 [manufactured by Croda Company], and linolenic acid under the trade name Crossenal LN80 [manufactured by Croda Company].

The various oil components described above can be used in appropriate combination for the purpose of controlling the absorption of cyclosporin.

In the cyclosporin-containing microemulsion preconcentrate composition according to the present invention, the composition ratio of cyclosporin: oil component on the basis of weight is preferably 1: 0.1-5, more preferably 1: 1: 1.

The fourth component in the cyclosporin-containing microemulsion preconcentrate composition according to the invention is a surfactant. The surfactant preferably has an HLB value of 1 to 20, for example, the following surfactants:

1) reaction products of natural or hydrogenated vegetable oils with ethylene glycol; Polyoxyethylene glycolated natural or hydrogenated vegetable oils; For example polyoxyethylene glycolated natural or hydrogenated castor oil. Surfactants commercially available under the trade names Cremophor RH 40, Cremophora RH 60, Cremophora EL, Nikkol HCO-40, Nikkol HCO-60 and the like can be used. Preferred surfactants for use in the compositions of the present invention are Cremopoa RH 40 and Cremopoa EL.

2) polyoxyethylene sorbitan fatty acid esters; Mono- and tri-lauryl, palmityl, stearyl and oleyl esters of polyoxyethylene sorbitan fatty acids, for example; For example, there is a brand name Tween and polyoxyethylene (20) sorbitan mono-laurate (trade name Tween 20) and polyoxyethylene (20) sorbitan mono-palmitate (trade name Tween 40) depending on the type of fatty acid. ), Polyoxyethylene (20) sorbitan mono-oleate (trade name Tween 80), and the like. Preferred surfactants for use in the compositions of the present invention are Tween 20 and Tween 40 of the surfactants.

3) polyoxyethylene-polyoxypropylene block copolymers; Surfactants marketed, for example, under the trade name poloxamer

4) ester group transfer products of natural vegetable oil triglycerides with polyalkylene polyols; Surfactants sold under the trade name Labrafil. Particularly preferred as a component of the composition of the present invention are Labrafil M 1944 CS, Labrafil WL 2609 BS, Labrasol and the like.

In the composition according to the present invention, the surfactants may be used alone or preferably in combination of two or more surfactants. The composition ratio of cyclosporin: surfactant based on weight is preferably 1: 2 to 10, more Preferably, it is suitable to be 1: 3-8.

Each component in the composition of the present invention preferably comprises a ratio of cyclosporin: cosurfactant: surfactant: oil = 1: 0.1-5: 2-10: 0.1-5 by weight, more preferably It is included in the ratio of 1: 1: 3: 3 ~ 8: 1 ~ 3

The cyclosporin-containing microemulsion preconcentrate composition of the present invention may include additives commonly used in medicines as needed. Such additives include, for example, antioxidants (e.g. tocopherol, butylated hydroxyanisole (BHA), etc.), viscosity modifiers, dissolution regulators, fragrances (e.g. peppermint oil), preservatives (e.g. benzyl alcohol, parabens, etc.) ), Pigments and the like.

The composition according to the present invention can be used in an oral dosage form such as a soft capsule, a hard capsule in which a junction is sealed with gelatin bending, oral solution, etc. according to a conventional method using a pharmaceutically acceptable additive in actual clinical application. have.

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

Example 1 (cyclosporin oral soft capsule)

50 g of cyclosporine as the active ingredient was added to 80 g of propylene carbonate and 80 g of triacetin as cosurfactant, and dissolved under stirring under heating. 150 g of Miglyol 812 as an oil was added to the resulting solution, and as a surfactant. 220 g of Morphoa RH 40 was added and stirred until a uniform solution was obtained. The obtained cyclosporine-containing composition was poured into a soft capsule maker to prepare a soft capsule containing 50 mg of cyclosporin per capsule.

According to the same method, a soft capsule of 1-B to 1-E having a composition shown in Table 1 was prepared while changing the co-surfactant.

