Hybrid Lipid-Polymeric Nanoparticles for Enhanced Bioavailability of Vardenafil in Hepatic Encephalopathy Prevention: A Drug Repurposing Approach

Hepatic encephalopathy (HE) is a severe neurological complication of liver failure with limited therapeutic options. Vardenafil dihydrochloride (VD), a PDE5 inhibitor, used for erectile dysfunction, shows potential for HE prophylaxis through cGMP elevation and neuroprotection, but it suffers poor oral bioavailability due to low solubility and first-pass metabolism. This study aimed to develop hybrid lipid-polymeric nanoparticles (HLPNPs) with piperine as a bioavailability enhancer for VD repurposing in HE prevention.

HLPNPs were prepared using homogenization/ultrasonication technique with glyceryl tripalmitate and Eudragit RS100. The helper polymer type (oleic acid, chitosan, sodium alginate) was evaluated using a one-factor experimental design on each of the particle size, polydispersity index, zeta potential, and entrapment efficiency. In vitro release studies, pharmacokinetics and therapeutic efficacy tests in a thioacetamide-induced HE mouse model were conducted.

Oleic acid emerged as the optimal helper polymer, yielding HLPNPs with 128±2.8 nm particle size, 0.173±0.07 PDI, -32±1.67 mV zeta potential, and 93±1.8% entrapment efficiency. In vitro release showed sustained VD release (~70% over 72h) following Korsmeyer-Peppas kinetics. Pharmacokinetic studies revealed a remarkable 9-fold improvement for the optimized formulation compared to standard VD, with C_max increasing from 9 ng/mL to 22 ng/mL. In the HE mouse model, the optimized formulation significantly improved liver enzymes (ALT, AST), reduced ammonia levels, and enhanced hippocampal BDNF, cGMP, GluR1, and P-CREB levels compared to standard VD treatment.

The piperine-enhanced HLPNPs successfully overcame VD's bioavailability limitations and demonstrated superior therapeutic efficacy in HE prevention. This innovative drug repurposing approach combining nanotechnology with bioavailability enhancement offers a promising strategy for expanding VD's therapeutic applications beyond erectile dysfunction to neurological conditions.