title: Preparation and evaluation of a self-nanoemulsifying drug delivery system loaded with Akebia saponin D-phospholipid complex.
abstract: 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 inn-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 greaterCmax1 (733.4±203.8 ng/mL) than ASD (437.2±174.2 ng/mL), and a greaterCmax2 (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,Tmax1 andTmax2 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.
  
  
  CONCLUSIONS
  These results indicated that APC-SNEDDS was a promising drug delivery system to enhance the oral bioavailability of ASD.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing.
authors.forename: Jinyang
authors.initials: J
authors.lastname: Shen
authors.affiliation: Shandong Provincial Traditional Chinese Medical Hospital & Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan.
authors.forename: Jianping
authors.initials: J
authors.lastname: Bi
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing.
authors.forename: Hongli
authors.initials: H
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing.
authors.forename: Ye
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Traditional Chinese Medical Hospital of Pukou District.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pharmaceutical and Biological Marine Resources Research and Development of Jiangsu Province, Nanjing University of Chinese Medicine.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Junping
authors.initials: J
authors.lastname: Kou
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions / Q000737:chemistry*; D005026:Ethylene Glycols / Q000737:chemistry; D005260:Female; D005989:Glycerides / Q000737:chemistry; D008297:Male; D010316:Particle Size; D010743:Phospholipids / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D004655:Emulsions; D005026:Ethylene Glycols; D005989:Glycerides; D010743:Phospholipids; D012503:Saponins; D013501:Surface-Active Agents; C534004:akebia saponin D; C022131:cremophor; D011092:Polyethylene Glycols; C010111:carbitol; C005953:monoolein
keywords: Akebia saponin D; oral bioavailability; phospholipid complex; self-nanoemulsifying drug delivery systems