| Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof -> Monitor Keywords |
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  Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, Polysaccharide, Dextrin Or DerivativeThe Patent Description & Claims data below is from USPTO Patent Application 20060166931. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to pharmaceutical compositions. More particularly, it relates to the inclusion complexes of butylphthalide, which is D,L-mixed or levorotary, with cyclodextrin or its derivatives, to a process for their preparation and the use thereof. BACKGROUND ART [0002] Butylphthalide is a water insoluble oily compound with the following formula: [0003] There are two optical isomers, levorotary and dextrorotary butylphthalide, due to the presence of a chiral carbon therein. Chinese patent application No. 98125618.X disclosed the use of levorotary butylphthalide in the preparation of pharmaceutical compositions for preventing thrombosis and platelet agglomeration. It was found that butylphthalide could regulate the function of NOS-NO-cGMP system and the metabolism of arachidonic acid in the neurocytes after ischemia. Chinese patent application No. 93117148.2 disclosed the use of racemic butylphthalide mixture in the preparation of pharmaceuticals for preventing and treating ischemia-induced diseases in mammals or human. [0004] Butylphtualide can be obtained by extraction from natural celery seed oil or by chemical synthesis, as described in Chinese patent application No. 99109673.8 and the prior reference: Junshan Yang, Yalun Su, Chinese Pharmaceutical Bulletin, 1984, 31; 671, which realized the availability of butylphthalide. [0005] The pharmaceutical formulations are required to release active agents quickly and exert therapeutic effects rapidly when they are used to treat ischemia-induced diseases or thrombosis. Usually, the formulations for treating acute disease are administrated by intravenous instillation. However, the butylphthalide can only be formulated into soft capsules for oral administration because of its oily characteristics. Therefore, solubility problem of the butylphthalide must be resolved firstly in order to obtain injectable dosage forms. [0006] For the purpose of investigation of the clinical value of butylphthalide, the present applicant has filed a Chinese patent application titled "A inclusion complex of butylphthalide with cyclodextrin derivatives, a process for its preparation and the use thereof" on Jun. 18, 2001, in which solubility problem of butylphthalide was resolved. However, the levorotatory butylphthalide was not mentioned in that application. DISCLOSURE OF THE INVENTION [0007] The present invention intends to provide inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof. In order to improve water-solubility of butylphthalide, it is complexed with cyclodextrin or its derivatives, wherein the butylphthalide is D,L-mixed or levorotary, and the inclusion complexes may be used to prepare various clinically applicable solid and liquid formulations. [0008] The embodiments according to the present invention are as follows: [0009] An inclusion complex of butylphthalide with cyclodextrin or its derivatives comprises butylphthalide and cyclodextrin or its derivatives, wherein the molar ratio of butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10. [0010] The butylphthalide mentioned above comprises D,L-mixed or levorotatory butylphthalide. [0011] The cyclodextrin mentioned above is selected from the group consisting of .alpha.-cyclodextrin, .beta.-cyclodextrin, and .gamma.-cyclodextrin. [0012] The derivatives of cyclodextrin mentioned above are selected from the group consisting of hydroxyethyl-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, dihydroxypropyl-.beta.-cyclodextrin, methyl-.beta.-cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, meltotriose cyclodextrin, carboxymethyl cyclodextrin, and sulfonylalkyl cyclodextrin. [0013] Among the derivatives of cyclodextrin mentioned above, hydroxypropyl-.beta.-cyclodextrin is preferred. [0014] A process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives is provided as follows: [0015] A solution with a concentration of 5-60% is prepared by adding cyclodextrin or its derivatives into a suitable solvent vehicle. A liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives is obtained by adding butylphthalide into the above solution, stirring to provide a clear and transparent solution without oil drops, wherein the molar ratio of butylphthalide to cyclodextrin or its derivatives is in the range of 1:1 to 1:10. [0016] The process mentioned above may further comprise drying the liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives at the temperature of 40-80.degree. C. to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives. [0017] The process mentioned above may also comprise concentrating the liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives until the concentration of cyclodextrin or its derivatives is 10-15% (W/V), cooling the solution for, e.g. about 12 hours to obtain white precipitate, filtering, and drying at 40-80.degree. C., to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives. [0018] A process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives according to another aspect of the present invention comprises placing cyclodextrin or its derivatives into a colloid mill or mortar, adding an appropriate amount of suitable solvent vehicle, and stirring the mixture to provide a paste; adding butylphthalide into the paste described above, grinding for about 1-5 hours to provide a homogenous and viscous paste, then filtering the paste, and drying at 40-80.degree. C. to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives, wherein the molar ratio butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10. [0019] A process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives according to yet another aspect of the present invention comprises adding cyclodextrin or its derivatives into a suitable solvent vehicle to obtain a solution with a concentration of 5-60%, dissolving the butylphthalide into an appropriate amount of ethanol with purity of 99%, mixing the two solutions, stirring, and drying to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives, wherein the molar ratio butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10. [0020] The drying method mentioned above may be any drying method, such as direct drying, spray drying, or freeze-drying. [0021] Examples of the above-mentioned solvent vehicles are water, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, glycerin, or acetone, or the mixture of any two or more above-mentioned solvent vehicles, wherein water is preferred. Continue reading... Full patent description for Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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