目的 制备含功能性油的水飞蓟宾超饱和自纳米乳(SLB-S-SNEDDS),并对其进行表征及体外评价研究,以提高难溶性药物水飞蓟宾的生物利用度.方法 铁氢化钾还原力与1,1-二苯基-2-苦肼基(DPPH)自由基清除实验筛选功能性油脂;伪三元相图考察乳化剂乳化能力;测定粒径、多分散指数(PDI)、Zeta电位等考察混合油相比例与载药量;相容性与溶出度实验筛选促过饱和物质并考察其质量浓度;从外观、粒径分布、自乳化效率、形态学等方面表征SLB-S-SNEDDS,并进行溶出度、抗氧化能力、细胞毒性等体外评价.结果 所得SLB-S-SNEDDS处方为(1)小麦胚芽油/Capryol 90-Cremophor ELP-Transcutol HP与(2)沙棘籽油/Capryol 90-Cremophor ELP-Transcutol HP,1 g基质(包含0.043 g小麦胚芽油或沙棘籽油、0.387 g Capryol 90、0.380 g Cremophor ELP、0.190 g Transcutol HP),水飞蓟宾的添加量为各组分平衡溶解度之和的20％,Soluplus的添加量为上述总质量的0.1％.小麦胚芽油、沙棘籽油体系分别为淡黄色、亮黄色透明状均一液体,2种体系自乳化分散后均呈近球形白色扁平乳滴,粒径约为50nm,乳化时间均为65 s.与药物原料及SLB-SNEDDS相比,SLB-S-SNEDDS中水飞蓟宾的累积溶出率8h内均维持在85％～110％,表明该体系能够显著提高药物的溶出度.SLB-S-SNEDDS与铁氰化钾反应后的吸光度(A值0.452～0.782,0.488～0.765)以及DPPH自由基清除率(39.09％～96.02％,30.54％～89.20％)均高于相应质量浓度下水飞蓟宾原料的A值与清除率(0.411～0.760,22.89％～63.21％),表明2种处方体系均能提高水飞蓟宾的抗氧化能力.细胞毒性实验结果显示,在5、10 μmol/L药物浓度下,水飞蓟宾原料组、水飞蓟宾S-SNEDDS组及其相应的空白S-SNEDDS组细胞生存率均＞90％,说明SLB-S-SNEDDS及其所用辅料对人克隆结肠腺癌细胞(Caco-2)毒性较小、安全性较好.结论 制备的含功能性油SLB-S-SNEDDS在提高水飞蓟宾累积溶出率的同时,增强了其抗氧化能力,为将超饱和自纳米乳(S-SNEDDS)用于改善难溶性药物水溶性及其生物活性提供有益参考.

The purpose of this investigation was to improve the solubility and oral bioavailability of daidzein via preparing nanosuspensions (NS) with steric stabilizers, electrostatic stabilizers, or a combination of both. Based on particle size and zeta potential, daidzein NS stabilized by HP-beta-CD, soy lecithin, HP-beta-CD + soy lecithin, TPGS, TPGS + SBE-beta-CD, SDS, or HPMC E5 + SDS were generated and characterized by scanning electron microscopy, powder X-ray diffraction, and Fourier transform-infrared spectroscopy. In addition, the stability, cytotoxicity, solubility, dissolution, and pharmacokinetics of NS were evaluated. The resulting daidzein NS were physically stable and biocompatible and presented as regular shapes with homogenous particle sizes of 360-600 nm and decreased crystallinity. Due to the increased solubility and dissolution rate, the oral bioavailability of daidzein NS in rats was 1.63-2.19 times greater than that of crude daidzein. In particular, among the investigated seven daidzein NS formulations, daidzein NS prepared with the costabilizers HPMC E5 + SDS is an optimal formulation for increased daidzein bioavailability. The present study proposes that the combined usage of steric and electrostatic stabilizers is a promising strategy for improving the bioavailability of water-insoluble flavonoid compounds by an NS approach.

Pharmaceutical cocrystals are a promising technology that can be used to improve the solubility of poor aqueous compounds. The objective of this study was to systematically investigate the solubility of myricetin (MYR) cocrystals, including their kinetic solubility, thermodynamic solubility, and intrinsic dissolution rate (IDR). The effects of pH, surfactant, ion concentration, and coformers on the cocrystal solubility were evaluated. Furthermore, single crystal structures of MYR, myricetin–isonicotinamide (MYR–INM) and myricetin–caffeine (MYR–CAF) cocrystals were analyzed to discuss the possible reasons for the enhancement of cocrystal solubility from the perspective of the spatial structure. The results indicated that the kinetic solubility of MYR cocrystals was modulated by pH and cocrystal coformer (CCF) ionization in buffer solution, while it primarily depended on the CCF solubility in pure water. In addition, the solubility of MYR cocrystals was increased in a concentration dependent fashion by the surfactant or ion concentration. The thermodynamic solubility of MYR–INM (1:3) cocrystals decreased with the increases of the pH value of the dissolution media. The IDR of MYR cocrystals was faster than that of MYR in the same medium and extremely fast in pH 4.5 buffer. The improved solubility of MYR cocrystals was probably related to the alternate arrangements of MYR and INM/CAF molecules and increased intermolecular distance. The present study provides some references to investigate the solubility behavior of pharmaceutical cocrystals.