Development of dissolving and hydrogel-forming microneedles for delivery of vancomycin hydrochloride

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) can cause harmful and potentially deadly infections, including neonatal sepsis. Vancomycin, a glycopeptide antibiotic, remains the most effective antibiotic to treat this condition. In the case of systemic diseases, vancomycin must be administered via intravenous injection. However, administration of vancomycin via this route has some associated drawbacks, such as the fact that the patient can experience pain and discomfort upon administration, as well as the possibility of transmission of blood borne infections as a result of needle-stick injuries. Vancomycin displays low absorption when administrated orally, due to the large molecular weight and low permeability in the gastrointestinal tract. As a consequence, utilising a novel transdermal drug delivery system to deliver vancomycin could prove a promising alternative. One approach that can be used to enhance transdermal drug delivery is microneedle (MN) technology. MN is micron-sized needles on a solid backing or support that can easily penetrate the skin’s stratum corneum barrier, accessing the viable epidermis and dermis. This thesis aimed to investigate the development of dissolving and hydrogel-forming MN for the facilitated delivery of vancomycin hydrochloride (VCL). VCL was formulated into dissolving MN (DMN), in combination with a variety of different excipients. In an alternate approach, VCL reservoirs, namely film dosage forms, lyophilised wafers and compressed tablets, were integrated with hydrogel-forming MN (HFMN). The physicochemical properties of the VCL-containing DMN, including mechanical strength, insertion ability and drug content, were evaluated. In vitro permeation studies were then carried out using the selected VCL-containing DMN and VCL reservoirs integrated with HFMN. Based on the outcomes of those studies, candidate VCL vehicles/MN were used in pharmacokinetic and biodistribution studies in an appropriate rat model. For the first time, VCL was successfully delivered transdermally into the systemic circulation using DMN and HFMN. The findings of this thesis explore the potential of appropriately formulated and characterised MN to enhance VCL delivery and bioavailability, with the potential to ameliorate approaches to the treatment of neonatal sepsis. Before these novel delivery systems can be employed in clinical settings however, pharmacodynamic assessments of VCL efficacy in models of infection must be determined, as well as considering patient compliance and industrial regulatory standards.

Date of Award	Dec 2020
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Indonesia Endowment Fund for Education (Lembaga Pengelola Dana Pendidikan/LPDP)
Supervisor	Ryan Donnelly (Supervisor), Aaron Courtenay (Supervisor) & Maeliosa McCrudden (Supervisor)