| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 6, 1999 |
| PATENT TITLE |
-------------------------------------------------------------------------------- Cyclosporin-containing emulsion composition |
| PATENT ABSTRACT | A stable emulsion composition containing cyclosporin, a polyalkyl ester of polycarboxylic acid in the form of liquid at ordinary temperature, an oil component having an I.O.B. of 0 to 0.25 in the form of a liquid at ordinary temperature, and a surfactant |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 19, 1998 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Neal et al., "In Vitro Anti-Leishmanial Activity of compounds in Current Clinical Use for Unrelated Diseases", Drugs Exp. Clin. Res. (1988), 14(10), 621-628, 1988 month unavailable. The Merck Index an Encyclopedia of Chemical, Drugs, and Biologicals, Tenth Edition, (merck & Co., Inc., Rahway, NJ, USA, 1983) p. 372, 1983 month unavilable. Sakaki, et al., "Mechanisms of Augmented resistance of Cyclosporin A treated Mice to Influenza Virus Infection by Trehalose-6,6'-dimycolate", Microbiol. Immunol., 36(10) pp. 1061-1075, (1992) month unavailable. The 19th Congress, International Federation of Societies of Cosmetic Chemists, pp. 71-133, (Jun. 7, 1976), Boston, Massachusetts. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A cyclosporin-containing oil-in-water type emulsion composition comprising (a) cyclosporin, (b) a polyalkyl ester of polycarboxylic acid in the form of a liquid at ambient temperature, (c) at least one oil component selected from the group consisting of triglycerides, synthetic ester oils, squalene, liquid paraffins and silicone oils having an I.O.B. of 0 to 0.25 in the form of a liquid at ambient temperature, (d) a surfactant and (e) crotamiton. 2. An emulsion composition as claimed in claim 1, wherein the content of the cyclosporin is 0.1 to 10% by weight, based on the total weight of the emulsion composition. 3. An emulsion composition as claimed in claim 1, wherein the content of the polyalkyl ester of polycarboxylic acid is 2 to 50% by weight, based on the total weight of the emulsion composition. 4. An emulsion composition as claimed in claim 1, wherein the content of the oil component is 1/50 of the total weight of the cyclosporin and the polyalkyl ester of polycarboxylic acid. 5. An emulsion composition as claimed in claim 1, wherein the content of the surfactant is 0.5 to 15% by weight, based on the total weight of the emulsion composition. 6. An emulsion composition as claimed in claim 1, wherein the polyalkyl ester of polycarboxylic acid is selected from the group consisting of dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, diisopropyl azelate, diisopropyl adipate, dibutyl adipate, and diisobutyl adipate. 7. An emulsion composition as claimed in claim 1, wherein the oil component having an I.O. B. of 0 to 0.25 in the form of a liquid at ambient temperature is selected from the group consisting of olive oil, soybean oil, oleyl oleate, diisopropyl myristate, cetyl myristate, squalane, liquid paraffin, and silicone oil. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
TECHNICAL FIELD The present invention relates to a novel cyclosporin-containing emulsion composition capable of containing cyclosporin in a high concentration, and having a superior stability and transdermal absorption, and no skin irritation. Cyclosporin is a cyclic peptide composed of 11 amino acids. Up until now, numerous types of natural or synthetic so-called "cyclosporin" called A-I etc. have been known. The "cyclosporin" referred to in the present invention includes these individual peptides and mixtures of these peptides. BACKGROUND ART Cyclosporin has been used as an immunosuppressant or antiinflammatory agent in organ transplants, for example, heart, lung, liver, kidney, pancreas, skin, cornea, and numerous other heterotransplants. In addition, it has been widely used for autoimmune diseases, for example, psoriasis gravis, Behcet's syndrome, Graves' disease, posterior uvetis, Crohn's disease, diabetes mellitus, ulcerative colitis, myasthenia gravis, rheumatoid arthritis, etc. Its efficacy in these has been reported. In particular, efficacy by oral administration has been confirmed up to now for psoriasis. Many clinical test results have been reported at present (for example, British Journal of Dermatology, vol. 122, suppl. 