Jo Kanghee, Kim Hyeongmin, Khadka Prakash, Jang Taejun, Kim Soo Jin, Hwang Seong-Ha, Lee Jaehwi
College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.
Asian J Pharm Sci. 2020 May;15(3):336-346. doi: 10.1016/j.ajps.2018.11.009. Epub 2019 Feb 14.
The therapeutic potential of saquinavir, a specific inhibitor of human immunodeficiency virus (HIV)-1 and HIV-2 protease enzymes, has been largely limited because of a low solubility and consequnt low bioavailability. Thus, we aimed to design a supersaturated self-microemulsifying drug delivery system (S-SMEDDS) that can maintain a high concentration of saquinavir in gastro-intestinal fluid thorugh inhibiting the drug precipitation to enhance the lymphatic transport of saquinavir and to increase the bioavailability of saquinavir considerably. Solubilizing capacity of different oils, surfactants, and cosurfactants for saquinavir was evaluated to select optimal ingredients for preparation of SMEDDS. Through the construction of pseudo-ternary phase diagram, SMEDDS formulations were established. A polymer as a precipitation inhibitor was selected based on its viscosity and drug precipitation inhibiting capacity. The S-SMEDDS and SMEDDS designed were administered at an equal dose to rats. At predetermined time points, levels of saquinavir in lymph collected from the rats were assessed. SMEDDS prepared presented a proper self-microemulsification efficiency and dispersion stability. The S-SMEDDS fabricated using the SMEDDS and hydroxypropyl methyl cellulose 2910 as a precipitation inhibitor exhibited a signficantly enhanced solubilizing capacity for saquinavir. The drug concentration in a simulated intestinal fluid evaluated with the S-SMEDDS was also maintained at higher levels for prolonged time than that examined with the SMEDDS. The S-SMEDDS showed a considerably enhanced lymphatic absoprtion of saquinavir in rats compared to the SMEDDS. Therefore, the S-SMEDDS would be usefully exploited to enhance the lymphatic absorption of hydrophobic drugs that need to be targeted to the lymphatic system.
沙奎那韦是一种人类免疫缺陷病毒（HIV）-1和HIV-2蛋白酶的特异性抑制剂，其治疗潜力因溶解度低及随之而来的生物利用度低而受到很大限制。因此，我们旨在设计一种过饱和自微乳化药物递送系统（S-SMEDDS），通过抑制药物沉淀来维持胃肠道液中高浓度的沙奎那韦，从而增强沙奎那韦的淋巴转运并显著提高其生物利用度。评估了不同油、表面活性剂和助表面活性剂对沙奎那韦的增溶能力，以选择制备SMEDDS的最佳成分。通过构建伪三元相图，建立了SMEDDS制剂。根据聚合物的粘度和药物沉淀抑制能力选择一种聚合物作为沉淀抑制剂。将设计的S-SMEDDS和SMEDDS以相等剂量给予大鼠。在预定时间点，评估从大鼠收集的淋巴中沙奎那韦的水平。制备的SMEDDS呈现出适当的自微乳化效率和分散稳定性。使用SMEDDS和羟丙基甲基纤维素2910作为沉淀抑制剂制备的S-SMEDDS对沙奎那韦的增溶能力显著增强。用S-SMEDDS评估的模拟肠液中的药物浓度也比用SMEDDS检测的浓度在更长时间内维持在较高水平。与SMEDDS相比，S-SMEDDS在大鼠中显示出沙奎那韦的淋巴吸收显著增强。因此，S-SMEDDS可有效用于增强需要靶向淋巴系统的疏水性药物的淋巴吸收。
