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

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) 58 kDa + poly (vinyl alcohol) 85–120 kDa + 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 ± 40 μg and 342 ± 34 μg of CAB-Na was deposited into 0.5 cm2 of excised neonatal porcine skin after 24 h, respectively. Based on these findings, the in vivo pharmacokinetics of MAP2 were investigated over 28 days using a Sprague-Dawley rat model. After 24 h patch application, MAP2 demonstrated an extended drug release profile and an observed Cmax of 53.4 ± 10.16 μg/mL, superior to that of an FDA-approved CAB-nanosuspension administered via intramuscular application (Cmax of 43.6 ± 5.3 μg/mL). Consequently, this tablet integrated MAP device is considered to be a viable option for the intradermal delivery of hydrophobic anti-HIV drugs.

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Materials

Cabotegravir sodium (CAB-Na) and cabotegravir long-acting (CAB LA) vials for intramuscular injection (CAB LA, 400 mg/2 mL) were provided by ViiV Healthcare (Brentford, UK). Polyvinylalcohol (PVA) molecular weight (m/w) of 85–120 kDa, 87%–89% hydrolysed, polyethyleneglycol (PEG) 10,000, Na2CO3 (sodium carbonate), acetonitrile (ACN) (HPLC grade), trifluoracetic acid, heparin, isoflurane, formic acid, citric acid, and phosphate buffered saline (PBS, pH 7.4) tablets were purchased from Sigma-Aldrich (Dorset, U.K). Gantrez® S-97(copolymer of methylvinylether and maleic acid 1500 kDa (m/w)), polyvinylpyrrolidone (PVP) K29–32 (58 kDa m/w) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) Cavitron™ W7HP7 Pharma were gifted from Ashland Inc. (Kidderminster, U.K.). All other materials and chemicals were of analytical reagent grade.

Fabiana Volpe-Zanutto, Lalitkumar K. Vora, Ismaiel A. Tekko, Peter E. McKenna, Andi Dian Permana, Akmal H. Sabri, Qonita K. Anjani, Helen O. McCarthy, Alejandro J. Paredes, Ryan F. Donnelly,
Hydrogel-forming microarray patches with cyclodextrin drug reservoirs for long-acting delivery of poorly soluble cabotegravir sodium for HIV Pre-Exposure Prophylaxis,
Journal of Controlled Release, Volume 348, 2022, Pages 771-785, ISSN 0168-3659,
https://doi.org/10.1016/j.jconrel.2022.06.028.


See also a poster presented by Fabiana Volpe-Zanutto on the topic:

Hydrogel-forming microarray patches with cyclodextrin drug reservoirs to enhance the long-acting delivery of the poorly soluble anti-HIV drug cabotegravir sodium
Hydrogel-forming microarray patches with cyclodextrin drug reservoirs to
enhance the long-acting delivery of the poorly soluble anti-HIV drug cabotegravir sodium
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