Efficient transdermal drug delivery via a lance-microneedle delivery system with thumb force application

Abstract

To address incomplete drug release in monolithic dissolving microneedle (DMN) patches caused by non-selective drug dispersion into the backing layer, this study employs the lance-inspired architecture to develop a lance-microneedle (LMN) patch. The LMN patch features a decoupled microshaft layer as the structural base and tip-loaded DMNs as dedicated drug reservoirs. The lance-inspired architecture endows DMNs with superior skin penetration capability, while integration with the accompanying springy applicator collectively achieves a stable DMN penetration depth of 1170 ± 100 μm. Complete dissolution and detachment of DMNs from the microshaft layer during insertion ensure complete payload release, thereby enabling precise transdermal delivery. In a semaglutide treatment experiment, Semaglutide-LMN patches applied to Sprague-Dawley rats effectively controlled glucose levels and moderated weight gain, highlighting the potential of the LMN delivery system in enhancing transdermal drug delivery efficacy.

Introduction

Intramuscular injections and oral medications are predominant methods for drug administration in humans [1]. However, intramuscular injections often cause pain or discomfort at the injection site. Oral medications, while convenient and user-friendly, suffer from reduced bioavailability due to the degradative effects of gastric acids and other digestive factors [2]. Transdermal drug delivery, which administers medications through the skin, is recognized as an effective and convenient alternative. This approach enhances bioavailability by avoiding first-pass metabolism and reducing drug degradation [[3], [4], [5]]. Dissolving microneedles (DMNs) constitute a groundbreaking advancement in transdermal drug delivery, engineered to effectively breach the skin barrier through a physical penetration mechanism [6]. Upon application, these DMNs encapsulate drugs [7], which are subsequently released gradually into the dermal layers as the DMNs dissolve [8,9]. This process not only simplifies drug administration but also significantly enhances drug bioavailability and provides a nearly pain-free experience [10], representing significant improvements over traditional delivery methods [11]. The effectiveness and versatility of DMNs have been demonstrated through their application in administering vaccines [12], hormones [13,14], and proteins [15] to humans, highlighting their potential for future healthcare applications. To enhance the drug delivery effectiveness of DMN patches, the researchers innovated the structure of the DMN patch to improve its adaptability to the characteristics of skin in different areas. For instance, Hang Ruan et al. designed a bilateral microneedle patch [16] to penetrate the nasal mucosal barrier, thereby improving drug delivery effectiveness in a single administration.

In the process of applying the DMN patch to human skin, the complex deformation of the skin limits the effective penetration of DMNs. The specific reasons can be summarized as follows: First, during microneedle insertion into the skin, the exerted pressure induces continuous compression and deformation of the dermis and epidermis, where insufficient microneedle length may hinder the ability to overcome the bulk elastic tissue compression of the skin. [17]. Second, non-axial pressure application (i.e., misalignment between the applied force and DMN orientation) induces downward skin deformation accompanied by lateral sliding, thereby generating off-axis forces that may lead to DMN bending or fracture. Finally, during DMN patch application, the elastic deformation of the skin acts as a buffer to the pressure applied on the patch, thereby diminishing the penetration efficiency of the DMNs. The superposition of these effects leads to significant variability in DMN penetration kinetics and depth distribution. Moreover, conventional DMN patches exhibit non-selective drug migration into the backing layer due to their monolithic design, which prevents drug confinement to the tips and results in incomplete drug release. These factors collectively and critically undermine intradermal drug delivery accuracy.

Employing the lance-inspired architecture, this study innovatively develops a lance-microneedle (LMN) patch (Fig. 1A) with a decoupled microshaft layer as the structural base and tip-loaded DMNs as dedicated drug reservoirs. The integration of the microshaft layer with DMNs achieves a total LMN length of 2250 μm, which provides sufficient mechanical support to overcome skin compression deformation, ensuring successful intradermal penetration. Furthermore, the integrated structural design between the microshaft layer and DMNs significantly enhances lateral resistance, maintaining DMN structural integrity during penetration. Additionally, the microshaft layer optimizes the mechanical transduction of externally applied pressure into axial penetration forces, thereby enhancing overall DMN penetration efficiency (Fig. 1B). To achieve precise transdermal drug delivery, the springy applicator is developed as an integrated component (Fig. 1C). The device is composed entirely of plastic components and utilizes the built-in elastic elements to achieve energy accumulation and release. This mechanism ensures that the LMN patch is propelled into the skin with controlled kinetic energy during each administration, reaching the predetermined penetration depth. Furthermore, the lance-inspired architecture improves the functional performance of the LMN patch by integrating dual-material properties between DMNs and microshafts to create a dissolution-driven detachment mechanism (Fig. 1D). For the DMN layer, we chose hydrophilic hyaluronic acid (HA) to form the drug carriers [18,19]. Hydrophobic polylactic acid (PLA) was selected to fabricate the microshaft layer. Once the LMN patch is applied to the skin, the DMNs dissolve under the influence of interstitial fluid and detach from the microshaft layer, releasing the encapsulated drugs, while the PLA microshaft layer maintains its integrity. This mechanism facilitates rapid DMN separation from the patch, establishing a foundation for precise drug delivery. Additionally, owing to the biodegradability of PLA through enzymatic action and its excellent biocompatibility [20,21], it helps minimize inflammatory or immune reactions that might occur upon contact between the LMN patch and the skin. The LMN delivery system, composed of the LMN patch and springy applicator, balances precise drug delivery with improved user comfort through simplified and accurate operability.

Semaglutide is a novel long-acting glucagon-like peptide-1 (GLP-1) analog designed to enhance insulin secretion and inhibit glucagon release [22,23]. In this study, we applied the Semaglutide-LMN patch to Sprague-Dawley (SD) rats using the LMN delivery system and monitored changes in glucose levels and body weight [24]. Results indicate that SD rats treated with the LMN patch showed reduced glucose levels 6 h post-application and less weight gain over seven days compared to controls. Given these findings, the LMN delivery system developed in this study demonstrates substantial potential for applications in transdermal drug delivery.

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Materials

Hyaluronic acid (HA, molecular weight <10,000 Da) was obtained from Shandong Kindscience Biotech Co., Ltd. Gentian violet solution was obtained from Jiangmen Hengjian Pharmaceutical Co., Ltd. Polydimethylsiloxane (PDMS) was obtained from Dongguan Tengda Silicone Technology Co., Ltd. Polylactic acid (PLA) grains were obtained from Guangdong Jinwei New Materials Technology Co., Ltd.

Zhiwei Luo, Shiming Du, Kangxun Zhao, Renhui Liao, Mengjia Chen, Xiaoping Cao, Xueqiu You, Efficient transdermal drug delivery via a lance-microneedle delivery system with thumb force application, Journal of Drug Delivery Science and Technology, Volume 111, 2025, 107165, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.107165.

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