In situ forming and mucoadhesive ophthalmic voriconazole/HPβCD hydrogels for the treatment of fungal keratitis

Díaz-Tomé, Victoria; García-Otero, Xurxo; Varela-Fernández, Rubén; Martín-Pastor, Manuel; Conde-Penedo, Andrea; Aguiar, Pablo; González‐Barcia, Miguel; Fernández‐Ferreiro, Anxo; Otero-Espinar, Francisco J.

doi:10.1016/j.ijpharm.2021.120318

Cited by 19 publications

(20 citation statements)

References 45 publications

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“…It is evident from the above molecular docking that the VRC molecule is completely embedded in the SBE-β-CD hydrophobic cavity with the orientation of the difluorophenyl ring (Phe) toward the wide rim and the triazole (Az) ring toward the narrow rim of the SBE-β-CD central cavity. In silico models of VRC complexed with HP-β-CD studied by Díaz-Tomé et al showed complete encapsulation of VRC in the CD cavity and was also in good agreement with NMR results . Miletic et al investigated the stability of VRC complexes with HP-β-CD via docking studies, which demonstrated that the inclusion of the difluorophenyl ring in the CD cavity resulted in the most stable inclusion compounds .…”

Section: Resultsmentioning

confidence: 70%

“…Also, the use of iv or oral route to treat ocular diseases involves unspecific drug absorption and blood retinal barrier (BRB) as the major constraint. Due to the lack of a treatment regimen, hospital pharmacies reformulate the commercial Vfend iv formulations for topical ocular delivery by diluting in the biocompatible ocular vehicles . However, shorter residence time associated with topical eye drops necessitates frequent dosing (every hour), which may increase the risk of side effects .…”

Section: Introductionmentioning

confidence: 99%

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Voriconazole–Cyclodextrin Supramolecular Ternary Complex-Loaded Ocular Films for Management of Fungal Keratitis

et al. 2021

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Fungal keratitis is one of the leading causes of ophthalmic mycosis affecting the vision due to corneal scarring. Voriconazole (VRC) is the most preferred azole antifungal agent for treating ocular mycotic infections. Ocular drug delivery is challenging due to the shorter corneal residence time of the formulation requiring frequent administration, leading to poor patient compliance. The present study aimed at improving the solubility, transcorneal permeation, and efficacy of voriconazole via the formation of cyclodextrin-based ternary complexes and incorporation of the complex into mucoadhesive films. A phase solubility study suggested a ∼14-fold improvement in VRC solubility, whereas physicochemical characterization confirmed the inclusion of VRC in the cyclodextrin inner cavity. In silico docking studies were performed to predict the docking conformation and stability of the inclusion complex. Complex-loaded films showed sustained release of voriconazole from the films and improved transcorneal permeation by ∼4-fold with an improved flux of 8.36 μg/(cm2 h) for ternary complex-loaded films compared to 1.86 μg/(cm2 h) for the pure VRC film. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and hen’s egg-chorioallantoic membrane test (HET-CAM) assays confirmed that the complexes and ocular films were nonirritant and safe for ocular administration. The antifungal study performed using Aspergillus fumigatus and Fusarium oxysporum suggested improved antifungal activity compared to the pure drug film. In conclusion, the supramolecular cyclodextrin ternary complex proved to be a promising strategy for enhancing the solubility and permeability and augmenting the antifungal activity of voriconazole in the management of fungal keratitis.

