Preparation Of Glimepiride Solubilizing System And Its Sustained-release Formulation By Mechanochemical Technology

Glimepiride(GM),the third generation sulfonylurea hypoglycemic drug,which is widely used in treatment of type II diabetes mellitus.Glimepiride belongs to class II drug in the biopharmaceutics classification system(BCS).It has good permeability but poor water solubility,which limits its clinical application.Mechanical ball milling technology is used to improve the solubility and bioavailability of insoluble drugs by reducing the particle size and crystallinity of drugs,along with new phase formation.Currently,mechanical ball milling technology is commonly used in the field of drug solubilization because of its significant advantages,such as no organic solvent involved in the preparation process,simple-efficient operation and low operating cost.In this paper,mechanochemical technology was applied to the study of glimepiride solubilization system to improve its solubility and bioavailability.The details are as follows:(1)Preparation of glimepiride/hydroxypropyl-?-cyclodextrin inclusion complex system by mechanical ball millingThe inclusion complex system of glimepiride was prepared by mechanical ball milling.The conditions of ball milling were optimized by response surface analysis.Phase solubility experiments showed that inclusion complex of glimepiride and hydroxypropyl-beta-cyclodextrin formed in the form of 1?1.The solubility and in vitro dissolution rate are significantly improved after the preparation of inclusion complex.The results of DSC,IR and SEM techniques indicate that,the particle size of glimepiride is significantly reduced,and the drug is bounded to the cavity ofhydroxypropyl-?-cyclodextrin in an amorphous form.Stability test shows that high high temperature and humidity should be avoided in storage of inclusion complex.(2)Preparation of glimepiride/hydroxypropyl-?-cyclodextrin/hydroxypropyl cellulose sustained-release inclusion complex by mechanical millingGlimepiride sustained-release inclusion complex system was prepared by mechanical ball milling.The solubility and dissolution rate are significantly improved,and drug dissolution is delayed with the addition of hydroxypropyl cellulose.XRD,IR and SEM were used to identify the inclusion complexes prepared by ball milling.The results indicate that glimepiride is bounded in the cavity of hydroxypropyl-?-cyclodextrin in an amorphous form.Stability experiments showed that the inclusion complexes prepared by ball milling had strong hygroscopicity and high humidity should be avoided during storage.(3)In vivo pharmacokinetics and pharmacodynamics studyThe release and absorption effects of the preparation in vivo were evaluated by pharmacokinetics and pharmacodynamics.It indicates that the bioavailability of glimepiride inclusion complex and its sustained-release inclusion complex are higher than that of the original drug,and its sustained-release inclusion complex could effectively delay the drug diffusion.Pharmacodynamic studies have shown that,ball milling products have obvious effects of decreasing bloud glucose,compared with raw materials,and sustained-release inclusion compounds can avoid hypoglycemia in a short time after taking medicine.