mPEG-PLA/TPGS mixed micelles via intranasal administration improved the bioavailability of lamotrigine in the hippocampus

作者：Yu, Anan; Lv, Jieqiong; Yuan, Fang; Xia, Zihua; Fan, Kaiyan; Chen, Gang; Ren, Jialin; Lin, Cuicui; Wei, Shijie^*; Yang, Fan^*

来源：International Journal of Nanomedicine, 2017, 12: 8353-8362.

DOI：10.2147/IJN.S145488

• epilepsy
• intranasal administration
• lamotrigine
• P-glycoprotein
• blood brain barrier
• TPGS

Purpose: This study aimed to develop a novel methoxy polyethylene glycol)-poly(lactide) (mPEG-PLA)/D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) mixed micelle drug delivery system to improve lamotrigine (LTG) distribution in the hippocampus. @@@ Methods: LTG-loadcd mPEG-PLA/TPGS mixed micelles and LTG-loadcd mPKG-PLA micelles were formulated, and their characteristics, particle size, surface morphology, and release behavior in vitro were researched. Then, a microdialysis sampling technique coupled with two validated chromatographic systems was developed for the continuous measurement of the protein-unbound form of LTG in the rat plasma and hippocampus after administering two kinds of micelles and LTG solution intranasally. @@@ Results: The drug loading and mean size of LTG-loaded micelles and LTG-loaded mixed micelles prepared with optimal formulation were 36.44%+/- 0.14%, 39.28%+/- 0.26%, 122.9, and 183.5 nm, respectively, with a. core-shell structure. The cumulative release rate in vivo of LTG-loaded mixed micelles was 84.21 % at 24 hours and showed more sustained release while that of LTG-loadcd micelles was 80.61 % at 6 hours. The T-max and area under concentration-time curve from zero to time of last quantifiable concentration of LTG solution, LTG-loaded micelles, and LTG-loaded mixed micelles were 55,35, and 15 minutes and about 5,384, 16,500, and 25,245 (min.mu g)/L in the hippocampus, respectively. @@@ Conclusion: The results revealed that LTG-loaded m PKG-PLA/TPGS mixed micelles enhanced the absorption of LTG at the nasal cavity and reduced the efflux of LTG in the brain, suggesting that the function of TPGS inhibited P-glycoprotein and LTG-loaded mPEG-PLA/TPGS mixed micelles had the potential to overcome refractory epilepsy.

• 出版日期2017
• 单位广东药科大学