MXPA00005507A - Cyclosporin-containing microemulsion preconcentrate composition - Google Patents

Abstract

The present invention relates to a microemulsion preconcentrate composition comprising (1) cyclosporin as an active component;(2) alkyl ester of polycarboxylic acid and/or carboxylic acid ester of polyols as a lipophilic solvent;(3) oil;and (4) surfactant. The composition according to the present invention is characterized in that it dissolves in an external phase such as water, artificial gastric fluid and artificial intestinal fluid by controlling the mixing ratio of the components thereby to get the microemulsion form of inner phase diameter of 100 nm or below. The composition according to the present invention can be formulated as the dosage form of a soft capsule, a hard capsule sealed with a gelatin banding at the conjugated portion, or an oral liquid preparation for oral administration. Especially, in the case that the composition according to the present invention is formulated in a soft capsule, the resultant capsule does not show the disadvantages of the prior arts such as the reactivity of hydrophilic solvent with gelatin shell of soft capsule and the volatility of hydrophilic solvent. It is because the existing patents use a hydrophilic solvent as an essential component of their compositions but the present invention does not use any hydrophilic solvent.

Description

PRECONCENTRATED COMPOSITION IN THE FORM OF MICROEMULSION CONTAINING CYCLOSPORINE TECHNICAL FIELD The present invention relates to a pre-concentrated composition in the form of a microemulsion comprising a cyclosporin as an active component; an alkyl ester of polycarboxylic acid and / or a carboxylic acid ester of polyols as a lipophilic solvent; an oil; and a surfactant.