36, 1990). In the case of oral administration, however, many side effects such so kidney toxicity, liver toxicity, specific to cyclosporin have been reported. Further, the bioavailability when orally administed is as low as about 30% and an amount of administration is difficult to determine due to the individual differences. Thus, there are many problems in treatment by oral administration. In view of the above situations, methods of treatment involving direct application to the diseased part the psoriasis for transdermal absorption have been tried out and the development of an effective external agent free from the above side effects is desired. However, since cyclosporin is an active agent characterized by a large molecular weight and a high hydrophobicity, transdermal absorption of cyclosporin cannot be expected in the case of some preparations in which cyclosporin is dispersed in lyophilic bases such as white petrolatum and liquid paraffin or hydrophilic base such as polyethylene glycols. Further, since cyclosporin dissolves well in methanol, ethanol, acetone, ether, chloroform, etc., external administration by a preparation in which cyclosporin is dissolved in an alcohol, particularly ethanol, has been considered. However, since crystals of cyclosporin easily precipitate after the alcohol evaporates, it is not possible to include the active ingredient at a high concentration and therefore it is not possible to ensure a sufficient amount for treatment be absorbed through the skin. Further, in the case of psoriasis or atopic dermatitis requiring long term continuous use, an alcohol-containing preparation cannot necessarily be said to be preferable when considering skin safety. As prior art relating to cyclosporin-containing compositions, emulsion preparations containing medium chain fatty acid diglycerides or monoglycerides are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-49733, emulsion compositions containing hydrophilic components, medium chain fatty acid triglycerides, and surfactants are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-121929, pharmaceutical compositions composed of fatty acid saccharide monoesters and diluents are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-235817, pharmaceutical compositions composed of fatty acid triglycerides, partical fatty acid glycerides, etc. are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-255623, and emulsion compositions containing medium chain fatty acid triglycerides, vegetable oils, surfactants, etc. are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-290809. However, even with these prior arts, since it was impossible to formulate the cyclosporin at a high concentration and, also since, the stability of the preparations was insufficient, these have not been yet commercialized. DISCLOSURE OF INVENTION Accordingly, the object of the present invention is to provide an emulsion composition having superior stability and excellent transdermal absorption as an external agent even when a high concentration of cyclosporin is formulated. In accordance with the present invention, there is provided a cyclosporin-containing oil-in-water type emulsion composition comprising (a) cyclosporin, (b) a polycarboxylate polyalkyl ester in the form of a liquid at ordinary temperature, (c) an oil component having an I.O.B. of 0 to 0.25 in the form of a liquid at ordinary temperature, and (d) a surfactant. BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be further explained in detail below with reference to the drawings. FIG. 1 is a graph showing drug permeation properties of the cream preparation of Example 2 and the gel preparation of Reference Example 1. FIG. 2 is a graph showing transdermal absorption properties of the cream preparation of Example 3 and the gel preparation of Reference Example 1. FIG. 3 is a graph showing the contact hypersensitivity inhibiting effect of the cream preparation of Example 3, the gel preparation of Reference Example 1, and control preparations not containing cyclosporin. