College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul 08826, Republic of Korea.
Advanced Geo-materials Research Department, Korea Institute of Geoscience and Mineral Resources, Pohang 37559, Republic of Korea.
J Control Release. 2023 Nov;363:525-535. doi: 10.1016/j.jconrel.2023.09.051. Epub 2023 Oct 9.
Bentonite (BT), an orally administrable natural clay, is widely used for medical and pharmaceutical purposes due to its unique properties, including swelling, adsorption and ion-exchange. However, its application as a matrix of amorphous solid dispersion (ASD) formulations is rarely reported, despite the fact that drugs can adsorb to BT in an amorphous state. The objective of this study was to explore the feasibility of BT as a water-insoluble ASD matrix for enhancing the oral bioavailability of poorly water-soluble drugs, including sorafenib (SF). We prepared a novel BT-based ASD of an SF-BT composite (SFBTC) by adsorbing SF onto BT under acidic conditions using the ionic interaction between cationic SF and negatively charged BT. Scanning electron microscopy (SEM), powder X-ray diffractometry (pXRD), and differential scanning calorimetry (DSC) analyses revealed that SF adsorbed to BT in an amorphous state at SF:BT ratios from 1:3 to 1:10. In pharmacokinetic studies in rats, SFBTC (1:3) significantly improved the oral bioavailability of SF, and the AUC of SFBTC (1:3) was 3.3-fold higher than that of NEXAVAR®, a commercial product of SF. An in vitro release study under sink conditions revealed that SFBTC (1:3) completely released SF in a pH-dependent manner, while a nonsink condition study indicated the generation of supersaturation under intestinal pH conditions. A kinetic solubility study showed that the release of SFBTC (1:3) followed the diffusion-controlled mechanism, which is a typical characteristic of water-insoluble matrix-based ASDs. The pharmacokinetic studies of drug-BT composites of various drugs belonging to BCS class II indicated that the pKa value of the adsorbed drugs is one of the most important factors determining their dissolution and oral bioavailability. These results suggest that BT could be a promising water-insoluble ASD matrix for improving the oral bioavailability of poorly water-soluble drugs, including SF.
膨润土（BT）是一种可口服的天然粘土，由于其独特的性质，如膨胀、吸附和离子交换，广泛用于医疗和制药用途。然而，尽管药物可以以无定形状态吸附到 BT 上，但将其作为无定形固体分散体（ASD）制剂的基质的应用却很少有报道。本研究旨在探索 BT 作为水不溶性 ASD 基质的可行性，以提高包括索拉非尼（SF）在内的水溶性差的药物的口服生物利用度。我们通过在酸性条件下利用阳离子 SF 与带负电荷的 BT 之间的离子相互作用，将 SF 吸附到 BT 上，制备了一种新型的 SF-BT 复合 BT 基 ASD（SFBTC）。扫描电子显微镜（SEM）、粉末 X 射线衍射（pXRD）和差示扫描量热法（DSC）分析表明，SF 以无定形状态吸附到 BT 上，SF:BT 比为 1:3 至 1:10。在大鼠的药代动力学研究中，SFBTC（1:3）显著提高了 SF 的口服生物利用度，SFBTC（1:3）的 AUC 是 NEXAVAR®（SF 的商业产品）的 3.3 倍。在溶出条件下的体外释放研究表明，SFBTC（1:3）以 pH 依赖性方式完全释放 SF，而非溶出条件研究表明在肠道 pH 条件下产生过饱和。动力学溶解度研究表明，SFBTC（1:3）的释放遵循扩散控制机制，这是水不溶性基质基 ASD 的典型特征。属于 BCS 类 II 的各种药物的药物-BT 复合材料的药代动力学研究表明，吸附药物的 pKa 值是决定其溶解和口服生物利用度的最重要因素之一。这些结果表明，BT 可能是一种有前途的水不溶性 ASD 基质，可提高包括 SF 在内的水溶性差的药物的口服生物利用度。
