IN VIVO EVALUATION OF THE BIOAVAILABILITY OF THE HYDROXIPROPYL-β-CYCLODEXTRIN/AMIODARONE INCLUSION COMPLEX.

Amiodarone (AMD) is an antiarrhythmic agent included in the 2nd class according to the biopharmaceutical classification of drug substances. The oral bioavailability of AMD in conventional pharmaceutical formulations exhibits large interindividual variations due to the rapid dealkylation of the molecule to desethylaminodarone (inactive metabolite) and due to low hydrosolubility. The complexation of the drug substance in the central cavity of various kinds of cyclodextrins is one of the most effective methods for optimizing the oral bioavailability of drug substances such as AMD, and it can be accomplished by complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD). The objective of the study was to evaluate the influence of complexation on the oral bioavailability of AMD. The HP-β-CD/AMD inclusion complex was prepared in a 1:1 molar ratio, using the lyophilization method. It was characterized in terms of physico-chemical proprieties, pharmacokinetics, release kinetics, and in vivo bioavailability. The study was conducted according to the legislation in force, using male, Wistar, white mice. The animals were grouped in 2 batches: Lot 1 (control batch) which received AMD·HCL and Lot 2 (positive control batch) which received HP-β- CD/AMD. The analysis of AMD peak plasma concentrations for AMD·HCl (Cmax = 165.67 ± 80.21 ng/mL) and HP-β-CD/AMD (C_max = 249.67 ± 94.50ng / mL) proved that HP-β- CD/AMD generates 1.5-fold higher average plasma concentrations and therefore those concentration levels are released concurrently. The analysis of areas under the curve for the variation of AMD plasma concentration in time (AUC_0-t), showed that the values were approximately 1.15-fold higher for HP-β-CD/AMD (AUC0-t = 0 ± 2.2h) than for AMD·HCl (AUC_0-t = 5.5 ± 1.9h). In conclusion, the results obtained confirmed that HP- β-CD is a type of cyclodextrin that can function as the host molecule for AMD in order to optimize oral bioavailability through formulation in modified-release oral therapeutic systems. [ABSTRACT FROM AUTHOR]