Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka.
Department of Pharmaceutical Physical Chemistry, College of Pharmaceutical Sciences, Matsuyama University.
Chem Pharm Bull (Tokyo). 2023;71(10):787-791. doi: 10.1248/cpb.c23-00335.
The aim of this study was to develop a self-micellizing solid dispersion of celecoxib (SMSD/CEL) with enhanced dissolution to suppress a delay in absorption under impairment of gastrointestinal (GI) secretion and motility induced by severe pain. Soluplus-based SMSD/CEL was prepared by lyophilization and physiochemically characterized. A pharmacokinetic study of orally-dosed CEL samples was carried out in rats with propantheline (PPT)-induced the impairment of GI secretion and motility. SMSD/CEL was micellized in aqueous media with a mean diameter of 153 nm, and it showed improved dissolution behavior of CEL under acidic conditions with 2.1-fold higher dissolved CEL at 120 min than crystalline CEL. SMSD/CEL was found to be in an amorphous state, and there was no significant crystallization even after storage under accelerated conditions for 8 weeks, indicating relatively high storage stability of the amorphous form. Orally-dosed crystalline CEL in PPT-treated rats showed a delayed mean absorption time (MAT) and area under the curve of plasma concentration versus time from 0 to 4 h (AUC) was reduced to 12% compared with that in normal rats, whereas SMSD/CEL suppressed the delay and decrease of absorption in PPT-treated rats. From these findings, SMSD/CEL might be efficacious to suppress poor and delayed absorption of CEL for better pain medication in the presence of impaired GI secretion and motility associated with severe pain.
本研究旨在开发一种具有自胶束化能力的塞来昔布固体分散体（SMSD/CEL），以增强溶解度，抑制因严重疼痛导致的胃肠道（GI）分泌和运动功能受损所引起的吸收延迟。采用冷冻干燥法制备了基于 Soluplus 的 SMSD/CEL，并对其进行了物理化学特性评价。在丙哌卡因（PPT）诱导的 GI 分泌和运动功能受损的大鼠中进行了口服 CEL 样品的药代动力学研究。SMSD/CEL 在水性介质中胶束化，平均粒径为 153nm，在酸性条件下，CEL 的溶解行为得到改善，120 分钟时溶解的 CEL 是结晶型 CEL 的 2.1 倍。SMSD/CEL 呈无定形态，即使在加速条件下储存 8 周后也没有明显结晶，表明无定形的相对高稳定性。在 PPT 处理的大鼠中，口服给予结晶型 CEL 后，平均吸收时间（MAT）延迟，从 0 到 4 小时的血药浓度-时间曲线下面积（AUC）减少至正常大鼠的 12%，而 SMSD/CEL 抑制了 PPT 处理的大鼠中吸收的延迟和减少。根据这些发现，SMSD/CEL 可能有效抑制 CEL 的吸收不良和延迟，以改善严重疼痛相关的 GI 分泌和运动功能受损时的疼痛治疗效果。
