Maliba Pharmacy College, Uka Tarsadia University, Gopal Vidyanagar, Bardoli Mahuva Road, Dist. Surat, Tarsadi, Gujarat, 394350, India.
Drug Deliv Transl Res. 2021 Jun;11(3):1166-1185. doi: 10.1007/s13346-020-00839-9.
Linagliptin (LGP), a novel anti-diabetic drug, is a DPP-4 inhibitor used in the treatment of type II diabetes. One of the major disadvantages of LGP is its low oral bioavailability (29.5%) due to first-pass metabolism and P-gp efflux. In an attempt to increase the oral bioavailability, LGP solid lipid nanoparticles (LGP-SLNs) were developed with poloxamer 188 and Tween 80 as P-gp inhibitors. LGP-SLNs were formulated using palmitic acid, poloxamer 188 and Tween 80 as lipid, surfactant and co-surfactant, respectively, by hot homogenization ultrasonication method and optimized using 3 full factorial designs. Particle size, entrapment efficiency (%EE) and drug release at 24 h were evaluated as responses. An optimized batch of LGP-SLNs (L12) was evaluated for intestinal transport of LGP by conducting in situ single-pass intestinal perfusion (SPIP), everted gut sac and Caco-2 permeability study. The pharmacokinetic and pharmacodynamic evaluation of L12 was carried out in albino Wistar rats. The mean particle size, polydispersity index, zeta potential and %EE of L12 were found to be 225.96 ± 2.8 nm, 0.180 ± 0.034, - 5.4 ± 1.07 mV and 73.8 ± 1.73%, respectively. %CDR of 80.96 ± 3.13% was observed in 24 h. The permeability values of LGP-SLNs in the absorptive direction were 1.82-, 1.76- and 1.74-folds higher than LGP-solution (LGP-SOL) in SPIP, everted gut sac and Caco-2 permeability studies, respectively. LGP-SLNs exhibited relative bioavailability of 300% and better reduction in glucose levels in comparison with LGP-SOL in rats. The enhanced oral bioavailability exhibited by LGP-SLNs bioavailability may be due to P-gp efflux inhibition and lymphatic targeting. Improved bioabsorption can cause reduction in dose, dose-related side effects and frequency of administration. Thus, LGP-SLNs can be considered promising carriers for oral delivery but clinical studies are required to confirm the proof of concept.Graphical abstract.
利格列汀（LGP）是一种新型抗糖尿病药物，属于二肽基肽酶-4（DPP-4）抑制剂，用于治疗 2 型糖尿病。LGP 的主要缺点之一是由于首过代谢和 P-糖蛋白外排，其口服生物利用度（29.5%）较低。为了提高口服生物利用度，用泊洛沙姆 188 和吐温 80 作为 P-糖蛋白抑制剂开发了 LGP 固体脂质纳米粒（LGP-SLNs）。LGP-SLNs 采用棕榈酸、泊洛沙姆 188 和吐温 80 分别作为脂质、表面活性剂和助表面活性剂，通过热匀化超声法制备，并采用 3 全因子设计进行优化。以粒径、包封效率（%EE）和 24 小时药物释放率作为响应。对优化后的 LGP-SLNs（L12）进行了体内单肠灌流（SPIP）、外翻肠囊和 Caco-2 通透性研究，以评估 LGP 的肠道转运。在白化 Wistar 大鼠中进行了 L12 的药代动力学和药效学评价。L12 的平均粒径、多分散指数、Zeta 电位和%EE 分别为 225.96±2.8nm、0.180±0.034、-5.4±1.07mV 和 73.8±1.73%。在 24 小时时观察到 80.96±3.13%的 CDR。在 SPIP、外翻肠囊和 Caco-2 通透性研究中，LGP-SLNs 在吸收方向的渗透值分别比 LGP 溶液（LGP-SOL）高 1.82、1.76 和 1.74 倍。与 LGP-SOL 相比，LGP-SLNs 在大鼠体内的相对生物利用度为 300%，且能更好地降低血糖水平。LGP-SLNs 表现出的口服生物利用度提高可能是由于 P-糖蛋白外排抑制和淋巴靶向。改善生物吸收可减少剂量、剂量相关的副作用和给药频率。因此，LGP-SLNs 可被视为口服给药的有前途的载体，但需要进行临床研究以证实这一概念。
