Barrier-Mediated Pulsatile Release

Abstract

A membrane-based approach to pulsatile delivery, termed here as Barrier-Mediated Pulsatile Release (BMPR), sequesters each chemical dose into its own stimuli-sensitive reservoir film, each covered by a stimulant barrier membrane to delay triggering for a prescribed period time. These barrier/depot pairs are then stacked sequentially, with the delay time for the next barrier commencing with the stimulation of the previous depot, assuring a controlled period between each pulse. This paper introduces the first generalized BMPR system, using hydrogel depots that can be adapted to a variety of stimulants, coupled with barriers that rely on sacrificial stimulant scavengers to provide controlled delay times spanning orders of magnitude. Poly(methyl methacrylate-co-dimethylamino ethyl methacrylate) hydrogels are used to demonstrate pulsatile release of multiple solutes triggered by buffered citric acid. Zinc oxide nanoparticles loaded in poly(vinyl alcohol) hydrogel barriers delay acid permeation to each depot. Depot thickness, pH, and buffer strength are each shown to affect the stimulant permeation, swelling, and solute diffusion rates from the depots, with different processes becoming rate-limiting under different conditions. The delay time for each barrier varies linearly with ZnO scavenger loading, scavenger center-of-mass, and the square of the barrier thickness, providing multiple pathways for tuning delay time over a wide range. BMPR devices releasing up to 10 pulses are demonstrated, with no inherent limit on the number of pulses possible.