PREVIOUS TECHNIQUE Cyclosporine is a superior molecular peptide compound consisting of 11 amino acids which achieves its potent immunosuppressive activity by inhibiting the growth and differentiation of T cells. There are many cyclosporins such as cyclosporin A, B, C, D, G, etc. ., depending on the structure of the constituent amino acids, but cyclosporin A is preferably used in the clinical field due to its pharmacological activity, and its indication and clinical effectiveness are well established in the art. Cyclosporine was discovered in Tolypocladium inflame tum grains by Borel et al. in 1976, and initially developed as an antibiotic. Subsequently, it was discovered during the safety test that cyclosporine inhibits the growth of lymphocytes, cyclosporine has become the focus of global attention as the only immunosuppressant that can specifically affect only lymphocytes, and has made possible the technical development of organ transplantation. Cyclosporin has a unique structure, which is a cyclic oligopeptide consisting of 11 amino acids. The seven amino acids of cyclosporin are methylated on the N atoms. The remaining four protonated nitrogen atoms can form intermolecular hydrogen bonds with carbonyl groups, which contribute substantially to the skeletal rigidity of cyclosporin. Therefore, it has a remarkably hydrophobic property and is relatively insoluble in water (for cyclosporin A, 0.04 mg / ml at 25 ° C). Because of such low water solubility of cyclosporin A, it is known that the bioavailability of cyclosporin A is 30% or less. It was reported that the absorption of such an insoluble compound is influenced to a large extent by the secretion of bile juices, the amount of fat in the food, etc. In the case of cyclosporin A, it has been reported that differences in absorption between different individuals are as great as approximately 5-50%. When ciclosporin is administered for a long time, it shows renal toxicity, liver toxicity, etc. Renal side effects include a reduction in glomerular filtration, an increase in proximal renal tubular absorption and chronic progressive deterioration of the nephroids. Cyclosporin has a large dose unit and a narrow therapeutic index as well as the properties, and the condition of the patient to be treated with cyclosporine is generally unstable. Therefore, it is very difficult to establish an optimal dose regimen of the drug for the survival of the transplanted patient through the maintenance of an efficient and constant blood concentration that can prohibit side effects and rejection. Numerous studies have been conducted to overcome the properties and to develop an improved pharmaceutical formulation. Such studies have concentrated mainly on the media that are used to solubilize cyclosporin. Typical examples include not only mixed solvent systems consisting of vegetable oil and surfactant, but also microspheres, formations of powder compositions utilizing adsorption, inclusion complexes, solid dispersions and numerous other formulations. An oral preparation containing cyclosporin as the main active ingredient has been marketed in the form of a solution and a soft capsule formulation. The preparation uses a mixed vehicle consisting of vegetable oil, surfactant and solvent to solubilize cyclosporine, but did not overcome the properties of cyclosporine, that is, low bioavailability of cyclosporin and large individual differences of the same. Therefore, the preparation has many problems in clinical use. The microemulsions were reported for the first time by J.H. Schulman in 1943 and since then, have been studied mainly for the application of cosmetics and as carriers of insoluble drugs. A microemulsion comprises two or more immiscible liquid materials, together with a surfactant as well as an emulsion, but is thermally stable and optically transparent unlike an emulsion. And the microemulsion has a very low surface tension and a small particle size of less than 100 nm, which together, result in superior absorption and permeation properties of the drug released by the microemulsion. The microemulsion is, in particular, very useful in the solubilization and improved absorption of insoluble drugs. However, since the formation of a microemulsion requires a lot of surfactant, severe mucosal irritation is caused by the preparation in the form of a microemulsion, and the volume of the dose becomes large. In the medical field, microemulsions have thus been used only for preparations that are applied to the skin, such as hair preparations, detergents, etc. In the case of cyclosporin as the relatively insoluble drug, U.S. Patent No. 4,388,307 describes an oral liquid preparation, which includes oil, surfactant, and ethanol as the hydrophilic solvent. This preparation is a pre-concentrate in the form of a microemulsion and, therefore, must be diluted with water before being administered orally. That which makes the acceptance of the patient is bad, and makes the control of the exact dose difficult. Since it is also uncomfortable to transport it, it is impossible to actually administer it to a patient who must be subjected to cyclosporine therapy for the remaining period of his life. To remove the advantages of liquid preparations, a pre-concentrate in the form of a microemulsion formulated in the form of a soft capsule has been developed. The preconcentrate in the form of microemulsion, hitherto, has comprised drug, hydrophilic solvent, surfactant and oil with the appropriate mixing ratio, and could form the microemulsion spontaneously through dissolution in the external phase, such as water and intestinal fluid. However, the hydrophilic solvent used as an essential component of the preconcentrate in the form of a microemulsion, permeates the gelatin cap of the capsule not only to volatilize, but also to soften the gelatin cap. It induces the instability of soft capsules. In the case of the cyclosporin soft capsule containing ethanol as a hydrophilic component, this preparation in capsule form must contain a large amount of ethanol to solubilize cyclosporin. However, since the ethanol permeates the gelatin cap of the capsule to volatilize even at normal temperature, the ethanol content is reduced over time. As a result, when the capsules are stored at low temperatures or at normal temperatures for a prolonged period, the crystallization of cyclosporin may occur. The change in composition results in a greater variation in the bioavailability of cyclosporin and, therefore, it is impossible to obtain a desired therapeutic effect reliably and reproducibly. In an effort to prevent the volatilization of the ethanol from the soft capsule preparations during storage, the soft capsules are enclosed in a special packaging material, such as an aluminum blister pack. However, the problem of the greatest variation in the bioavailability of cyclosporine remains despite the use of special packaging, since it is impossible to completely prevent the change in ethanol content over time. Using special packaging can help increase manufacturing costs and medicine fees. To improve the disadvantages of the use of ethanol as a hydrophilic surfactant, methods of using non-ethanolic components as hydrophilic cosurfactants have also been proposed. U.S. Patent No. 5,342,625 discloses a soft capsule preparation formulated with a concentrate in the form of a microemulsion which solves such problems. This patent discloses a pharmaceutical composition in the form of an emulsion concentrate in which a C? -5 alkyl or tetrahydrofurfuryl di or pharmaceutically acceptable partial ether of a mono or polyoxyalkanediol of low molecular weight, for example, diethylene glycol monoethyl ether (e.g. , Transcutol), tetrahydrofurfuryl alcohol, polyethylene glycol ether (for example Glycofurol), 1,2-propylene glycol are used as a hydrophilic solvent, and ethanol is used as a hydrophilic cosolvent. However, all the hydrophilic solvents used in this patent are glycols having the alcohol group (-OH) in their structure. Since such glycols contain the -OH group they are very hygroscopic, absorb moisture present in the atmosphere and also have a high permeability to the gelatin cap. Therefore, it is very difficult to formulate a composition containing such a glycolic surfactant in a soft capsule preparation. In the encapsulation and the first drying steps, at the time of preparing soft capsules, particularly, the water that is present in the cap of the capsule is absorbed towards the contents of the capsule in an amount corresponding to 20% of the solvent • 5 hygroscopic to cause the change in the constitutional composition relationship. And then, in the step of drying them, the water is distributed again in the gelatin cap and volatilizes from the inside of the capsule to the outside through the cap of the capsule The materials of the composition containing the capsule also migrate towards the cap of the capsule together with the water. Therefore, the constitutional relationship of the composition according to this patent changes to a great extent, and the change in the appearance of the preparation due to such phenomenon causes the production yield of the capsule to decrease. The hydrophilic solvents used in the formulation described by the previous US Patent • also has the effect of softening the gelatin cap of the capsule, and induce the pharmaceutical problem that the stability of the appearance of the gelatin capsule is greatly reduced. This problem becomes even more serious when a plasticizer is used for the gelatin, for example propylene glycol, glycerin, etc., as a solvent hydrophilic. The use of propylene glycol as the main solvent is, therefore, highly limited. Propylene glycol can be used generally in about 5% or less of the contents of the capsule, and can be used in about 10% or less together • 5 with a hardening agent for the gelatine cap at most. The stability of the appearance of the gelatin cap is greatly reduced when propylene glycol is used in an amount that exceeds the limits of the soft capsule content. 10 Korean Patent Application No. 94-13945 describes a composition containing cyclosporin to be • formulated in a soft capsule (brand: Neoplanta®) that uses dimethylisosorbide as the hydrophilic cosurfactant to mitigate such disadvantages. This patent describes the The preparation of a soft capsule using dimethylisosorbide which does not show the appearance of the soft capsule and the change in the content of the ingredients, since the dimethylisosorbide has no substantial permeability to the gelatin cap.

Comparison with the other hydrophilic co-reactants used in the prior art. Dimethylisosorbide, which is marketed under the trademark Arlasorve®, ie 1,: 3,6-dianhydro-2, 5-dimethyl-D-glucitol, is a solvent that has been used generally as an enhancer of percutaneous absorption only for topical pharmaceutical ointments or cosmetics such as lotions. As mentioned above, a conventional microemulsion requires more surfactant than a general emulsion. Therefore, in the case of a drug that is continuously administered to the patient throughout his life after transplantation of an organ, for example, cyclosporin, the toxicity of the solvent and the surfactant contained in the preparation of the microemulsion by the administration In the long term, it must also be considered. In this regard, the LD50 value of dimethylisosorbide is 5.68 ml / kg (rat, orally). The value of the LD50 (rat, orally) of the organic solvent of which the toxicity has been relatively well known is as follows: Acetonitrile, 3.8 g / kg; acetone 10.7 ml / kg; benzene, 3.8 ml / kg; toluene, 7.53 g / kg; isopropanol, 5.8 g / kg; and butanol, 4.36 g / kg. It is expected that long-term oral administration of the dimethyl isosorbide-containing composition may cause problems. In addition, the pharmaceutical problems were not largely solved by the use of dimethylisosorbide, since the dimethylisosorbide still has the properties, the reactivity with the gelatin capsule of the soft capsule, and the volatility, and shows a limitation as a hydrophilic solvent.

