Antifungal Combination Eye Drops for Fungal Keratitis Treatment

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2023 Jan 21

PMID 36678663

Authors

Victoria Diaz-Tome

Carlos Bendicho-Lavilla

Xurxo Garcia-Otero

Ruben Varela-Fernandez

Manuel Martin-Pastor

Jose Llovo-Taboada

Pilar Alonso-Alonso

Pablo Aguiar

Miguel Gonzalez-Barcia

Anxo Fernandez-Ferreiro

Francisco J Otero-Espinar

Affiliations

Soon will be listed here.

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.

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References

Wu P, Lai C, Tan H, Ma D, Hsiao C . The successful medical treatment of a case of Paecilomyces lilacinus keratitis. Cornea. 2010; 29(3):357-8. DOI: 10.1097/ICO.0b013e3181af7626. View

Jambhekar S, Breen P . Cyclodextrins in pharmaceutical formulations II: solubilization, binding constant, and complexation efficiency. Drug Discov Today. 2015; 21(2):363-8. DOI: 10.1016/j.drudis.2015.11.016. View

ODAY D, Head W, Robinson R, Clanton J . Corneal penetration of topical amphotericin B and natamycin. Curr Eye Res. 1986; 5(11):877-82. DOI: 10.3109/02713688609029240. View

Anutarapongpan O, Thanathanee O, Suwan-Apichon O . Penicillium keratitis in a HIV-infected patient. BMJ Case Rep. 2016; 2016. PMC: 5015160. DOI: 10.1136/bcr-2016-216139. View

Fernandez-Ferreiro A, Silva-Rodriguez J, Otero-Espinar F, Gonzalez-Barcia M, Lamas M, Ruibal A . Positron Emission Tomography for the Development and Characterization of Corneal Permanence of Ophthalmic Pharmaceutical Formulations. Invest Ophthalmol Vis Sci. 2017; 58(2):772-780. DOI: 10.1167/iovs.16-20766. View

Abdelkader H, Fathalla Z, Moharram H, Ali T, Pierscionek B . Cyclodextrin Enhances Corneal Tolerability and Reduces Ocular Toxicity Caused by Diclofenac. Oxid Med Cell Longev. 2018; 2018:5260976. PMC: 5831967. DOI: 10.1155/2018/5260976. View

Boddu S, Gunda S, Earla R, Mitra A . Ocular microdialysis: a continuous sampling technique to study pharmacokinetics and pharmacodynamics in the eye. Bioanalysis. 2010; 2(3):487-507. DOI: 10.4155/bio.10.2. View

Al-Badriyeh D, Neoh C, Stewart K, Kong D . Clinical utility of voriconazole eye drops in ophthalmic fungal keratitis. Clin Ophthalmol. 2010; 4:391-405. PMC: 2866570. DOI: 10.2147/opth.s6374. View

Cruz J, Becker B, Morris K, Larive C . NMR characterization of the host-guest inclusion complex between beta-cyclodextrin and doxepin. Magn Reson Chem. 2008; 46(9):838-45. DOI: 10.1002/mrc.2267. View

10.

Malhotra S, Khare A, Grover K, Singh I, Pawar P . Design and Evaluation of Voriconazole Eye Drops for the Treatment of Fungal Keratitis. J Pharm (Cairo). 2015; 2014:490595. PMC: 4590801. DOI: 10.1155/2014/490595. View

11.

Moiseev R, Morrison P, Steele F, Khutoryanskiy V . Penetration Enhancers in Ocular Drug Delivery. Pharmaceutics. 2019; 11(7). PMC: 6681039. DOI: 10.3390/pharmaceutics11070321. View

12.

Johnson M, MacDougall C, Ostrosky-Zeichner L, Perfect J, Rex J . Combination antifungal therapy. Antimicrob Agents Chemother. 2004; 48(3):693-715. PMC: 353116. DOI: 10.1128/AAC.48.3.693-715.2004. View

13.

Jiang T, Tang J, Wu Z, Sun Y, Tan J, Yang L . The combined utilization of Chlorhexidine and Voriconazole or Natamycin to combat Fusarium infections. BMC Microbiol. 2020; 20(1):275. PMC: 7487579. DOI: 10.1186/s12866-020-01960-y. View

14.

Loftsson T, Stefansson E . Cyclodextrins and topical drug delivery to the anterior and posterior segments of the eye. Int J Pharm. 2017; 531(2):413-423. DOI: 10.1016/j.ijpharm.2017.04.010. View

15.

Ceulemans J, Ludwig A . Optimisation of carbomer viscous eye drops: an in vitro experimental design approach using rheological techniques. Eur J Pharm Biopharm. 2002; 54(1):41-50. DOI: 10.1016/s0939-6411(02)00036-x. View

16.

Maschmeyer G, Haas A . Voriconazole: a broad spectrum triazole for the treatment of serious and invasive fungal infections. Future Microbiol. 2007; 1(4):365-85. DOI: 10.2217/17460913.1.4.365. View

17.

Selvam A, Geetha D . Ultrasonic studies on lamivudine: beta-cyclodextrin and polymer inclusion complexes. Pak J Biol Sci. 2008; 11(4):656-9. DOI: 10.3923/pjbs.2008.656.659. View

18.

Shukla P, Kumar M, Keshava G . Mycotic keratitis: an overview of diagnosis and therapy. Mycoses. 2008; 51(3):183-99. DOI: 10.1111/j.1439-0507.2007.01480.x. View

19.

Brewster M, Loftsson T . Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007; 59(7):645-66. DOI: 10.1016/j.addr.2007.05.012. View

20.

Diaz-Tome V, Garcia-Otero X, Varela-Fernandez R, Martin-Pastor M, Conde-Penedo A, Aguiar P . In situ forming and mucoadhesive ophthalmic voriconazole/HPβCD hydrogels for the treatment of fungal keratitis. Int J Pharm. 2021; 597:120318. DOI: 10.1016/j.ijpharm.2021.120318. View