International Journal of Nanomedicine (Sep 2019)
Mechanistic studies on the absorption enhancement of a self-nanoemulsifying drug delivery system loaded with norisoboldine-phospholipid complex
Abstract
Jing Zhang,1,* Xiaoxia Wen,1,* Yue Dai,2 Yufeng Xia11Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China; 2Department of Traditional Chinese Medicine and Pharmacology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China *These authors contributed equally to this workCorrespondence: Yufeng XiaDepartment of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing 211198, ChinaTel +86 25 83271400Fax +86 25 85301528Email [email protected] DaiDepartment of Traditional Chinese Medicine and Pharmacology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, ChinaEmail [email protected]: Norisoboldine (NOR), the main isoquinoline alkaloid constituent in Radix Linderae, was demonstrated to have an outstanding anti-arthritis activity. However, a poor oral bioavailability of NOR creates a barrier for its development and application.Methods: A new self-nanoemulsifying drug delivery system (SNEDDS) loaded with the phospholipid complex (PC) was designed to improve the oral bioavailability of NOR. NOR-PC was prepared by solvent evaporation method with a mixture of phospholipid and NOR at a mass ratio of 3:1. The property of PC is to improve the liposolubility of NOR, and made PC embedded in the drug delivery system. The physicochemical property of NOR-PC was characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). According to the ability to dissolve NOR-PC, the oil and cosurfactant were chosen. The surfactant was selected based on its emulsification efficiency in SNEDDS. Pseudo-ternary phase diagram was created to select the best formulation of NOR-PC-SNEDDS, and the pharmacokinetic parameters were detected in rats. In addition, intestinal lymphatic transport and liver microsome experiment were studied to gain insight into the mechanism for NOR-PC-SNEDDS increasing the oral bioavailability of NOR.Results: Solubility detection showed that the PC significantly improved the liposolubility of NOR. NOR-PC-SNEDDS was prepared using NOR-PC, Ethyl oleate, Labrasol, Cremophor EL and transcutol HP at a weight ratio of 1:2:3.36:2.24:2.4 (w/w/w/w/w). The particle size and zeta potential of NOR-PC-SNEDDS were 36.72±1.47 nm and −4.91±0.49 mV after dilution with distilled water at a ratio of 1:50 (w/w). The absolute bioavailability of NOR in the NOR-PC-SNEDDS group significantly increased and the value was 372% in relative to NOR group. Further studies indicated that NOR-PC-SNEDDS promoted the oral bioavailability of NOR by enhancing intestinal lymphatic absorption and inhibiting Phase II metabolism of NOR.Conclusion: These findings suggested that NOR-PC-SNEDDS was able to promote the oral bioavailability of NOR, which provided a foundation for the further development and application of NOR.Keywords: norisoboldine, oral bioavailability, self-nanoemulsifying drug delivery system, lymphatic absorption, Phase II metabolism
