Transdermal delivery of enfuvirtide using dissolving microneedles integrated with novel insertion and removal indicator

Abstract

Enfuvirtide, the first HIV fusion inhibitor, exhibits remarkable antiviral efficacy and a favourable safety profile compared with antiretroviral therapy alone. However, its clinical application is constrained by the necessity for subcutaneous administration and the high incidence of injection site reactions (ISRs) in 98 % of patients. This study seeks to overcome these limitations by developing dissolving microneedle array patches (DMAPs), offering a painless and efficient alternative for enfuvirtide delivery. Two bilayer DMAP designs featuring poly(vinyl pyrrolidone) (PVP) based-hydrophilic and poly(lactic acid) (PLA)-based hydrophobic baseplates were engineered, incorporating a novel PLA-silica baseplate as a colorimetric dissolution indicator for visual feedback on successful patch insertion and timely removal. The DMAPs with embedded indicators exhibited a rapid color change from yellow to green within 3 min of insertion into the rats' dorsal skin. This change was triggered by hydration of the dye crystal violet encapsulated in silica, as interstitial fluid migrated from the needle shafts to the baseplate. A subsequent transition to purple occurred within 2 h due to further dye hydration, indicating complete needle dissolution and successful delivery of enfuvirtide. In vivo studies on Sprague Dawley rats demonstrated that enfuvirtide achieved a C_max of 1864 ± 480 ng/mL at 0.5 h with the PLA-silica DMAP, compared to 973 ± 200 ng/mL at 1 h with the PVP-baseplate DMAP. Both formulations exhibited biocompatibility and safety in vivo, with the PLA-silica DMAP supporting rapid drug release suitable for short-term applications, while the PVP-based DMAP offered potential for long-term use without irritation. These findings underscore DMAPs as a promising alternative to subcutaneous injection of enfuvirtide, capable of reducing ISRs and potentially enhancing patient adherence. Notably, this work introduced an innovative solution for prompt patch removal upon complete drug delivery, effectively addressing dosing inconsistencies and enabling individualised administration, which is crucial for ensuring the reliability and patient acceptability for widespread adoption of this technology.

Keywords: Dissolving microneedles; Enfuvirtide; Transdermal drug delivery; indicator.