Mechanochemical Preparation Of α-lipoic Acid Systems With Enhanced Solubility And Investigation On Its Controlled-release Formulation

Lipoic acid(LA)is a first-line drug for the treatment of diabetic neuropathy and known as "the universal antioxidant".However,there are still some limitations in the clinical application of LA.It is easy to initiate polymerization because of the five-membered rings structure,resulting in reduced biological activity.Since the plasma half-life of LA is only 30 min,it is necessary to frequent administration to maintain a certain amount of plasma concentration,which increases the patients’ physical and economic burden.In order to overcome these problems,mechanochemical technology was used to prepare LA systems coupled with solid dispersion technology,inclusion technology,etc.,which enhanced solubility,dissolution rate,stability and the oral bioavailability.The sustained release tablet of LA was prepared to control the release rate of LA and improve patient compliance.The main contents of this thesis include the following parts.(1)We briefly introduces the pathogenesis of diabetes mellitus and its complications,the strategies to increase solubility of poor-soluble drugs,as well as the development of mechanochemistry,and its pharmaceutical application were reviewed.(2)Mechanochemistry was used to prepare the solid dispersion of LA and disodium glycyrrhizinate,and the preparation process was optimized.The solid dispersion system can greatly improve the dissolution rate and water solubility which was proved by In vitro dissolution and solubility experiments.(3)Mechanochemistry was used to prepare cyclodextrin inclusion complex of LA,and the ternary complex system of LA,hydroxypropyl-β-cyclodextrin and sodium carbonate was prepared based on the pH control technology.The experiments show that the solubility of LA can reach 34.7 mg / mL in water by the ternary complex system.(4)Mechanochemistry was used to prepare sustained release solid dispersion system of LA,and the preparation process was optimized.This sustained release solid dispersion system shows a good sustained release effect.(5)On the basis of LA sustained-release solid dispersion,LA sustained-release tablet was prepared and the best prescription process was determined.HPLC method was established for the determination of the related substances of LA sustained-release tablet.The stability of the sustained-release tablets was investigated to determine the storage conditions.