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will now be explained in detail. The present inventors found that, when a polyalkyl ester of polycarboxylic acid for a lyophilic component is used, it is possible to formulate cyclosporin at a high concentration and further possible to obtain a cyclosporin emulsion composition which is stable as a preparation. The amount of the cyclosporin formulated in the present invention is preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, based on the weight of the emulsion composition. The polyalkyl ester of polycarboxylic acid formulated in the present invention may be those which are liquid at ordinary temperature. The esters having a total carbon atom number of 10 to 25 are preferable and the esters of a polycarboxylic acids having at least two carboxyl groups and linear or branched alcohols, in which the carboxyl group may be an aliphatic group, aromatic aliphatic group, or aromatic group having the carboxyl groups bonded aliphatically or aromatically are preferable. In the present invention, a partial ester compound may also be used. These esters may be used alone or in the mixture of two kinds or more. The content is not particularly limited as far as the cyclosporin can be dissolved. 2 to 50% by weight, more preferably 5 to 40% by weight, particularly preferably 5 to 30% by weight, based on the weight of the emulsion composition. Specific examples of the polyalkyl ester polycarboxylic acid include, adipic dialkyl esters of a total of 12 to 22 carbon atoms, pimelic dialkyl esters having a total of 13 to 23 carbon atoms, dialkyl suberate azelaic dialkyl esters having a total of 13 to 21 carbon atoms, sebacic dialkyl esters having a total of 14 to 22 carbon atoms, phthalic dialkyl esters having a total of 14 to 24 carbon atoms (however, these alkyl groups may be straight or branched and the alkyl portion of the dialkyl may be the same or different), etc. Preferable examples among these are dibutyl phthalate, diethyl phthalate, diisobutyl phthalate, dibutyl sebacate, diethyl sebacate, diisopropyl azelate, diisopropyl adipate, dibutyl adipate, and diisobutyl adipate. The content of the cyclosporin is, as mentioned above, preferably 0.1 to 15% by weight. If the content is too small, the preparation is easily made, but there is a tendency for the pharmacological effect to become inferior, and therefore, this is not preferable. Conversely, if the content is too much, it is necessary to formulate a large amount of the polyalkyl ester of polycarboxylic acid for dissolving the cyclosporin and, as a result, the polarity may become high, and therefore the emulsion composition will become unstable. Note that if an oil component having an I.O.B. of 0 to 0.25 is added, a stable emulsion composition can be obtained even if a large amount of a polyalkyl ester of polycarboxylic acid is formulated. As the oil component having an I.O.B. of 0 to 0.25, a triglyceride (e.g., olive oil, soybean oil, rapeseed oil, coconut oil, etc.), a synthetic ester oil (e.g., oleyl oleate, isopropyl myristate, cetyl myristate, etc.), or squalane, liquid paraffin, silicone oil, etc. may be used. Further, these oil components may be used alone or in any mixture thereof. The oil component preferably has a molecular weight of at least about 200 and preferably is in the form of a liquid at ordinary temperature from the standpoint of handling. The content of the oil component is preferably 1/50 to an equal amount, more preferably 1/20 to 1/2, of the total weight of the cyclosporin and the polyalkyl ester polycarboxylic acid. When the content of the oil component is too small, it is not preferable from the standpoint of the stability of the emulsion composition, while conversely the content is too large, a content sometimes leads to precipitation of crystals of the cyclosporin. According to the present invention, it is possible to formulate one or more types of oil components having an I.O.B. of more than 0.25 to but not more than 0.85 in the form of a liquid at ordinary temperature as a solution of the cyclosporin to the polyalkyl ester polycarboxylic acid. If a small amount of the oil component is added, it is possible to greatly reduce the amount of the polyalkyl ester polycarboxylic acid used and, further, to enable a large amount of cyclosporin to be dissolved, and therefore, is convenient. As the oil component, specifically, crotamiton, benzyl alcohol, phenetyl alcohol, higher alcohol (e.g., 2-octyldodecanol, oleyl alcohol, 2-hexyldecanol, etc.), higher fatty acids (e.g., oleic acid, linolic acid, linoleic acid, etc.), etc. may be used. Particularly, crotamiton is preferred. The content of the oil component is preferably 0.1 to 10% by weight more preferably 0.5 to 5% by weight, based on the total weight of the cyclosporin and the polyalkyl ester polycarboxylic acid. The content of the polyalkyl ester of polycarboxylic acid in this case is 5 to 30% by weight. Note that the I.O.B. (i.e., Inorganic Organic Balance) referred to in the present invention is the ratio of the inorganic and organic property calculated in accordance with the method of calculation of Fujita described in "Kagaku no Ryoeki", Vol. 11, No. 10, pp. 719 to 725 (1957), that is, the value given by the following formula: I.O.B.