‘Enhancing intranasal transport: levetiracetam-loaded nanospheres journey from nose to brain—optimization via Box–Behnken design and comprehensive in vitro/in vivo assessment’

Abstract Objective The aim of this work was to formulate and develop LEV loaded nanospheres in situ nasal gel. Significance This is an efficient therapy for epilepsy via brain targeting to increase bioavailability and reduce the dose frequency. Method This study looked at the impact of process factors (polymer amount (mg) (50,7 5, and 100), poloxamer 188 concentration (0.5, 1, and 1.5), and polymer type (Eudragit S100, Eudragit L100, and Eudragit RS 100)) on the responses (particle size (nm), entrapment efficiency (%), and zeta potential (mV) in order to optimize LEV-loaded nanospheres utilizing Box–Behnken design. The design expert software was used to perform the process of optimization categorically. Using the nanoprecipitation process, LEV-loaded nanospheres were effectively formulated, which were then evaluated by FTIR and DSC for drug-polymer interaction, TEM, zeta potential, and particle size. Results The optimized nanospheres formulation, which had the composition of 100 mg Eudragit S100 and 1.5% poloxamer 188, showed a particle size of 79.07 nm, % entrapment efficiency of 99.74%, and a zeta potential of −40.6 mV. DSC thermogram and FTIR spectrum showed no interaction between drug and polymer used. TEM image indicates spherical shape of the nanosphere formulation, LEV-loaded nanospheres in situ nasal gels were prepared using Na CMC at different concentrations (0.5, 1, and 1.5). NG3 (1.5% NaCMC) showed the best characterization of in situ nasal gel (gelation time of 18 s, gelation temperature of 28.6 °C and % drug release of 73%). In ex-vivo permeation study, the amount of LEV permeated from LVT loaded nanospheres in situ nasal gel (NG3) and the plain LVT in situ nasal gel were 75.5 and 67.8, respectively. NG3 confirmed higher permeability so it was chosen for in vivo pharmacokinetic study. It showed absolute bioavailability five folds greater than the IV route of administration. Conclusions LEV-loaded nanospheres in situ nasal gels enhanced its tissue permeability and pass BBB directly which bypass the first pass metabolism in liver. So the bioavailability increases. Graphical Abstract