Patient-Friendly, Olfactory-Targeted, Stimuli-Responsive Hydrogels for Cerebral Degenerative Disorders Ensured > 400% Brain Targeting Efficiency in Rats.

Abstract

Non-invasive brain therapy for chronic neurological disorders is in high demand. Vinpocetine (VIN) tablets for cerebrovascular degenerative disorders ensued < 7% oral bioavailability. The olfactory pathway (providing direct brain access) can improve VIN pharmacokinetic/pharmacodynamic profile. In this context, VIN hydrogels based on temperature-, pH-, and ion-triggered gelation in physiological milieu were formulated. Poloxamer-chitosan (PLX-CS) and carbopol-HPMC-alginate (CP-HPMC-SA) systems were optimized for appropriate gelation time, temperature, and pH. PLX-CS-hydrogels exhibited strong mucoadhesion for > 8h, while CP-HPMC-SA hydrogels were mucoadhesive in simulated nasal fluid, owing to pH and ion-activated gelation. Along with prolonged mucosal residence, hydrogels confirmed sustained VIN release (> 24h), especially from CP-HPMC-SA hydrogels. As proof of concept, brain exposure of intranasal VIN hydrogels was investigated in rats versus VIN-IV bolus. PLX-CS provided 146% increase in AUC0-30 and 3-fold maximum brain concentration (BCmax) relative to IV bolus. BCmax was reached after 4h versus 1h (IV bolus). CP-HPMC-SA hydrogel showed superior brain targeting efficiency (460%) and brain direct transport percentage (78.23%). VIN plasma pharmacokinetics confirmed 45-60% reduction in AUCplasma versus IV bolus, while PCmax of CP-HPMC-SA and PLX-CS represented 17 and 28% that of IV bolus, respectively. Olfactory-targeted hydrogels grant effective, sustainable VIN brain level with minimal systemic exposure, thus, assuring lower dose, dose frequency, side effects, and per se better patient compliance.