Development, Optimization and Evaluation of Thermo-responsive In-situ Nasal Gel of Levodopa and Entacapone for Brain-targeted Drug Delivery

Parkinson's disease is a neurodegenerative condition that includes mobility problems like decreased function, trouble with movements, stiffness, and shivering. Levodopa is the medicine of preference to cure Parkinson's; however, it has limited CNS absorption due to substantial degradation in the periphery by aromatic amino acid decarboxylase or catechol-O-methyltransferase. As a result, a peripheral amino acid decarboxylase blocker, Carbidopa, and a catechol-O-methyltransferase inhibitor, Entacapone, are given along with Levodopa. Hence, the presented work's goal was to develop a thermoreversible in-situ nasal gel showing nose-to-brain administration of Levodopa and Entacapone to enhance CNS absorption and limit the enzymatic breakdown of Levodopa in the periphery. To formulate the in-situ nasal gels, Poloxamer-407, Hydroxypropyl methylcellulose, and Carbopol-934 were used as thermos-responsive and gel-forming polymers in varying ratios. The gels containing drugs Levodopa and Entacapone were prepared by the cold technique and optimized using 32 factorial design. Gel strength, drug content, bioadhesion potential, pH, rheology, gelation period and temperature, ex-vivo permeation, kinetic study, and stability study were conducted, and the optimum batch was finalized using optimization, in-vitro study, and stability data. At intranasal temperature, the preparations gelled, while the gelling period was found to be shorter as compared to the mucociliary clearance rate. Because of higher gel strength and bioadhesion, the intranasal retention was observed to be longer. During the ex-vivo trials on the goat’s nasal cavity, the intranasal gel preparations exhibited 98.8% absorption of Levodopa and 97.9% absorption of Entacapone within 12 hours. The kinetic plots obtained indicated that the drug release follows Higuchi and Zero-order models. Also, the results of the stability study showed that the optimum batch of in-situ gel was stable and safe throughout the study. The aim of this work was achieved by successful brain-targeted drug delivery with enhanced CNS absorption, thereby preventing first-pass metabolism or peripheral enzymatic degradation of Levodopa. Despite being in its early stages, the in-situ gelation technique showed great promise as a novel foundation holding the potential to manage Parkinson’s; however, more in-vivo research is needed to support these findings.