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Posaconazole micelles for ocular delivery: in vitro permeation, ocular irritation and antifungal activity studies

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Abstract

Posaconazole (PSC) is a triazole group anti-fungal agent with the widest spectrum. Although there is no commercially available ocular dosage form, its diluted oral suspension preparation (Noxafil®) is used as off-label in topical treatment of severe keratitis and sclerokeratitis in the clinic. However, ocular bioavailability of PSC suspension form is extremely low due to its highly lipophilic character. Thus, there is a clinical need to improve its ocular bioavailability and to develop novel delivery system for the treatment of ocular fungal infections. Herein, we studied ex vivo permeation, penetration, anti-fungal activity, and Hen’s Egg Test-Chorioallantoic Membrane (HET-CAM) toxicity tests in order to assess ocular targeting of PSC micelles, which were optimized in our previous study. The results indicated that micellar carrier system increased the permeability of PSC to eye tissues. Micelles showed higher affinity to ocular tissues than that of commercial oral suspension of PSC (Noxafil®). In vitro anti-fungal activity data also confirmed the efficacy of PSC loaded micellar formulations against Candida. albicans strains. The relative safety of the optimized micelles on the ocular tissue was shown with the HET-CAM toxicity test. In conclusion, micellar systems could be a promising strategy for the effective and safe delivery of PSC in the treatment of ocular fungal infections.

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Availability of data and materials

The datasets generated or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BCS:

Biopharmaceutics Classification System

CMC:

Critical micelle concentration

Deff:

Diffusion coefficients

F127:

Pluronic F127

F68:

Pluronic F68

HET-CAM:

Hen’s Egg Test-Chorioallantoic Membrane (HET-CAM)

HLB:

Hydrophilic/lipophilic balance

HPLC:

High-pressure liquid chromatography

HPLC:

International unit

JSS:

Steady-state flux

MIC:

Minimum inhibitor concentration

Papp:

Permeability coefficient

PEG:

Polyethylene glycol

P-gp:

P-glycoprotein

PSC:

Posaconazole

SD:

Standard deviation

TJs:

Tight junctions

TPGS:

D-a-Tocopheryl polyethylene glycol 1000 succinate

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Acknowledgements

The authors are grateful to BASF-Turkey for their support by Kolliphor TPGS, Pluronic F127 and Pluronic F68. Also, they thank Çekmece slaughterhouse and meat products for their support by isolated eyes supply.

Funding

The present work was supported by the Research Fund of Istanbul University (Project No: 20958).

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey

    Meltem Ezgi Durgun, Emine Kahraman, Sevgi Güngör & Yıldız Özsoy

  2. Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey

    Mayram Hacıoğlu

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  1. Meltem Ezgi Durgun
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Contributions

The submitted work is based primarily on MED’s doctoral dissertation. Encouragement to investigate PSC-loaded micelles as potential nanocarriers for ocular application, supervision of the project and the findings of this work were provided by YÖ. Methodology and performation of the experiments [MED] except for the microbiological studies: [MH]. Literature search and implementing the review of the literature: [MED]; writing—the draft preparation: [MED]; review and editing: [MED, EK, SG and YÖ]; funding acquisition: [YÖ]; resources: [Research Fund of Istanbul University]. The first draft of the manuscript was written by [MED] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Meltem Ezgi Durgun.

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Durgun, M.E., Kahraman, E., Hacıoğlu, M. et al. Posaconazole micelles for ocular delivery: in vitro permeation, ocular irritation and antifungal activity studies. Drug Deliv. and Transl. Res. 12, 662–675 (2022). https://doi.org/10.1007/s13346-021-00974-x

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