Voriconazole nanosuspension-loaded ocular bilayer dissolving microneedle patch for the management of fungal keratitis
Bibliographic record
Abstract
Fungal keratitis (FK), caused by fungi like Aspergillus, Fusarium, and Candida, accounts for 20-60% of microbial keratitis cases and over 1 million visual impairments annually. Voriconazole (VOR) is effective against FK, but its eye drop formulations suffer from poor bioavailability, while intrastromal injections are invasive and carry risks. This study aimed to address these challenges by formulating a VOR nanosuspension (NS) and fabricating an ocular bilayer dissolving microneedle array patch (dMAP) incorporating the VOR NS for localized drug delivery to the cornea. The VOR NS was prepared using an aqueous media milling method with polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) as stabilizer and cryoprotectant, resulting in stable nanosized particles with a mean size of 270.11 ± 5.82 nm and a PDI of 0.217 ± 0.019. The formulation demonstrated a 1.71-fold increase in saturation solubility and a high drug content (72.5%). Both VOR NS and free VOR were incorporated into the MAP tips using a two-layer casting method. The VOR NS-loaded bilayer dMAP exhibited higher drug content (118.84 ± 20.67 µg) compared to the free VOR-loaded bilayer dMAP (83.08 ± 2.69 µg). Additionally, they demonstrated superior mechanical strength, greater insertion depth (~ 390 μm), and faster tip dissolution in excised porcine corneal tissue (~ 5 min) compared to the free VOR-loaded bilayer dMAP. Ex vivo studies showed that the VOR NS-loaded bilayer dMAP deposited 47.38 ± 8.08 µg of drug into the porcine cornea, 2.31 times more than the free VOR-loaded bilayer dMAP (20.43 ± 6.11 µg), closely approximating the clinical dose used in VOR intrastromal injections (50 µg/0.1 mL). Furthermore, the disc diffusion assay revealed that VOR NS and VOR NS-loaded bilayer dMAP had greater antifungal activity against Candida albicans and Aspergillus fumigatus compared to free VOR and free VOR-loaded bilayer dMAP. Biocompatibility was confirmed through a human corneal epithelial cell viability assay, and ocular irritation potential was evaluated using the HET-CAM assay, revealing a safe and non-irritant profile. Thus, this innovative NS-MAP hybrid system offers efficient drug delivery with minimal invasiveness and could potentially improve therapeutic outcomes in the management of FK.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".