Hydrogel-forming microarray patches with solid dispersion reservoirs for transdermal long-acting microdepot delivery of a hydrophobic drug

Hydrogel-forming microarray patches (HF-MAPs) are used to circumvent the skin barrier and facilitate the noninvasive transdermal delivery of many hydrophilic substances. However, their use in the delivery of hydrophobic agents is a challenging task. This work demonstrates, for the first time, the successful transdermal long-acting delivery of the hydrophobic atorvastatin (ATR) via HF-MAPs using poly(ethylene)glycol (PEG)-based solid dispersion (SD) reservoirs. PEG-based SDs of ATR were able to completely dissolve within 90 s in vitro. Ex vivo results showed that 2.05 ± 0.23 mg of ATR/0.5 cm² patch was delivered to the receiver compartment of Franz cells after 24 h.

The in vivo study, conducted using Sprague Dawley rats, proved the versatility of HF-MAPs in delivering and maintaining therapeutically-relevant concentrations (> 20 ng·mL⁻¹) of ATR over 14 days, following a single HF-MAP application for 24 h. The long-acting delivery of ATR suggests the successful formation of hydrophobic microdepots within the skin, allowing for the subsequent sustained delivery as they gradually dissolve over time, as shown in this work. When compared to the oral group, the use of the HF-MAP formulation improved the overall pharmacokinetics profile of ATR in plasma, where significantly higher AUC values resulting in ∼10-fold higher systemic exposure levels were obtained.

Highlights

• A novel method for the transdermal depot delivery of hydrophobic agents through hydrogel-forming microarray patches.
• The incorporation of ATR in PEG-based SD reservoirs was effective in facilitating its transdermal delivery via HF-MAPs.
• A single application of HF-MAPs for 24 h in vivo resulted in a sustained release of therapeutic levels of ATR over 2 weeks.
• In vivo studies results had proven, for the first time, the depot formation of ATR within the skin.

This novel system offers a promising, minimally-invasive, long-acting alternative delivery system for ATR that is capable of enhancing patient compliance and therapeutic outcomes. It also proposes a unique promising platform for the long-acting transdermal delivery of other hydrophobic agents.

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Materials

Atorvastatin hemicalcium trihydrate was purchased from Cangzhou Enke Pharma-tech Co., Limited, Hebei Province, China. Gantrez® S-97, a copolymer of methylvinylether and maleic acid (PMVE/MA) with a molecular weight of 1500 kDa, was gifted by Ashland, Kidderminster, UK. Poly (ethylene glycol) (PEG) with average MWs of 10,000, 8000, 6000, 600, 400, and 200 Da, methanol and acetonitrile for high-performance liquid chromatography (HPLC), phosphate-buffered saline (PBS) pH 7.4 tablets, and sodium carbonate (Na₂CO₃) were all purchased from Sigma–Aldrich, Dorset, UK. All other chemicals used were of analytical reagent grade.

Yara A. Naser, Ismaiel A. Tekko, Lalitkumar K. Vora, Ke Peng, Qonita K. Anjani, Brett Greer, Christopher Elliott, Helen O. McCarthy, Ryan F. Donnelly, Hydrogel-forming microarray patches with solid dispersion reservoirs for transdermal long-acting microdepot delivery of a hydrophobic drug, Journal of Controlled Release, Volume 356, 2023, Pages 416-433, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2023.03.003.