Development of oral formulation of nano sorafenib for the treatment of Hepatocellular carcinoma

Abstract

Orally delivered molecularly targeted, small molecule drugs play a significant role in managing cancer as a chronic disease. However, due to the poor oral-bioavailability of some of these molecules, high-dose administration is required leading to dose-limiting toxicity especially when delivered daily for a long duration. Here, we report an oral nanoformulation for small molecule multi-kinase inhibitor, sorafenib tosylate, showing nearly two-fold enhancement in the oral-bioavailability and enhanced therapeutic efficacy with better safety profile compared to current clinical formulation. Using a scalable process involving high pressure homogenization, sorafenib was loaded into albumin nanocarrier at ~ 50 w/w%. Repeated preparation of gram-scale batches (n=7) showed average particle size of 180+9nm, encapsulation efficiency 95±2% and drug-loading efficiency 48±0.7%. Further, surface engineering with a mucoadhesive layer on nanoparticles (referred as ABSORF) resulted in the final size of 299+38nm and surface charge -54+8mV. Single-dose and multi-dose pharmacokinetic studies showed 2-fold enhancement in the plasma concentration of sorafenib compared to current clinically used tablets. Antitumor efficacy studies in the orthotopic rat liver tumor model showed significant tumor regression (p value = 0.0037) even at half dose (eqv. to 200mg of human equivalent dose) of ABSORF compared to clinical control (eqv. to 400mg). Biodistribution of sorafenib from ABSORF was higher in the liver; however, liver and kidney function test parameters were comparable with that of the 2x dose of clinical control. No abnormalities and signs of toxicity were seen in the histopathological analysis for ABSORF treated animals. In summary, we demonstrate a scalable preparation of small molecule drug loaded nanoformulation with ~ 2 fold enhancement in oral bioavailability, improved anti tumor efficacy and acceptable toxicity profile... newline