Study on the improvement of bioavailability and hepatoprotective effect of silybin-7-eicosanedioate long-acting injection based on prodrug technology.

Chronic hepatitis (CH) is a prevalent liver disease with poor clinical treatment efficacy due to the low bioavailability and short half-life of oral silybin (SLB) formulations. This study employed a long-chain fatty acid prodrug strategy to synthesize four SLB prodrugs (SLB-7-DDDA, SLB-7-TDDA, SLB-7-HDDA, SLB-7-ODDA), among which SLB-7-ODDA was identified as the optimal candidate owing to its lowest degradation rate (purity > 95%). SLB-7-ODDA long-acting suspension injection (SLB-7-ODDA-LAIS) was prepared via wet ball milling, which showed uniform particle size distribution, excellent redispersibility, and sustained-release properties in vitro. In vivo studies conducted in rats revealed that SLB-7-ODDA-LAIS exhibited a relative bioavailability of 613.60% compared with marketed SLB capsules, along with significantly prolonged half-life. It also exerted significant hepatoprotective effects against CCl4-induced CH by reducing serum transaminase levels, enhancing hepatic antioxidant capacity and alleviating liver fibrosis, and showed no significant muscle irritation. This formulation offers a novel long-acting therapeutic strategy for CH and a technical basis for enhancing the in vivo performance of low-bioavailability drugs.