Ultrafast-dissolving voriconazole-cyclodextrin complex-based ocular microneedle patch: a novel approach for the treatment of fungal keratitis

Abstract

Fungal keratitis (FK) is a leading cause of corneal blindness worldwide. Although voriconazole (VOR) is effective, its poor corneal permeability limits its topical use, whereas intrastromal injections are invasive and risky. Over the past 9 years, dissolving microneedle array patches (dMAPs) has emerged as a promising approach for ocular drug delivery; however, these methods face challenges in delivering poorly soluble drugs that can form depots within the cornea, delay drug release into surrounding tissues, and require longer application times than conventional methods, such as intrastromal injections and eye drops.

This study presents an ultrafast-dMAP incorporating a VOR/sulfobutylether-β-cyclodextrin (SBE-β-CD) inclusion complex as a novel ocular delivery system for localized FK treatment. The VOR/SBE-β-CD inclusion complex, prepared via freeze-drying, showed a marked increase in VOR solubility. Using an optimized concentration of inclusion complex, dMAPs were fabricated through a micromoulding technique, resulting in strong mechanical integrity and efficient insertion capability. Ex vivo studies on porcine eyes demonstrated complete dMAP tip dissolution within 15 s, which was significantly faster than that of conventional polymer-based dMAPs. Compared with the solution formulation, the dMAP resulted in a 3.06-fold increase in corneal drug permeation and a 2.2-fold increase in drug deposition.

Additionally, these compounds displayed potent in vitro antifungal activity against Candida albicans and Aspergillus fumigatus, which was attributed to improved drug solubility. Cytocompatibility and HET-CAM assays confirmed the nonirritant and biocompatible nature of the formulation. Overall, the present study, for the first time, reports a VOR/SBE-β-CD-based ultrafast-dMAP for ocular drug delivery, providing a minimally invasive and highly efficient alternative to conventional topical and intrastromal antifungal therapies. These findings demonstrate its strong potential for clinical translation, but further validation through in vivo studies is needed.

Introduction

Fungal infection of the cornea by pathogens such as Aspergillus, Fusarium, and Candida causes severe inflammation and tissue damage, often leading to vision loss or blindness (Wang et al., 2025). Globally, fungal keratitis (FK) affects 1–1.4 million people annually, with over 600,000 cases resulting in irreversible blindness (Brown et al., 2021). Risk factors include prolonged contact lenses use, corneal trauma, immune suppression, and preexisting ocular conditions (Atta et al., 2022). FK treatment relies on antifungal agents delivered topically, systemically, or via intrastromal/intracameral injection (Awad et al., 2024, Ghenciu et al., 2024). However, topical therapy provides <5% bioavailability due to tear clearance and limited permeability; systemic therapy may be toxic and ineffective at the corneal level; and intrastromal injection risks injury (Garg et al., 2018, Maharana et al., 2016). Voriconazole (VOR), a second-generation triazole, has broad antifungal activity against Aspergillus, Fusarium, and Candida, the main pathogens of FK. It works by inhibiting the fungal cytochrome P450-dependent enzyme lanosterol 14α-demethylase (CYP51) (Lee et al., 2009). It is currently used in clinical settings for the off-label treatment of recalcitrant FK when the first-line drug, natamycin, does not show efficacy. Although approved for systemic mycoses, no FDA-approved ophthalmic VOR formulation exists. Clinically, a 1% w/v topical ophthalmic solution is often compounded from the IV form. While topical delivery is noninvasive, precorneal loss from tear drainage and poor permeability limit bioavailability to <5%. Intrastromal injection (50 µg/mL) achieves higher corneal drug levels but is invasive and carries risks of complications, including permanent corneal damage (Konar et al., 2020, Soleimani et al., 2020, Zemba et al., 2023). These challenges highlight the need for advanced ocular delivery systems that improve VOR bioavailability and patient compliance.

Over the past 18 years, microneedle (MN) technology has evolved as a minimally invasive and highly promising approach for ocular drug delivery (Gade et al., 2024, Glover et al., 2023, Hutton et al., 2025, Jiang et al., 2008, Jiang et al., 2007). Among MN types, dissolving microneedle array patches (dMAPs) are notable for efficient drug delivery without residual sharps (Thakur Singh et al., 2017, Vora et al., 2023, Vora et al., 2021). The use of dMAPs for ocular drug delivery was first reported in 2016 (Thakur et al., 2016). Since then, several studies have developed dMAPs using water-soluble polymers such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and hyaluronic acid (HA) (Albadr et al., 2022, Alrbyawi et al., 2024, Faizi et al., 2024, Wu et al., 2023, 2022). Unlike conventional dosage forms such as eye drops, inserts, and contact lenses, these MN systems embed drugs within a dissolvable polymer matrix that dissolves upon corneal insertion, bypassing the tear film and epithelium for efficient local delivery (Aghaei et al., 2026, Gowda et al., 2025a). Research has demonstrated that dMAPs substantially improve corneal drug delivery compared with topical formulations and offer a safer, less invasive alternative to intrastromal injections while maintaining therapeutic drug levels (Mahfud et al., 2023, Putri et al., 2024, Shi et al., 2022).

