HK1034444A - Cyclosporin-containing microemulsion preconcentrate composition - Google Patents

Description

Cyclosporin-containing microemulsion preconcentrate composition

Technical Field

The present invention relates to a microemulsion preconcentrate composition comprising cyclosporin as an active ingredient, a polycarboxylic acid alkyl ester and/or a polyhydric alcohol carboxylic acid ester as a lipophilic solvent, an oil, and a surfactant.

Background

Cyclosporin is a high molecular peptide compound consisting of 11 amino acids, which can achieve its potent immunosuppressive activity by inhibiting the growth and differentiation of T cells. There are various cyclosporins, such as cyclosporine A, B, C, D, G and the like, depending on the structure of the constituent amino acids, but cyclosporine a is preferred in the clinical field because the pharmacological activity and clinical indications and utility of this substance are known in the art. Cyclosporin was discovered by Borel et al in Tolypocladium inflatum gams in 1976 and was first developed as an antibiotic. After finding that cyclosporin inhibits the growth of lymphocytes in safety experiments, cyclosporin has received worldwide attention as the only immunosuppressant capable of specifically acting only on lymphocytes, and technological development in organ transplantation has become possible.

Cyclosporine has a unique structure and is a cyclic oligopeptide consisting of 11 amino acids. The 7 amino acids of cyclosporin are N-methylated. The 4 still remaining protonated nitrogen atoms may form intermolecular oxygen bonds with the carbonyl group, which contributes substantially to the rigidity of the cyclosporine backbone. Thus, cyclosporin has significant hydrophobic properties and is relatively insoluble in water (0.04 mg/ml at 25 ℃ for cyclosporin A). Due to such low water solubility of cyclosporin a, its bioavailability is known to be 30% or less. It has been reported that absorption of these insoluble compounds is greatly affected by factors such as bile secretion, amount of fat in food, and the like. For cyclosporin a, a difference in absorption between individuals of 5-50% has been reported. Cyclosporin exhibits side effects such as renal toxicity and hepatic toxicity when administered for a long period of time. Nephrotoxic side effects include a decrease in glomerular filtration, an increase in proximal tubular reabsorption, and chronic progressive injury of the kidney.

Cyclosporin has a large dosage unit, a narrow therapeutic index and the above properties, and the symptoms of patients to be treated with cyclosporin are often unstable. Therefore, it is very difficult to determine an optimal drug dosage course for organ transplant patients by maintaining efficacy and constant blood concentration capable of inhibiting side effects and rejection. Most studies have overcome the above properties and have developed improved pharmaceutical formulations. These studies have focused primarily on increasing the solubility of cyclosporine. Typical examples include not only a mixed solvent system consisting of vegetable oil and surfactant, but also microspheres, powder composition preparations using adsorption, inclusion compounds, solid dispersions, and other various preparations. Oral formulations containing cyclosporin as a main active ingredient have been commercialized, in the form of solutions and soft capsule formulations. The formulations shown use a mixed carrier consisting of vegetable oil, surfactant and solvent to solubilize cyclosporine, but do not overcome the properties of cyclosporine, i.e., low bioavailability of cyclosporine and large individual variation. Therefore, there are still many problems in clinical application of these preparations.

Schulman first reported a microemulsion in 1943 and since then mainly used in cosmetics and as a carrier for water-insoluble drugs. Microemulsions, like emulsions, include two or more immiscible liquid materials and a surfactant, but unlike emulsions, are thermally stable and transparent. Microemulsions have very low surface tension and small particle size below 100nm, which together give high absorption and permeation properties of drugs transported through microemulsions. In particular, the microemulsion is very useful in solubilizing and improving the absorption of the water-insoluble drug. However, because of the large amount of surfactant required to form the microemulsion, the microemulsion can cause severe mucosal irritation and can result in very large dosage volumes. In the medical field, microemulsions are used only in preparations for application to the skin, such as hair preparations, detergents, etc.

In the case of cyclosporin, which is a relatively water-insoluble drug, U.S. patent No. 4,388,307 discloses an oral liquid preparation comprising an oil, a surfactant, and ethanol as a hydrophilic solvent. The formulation is a microemulsion preconcentrate and therefore requires dilution with water prior to oral administration. This makes patient compliance poor and precise dose control difficult. It is also inconvenient to carry, making it impossible to administer drugs to patients who must undergo cyclosporin therapy for the remainder of their lives in practice.

To eliminate the above-mentioned disadvantages of liquid formulations, microemulsion preconcentrates formulated in the form of soft capsules have been developed. Up to now, the micro-emulsion preconcentrate includes a drug, a hydrophilic solvent, a surfactant, and an oil in an appropriate mixing ratio, and can spontaneously form a micro-emulsion by dissolving in an external phase such as water and intestinal fluid. However, the hydrophilic solvent used as an essential component of the micro-emulsion concentrate permeates the gelatin shell of the capsule, which not only volatilizes but also softens the gelatin shell. These all increase the instability of the soft capsules.

If the cyclosporin soft capsule contains ethanol as a hydrophilic ingredient, the capsule preparation must contain a large amount of ethanol to increase the solubility of cyclosporin. However, since ethanol can permeate the gelatin shell of the capsule and volatilize even at room temperature, the amount of ethanol decreases with time. As a result, when the capsules are stored at low or normal temperatures for extended periods of time, crystallization of cyclosporine may result. Variations in the composition result in very large variations in the bioavailability of cyclosporine and therefore the desired therapeutic effect cannot be reliably and reproducibly achieved. To prevent evaporation of ethanol from the softgel formulation during storage, the softgel may be enclosed in a special packaging material, such as an aluminum blister pack. However, despite the use of said special packaging, there is still the problem of a large variation in cyclosporine bioavailability, since it is not possible to completely prevent the variation of the ethanol content with time. In addition, the use of the above-mentioned special package increases the manufacturing cost and the medical expenses.

