Intranasal delivery of tetrabenazine nanoemulsion via olfactory region for better treatment of hyperkinetic movement associated with Huntington's disease: Pharmacokinetic and brain delivery study
Intranasal delivery of tetrabenazine nanoemulsion via olfactory region for better treatment of hyperkinetic movement associated with Huntington's disease: Pharmacokinetic and brain delivery study
复制标题
DOI：
10.1016/j.chemphyslip.2020.104917
复制
发表时间：
2020-08-01
影响因子：
3.4
通讯作者：
Baboota, Sanjula
中科院分区：
文献类型：
--
作者：
Arora, Anmol;Kumar, Shobhit;Baboota, Sanjula
Tetrabenazine通过消耗突触前囊泡中的单胺来减少与亨廷顿氏病相关的舞蹈病症状。它具有较低的水溶性和首过代谢，因此具有较低的口服生物利用度。本研究的目的是研制负载丁苯那嗪的鼻用纳米乳，以更好地管理和治疗亨廷顿病相关的运动亢进。采用设计质量（QbD）方法对纳米乳的配方和优化进行了统计多元分析。优化后的微滴粒径为106.80 +/- 1.96 nm， PDI值为0.198 +/- 0.005，zeta电位为-9.63 +/- 0.63 mV。体外药物渗透研究发现，与丁苯那嗪悬浮液相比，该制剂的渗透性增加了1.68倍。MTT实验显示，负载四苯那嗪的纳米乳在1/2倍C-max、C-max和2倍C-max下的细胞活力优于安慰剂和药物水溶液。经鼻给药四苯那嗪纳米乳脑内药代动力学参数为C-max = 3.497 +/- 0.275 μ g/mL， AUC(0-12) = 29.196 +/- 0.870 μ g h/mL，消除速率常数(k(e)) = 0.097 +/- 0.012h(-1)；血浆药代动力学参数为C-max = 1.400 +/- 0.084 μ g/mL， AUC(0-12) = 12.925 +/- 0.340 μ g h/mL, k(e) = 0.061 +/- 0.010 h（-1）。猪鼻黏膜的组织病理学研究表明，载丁苯那嗪纳米乳处理后，鼻黏膜保持完整。因此，从研究中可以得出结论，优化的四苯那嗪纳米乳配方是稳健的，其通过鼻腔给药是治疗亨廷顿病相关运动亢进的可行替代途径。
Tetrabenazine reduces chorea symptoms associated with Huntington's disease by depleting monoamines in pre-synaptic vesicles. It exhibits low aqueous solubility and undergoes first pass metabolism due to which it has low oral bioavailability. The aim of present work was to formulate intranasal tetrabenazine loaded nanoemulsion for better management and treatment of hyperkinesia related with Huntington's disease. A quality by design (QbD) technique was employed as statistical multivariate approach for formulation and optimization of nanoemulsion. Optimized formulation showed droplet size of 106.80 +/- 1.96 nm with polydispersity index (PDI) value of 0.198 +/- 0.005 and -9.63 +/- 0.63 mV zeta potential. Ex-vivo drug permeation studies were carried out and found that the formulation has an augmented permeation by 1.68 times as compared to tetrabenazine suspension. MTT assay on neuro-2a cell lines showed that tetrabenazine loaded nanoemulsion displayed better cell viability than placebo and aqueous drug solution at 1/2 x C-max, C-max and 2 x C-max. Pharmacokinetic parameters in brain after intranasal administration of tetrabenazine nanoemulsion were found to be C-max = 3.497 +/- 0.275 mu g/mL, AUC(0-12) = 29.196 +/- 0.870 mu g h/mL and elimination rate constant (k(e)) = 0.097 +/- 0.012h(-1) where as in plasma the pharmacokinetic parameters were C-max = 1.400 +/- 0.084 mu g/mL, AUC(0-12) = 12.925 +/- 0.340 mu g h/mL and k(e) = 0.061 +/- 0.010 h(-1). Histopathological studies of porcine nasal mucosa showed that nasal mucosa remains intact when treated with tetrabenazine loaded nanoemulsion. Thus it can be concluded from study that optimized nanoemulsion formulation of a tetrabenazine was robust and its delivery through nasal route is a viable alternative to other routes of administration for treatment of hyperkinesia associated with Huntington's disease.