Novel diphenyl dimethyl bicarboxylate provesicular powders with enhanced hepatocurative activity: Preparation, optimization, in vitro/in vivo evaluation

摘要

Diphenyl dimethyl bicarboxylate (DDB) is a hepatocurative agent used for treatment of various liver diseases. However, DDB therapeutic effectiveness is restricted by its low oral bioavailability that arises from its poor solubility and dissolution. Aiming at surmounting the aforementioned restrictions, DDB provesicular dry powders exemplified by proniosomes and proliposomes were prepared using film-deposition technique employing sorbitol as a carrier. Upon dilution with water, the provesicular powders rapidly transformed into vesicular dispersions, either liposomes or niosomes, which were characterized regarding their percent encapsulation efficiency (EE%), vesicle size and distribution, morphology and in vitro drug release. The revealed optimal provesicular powder was exposed to solid state characterization, stability testing and in vivo performance evaluation. Results showed that provesicular powders with acceptable flowability can be prepared using a weight ratio of lipids mixture to sorbitol of 1:20. Proniosomal powder composed of Tween 80:cholesterol:stearylamine in molar ratio 7:3:0.5 loaded on sorbitol was selected as the optimal formulation as it showed the highest EE% and dissolution enhancement for DDB. The elevated levels of liver enzymes in hepatically injured Albino Wister rats were significantly reduced (P < 0.05) after oral administration of the optimal proniosomal powder in comparison to free DDB. This improvement was confirmed histopathologically by minimizing the associated hepatic injury. Accordingly, proniosomes can be assertively considered as a promising stable precursor for immediate preparation of niosomal carrier for DDB with enhanced dissolution and hepatocurative activity.