BIAL - Portela & Cª, S.A., Avenida da Siderugia Nacional, 4745-457 Trofa, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
BIAL - Portela & Cª, S.A., Avenida da Siderugia Nacional, 4745-457 Trofa, Portugal.
Eur J Pharm Sci. 2019 Sep 1;137:105011. doi: 10.1016/j.ejps.2019.105011. Epub 2019 Jul 19.
Resveratrol is a drug with high potential for clinical application based on experimental models. Though, resveratrol translation to clinical use has not been successful yet due to its poor pharmacokinetics, related to poor solubility and fast metabolism. The use of drug delivery systems, namely self-emulsifying drug delivery systems (SEDDS), may be a viable strategy to overcome the poor in vivo performance of resveratrol. In this work, a rational development of two different ternary SEDDS was conducted. Experimental data showed that quantitative variations on SEDDS composition impacted dispersion and robustness to dilution of SEDDS, as well as loading capacity and droplet size. Formulations composed of Lauroglycol® 90/Labrasol®/Capryol® PGMC (12.5/75.0/12.5) (Lau/Lab/Cap) and Tween® 80/Transcutol®/Imwitor® 742 (33.3/33.3/33.3) (T80/Trans/Imw) featured improved performance and were selected for further studies. T80/Trans/Imw formulation yield faster emulsification and originated smaller droplet size, with lower cumulative percentile of 90% of particles (D) (below 200 nm), as compared to the than Lau/Lab/Cap formulation. Higher resveratrol permeation rate was observed in Caco-2 cell monolayer permeability studies for both formulations as compared to the free drug. Reduction of the metabolization and/or efflux of resveratrol was also noticed in the case of SEDDs, as suggested by the increased recovery of total drug. Plasmatic drug concentrations in rats observed after oral gavage indicate that both formulations provided faster resveratrol absorption than free drug, resulting in shorter T values (30 min vs. 2 h). No statistically significant differences were observed for AUC values of both formulations and the free drug. Still, C for the Lau/Lab/Cap SEDDs formulation was 2-fold higher than for the free drug. These findings suggest that SEDDS can increase resveratrol solubility and reduce its metabolization, resulting in an overall improvement of its oral pharmacokinetics profile.
白藜芦醇是一种基于实验模型具有高临床应用潜力的药物。然而，由于其较差的药代动力学特性，包括较差的溶解度和快速的代谢，白藜芦醇的临床应用尚未成功。使用药物传递系统，即自乳化药物传递系统（SEDDS），可能是克服白藜芦醇体内性能不佳的可行策略。在这项工作中，我们合理地开发了两种不同的三元 SEDDS。实验数据表明，SEDDS 组成的定量变化会影响 SEDDS 的分散性和对稀释的稳定性，以及载药量和液滴大小。由 Lauroglycol®90/Labrasol®/Capryol®PGMC（12.5/75.0/12.5）（Lau/Lab/Cap）和 Tween®80/Transcutol®/Imwitor®742（33.3/33.3/33.3）（T80/Trans/Imw）组成的配方具有更好的性能，因此被选用于进一步的研究。T80/Trans/Imw 配方具有更快的乳化速度，并产生更小的液滴尺寸，其累积 90%的颗粒（D）（小于 200nm）的百分位数更低，而 Lau/Lab/Cap 配方则更低。与游离药物相比，在 Caco-2 细胞单层渗透性研究中，两种配方均观察到白藜芦醇的渗透性更高。SEDDS 还减少了白藜芦醇的代谢和/或外排，这从总药物的回收率增加可以看出。口服灌胃后大鼠的血浆药物浓度表明，与游离药物相比，两种配方均能更快地吸收白藜芦醇，使 T 值（30 分钟 vs. 2 小时）更短。两种配方和游离药物的 AUC 值均无统计学差异。然而，Lau/Lab/Cap SEDDS 配方的 C 值仍比游离药物高 2 倍。这些发现表明，SEDDS 可以提高白藜芦醇的溶解度并减少其代谢，从而整体改善其口服药代动力学特征。
