In Vitro And In Vivo Kinetic Characteristics Of Chitosan-Pectin-Based Matrix Of Levodopa And Carbidopa

Abstract

Background: Parkinson's disease is a progressive neurodegenerative disorder that causes disability usually among the elderly. Levodopa remains the drug of choice in the management of Parkinson's disease. Levodopa is extensively metabolized in the periphery by aromatic amino acid decarboxylases; thus, it is routinely co-administered with carbidopa, a peripheral decarboxylase inhibitor. Although the aforementioned combination therapy is effective, there is variable absorption and fluctuating plasma levels of levodopa after oral administration. New oral levodopa plus carbidopa (levodopa/carbidopa) formulations are needed to overcome this irregular absorption and maintain near constant plasma concentrations. Aim: The aim of this study was to evaluate the kinetic characteristics of chitosan-pectin-based multiparticulate matrix of levodopa/carbidopa, using in vitro and in vivo models. Methodology: Pectin was extracted from cocoa pod husk with hot aqueous solution. Preparation of the chitosan-pectin-based matrix was done by the wet granulation. The formulations were evaluated for drug-excipient compatibility, drug content, flowability and precompression properties and in vitro release. In evaluating in vivo pharmacokinetic and biodistribution characteristics, male Sprague Dawley rats were administered either chitosan-pectin based matrix of levodopa/carbidopa, Sinemet CR (a controlled release formulation of levodopa/carbidopa) or levodopa/carbidopa immediate release powder (20/5 mg/kg) via the oral route every 12 hours. After the third dose, tail vein samples and brain tissues were taken at predetermined times. Pharmacokinetic parameters (Cmax, Tmax, AUC and t1/2) of levodopa were estimated for the various treatment, levels of levodopa in rat brains were estimated and compared. Results: The yield of cocoa pod husk pectin extracted with hot aqueous solution was 7.91%. The excipients for drug formulation were compatible with levodopa/carbidopa. The content of levodopa and carbidopa in the various formulations were within the acceptance criteria (not less than 90% and not more than 110% of the stated amount) with the exception of F5. There was controlled and sustained release of levodopa and carbidopa in vitro. In vivo pharmacokinetic studies showed kinetic profiles of levodopa/carbidopa multiparticulate matrix as compared to the conventional control release formulation. The AUC0-24 for optimized levodopa/carbidopa multiparticulate matrix (F3: 484.98 ± 18.70; F4: 535.60 ± 33.04), and Cmax (F3: 36.28 ± 1.52; F4: 34.80 ± 2.19 μg/mL) were relatively higher than Sinemet CR (AUC0-24 262.84 ± 16.73 and Cmax 30.62 ± 3.37 μg/mL). Conclusion: Findings from the study suggest that chitosan-pectin based matrix of levodopa/carbidopa may have the potential to control and maintain therapeutic concentrations of levodopa in circulation over a period of time.