Assessment of leachables and extractables in “super-swelling” hydrogel-forming microarray patches

Abstract

Hydrogel-forming microarray patches (MAPs) offer a minimally invasive platform for transdermal drug delivery, enabling systemic absorption of active pharmaceutical ingredients. Unlike dissolving MAPs, which deposit their entire polymer matrix into the skin, hydrogel-forming MAPs remain intact upon removal, reducing polymer exposure while delivering higher drug doses than dissolving or coated MAPs. Moreover, they have demonstrated excellent biocompatibility and do not cause skin or systemic issues, even with repeated application in humans. This study assessed the leachable and extractable compounds from hydrogel-forming MAPs composed of Gantrez^® S-97, PEG 10,000, and sodium carbonate under various conditions. Under physiological conditions (37°C in water), minimal PEG 10,000 leaching (10.4 ± 2.0%) and negligible Gantrez^® S-97 extraction (< 2%) confirmed the hydrogel matrix’s stability and safety. However, stress testing in DMSO at 70°C led to increased PEG 10,000 extraction (up to 32.9 ± 6.1%) and minor Gantrez^® S-97 degradation, likely due to ester hydrolysis. These findings highlight the robustness of hydrogel-forming MAPs, ensuring minimal systemic exposure to unbound polymers while maintaining effective drug delivery. The results support their potential for chronic therapeutic applications requiring repeated dosing. Further clinical studies are needed to validate these findings, facilitating regulatory approval and broader adoption across diverse medical applications.

Introduction

Hydrogel-forming microarray patches (MAPs) represent an advanced transdermal drug delivery platform, providing a minimally invasive method for systemic absorption of active pharmaceutical ingredients. These MAPs are produced through a crosslinking process between hydrophilic polymers and a crosslinking agent, forming an insoluble yet swellable polymer network due to ester bond formation during crosslinking [1]. Upon application to the skin, they absorb interstitial fluid, causing the hydrogel matrix to swell, which facilitates drug diffusion from an attached reservoir layer into the dermal microcirculation, ultimately achieving systemic absorption [2]. Unlike other MAP types, hydrogel-forming MAPs do not contain active compounds within the needle structure [3, 4], instead, drugs are stored in a separate reservoir positioned on top of the patch. This design enables the delivery of high doses of a wide range of compounds [1, 3, 5,6,7,8,9,10,11,12]. Hydrogel-forming MAPs remain macroscopically intact even after five days of application [13, 14]. Previous studies have demonstrated their excellent biocompatibility [5], with no reported skin irritation or systemic adverse effects, even after repeated applications in humans [15].

We have previously demonstrated that Gantrez® S-97, crosslinked with PEG 10,000, possesses the capability, in terms of mechanical strength, to pierce the stratum corneum [16]. The term’super swelling’was used due to the addition of anhydrous sodium carbonate (Na2CO3) as a modifying agent, which reduces the ester-based crosslinking through the formation of sodium salt with the free acid groups of Gantrez® S-97 [16]. The ability of super swelling hydrogel-forming MAPs to deliver a range of drugs with diverse physicochemical properties has been reported [3, 7, 16,17,18]. Furthermore, our extensive studies have demonstrated that hydrogel-forming MAPs are biocompatible, possess intrinsic antimicrobial characteristics, and inhibit microbial proliferation [2, 19, 20]. Repeat application of these MAPs to the skin of human volunteers, followed by a 24-h retention period, did not result in any adverse effects on skin barrier function, skin appearance, or systemic indicators of infection, immunity, inflammation, or allergies [21]. We have also shown that human volunteers can consistently insert these MAPs into their own skin, even when the patch size exceeds the conventional range of 1–2 cm2 normally observed in microneedle systems [20, 22, 23].

Given the performance of hydrogel-forming MAPs, which absorb interstitial fluid before facilitating drug permeation from the reservoir into deeper skin layers, it is crucial to assess the compounds released during the swelling process. While the materials used in the fabrication of hydrogel-forming MAPs, such as poly(ethylene glycol) (PEG) and Gantrez® S-97, are components of approved drugs and medical products, respectively, there remains a possibility that polymers released from the system could enter systemic circulation and be primarily excreted via the kidneys. However, it is widely recognised that glomerular filtration retains substances with a high molecular weight (cutoff 30–50 kDa) [24]. Given that Gantrez® S-97 has a molecular weight of 1,200 kDa, its potential filtration by the glomerulus warrants careful consideration. Therefore, determining leachable and extractable compounds is essential for the translation of this technology, a focus addressed for the first time in this study. Extractables are defined as organic or inorganic chemical entities that can be released from a material under exaggerated conditions, such as strong solvents, elevated temperatures, or prolonged exposure, and are used to simulate worst-case scenarios [25, 26]. In contrast, leachables are compounds that migrate from the material under normal use conditions, such as during application to the skin or contact with biological tissues, and therefore represent actual patient exposure [25,26,27]. Identifying and quantifying potential leachables, compounds that may migrate into the patient during normal use, provides critical safety insights for hydrogel-forming MAPs [28, 29].

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Materials

Gantrez® S-97, with a molecular weight of 1,200 kDa is a copolymer of methylvinylether and maleic acid (PMVE/MA) and was supplied by Ashland (Kidderminster, UK). Phosphate buffered saline (PBS) tablets with a pH of 7.4, polyethylene glycol (PEG) with a molecular weight of 10 kDa, dimethyl sulfoxide (DMSO) and sodium bicarbonate were purchased from Sigma-Aldrich (Dorset, UK). A water purifying system produced ultrapure water (Elga PURELAB DV 25, Veolia Water Systems, Dublin, Ireland).

Anjani, Q.K., McKenna, P.E., Larrañeta, E. et al. Assessment of leachables and extractables in “super-swelling” hydrogel-forming microarray patches. Drug Deliv. and Transl. Res. (2025). https://doi.org/10.1007/s13346-025-01880-2

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