The study summarizes the development of an orally active nanoformulation of a potent but one of the least explored molecules, lisofylline (LSF), in type 1 diabetes (T1D). LSF undergoes rapid metabolism, resulting in poor oral bioavailability and short half-life. In this work, to improve its pharmacokinetic (PK) properties, LSF was encapsulated in the form of its ester prodrug [LSF-linoleic acid (LA) prodrug] into biodegradable self-assembling polymeric micelles [LSF-LA PLM, size: 149.3 nm; polydispersity index: 0.209; critical micelle concentration (cmc); 5.95 μg/mL and Nagg: 14.82 at 10 cmc] of methoxypoly(ethylene glycol)-b-poly(carbonate-co-l-lactide) (mPEG-b-P(CB-co-LA)) block copolymer. LSF-LA PLM was found to be equally effective as the LSF-LA prodrug in cell culture studies in insulin-secreting MIN6 cells and showed excellent stability in simulating biological fluids and plasma. PK of LSF-LA PLM (10 mg/kg dose) revealed a significant improvement in oral bioavailability of LSF (74.86%; 3.3-fold increase in comparison to free LSF) and drastic reduction in the drug metabolism. Further, LSF-LA PLM showed a significant reduction in fasting glucose levels and increase in insulin levels by intraperitoneal as well oral routes in a streptozotocin (STZ)-induced T1D rat model. Production of inflammatory cytokines (TNF-α and IFN-γ) and different biochemical markers for liver and kidney functions were much reduced in diabetic animals after treatment with LSF-LA PLM. LSF-LA PLM-treated pancreatic sections showed minimal infiltration of CD4+ and CD8+ T-cells as indicated by hematoxylin/eosin staining and immunohistochemical analysis.
Keywords: lisofylline prodrug; mPEG-b-P(CB-co-LA); oral delivery; scale up; self-assembly; type 1 diabetes.