To improve the above-mentioned drawbacks of using ethanol as a hydrophilic co-surfactant, a method of using a non-ethanol component as a hydrophilic co-surfactant has also been proposed. U.S. patent No. 5,342,625 discloses a soft capsule formulation formulated with a microemulsion concentrate, which solves the above problems. This patent discloses a pharmaceutical composition in the form of a microemulsion concentrate using a pharmaceutically acceptable C of a low molecular mono-or polyoxyalkylene glycol_1-5Alkyl or tetrahydrofurfuryl di-or partial ethers as hydrophilic solvents, for example diethylene glycol monoethyl ether (such as Transcutol), tetrahydrofurfuryl alcohol polyglycol ether (such as Glycofurol), 1, 2-propanediol, and ethanol as hydrophilic auxiliary solvent. However, all hydrophilic solvents used in this patent are glycols having alcohol groups (-OH) in their structure. Since these diols containing-OH groups have very high hygroscopicity, they absorb moisture in the air and have high permeability to gelatin shells. It is therefore very difficult to formulate compositions comprising such glycol cosurfactantsMaking into soft capsule. Specifically, in the preparation of soft capsules, in the encapsulation and first drying step, water present in the capsule shell is absorbed into the capsule in an amount corresponding to 20% of the hygroscopic solvent, resulting in a change in the composition ratio of the composition. And in its drying step, the water is redistributed in the gelatin shell and evaporated from the inside of the capsule to the outside through the capsule shell. The constituent substances in the capsule also migrate with the water to the capsule shell. Therefore, the composition ratio of the composition according to the patent is greatly changed, and the production amount of the capsule is decreased by the change in the appearance of the preparation due to the above phenomenon.

The hydrophilic solvent used in the formulation disclosed in the above-mentioned us patent also has a softening effect on the gelatin shell of the capsule and causes a pharmaceutical problem that the appearance stability of the gelatin capsule is greatly reduced. This problem becomes more serious when a plasticizer for gelatin, such as propylene glycol, glycerin, etc., is used as a hydrophilic solvent. Therefore, the use of propylene glycol as the main solvent is greatly limited. Propylene glycol is typically used in an amount of 5% or less of the capsule content, and at maximum about 10% or less may be used, with the hardener of the gelatin shell. If the amount of propylene glycol used as the content of the soft capsule exceeds the above range, the appearance stability of the gelatin shell is greatly lowered. Korean patent application No. 94-13945 discloses a cyclosporin-containing composition (trade name: Neoplanta) formed into soft capsules^_) Which uses dimethylisosorbide ether (isosorbide) as a hydrophilic co-surfactant to alleviate the above-mentioned drawbacks. This patent states that the soft capsule formulation using dimethylisosorbide ether does not undergo changes in the appearance of the soft capsule and changes in the content of ingredients because dimethylisosorbide ether is substantially impermeable to the gelatin shell as compared to other hydrophilic co-surfactants used in the prior art.

Dimethyl isosorbide ether is available under the trade name Arlasolve^_One solvent sold, namely, 1, 4: 3, 6-dianhydro-2, 5-dimethyl-D-glucitol, which is generally used only as a skin absorption enhancer in topical pharmaceutical ointments or cosmetics such as lotions。

As described above, the conventional mini-emulsion requires a larger amount of surfactant than the conventional emulsion. Thus, for drugs, such as cyclosporine, which require continuous administration at all times after organ transplantation in a patient, the toxicity of the solvents and surfactants contained in the microemulsion formulation should also be considered for long-term administration. In this case, LD of dimethyl isosorbide₅₀The value was 5.63 mg/kg (murine, oral). LD of known toxic organic solvents₅₀(murine, oral) the following: acetonitrile, 3.8 g/kg; acetone, 10.7 g/kg; 3.8 g/kg of benzene; toluene, 7.53 g/kg; isopropanol, 5.8 g/kg; and butanol, 4.36 g/kg. It is predicted that long term oral administration of compositions comprising dimethyl isosorbide ethers may cause problems. In addition, the use of dimethyl isosorbide does not improve much the pharmaceutical problems, since dimethyl isosorbide still has the following properties: it is reactive with gelatin shell of soft capsule, and volatile, so that it has limitation as a hydrophilic solvent.

U.S. patent No. 5,583,105 discloses oral multiple emulsions containing cyclosporin where ethanol and tocopherol polyethylene glycol 1000 succinate as a surfactant are used as the primary carrier and an oil or polycarboxylic acid alkyl ester is used as a lipophilic or amphoteric solvent. The patent states that alkyl polycarboxylates can be substituted for the oil selectively, and the patent also uses acetyl triethyl citrate specifically for formulating cyclosporine. However, cyclosporin preparations are still essentially constituted using ethanol which is a hydrophilic and volatile solvent in itself. As described above, cyclosporin formulations that use ethanol to solubilize cyclosporin have problems with drug stability, such as ethanol evaporation through the gelatin shell of the capsule during storage. Tocopheryl polyethylene glycol 1000 succinate is used as a surfactant in this patent, which is the esterification product of tocopheryl acid succinate with polyethylene glycol and releases tocopherols upon absorption into the body. The patent discloses that free tocopherol reduces nephrotoxicity. However, it has not been confirmed until now that there is a drug interaction between cyclosporin and free tocopherol which may be absorbed into the body, and the amount of the composition administered exceeds the conventional dose in the case of long-term treatment. In addition, it is generally known that fat-soluble vitamins such as tocopherol can induce side effects when accumulated in the body.

As mentioned above, the microemulsion preconcentrate according to the prior art includes a hydrophilic solvent, an oil and a surfactant as essential and major ingredients. In forming such microemulsion preconcentrates into soft capsules, it is generally known that a hydrophilic solvent reacts with the gelatin shell of soft capsules, thereby softening the shell and volatilizing through the gelatin shell, and the above phenomenon causes a serious problem in formulation stability. Dimethyl isosorbide has been used as a new hydrophilic solvent to ameliorate the above disadvantages, but this material also has limitations as a primary vehicle due to toxicity, and still has the disadvantages of hydrophilic solvents.

The present inventors have studied to develop cyclosporin-containing compositions which improve the drawbacks of the prior art various pharmaceutical preparations and are suitable for forming into soft capsule dosage forms. The inventors of the present invention have developed a novel cyclosporin-containing microemulsion preconcentrate comprising a lipophilic solvent, a surfactant and an oil, instead of a hydrophilic solvent, which may cause a defect in drug stability, using the lipophilic solvent. It has been proved that a micro-emulsion using a lipophilic solvent instead of a hydrophilic solvent can overcome various problems of the prior art, and thus the present invention has been completed.

DISCLOSURE OF THE INVENTION

The present invention relates to a cyclosporin-containing microemulsion preconcentrate composition comprising (1) cyclosporin as an active ingredient; (2) polycarboxylic acid alkyl esters and/or polyhydric alcohol carboxylic acid esters as lipophilic solvents; (3) an oil; and (4) a surfactant.

