Enhanced brain delivery of lamotrigine with Pluronic® P123-based nanocarrier

Abstract

Jian-Sheng Liu,1,* Jian-Hong Wang,1,* Jie Zhou,2 Xing-Hua Tang,1 Lan Xu,1 Teng Shen,2 Xun-Yi Wu,1 Zhen Hong1 1Department of Neurology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: P-glycoprotein (P-gp) mediated drug efflux across the blood­–brain barrier (BBB) is an important mechanism underlying poor brain penetration of certain antiepileptic drugs (AEDs). Nanomaterials, as drug carriers, can overcome P-gp activity and improve the targeted delivery of AEDs. However, their applications in the delivery of AEDs have not been adequately investigated. The objective of this study was to develop a nano-scale delivery system to improve the solubility and brain penetration of the antiepileptic drug lamotrigine (LTG).Methods: LTG-loaded Pluronic® P123 (P123) polymeric micelles (P123/LTG) were prepared by thin-film hydration, and brain penetration capability of the nanocarrier was evaluated.Results: The mean encapsulating efficiency for the optimized formulation was 98.07%; drug-loading was 5.63%, and particle size was 18.73 nm. The solubility of LTG in P123/LTG can increase to 2.17 mg/ml, making it available as a solution. The in vitro release of LTG from P123/LTG presented a sustained-release property. Compared with free LTG, the LTG-incorporated micelles accumulated more in the brain at 0.5, 1, and 4 hours after intravenous administration in rats. Pretreatment with systemic verapamil increased the rapid brain penetration of free LTG but not P123/LTG. Incorporating another P-gp substrate (Rhodamine 123) into P123 micelles also showed higher efficiency in penetrating the BBB in vitro and in vivo.Conclusion: These results indicated that P123 micelles have the potential to overcome the activity of P-gp expressed on the BBB and therefore show potential for the targeted delivery of AEDs. Future studies are necessary to further evaluate the appropriateness of the nanocarrier to enhance the efficacy of AEDs. Keywords: antiepileptic drug, lamotrigine, polymeric micelles, P-glycoprotein, pluronic, nanocarrier