Preparation and evaluation of a self-nanoemulsifying drug delivery system loaded with Akebia saponin D–phospholipid complex

摘要

Background: 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. Methods: 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. Results: The liposolubility significantly increased 11.4-fold after formation of APC, which was?verified by the solubility test in n-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 C_max1 (733.4±203.8?ng/mL) than ASD (437.2±174.2?ng/mL), and a greater C _max2 (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, T _max1 and T _max2 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. Conclusion: These results indicated that APC-SNEDDS was a promising drug delivery system to enhance the oral bioavailability of ASD.