The first major component of the cyclosporin-containing microemulsion preconcentrate according to the present invention is cyclosporin as an active ingredient. Preferably cyclosporin a.

The second main component of the composition according to the invention is a lipophilic solvent. The lipophilic solvent used in the composition of the present invention, which is at least one selected from polycarboxylic acid alkyl esters, can overcome the disadvantages of the hydrophilic solvent.

Alkyl esters of polycarboxylic acids which can be used in the compositions according to the invention are polycarboxylic acids having from 2 to 10, preferably from 3 to 5, carboxyl groups and C_1-10Esterification products of alcohols.

The polyol carboxylates useful in the present invention are polyols having 2-10, preferably 3-5 hydroxyl groups with C₂-C₁₁Esterification products of carboxylic acids.

The polycarboxylic acid alkyl esters and the polyhydric alcohol carboxylic acid esters which can be used as lipophilic solvents in the composition of the present invention are odorless and colorless oils when in a liquid state. And they have a boiling point above 250 ℃. They do not volatilize at high temperature during the preparation of soft capsules as well as under storage at room temperature, and therefore can ensure the stability of formulations containing these substances. In addition, the lipophilic solvent does not have as severe hygroscopicity as the glycol-based substance, does not dissolve the gelatin shell, and does not induce a change in the composition due to non-volatility and impermeability to the gelatin shell. The polycarboxylic acid alkyl ester and/or the polyhydric alcohol carboxylic acid ester are lipophilic solvents which can be used for solubilizing water-insoluble drugs such as cyclosporin without causing problems in preparation and storage of the product.

Alkyl polycarboxylates which may be preferred for use in the compositions of the present invention include triethyl citrate, tributyl citrate, acetyltributyl citrate, acetyltriethyl citrate, and the like. Polyol carboxylates that may be preferred for use in the compositions of the present invention include triacetin and the like. They may be used alone or in the form of a mixture of two or more. When the mixture is used, the mixing ratio is not particularly limited.

In the cyclosporin-containing microemulsion preconcentrate composition according to the present invention, the weight ratio of the lipophilic solvent to the cyclosporin is preferably 1: 0.1 to 5, more preferably 1: 1 to 3.

The microemulsion preconcentrate composition using a lipophilic solvent and comprising cyclosporin according to the present invention does not have the pharmaceutical disadvantages caused by hydrophilic solvents, which are essential components in the prior art compositions. Another advantage is that the use of the lipophilic solvent not only substantially increases the action of cyclosporin, but also provides many advantages because the lipophilic solvent does not react with the gelatin shell of soft capsules and is not volatile. That is, the lipophilic solvent neither changes the appearance of the capsule nor precipitates the active ingredient cyclosporine. In addition, it reduces the manufacturing cost, has economical effects, and does not cause the problem of solvent toxicity even in patients who administer the capsule for a long period of time.

The third essential component of the composition according to the invention is an oil. Oils useful in the compositions of the present invention include vegetable oils; esterification products of vegetable oils; animal oils and derivatives thereof; and unsaturated long chain fatty acids. They may be used alone or in the form of a mixture of two or more. If a mixture, selection may be made in only one subgroup of the classes; or in two or more subgroups of said classification.

Examples of vegetable oils which may be used in the compositions of the present invention are corn oil, borage oil, sesame oil, primrose oil, peanut oil, olive oil and the like. Refined vegetable oils are preferred.

The refined vegetable oil has high purity and low content of impurities, and can control the content of unsaturated long-chain fatty acid. Therefore, they are mainly used for total venous nutrition, for treating wasting diseases such as diabetic neuropathy, rheumatoid arthritis, etc., and can be used as a carrier for solubilizing unstable drugs. Refined vegetable oils that can be refined by a chromatographic refining step are more transparent than ordinary oils. Because oxidizing agents such as aldehydes, alcohols, ketones, etc. have been removed from them, refined oils are more resistant to oxidation than regular oils. And because the polar materials and water content in the refined oil are greatly reduced, they have a more preferable solubilization effect on the drug than the conventional oil. Commercially available refined vegetable oils typically 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. Commercially available refined vegetable oils have various contents of unsaturated fatty acids according to the kind of vegetable oil. Therefore, an oil having an appropriate unsaturated fatty acid content can be selected and used as desired.

Examples of refined vegetable oils as preferred oils for the composition according to the invention are superfinished corn oil, borage oil, sesame oil, primrose oil, peanut oil and olive oil, which are commercially available under the trade name superfinished oil (Croda Co.). The preferred form of oil for use in the compositions of the invention is one in which the high gamma linolenic acid content of the oil is increased by more than 50%. An example of such an oil is concentrated borage oil (Croda Co.) under the trade name Crossential.

As other oil ingredients that may be used in the compositions of the present invention, the esterification products of vegetable oils include: esterification products of vegetable oils with glycerol; (ii) the esterification product of a vegetable oil with a monohydric alcohol; (iii) esterification products of vegetable oils with triacetin; and (iv) esterification products of vegetable oils with polyglycerols. The esterification of the vegetable oil means that fatty acids contained in the vegetable oil undergo an esterification reaction. The esterification product is a mixture of various components, which can be separated and purified to form a pure target substance. This pure material can then be used as the oil component in the composition of the present invention. In addition, the fatty acids contained in the vegetable oil can be isolated and purified and then subjected to esterification reaction to form the product alone.

Among the esterification products of vegetable oils, the esterification products of vegetable oils with glycerol are preferably used. The product comprises fatty acid triglycerides; a monoglyceride; mono-and diglycerides; and mixtures of the two.

As the esterification product of vegetable oil and glycerin, fatty acid triglyceride can be used. The fatty acid triglyceride is preferably C₈-C₁₂Medium Chain Triglycerides (MCT). MCT is prepared by esterification of fatty acids extracted from palm oil with glycerol and is a triglyceride of medium-chain fatty acids, the predominant fatty acids being capric acid (50-80%) and caprylic acid (20-50%). MCT has many advantages over normal vegetable oils. The emulsion using the medium chain fatty acid is more stable than the conventional emulsion because MCT has higher stability to oxidation reaction than the conventional oil and has a greater density (0.94-0.95) close to the density of water. In addition, because MCTs are less hydrophobic than vegetable oils, higher concentrations of active ingredients can be obtained when using MCTs to make the compositions of the present invention without significantly increasing the viscosity of the composition. This means that MCT is an oil well suited for large doses of drugs, which make the concentration of active ingredient to the carrier as high as 10%, and it is also suitable for drugs that are very low in polarity and therefore sparingly soluble in water, such as cyclosporine. MCTs have been sold under the following trade names: sefol 860, Sefol 870, Sefol 880, Miglyol 810, Miglyol 812, Miglyol 818, Labrafac CC, and the like.

