Investigation of drug-polymer miscibility, biorelevant dissolution, and bioavailability improvement of Dolutegravir-polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer solid dispersions

Abstract

The aim of the current study was to prepare the efficacious amorphous solid dispersion of poorly water-soluble compound, Dolutegravir. After theoretical and experimental determination of drug-polymer miscibility, polyvinyl caprolactam-polyvinyl acetate-polyethylne glycol graft copolymer was chosen as a polymer. The solid dispersions of Dolutegravir were prepared by quench cooling and solvent evaporation method. Though quench cooling successfully stabilized the drug into amorphous form, solvent evaporation technique failed to render the drug completely amorphous. Owing to the negative Gibbs free energy at room temperature, the prepared dispersions were found stable at room temperature for 60 days. To resolve the overlapping contribution of micellar solubilization and amorphicity in improving the dissolution characteristics of Dolutegravir, the in vitro dissolution studies were performed in USP phosphate buffer as well as bio-relevant media. The dissolution advantage between prepared dispersions and pure drug in USP phosphate buffer was found bridged in the bio-relevant media. For this, the micellar solubilization driven dissolution of Dolutegravir in the presence of bile and lecithin micelles was thought as a contributing factor. Nevertheless, the dissolution advantage of dispersions prepared by quench cooling method was found endured in FeSSIF, which was thought to be due to its amorphicity leading to molecular level dissolution. Subsequently, the dissolution advantage was translated into the improved flux. Further, in vivo oral bioavailability was investigated for the dispersion prepared by quench cooling by using crystalline Dolutegravir as a control. The overall exposure of Dolutegravir was improved by 1.7 fold (AUC), while the maximum plasma concentration (Cmax) demonstrated 2 fold increase after comparing with crystalline Dolutegravir.