College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Pkwy, Queens, New York 11439.
College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Pkwy, Queens, New York 11439.
J Pharm Sci. 2020 May;109(5):1752-1764. doi: 10.1016/j.xphs.2020.01.031. Epub 2020 Feb 7.
Medium-chain (MC) and long-chain (LC) lipids are used for development of self-emulsifying drug delivery systems (SEDDS). MC lipids are often preferred because of their ability to form stable microemulsions with relatively high drug solubilization capacity. On the other hand, LC lipids could be more biocompatible as most endogenous and dietary lipids are LC glycerides. They also maintain high drug solubilization capacity after digestion. The present study was undertaken to determine the cytotoxicity of LC lipids and their formulations on Caco-2 cells of 1-day, 5-day, and 21-day maturity. The results were compared with the cytotoxicity profiles of MC lipids reported previously from our laboratory. The cell viability and cell membrane integrity were, respectively, determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the lactate dehydrogenase assay. The cytotoxicity was partially due to lipid surfactant-induced membrane rupture, and it was influenced by cell maturity and formulation composition. The lipid-surfactant combinations showed greater tolerance than surfactants alone, and LC-SEDDS were well-tolerated at almost 10-fold higher concentration than corresponding MC-SEDDS. Furthermore, the cytotoxicity of digestion end products of both LC and MC triglycerides in the presence of 3 mM sodium taurocholate was compared on 21-day Caco-2 cultures by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The LC lipid formulations showed better tolerance than MC lipid formulations after digestion. Thus, although MC and LC lipids are well-tolerated at doses normally administered to humans, LC lipids show much better safety than MC lipids in a cell-culture model.
中链（MC）和长链（LC）脂质用于开发自乳化药物传递系统（SEDDS）。由于 MC 脂质能够与相对较高的药物溶解度形成稳定的微乳液，因此常被优先选用。另一方面，LC 脂质可能更具生物相容性，因为大多数内源性和膳食脂质都是 LC 甘油酯。它们在消化后也能保持较高的药物溶解度。本研究旨在确定 LC 脂质及其制剂对 1 天、5 天和 21 天成熟的 Caco-2 细胞的细胞毒性。将结果与我们实验室先前报道的 MC 脂质的细胞毒性谱进行比较。使用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐测定法和乳酸脱氢酶测定法分别测定细胞活力和细胞膜完整性。细胞毒性部分归因于脂质表面活性剂诱导的膜破裂，并且受细胞成熟度和制剂组成的影响。脂质-表面活性剂组合的耐受性大于单独的表面活性剂，LC-SEDDS 的耐受性比相应的 MC-SEDDS 高近 10 倍。此外，通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐测定法比较了在存在 3mM 牛磺胆酸钠的情况下，LC 和 MC 甘油三酯的消化终产物在 21 天 Caco-2 培养物中的细胞毒性。LC 脂质制剂在消化后显示出比 MC 脂质制剂更好的耐受性。因此，尽管 MC 和 LC 脂质在通常给予人类的剂量下具有良好的耐受性，但在细胞培养模型中，LC 脂质比 MC 脂质具有更好的安全性。
