Microneedle technology for the potentially long-acting delivery of simvastatin for the treatment of hyperlipidemia

Abstract

Hyperlipidaemia and its cardiovascular complications are the leading cause of mortality and disability worldwide. Simvastatin (SIM) is one of the most commonly prescribed lipid-lowering agents that can significantly reduce the low-density lipoprotein (LDL) levels by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. However, it undergoes extensive first-pass metabolism and possesses low water solubility, resulting in extremely low oral bioavailability. Furthermore, frequent daily doses may cause poor patient compliance and adverse effects caused by the plasma fluctuations. This thesis explores the development of polymeric microneedle (MN) system to facilitate the intradermal delivery efficiency and improved bioavailability of SIM, as well as achieving long-acting delivery. Initially, SIM was formulated into nanocrystals (NCs) using a wet media milling technique at laboratory scale to improve the dissolution rate and were subsequently incorporated into the dissolving microneedles (DMNs). A novel trilayer DMN design was developed for rapid separation. The ex vivo permeation and in-skin deposition of SIM NCs-loaded DMNs were evaluated and their performance were compared with coarse SIM-incorporated DMNs. Furthermore, another novel effervescent hollow MNs (EMNs) were developed with a strong focus on circumventing the instability factors in the conventional fabrication process of DMNs and delivering the SIM dry powder directly into the skin. The outer polymeric shell was selected based on the mechanical properties, size of the micro-cavities and dissolution time. These were compared with a crude SIM powder-laden dissolvable hollow MN (PMN) as a control group. Subsequently, pharmacokinetic profiles of SIM NCs loaded DMNs and SIM EMNs in comparison to oral gavage were investigated in vivo using Sprague Dawley rats. This thesis explored, for the first time, that two MN strategies can considerably elevate the bioavailability of SIM and maintain the therapeutically relevant plasma concentration for 15 days following a single application of 24 h.

Thesis embargoed until 31st July 2026

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Ryan Donnelly (Supervisor) & Alejandro Paredes (Supervisor)