PowderInjector microneedles: smart cavity microneedles as a novel intradermal delivery system for high doses of niacinamide

Abstract

Niacinamide (NIA) is widely used in cosmetic formulations due to its anti-inflammatory and antioxidant properties. However, its hydrophilic nature (log p =  − 0.35) limits penetration through the stratum corneum (SC), necessitating advanced delivery systems. While formulation-enhancement technologies (penetration enhancers, liposomes) still face the SC diffusion barrier, dissolving microneedles (DMNs) bypass the SC. As micron-scale needles made from biocompatible polymers in which the cargo is incorporated, DMNs can limit cargo loading capacity and can compromise stability.

Therefore, the aim of this study was to develop novel high-loading ‘’PowderInjector’’ DMNs (powder-laden, cavity DMNs). Hence, traditional DMNs with NIA in the polymeric matrix (D1) were compared to cavity DMNs containing NIA in powder form only (D2) and cavity DMNs with a concentrated NIA shell and powder-filled cavity (D3). The DMNs were evaluated for mechanical properties, insertion efficiency, dissolution time, loading capacity and intradermal delivery.

The cavity DMNs demonstrated well-defined powder cores up to 0.6 mm (approximately 50 %) of the needle length. NIA content was 3-fold higher in D3 (∼2060 ± 288 µg) compared to D1 (711 ± 286 µg), with better preservation of NIA crystallinity. All DMNs had sufficient structural integrity for insertion with enhanced efficiency in the cavity DMNs. NIA flux rates within the skin were higher in D3 (272.14 ± 48.20 μg/cm²/h) compared to the serum (37.95 ± 16.07 μg/cm²/h) used as a control. Moreover, D3 achieved higher NIA deposition in the dermis (3.778 ± 1.982 %) in comparison to the serum (0.203 ± 0.124 %).

Results demonstrated that PowderInjector DMNs offer a novel platform for enhanced topical delivery of NIA in the stable powder form, combining higher loading capacity with improved transdermal delivery and skin deposition.

Introduction

The skin, the body’s outermost and largest organ, functions as a sophisticated and dynamic interface, mediating the complex interplay between our internal physiological environment and the external world (Costeris et al., 2021, Fink et al., 2006, Fink et al., 2001, Jaeger et al., 2018, Tuckman, 2017). Its critical roles in protecting against environmental factors, regulating body temperature, and processing sensory information underscore its paramount importance in maintaining overall health and well-being. In the contemporary landscape of cosmetic science, the pursuit of healthy, youthful, and aesthetically pleasing skin has become a central objective, driving the relentless development of innovative topical formulations (Costeris et al., 2021, Fink et al., 2006, Fink et al., 2001, Jaeger et al., 2018, Tuckman, 2017). The desire for flawless skin is not merely a matter of vanity, but reflects a deeper societal emphasis on self-care, well-being, and the projection of a positive self-image (Huang et al., 2022). Consequently, the cosmetic industry has witnessed a surge in demand for products that can effectively address a multitude of dermatological concerns and enhance skin’s natural beauty.

Among the plethora of active ingredients employed in modern skincare, niacinamide (NIA), a biologically active form of vitamin B3, has emerged as a cornerstone due to its remarkable versatility and efficacy (Marques et al., 2024, Ong and Goh, 2024). This compound exhibits a wide array of beneficial properties, including potent anti-inflammatory, antioxidant, regulation of sebum production, enhancement of skin barrier function through role in ceramide synthesis and stimulation of collagen and elastin production. Furthermore, NIA has skin-brightening effects, making it an indispensable component in formulations designed to combat acne vulgaris, rosacea, hyperpigmentation, and the visible signs of aging, such as fine lines and wrinkles. However, the therapeutic potential of NIA is significantly hampered by the inherent barrier function of the stratum corneum (SC), the outermost layer of the skin (Nowak et al., 2020, Somboon et al., 2025). This layer, composed of tightly packed corneocytes embedded in a complex lipid matrix, acts as a formidable obstacle to the penetration of exogenous substances, including NIA.

The challenge of delivering NIA effectively to the deeper layers of the skin, where it can exert its therapeutic effects, is further exacerbated by its hydrophilic nature. While this property is advantageous for its water solubility and biological activity, it significantly limits its ability to passively diffuse through the lipophilic environment of the SC. Traditional topical formulations, such as creams, lotions, and serums, often struggle to overcome this barrier, resulting in low bioavailability of NIA at the target sites (Ong and Goh, 2024). Consequently, these formulations necessitate the use of high concentrations of the active ingredient to achieve therapeutic efficacy, which can lead to skin irritation, sensitization, and reduced patient compliance due to the discomfort associated with frequent applications and prolonged exposure (Bissett et al., 2009).

Beyond the challenges posed by the skin barrier function and NIA hydrophilicity, the development of effective delivery systems is further complicated by the inherent limitations of conventional nanoformulations. While nanotechnology has offered promising avenues for enhancing drug delivery, the application of nanocarriers, such as liposomes, nanoparticles, and nanoemulsions, for NIA delivery presents its own set of challenges (Basto et al., 2021, Dewi et al., 2024, Offerta et al., 2016, Ong and Goh, 2024, Pelikh et al., 2019). These include issues related to the limited encapsulation efficiency, stability and controlled release of NIA from the nanocarriers, as well as the potential for aggregation and premature drug leakage. Moreover, the penetration of nanocarriers through the SC is still subject to the same barrier limitations, and their effectiveness is often dependent on their size, surface charge, and composition (Abraham et al., 2024). The use of serum-based formulations, while popular, also suffers from similar drawbacks, including limited penetration and the need for frequent reapplication, often leading to a “tacky” feel and poor user experience.

