Hydrogel-forming microarray patches with cyclodextrin drug reservoirs for long-acting delivery of poorly soluble cabotegravir sodium for HIV Pre-Exposure Prophylaxis.

Abstract

Hydrogel-forming microarray patches (HF-MAPs) offer minimally invasive, pain-free and prolonged drug delivery. These devices are designed to be self-administered and self-disabling, avoiding contaminated sharps waste generation. Cabotegravir sodium (CAB-Na) is a poorly soluble anti- human immunodeficiency virus (HIV) drug for the treatment and pre-exposure prophylaxis of HIV infection that lends itself to depot formation following intradermal delivery but presents significant challenges when delivered via HF-MAPs, whose nature is aqueous. Herein, we have investigated, for the first time, the use of hydroxypropyl-β-cyclodextrin (HP-β-CD) to enhance the solubility of CAB-Na, and its effect on intradermal delivery via HF-MAPs. Accordingly, tablet reservoirs containing CAB-Na and HP-β-CD were formulated. These novel reservoirs were combined with two different HF-MAP formulations (MAP1 (Gantrez S97®+poly (ethylene glycol) 10,000+Na2CO3) and MAP2 (poly (vinyl pyrrolidone) 58kDa+poly (vinyl alcohol) 85-120kDa+citric acid)) to form fully integrated MAP devices which were tested in both ex vivo and in vivo settings. Ex vivo skin deposition results for MAP1 and MAP2 showed that 141±40μg and 342±34μg of CAB-Na was deposited into 0.5cm2 of excised neonatal porcine skin after 24h, respectively. Based on these findings, the in vivo pharmacokinetics of MAP2 were investigated over 28days using a Sprague-Dawley rat model. After 24h patch application, MAP2 demonstrated an extended drug release profile and an observed Cmax of 53.4±10.16μg/mL, superior to that of an FDA-approved CAB-nanosuspension administered via intramuscular application (Cmax of 43.6±5.3μg/mL). Consequently, this tablet integrated MAP device is considered to be a viable option for the intradermal delivery of hydrophobic anti-HIV drugs.