U.S. Patent No. 5,583,105 describes the oral multiple emulsion comprising cyclosporin, in which ethanol and tocopheryl polyethylene glycol 1000 succinate, which is a surfactant, are used as an essential vehicle, and in which polycarboxylic acid alkyl esters or oils are used as a lipophilic or amphiphilic solvent. This patent discloses that alkyl esters of polycarboxylic acid can be used selectively in place of oil, and this patent, in particular, used acetyl triethyl citrate for the formulation of cyclosporin. However, ethanol, which is a hydrophilic and volatile solvent, was also used essentially to constitute the cyclosporin formulation. As mentioned above, cyclosporin preparations using ethanol for the solubilization of cyclosporin show the problem of pharmaceutical stability, due to the volatilization of the ethanol through the gelatin cap of the capsule, during storage. The tocopheryl polyethylene glycol 1000 succinate, which was used as a surfactant in this patent, is a product of the esterification of tocopheryl acid succinate with polyethylene glycol, and releases tocopherol after being absorbed into the body. This patent discloses that free tocopherol can reduce renal toxicity. However, it has not been verified yet, and there could be a drug interaction between cyclosporin and free tocopherol, which can be absorbed in the body exceeding the usual dose depending on the amount of composition administered, for a prolonged therapy. In addition, it has been generally known that lipid-soluble vitamins, such as tocopherol, induce adverse side effects by accumulation in the body. As mentioned above, the pre-concentrates in the form of microemulsion according to the above techniques comprise hydrophilic solvent, oil and surfactant as the essential and primary composition. In the case of the formulation of those preconcentrated in the form of a microemulsion as soft capsules, it has generally been known that the hydrophilic solvent reacts with the gelatin cap of the soft capsule, thereby softening the cap, and volatilizing through the cap. of gelatin, and that such phenomenon induces serious problems of stability of the preparation. There was an attempt to improve those disadvantages by using dimethylisosorbide as a new hydrophilic solvent, but this material has a limit as a primary vehicle due to the toxicity thereof and still has the disadvantage of the hydrophilic solvent. The inventors of the present invention have studied the development of a composition containing cyclosporin which could compensate for the disadvantages involved in the various pharmaceutical preparations of the prior art and which is suitable for formulation in the soft gelatin capsule. The inventors of the present invention developed the new preconcentrate in the form of microemulsion containing cyclosporin, which comprises lipophilic solvent, surfactant and oil, using lipophilic solvent instead of hydrophilic solvent, which causes the disadvantage of the pharmaceutical stability. It was identified that the preconcentrate in the form of a microemulsion using a lipophilic solvent instead of a hydrophilic solvent can overcome the various problems of the prior art and thus the present invention was completed.

DESCRIPTION OF THE INVENTION The present invention relates to a pre-concentrated composition in the form of a microemulsion containing cyclosporin comprising (1) cyclosporin as an active ingredient; (2) alkyl ester of polycarboxylic acid and / or carboxylic acid ester of polyols as a lipophilic solvent; (3) oil; and (4) surfactant. The first essential component of the preconcentrated composition in the form of microemulsion containing cyclosporin according to the present invention is cyclosporin as an active ingredient. Cyclosporin A is preferred.