As esterification products of other types of vegetable oils with glycerol, mono-and diglycerides can be used. "Mono-and diglycerides" means a mixture of mono-and diglycerides of fatty acids. Mono-and diglycerides are oils which can be obtained by esterifying fatty acids contained in vegetable oils with glycerin, followed by separation and purification, and have many kinds according to the kind of fatty acids and the degree of esterification. It is preferred to use mono-and diglycerides having a ratio of monoglycerides to total glycerides of at least 40%, preferably at least 90%, and wherein the fatty acid is C₁₆-C₁₈Long chain fatty acids. More preferably, the mono-and diglycerides contain C₁₈Monoglyceride of fatty acid as its main component. These compounds have been sold under the following trade names: GMO AVl (Croda Co.), ATMOS300(ICI Co.), GMOrphic-80 (Eastman Co.), etc. In particular, GMOrphic-80 is a pure monoglyceride without diglycerides, as it is prepared by separating only monoglycerides after esterification using molecular distillation. Thus, GMOrphic-80 is a combination of the inventionMore preferred is an oil component.

Among the esterification products of vegetable oils, the esterification products of vegetable oils with monohydric alcohols can be used secondly. There are many kinds of the products according to the kinds of the vegetable oils involved in the reaction. Representative examples include: crossential GLO E50 (concentrated borage oil ethyl ester, Croda Co.), which is the esterification product of borage oil with ethanol: and Nikkol EOO (ethyl olive oleate; NikkolCo.), which is an esterification product of olive oil with ethanol. The product may also be prepared using only the fatty acid component isolated from the vegetable oil instead of using the total "vegetable oil" component. Examples of such products include ethyl oleate, ethyl linoleate, isopropyl palmitate, isopropyl myristate, and the like.

Among the esterification products of vegetable oils, the esterification product of vegetable oil with triacetin can be used thirdly. Examples of such products include: mono-and di-acetylated monoglycerides; and diacetylated monoglycerides. Preferably C₁₄-C₂₀Diacetylated monoglycerides of fatty acids. The diacetylated monoglycerides are the esterification product of an edible oil with triacetin. The diacetylated monoglycerides are used as additives in food and as plasticizers in pharmaceuticals and are sold under the tradenames Mivacet 9-40, Mivacet 9-45, and the like. The product is obtainable by esterification of a triglyceride with triacetin.

Among the esterification products of vegetable oils, an esterification product of a fatty acid with polyglycerin, that is, a polyglycerin fatty acid ester, can be used fourth. Examples of polyglycerols used in the esterification reaction include diglycerol, tetraglycerol, hexaglycerol, decaglycerol, and the like. Examples of fatty acids reacted with these polyglycerols include oleic acid, linoleic acid, stearic acid, and the like. Examples of polyglycerol fatty acid esters include Plurol Oleique CC 497 (polyglycerol oleate, Gattefose Co.), Plurol Stearique (polyglycerol palmitoyl stearate, Gattefose Co.), DGMO-C (diglycerol monooleate, Nikkol Co.), Tetraglyn 1-0 (tetraglycerol monooleate, Nikkol Co.), Hexaglyn 1-0 (hexaglycerol monooleate, Nikkol Co.), Hexaglyn 5-0 (hexaglycerol monooleate, Nikkol Co.), Decaglyn 5-0 (hexaglycerol pentaoleate, Nikkol Co.), Decaglyn 10-0 (decaglycerol decaoleate, Nikkol Co.), and the like.

In addition, animal oils and derivatives thereof may also be used as the oil component in the compositions of the present invention. A first example of animal oil and its derivatives is squalene. Squalene is obtained from liver oil of shark, is colorless and transparent oil, and has chemical name of hexamethyltetracosahexaene. Compared with common animal oil, squalene has more excellent stability to oxidation reaction and lower melting point. Therefore, it can effectively dissolve cyclosporin. Hydrogenated squalene can also be used as an oil component in a cyclosporin-containing microemulsion preconcentrate composition. Examples of commercially available products of Squalene include Squalene EX (Nikkol Co.), Squalene (Nikkol Co.), and the like.

A second example of animal oils and their derivatives includes omega-3 essential fatty acids, oils of ethyl esterified forms of the fatty acids, and oils of triglyceride forms of the fatty acids. "omega-3 essential fatty acids" are animal oils in which the fatty acid component is tetracosapentaenoic acid and docosahexaenoic acid. Examples of commercially available products of "omega-3 essential fatty acids" include Incromega F2250(Croda Co.) and Incromega F2628(Croda Co.). Examples of commercially available products of the ethyl esterified form of the fatty acid include Incromega E2251(Croda Co.), Incromega F2573(Croda Co.), and the like. Examples of commercially available products in the triglyceride form of the fatty acids include incomega TG2162(Croda Co.), incomega TG2779(Croda Co.), incomega TG2928(Croda Co.), and the like.

Furthermore, unsaturated long chain fatty acids may be used as the oil component in the compositions of the present invention. Examples of such fatty acids include oleic acid, linoleic acid, linolenic acid, and the like. Examples of commercially available products are:

crossential 094(Croda Co.), a commercially available product of oleic acid;

crossential L99(Croda Co.), a commercially available product of linoleic acid;

crossential LN80(Croda Co.), which is a commercially available product of linolenic acid.

The various oils may be used in appropriate mixing ratios to control cyclosporin absorption. In the cyclosporin-containing microemulsion preconcentrate composition according to the present invention, the weight ratio of the oil component to the cyclosporin is preferably l: 0.1 to 5, more preferably 1: 1 to 3.