=.SIGMA.(inorganic property)/.SIGMA.(organic property) As the surfactant, any surfactants such as anionic surfactants (esters: sorbitan fatty acid ester, glycerol fatty acid ester, decaglycerol fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, etc., ethers: polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, etc.), ionic surfactants (sodium lauryl sulfate, sodium cetyl sulfate, etc.), bipolar surfactants (betaine, aminocarboxylic acid, etc.) may be used. These may be used alone or in any mixture thereof. The content is preferably 0.5 to 15% by weight, more preferably 1 to 10% by weight, particularly preferably 1 to 7% by weight, based on the total weight of the emulsion composition. If the amount of the surfactant is too small, there is a danger of the emulsion composition becoming unstable, while if too large, there is a danger of the feeling at use becoming rough. When the preparation is made a cream preparation, naturally, it is of course possible to add a solid higher fatty acid (e.g., palmitic acid, stearic acid, behenic acid, etc.) or higher alcohol (e.g., cetyl alcohol, stearyl alcohol, behenyl alcohol, etc.). Further, it is possible to add a semisolid oil component (e.g., vaseline, hydrogenated oil, etc.). Further, it is possible to thicken the preparation by adding a water soluble polymer to form the cream preparation. As the water soluble polymer in this case, for example, a carboxylvinyl polymer, sodium carboxylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, etc. may be used. These may be used alone or in any mixture thereof. Further, a neutralizing agent for adjusting the pH of the preparation (e.g., inorganic bases such as sodium hydroxide, potassium hydroxide, and ammonia water and organic bases such as triethylamine, triethanolamine, and diisopropanolamine) may be used. If desired, it is also possible to add a humectant (e.g., propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerine, etc.), preservative (e.g., methyl p-hydroxylenzoate, ethyl paraven, propyl paraven, benzalkonium chloride, benzethonium chloride, etc.), antioxidant (e.g., dibutylhydroxytoluene, ascorbic acid, d1-.alpha.-tocopherol, sodium edetate, etc.) When an emulsion or cream is formed, as one aspect of the present invention, water is an essential component. The water is included preferably in an amount of 20 to 90% by weight. The cyclosporin-containing preparation according to the present invention may be produced in any process for producing emulsion compositions known to these skilled in the art. For example, it may be produced by adding cyclosporin to a polyalkyl ester of polycarboxylic acid, followed by heating the same to dissolve, then gradually adding an oil component while cooling to room temperature to obtain an oil phase. On the other hand, the aqueous phase is produced by adding a surfactant to a humectant, followed by heating the same to dissolve, then adding water thereafter, the oil phase is added to the aqueous phase under high speed stirring to effect the emulsification, whereby a cyclosporin-containing emulsion composition can be obtained. In the present invention, a stable emulsion composition can be obtained regardless of the particle size of the emulsion, and therefore, the emulsification may be effected by an ordinary homomixer. However, it is also possible to produce the same by a high speed rotary type emulsifier such as an ultrasonic homogenizer (made by Ultrasonic Co. of the U.S.) or a Polytron emulsifier (Polytron.RTM. Type PT45/50 made by Kinematika of Switzerland). Further, to obtain an emulsion composition having a fine emulsion particle size, a pressurizing emulsifier such as a Manton-Gaulin homogenizer (Type 15M-8TA of Gaurin Co. of the U.S.) or a microfluidizer (Type 110T of Microfluidizer Co. of the U.S.) may be used |
| PATENT EXAMPLES | Available on request |
| PATENT PHOTOCOPY | Available on request |
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