The second essential component of the composition according to the present invention is a lipophilic solvent. The lipophilic solvent, which is used in the composition according to the present invention to overcome the disadvantage of the hydrophilic solvent, is at least one member selected from alkyl esters of polycarboxylic acid. The alkyl esters of polycarboxylic acid which can be used in the composition according to the present invention are products of the esterification of polycarboxylic acids having carboxylic groups of 2-10, preferably 3-5, with C? -C? O alcohols. The carboxylic acid esters of the polyols which can be used in the composition according to the present invention are the esterification products of polyols having hydroxyl groups of 2~10, preferably 3~5, with C2 carboxylic acids. ~ Cn. The alkyl esters of polycarboxylic acid and the carboxylic acid esters of polyols which can be used as a lipophilic solvent in the composition according to the present invention are odorless and colorless oils in the liquid state. And its boiling point is greater than 250 ° C. It is not volatilized in the high temperature condition during the procedure for the preparation of the soft capsule, as well as the state of storage at room temperature, therefore, they can ensure the stability of the preparation comprising them. In addition, the lipophilic solvent does not show such severe hygroscopic property that the glycols show, it does not dissolve in the gelatin cap, and it does not induce the change in composition due to the non-volatility and non-permeability of the gelatin cap. The alkyl esters of polycarboxylic acid and / or carboxylic acid esters of polyols are lipophilic solvents, which can be applied to the solubilization of insoluble drugs such as cyclosporin, and do not induce the problem of stability of the preparation at the time of administration. preparation and storage of the product. The alkyl esters of carboxylic acid which may be preferably used in the composition according to the present invention comprise triethyl citrate, tributyl citrate, acetylbutyryl citrate, acetyltriethyl citrate, etc. The carboxylic acid esters of the polyols which can be preferably used in the composition according to the invention comprise triacetin, etc. They can be used alone or in a mixture of two types or more. When the mixture is used, the mixing ratio is not particularly limited. In the composition of the preconcentrate in the form of microemulsion containing cyclosporin. according to the present invention, the ratio of lipophilic solvent to cyclosporin is preferably in the range of 1: 0.1-5, more preferably 1: 0.1 ~ 3 by weight. The preconcentrate composition in the form of microemulsion containing cyclosporin using lipophilic solvent according to the present invention does not show the pharmaceutical disadvantage, which can be induced by the hydrophilic solvent, an essential component in the composition of the prior art. In a further remarkable aspect, the use of the lipophilic solvent may not only provide the effect of sufficient solubilization of the cyclosporin, but also many advantages, because the lipophilic solvent does not react with the gelatin cap of the soft capsule and is not volatile . That is to say, that the lipophilic solvent does not change the appearance of the capsule, nor cause the precipitation of cyclosporine with an active ingredient. In addition, it reduces the manufacturing cost to provide an economical effect, and furthermore it does not show any problem of solvent toxicity in the patient administered with the capsule for a prolonged time. The third essential component of the composition according to the present invention is oil. The oil that can be used in the composition of the present invention comprises vegetable oils; esterification products of vegetable oils; animal oils derived therefrom; long chain, unsaturated fatty acids. They can be used alone or as a mixture of two types or more. In the case of mixing, the selection can be made only in a small group of such classification; or in two or more small groups of the classification. Examples of vegetable oils that can be used in the composition of the present invention are corn oil, borage oil, sesame oil, primrose oil, peanut oil, olive oil, etc. Refined vegetable oils are preferred. Refined vegetable oils have high purity and low impurity content, and the content of unsaturated long chain fatty acids can be controlled. Therefore, they have been used mainly in parenteral nutrition, for debilitating diseases such as diabetic nerve disease, rheumatoid arthritis, etc. and as a vehicle for the stabilization of unstable drugs. Refined vegetable oils, which pass through a refining process by chromatography, are more transparent than general oils. Because oxidants such as aldehydes, alcohols, ketones, etc. they are removed from them, they are more resistant to oxidation than general oils. And because the content of polar materials and water of them is highly reduced, they have a more excellent solubilization effect for drugs than general oils. Commercial refined vegetable oils generally have a peroxide value of 0.5 or less, an anicidine index of 0.2 ~ 0.5, and an acid number of 0.1 ~ 1.0 or less. Commercial refined vegetable oils have various unsaturated fatty acid contents depending on the type of vegetable oil. The oil that has the appropriate content of unsaturated fatty acids for the requirements, therefore, can be selected and used. Examples of refined vegetable oils, which are the preferable oils of the composition according to the present invention, are corn oil, borage oil, sesame oil, primrose oil, peanut oil and superrefined olive oil, which are found in the market as the brand Superrefined oil (Croda Co.). The most preferable oil that can be used in the composition according to the present invention is the way in which the self-content of gamma-linolenic acid in the oil is increased by more than 50%. The example of that oil is branded concentrated borage oil Crossential (Croda Co.). As another component of the oil that can be used in the composition according to the present invention, the esterification products of vegetable oils comprise i) the product of esterification of vegetable oil with glycerin; ii) the product of the esterification of vegetable oil with monohydric alcohol; iii) the product of the esterification of vegetable oil with triacetin; and iv) the product of the esterification of vegetable oil with polyglycerol. The esterification of the vegetable oil means that the fatty acids contained in the vegetable oils are subjected to the esterification reaction. The products of the esterification, a mixture of several components, can be separated and refined to form a material that is presumed to be pure. And then, this pure material can be used as an oily component in the composition of the present invention. In addition, the fatty acids contained in vegetable