Fungal keratitis, a highly blinding eye disease, is caused by fungal infection of the cornea and second only to cataract in developing countries [1], [2]. The etiology of fungal keratitis is related to a variety of factors, including: post-traumatic infection, widespread use of antibiotics and hormones and low immunity to eye surgery infection[3]. At present, more than 100 kinds of fungi have been found to cause fungal keratitis and the main pathogens include Fusarium, Aspergillus and Candida[4]. Among them, Fusarium and Aspergillus are filamentous fungi and keratitis caused by these two pathogens is usually caused by injury to the cornea during outdoor work[5], [6]. The early symptoms of fungal keratitis are not obvious, only red eyes, eye pain, photophobia and tears. However, with the development of the disease, fungal keratitis will lead to corneal epithelial defects, corneal stroma gray or white infiltration, if not timely treatment may develop to corneal perforation, intraocular infection and even blindness[7].

The medications commonly used to treat fungal keratitis are polyenes (such as amphotericin B, natamycin) and azoles (such as voriconazole (VCZ), fluconazole, itraconazole)[8]. Among them, VCZ is a new triazole antifungal drug, which inhibits the growth and reproduction of fungi by blocking the synthesis of ergosterol. It has the characteristics of antibacterial spectrum, strong antifungal effect and good corneal permeability[9], [10], [11]. Compared with amphotericin B, fluconazole and itraconazole, VCZ has better antifungal activity, safety and tolerability[9]. However, due to the very poor solubility of VCZ and the poor stability of the solution in long-term storage, the VCZ dosage forms on the market are only tablets, capsules and sterile powders[12]. The methods for the treatment of fungal keratitis are oral administration, intravenous administration and topical eye drops. Among them, local eye drop administration has fewer systemic side effects than intravenous and oral administration. However, the VCZ eye drops for the topical treatment of fungal keratitis not only requires the preparation of sterile powder, but also has a low bioavailability (< 5 %) due to the special physiological structure of the eye[11], [13], [14]. These factors greatly limit the application of VCZ in the treatment of fungal keratitis.

In order to improve the ocular bioavailability of drugs, several new drug delivery strategies have been developed, including liposomes, nanoparticles, gels, and corneal stromal injection[15], [16], [17]. Corneal stromal injection is the direct injection of drugs into the corneal stroma layer, which provides a high drug concentration at the site of infection and has a good therapeutic effect. However, this behavior has a large risk and poor patient compliance[18]. Therefore, it is still necessary to find a safer and more effective way of ocular administration.

Soluble microneedle (MN) is a minimally invasive technology and has been widely used in the study of transdermal drug delivery in the past decade, resulting from that its advantages are safe, effective, painless and easy to administer. It can improve the bioavailability of the drug by penetrating the stratum corneum of the skin and then slowly dissolving to release the drug[19]. The advantages of soluble MN have also aroused the curiosity of researchers to explore whether they can be used for ocular drug delivery to overcome the corneal barrier and improve the ocular bioavailability of drugs. Roy[20] loaded liposomal amphotericin B into the tip of a soluble MN prepared by polyvinyl alcohol and polyvinylpyrrolidone for the treatment of fungal keratitis. Pharmacodynamic results showed that liposomal amphotericin B loaded MN was more effective in inhibiting fungal propagation than free amphotericin B eye drops and liposomal amphotericin B eye drops. Shi[21] has loaded fluconazole into soluble MN prepared by polylactic acid (PLA) and hyaluronic acid (HA) for the treatment of fungal keratitis. The MN can not only pierce the corneal epithelial cells, but also form a gel after dissolving, which can which can improve the bioavailability of the drug by prolonging the retention time in the eye. The pharmacodynamic results showed that the therapeutic effect of this MN on fungal keratitis was similar to that of intrastromal injection.

Although soluble MN prepared with hyaluronic acid has a good therapeutic effect, VCZ is difficult to dissolve in water-soluble HA due to its strong lipid solubility. Polyethylene glycol-15-hydroxystearate (HS-15) is a non-ionic surfactant, which can form micelles in water when its critical micellar concentration is exceeded. A large number of studies have shown that HS-15 can significantly improve the solubility of poorly soluble drugs in water and increase the absorption of drugs. Its micelles have small particle size, high drug loading capacity and stability, and can be used as a carrier for ocular drug delivery[22], [23], [24].

Combining the dual advantages of micelles and MN, and loading VCZ micelles into soluble MN, VCZ is present in the MN in the form of solid, avoiding the problem of instability of VCZ in aqueous solution. Therefore, in this work, an film hydration method was utilized to obtain VCZ-loaded HS-15 micelles, and then it was mixed with HA and polyvinylpyrrolidone K30 (PVP K30), which have good biocompatibility approved by Food and Drug Administration (FDA), to prepare soluble MN in a certain ratio[25]. The feasibility of VCZ-MN in the treatment of fungal keratitis was investigated by investigating its mechanical strength, corneal insertion, dissolution, corneal permeability and pharmacokinetics in rabbits. The finding of this study can provide a theoretical basis for the treatment of fungal keratitis with soluble MN.