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Section: Resultsmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Voriconazole–Cyclodextrin Supramolecular Ternary Complex-Loaded Ocular Films for Management of Fungal Keratitis

et al. 2021

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“…The concentration of cyclodextrin (HPβCD) required to solubilize 1% ( w / v ) of voriconazole was established at 20% ( w / v ) in previous studies by using voriconazole solubility diagrams [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

“…The concentrations of both drugs were determined by the UHPLC method previously described (see the Ultra-High-Performance Liquid Chromatography section). Apparent permeability (Papp) and flux across the membrane were calculated as described in previous studies [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

Antifungal Combination Eye Drops for Fungal Keratitis Treatment

et al. 2022

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Fungal keratitis (FK) is a corneal mycotic infection that can lead to vision loss. Furthermore, the severity of FK is aggravated by the emergence of resistant fungal species. There is currently only one FDA-approved formulation for FK treatment forcing hospital pharmacy departments to reformulate intravenous drug preparations with unknown ocular bioavailability and toxicity. In the present study, natamycin/voriconazole formulations were developed and characterized to improve natamycin solubility, permanence, and safety. The solubility of natamycin was studied in the presence of two cyclodextrins: HPβCD and HPγCD. The HPβCD was chosen based on the solubility results. Natamycin/cyclodextrin (HPβCD) inclusion complexes characterization and a competition study between natamycin and voriconazole were conducted by NMR (Nuclear Magnetic Resonance). Based on these results, several eye drops with different polymer compositions were developed and subsequently characterized. Permeability studies suggested that the formulations improved the passage of natamycin through the cornea compared to the commercial formulation Natacyn®. The ocular safety of the formulations was determined by BCOP and HET-CAM. The antifungal activity assay demonstrated the ability of our formulations to inhibit the in vitro growth of different fungal species. All these results concluded that the formulations developed in the present study could significantly improve the treatment of FK.

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“…The addition of gelatin to a chitosan/β-glycerophosphate hydrogel can reduce the gelation temperature (to ∼34 °C) and prolong the release of a hydrophobic drug for weeks to months [ 38 ]. There have been many studies using different hydrogels as platforms for topical ophthalmic antibiotics and antifungal agents to treat keratitis [ 39 , 40 , 41 , 42 , 43 , 44 ]. However, none were applicated with chitosan/gelatin/β-glycerophosphate hydrogel.…”

Section: Introductionmentioning

confidence: 99%

Development of topical chitosan/ β-glycerophosphate-based hydrogel loaded with levofloxacin in the treatment of keratitis: An ex-vivo study

Chang

Cheng

et al. 2022

Heliyon

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Staphylococcus species are responsible for most cases of post-operative endophthalmitis. Topical ocular drug was applied for post-operative infection prevention, but the way of delivery encounters many challenges in terms of patient's compliance, drug efficacy, and drug penetration. We used the levofloxacin-loaded chitosan/gelatin/ β-glycerophosphate hydrogel sustained releasing system with good in vitro anti-bacterial efficacy and biocompatibility, which we had previously designed, for ex vivo keratitis model to test the preclinical drug efficacy and to determine drug level in the anterior chamber of the eye. The result showed that the ex-vivo corneal keratitis model with S. aureus infection revealed mild opacity over the central cornea with stromal infiltrate, but without obvious stromal infiltration post levofloxacin-loaded hydrogel treatment after 24 h of infection. Quantification of viable bacteria showed a significant anti-bacterial activity. The histological evidence also showed no visible S. aureus after levofloxacin-loaded hydrogel treatment, with a significant anti-inflammatory effect. We also examined the drug concentration in the aqueous humor 24 h after instilling one drop of the levofloxacin-loaded hydrogel. The concentration achieved to a desired drug level. These results suggested that by the ex-vivo model, levofloxacinloaded hydrogel can be applied for treatment in post-operative endophthalmitis or keratitis after the ophthalmic surgery.

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In situ forming and mucoadhesive ophthalmic voriconazole/HPβCD hydrogels for the treatment of fungal keratitis

Cited by 19 publications

References 45 publications

Voriconazole–Cyclodextrin Supramolecular Ternary Complex-Loaded Ocular Films for Management of Fungal Keratitis

Voriconazole–Cyclodextrin Supramolecular Ternary Complex-Loaded Ocular Films for Management of Fungal Keratitis

Antifungal Combination Eye Drops for Fungal Keratitis Treatment

Development of topical chitosan/ β-glycerophosphate-based hydrogel loaded with levofloxacin in the treatment of keratitis: An ex-vivo study

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