Amphotericin B PLGA nanoparticles loaded dissolving microneedle patches in treating cutaneous fungal infections

Abstract

Cutaneous fungal infections pose a significant health challenge, particularly in deeper skin layers where topical treatments are ineffective. Amphotericin B (AmB) is the gold standard for treating fungal infections, but its poor solubility limits its transdermal delivery. In this work, AmB was loaded into polylactic-co-glycolic acid nanoparticles (PLGA NP) via the solvent deposition method. The resulting NP had an average size of 311.54 ± 2.08 nm and a polydispersity index (PDI) of 0.22 ± 0.12. After reconstitution, the particle size decreased to 209.89 ± 1.10 nm, with a PDI of 0.10. The encapsulation efficiency was 98.59 ± 0.10%. These AmB-loaded PLGA NP were then incorporated into dissolving microneedles (MNs) using a sequential loading method. The MNs demonstrated adequate mechanical strength to deliver the NP into the deep dermal layers, with an insertion depth of 363.5 μm and a height reduction of only 3.56 ± 2.10% under compression. In vitro release studies revealed an initial burst release of 60% within 1 h, followed by a slower release over four days. Ex vivo skin deposition and permeation studies demonstrated remarkable deposition of the drug into the dermis skin layers. This delivery system offers significant potential for treating cutaneous fungal infections, combining the benefits of sustained drug release and targeted delivery to deep skin layers.

Introduction

Cutaneous fungal infections represent a significant burden on global public health, affecting 20–25% of the population [1]. These infections, which are caused primarily by various fungal species belonging to dermatophytes, yeasts and molds, manifest predominantly on the skin, hair and nails. Superficial infections, which typically affect the outermost layers of the skin, can be managed by topical formulations. However, infections that penetrate the dermis in deep tissues and sometimes extend into subcutaneous tissues pose great therapeutic challenges in diagnosis and management because of their depth and potential resistance to standard antifungal agents used for superficial infections [2]. Currently, the available topical therapies are not efficient at permeating the skin barrier and thus cannot concentrate the drug within the area of the infection. Systemic therapies (oral or intravenous) are often the treatment of choice even though they fail to result in a high local concentration in the skin and lead to potential systemic toxicity as well as interactions with other medications [3].

As an alternative, microneedles (MNs), featuring micron-sized needles (25–2000 μm in height) arranged in an array, offer a minimally invasive alternative to enhance the permeability of drugs or drug formulations into deeper layers of the skin [4]. These patches can breach the skin barrier directly with sharp needles that are short enough to ensure painless application, facilitating self-administration. MNs are categorized into various types depending on their delivery mechanisms and materials, including hollow, solid, coated, dissolving, and hydrogel subtypes [5]. Dissolving MNs are designed to dissolve upon application to the skin, thereby efficiently releasing their payload without leaving residual materials [6]. This design, which uses water-soluble materials as matrices, allows rapid drug or formulation delivery into the deep skin layers through matrix dissolution, thereby eliminating any risk of sharp hazards [7].

Antifungal agents often require prolonged administration for both clinical and mycological treatment. Long-acting formulations provide advantages by enabling constant antibiotic delivery to the infection sites and sustaining drug release over time. This approach maintains consistent drug levels that effectively inhibit microbes, reducing the necessity for frequent administration [8]. Additionally, it maximizes antibiotic therapeutic effects while minimizing the development of antibiotic resistance. Polymeric nanoparticles (NP) have shown great potential for optimizing pharmacokinetics (including prolonged release of the drug with tissue retention), improving efficacy and enhancing compliance. Additionally, they offer clear advantages, such as prolonged shelf-life at room temperature and lower production costs compared with lipid formulations [9]. Among polymeric NP, those based on poly(lactic-co-glycolic acid) (PLGA) stand out because of their nontoxicity, biodegradability and biocompatibility [[10], [11], [12]].

Amphotericin B (AmB), a potent macrolide polyene antifungal agent with a long history of use, remains the ‘gold standard’ therapy for invasive fungal infections because of its relatively broad spectrum of activity and minimal resistance development [13]. As an asymmetrical, cyclic molecule with one hydrophobic and one hydrophilic face, AmB is notorious for its very limited solubility and permeability profile, resulting in neglected oral bioavailability. Permeation through the stratum corneum via conventional transdermal formulations is limited to drugs with molecular weights of less than 500 Da and balanced lipophilicity. Therefore, AmB is predictably difficult to permeate through the skin because of its physicochemical characteristics and high molecular weight (924 Da) [14]. MNs patches present a promising platform for enhancing intradermal delivery of this ‘difficult to deliver’ therapy [[15], [16], [17]]. Here, we loaded AmB into PLGA NP and then incorporated the AmB PLGA NP into dissolving MNs for the treatment of cutaneous fungal infections.

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Materials

PLGA with a 50:50 M ratio of lactide:glycolide (inherent viscosity: 0.55–0.75 dL/g) was purchased from Lactel® (Birmingham, AL, USA). AmB was supplied by Cayman Chemical Company (purity specification ≥95%, Ann Arbor, MI, USA). Poly(vinyl alcohol) MW 9–10 kDa (PVA), Kolliphor® HS 15 (Solutol) and sodium lauryl sulfate (SLS) were both obtained from Sigma-Aldrich (Poole, Dorset, UK). Plasdone™ K-29/32 (poly(vinylpyrrolidone), PVP), (MW 58 kDa) was obtained from Ashland (Kidderminster, UK). Dimethyl sulfoxide (DMSO) and glycerine were acquired from VWR International Limited, Leicestershire, UK. All reagents were of analytical grade unless otherwise stated.

Ke Peng, Aiman Abu Ammar, Achmad Himawan, Xianbing Dai, Ross Duncan, Brendan F. Gilmore, Ryan F. Donnelly, Lalitkumar K. Vora, Amphotericin B PLGA nanoparticles loaded dissolving microneedle patches in treating cutaneous fungal infections, Journal of Drug Delivery Science and Technology, Volume 106, 2025, 106697, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.106697.

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