Abstract
Background: The anti-anginal agent ivabradine hydrochloride acts by selective and specific inhibition of the cardiac pacemaker current. The oral bioavailability of ivabradine is approximately 40% because of first-pass effect in liver and intestines.
Objective: The present study targets QbD abetted formulation and in vivo evaluation of transdermal patch to avoid limitations allied with oral administration.
Method: Transdermal patch was prepared using HPMC K15 and ethyl cellulose by solvent evaporation technique. D-optimal mixture design was applied to study the effects of critical process parameters, HPMC K15 and Ethyl cellulose ratio on critical quality attributes, permeation flux, cumulative amount of drug permeated, per cm2 of skin at 12 and 24 h. The optimized batch was evaluated for in vitro dissolution, physicochemical parameters, drug release and pharmacokinetic study, using developed bioanalytical method.
Results: Transdermal patch containing HPMC K15 and ethyl cellulose (66.132: 33.868) showed control release and acceptable physicochemical properties. Chromatographic separation of analytes, Ivabradine hydrochloride and Verapamil hydrochloride, internal standard, was achieved on C18 column (250 x 4.6 mm, 5µm) using methanol: 5mM disodium hydrogen phosphate buffer (80:20, %v/v), at 1 ml/min flow rate and 287nm. This proposed bioanalytical method was further applied for pharmacokinetic studies of prepared transdermal patch after single application to Wistar rats. It exhibits higher AUC, mean residence time, and longer t1/2 as compared to marketed formulation.
Conclusion: The successful verification of safety and pharmacokinetic profile of IH transdermal patch advocated the suitability of formulation for transdermal use and an efficient alternative of oral administration.
Keywords: Ivabradine hydrochloride, transdermal patch, D-optimal mixture design, in vivo study, bioanalytical, pharmacokinetic.
Graphical Abstract
24
4
1