采用 Box-Behnken 设计开发雷贝拉唑固体超饱和胶束以提高溶解和口服生物利用度。
Development of a Solid Supersaturable Micelle of Revaprazan for Improved Dissolution and Oral Bioavailability Using Box-Behnken Design.
机构信息
College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
Department of Psychology, York University, Toronto, Ontario, Canada.
出版信息
Int J Nanomedicine. 2021 Feb 17;16:1245-1259. doi: 10.2147/IJN.S298450. eCollection 2021.
PURPOSE
To enhance the oral bioavailability of revaprazan (RVP), a novel solid, supersaturable micelle (SSuM) was developed.
METHODS
Surfactants and solid carriers were screened based on a solubility and a flowability test, respectively. Supersaturating agents, including Poloxamer 407 (P407), were screened. The SSuM was optimized using a Box-Behnken design with three independent variables, including Gelucire 44/14:Brij L4 (G44/BL4; X) and the amounts of Florite PS-10 (FLO; X) and Vivapur 105 (VP105; X), and three response variables, ie, dissolution efficiency at 30 min (Y), dissolution enhancing capacity (Y), and Carr's index (Y). The solid state property was evaluated, and a dissolution test was conducted. RVP, Revanex, solid micelle (P407-free from the composition of SSuM), and SSuM were orally administrated to rats (RVP 20 mg equivalent/kg) for in vivo pharmacokinetic study.
RESULTS
G44 and BL4 showed great solubility, with a critical micelle concentration range of 119.2-333.0 μg/mL. P407 had an excellent supersaturating effect. FLO and VP105 were selected as solid carriers, with a critical solidifying ratio (g/mL) of 0.30 and 0.91, respectively. With optimized values of X (-0.41), X (0.31), and X (-0.78), RVP (200 mg)-containing SSuM consisting of G44 (253.8 mg), BL4 (106.2 mg), FLO (99.3 mg), VP105 (199.8 mg), and P407 (40 mg) was developed, resulting in Y (40.3%), Y (0.008), and Y (12.3%). RVP existed in an amorphous state in the optimized SSuM, and the SSuM formed a nanosized dispersion in the aqueous phase, with approximately 71.7% dissolution at 2 h. The optimized SSuM improved the relative bioavailability of RVP in rats by approximately 478%, 276%, and 161% compared to raw RVP, Revanex, and solid micelle, respectively.
CONCLUSION
The optimized SSuM has great potential for the development of solidified formulations of poorly water-soluble drugs with improved oral absorption.
目的
为了提高雷瓦拉唑（RVP）的口服生物利用度，开发了一种新型固态超饱和胶束（SSuM）。
方法
分别基于溶解度和流动性测试筛选表面活性剂和固体载体。筛选了增溶剂，包括泊洛沙姆 407（P407）。采用 Box-Behnken 设计，以 Gelucire 44/14：Brij L4（G44/BL4；X）和 Florite PS-10（FLO；X）和 Vivapur 105（VP105；X）的用量为三个独立变量，以及三个响应变量，即 30 分钟时的溶解效率（Y）、溶解增强能力（Y）和 Carr 指数（Y），对 SSuM 进行了优化。评估了固体状态特性，并进行了溶解试验。将 RVP、Revanex、无（不包含 SSuM 组成成分的）固体胶束和 SSuM 以 20mg 等效 RVP/kg 的剂量给大鼠口服，进行体内药代动力学研究。
结果
G44 和 BL4 具有很大的溶解度，临界胶束浓度范围为 119.2-333.0μg/mL。P407 具有出色的超饱和效果。FLO 和 VP105 被选为固体载体，临界固化比（g/mL）分别为 0.30 和 0.91。通过优化的 X（-0.41）、X（0.31）和 X（-0.78）值，开发了包含 G44（253.8mg）、BL4（106.2mg）、FLO（99.3mg）、VP105（199.8mg）和 P407（40mg）的含有 RVP（200mg）的 SSuM，得到 Y（40.3%）、Y（0.008）和 Y（12.3%）。优化后的 SSuM 中 RVP 呈无定形状态，SSuM 在水相形成纳米分散体，在 2 小时时约有 71.7%的药物溶解。与原料药、Revanex 和固体胶束相比，优化后的 SSuM 使 RVP 的相对生物利用度分别提高了约 478%、276%和 161%。
结论
优化后的 SSuM 具有很大的潜力，可以开发具有改善口服吸收的难溶性药物的固态制剂。
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