Abstract

IN-SITU NASAL GEL OF LEVODOPA FOR BRAIN TARGETING USING CHITOSAN – THIOGLYCOLIC ACID CONJUGATE AND MUSK KETONE BY EFFLUX TRANSPORT MODULATION

Sandhya Goyal and Saahil Arora*

ABSTRACT

Conventional levodopa therapy has problems like peripheral oxidation, poor penetration through blood brain barrier and efflux through the P-gp efflux pump that limits the drug bioavailability. The rationale of project was aimed to formulate and evaluate pluronic thermosensitive nasal gel of levodopa for brain targeting using chitosan-thioglycolic acid conjugate as P-gp efflux transport inhibitor and nitromusk (musk ketone) as fragrance compound that stimulates the sensation and thus permeability in the nasal cavity. Synthesised thiolated chitosan was used for preparation of levodopa nanoparticles (NPs) by ionic gelation method and Pluronic i.e. PF127 was used for the purpose of thermoreversible gel formation. The optimised thiolated chitosan NPs showed 222.6 nm particle size, 0.296 PDI and +27.91mV zeta potential, confirming the stability of formulation and drug entrapment efficiency of NPs was found to be 76±1.2 %. The release of the drug from the thiolated chitosan NPs in PBS pH 6.4 showed non-fickian diffusion. The release profile indicated the suitability of CS-TGA derivative in nasal pH range of 5.5. In-vivo pharmacokinetic studies with the levodopa in saline, levodopa in CS-TGA NPs, levodopa in CS-TGA NPs in pluronic gel and gel with musk ketone showed enhanced bioavailability in brain (AUC-1.4 times) with more MRT (2.3 times) in case of CS-TGA nanoparticles dispersed in thermosensitive formulation with musk ketone in comparison to plain drug solution. However CS-TGA NPs without gel formulation showed more bioavailability (1.15 times) of drug level in brain compare to NPs in gel in presence of musk ketone but drug retention time in brain was 2 times less, because of low efflux through the P-lycoprotein in presence of musk ketone and pluronic gel. The results justified our rationale in selecting thiolated chitosan in presence of in-situ pluronic gel and musk ketone for enhanced bioavailability of levodopa in brain through nasal route.

Keywords: Levodopa, Chitosan-thioglycolic acid conjugate, Musk ketone, Parkinson’s disease, Thermosensitive gel.