State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing.
Shandong Provincial Traditional Chinese Medical Hospital & Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan.
Int J Nanomedicine. 2016 Sep 26;11:4919-4929. doi: 10.2147/IJN.S108765. eCollection 2016.
Akebia saponin D (ASD) exerts various pharmacological activities but with poor oral bioavailability. In this study, a self-nanoemulsifying drug delivery system (SNEDDS) based on the drug-phospholipid complex technique was developed to improve the oral absorption of ASD.
ASD-phospholipid complex (APC) was prepared using a solvent-evaporation method and characterized by infrared spectroscopy, differential scanning calorimetry, morphology observation, and solubility test. Oil and cosurfactant were selected according to their ability to dissolve APC, while surfactant was chosen based on its emulsification efficiency in SNEDDS. Pseudoternary phase diagrams were constructed to determine the optimized APC-SNEDDS formulation, which was characterized by droplet size determination, zeta potential determination, and morphology observation. Robustness to dilution and thermodynamic stability of optimized formulation were also evaluated. Subsequently, pharmacokinetic parameters and oral bioavailability of ASD, APC, and APC-SNEDDS were investigated in rats.
The liposolubility significantly increased 11.4-fold after formation of APC, which was verified by the solubility test in -octanol. Peceol (Glyceryl monooleate [type 40]), Cremophor EL (Polyoxyl 35 castor oil), and Transcutol HP (Diethylene glycol monoethyl ether) were selected as oil, surfactant, and cosurfactant, respectively. The optimal formulation was composed of Glyceryl monooleate (type 40), Polyoxyl 35 castor oil, Diethylene glycol monoethyl ether, and APC (1:4.5:4.5:1.74, w/w/w/w), which showed a particle size of 148.0±2.7 nm and a zeta potential of -13.7±0.92 mV after dilution with distilled water at a ratio of 1:100 (w/w) and good colloidal stability. Pharmacokinetic studies showed that APC-SNEDDS exhibited a significantly greater 1 (733.4±203.8 ng/mL) than ASD (437.2±174.2 ng/mL), and a greater 2 (985.8±366.6 ng/mL) than ASD (180.5±75.1 ng/mL) and APC (549.7±113.5 ng/mL). Compared with ASD, 1 and 2 were both remarkably shortened by APC-SNEDDS. The oral bioavailability in rats was enhanced significantly to 183.8% and 431.8% by APC and APC-SNEDDS, respectively.
These results indicated that APC-SNEDDS was a promising drug delivery system to enhance the oral bioavailability of ASD.
三叶木通皂苷 D（ASD）具有多种药理活性，但口服生物利用度较差。本研究采用药物-磷脂复合物技术，制备自微乳给药系统（SNEDDS）以提高 ASD 的口服吸收。
采用溶剂挥发法制备 ASD-磷脂复合物（APC），并通过红外光谱、差示扫描量热法、形态观察和溶解度试验对其进行表征。根据溶解 APC 的能力选择油相和助表面活性剂，根据在 SNEDDS 中的乳化效率选择表面活性剂。构建伪三元相图以确定 APC-SNEDDS 的最佳配方，通过测定粒径、测定 Zeta 电位和形态观察对其进行表征。还评价了优化配方的耐稀释性和热力学稳定性。随后，在大鼠体内研究了 ASD、APC 和 APC-SNEDDS 的药代动力学参数和口服生物利用度。
形成 APC 后，其脂溶性显著提高了 11.4 倍，这通过在正辛醇中的溶解度试验得到了验证。选择 Peceol（Glyceryl monooleate [type 40]）、Cremophor EL（聚氧乙烯 35 蓖麻油）和 Transcutol HP（二乙二醇单乙基醚）分别作为油相、表面活性剂和助表面活性剂。最佳配方由 Glyceryl monooleate（type 40）、聚氧乙烯 35 蓖麻油、二乙二醇单乙基醚和 APC（1:4.5:4.5:1.74，w/w/w/w）组成，稀释 1:100（w/w）的蒸馏水后粒径为 148.0±2.7nm，Zeta 电位为-13.7±0.92mV，胶体稳定性良好。药代动力学研究表明，与 ASD（437.2±174.2ng/mL）相比，APC-SNEDDS 显著增加了 1（733.4±203.8ng/mL）和 2（985.8±366.6ng/mL），与 ASD（549.7±113.5ng/mL）和 APC（549.7±113.5ng/mL）相比，2 也显著增加。与 ASD 相比，APC-SNEDDS 显著缩短了 1 和 2 的半衰期。与 ASD 相比，APC 和 APC-SNEDDS 分别使 ASD 的口服生物利用度显著提高到 183.8%和 431.8%。
这些结果表明，APC-SNEDDS 是一种有前途的药物传递系统，可提高 ASD 的口服生物利用度。
