Intranasal delivery of tetrabenazine nanoemulsion via olfactory region for better treatment of hyperkinetic movement associated with Huntington's disease: Pharmacokinetic and brain delivery study

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.