The fourth essential ingredient of the composition according to the invention is a surfactant. A pharmaceutically acceptable surfactant may be used, provided that it is miscible with the oil and the lipophilic solvent component to form an emulsion in the outer phase under gentle stirring, and the particle size in the inner phase can be adjusted to 100nm or less by controlling the composition ratio. The surfactants useful for this purpose preferably have an HLB value of from 1 to 20, and examples thereof are as follows:

a reaction product of a natural or hydrogenated vegetable oil and ethylene glycol, i.e., a pegylated natural or hydrogenated vegetable oil: for example, a pegylated natural or hydrogenated castor oil. Commercially available surfactants under the following trade names may be used in the compositions of the present invention: cremophor RH40, Cremophor RH60, Cremophor EL, Nikkol HCO-40 and Nikkol HCO-60. Cremophor RH40 and Cremophor EL are preferred.

(ii) polyoxyethylene sorbitan fatty acid esters, i.e., mono-and trilauryl, palmityl, stearyl and oleoyl esters; such as products sold under the trade name "Tween", which include polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyethylene (20) sorbitan monooleate (Tween 80), etc., depending on the kind of fatty acid. Preferably, Tween 20 and Tween 40 are used in the composition according to the invention.

(iii) polyoxyethylene fatty acid esters, such as polyoxyethylene stearate known and marketed under the trade name of Myrj, and polyoxyethylene fatty acid esters known and marketed under the trade name "Cetiol HE".

(iv) polyoxyethylene-polyoxypropylene copolymer, such as the type known commercially under the trade names "Pluronic" and "Emkalyx".

(v) polyoxyethylene-polyoxypropylene block copolymers, such as the type known commercially under the trade name "Poloxamer".

(vi) dioctyl succinate, dioctyl sodium sulfosuccinate, two- [ 2-ethyl hexyl ] -succinate or sodium dodecyl sulfate.

(vii) phospholipids, in particular lecithins, especially soy lecithin.

(viii) bile salts, e.g. alkali metal salts, sodium taurocholate.

(ix) trans-esterification products of triglycerides and polyalkylene polyols of natural vegetable oils, for example of the type known to be commercially available under the Labrafil trade name. Specifically, Labrafil M1944 CS, Labrafil WL 2609 BS, Labrasol, etc. are preferably used in the composition of the present invention.

(x) esterification products of mono-, di-and mono/diglycerides, especially caprylic and capric acid, with glycerol.

(xi) sorbitan fatty acid esters, for example of the type known commercially under the trade name Span.

(xii) pentaerythritol fatty acid esters and polyalkylene glycol ethers, such as pentaerythritol dioleate, pentaerythritol distearate, pentaerythritol monolaurate, pentaerythritol polyglycol ether and pentaerythritol monostearate and pentacrythrite fatty acid esters.

(xiii) sterols and derivatives thereof, for example cholesterol and derivatives thereof, especially phytosterols, such as products including sitosterol, campesterol or stigmasterol, and ethylene oxide adducts thereof, for example soya sterol and derivatives thereof, such as known under the trade name Generol.

(xiv) polyethylene glycol 66012-hydroxystearate, for example, of the type known commercially under the trade name Solutol HS 15.

(xv) polyethylene glycol fatty acid esters, which are classified into stearate, laurate, oleate, etc., depending on the type of fatty acid. Polyethylene glycol monooleate is preferred, and examples of commercially available products thereof are MYO-2, MYO-6, MYO-10 and the like.

(xvi) di-alpha-tocopheryl polyethylene glycol 1000 succinate.

More preferred surfactants for use in the compositions of the present invention are polyoxyethylenated natural or hydrogenated vegetable oils, polyoxyethylene sorbitan fatty acid esters, trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols, and polyethylene glycol fatty acid esters.

The surfactants may be used alone or in the form of a mixture of two or more. In the cyclosporin-containing microemulsion preconcentrate composition according to the present invention, the weight ratio of the oil component to the cyclosporin is preferably 1: 2 to 10, more preferably 1: 3 to 8.

In the cyclosporin-containing microemulsion preconcentrate composition according to the present invention, the mixing ratio of the four basic components by weight is cyclosporin: lipophilic solvent: surfactant: oil = 1: 0.1-5: 2-1O: o.1-5, more preferably 1: 1-3: 3-8: 1-3.

The composition according to the present invention is characterized in that it is soluble in an external phase such as water, artificial gastric juice and artificial intestinal juice by controlling a mixing ratio of the components and thus is obtained in the form of a micro-emulsion having an internal phase diameter of 100nm or less.

The cyclosporin-containing composition according to the present invention may further comprise any pharmaceutically acceptable additive, if necessary. Examples of such additives include antioxidants (e.g., tocopherol, Butylated Hydroxyanisole (BHA), etc.), viscosity control agents, dissolution control agents, flavoring agents (e.g., peppermint oil, etc.), preservatives (e.g., benzyl alcohol, parabens, etc.), and coloring agents.

In clinical use, the composition according to the present invention may be formulated into a soft capsule, a hard capsule dosage form sealed with a gelatin band at the junction portion, or an oral liquid preparation for administration to a patient by oral administration. The composition of the present invention is formulated into soft capsules by a conventional method, for example, cyclosporin is dissolved in a lipophilic solvent ingredient under warming, the oil and surfactant are added to the resulting solution, the ingredients are uniformly mixed, and then, if necessary, pharmaceutically acceptable additives are added, and finally, the resulting mixture-the composition according to the present invention is formulated into soft capsules using a machine for preparing soft capsules.

The microemulsion preconcentrate prepared by using a lipophilic solvent instead of a hydrophilic solvent according to the present invention, particularly when used in the form of a soft capsule, produces a higher blood cyclosporin concentration than the commercial products of cyclosporin soft capsules, and the composition of the resulting capsules does not undergo any change over time due to volatilization and permeation of the ingredients. In addition, it reduces manufacturing costs and solvent toxicity which can be problematic over long-term treatment. Thus, the cyclosporin-containing composition according to the invention improves the cyclosporin soft capsules of the prior art.

Brief Description of Drawings

For a better understanding of the nature and objects of the present invention, reference will now be made to the following more detailed description, taken in conjunction with the accompanying drawings, in which:

FIG. 1 shows the oral administration of a commercial cyclosporin product (Sandimmun) to dogs^_Comparative formulation) and the cyclosporine-containing microemulsion preconcentration composition according to the present invention (experimental formulation) were compared to each other in the following data curve (diamond-solid: comparative formulation, mouth-to-mouth: experimental formulation 6-a, Δ - Δ: experimental preparation 7-B, ■ - ■: experiment preparation 8-C, a-solidup: experimental formulation 9-D).

