Title:Optimization of Ivabradine Hydrochloride Transdermal Patch by D-Optimal Mixture Design: In Vitro and In Vivo Evaluation
Volume: 12
Issue: 2
Author(s): Kalpana G. Patel, Vaishali T. Thakkar*, Kartik H. Dudhat, Mitesh H. Motisariya, Purvi A. Shah, Nirav V. Patel, Kirti V. Patel, Tosha S. Pandya, Jenee R. Christian and Tejal R. Gandhi
Affiliation:
- Department of Pharmaceutics, Anand Pharmacy College, Anand-388001 Gujarat,India
Keywords:
Ivabradine hydrochloride, transdermal patch, D-optimal mixture design, in vivo study,
bioanalytical, pharmacokinetic.
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.