Ingredient Prescription (mg / capsule) Example 1-A Example 1-B Example 1-C Example 1-D Example 1-E Active ingredient Cyclosporine 50.0 50.0 50.0 50.0 50.0 Cosurfactant Propylene carbonate 80.0 100.0 100.0 50.0 20.0 Triethyl citrate 50.0 50.0 Triacetin 80.0 20.0 50.0 100.0 Surfactants Cremopoa RH 40 220.0 180.0 150.0 180.0 90.0 Labrador WL 2609 BS 100.0 70.0 50.0 Twin 20 50.0 50.0 oil Shepol 880 100.0 120.0 90.0 100.0 Linoleic acid 50.0 50.0 Miggliol 812 150.0 sum 580.0 500.0 570.0 590.0 510.0

Example 2. Preparation of cyclosporin oral soft capsule

According to the same method as in Example 1, 2-A to 2-E soft capsules having the composition shown in Table 2 were prepared.

Ingredient Prescription (mg / capsule) Example 2-A Example 2-B Example 2-C Example 2-D Example 2-E Active ingredient Cyclosporine 50.0 50.0 50.0 50.0 50.0 Cosurfactant Triethyl citrate 70.0 50.0 70.0 50.0 Triacetin 50.0 50.0 50.0 Propylene carbonate 70.0 50.0 20.0 50.0 20.0 Surfactants Cremopoa RH 60 100.0 210.0 250.0 100.0 50.0 Twin 20 100.0 100.0 150.0 oil GM Mall Pick 80 30.0 50.0 30.0 Plurol Olake CC 497 30.0 50.0 30.0 30.0 Ultrafine corn oil 100.0 Squalene extract 100.0 100.0 80.0 30.0 90.0 sum 550.0 510.0 550.0 530.0 520.0

Example 3. Preparation of cyclosporin oral soft capsule

According to the same method as in Example 1 above to prepare a soft capsule of 3-A to 3-E having a composition shown in Table 3 below.

Ingredient Prescription (mg / capsule) Example 3-A Example 3-B Example 3-C Example 3-D Example 3-E Active ingredient Cyclosporine 50.0 50.0 50.0 50.0 50.0 Cosurfactant Triethyl citrate 80.0 50.0 10.0 60.0 Triacetin 100.0 50.0 10.0 40.0 Propylene carbonate 30.0 20.0 20.0 120.0 30.0 Surfactants Cremopoa EL 150.0 210.0 50.0 20.0 Poloxamer124 20.0 50.0 40.0 150.0 Labrasol 50.0 100.0 100.0 50.0 oil Incromega TG2779 150.0 100.0 80.0 100.0 50.0 Linoleic acid 20.0 60.0 70.0 Decaglin 5-0 50.0 30.0 sum 510.0 520.0 510.0 500.0 530.0

Example 4 Preparation of Cyclosporin Oral Soft Capsule

According to the same method as in Example 1, 4-A to 4-E soft capsules having the composition shown in Table 4 were prepared.

Ingredient Prescription (mg / capsule) Example 4-A Example 4-B Example 4-C Example 4-D Example 4-E Active ingredient Cyclosporine 50.0 50.0 50.0 50.0 50.0 Cosurfactant Triethyl citrate 80.0 120.0 20.0 50.0 Triacetin 100.0 10.0 20.0 Propylene carbonate 60.0 20.0 20.0 100.0 80.0 Surfactants Cremopoa RH 40 200.0 210.0 220.0 250.0 200.0 oil Miggliol 812 150.0 50.0 100.0 Plurol Olake CC 497 40.0 30.0 100.0 20.0 GM Mall Pick 80 70.0 20.0 Incromega F2250 50.0 30.0 Linolenic acid 20.0 40.0 Crosenhal GLO E50 60.0 30.0 Ethyl linoleate 120.0 30.0 10.0 sum 580.0 600.0 600.0 600.0 600.0

Example 5. Preparation of cyclosporin oral soft capsule

To the composition of the present invention was added a pharmaceutically acceptable additive as shown in Table 5 to prepare a soft capsule of 5-A to 5-E according to the same method as in Example 1.