To circumvent the limitations of traditional topical formulations and nanoformulations, microneedle (MN) technology has emerged as a revolutionary approach for transdermal drug delivery (Bae et al., 2022, Hakozaki et al., 2006, Lv et al., 2023, Shin et al., 2019, Zhou and Banga, 2011). MNs are miniature devices, typically fabricated from biocompatible polymers, that feature an array of micron-sized needles designed to create transient microchannels in the SC (Gupta et al., 2011, Li et al., 2025, Ripolin et al., 2017). These channels provide a direct pathway for the delivery of therapeutic agents into the viable epidermis and dermis, bypassing the skin barrier function and enhancing drug bioavailability (Dawud and Abu Ammar, 2023). MNs offer several advantages over conventional topical formulations, including the ability to achieve targeted and controlled drug delivery, reduce systemic exposure, and improve patient compliance due to their minimally invasive nature (Brogden et al., 2012, Coulman et al., 2009, Kim et al., 2014). The concept of MNs is rooted in the principle of creating temporary disruptions in the skin barrier, allowing for direct access to the underlying tissues (Haq et al., 2009). These disruptions, while creating pathways for drug delivery, are designed to be minimally invasive, causing minimal discomfort and rapidly healing. The needles, typically ranging in length from tens to hundreds of micrometers, are carefully designed to penetrate the SC without reaching nerve endings or blood vessels, ensuring a painless and safe delivery experience (Brogden et al., 2013, Morris et al., 2023, Prausnitz, 2004).

Despite the significant advancements in MN technology, challenges persist in achieving efficient and controlled delivery of NIA, particularly in high doses. Current MN designs often rely on the encapsulation of NIA within polymeric matrices, which can limit the drug loading capacity and control over release kinetics (Quinn and Donnelly, 2018). The use of liquid-based formulations for MN fabrication, while offering flexibility in drug incorporation, can lead to drug instability, particularly for sensitive hydrophilic molecules like NIA, and necessitate complex processing steps, such as lyophilization or solvent evaporation. Furthermore, the release of NIA from polymeric matrices can be influenced by factors such as polymer degradation, swelling, and diffusion, which can result in unpredictable release profiles and suboptimal therapeutic outcomes.

To address these multifaceted limitations, this study, for the first time, introduces ‘’PowderInjector’’ microneedles, a novel intradermal delivery system featuring smart cavity microneedles designed for the efficient delivery of high dose NIA powder. These microneedles are fabricated with thin polymeric shells and small polymeric tips, minimizing the polymer content, this cavity design is considered smart as it protects the drug in its intact form (i.e., without chemical interaction with the matrix) and facilitates rapid shell dissolution in response to skin interstitial fluid. This responsive behaviour enables precise, targeted deposition of NIA powder directly into deeper skin layers, where it dissolves in situ. The design thus integrates passive structural optimization with biologically responsive release, enhancing both delivery efficiency and drug stability. By directly encapsulating NIA powder within the smart cavities of the MN structure, we aim to significantly enhance drug loading capacity, achieve precise control over release kinetics, and thereby improve the overall therapeutic efficacy of NIA delivery to the skin. This innovative approach offers substantial advantages over conventional MN designs, including simplified high-dose drug loading that eliminates complex encapsulation processes, tailored controlled release through optimized MN material selection and fabrication, and the enhanced stability afforded by the powder form of NIA (Chen et al., 2017, He et al., 2024, Kim et al., 2020). Furthermore, the smart cavity microneedles, engineered for targeted intradermal deposition, minimize surface drug loss and reduce the risk of skin irritation seen in topical formulations (Bissett et al., 2009). Therefore, this study aims to demonstrate the feasibility and efficacy of PowderInjector microneedles as a novel intradermal delivery system for high-dose NIA powder, paving the way for more effective and patient-friendly dermatological applications. By overcoming the limitations of current delivery systems, this research seeks to establish PowderInjector microneedles as a superior method for enhancing skin health and aesthetics through precise intradermal NIA delivery. Therefore, in this study, novel, high-load, powder-laden cavity dissolving microneedles (DMNs) (i.e. of PowderInjector microneedles) were developed. To evaluate their performance, traditional DMNs, where NIA was dissolved within the polymeric matrix (D1), were compared to cavity DMNs containing NIA in powder form only (D2) and cavity DMNs containing NIA in powder form combined with a concentrated NIA shell (D3). All fabricated DMNs were subsequently characterized regarding their morphology, mechanical properties, insertion profile, dissolution time, drug loading, weight variation, chemical interactions, and thermal stability. The intradermal delivery of NIA using the powder-laden cavity DMNs with the highest concentration was compared to that of NIA serum.

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Materials

Poly(vinyl alcohol) (PVA) of two molecular weights (9–10 kDa and 31–50 kDa), methanol (HPLC-grade), niacinamide (NIA), 2,2-diphenyl-1-picrylhydrazyl (DPPH), gallic acid (GA) and phosphate buffered saline (PBS) tablets were obtained from Sigma-Aldrich (ENG, UK). Polyvinylpyrrolidone (PVP, Plasdone™ K-29/32) was sourced from Ashland (ENG, UK). High transparency resin (405 nm) was obtained from NOVA3D (ENG, UK). Niacinamide 10 % serum was purchased from The Ordinary (ON, Canada). Ultrapure water was obtained from a water purification system (ELGA PURELAB DV 25, Veolia Water Systems, DUB, Ireland).

Abraham M. Abraham, Oluwamayowa Emmanuella Afolabi, Qonita Kurnia Anjani, Ryan F. Donnelly, PowderInjector microneedles: smart cavity microneedles as a novel intradermal delivery system for high doses of niacinamide, International Journal of Pharmaceutics, Volume 683, 2025, 125992, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125992.