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Published on: September 27, 2021
Ultrafast-dissolving voriconazole-cyclodextrin complex-based ocular microneedle patch: a novel approach for the
B H Jaswanth Gowda1, Anjali K Pandya2, Shilpkala Gade2
1Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to be University), Mangalore 575 018, Karnataka, India; School of Pharmacy, Queen's University Belfast, Medical Biology Centre, Belfast BT9 7BL, United Kingdom.
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.
Insights
This study developed ultrafast dissolving microneedle array patches (dMAPs) for fungal keratitis treatment. The novel voriconazole (VOR) system enhances corneal drug delivery, offering a safer, more effective alternative to current therapies.
Area of Science:
- Ophthalmology and Pharmaceutical Sciences
- Drug Delivery Systems
- Biomaterials
Background:
- Fungal keratitis (FK) is a major cause of corneal blindness globally.
- Current treatments like topical voriconazole (VOR) have poor corneal permeability, and intrastromal injections are invasive.
- Existing dissolving microneedle array patches (dMAPs) face challenges with poorly soluble drugs and prolonged release times.
Purpose of the Study:
- To develop a novel, ultrafast-dissolving microneedle array patch (dMAP) for enhanced ocular drug delivery of voriconazole (VOR).
- To improve VOR solubility and corneal permeation for effective fungal keratitis treatment.
- To create a minimally invasive alternative to conventional FK therapies.
Main Methods:
- Fabrication of an ultrafast-dMAP system incorporating a voriconazole/sulfobutylether-β-cyclodextrin (VOR/SBE-β-CD) inclusion complex using freeze-drying and micromoulding.
- Evaluation of dMAP mechanical integrity, insertion capability, and dissolution time in ex vivo porcine eyes.
- Assessment of corneal drug permeation and deposition compared to solution formulations.
- In vitro antifungal activity testing against Candida albicans and Aspergillus fumigatus.
- Cytocompatibility and irritation potential assessed via cell viability and HET-CAM assays.
Main Results:
- The VOR/SBE-β-CD inclusion complex significantly increased VOR solubility.
- Fabricated dMAPs exhibited strong mechanical integrity and efficient insertion.
- dMAPs dissolved completely within 15 seconds, significantly faster than conventional dMAPs.
- Corneal drug permeation increased 3.06-fold and deposition 2.2-fold compared to solution.
- The formulation showed potent in vitro antifungal activity and was confirmed to be non-irritant and biocompatible.
Conclusions:
- An ultrafast-dMAP incorporating a VOR/SBE-β-CD complex provides an efficient and minimally invasive ocular drug delivery system.
- This novel system significantly enhances corneal drug permeation and deposition for fungal keratitis treatment.
- The VOR/SBE-β-CD ultrafast-dMAP represents a promising alternative to current topical and intrastromal antifungal therapies, warranting further in vivo investigation.