Ingredient Prescription (mg / capsule) Example 5-A Example 5-B Example 5-C Example 5-D Example 5-E Active ingredient Cyclosporine 50.0 50.0 50.0 50.0 50.0 Cosurfactant Triethyl citrate 100.0 80.0 50.0 30.0 Triacetin 30.0 100.0 50.0 30.0 Propylene carbonate 20.0 50.0 50.0 50.0 70.0 Surfactants Cremopoa RH 40 180.0 210.0 220.0 220.0 250.0 oil Tetraglin 1-O 40.0 10.0 30.0 20.0 Mivasset 9-40 10.0 30.0 GM Mall Pick 80 30.0 30.0 20.0 Oleic acid 120.0 100.0 100.0 50.0 Concentrated Western Oil 120.0 80.0 Antioxidant Tocopherol 0.7 1.0 3.0 1.5 2.0 sum 580.7 551.0 553.0 571.5 582.0

Examples 6-10. Preparation of cyclosporin oral hard capsule

In the same composition and method as in Examples 1 to 5, the drug was dissolved and filled into hard gelatin capsules, and then the junction was sealed with gelatin bending to prepare a hard capsule.

Experimental Example 1

In vivo bioavailability comparison test using a dog to compare the pharmacological effects of the cyclosporin-containing microemulsion preconcentrate composition (test preparation) prepared according to the present invention with a composition (control formulation) manufactured and marketed according to the prior art. Was carried out. Examples 1-D, 2-B, 3-D and 4-C soft capsules were used as test formulations, and commercially available Sandimmun 100 mg soft capsules were used as a control formulation.

A total of 15 dogs (male, weight 11.0-15.0 kg) were used as test animals, and three dogs were tested for the bioavailability of the drug. Each formulation was administered in an amount corresponding to 100 mg as cyclosporine per dog, and then 50 ml of water was supplied. Food was supplied from 4 hours after drug administration. After administration of the drug, blood was drawn from the abdominal vein at a predetermined time of 2 ml. Collected blood was stored frozen at -18 ℃ and the analysis of blood cyclosporin was analyzed by RIA method.

The concentration of the cyclosporin in the blood was shown in FIG. 1 with respect to time, and the pharmacokinetic parameters of the cyclosporin were calculated from the experimental results to obtain the results shown in Table 6.

Comparison test results of bioavailability of the test formulation of the present invention and commercially available dogs Pharmacokinetic Variables Test formulation Commercially available Example 1-D Example 2-B Example 3-D Example 4-C AUC _0-24h ( _ngh / ml) 5457.36 4553.32 5147.00 5815.48 2449.03 C _max (ng / ml) 1205.0 1008.7 1094.2 1205.3 512.35 T _max (h) 2.5 2.0 2.0 1.5 2.0

The cyclosporin-containing microemulsion preconcentrate composition prepared using a lipophilic solvent according to the present invention is not only the highest blood concentration (C _max ) of the cyclosporine but also the blood as shown in FIGS. 1 and 6 when compared to commercially available preparations according to the prior art. The area under the curve (AUC) of the concentration curve was significantly higher. In the case of AUC, the test preparation 1-D is 2.23 times, 2-B is 1.86 times, 3-D is 2.10 times, and 4-C is 2.36 times higher than that of the control. Showed.

From the results of the experimental example, it was confirmed that the cyclosporin-containing microemulsion preconcentrate composition according to the present invention can exhibit an excellent cyclosporin medicinal effect by showing two times higher bioavailability compared to the preparation of the prior art.

Claims (22)