Modes for carrying out the invention

The present invention will be described in more detail below with reference to examples and experiments, but these examples and experiments are not intended to limit the present invention.

Example 1: oral cyclosporin soft capsule

Soft capsules according to the present invention comprising the components 1-A in Table 1 were prepared as follows.

Cyclosporin a50g as an active ingredient was dissolved in 150g of triethyl citrate as a lipophilic solvent ingredient while stirring and heating. 125g of Miglyol 812 as an oil component and 225g of Cremophor RH40 as a surfactant component were added to give a mixture, and the mixture was stirred until a homogeneous solution was formed. The resulting composition is poured into a machine for preparing soft capsules, and then encapsulated according to a conventional method to prepare soft capsules. Each capsule contained 50mg of cyclosporin a.

Soft capsule formulations of examples 1-B to 1-D having the components listed in Table 1 were prepared according to the above-described method.

TABLE 1

Composition (I)			Composition (mg/capsule)
						Example 1-A	Practice ofExample 1-B	Example 1-C			Examples 1 to D
			Active ingredient	Cyclosporin A								50．0	50．0	50．0			50．0
Lipophilic solvent	Citric acid triethyl ester					150．0					50．0
			Glycerol triacetate									125．0
	Acetyl triethyl citrate							150．0			100．0
			Surface active agent	Cremophor RH 40								225．0	175．0	180．0			90．0
Tween 20						75．0	50．0			150．0
				Oil	Miglyol 812						125．0	125．0	110．0			110．0
Total of			550．0				550．0	540．0									550．0

Example 2: oral cyclosporin soft capsule

Soft capsule formulations of examples 2-A to 2-F having the components listed in Table 2 were prepared according to the method of example 1.

TABLE 2

Composition (I)	Composition (mg/capsule)
						Example 2A	Example 2-B	Example 2-C	Example 2D	Examples 2 to E	Example 2-F
	Active ingredient	Cyclosporin A		50．0	50．0							50．0	50．0	50．0	50．0
Lipophilic solvent						Citric acid triethyl ester		120．0		80．0						40．0
	Glycerol triacetate			140．0									40．0	50．0
						Citric acid tributyl ester										40．0
	Citric acid acetyl tributyl ester				40．0
						Acetyl triethyl citrate		20．0	10．0		80．0
	Surface active agent	CremophorRH 60		200．0	210．0							220．0	150．0	70．0
Tween 20							20．0		70．0	150．0	220．0
		Oil	GMOrphic80		50．0							80．0		130．0	30．0	30．0
DGMO-C						100．0		50．0		50．0
			Mivacet9-45									70．0	80．0		50．0	100．0
Total of	540．0					580．0	520．0	480．0	480．0	490．0

Example 3: oral cyclosporin soft capsule

Soft capsule formulations of examples 3-A to 3-F having the components listed in Table 3 were prepared according to the method of example 1.

TABLE 3

Composition (I)	Composition (mg/capsule)
						Example 3A	Example 3B	Example 3-C	Example 3D	Examples 3 to E	Example 3-F
	Active ingredient	Cyclosporin A		50．0	50．0							50．0	50．0	50．0	50．0
Lipophilic solvent						Citric acid triethyl ester		80．0		80．0
	Glycerol diacetate			110．0
						Citric acid tributyl ester		30．0	20．0		120．0
	Citric acid acetyl tributyl ester		10．0		40．0								100．0
						Acetyl triethyl citrate		20．0	10．0							150．0
	Surface active agent	CremophorEL		150．0	210．0							220．0		70．0
Tween 20							20．0		150．0	150．0
		MYO-2		60．0	30．0								30．0	30．0	180．0
Labrafi1						50．0		50．0		50．0
		Oil	Ultra-refined borage oil		150．0							100．0	120．0	130．0	100．0	130．0
Total of	600．0					550．0	560．0	480．0	550．0	510．0

Example 4: oral cyclosporin soft capsule

Soft capsule formulations of examples 4-A to 4-F having the components listed in Table 4 were prepared according to the method of example 1.

TABLE 4

Composition (I)	Composition (mg/capsule)
						Example 4A	Example 4-B	Example 4-C	Example 4-D	Examples 4 to E	Example 4-F
	Active ingredient	Cyclosporin A		50．0	50．0							50．0	50．0	50．0	50．0
Lipophilic solvent						Glycerol triacetate		80．0		120．0						50．0
	Citric acid acetyl tributyl ester			130．0									20．0	100．0
						Acetyl triethyl citrate			20．0		130．0				30．0
	Surface active agent	CremophorRH 40		200．0	210．0							220．0	180．0	250．0			200．0
Oil						Miglyol 812			90．0
	Plurol oleiqueCC 497			40．0	70．0							100．0	20．0
						GMOrphic 80		70．0			10．0
	Ultra-refined olive oil				10．0								30．0
						Linolenic acid									40．0
	CrossentialGLO E50				60．0							30．0		150．0
						Linoleic acid ethyl ester		80．0							50．0
	Total of	480．0	540．0	530．0	500．0							540．0	500．0

Example 5: oral cyclosporin soft capsule

Soft capsule formulations of examples 5-A to 5-E having the components listed in Table 5 were prepared according to the method of example 1.

TABLE 5

Composition (I)	Composition (mg/capsule)
					Example 5A	Example 5-B	Example 5-C	Example 5-D	Examples 5 to E
	Active ingredient	Cyclosporin A		50．0						50．0	50．0	50．0	50．0
Lipophilic solvent					Citric acid triethyl ester		100．0		80．0						90．0
	Acetyl triethyl citrate		30．0	120．0							120．0
					Surface active agent	CremophorRH 40		180．0	210．0				220．0	220．0	250．0
Oil	Tetraglyn l-0		100．0	80．0						80．0
					Mivacet 9-40			20．0					110．0
	GMOrphic 80		10．0	30．0							20．0	50．0
					Oleic acid ethyl ester				40．0
	Linoleic acid ethyl ester		30．0							30．0	10．0	80．0
					Antioxidant agent	Tocopherol		0．7	1．0				3．0	1．5	2．0
Total of	500．7	511．0	503．0	531．5						522．0

Example 6: oral cyclosporin soft capsule

Soft capsule formulations of examples 6-A to 6-D having the components listed in Table 6 were prepared according to the method of example 1. Each capsule contained 100mg of cyclosporin a.

