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.

Description

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 pharmaceutic...

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Benefits of technology

[0023] Not wish to be bound by any theory, the inventors believe that cyclodextrin or its derivatives could trap the butylphthalide into their tubular structure to generate an inclusion complex of butylphthalide with cyclodextrin or its derivatives, thereby improving the water-solubility of butylphthalide. Accordingly, the active ingredient butylphthalide in the form of inclusion complexes can be directly applied in solid or liquid dosage forms. Limitations such as poor water-solubility, disability to be directly applied in solid, especially injectable dosage forms can be overcome.

[0024] Cyclodextrin or its derivatives are water-soluble pharmaceutical excipients with little toxicity. The inclusion complexes of butylphthalide with cyclodextrin or its derivatives prepared thereby are suitable to be formulated into various liquid and solid dosage forms. The inclusion complexes have the advantages such as good water-solubility and little vascular irritation. The solubility of inclusion complex of butylphthalide with hydroxypropyl-o-cyclodextrin in water at 25° C. is 924 mg / 100 ml. The inclusion complex is particularly applicable for preparing liquid dosage forms. The present invention overcomes the limitation that butylphthalide cannot be used to prepare liquid formulations. Due to the fact that the water-solubility is improved, the resulting solid dosage forms have the advantages such as rapid disintegration, good solubility and high bioavailability, which is more applicable for clinical use.

[0027] The assay suggests that instillation of the inclusion complex has little vascular irritation, and that the inclusion complex can be used to produce injectable dosage forms.

Problems solved by technology

However, the butylphthalide can only be formulated into soft capsules for oral administration because of its oily characteristics.

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