(1) cyclosporin as the active ingredient; (2) triacetin or triethyl citrate alone or as a mixture of both and propylene carbonate as cosurfactant; (3) oils; And (4) A cyclosporine-containing pharmaceutical composition comprising a surfactant. The cyclosporin-containing pharmaceutical composition according to claim 1, wherein the cyclosporin is cyclosporin A. 2. The cyclosporine-containing pharmaceutical composition according to claim 1, wherein the composition ratio is 1: 0.1 to 5 by weight when using a mixture of propylene carbonate and triethyl citrate as cosurfactant. 2. The cyclosporine-containing pharmaceutical composition according to claim 1, wherein when the mixture of propylene carbonate and triacetin is used as the cosurfactant, the composition ratio is 1: 0.1-5 by weight. The cyclosporine-containing pharmaceutical composition according to claim 1, wherein the ratio of each of propylene carbonate, triethyl citrate, and triacetin as a cosurfactant is in a weight ratio of 1: 0.1-5: 0.1-5. The method of claim 1, wherein the oil is a vegetable oil; Esterification reaction products of vegetable oils; Animal oils and derivatives thereof; And cyclosporin-containing pharmaceutical composition, characterized in that the single component or a mixture of two or more selected from the group consisting of higher unsaturated fatty acids. 7. The cyclosporine-containing pharmaceutical composition according to claim 6, wherein the vegetable oils are purified vegetable oils. 8. The cyclosporine-containing pharmaceutical composition according to claim 7, wherein the purified vegetable oils are a group consisting of corn oil, borage oil, sesame oil, primrose oil, peanut oil, and olive oil in a crude form. 7. The process of claim 6 wherein the esterification products of vegetable oils are Iii) esterification products of vegetable oils with glycerin; Ii) esterification products of vegetable oils with monohydric alcohols; And Iii) cyclosporine-containing pharmaceutical composition, characterized in that the group consists of esterification products of vegetable oils with polyglycerols 10. The process of claim 9, wherein the esterification product of the vegetable oil with glycerin is triglycerides of fatty acids; Mono-glycerides; And a cyclosporine-containing pharmaceutical composition, characterized in that the group consists of mono- and di-glycerides. 11. The cyclosporine-containing pharmaceutical composition according to claim 10, wherein the triglyceride of fatty acid is triglyceride of intermediate fatty acid having 8 to 12 carbon atoms. 11. The cyclosporin-containing pharmaceutical composition according to claim 10, wherein the mono- and di-glycerides of fatty acids are mono- and di-glycerides of higher fatty acids having 16 to 18 carbon atoms. 10. The cyclosporine-containing pharmaceutical composition according to claim 9, wherein the esterification product of the vegetable oil with the monohydric alcohol is a group consisting of boric oil and esterification reaction products of the olive oil with the monohydric alcohol. The cyclosporine-containing pharmaceutical composition according to claim 9, wherein the esterification product of the vegetable oil with the monohydric alcohol is a group consisting of ethyl oleate, ethyl linoleate, isopropyl palmitate, and isopropyl myristate. 10. The cyclosporine-containing pharmaceutical according to claim 9, wherein the esterification product of the vegetable oil with the polyglycerol is a group consisting of the products by esterification of di-, tetra-, hexa- and deca-glycerol with a fatty acid. Composition. The method of claim 6, wherein the animal oil and derivatives thereof are squalene; Omega-3 essential fatty acids; Oils in esterified form of omega-3 essential fatty acids and monoalcohols; And a group consisting of oils in the triglyceride form of omega-3 essential fatty acids. The cyclosporine-containing pharmaceutical composition according to claim 1, wherein the surfactant is a surfactant having an HLB of 1-20. 18. The method of claim 17, wherein the surfactant is selected from polyoxyethylene glycolated natural or hydrogenated vegetable oils; Polyoxyethylene sorbitan fatty acid esters; Polyoxyethylene-polyoxypropylene block copolymers; And a cyclosporine-containing pharmaceutical composition, characterized in that it is a single component or a mixture of two or more selected from ester group transfer reaction products of natural vegetable oil triglycerides and polyalkylene polyols. The cyclosporin-containing pharmaceutical composition according to claim 1, wherein the composition ratio of cyclosporin: co-surfactant: surfactant: oil is 1: 0.1-5: 2-10: 0.1-5 by weight. 20. The cyclosporine-containing pharmaceutical composition according to claim 19, wherein the composition ratio of cyclosporin: co-surfactant: surfactant: oil is 1: 1 to 3: 3 to 8: 1: 1-3 by weight. The cyclosporine-containing pharmaceutical composition according to claim 1, further comprising pharmaceutically acceptable additives such as antioxidants, viscosity modifiers, dissolution modifiers, fragrances, preservatives, and pigments. A pharmaceutical formulation containing the composition according to claim 1, wherein the dosage form is a soft capsule, a hard capsule or a liquid oral solution in which the junction is sealed by gelatin bending.