Although dMAPs are designed to rapidly dissolve and release their drug payload into target ocular tissues, their typical dissolution times range from 60-300 s, which is significantly longer than the delivery duration of intrastromal injections, which are generally less than 20 s (Gowda et al., 2025a, Wu et al., 2022). Recent studies have demonstrated that the use of highly water-soluble cyclodextrins (CDs), such as sulfobutylether-β-cyclodextrin (SBE-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD), as standalone materials enables the fabrication of ultrafast-dMAPs for transdermal drug delivery (Wang et al., 2023, 2022). These CD-based systems exhibit much faster dissolution than conventional polymer-based dMAPs do and therefore could reduce the ocular drug delivery duration to just a few seconds. An additional limitation of conventional dMAPs lies in their frequent incorporation of poorly soluble drugs in their insoluble form. Upon application of dMAPs, these drugs can form depots within ocular tissues, leading to delayed release owing to their limited solubility (Gowda et al., 2025a, Wu et al., 2022). For instance, free VOR (MW: 349.31 g/mol) has a low aqueous solubility of 0.6–0.7 mg/mL. Our previous study on VOR NS-loaded dMAPs demonstrated drug depot formation upon application to the cornea (Gowda et al., 2025a). In contrast, CDs such as SBE-β-CD possess an intrinsic ability to improve the aqueous solubility of poorly soluble drugs. This property facilitates more efficient ocular drug delivery through dMAPs, preventing depot formation and promoting uniform drug dispersion. Importantly, the VOR/SBE-β-CD inclusion complex (Vfend® IV) has already received FDA approval for intravenous (IV) administration and has demonstrated clinical applicability in ophthalmic formulations, including eye drops and intrastromal injections. This existing regulatory endorsement supports the compatibility and translational potential of using the VOR/SBE-β-CD inclusion complex in ocular dMAP systems. Nevertheless, SBE-β-CD can self-associate and aggregate to form supramolecular crosslinked networks, which endow dMAPs with enhanced structural integrity and superior mechanical strength (Wang et al., 2022).

Therefore, the VOR/SBE-β-CD inclusion complex was developed and subsequently incorporated into dMAPs to enhance intracorneal drug delivery. This strategy aimed to address the limitations of conventional dMAPs and existing VOR ophthalmic formulations. Although some studies have developed SBE-β-CD-based dMAPs for ocular applications, they have used them in combination with conventional polymers such as PVA or PVP, which increases the MN dissolution time (Mahfufah et al., 2024). To the best of our knowledge, this is the first study to develop dMAPs using SBE-β-CD as a standalone matrix-forming material for ocular drug delivery and the first to employ an 8 × 2 MN configuration for this purpose. Previous studies employing arrays with higher needle densities, such as 10 × 10, have reported incomplete insertion at the peripheral regions, primarily attributed to the large, flat, and rigid nature of the dMAP baseplate (Hu et al., 2025). To address this limitation, the present work designed arrays with a lower needle density, specifically, an 8 × 2 arrangement comprising 16 MNs in total. The mechanical strength, insertion efficiency, dissolution behaviour, ex vivo corneal permeation and deposition, ocular irritation potential, cytocompatibility, and antifungal efficacy of the developed VOR/SBE-β-CD inclusion complex-based dMAPs were systematically evaluated. These results collectively demonstrate that the developed system offers a promising and localized approach for the effective management of FK.

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Materials

Voriconazole (MW = 349.3 Da) was purchased from Cangzhou Enke Pharma-Tech Co., Ltd. (Cangzhou, China). Captisol® (sulfobutylether beta-cyclodextrin, SBE-β-CD; degree of substitution ≈ 6.5) was kindly provided by CyDex Pharmaceuticals, Inc. (Kansas, USA). Phosphate-buffered saline (PBS, pH 7.4) was purchased from Sigma Aldrich (Dorset, UK). Parafilm® M (≈130 µm thickness), an olefin-based material, was purchased from Bemis® (Wisconsin, USA). Polydimethylsiloxane (MED-4011) was obtained from NuSil Technology, LLC (Carpinteria, USA). Liquid silicone rubber (SILASTIC™ RTV-4250-S) was obtained from WP Notcutt Ltd. (Surrey, UK). Ultrapure water was obtained via a water purification system from Elga PURELAB DV 25, Veolia Water Systems (Dublin, Ireland). All other chemicals and reagents used were of analytical grade.

B.H. Jaswanth Gowda, Anjali K. Pandya, Shilpkala Gade, Ross M. Duncan, Mohammed Gulzar Ahmed, Yiwei Tian, Ryan F. Donnelly, Raghu Raj Singh Thakur, Lalitkumar K. Vora, Ultrafast-dissolving voriconazole-cyclodextrin complex-based ocular microneedle patch: a novel approach for the treatment of fungal keratitis, International Journal of Pharmaceutics, Volume 699, 2026, 127001, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.127001.

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