Intranasal dolutegravir sodium loaded nanoparticles of hydroxypropyl-beta-cyclodextrin for brain delivery in Neuro-AIDS

Abstract

Dolutegravir sodium (DTG) loaded nanoparticles (NPs) were prepared by cross-linking Hydroxypropyl-β-cyclodextrin (HPβCD) with diphenyl carbonate to enhance its CNS uptake via intranasal delivery. NPs were characterized for various parameters like size, drug loading, in vitro release, safety and CNS uptake and optimized using quadratic response surface methodology (RSM) employing 2-factor, 5-level circumscribed central composite design. The batch of NPs containing DTG:HPβCD; 1:4.16 was considered optimum as uniform small NPs (size; 81±3 nm, PDI 0.378 ± 0.04) with high drug loading (14.9 ± 1.4%) and entrapment efficiency (77 ± 3.35%). NPs produced sustained drug release (89.51 ± 0.56% in 6 h) by Fickian diffusion mechanism, they provided 2.54 folds greater permeability of DTG compared to free drug and were non-toxic to L929 cell line. Significantly higher concentration of DTG in the CSF (24.89±4.56μg/mL) and higher CSF:Plasma ratio(1.64) was achieved from intranasal NPs as compared to the reported DTG concentration in the CSF (18 ng/mL) and CSF:Plasma ratio (0.11–0.66) following oral administration of tablet. High brain drug transport percentage (83.47%) from intranasal NPs confirms nose to brain transport of the drug. Gamma scintigraphy studies in rats revealed enhanced CNS uptake of drug from NPs. These results suggest that the present investigation hold promise for management of Neuro-AIDS.