TABLE 6

Composition (I)			Composition (mg/capsule)
						Example 6A	Example 6-B	Example 6-C			Example 6-D
			Active ingredient	Cyclosporin A								100．0	100．0	100．0			100．0
Lipophilic solvent	Citric acid triethyl ester					50．0					150．0
			Glycerol triacetate		100．0							250．0	150．0			20．0
	Citric acid tributyl ester							50．0			20．0
			Surface active agent	Cremophor RH 40								450．0	300．0	200．0			450．0
Tween 20						150．0	200．0
				Oil	GMOrphic 80						80．0
DGMO-C		220．0								230．0
					Tetraglyn 1-0							50．0	150．0
Sefol 880			150．0							50．0
					Super refined borage oil							50．0	150．0
Total of			1000．0				1050．0	1000．0									1020．0

Example 7: oral cyclosporin soft capsule

Soft capsule formulations of examples 7-A to 7-D having the components listed in Table 7 were prepared according to the method of example 1. Each capsule contained 100mg of cyclosporin a.

TABLE 7

Composition (I)			Composition (mg/capsule)
						Example 7-A	Example 7-B	Example 7-C			Example 7-D
			Active ingredient	Cyclosporin A								100．0	100．0	100．0			100．0
Lipophilic solvent	Citric acid triethyl ester					180．0					150．0
			Glycerol triacetate									250．0	200．0			40．0
	Surface active agent	Cremophor RH 40				350．0	300．0	200．0			450．0
Tween 20					150．0							200．0
		Oil	P1tirol o1eique CC497			100．0		50．0			150．0
Tetraglyn 1-0					80．0							50．0
			GMOrphic 80					50．0
Nikkol E00					120．0							150．0
			Crossential GLOE50				100．0	150．0			150．0
Total of					930．0							1100．0	950．0			1040．0

Example 8: oral cyclosporin soft capsule

Soft capsule formulations of examples 8-A to 8-D having the components listed in Table 8 were prepared according to the method of example 1. Each capsule contained 100mg of cyclosporin a.

TABLE 8

Composition (I)			Composition (mg/capsule)
						Example 8-A	Example 8-B	Example 8-C			Example 8-D
			Active ingredient	Cyclosporin A								100．0	100．0	100．0			100．0
Lipophilic solvent	Citric acid triethyl ester					100．0					150．0
			Glycerol diacetate		100．0							250．0	200．0			40．0
	Surface active agent	Cremophor RH 40				380．0	300．0	200．0			420．0
Tween 80					150．0							200．0
		Oil	Plurol oleique CC497			100．0		120．0			50．0
GMOrphic 80					100．0							50．0
			Incromega F2250			100．0					70．0
Incromega E2251												150．0
			Incromega TG2779					150．0			80．0
Total of					980．0							1000．0	970．0			910．0

Example 9: oral cyclosporin soft capsule

Soft capsule formulations of examples 9-A to 9-D having the components listed in Table 9 were prepared according to the method of example 1. Each capsule contained 100mg of cyclosporin a.

TABLE 9

Composition (I)			Composition (mg/capsule)
						Example 9-A	Example 9B	Example 9-C			Example 9-D
			Active ingredient	Cyclosporin A								100．0	100．0	100．0			100．0
Lipophilic solvent	Citric acid triethyl ester					150．0		100．0
			Glycerol triacetate		50．0							250．0	100．0			210．0
	Surface active agent	Cremophor RH 40				400．0	300．0	100．0			430．0
Tween 20					150．0							300．0			70．0
		Cremophor EL									70．0
Poloxamer 124															70．0
		Oil	P1urol oleique CC497			70．0		120．0
GMOrphic 80					80．0							50．0
			Decaglyn 5-0			150．0
Oleic acid												150．0	50．0
			Linoleic acid								115．0
Labrafac CC													50．0			285．0
			Total of			1000．0	1000．0	920．0			1350．0

Example 10: oral cyclosporin soft capsule

The soft capsule formulations of examples 10-A to 10-D having the components listed in Table 10 were prepared according to the method of example 1. Each capsule contained 100mg of cyclosporin a.

Watch 10

Composition (I)			Composition (mg/capsule)
						Example 10-A	Example 10-B	Example 10-C			Example 10-D
			Active ingredient	Cyclosporin A								100．0	100．0	100．0			100．0
Lipophilic solvent	Citric acid triethyl ester					100．0					50．0
			Glycerol triacetate		100．0							200．0	200．0			100．0
	Surface active agent	Cremophor RH 40				350．0	200．0	100．0			450．0
Tween 80					180．0							300．0
		Oil	Plurol oleique CC497			50．0		50．0
GMOrphic 80					50．0							150．0
			Tetraglyn 5-0			200．0
Squalene EX												150．0	200．0
			Squalene								200．0
Total of					950．0							980．0	950．0			900．0

Examples 11 to 20: orally administered hard cyclosporin capsules

A microemulsion preconcentrate composition containing cyclosporin was prepared according to the same composition and method as in examples 1 to 10, and then filled into hard gelatin capsules. The joined portions of the hard capsules were sealed with a gelatin band, thereby producing hard capsules containing 50 or 100mg of cyclosporin a per capsule.

Experimental example 1

To compare the pharmacological effects of the cyclosporin-containing microemulsion preconcentrate composition according to the present invention with commercial products prepared according to the prior art, comparative bioavailability experiments were performed with dogs as follows. As the experimental formulation according to the invention, the soft capsules of examples 6-A, 7-B, 8-C and 9-D were used, whereas the commercial product Sandimmun was used^_100-mg Soft Capsule as controlAnd (3) preparing.

In this bioavailability study, 15 bitches weighing 11.0-15.0 kg were used and each group consisted of 3 dogs. Water was supplied alone 18 hours prior to dosing, with no other food. The soft capsule formulation was administered to dogs at a dose of 100mg cyclosporin A per dog, followed immediately by 50ml water. Food was supplied 4 hours after the administration. A2 ml venous blood sample was taken as a baseline cyclosporin A value from the cephalic vein prior to administration, and then 2ml blood samples were taken at prescribed time intervals after administration. Blood samples were frozen at-18 ℃ until analysis was performed. Blood concentration of cyclosporin A was analyzed by RIA (radioimmunoassay).

The dog whole blood cyclosporin a concentration-time curves for each formulation are shown in fig. 1, and the pharmacokinetic parameters calculated from the experimental data are shown in table 11.

