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

PURPOSE: Ivabradine hydrochloride is selective pacemaker current (If) ion channel inhibitor used in case of chronic heart failure (CHF) with superior efficacy and lower side effects than most ß-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. MATERIALS AND METHODS: 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. RESULTS: 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 Cmax and half-life of both formulae in comparison to market product (Procoralan®) with a 2.54- and 1.85-folds increase in bioavailability, respectively. CONCLUSION: 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.

Inhibitory effect of sesamin on ivabradine metabolism in rats.

In this work, the aim of our study was to assess whether sesamin could influence the pharmacokinetics of ivabradine and its active metabolite N-desmethylivabradine in rats. At the begining, 12 healthy male Sprague-Dawley rats were randomly divided into two groups: The rats were received an oral administration of 1.0mg/kg ivabradine alone (the control group), and the rats were given 1.0mg/kg ivabradine co-administered with 50mg/kg sesamin by gavage (the test group). After that, blood samples were collected from the tail vein of rats, and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) were used for determing the plasma concentrations of ivabradine and N-desmethylivabradine in rats. Finally, the pharmacokinetic parameters were estimated using DAS 2.0 software. As the results, the pharmacokinetic parameters (t1/2, Cmax, AUC (0-t) and AUC (0-oo)) of ivabradine in the control group were significantly lower than those in the test group (P<0.05). Moreover, sesamin significantly decreased t1/2, Cmax, AUC(0-t) and AUC(0-oo) of N-desmethylivabradine when compared to the control. These results demonstrated that sesamin increases plasma concentration of ivabradine and decreases N-desmethylivabradine conversely. Hence, our data indicated sesamin could influence the pharmacokinetic profile of ivabradine in rats, which might cause food-drug interaction in humans.

Pharmacokinetic profile of ivabradine hemisulfate sustained-release tablets administered in Chinese healthy volunteers: An open-label, randomized, single-dose, three-period crossover study.

We aimed to determine the pharmacokinetics and safety of three single oral doses (5, 10 and 15 mg) of ivabradine hemisulfate sustained-release tablets in healthy Chinese volunteers. A total of 12 volunteers (six males and six females) were randomized to receive a single oral dose of ivabradine hemisulfate sustained-release tablets 5, 10 or 15 mg, with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 48 h after drug administration, and the concentrations of ivabradine and N-desmethyl ivabradine were determined by HPLC-tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis. After administering single doses of 5, 10 and 15 mg, the mean maximum concentration (Cmax ) levels of ivabradine were 4.36, 7.29 and 12.62 ng/mL, and the mean area under the curve from time 0 to 48 h (AUC0-48 ) values were 55.66, 101.16 and 182.09 h·ng/mL, respectively. The mean Cmax levels of N-desmethyl ivabradine were 1.05, 2.03 and 3.16 ng/mL, and the mean AUC0-48 values were 20.61, 39.44 and 65.72 h·ng/mL, respectively. The median time of maximum concentration (Tmax ) levels of ivabradine and N-desmethyl ivabradine were 5 h for all three doses tested. The pharmacokinetic properties of ivabradine hemisulfate sustained-release tablets were linear at doses from 5 to 15 mg. Ivabradine hemisulfate sustained-release tablet appears to be well tolerated in these healthy volunteers.