Antifungal Combination Eye Drops for Fungal Keratitis Treatment

Díaz-Tomé, Victoria; Bendicho-Lavilla, Carlos; García-Otero, Xurxo; Varela-Fernández, Rubén; Martín-Pastor, Manuel; Llovo-Taboada, José; Alonso-Alonso, Pilar; Aguiar, Pablo; González-Barcia, Miguel; Fernández-Ferreiro, Anxo; Otero-Espinar, Francisco J.

doi:10.3390/pharmaceutics15010035

Open AccessArticle

Antifungal Combination Eye Drops for Fungal Keratitis Treatment

by

Victoria Díaz-Tomé

^1,2,3,4

,

Carlos Bendicho-Lavilla

^1,2,3,

Xurxo García-Otero

^1,2,3,5

,

Rubén Varela-Fernández

¹

,

Manuel Martín-Pastor

⁶

,

José Llovo-Taboada

⁷,

Pilar Alonso-Alonso

⁷,

Pablo Aguiar

⁵,

Miguel González-Barcia

⁸,

Anxo Fernández-Ferreiro

^4,8,*

and

Francisco J. Otero-Espinar

^1,2,3,*

¹

Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), 15705 Santiago de Compostela, Spain

²

Institute of Materials iMATUS, University of Santiago de Compostela (USC), 15706 Santiago de Compostela, Spain

³

Paraquasil Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain

⁴

Clinical Pharmacology Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain

⁵

Molecular Imaging Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain

⁶

Nuclear Magnetic Resonance Unit, Research Infrastructures Area, Universidade de Santiago de Compostela Campus Vida, 15705 Santiago de Compostela, Spain

⁷

Microbiology Department, University Clinical Hospital Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain

⁸

Pharmacy Department, University Clinical Hospital Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain

^*

Authors to whom correspondence should be addressed.

Pharmaceutics 2023, 15(1), 35; https://doi.org/10.3390/pharmaceutics15010035

Submission received: 10 November 2022 / Revised: 12 December 2022 / Accepted: 20 December 2022 / Published: 22 December 2022

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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Abstract

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.

Keywords: fungal keratitis; cyclodextrin; natamycin; voriconazole; PET/CT imaging; nuclear magnetic resonance; cyclodextrin aggregates

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MDPI and ACS Style

Díaz-Tomé, V.; Bendicho-Lavilla, C.; García-Otero, X.; Varela-Fernández, R.; Martín-Pastor, M.; Llovo-Taboada, J.; Alonso-Alonso, P.; Aguiar, P.; González-Barcia, M.; Fernández-Ferreiro, A.; et al. Antifungal Combination Eye Drops for Fungal Keratitis Treatment. Pharmaceutics 2023, 15, 35. https://doi.org/10.3390/pharmaceutics15010035

AMA Style

Díaz-Tomé V, Bendicho-Lavilla C, García-Otero X, Varela-Fernández R, Martín-Pastor M, Llovo-Taboada J, Alonso-Alonso P, Aguiar P, González-Barcia M, Fernández-Ferreiro A, et al. Antifungal Combination Eye Drops for Fungal Keratitis Treatment. Pharmaceutics. 2023; 15(1):35. https://doi.org/10.3390/pharmaceutics15010035

Chicago/Turabian Style

Díaz-Tomé, Victoria, Carlos Bendicho-Lavilla, Xurxo García-Otero, Rubén Varela-Fernández, Manuel Martín-Pastor, José Llovo-Taboada, Pilar Alonso-Alonso, Pablo Aguiar, Miguel González-Barcia, Anxo Fernández-Ferreiro, and et al. 2023. "Antifungal Combination Eye Drops for Fungal Keratitis Treatment" Pharmaceutics 15, no. 1: 35. https://doi.org/10.3390/pharmaceutics15010035

APA Style

Díaz-Tomé, V., Bendicho-Lavilla, C., García-Otero, X., Varela-Fernández, R., Martín-Pastor, M., Llovo-Taboada, J., Alonso-Alonso, P., Aguiar, P., González-Barcia, M., Fernández-Ferreiro, A., & Otero-Espinar, F. J. (2023). Antifungal Combination Eye Drops for Fungal Keratitis Treatment. Pharmaceutics, 15(1), 35. https://doi.org/10.3390/pharmaceutics15010035

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Antifungal Combination Eye Drops for Fungal Keratitis Treatment

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