Development and Characterization of Levodopa Loaded Pharmacosomes for Brain Targeting via Intranasal Route: Pharmacodynamic Evaluation in Rats

Abstract

Parkinson’s is the second most common progressive neurodegenerative disease and affects 1-2% people over the age 50. Levodopa is the drug of choice in the treatment of Parkinson’s disease and exhibits low oral bioavailability (30%) and very low brain uptake. In an attempt to improve brain uptake and to avoid degradation of levodopa in peripheral circulation, brain targeting of levodopa loaded pharmacosomes via nasal route has been investigated. Pharmacosomes are colloidal dispersions of drug covalently bound to lipids and may exist as ultrafine vesicular, micellar or hexagonal aggregates, depending on the chemical structure of the drug-lipid complex. Pharmacosomes loaded with levodopa were prepared by solvent evaporation method and the optimized formulation contained levodopa and egg lecithin in the ratio of 1:3. The mean globule size, PDI, zeta potential, drug content, entrapment efficiency and drug release of formulation (F5) were 123.2nm, 0.211, -29.1mV, 96%, 99.97% and 62.1% respectively. Permeation enhancer, chitosan was incorporated at 0.5% concentration to optimal formulation (F7). The mean globule size, PDI, zeta potential, drug content, entrapment efficiency and drug release of optimised formulation (F7) were 125.5nm, 0.115, +33.7mV, 96.5%, 99.98% and 91.2% respectively. Formation of covalent bond between levodopa and lecithin was confirmed by FTIR spectra showing peak at 1639.9 cm-1. Ex-vivo permeation studies using Franz diffusion cell on porcine nasal mucosa showed flux of 96.61 µg/cm2 /h and 302µg/cm2 /h. The steady state flux of F5 and F7 formulations was significantly high (P<0.001) and enhancement ratio was 2.26 and 3.12 times respectively compared to drug solution. Anti-parkinson’s activity of optimized formulation (F7), drug solution via nasal route was compared with drug solution administered orally, in rotenone induced male wistar rats. Group treated with optimized pharmacosomes formulation (F7) showed significant recovery in rat weight (43%), locomotor activity by photo actometer (90%) and grip strength on retard (65%) compared to drug solution treated orally showed recovery in rat weight (32%), locomotor activity by photo actometer (57%) and grip strength on rotarod(30%). Biochemical parameters measured in brain homogenate showed significant reduction in induced levels of nitric oxide (82%), total protein (88%) and lipid peroxides (73%) and significant increase in reduced Glutathione (67%). Whereas drug solution treated via orally showed significantly less activity in the reduction of nitric oxide (28%), total protein (59%) and lipid peroxidation (33%) and reduced glutathione (10%).

Keywords: Brain targeting; Levodopa; Nasal delivery; Parkinson’s disease; Pharmacosomes