oils can be separated and refined, and then reacted by esterification to form the products separately. In the esterification products of vegetable oils, the product of esterification of vegetable oil with glycerin can be used first. The product comprises triglycerides of fatty acid; monoglycerides; mono and diglycerides, or a mixture of two of them. As a kind of esterification product of vegetable oil with glycerin, triglycerides of fatty acid can be used. The medium chain fatty acid triglyceride of C ~ C 2 (MCT) is the preferred fatty acid triglyceride. MCT is prepared by the esterification of fatty acids extracted from palm oil with glycerin, and its triglyceride of medium chain fatty acids, of which the main fatty acids are capric acid (50-80%) and caprylic acid (20). -fifty%). Compared to general vegetable oils, the MCT provides many advantages. Because the MCT is more stable against oxidation and a higher density with a close value (0.94-0.95) to the density of water than a general oil, an emulsion that uses medium chain fatty acid is more stable than emulsions general. In addition, because the MCT is less hydrophobic than vegetable oils, it is possible to obtain a higher concentration of the active ingredient without a significant implement in the viscosity of the composition, when the composition of the present invention is prepared using MCT. This means that the MCT is a very suitable oil for the drug of which the dose is large, so that the concentration of the active ingredient in the carrier is as high as 10% and which has a very low polarity and therefore , it is very slightly soluble in water, for example, cyclosporine. The MCT has been marketed under the brand name of Sefol 860, Sefol 870, Sefol 880, Miglyol 810, Miglyol 812, Miglyol 818, Labrafac CC, etc. As another class of the esterification product of vegetable oil with glycerin, mono and diglycerides can be used. The name "mono and diglycerides" means the form of a mixture of glycerol mono- and diesters of a fatty acid. The mono and diglycerides are an oil, which is obtained through the esterification of fatty acids contained in vegetable oil with glycerin, followed by separation and refining, and has many types depending on the type of fatty acid and the type of esterification. Preferably, mono- and diglycerides can be used, the ratio of monoglyceride to total glycerides being at least 40%, preferably at least 90%, and of which the fatty acid is an upper chain of Ci6. C? S. It is more preferable that the mono- and diglycerides contain a monoglyceride of C? 8 fatty acid as their main component. Such compound has been marketed under the brand GMO AVI (Croda Co.), ATMOS 300 (ICI Co.), GMOrphic-80 (Eastman Co.), etc. Especially, GMOrphic-80 is a pure monoglyceride that has no diglyceride, because it is prepared through the isolation of monoglyceride only using molecular distillation followed by a subsequent esterification. Accordingly, GMOrphic-80 is an example of a much more preferable oily component in the composition according to the present invention. In the esterification products of vegetable oils, the product of the esterification of vegetable oils with monohydric alcohol can be used in the second place. There are many types of the product according to the types of vegetable oil involved in the reaction. The representative example comprises Crossential GLO E50 (ethyl ester of borage oil concentrate; Croda Co.), which is the product of the esterification of borage oil with ethanol, and Nikkol E00 (ethyl olive oleate, Nikkol Co.), which is the product of the esterification of olive oil with ethanol. The product can also be prepared using only the isolated fatty acid component of vegetable oil instead of using all the components of the "vegetable oil". Examples of this product include ethyl oleate, ethyl linoleate, isopropyl palmitate, isopropyl myristate, etc. In the esterification products of vegetable oils, the product of the esterification of vegetable oils with triacetin can be used thirdly. Examples of such a product comprise mono and diacetylated monoglycerides; and diacetylated monoglycerides. The diacetylated monoglyceride of C fatty acid? ~ C2o is the preferred one. Diacetylated monoglyceride is the product of the esterification of edible oils with triacetin. Diacetylated monoglyceride is used as an additive in food and as a plasticizer in medicines, and has been marketed under the brand Mivacet 9-40, Mivacet 9-45, etc. The product can be obtained from the esterification of triglycerides with triacetin. In the esterification products of vegetable oils, the product of the esterification of fatty acid with polyglycerol, ie, polyglycerol fatty acid ester, can be used in the fourth place. Examples of polyglycerol used in the esterification include diglycerol, tetraglycerol, hexaglycerol, decaglycerol, decaglycerol, etc. Examples of fatty acid reactive with those polyglycerols include oleic acid, linoleic acid, stearic acid, etc. Examples of the polyglycerol fatty acid ester include Plurol Oleique CC 497 (polyglyceryl oleate, Gattefosse Co.), Plurol Stearique (polyglyceryl palmitostearate, Gattefosse Co.), DGMO-C (diglyceryl monooleate, Nikkol Co.), Tetraglyn 1-0 (tetraglyceryl monooleate, Nikkol Co.), Hexaglyn 1-0 (hexaglyceryl monooleate, Nikkol Co.), Hexaglyn 5-0 (hexaglyceryl pentaoleate, Nikkol Co.), Decaglyn 5-0 (Deglyceryl pentaoleate Nikkol Co.), Decaglyn 10-0 (Decaglyceryl Decaoleate, Nikkol Co.), etc. In addition, animal oils and derivatives thereof can be used as an oily component in the composition according to the present invention. The first example of animal oils and derivatives thereof is squalenes. Squalene, which is obtained from shark liver oil, is a colorless and transparent oil and its chemical name is hexamethyltetracosa-hexane. Compared to oxidation and has a lower melting point. Therefore, it could dissolve cyclosporine effectively. Hydrogenated squalene can also be used as an oily component in the pre-concentrated composition in the form of a microemulsion comprising cyclosporin. Examples of commercial squalene products include Squalene EX (Nikkol Co.), Squalene (Nikkol Co.), etc. The second example of animal oils and derivatives thereof comprises omega-3 essential fatty acids, an esterified ethyl oil of the fatty acids and a triglyceride oil of the fatty acids. The "omega-3 essential fatty acids" are animal oils of which the fatty acid component is eicosapentaenoic acid and docosahexaenoic acid. Examples of commercial products of "omega-3 essential fatty acids" include Incromega F2250 (Croda Co.) and Incromega F2628 (Croda Co.). Examples of commercial products of the ethyl ester form of fatty acids include Incromega E2251 (Croda Co.), Incromega F2573 (Croda Co.), etc. Examples of commercial product in the form of triglyceride of the fatty acids include Incromega TG2162 (Croda Co.), Incromega TG2779 (Croda Co.), Incromega TG2928 (Croda Co.), Etc.

