College of Chemistry and Chemical Engineering, Taishan University, Tai'an, People's Republic of China.
School of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.
Drug Des Devel Ther. 2022 May 23;16:1531-1546. doi: 10.2147/DDDT.S356967. eCollection 2022.
The purpose of this work was to develop an ivacaftor self-nanoemulsion drug delivery system (IVA-SNEDDS) using the newly developed double headed miscellaneous lipid (DHML) as oil phase to reduce the food effect and inter-individual absorption variability of IVA.
The lipids with the greatest solubility to IVA were selected as the oil phase of IVA-SNEDDS by saturation solubility method. Then, among different surfactants and co-surfactants, those with good emulsifying ability for the selected oil phase were selected, and the proportion of surfactant and co-surfactant was further selected by pseudo-ternary phase diagram. The prepared IVA-SNEDDS were screened and evaluated in vitro and in beagle dogs.
The optimized IVA-SNEDDS formulation consisting of DHML, Tween 80, and Transcutol HP with the weight ratio of 2:2:1 was physically stable and it was easy to disperse in water, pH 1.2 hydrochloric acid and pH 6.8 phosphate buffer solution, and generated a fine homogeneous nanoemulsion, with mean globule size less than 75 nm regardless of dilution ratio. In vitro drug release studies showed that the drug in IVA-SNEDDS could be completely released in a short time, while the drug release in IVA-suspension was less than 1% at 60 min. In vivo, using IVA-suspension (Fed) as a reference, the relative oral bioavailability of IVA-suspension (Fasted), IVA-SNEDDS (Fasted), and IVA-SNEDDS (Fed) were 23.35%, 153.63%, and 149.89%, respectively. This showed that IVA-SNEDDS could eliminate the positive food effect, improve the oral bioavailability, and reduce the IVA absorption difference between individuals.
As the oil phase of SNEDDS, DHML can significantly improve the drug solubility and drug loading of IVA-SNEDDS. Moreover, DHML was easily emulsified and can effectively form a nanoemulsion in vivo and in vitro. The prepared IVA-SNEDDS can reduce the inter-individual absorption variability of IVA, eliminate its food effect and improve its oral bioavailability.
本研究旨在开发一种以新型双头混合脂质（DHML）作为油相的伊伐卡托自微乳给药系统（IVA-SNEDDS），以降低 IVA 的食物效应和个体间吸收变异性。
采用饱和溶解度法选择对 IVA 溶解度最大的脂质作为 IVA-SNEDDS 的油相。然后，在不同的表面活性剂和助表面活性剂中，选择对所选油相具有良好乳化能力的物质，并通过伪三元相图进一步选择表面活性剂和助表面活性剂的比例。对制备的 IVA-SNEDDS 进行了体外和在比格犬体内的筛选和评价。
优化的 IVA-SNEDDS 配方由 DHML、Tween 80 和 Transcutol HP 组成，重量比为 2:2:1，物理性质稳定，易于分散在水中、pH1.2 盐酸和 pH6.8 磷酸盐缓冲液中，并生成均匀的纳米乳，平均粒径均小于 75nm，无论稀释倍数如何。体外药物释放研究表明，IVA-SNEDDS 中的药物能够在短时间内完全释放，而 IVA 混悬剂在 60min 时的药物释放量小于 1%。在体内，以 IVA 混悬剂（Fed）为参比制剂，IVASNEDDS（Fed）、IVA-SNEDDS（Fast）和 IVA-SNEDDS（Fed）的相对口服生物利用度分别为 23.35%、153.63%和 149.89%。这表明 IVA-SNEDDS 可以消除阳性食物效应，提高口服生物利用度，降低 IVA 个体间吸收差异。
作为 SNEDDS 的油相，DHML 能显著提高 IVA-SNEDDS 的药物溶解度和载药量。此外，DHML 易于乳化，能在体内外有效地形成纳米乳。所制备的 IVA-SNEDDS 可降低 IVA 的个体间吸收变异性，消除其食物效应，提高其口服生物利用度。
