Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Eur J Pharm Sci. 2018 Nov 1;124:188-198. doi: 10.1016/j.ejps.2018.08.026. Epub 2018 Aug 23.
This study aimed to improve dissolution rate of valsartan in an acidic environment and consequently its oral bioavailability by solid dispersion formulation. Valsartan was selected as a model drug due to its low oral bioavailability (~23%) caused by poor solubility of this drug in the low pH region of gastrointestinal tract (GIT) and presence of absorption window in the upper part of GIT. Solid dispersions were prepared by solvent evaporation method with Eudragit® E100, Soluplus® or polyvinylpyrrolidone K25 (PVP K25) in drug:polymer weight ratios of 1:1, 1:2, 1:4 and 1:6 and further subjected to solid-state characterization and in vitro drug dissolution testing in 0.1 M HCl. The expected drug plasma concentration vs. time profiles after oral administration of the selected solid dispersion formulations were predicted using physiologically-based in silico modeling. Fast and complete dissolution of valsartan, with >80% of dissolved drug within the first 10 min of testing, was observed only from solid dispersions prepared with Eudragit® E100 in drug:polymer ratios of 1:2, 1:4 and 1:6. In all other samples, valsartan dissolution was slow and incomplete. Solid-state characterization showed amorphous nature of both pure drug and solid dispersion samples, as well as favourable intermolecular interactions between valsartan and polymers over interactions between drug molecules. The constructed in silico model predicted >40% of increase in valsartan bioavailability, C and AUC values from selected solid dispersion formulations compared to conventional solid oral dosage form such as IR capsules. Based on the results of the in vitro-in silico study, formulation of solid dispersions of valsartan with Eudragit® E100 polymer can be considered as a promising approach for improving valsartan bioavailability.
本研究旨在通过固体分散体配方提高缬沙坦在酸性环境中的溶出速率，从而提高其口服生物利用度。选择缬沙坦作为模型药物，是因为其在胃肠道（GI）的低 pH 区域溶解度低，以及 GI 上部存在吸收窗，导致其口服生物利用度较低（约 23%）。固体分散体通过溶剂蒸发法制备，以 Eudragit® E100、Soluplus®或聚乙烯吡咯烷酮 K25（PVP K25）为聚合物，药物：聚合物的重量比为 1:1、1:2、1:4 和 1:6，并进一步进行固态特征分析和在 0.1 M HCl 中的体外药物溶出试验。使用基于生理的计算模型预测口服选定的固体分散体配方后的预期药物血浆浓度-时间曲线。只有用 Eudragit® E100 以药物：聚合物的重量比为 1:2、1:4 和 1:6 制备的固体分散体才能快速完全溶解缬沙坦，在测试的前 10 分钟内超过 80%的药物溶解。在所有其他样品中，缬沙坦的溶解速度较慢且不完全。固态特征分析表明，纯药物和固体分散体样品均具有无定形性质，以及缬沙坦和聚合物之间的有利分子间相互作用，超过药物分子之间的相互作用。构建的计算模型预测，与传统的固体口服剂型（如 IR 胶囊）相比，从选定的固体分散体配方中，缬沙坦的生物利用度、C 和 AUC 值增加了 40%以上。基于体外-计算研究的结果，用 Eudragit® E100 聚合物制备缬沙坦的固体分散体可以被认为是提高缬沙坦生物利用度的一种有前途的方法。
