Abstract
In this work, ultrahigh drug-loaded chitosan (Ch)/K-carrageenan (Kc) polyelectrolyte complex (PEC) beads were formed in situ by cross-linking in a glutaraldehyde-saturated atmosphere and were prepared on superhydrophobic substrates fabricated by spraying glass surfaces with ready-made spray for domestic use (NeverWet®). Verapamil hydrochloride (VP), a highly hydrophilic drug with a short biological half-life, was incorporated into a series of Ch-based and/or Ch/Kc-PEC-based beads to control its release profile in vivo. The formulation of VP-loaded beads was optimized using stepwise statistical designs based on a prespecified criterion. Several characteristics of the prepared beads, such as entrapment efficiency (EE%), in vitro drug release, swelling ratio, size and surface microstructure as well as molecular interactions between the drug and formulation ingredients, were investigated. In vivo pharmacokinetic (PK) studies were carried out using the rabbit model to study the ability of the optimized VP-loaded beads to control the absorption rate of VP. Results revealed that the prepared superhydrophobic substrates were able to fabricate VP-loaded beads with extremely high EE exceeding 90% w/w compared to only 27.80% when using conventional ionotropic gelation technique. PK results showed that the rate of VP absorption was well controlled following oral administration of the optimized beads to six rabbits compared to a marketed VP immediate release (IR) tablet, as evidenced by a 2.2-fold increase in mean residence time (MRT) and 5.24-fold extension in half value duration (HVD) over the marketed product without any observed reduction in the relative oral bioavailability.
Highlights
Controlled-release multiparticulate systems designed to deliver highly hydrophilic drugs with relatively short biological half-lives offer many therapeutic and clinical benefits due to reduction in dosing frequency. They are well known to be uniformly distributed in the gastrointestinal tract (GIT), resulting in more uniform absorption with no risk of dose dumping compared to single unit systems [1,2]
Rabbits were housed according to National Institute of Health guidelines, and the study protocol was approved by Research Ethics Committee (REC) for experimental and clinical studies at Faculty of Pharmacy, Cairo University, Cairo, Egypt (PI (1343, 30/10/2017))
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Summary
Controlled-release multiparticulate systems designed to deliver highly hydrophilic drugs with relatively short biological half-lives offer many therapeutic and clinical benefits due to reduction in dosing frequency. They are well known to be uniformly distributed in the gastrointestinal tract (GIT), resulting in more uniform absorption with no risk of dose dumping compared to single unit systems [1,2]. Hydrophilic drugs are generally difficult to encapsulate using conventional encapsulation techniques due to their rapid diffusion from the prepared systems to the external aqueous phase, which makes their formulation more challenging [3,4]. Superhydrophobic substrates recently stepped into the field of pharmaceutical research due to their ease and suitability for the preparation of environmentally-friendly highly loaded polymeric beads, few studies have been carried out to widen such application
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