Simultaneous Optimization of Oral and Transdermal Nanovesicles for Bioavailability Enhancement of Ivabradine...

Ivabradine hydrochloride is selective pacemaker current (I_f) ion channel inhibitor used in case of chronic heart failure (CHF) with superior efficacy and lower side effects than most β-blockers. However, the drug suffers from low bioavailability (≈40%) due to extensive first-pass metabolism. Hence, this work aims to formulate nanovesicular platforms to enhance their bioavailability both orally and transdermally.

A central composite face-centered design was employed to formulate the nanovesicles, both phosphatidylcholine: drug ratio and percentage of pluronic F68 were used as independent variables. The nine developed formulae were characterized in terms of vesicle size (nm), polydispersity index, zeta potential (mV), entrapment efficiency (%). Decreasing vesicle size, increasing negative value of the zeta potential, and increasing entrapment efficiency were the chosen constraints to optimize the engineered nanovesicles. The candidate formula was subjected to further investigation including lyophilization, loading into carbopol gel, in vitro release, imaging with a transmission electron microscope, histopathological examination, in vitro cytotoxicity study and in vivo pharmacokinetics.

The optimized nanovesicular formula was composed of lipid: drug ratio of 3.91:1 and 100% pluronic as a stabilizer. It has particle size, zeta potential and entrapment efficiency of 337.6 nm, -40.5 mV and 30.5, respectively. It was then lyophilized in the presence of 5% trehalose as a cryoprotectant, dispersed in 0.5% carbopol to develop the transdermal gel. The two different forms of the candidate formula (lyophilized and gel form) displayed sustained drug release in comparison to drug solution. The histopathological and cytotoxicity studies showed that the optimized formula was safe and highly biocompatible. The pharmacokinetics parameters measured declared a higher C_max and half-life of both formulae in comparison to market product (Procoralan^®) with a 2.54- and 1.85-folds increase in bioavailability, respectively.

Hence, the developed nanovesicles can be reported as the first nanoplatforms to be used for simultaneous ivabradine delivery by both oral and topical routes with enhanced oral and transdermal drug delivery. The developed nanoplatforms hence can be further used to formulate other drugs that suffer from low bioavailability due to extensive first-pass metabolism.