BIAL-Portela & Cª, S.A., Avenida da Siderugia Nacional, 4745-457 Trofa, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, University of 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.
Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas de Araraquara, Drugs and Pharmaceuticals, Brazil.
Int J Pharm. 2021 Feb 15;595:120245. doi: 10.1016/j.ijpharm.2021.120245. Epub 2021 Jan 21.
Resveratrol is a very promising anti-oxidant drug candidate with low oral bioavailability due to its intrinsic poor water solubility, intestinal efflux and metabolization mechanisms. Resveratrol solubility high-throughput screening with different carriers was performed showing an enhancement above 2000-fold with Soluplus® and Tween® 80. The former was selected as a carrier at the ratio of resveratrol: Soluplus® (1:2). Then, third-generation solid dispersions were developed with Gelucire® and poloxamer 407 at 5 and 15% to resveratrol: Soluplus® (1:2). All formulations enhanced solubility around 2-fold when compared to resveratrol: Soluplus® (1:2) solid dispersion. Caco-2 cells permeability studies showed that both surfactants increased drug permeability and the fraction recovered (2-fold) suggesting that these could reduce efflux mechanism and metabolism. Formulation with 15% poloxamer 407 demonstrated most promising results and was selected for further studies. In in vivo studies, resveratrol:Soluplus®: poloxamer 407 (1:2-15%) third generation solid dispersion presented an AUCo-t of 279 ± 54 ng.h/mL and a Cmax of 134 ± 78 ng/mL, 2.5 fold higher than solid dispersion without poloxamer 407. This work reports the development of third-generation solid dispersion that significantly improved resveratrol bioavailability. This was accomplished by an increased solubility and most probably by reducing intestinal efflux and metabolism mechanisms.
白藜芦醇由于其内在的低水溶性、肠道外排和代谢机制，口服生物利用度很低，是一种很有前途的抗氧化药物候选物。用不同载体对白藜芦醇的高溶解性进行高通量筛选，结果表明 Soluplus®和 Tween® 80 的增溶效果超过 2000 倍。选择前者作为载体，其与白藜芦醇的比例为 1:2。然后，用 Gelucire®和聚氧乙烯 407 以 5%和 15%的比例开发第三代固体分散体，与白藜芦醇：Soluplus®（1:2）。与白藜芦醇：Soluplus®（1:2）固体分散体相比，所有配方的溶解度均提高了约 2 倍。Caco-2 细胞通透性研究表明，两种表面活性剂均能增加药物的通透性和回收率（增加 2 倍），提示这两种表面活性剂可能减少外排机制和代谢。含 15%聚氧乙烯 407 的配方表现出最有希望的结果，并被选为进一步研究。在体内研究中，白藜芦醇：Soluplus®：聚氧乙烯 407（1:2-15%）第三代固体分散体的 AUCo-t 为 279±54ng.h/mL，Cmax 为 134±78ng/mL，比不含聚氧乙烯 407 的固体分散体高 2.5 倍。本研究报告了第三代固体分散体的开发，显著提高了白藜芦醇的生物利用度。这是通过增加溶解度，并且很可能通过减少肠道外排和代谢机制来实现的。