In addition, long chain, unsaturated fatty acids can be used as an oily component in the composition according to the present invention. Examples of such fatty acids include oleic acid, linoleic acid, linolenic acid, etc. There are examples of its commercial products such as Crossential 094 (Croda Co.), which is the commercial product of oleic acid; Crossential L99 (Croda Co.), which is the commercial product of linoleic acid; and Crossential LN80 (Croda Co.), which is the commercial product of linolenic acid. The different oils can be used with combinations of the appropriate ratio with the absorption of the control cyclosporin. In the composition of the preconcentrate in the form of microemulsion containing cyclosporin according to the present invention, the ratio of oil component to cyclosporin is preferably in the range of 1: 0.1-5, more preferably 1: 1-3 by weight. The fourth essential component of the composition according to the present invention is a surfactant. Any pharmaceutically acceptable surfactant can be used, provided that it is miscible with both components of the oily and lipophilic solvent to form an emulsion under moderate agitation in the external phase and the particle diameter in the internal phase can be adjusted to 100 nm or less by controlling the ratio of its constitution. The surfactants that can be used for this purpose preferably have an HLB value of 1-20, and examples thereof are as follows: i) Reaction products of natural or hydrogenated vegetable oils and ethylene glycol; that is, natural or hydrogenated polyoxyethylene glycol vegetable oils: for example natural or hydrogenated polyoxyethylene glycolic castor oils. The surfactants marketed under the Cremophor RH40, Cremophor RH60, Cremophor EL, Nikkol HCO-40 and Nikkol HCO-60 brands can be used in the composition according to the present invention. Cremophor RH40 and Cremophor EL are preferred. ii) Polyoxyethylene sorbitan fatty acid esters: for example, mono and trilauryl, palmityl, stearyl or oleyl esters; for example the products of the brand "Tween", which include the polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyethylene (20) sorbitan monolaurate (Tween 80) . Depending on the type of fatty acid, it may be preferable to use Tween 20 and Tween 40 in the composition according to the present invention. iii) Polyoxyethylene fatty acid esters: for example, esters of polyoxyethylene stearic acid of the type known and commercially available under the trademark Myrj, as well as polyoxyethylene fatty acid esters known and commercially available under the trademark "Cetiol HE". iv) Polyoxyethylene-polyoxypropylene copolymers: for example of the type known and commercially available under the trademark "Pluronic" and "Emkalyx". v) Polyoxyethylene-polyoxypropylene block copolymers: for example of the type known and commercially available under the name of "Poloxamer". vi) Dioctylsuccinate, sodium dioctylsulfo-succinate, di- [2-ethylhexyl] -succinate or sodium lauryl sulfate. vii) Phospholipids, in particular lecithins: especially, soy lecithin. viii) Bile salts: for example alkali metal salts, for example sodium taurocholate. ix) Transesterification products of triglycerides of natural vegetable oil and polyalkylene glycols; for example of the type known and commercially available under the Labrafil brand. Especially, Labrafil M 1944 CS, Labrafil WL 2609 BS, Labrasol, etc., can preferably be used in the composition according to the present invention. x) Mono, di and mono / diglycerides: especially products of the esterification of caprylic or capric acid with glycerol. xi) Sorbitan fatty acid esters: for example, of the type known commercially available under the trademark of Span. xii) Pentaerythritol fatty acid esters and polyalkylene glycol ethers, for example pentaerythrite dioleate, distearate, monolaurate, polyglycol ether and monostearate as well as esters of pentaerythritol fatty acid. xiii) Sterols and derivatives thereof, for example cholesterols and derivatives thereof, in particular phytosterols: for example products comprising cytosterol, campesterol or sigmasterol, and ethylene oxide adducts thereof, for example sodium sterols or derivatives of them, such as those known under the Generol brand. xiv) 12-Hydroxystearate polyethylene glycol 660: for example, of the type known and commercially available under the trademark of Solutol HS 15. xv) Fatty acid esters of polyethylene glycol: according to the type of fatty acid attached, they can be classified into -stearate, -laurate, -oleate, etc. The polyethylene glycol monooleate is preferred, and the examples of its commercial product are MYO-2, MYO-6, MYO-10, etc. xvi) Di-a-tocopheryl polyethylene glycol 1000 succinate. The surfactants that can be used more preferably in the composition according to the present invention are natural or hydrogenated polyoxyethylene glycolized vegetable oils; esters of polyoxyethylene sorbitan fatty acid; transesterification products of triglycerides of natural vegetable oil and polyalkylene glycols; and fatty acid esters of polyethylene glycol. The surfactants can be used alone or as a mixture of two types or more. In the pre-concentrate composition in the form of a microemulsion containing cyclosporin according to the present invention, the ratio of the oil component to cyclosporin is preferably in the range of 1: 2-10, more preferably 1: 3-8 by weight. In the pre-concentrate compositions in the form of microemulsion containing cyclosporin according to the present invention, the four essential components should preferably be present in the cyclosporin mixing ratio: lipophilic solvent: surfactant: oil = 0.1-5: 2-10: 0.1-5, more preferably in the cyclosporin mixing ratio: lipophilic solvent: surfactant: oil = 1: 1-3: 3-8: 1-3, on the basis of weight. The composition according to the present invention is characterized in that it is dissolved in an external phase such as water, artificial gastric fluid and artificial intestinal fluid controlling the mixing ratio of the components to obtain, therefore, the microemulsion form with a diameter of the internal phase of 100 mm or less. The cyclosporin-containing composition according to the present invention may further comprise any necessary pharmaceutically acceptable additives. Examples of additives include an antioxidant (e.g., tocopherol, butylated hydroxyanisole (BHA), etc.), viscosity control agent, agent for the control of dissolution, flavor (e.g., peppermint oil, etc.). ) preservatives (for example, benzyl alcohol, parabens, etc.) and coloring agents. For clinical use, the composition according to the present invention can be formulated as a dosage form of a soft capsule, a hard capsule sealed with a strip of gelatin in the conjugate portion, or an oral liquid preparation for oral administration of a patient. The composition of the present invention can be formulated into soft capsules by the conventional method, for example, by dissolving the cyclosporin in the lipophilic solvent component under moderate heating, by adding the oil and surfactant components to the resulting solution, uniformly mixing the constituents, then, if necessary, adding pharmaceutically acceptable additives, and finally formulating the resulting mixture, ie the composition according to the present invention, in capsules using a machine for preparing soft capsules. The preconcentrate in the form of a microemulsion prepared with a lipophilic solvent instead of a hydrophilic solvent according to the present invention, especially used as the soft capsule dosage form, produces a higher blood concentration of the cyclosporin than the commercial product of the cyclosporin soft capsule. , and the resulting capsule exhibits no change in composition over time due to volatilization and permeation of the components. In addition, it reduces the cost of manufacturing and the toxicity of the solvent, which are a problem in long-term therapy. The cyclosporin-containing composition according to the present invention, therefore, represents an improvement over the cyclosporin soft capsules of the prior art.

