Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576 104, Karnataka, India.
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576 104, Karnataka, India.
Eur J Pharm Sci. 2020 Jan 15;142:105137. doi: 10.1016/j.ejps.2019.105137. Epub 2019 Nov 6.
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.
本研究的目的是制备水溶性差的化合物多替拉韦的有效无定形固体分散体。在理论和实验确定药物-聚合物混溶性后，选择聚维酮己内酰胺-醋酸乙烯酯-聚乙二醇接枝共聚物作为聚合物。通过淬火冷却和溶剂蒸发法制备多替拉韦的固体分散体。虽然淬火冷却成功地将药物稳定在无定形状态，但溶剂蒸发技术未能使药物完全无定形。由于室温下的负吉布斯自由能，制备的分散体在室温下 60 天内稳定。为了解决胶束增溶和无定形性在改善多替拉韦溶解特性方面的重叠贡献，在 USP 磷酸盐缓冲液和生物相关介质中进行了体外溶解研究。在 USP 磷酸盐缓冲液中，发现与纯药物相比，制备的分散体具有溶解优势，但在生物相关介质中，这种优势被桥接。对于这一点，认为胆汁和卵磷脂胶束存在时多替拉韦的胶束增溶驱动溶解是一个贡献因素。然而，在 FeSSIF 中，通过淬火冷却法制备的分散体的溶解优势被认为是由于其无定形性导致分子水平溶解而得以维持。随后，将溶解优势转化为改善的通量。此外，通过使用晶型多替拉韦作为对照，研究了通过淬火冷却法制备的分散体的体内口服生物利用度。与晶型多替拉韦相比，多替拉韦的总体暴露量提高了 1.7 倍（AUC），而最大血浆浓度（Cmax）增加了 2 倍。
