Development and evaluation of rivastigmine-loaded microneedle systems for long-acting transdermal treatment of Alzheimer’s disease

Abstract

Alzheimer’s disease requires long-term symptomatic treatment that can be administered reliably in patients with cognitive decline. Rivastigmine (RVA), an acetylcholinesterase and butyrylcholinesterase inhibitor, is available as oral and transdermal products, but current products remain limited by gastrointestinal adverse effects, short systemic exposure after oral dosing, fixed patch dose strengths, local skin reactions and daily patch replacement. This thesis investigated whether polymeric microneedle systems could provide greater control over RVA loading, release, skin deposition and transdermal permeation.

Two strategies were examined. Hydrogel-forming microneedle array patches (HMAPs) were designed to form swollen conduits between an external reservoir and viable skin, whereas dissolving microneedles (DMNs) were designed to deposit drug-containing polymeric matrices within the skin. An HMAP formulation based on PVA/PVP/citric acid was selected and combined with lyophilised RVA reservoirs prepared with different HPMC contents. Ex vivo permeation studies showed that increasing HPMC content reduced 24 h RVA permeation, indicating that reservoir composition was a key formulation variable for drug release through the swollen HMAP network. For DMNs, direct incorporation of free RVA enabled measurable drug loading, but higher RVA content reduced mechanical strength. Compared with needle-free films, RVA-loaded DMNs increased ex vivo permeation across neonatal porcine skin. Pre-formulating RVA as a nanoemulsion slowed permeation and increased relative skin retention, consistent with an additional partitioning step after DMN dissolution. This strategy was then extended to DMNs containing rivastigmine tartrate-loaded lipid nanoparticles with varied solid-to-liquid lipid ratios. Higher solid lipid content favoured skin retention, whereas higher liquid lipid content promoted permeation.

Microneedle insertion enabled RVA delivery across the skin barrier. In the HMAP systems, reservoir composition altered 24 h permeation, whereas DMN performance depended on drug form, polymer matrix and lipid carrier composition. These variables shifted the balance between transdermal permeation and skin retention and should be examined in studies extending beyond 24 h.

Thesis is embargoed until 31 December 2031.

Date of Award	Dec 2026
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Ryan Donnelly (Supervisor) & Alejandro Paredes (Supervisor)