Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Etiler 06330, Ankara, Turkey.
Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Etiler 06330, Ankara, Turkey; Department of Pharmaceutical Technology, Faculty of Pharmacy, Zonguldak Bulent Ecevit University, Esenkoy, 67600, Zonguldak, Turkey.
Eur J Pharm Sci. 2022 Jul 1;174:106159. doi: 10.1016/j.ejps.2022.106159. Epub 2022 Mar 6.
This study aimed to develop and optimize a self-nanoemulsifying drug delivery system (SNEDDS) of bosentan (BOS) to solve its poor oral bioavailability due to low water solubility. A pseudo-ternary phase diagram was created based on the solubility and emulsification studies. The major components of the formulation were selected as glyceryl monolinoleate (lipid), polyoxyl 40 hydrogenated castor oil (surfactant), and caprylocaproyl polyoxyl-8 glycerides (co-surfactant). The composition of BOS-SNEDDS was optimized using the Box-Behnken design (BBD) and then was characterized for various physicochemical properties. The in vitro dissolution, in vitro lipolysis, and ex-vivo permeability studies were performed and compared to SNEDDS and reference tablets. The fasted and fed state bioavailability of BOS-loaded SNEDDS was evaluated in Wistar rats (n = 6) compared to the reference. The prepared SNEDDS were thermodynamically stable with a droplet size of 17.11 nm, a polydispersity index of 0.180, and an emulsification time of <1 min. The BOS-loaded SNEDDS showed 3.0, 7.97, 4.23, and 4.94-fold increases in the percentages of cumulative dissolution compared to reference tablets in FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2, respectively. The permeation study showed that the SNEDDS increased the drug permeation by 3.36, 19.2, 16.4, and 16.6-fold in FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2, respectively. The enhancement of in vitro dissolution, in vitro lipolysis, and ex-vivo permeability was found significant (p < 0.05). SNEDDS was increased the C and AUC 1.67 and 2.12-fold and 5.15 and 1.84-fold in fasted and fed state compared to the reference, respectively. The in vitro-in vivo relationship has been successfully performed for SNEDDS. These results indicated that the SNEDDS formulation could be a promising delivery system that enhances the absorption and oral bioavailability of BOS.
本研究旨在开发和优化波生坦（BOS）的自微乳给药系统（SNEDDS），以解决其由于低水溶性导致的口服生物利用度差的问题。根据溶解度和乳化研究创建了伪三元相图。制剂的主要成分选择为甘油单亚油酸酯（脂质）、聚氧乙烯 40 氢化蓖麻油（表面活性剂）和辛酸/癸酸甘油酯聚氧乙烯-8（助表面活性剂）。使用 Box-Behnken 设计（BBD）优化 BOS-SNEDDS 的组成，然后对其进行各种物理化学性质的表征。进行了体外溶出度、体外脂肪酶解和离体渗透性研究，并与 SNEDDS 和参比片剂进行了比较。与参比相比，在 Wistar 大鼠（n=6）中评估了载 BOS 的 SNEDDS 的空腹和进食状态生物利用度。制备的 SNEDDS热力学稳定，粒径为 17.11nm，多分散指数为 0.180，乳化时间<1min。与参比片剂相比，载 BOS 的 SNEDDS 在 FaSSIF、FeSSIF、FaSSIF-V2 和 FeSSIF-V2 中的累积溶解百分比分别增加了 3.0、7.97、4.23 和 4.94 倍。渗透研究表明，SNEDDS 分别使 FaSSIF、FeSSIF、FaSSIF-V2 和 FeSSIF-V2 中的药物渗透增加了 3.36、19.2、16.4 和 16.6 倍。体外溶出度、体外脂肪酶解和离体渗透性的增强均具有显著意义（p<0.05）。与参比相比，SNEDDS 在空腹和进食状态下分别使 C 和 AUC 增加了 1.67 和 2.12 倍和 5.15 和 1.84 倍。成功地进行了 SNEDDS 的体外-体内相关性研究。这些结果表明，SNEDDS 制剂可能是一种有前途的给药系统，可增强 BOS 的吸收和口服生物利用度。
