Chitosan-Coated Hydroxypropylmethyl Cellulose Microparticles of Levodopa (and Carbidopa): In Vitro and Rat Model Kinetic Characteristics

Background: Parkinson's disease is a neurodegenerative disorder, and a major cause of disability. Levodopa, a prodrug of dopamine, remains the gold standard in the pharmacological management of Parkinson's disease. Despite several attempts to improve the clinical efficacy of levodopa, new oral levodopa formulations are needed to overcome irregular absorption and variable plasma concentrations.

Objective: The aim of this study was to evaluate the in vitro and in vivo kinetic properties of chitosan-coated hydroxypropylmethyl cellulose microparticles of levodopa (and carbidopa).

Methods: Microparticles were formulated by encapsulating levodopa powder in chitosan-coated hydroxypropylmethyl cellulose using the spray-drying method. Levodopa microparticles were evaluated for size, zeta potential, drug loading capacity, encapsulation efficiency and in vitro release. In evaluating in vivo pharmacokinetics, Sprague Dawley rats were administered either levodopa/carbidopa powder, levodopa/carbidopa microparticles, or Sinemet CR (a controlled release formulation of levodopa/carbidopa). The dose of respective formulations administered was 20/5 mg/kg; 20 mg levodopa combined with 5 mg carbidopa per kilogram body weight of animals. Treatments were administered via the oral route every 12 hours. Blood samples were collected after predetermined times following the third dose. Plasma was obtained from blood collected, and levodopa levels determined by HPLC. Pharmacokinetic parameters, including C, T, AUC, and t of the various formulations, were estimated.

Results: The mean (SD) size of levodopa microparticles was 0.5 (0.05) µm with polydispersity index of 0.41 and a zeta potential of 10.8 mV. Of the expected 20% drug loading, the actual drug loading capacity of levodopa microparticles was found to be 19.1%, giving an encapsulation efficiency of 95.7%. The in vitro release kinetics of levodopa microparticles showed a controlled and sustained release, with about 80% release occurring after 12 hours. In vivo pharmacokinetic studies showed that rats administered levodopa/carbidopa microparticles had greater AUC (612.7 [17.42] ng.h/mL) and higher C (262.4 [38.86] ng/mL) compared with Sinemet CR: AUC 354.7 (98.09) ng.h/mL and C 95.5 (20.87) ng/mL. However, Sinemet CR had a much longer half-life (6.1 [2.58] hours) compared with levodopa/carbidopa microparticles (2.0 [0.31] hours).

Conclusions: Findings from this study suggest that chitosan-coated hydroxypropylmethyl cellulose microparticles of levodopa/carbidopa may give relatively high levels of levodopa in circulation. ( 2020; 81:XXX-XXX)© 2020 Elsevier HS Journals, Inc.