PLGA Nanoparticles Based Mucoadhesive Nasal In Situ Gel for Enhanced Brain Delivery of Topiramate

Oral Topiramate therapy is associated with systemic adverse effects including paresthesia,abdominal pain, and fluctuations in plasma levels. The purpose of this research was to develop an intranasal in situ gel based system comprising Topiramate polymeric nanoparticles and evaluate its potential both in vitro and in vivo. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles prepared by nanoprecipitation method were added into the in situ gelling system of Poloxamer 407 and HPMC K4M. Selected formulation (TG5) was evaluated for physicochemical properties, nasal permeation and in vivo pharmacokinetics in rats.

PLGA nanoparticles (O1) exhibited low particle size (~ 144.4 nm), good polydispersity index (0.202), negative zeta potential (-12.7 mV), and adequate entrapment efficiency (64.7%). Developed in situ gel showed ideal pH (6.5), good gelling time (35 s), gelling temperature(37℃), suitable viscosity (1335 cP)and drug content of 96.2%. In vitro drug release conformedto Higuchi release kinetics, exhibiting a biphasic pattern of initial burst release and sustained release for 24 h. Oral administration of the drug to Sprague–Dawley rats (G3) showed higher plasma C_max(504 ng/ml, p < 0.0001) when compared to nasal delivery of in situ gel (G4) or solution (G5).

Additionally, AUC_0-α of G3 (8786.82 ng/ml*h) was considerably higher than othergroups. Brain uptake data indicates a higher drug level with G4 (112.47 ng /ml) at 12 h when compared to G3. Histopathological examination of groups; G1 (intranasal saline), G2(intranasal placebo), G3, G4, and G5 did not show any lesions of pathological significance. Overall, the experimental results observed were promising and substantiated the potential of developed in situ gel for intranasal delivery.

Materials

Topiramate was procured from Taj Pharmaceuticals, Mumbai, India. PLGA (Resomer RG750S) was kindly gifted by Evonik India, Mumbai, India. Poloxamer 407, Poloxamer 188 and Tween 80 were provided as gift samples by BASF, Mumbai, India and Mohini Organics, Mumbai, India, respectively. Hydroxypropyl methylcellulose K4M was received as a gift sample from Colorcon, Mumbai, India. Polyvinyl alcohols (PVA, MW 13,000–25,000 and 85,000–1,24,000), Acetone, benzalkonium chloride, and glycerolwere procured from S.D. Fines Chemicals, Mumbai, India.

Tanna, V., Vora, A., Shah, P. et al. PLGA Nanoparticles Based Mucoadhesive Nasal In Situ Gel for Enhanced Brain Delivery of Topiramate. AAPS PharmSciTech 25, 205 (2024). https://doi.org/10.1208/s12249-024-02917-4