Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Eur J Pharm Sci. 2021 Nov 1;166:105931. doi: 10.1016/j.ejps.2021.105931. Epub 2021 Jul 10.
At present, oral chemotherapy showing the advantages of non-invasiveness, convenience, and high patient compliance, is gradually replacing traditional intravenous chemotherapy to treat patients with cancer. RA-XII, a unique natural cyclopeptide, exhibits various biological activities, such as anti-tumor, anti-angiogenic, and anti-metastatic activities. Designing an orally available formulation of RA-XII is of great importance in the development of clinically useful anticancer agents. However, RA-XII shows low oral bioavailability in rats due to its poor solubility and low permeability. To overcome these limitations, in this work, a natural deep eutectic solvent (NADES) was designed to efficiently deliver RA-XII by oral administration. A novel NADES composed of betaine and mandelic acid in the molar ratio of 1:1 (Bet-Man NADES) was successfully prepared based on a binary phase diagram of Bet and Man. Acute toxicity studies indicated that Bet-Man NADES was well tolerated with acceptable toxicity. In Bet-Man NADES solutions, the solubility of RA-XII was increased by up to 17.54-fold, and the diffusion and permeability of RA-XII carried out in a Franz cell was also significantly improved 10.35 times. In terms of biopharmaceutical classification this is translated into a change for RA-XII from class IV to class II systems. More importantly, Bet-Man NADES was transferred into the solid formulation by the inclusion of a polymer, and amorphous solid dispersions based on Bet-Man NADES (PVP K30/NADES/RA-XII, ASDs) were successfully prepared to improve uniformity, apparent solubility, dissolution, and cytotoxicity in vitro. Consequently, the oral bioavailability of RA-XII in NADES solutions and ASDs was enhanced by approximately 11.58 and 7.56 times compared with that of pure RA-XII in 0.5% CMCNa. Thus, it can be seen that a natural deep eutectic solvent and its modified amorphous solid dispersions are appropriate novel strategies for improving dissolution rate and bioavailability of poor soluble natural products such as RA-XII.
目前，口服化疗以其非侵入性、方便和高患者依从性的优势，逐渐取代传统的静脉化疗，用于治疗癌症患者。RA-XII 是一种独特的天然环肽，具有多种生物活性，如抗肿瘤、抗血管生成和抗转移活性。设计一种可口服的 RA-XII 制剂对于开发临床有用的抗癌药物非常重要。然而，由于 RA-XII 的溶解度和渗透性低，其在大鼠体内的口服生物利用度较低。为了克服这些限制，在这项工作中，设计了一种天然深共晶溶剂 (NADES) 通过口服给药来有效地输送 RA-XII。根据甜菜碱和扁桃酸的二元相图，成功制备了一种新型摩尔比为 1:1 的甜菜碱和扁桃酸组成的 NADES（Bet-Man NADES）。急性毒性研究表明，Bet-Man NADES 具有良好的耐受性和可接受的毒性。在 Bet-Man NADES 溶液中，RA-XII 的溶解度提高了 17.54 倍，在 Franz 细胞中进行的扩散和渗透性也显著提高了 10.35 倍。就生物药剂学分类而言，这使得 RA-XII 从 IV 类系统变为 II 类系统。更重要的是，通过包含聚合物，将 Bet-Man NADES 转化为固体制剂，并成功制备了基于 Bet-Man NADES 的无定形固体分散体（PVP K30/NADES/RA-XII，ASDs），以提高均匀性、表观溶解度、体外溶解和细胞毒性。因此，与纯 RA-XII 在 0.5%CMCNa 中的口服生物利用度相比，RA-XII 在 NADES 溶液和 ASDs 中的口服生物利用度分别提高了约 11.58 倍和 7.56 倍。因此，可以看出，天然深共晶溶剂及其改性的无定形固体分散体是提高 RA-XII 等难溶性天然产物溶解速率和生物利用度的合适的新型策略。
