Dissolution and Bioavailability Enhancement of Efavirenz by Hot Melt Extrusion Technique

Abstract

The aim of this study is to improve dissolution and bioavailability of poorly water soluble Efavirenz (Efv), a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Its effectiveness can be attributed to its long half-life (t1/2) of 52–76 h after single dose. Formulation of poorly water soluble drug for oral delivery is one of the biggest challenges. Amongst the available approaches, the novel solid dispersion (SD) technique known as hot melt extrusion (HME) has often proved to be the most widely used method in improving dissolution and bioavailability of the drugs because of its various advantages. Dissolution enhancement of Efv was done by HME technology where crystalline form of API is converted to amorphous form using hydrophilic polymer like Kollidon VA64. Surfactants like Polyethylene glycol (PEG 4000), polyoxy 35 castor oil (Chremophor EL) and Sorbiton monolaurate (Montane 20PHA) were used as plasticizer for process feasibility. Physical mixtures of drug, polymer and surfactant were prepared in ratio of 1:1:0.1. These physical mixtures were subjected to melt and the resultant formulations were subjected to physical characterization, dissolution, permeability and in vivo testing. Pharmacokinetics of Efv was studied in rats. Drug efflux pumps like P-glycoprotein (P-gp) were recognized to posses’ functional role in determining the pharmacokinetics of drugs. Inhibition of P-gp improves intestinal absorption and tissue distribution while reducing the substrate metabolism and its elimination. Drug release showed comparative similar release for all the HME formulations while the permeability studies showed improved permeability of formulations containing Sorbiton Monolaurate and PEG 4000. In comparison to the Non HME (NHME) formulation, the SD prepared with KollidonVA64 (drug: polymer 1:1) by HME process showed a significant enhancement in permeability with all the three surfactants. SD prepared by PEG 4000 resulted in 106.98% enhancement in extent of absorption. In conclusion, solid dispersion prepared using certain polymer could serve as a promising formulation approach to enhance the dissolution and bioavailability of Efv.