BRIEF DESCRIPTION OF THE DRAWINGS To fully understand the nature and objects of the invention, reference should be made to the following detailed description taken in conjunction with the accompanying drawings, in which: Figure 1 shows the blood-time concentration profiles of the cyclosporine after oral administration of the commercial product of cyclosporin (Sandimmun comparative preparation) and the microemulsion preconcentrated compositions containing cyclosporin according to the present invention (test preparations), to dogs (-, comparative preparation, DD, test preparation 6-A;? -?, test preparation 7-B; BH, test preparation 8-C; AA, test preparation 9-D).

MODES FOR CARRYING OUT THE INVENTION The present invention is described in more detail by the examples and experiments as shown below, but is not confined to such scopes.

Example 1. Soft Cyclosporin Capsule for Oral Irrigation The soft capsule containing the composition of 1-A in Table 1 according to the present invention was prepared by the following procedure: 50 g of cyclosporin A was dissolved as an active ingredient in 150 g of triethyl citrate as a component of the lipophilic solvent with stirring and heating. 125 g of Miglyol 812 was added as an oily component and 225 g of Cremophor RH 40 as a surfactant component to obtain the mixture, which was stirred until a homogeneous solution was formed. The resulting composition was poured into a machine to prepare soft capsules and then encapsulated according to conventional methods to produce soft capsules. Each capsule had 50 mg of cyclosporin A. The soft capsule preparations of Examples 1-B to 1-D, which have the compositions given in the following Table 1, were also prepared according to such method.

Table 1 Table 1 (continued) Example 2 Soft cyclosporin capsule for oral administration The soft capsule preparations of Examples 2-A to 2-F, having the compositions given in the following Table 2, were prepared according to the method of Example 1.

Table 2 Example 3. Soft Cyclosporin Capsule for oral administration The soft capsule preparations of Examples 3-A to 3-F, having the compositions given in the following Table 3, were prepared according to the method of Example 1.

Table 3 Table 3 (continued) Example 4. Soft cyclosporin capsule for oral administration The soft capsule preparations of Examples 4-A to 4-F, having the compositions given in the following Table 4, were prepared according to the method of Example 1.

Table 4 Table 4 (continued) Example 5. Soft cyclosporin capsule for oral administration The soft capsule preparations of Examples 5-A to 5-E, having the compositions given in the following Table 5, were prepared according to the method of Example 1.

Table 5 Table 5 (continued) Example 6. Soft capsule of cyclosporin for oral administration The soft capsule preparations of Examples 6-A to 6-D, having the compositions given in the following Table 6, were prepared according to the method of Example 1.

These soft capsules contain 100 mg of cyclosporin A per capsule. Table 6 Table 6 (continued) Example 7. Soft capsule of cyclosporin for oral administration The soft capsule preparations of Examples 7-A to 7-D, having the compositions given in the following Table 7, were prepared according to the method of Example 1. Those soft capsules They contain 100 mg of cyclosporin A per capsule.

Table 7 Table 7 (continued) Example 8. Soft cyclosporin capsule for oral administration The soft capsule preparations of Examples 8-A to 8-D, having the compositions given in the following Table 8, were prepared according to the method of Example 1. Those soft capsules They contain 100 mg of cyclosporin A per capsule.

Table 8 Table 8 (continued) Example 9. Soft capsule of cyclosporin for oral administration The soft capsule preparations of Examples 9-A to 9-D, having the compositions given in the following Table 9, were prepared according to the method of Example 1. These soft capsules They contain 100 mg of cyclosporin A per capsule.

Table 9 Table 9 (continued) Example 10. Soft capsule of cyclosporin for oral administration The soft capsule preparations of Examples 10-A to 10-D, having the compositions given in the following Table 10, were prepared according to the method of Example 1. These soft capsules They contain 100 mg of cyclosporin A per capsule.

Table 10 Examples 11-20. Hard Cyclosporin capsule for oral administration Concentrate compositions in the form of microemulsion containing cyclosporin were prepared in the same compositions by the methods of Examples 1-10, and were then filled into hard gelatin capsules. The conjugated portion of the hard capsules was sealed with a gelatin band to produce hard gelatin capsules containing 50-100 mg of cyclosporin A per capsule.

EXPERIMENTAL EXAMPLE 1. To compare the pharmacological effect of the pre-concentrated composition in the form of microemulsion containing cyclosporin according to the present invention with that of the commercial product prepared according to the prior art, bioavailability comparison experiments were conducted using dogs as follow. The soft capsules of Examples 6-A, 7-B, 8-C and 9-D were used as test preparations according to the present invention, and 100 mg Sandimmun® soft capsules, which are the commercial product, which were used as a comparative preparation.

In this bioavailability study, male dogs were used, weighing 11.0-15.0 kg, and each group consisted of 3 dogs. No food was provided except water to the dogs for 18 hours before drug administration. Each of the dogs was given soft capsule preparations with the dose of cyclosporin A of 100 mg per dog, and then 50 ml of water was immediately administered. 4 hours after the administration of the drug, food was provided. Venous blood samples of 2 ml were removed from the cephalic vein before administration of the drug to determine the basal levels of cyclosporin A, and at scheduled time intervals after dosing. The blood samples were frozen below -18 ° C until the test. Cyclosporin A concentrations in blood were analyzed by the RIA (radioimmunoassay) method. "Cyclosporin A concentration tests in whole dog blood against the time of each of the preparations are presented in Figure 1, and the pharmacokinetic parameters were calculated from the experimental data given in the following Table 11.

Table 11. Bioavailability of the test preparation of the present invention and the comparative preparation.

As shown in Figure 1 and Table 11, preconcentrate compositions in the form of microemulsion containing cyclosporin using lipophilic solvent according to the present invention showed an AUC (area under the curve of blood concentration of cyclosporin A ) very large, as well as a Cmax (maximum blood cyclosporin A concentration) greater than the comparative preparation. Compared with the comparative preparation the AUC of cyclosporin A after oral administration of the test preparations 6-A, 7-B, 8-C and 9-D were 2.21, 1.83, 1.80 and 2.29 times, respectively, and, that is, that the test preparations showed a higher absorption pattern.

