Pharmacokinetic Evaluation of Chitosan Coated Hydroxypropylmethyl Cellulose (HPMC) Microparticles of Levodopa and Carbidopa

Abstract

Background: Levodopa, a prodrug of dopamine, remains the gold standard in the treatment of Parkinson’s disease. Current levodopa drugs are formulated in combination with an aromatic amino acid decarboxylase inhibitor, carbidopa, to prevent peripheral metabolism of levodopa. However, chronic use of levodopa is associated with potentially disabling motor complications and side effects, which arise from variable plasma concentration of the drug. Several attempts have been made to improve the formulation and drug delivery of levodopa with the aim of providing constant plasma levels in order to improve the drug’s efficacy. Microparticluate drug delivery systems have shown potentiality to deliver drugs at their target sites over a long of period of time while maintaining constant plasma concentrations. The aim of this study was to formulate and evaluate the pharmacokinetics of chitosan coated hydroxypropylmethyl cellulose (HPMC) microparticles of levodopa and carbidopa using in vitro and in vivo models. Methodology: Microparticles were formulated by encapsulating levodopa/carbidopa powders in HPMC using the spray-drying method. The levodopa microparticles were evaluated for size, drug content, percentage drug loading capacity, encapsulation efficiency and in vitro release profile. For pharmacokinetic evaluation, Sprague Dawley rats were administered either levodopa/carbidopa powder, levodopa/carbidopa microparticles or Sinemet CR (a controlled release formulation of levodopa/carbidopa). Blood samples were collected after predetermined times after the third dose. Plasma was obtained from blood and levodopa levels determined by high performance liquid chromatography. Pharmacokinetic parameters; maximum plasma concentration (Cmax), the time it takes to achieve this peak (Tmax), area under the curve (AUC) and half-life (t1/2) of were estimated from concentration-time curves. Results: The particle size obtained ranged between 0.04 μm to 6 μm with a mean size of 0.2 μm. Of the expected 20% drug loading, the actual drug loading capacity of the microparticles was found to be 19.1%, giving an encapsulation efficiency of 95.6%. The in vitro release kinetics showed a controlled and sustained drug release profile of levodopa microparticles with 80% drug release occurring at 12 h. In vivo pharmacokinetic studies showed a kinetic profile of levodopa/carbidopa microparticles as compared to the conventional control release formulation. The AUC (704.5 ± 85.37), and Cmax (262.4 μg/mL) of levodopa/carbidopa microparticles were relatively higher than Sinemet CR (AUC 252.7 ± 33.88 and Cmax 128.8 μg/mL). Conclusion: Findings from the study suggest that levodopa/carbidopa microparticles may give adequate levels of levodopa plasma concentration over a period of time.