Design, formulation and evaluation of novel dissolving microarray patches containing a long-acting rilpivirine nanosuspension

Abstract

One means of combating the spread of human immunodeficiency virus (HIV) is through the delivery of long-acting, antiretroviral (ARV) drugs for prevention and treatment. The development of a discreet, self-administered and self-disabling delivery vehicle to deliver such ARV drugs could obviate compliance issues with daily oral regimens. Alternatives in development, such as long-acting intramuscular (IM) injections, require regular access to health care facilities and disposal facilities for sharps. Consequently, this proof of concept study was developed to evaluate the use of dissolving microarray patches (MAPs) containing a long-acting (LA) nanosuspension of the candidate ARV drug, rilpivirine (RPV). MAPs were mechanically strong and penetrated skin in vitro, delivering RPV intradermally. In in vivo studies, the mean plasma concentration of RPV in rats (431 ng/ml at the Day 7 time point) was approximately ten-fold greater than the trough concentration observed after a single-dose in previous clinical studies. These results are the first to indicate, by the determination of relative exposures between IM and MAP administration, that larger multi-array dissolving MAPs could potentially be used to effectively deliver human doses of RPV LA. Importantly, RPV was also detected in the lymph nodes, indicating the potential to deliver this ARV agent into one of the primary sites of HIV replication over extended durations. These MAPs could potentially improve patient acceptability and adherence to HIV prevention and treatment regimens and combat instances of needle-stick injury and the transmission of blood-borne diseases, which would have far-reaching benefits, particularly to those in the developing world.

Design, Formulation, and Evaluation of Novel Dissolving Microarray Patches Containing Rilpivirine for Intravaginal Delivery

“…Plasma concentrations of RPV subsequently decreased to 56.1 ± 36.6 ng mL −1 at 28 days and were maintained in this region up to the experimental end point of 56 days. In the comparator IM study that was previously published, those rats treated with RPV LA via IM injection (1.8 mg) exhibited a comparable initial RPV plasma concentration of 175.5 ± 197.6 ng mL −1 , one day post‐IM injection and no samples had RPV concentrations above the LoQ of the HPLC system at the 7 day time point. Interestingly, the mean RPV plasma concentration after IM administration at 56 days (118.9 ± 54.2 ng mL −1 ) was comparable to that achieved via RPV LA intravaginal MAP at the same time point (116.5 ± 54 ng mL −1 ).…”

“…The dissolution profiles of RPV LA MAPs have previously been described, with the very slow dissolution of the needles being attributed to the high content of hydrophobic RPV LA in the needles of the MAPs . The insertion profiles of the RPV LA MAPs into excised bovine vaginal tissue were then evaluated.…”

“…Ethical permission for all in vivo experiments was obtained from the Queen's University Belfast, Biological Services Unit (BSU) and all researchers carrying out the work held Personal Licenses from the UK Home Office. MAP delivery of RPV LA, compared to IM delivery of RPV LA as a positive control, was assessed in vivo using female Sprague Dawley rats aged between 9 and 13 weeks upon commencement of each arm of the study and between 14 and 17 weeks upon completion of the study. Experiments were planned and implemented according to the policy of the Federation of European Laboratory Animal Science Associations and the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes, with implementation of the principles of the 3Rs (replacement, reduction, refinement).…”

“…The present study was designed, in collaboration with PATH and Janssen Pharmaceutica, to address the need for alternative delivery systems for HIV PrEP, with specific focus on delivery of an ARV drug, namely RPV LA, to the vaginal epithelium. This study builds upon work previously carried out in our research group, where we described the formulation, development and in vivo testing of dissolving microarray patches (MAPs) incorporating RPV LA for intradermal delivery . MAPs are micrometer‐scale devices, which have undergone extensive research in the fields of intradermal drug and vaccine delivery and have also been used in combination with nanosuspensions but had never before been used in the delivery of a LA nanosuspension, the potential of which we had previously theorized .…”

“…Building upon the outcomes of these focus group discussions and the work previously carried out in our research group to deliver RPV LA intradermally, the present study describes the formulation, mechanical testing, and in vivo evaluation of dissolving MAPs for delivery of RPV LA via the vaginal epithelium. It is hoped that, in time, a MAP device, such as that described here, could be successfully used in a discrete, self‐administered regimen for delivery of HIV PrEP to one of the main sites of HIV transmission.…”