From the results of the Experimental example as mentioned above, it was certified that the composition of the present invention has a higher bioavailability of two or more times compared to the prior art preparation., and can show the excellent effect of ciclosporin. In addition, the pre-concentrate composition in the form of a microemulsion containing cyclosporin according to the present invention provides the excellent preparation of cyclosporin which can overcome the various advantages, ie the formation of cyclosporin precipitation due to evaporation of the solvent, unexpected change of the bioavailability of cyclosporine induced by the precipitation of the drug, undesirable change of the external appearance of the preparation, increase of the cost of production due to the use of special packages, etc. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (24)

1. CLAIMS Having described the invention as above, the contents of the following claims are claimed as property. A pre-concentrate composition in the form of a microemulsion containing cyclosporin, characterized in that it comprises: 1) a cyclosporin as an active ingredient; 2) an alkyl ester of polycarboxylic acid and / or carboxylic acid ester of polyols as a lipophilic solvent. 3) an oil; and 4) a surfactant.
2. 2. The composition according to claim 1, characterized in that the cyclosporin is cyclosporin A.
3. 3. The composition according to claim 1, characterized in that the alkyl ester of the polycarboxylic acid is at least one member selected from the group consisting of triethyl citrate, tributyl citrate, acetyl tributyl citrate and acetyltriethyl citrate.
4. 4. The composition according to claim 1, characterized in that the carboxylic acid ester of polyols is triacetin.
5. 5. The composition according to claim 1, characterized in that the oil is at least one member selected from the group consisting of a vegetable oil; a product of the esterification of vegetable oil; an animal oil or derivative thereof; and a long chain unsaturated fatty acid.
6. 6. The composition according to claim 5, characterized in that the vegetable oil is a refined vegetable oil. - 7.
7. The composition in accordance with the claim 6, characterized in that the refined vegetable oil is at least one member selected from super-refined forms of corn oil, borage oil, sesame oil, primrose oil, peanut oil and olive oil.
8. The composition according to claim 5, characterized in that the product of the esterification of vegetable oil is: i) a product of the esterification of vegetable oil with glycerin; ii) a product of the esterification of vegetable oil with monohydric alcohol; iii) a product of the esterification of vegetable oil with triacetin; and iv) a product of the esterification of vegetable oil with polyglycerol.
9. 9. The composition according to claim 8, characterized in that the esterification product of vegetable oil with glycerin is triglyceride of fatty acid; mono-glycerides; mono and di glycerides or a mixture of two thereof.
10. The composition according to claim 9, characterized in that the fatty acid triglyceride is a medium chain triglyceride of C8 ~ C18 fatty acid.
11. 11. The composition according to claim 9, characterized in that the mono and diglycerides they are mono and diglycerides of Cig-Cis-12 fatty acid.
12. The composition according to claim 8, characterized in that the product of the esterification of the vegetable oil with monohydric alcohol is a product of the esterification of borage oil or olive oil. with monohydric alcohol.
13. The composition according to claim 8, characterized in that the product of the esterification of the vegetable oil with monohydric alcohol is at least one member selected from the group consisting of ethyl oleate, ethyl linoleate, isopropyl palmitate and isopropyl myristate. .
14. The composition according to claim 8, characterized in that the product of the esterification of the vegetable oil with triacetin is mono- and diacetylated monoglyceride of C? 4 ~ C2o fatty acid.
15. 15. The composition according to claim 8, characterized in that the esterification product of the vegetable oil with polyglycerol is an oil formed from the esterification of fatty acid with di, tetra, hexa or decaglycerol.
16. 16. The composition according to claim 5, characterized in that the animal oil and the derivative thereof is at least one component selected from the group consisting of squalenes; essential fatty acids omega-3; oils formed from the esterification of omega-3 essential fatty acid with monohydric alcohol; and oils in the form of triglycerides of the essential omega-3 fatty acid.
17. 17. The composition according to claim 1, characterized in that the surfactant has a HLB value of 1-2Ó.
18. The composition according to claim 17, characterized in that the surfactant is at least one member selected from the group consisting of natural or hydrogenated polyoxyethylene glycolised vegetable oils; esters of polyoxyethylene sorbitan fatty acid; esters of polyoxyethylene fatty acid; polyoxyethylene-polyoxypropylene copolymers; polyoxyethylene-polyoxypropylene block copolymers; dioctyl succinate, sodium dioctyl sulfosuccinate, di- [2-ethylhexyl] -succinate or sodium lauryl sulfate; phospholipids; bile salts; products of transesterification of triglycerides of natural vegetable oils and polyalkylene polyols; mono, di and mono / diglycerides; sorbitan fatty acid esters; esters of pentaerythritol fatty acids and polyalkylene glycol esters, and pentaerythritol fatty acid esters; sterols and derivatives thereof; Polyethylene glycol 12-hydroxystearate 660; fatty acid esters of polyethylene glycol; and di-a-tocopheryl-polyethylene glycol 1000 succinate.
19. The composition according to claim 18, characterized in that the surfactant is at least one member selected from the group consisting of natural or hydrogenated polyoxyethylene glycollated vegetable oils; esters of polyoxyethylene sorbitan fatty acid; Transesterification products of triglycerides of natural vegetable oils and polyalkylene polyols and fatty acid esters of polyethylene glycol.
20. The composition according to claim 19, characterized in that the surfactant is at least one member selected from the group consisting of natural or hydrogenated polyoxyethylene glycolised vegetable oils; and polyoxyethylene sorbitan fatty acid esters.
21. 21. The composition according to claim 1, characterized in that the cyclosporin, the lipophilic solvent, the surfactant and the oil component are present in the mixture in a ratio of 1: 0.1-5: 2-10: 0.1-5 based on the weight.
22. The composition according to claim 1, characterized in that the cyclosporin, the lipophilic solvent, the surfactant and the oil component are present in the mixture in a ratio of 1: 1-3: 3-8: 1-3 on the Weight basis.
23. 23. The composition according to claim 1, characterized in that it comprises at least one species of pharmaceutically acceptable additives selected from the group consisting of antioxidant, viscosity control agent, dissolution control agent, flavor, preservatives and coloring agents.
24. 24. A pharmaceutical formulation, characterized in that it comprises the composition according to claim 1, characterized in that the dosage form is a soft capsule, a hard capsule sealed with a band of gelatin in the conjugate portion or an oral liquid preparation.