Lymph-targeted intradermal delivery of antiretroviral agents via dissolving polymeric microarray patches

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) <i>via</i> 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 <i>via</i> MAPs in comparison to intramuscular injection were investigated <i>in vivo</i> 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 <i>via</i> 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.<br><br><i>Thesis embargoed until 31 December 2026</i>.