Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof

Abstract

The present invention relates to the inclusion complexes of butylphthalide, which is D,L-mixed or levorotatory, with cyclodextrin or cyclodextrin derivatives, to a process for their preparation and the use thereof. In the invention, the butylphthalide is complexed with cyclodextrin or cyclodextrin derivatives, preferably with hydroxypropyl-β-cyclodextrin, in order to increase the water-solubility of butylphthalide, develop clinical solid or liquid formulations and improve the therapeutic effect of butylphthalide. The inclusion complex, in which the molar ratio of butylphthalide to cyclodextrin or cyclodextrin derivatives is in the range of 1:1-10, can be used to prepare infusion, injection, injectable powder, liquids for oral administration, syrup, tablets, granules, dispersible tablets and others.

1 . An inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives, comprising butylphthalide and cyclodextrin or cyclodextrin derivative, wherein the molar ratio of butylphthalide to cyclodextrin or cyclodextrin derivatives is 1:1-10.  
     
     
         2 . The inclusion complex according to  claim 1 , wherein said butylphthalide is D,L-mixed or levorotatory butylphthalide.  
     
     
         3 . The inclusion complex according to  claim 1 , wherein said cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.  
     
     
         4 . The inclusion complex according to  claim 1 , wherein said cyclodextrin derivatives are selected from the group consisting of hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, meltotriose cyclodextrin, carboxymethyl cyclodextrin and sulfonylalkyl cyclodextrin.  
     
     
         5 . The inclusion complex according to  claim 1  or  4 , wherein the cyclodextrin derivative is hydroxypropyl-β-cyclodextrin.  
     
     
         6 . A process for preparing the inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives, comprising the steps of adding cyclodextrin or cyclodextrin derivatives into a suitable solvent vehicle to obtain a solution with a concentration of 5-60%, adding butylphthalide into the solution, stirring to obtain a liquid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives.  
     
     
         7 . The process according to  claim 6 , further comprising the step of drying the liquid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives to obtain a solid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives.  
     
     
         8 . The process according to  claim 6 , further comprising the steps of concentrating the liquid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives into a solution with a concentration of 10-15% (W/V), cooling to obtain white precipitate, filtering, and drying to obtain a solid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives.  
     
     
         9 . A process for preparing the inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives, comprising the steps of placing the cyclodextrin or cyclodextrin derivatives into a colloid mill or mortar, adding a suitable solvent vehicle to obtain a paste, adding butylphthalide into the paste, filtering, and drying to obtain a solid inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives.  
     
     
         10 . A process for preparing the inclusion complex of butylphthalide with cyclodextrin or cyclodextrin derivatives, comprising the steps of adding cyclodextrin or cyclodextrin derivatives into a suitable solvent vehicle to obtain a solution with a concentration of 5-60%, dissolving butylphthalide into a selected 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 cyclodextrin derivatives.  
     
     
         11 . The process according to  claim 6 ,  9  or  10 , wherein said suitable solvent vehicle is selected from the group consisting of water, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, glycering, acetone, and a mixed solvent vehicle of any two or more of the solvent vehicles.  
     
     
         12 . A pharmaceutical composition comprising a therapeutically effective amount of the inclusion complex according to  claim 1  and a suitable carrier.  
     
     
         13 . The pharmaceutical composition according to  claim 12  in a liquid dosage form.  
     
     
         14 . The pharmaceutical composition according to  claim 12  in a solid dosage form.  
     
     
         15 . A method of treating ischemia-induced disease comprising administering a therapeutically effective amount of the inclusion complex according to  claim 1  to a patient.  
     
     
         16 . A method of treating thrombosis comprising administering a therapeutically effective amount of the inclusion complex according to  claim 1  to a patient.