Table 11: bioavailability of the Experimental and comparative formulations of the invention

Pharmacokinetic parameters	Experimental preparation			Comparative formulation
						Example 6A	Example 7-B	Example 8-C		Example 9-D
	AUC0-24(ng·h／ml)	5910．4	4887．7	4807．4									6121．7	2671．4
Cmax(ng／ml)						1224．3	987．26	1026．3		1118．0	512．0
	Tmax(h)	1．5	1．5	2．0								2．0	2．0

As can be seen from FIG. 1 and Table 11, the cyclosporin-containing microemulsion preconcentrate composition using a lipophilic solvent according to the present invention shows a greater AUC (area under the cyclosporin A blood concentration curve) and a higher C than the comparative formulation_max(maximum blood concentration of cyclosporin A). Compared with the comparative preparation, the experimental preparation 6-A for oral administration,The AUC of cyclosporin A after 7-B, 8-C and 9-D were 2.21, 1.83, 1.80 and 2.29 times, respectively, that is to say that the experimental formulation showed high absorption.

As can be seen from the results of the above experimental examples, the composition of the present invention has bioavailability 2 times or more as much as that of the prior art formulation, and also shows excellent cyclosporin effect. In addition, the cyclosporin-containing microemulsion preconcentrate composition according to the present invention provides excellent cyclosporin formulations which overcome various disadvantages, i.e., formation of cyclosporin precipitates due to evaporation of solvents, unacceptable alteration in bioavailability of cyclosporin caused by drug precipitation, undesirable change in appearance of formulations, and increase in production cost due to the use of special packaging, etc.

Claims (24)

1. A cyclosporin-containing microemulsion preconcentrate composition comprising:

1) a cyclosporin as an active ingredient, which is a drug,

2) polycarboxylic acid alkyl esters and/or polyhydric alcohol carboxylic acid esters as lipophilic solvents,

3) oil, and

4) a surfactant.

2. A composition according to claim 1 wherein the cyclosporin is cyclosporin a.

3. The composition of claim 1, wherein the alkyl polycarboxylate is at least one member selected from the group consisting of: triethyl citrate, tributyl citrate, acetyl tributyl citrate, and acetyl triethyl citrate.

4. The composition of claim 1, wherein the polyol carboxylic acid ester is triacetin.

5. The composition of claim 1, wherein the oil is at least one member selected from the group consisting of: vegetable oils, esterification products of vegetable oils, animal oils and their derivatives, and unsaturated long chain fatty acids.

6. The composition of claim 5, wherein the vegetable oil is a refined vegetable oil.

7. The composition of claim 6, wherein the refined vegetable oil is at least one member selected from the group consisting of: corn oil, borage oil, sesame oil, primrose oil, peanut oil and olive oil in super-refined form.

8. The composition of claim 5, wherein the esterification product of the vegetable oil is:

i) esterification products of vegetable oils with glycerol;

ii) esterification products of vegetable oils with monohydric alcohols;

iii) esterification products of vegetable oils with triacetin; and

iv) esterification products of vegetable oils with polyglycerols.

9. The composition of claim 8, wherein the esterification product of vegetable oil with glycerol is a fatty acid triglyceride, a monoglyceride, a mono-and diglyceride, or a mixture thereof.

10. The composition of claim 9, wherein the fatty acid triglyceride is C₈-C₁₂Medium chain triglycerides.

11. The composition of claim 9, wherein the mono-and diglycerides are C₁₆-C₁₈Fatty acid mono-and diglycerides.

12. The composition of claim 8, wherein the esterification product of vegetable oil with a monohydric alcohol is an esterification product of borage oil or olive oil with a monohydric alcohol.

13. The composition of claim 8, wherein the esterification product of a vegetable oil with a 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 of claim 8, wherein the esterification product of vegetable oil and triacetin is C₁₄-C₂₀Fatty acid mono-and diacetylated monoglycerides.

15. The composition of claim 8, wherein the esterification product of a vegetable oil with a polyglycerol is an oil formed by esterification of a fatty acid with a di-, tetra-, hexa-or decaglycerol.

16. The composition of claim 5, wherein the animal oil and its derivatives are at least one member selected from the group consisting of: squalene, omega-3 essential fatty acids, oils formed by esterification of omega-3 essential fatty acids with monohydric alcohols, and oils in the form of triglycerides of omega-3 essential fatty acids.

17. The composition of claim 1, wherein the surfactant has an HLB value of 1-20.

18. The composition of claim 17, wherein the surfactant is at least one member selected from the group consisting of: pegylated natural or hydrogenated vegetable oils, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene-polyoxypropylene block copolymers, dioctyl succinate, dioctyl sodium sulfosuccinate, di- [ 2-ethylhexyl ] -succinate or sodium lauryl sulfate, phospholipids, bile salts, trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols, mono-, di-and mono/diglycerides, sorbitan fatty acid esters, pentaerythritol fatty acid esters, polyalkylene glycols and pentaerythritol fatty acid esters, sterol ethers and derivatives thereof, polyethylene glycol 66012-hydroxystearate, polyethylene glycol fatty acid esters, and di-alpha tocopheryl polyethylene glycol 1000 succinate.

19. The composition of claim 18, wherein the surfactant is at least one member selected from the group consisting of: pegylated natural or hydrogenated vegetable oils, polyoxyethylene sorbitan fatty acid esters, trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols, and polyethylene glycol fatty acid esters

20. The composition of claim 19, wherein the surfactant is at least one member selected from the group consisting of: pegylated natural or hydrogenated vegetable oils, and polyoxyethylene sorbitan fatty acid esters.

21. The composition according to claim 1, wherein the weight mixing ratio of cyclosporin, lipophilic solvent, surfactant and oil is 1: 0.1-5: 2-10: 0.1-5.

22. A composition according to claim 21 wherein the cyclosporin lipophilic solvent surfactant oil is present in a ratio of 1: 1 to 3: 3 to 8: 1 to 3 by weight.

23. The composition of claim 1, further comprising at least one pharmaceutically acceptable substance selected from the group consisting of: antioxidants, viscosity control agents, dissolution control agents, flavoring agents, preservatives, and coloring agents.

24. A pharmaceutical preparation comprising the composition of claim 1, wherein the dosage form is a soft capsule, a hard capsule sealed with a gelatin band at the junction, or an oral liquid dosage form.