Bioenhanced advanced third generation solid dispersion of tadalafil: Repurposing with improved therapy in pyelonephritis

Abstract

Tadalafil (TDL) a BCS-II drug is recently reported for repurposing nephroprotective effect in Pyelonephritis (PN). However, poor water solubility and dissolution rate limited oral bioavailability pose serious challenges in its therapeutic applications. We present an advanced third generation Solid Dispersion (SD) of TDL comprising a polymer in combination with a Self Micro-emulsifying Composition (SMEC) to achieve high drug loading, improved stability and rapid dissolution of TDL for enhancing bioavailability and efficacy in PN. TDL-SMEC-SD was coated onto rapidly disintegrating inert tablet cores which disintegrated rapidly in water to release SD as a film. TDL-SMEC-SD was evaluated for in-vivo oral bioavailability and in-vivo efficacy in lipopolysaccharide-induced PN in rats. TDL exhibited high solubility (45.6 mg/ml) in the SMEC. TDL-SMEC-SD exhibited remarkably high TDL loading (45%w/w), exceptionally low contact angle (9°), rapid in-vitro release (t50 7.3 min), microemulsion formation (globule size ~100 nm) in aqueous dispersion, and stability as per ICH guidelines. SEM, DSC, and XRD confirmed high physical stability. A relative bioavailability of 350% and 150% compared to TDL and TDL-SD without SMEC respectively, established the superiority of TDL-SMEC-SD. A significant reduction in serum creatinine, blood urea nitrogen and nitric oxide levels in the lipopolysaccharide-induced PN confirmed the benefit of the TDL-SMEC-SD. The advanced third generation SMEC SDs presents the possibility of platform technology for bioenhancement of poorly water soluble drugs.