International Journal of Nanomedicine (May 2019)
Mixed micelles loaded with the 5-benzylidenethiazolidine-2,4-dione derivative SKLB023 for efficient treatment of non-alcoholic steatohepatitis
Abstract
Yanping Li,1 Ting Zhang,2 Qinhui Liu,1 Jinhang Zhang,1 Rui Li,1 Shiyun Pu,1 Tong Wu,1 Liang Ma,3 Jinhan He11Laboratory of Clinical Pharmacy and Adverse Drug Reaction; 2Department of Pharmacy; 3Division of Nephrology, Kidney Research Institute, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, People’s Republic of ChinaBackground: SKLB023, a novel 5-benzylidenethiazolidine-2,4-dione based-derivative, specifically inhibits inducible nitric oxide synthase and shows promise for treating non-alcoholic steatohepatitis (NASH). However, its poor water solubility and low bioavailability limits its clinical use. Here the drug was loaded into phosphatidylcholine-bile salt-mixed micelles (PBMM/SKLB023) to overcome these limitations.Methods: PBMM/SKLB023 was developed using a simple co-precipitation method, and formulation parameters were optimized. The pharmacokinetics of PBMM/SKLB023 were investigated in Wistar rats, and therapeutic efficacy was assessed in a mouse model of NASH induced by a diet deficient in methionine- and choline.Results: PBMM/SKLB023 particles were 11.36±2.08 nm based on dynamic light scattering, and loading the drug into micelles improved its water solubility 300-fold. PBMM/SKLB023 inhibited proliferation and activation of HSC-T6 cells more strongly than free SKLB023. PBMM/SKLB023 showed longer mean retention time and higher bioavailability than the free drug after intravenous injection in Wistar rats. In the mouse model of NASH, PBMM/SKLB023 alleviated hepatic lipid accumulation, inflammation, and fibrosis to a significantly greater extent than free SKLB023.Conclusion: PBMM/SKLB023 shows therapeutic potential for treating NASH and liver fibrosis.Keywords: phosphatidylcholine-bile salt-mixed micelles, bioavailability, solubilizing efficiency, NASH
