Engineering and in vitro evaluation of semi-dissolving, hydrogel-forming polymeric microneedles for sustained-release drug delivery

Abstract

Polymeric microneedle array patches (MAPs) offer a painless and convenient way for delivering drugs across various biological membranes, including the skin, the cornea and various mucosal surfaces. Conventionally, dissolving MAPs provide rapid drug release but have a limited drug-loading capacity. Hydrogel-forming MAPs can prolong drug release typically for no more than several weeks but often involve harsh manufacturing conditions, such as elevated temperatures above 60 °C for chemical crosslinking. For both types of MAPs, the drug release kinetics depends greatly on the physical properties of the polymers used. However, common polymers used for MAP formulation are very constrained in their ability to balance often conflicting requirements in terms of water solubility, swellability, mechanical strength and manufacturability. To overcome these constraints, this study presents a semi-dissolving, hydrogel-forming MAP formulation approach based on a dual-domain polymeric system, consisting of physically and functionally distinct water-soluble polyvinylpyrrolidone and insoluble chitosan-hydrogel domains. In this unique formulation approach, robust MAPs were produced via micromoulding, using only a hydroalcoholic solvent system and mild temperatures ≤ 37 °C. The drug payload was incorporated into the entire baseplate of the MAPs using one-pot synthesis, which offers not just a high drug-loading capacity but also ease of manufacture. The MAPs extended the in vitro release of dexamethasone sodium phosphate (DSP), a highly hydrophilic drug, to over two months. Kinetic modelling showed that drug release from the MAPs followed non-Fickian transport. The DSP released from the MAPs retained potent anti-inflammatory activity in ex vivo human peripheral blood mononuclear cells. Using microscopy, timelapse imaging and kinetic data, the mechanism of drug release was captured in terms of the structural transformation of the polymeric matrix following hydration. It is proposed that this formulation approach may be extended to other dosage forms, such as implants, to modulate the release of a multitude of drugs, including biologics.

Keywords: Crosslinking; Microneedle array patch; Non-Fickian drug release; Polymer matrix; Skin; Transdermal.