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

Abstract

Purpose 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. 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 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. 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.

Compritol-Based Nanostrucutured Lipid Carriers (NLCs) for Augmentation of Zolmitriptan Bioavailability via the Transdermal Route: In Vitro Optimization, Ex Vivo Permeation, In Vivo Pharmacokinetic Study

“…The mean PS and PDI of the prepared NLCs were measured by a Malvern Zetasizer (Zetasizer Nano ZS, Malvern Instruments, Worcestershire, UK) utilizing dynamic light scattering technique. The measurements were performed after dilution (10 folds) by double distilled water [ 32 , 41 ]. The electrophoretic movement of the particles in the electrical field was monitored during the ZP evaluation.…”

“…The dissolution profiles of the prepared NLCs and the amount of the drug released after 6 h (Q6h) were determined utilizing USP dissolution apparatus I for 6 h at 35 °C ± 0.5 by applying the membrane diffusion technique [ 32 ]. Before use, the cellulose membrane was soaked in double distilled water overnight [ 43 ].…”

“…The experiments were performed in triplicate and the mean percentages released ± SD were calculated and plotted against their respective time intervals. The permeation of ZMP solution was carried out simultaneously to validate that the cellulose membrane is not a delaying factor for drug permeation [ 32 ]. Models of zero, first and Higuchi diffusion [ 46 ] were used to fit the drug release profiles.…”

“…The transdermal drug delivery route has significant advantages over the conventional oral route. It can provide more patient compliance [ 30 ], especially in patients with vomiting and gastric problems—a common manifestation of migraine—more stable serum drug levels [ 31 ], pain-free drug administration, avoiding hepatic first-pass metabolism [ 32 ] and drug degradation in the gastrointestinal tract [ 33 ], food–drug interaction and reducing side effects [ 34 , 35 ]. Several attempts have been reported for employing NLCs as a nanoparticulate system for transdermal drug delivery [ 36 , 37 ].…”

Thiolated Chitosan Microneedle Patch of Levosulpiride from Fabrication, Characterization to Bioavailability Enhancement Approach

“…A TDDS is oftently used drug delivery route for increasing the bioavailability of BCS class IV drugs. Patients can self-administer TDDS easily and quickly, thus achieving higher patient compliance [ 13 , 14 , 15 ] and preventing first-pass metabolism by the liver [ 16 , 17 ]. The skin, especially the upper stratum corneum, is the main barrier to transdermal drug delivery [ 18 ].…”