Formulation Technology Research Laboratories, Daiichi Sankyo., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Department of Materials Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
J Pharm Sci. 2022 Nov;111(11):3141-3148. doi: 10.1016/j.xphs.2022.08.009. Epub 2022 Aug 24.
Solid dispersions are one of methods for solubilizing water-insoluble drugs. To enhance the bioavailability, maintenance of the supersaturated state and absorption of the dissolved drug in the gastrointestinal tract are important. We designed and synthesized amphiphilic 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers as carriers for solid dispersions and evaluated the dissolution behavior in test solutions with different pH and additives. Solid dispersion of troglitazone with amphiphilic MPC copolymers having both aromatic rings and urethane bonds in the side chains showed rapid dissolution and excellent supersaturation maintenance. It was indicated that the balance between the interactions with drug molecules and the water affinity of the polymer should be considered when carriers for solid dispersions are designed. In addition, cell membrane permeability of the solid dispersion with the amphiphilic MPC copolymer was evaluated by the Dissolution / Permeation system, which consists of two liquid chambers and a monolayer of epithelial cells that mimics the intestinal dissolution and permeation process. Further, blood concentration of the drug when solid dispersions were orally administered in mice was also evaluated. The cell membrane permeability and oral absorbability were significantly improved, compared to the solid dispersions with poly(N-vinylpyrrolidone) and suspension or solution of crystalline troglitazone.
固体分散体是提高水不溶性药物溶解度的方法之一。为了提高生物利用度，维持药物在胃肠道中的过饱和状态和溶解状态是很重要的。我们设计并合成了具有芳环和氨酯键的两亲性 2-甲基丙烯酰氧乙基磷酸胆碱（MPC）共聚物作为固体分散体的载体，并在不同 pH 值和添加剂的测试溶液中评价了其溶解行为。具有芳环和氨酯键的两亲性 MPC 共聚物的曲格列酮固体分散体具有快速溶解和优异的过饱和维持能力。这表明在设计固体分散体载体时，应考虑与药物分子的相互作用和聚合物亲水性之间的平衡。此外，通过由两个液体腔室和模仿肠道溶解和渗透过程的单层上皮细胞组成的溶解/渗透系统，评估了具有两亲性 MPC 共聚物的固体分散体的细胞膜通透性。进一步，还在小鼠中评估了口服给予固体分散体时药物的血药浓度。与聚（N-乙烯基吡咯烷酮）的固体分散体和结晶曲格列酮的混悬液或溶液相比，固体分散体的细胞膜通透性和口服吸收性显著提高。
