National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, People's Republic of China.
School of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, People's Republic of China.
AAPS PharmSciTech. 2020 Feb 13;21(3):90. doi: 10.1208/s12249-019-1616-4.
Puerarin is widely used as a therapeutic agent to cardiovascular diseases in clinics in China through intravenous administration, which could elicit adverse drug reactions caused by cosolvents, hindering its application in clinics. Therefore, the development of oral dosage is urgently needed. In our previous studies, we proved that the bioavailability of puerarin increased as particle sizes of nanocrystals decreased; however, we have not optimized the best process parameters for nanocrystals. In this study, we aim to fabricate fine nanocrystals (with smallest particle size) by Box-Behnken design and study the intestinal permeability of puerarin and its nanocrystals via employing everted gut sac model and in situ perfusion model. The results showed that the Box-Behnken design could be used to optimize the producing parameters of puerarin nanocrystals, and the particle sizes of fine nanocrystals were about 20 nm. Results of everted gut sacs showed that the polyvinylpyrrolidone (PVP) and verapamil had no influence on the absorption of puerarin and nanocrystals, and the nanocrystals could increase the P of puerarin for 2.2-, 2.9-, and 2.9-folds, respectively, in duodenum, jejunum, and ileum. Enhanced Ka and Peff were observed on the nanocrystal group, compared with puerarin, and PVP and verapamil had no influence on the absorption of nanocrystals, while the absorption of puerarin was influenced by P-gp efflux. Combining the results mentioned above, we can conclude that the Box-Behnken design benefits the optimization for preparation of nanocrystals, and the nanocrystals could enhance the intestinal absorption of puerarin by enhanced permeability and inhibited P-gp efflux.
葛根素在中国临床上广泛用作治疗心血管疾病的药物，通过静脉注射给药，这可能会引起溶剂的不良反应，从而阻碍其在临床上的应用。因此，急需开发口服制剂。在我们之前的研究中，我们证明了葛根素的生物利用度随着纳米晶体粒径的减小而增加；然而，我们尚未优化纳米晶体的最佳工艺参数。在这项研究中，我们旨在通过 Box-Behnken 设计制备细纳米晶体（最小粒径），并通过外翻肠囊模型和原位灌流模型研究葛根素及其纳米晶体的肠道通透性。结果表明，Box-Behnken 设计可用于优化葛根素纳米晶体的生产参数，细纳米晶体的粒径约为 20nm。外翻肠囊的结果表明，聚乙烯吡咯烷酮（PVP）和维拉帕米对葛根素和纳米晶体的吸收没有影响，纳米晶体可分别将葛根素的 P 增加 2.2、2.9 和 2.9 倍，在十二指肠、空肠和回肠中。与葛根素相比，纳米晶体组观察到 Ka 和 Peff 增加，PVP 和维拉帕米对纳米晶体的吸收没有影响，而 P-gp 外排影响葛根素的吸收。结合上述结果，我们可以得出结论，Box-Behnken 设计有利于纳米晶体的制备优化，纳米晶体可以通过增强通透性和抑制 P-gp 外排来增强葛根素的肠道吸收。
