School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, Jiangsu, People's Republic of China.
Jiangxi QingFeng Pharmaceutical Co., Ltd, Ganzhou, 341000, Jiangxi, People's Republic of China.
Drug Des Devel Ther. 2021 Feb 12;15:557-576. doi: 10.2147/DDDT.S292417. eCollection 2021.
The aim of the present study was to develop an optimized Genkwanin (GKA)-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation to enhance the solubility, intestinal permeability, oral bioavailability and anti-colitis-associated colorectal cancer (CAC) activity of GKA.
We designed a SNEDDS comprised oil phase, surfactants and co-surfactants for oral administration of GKA, the best of which were selected by investigating the saturation solubility, constructing pseudo-ternary phase diagrams, followed by optimizing thermodynamic stability, emulsification efficacy, self-nanoemulsification time, droplet size, transmission electron microscopy (TEM), drug release and intestinal permeability. In addition, the physicochemical properties and pharmacokinetics of GKA-SNEDDS were characterized, and its anti-colitis-associated colorectal cancer (CAC) activity and potential mechanisms were evaluated in AOM/DSS-induced C57BL/6J mice model.
The optimized nanoemulsion formula (OF) consists of Maisine CC, Labrasol ALF and Transcutol HP in a weight ratio of 20:60:20 (w/w/w), in which ratio the OF shows multiple improvements, specifically small mean droplet size, excellent stability, fast release properties as well as enhanced solubility and permeability. Pharmacokinetic studies demonstrated that compared with GKA suspension, the relative bioavailability of GKA-SNEDDS was increased by 353.28%. Moreover, GKA-SNEDDS not only significantly prevents weight loss and improves disease activity index (DAI) but also reduces the histological scores of inflammatory cytokine levels as well as inhibiting the formation of colon tumors via inducing tumor cell apoptosis in the AOM/DSS-induced CAC mice model.
Our results show that the developed GKA-SNEDDS exhibited enhanced oral bioavailability and excellent anti-CAC efficacy. In summary, GKA-SNEDDS, using lipid nanoparticles as the drug delivery carrier, can be applied as a potential drug delivery system for improving the clinical application of GKA.
本研究旨在开发一种优化的京尼平（GKA）载药自微乳给药系统（SNEDDS），以提高 GKA 的溶解度、肠道通透性、口服生物利用度和抗结肠炎相关结直肠癌（CAC）活性。
我们设计了一种 SNEDDS，包含油相、表面活性剂和助表面活性剂，用于 GKA 的口服给药，通过考察饱和溶解度、构建伪三元相图，然后优化热力学稳定性、乳化效果、自微乳形成时间、粒径、透射电子显微镜（TEM）、药物释放和肠道通透性，选择最佳配方。此外，对 GKA-SNEDDS 的理化性质和药代动力学进行了表征，并在 AOM/DSS 诱导的 C57BL/6J 小鼠模型中评价了其抗结肠炎相关结直肠癌（CAC）活性及其潜在机制。
优化的纳米乳液配方（OF）由 Maisine CC、Labrasol ALF 和 Transcutol HP 以 20:60:20（重量比）组成，OF 具有多项改进，具体表现为粒径小、稳定性好、释放快、溶解度和渗透性增强。药代动力学研究表明，与 GKA 混悬液相比，GKA-SNEDDS 的相对生物利用度提高了 353.28%。此外，GKA-SNEDDS 不仅显著防止体重减轻和改善疾病活动指数（DAI），而且通过诱导肿瘤细胞凋亡，降低炎症细胞因子水平的组织学评分，抑制 AOM/DSS 诱导的 CAC 小鼠模型中结肠肿瘤的形成。
我们的结果表明，所开发的 GKA-SNEDDS 具有增强的口服生物利用度和优异的抗 CAC 疗效。总之，使用脂质纳米粒作为药物载体的 GKA-SNEDDS 可作为改善 GKA 临床应用的潜在药物传递系统。
