AbstractHuman immunodeficiency virus (HIV) is a major global public health issue that currently affects approximately 38 million people across the world. Considerable advances in development of highly active antiretroviral therapy (HAART) have dramatically increased the life expectancy and quality of life of infected individuals. However, HIV is still a chronic disease that requires lifelong treatment. The virus persists in latent reservoirs within the body that are resistant to HAART and therapy interruption leads to rebound viraemia. Consequently, the suppression of these reservoirs is one of the main challenges in the ongoing fight against HIV. The lymphatic system, particularly the lymph nodes, have a large population of HIV-targeted immune cells and are one of the main viral replication sites. Nevertheless, currently used antiretroviral agents penetrate to lymph nodes insufficiently and, hence, novel drug delivery systems for enhanced lymphatic uptake of antiretrovirals are highly desirable. Intradermal application of nanoparticles can have a positive impact on the lymphatic availability of therapeutic agents, but common intradermal injections come with many drawbacks. Dissolving polymeric microarray patches (MAPs) are minimally-invasive and self-disabling delivery systems that can be employed for intradermal administration of various compounds. This thesis explores, for the first time, the lymph-targeted intradermal delivery of the antiretroviral agents rilpivirine (RPV) and cabotegravir (CAB) via dissolving MAPs. RPV and CAB were formulated as nanocrystals and subsequently incorporated into MAPs with a strong focus on increased lymphatic uptake. MAP micromoulds were customised for reproducible and time-efficient fabrication of MAPs and a high theoretical drug load. Nanocrystals were produced utilising a rationalised laboratory scale wet bead-milling system. Drug-loaded MAPs were selected based on their robustness for efficient skin insertion, high payload and fast separation of individual drug-loaded microneedles (MN) from their respective MAP backing layers for effective in-skin deposition and short application times. Pharmacokinetic and biodistribution profiles of RPV and CAB after intradermal application via MAPs in comparison to intramuscular injection were investigated in vivo in Sprague Dawley rats. This thesis provides convincing evidence that this novel delivery strategy could greatly enhance lymphatic uptake of antiretroviral agents compared to conventional HAART. The effect of elevated drug concentration levels in lymph nodes after intradermal application via MAPs on the suppression of viral reservoirs will now need to be studied in suitable infection models. Input from end-users, healthcare professionals, regulatory authorities and key stake holders will also need to be considered for successful commercialisation of antiretroviral MAP products.
Thesis embargoed until 31 December 2026.
|Date of Award||Dec 2021|
|Sponsors||Northern Ireland Department for the Economy|
|Supervisor||Ryan Donnelly (Supervisor) & Eneko Larrañeta (Supervisor)|
- Microarray patches
- lymphatic targeting