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Design of ophthalmic micelles loaded with diclofenac sodium: effect of chitosan and temperature on the block-copolymer micellization behaviour

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Abstract

Diclofenac sodium 0.1% is a commonly used NSAID with well-documented clinical efficacy in reducing postoperative inflammation; however, its corneal tolerability and ophthalmic tissue bioavailability require further improvement. Advanced micellar delivery systems composed of block-copolymers and chitosan showing fine balance between the mucoadhesion and mucus permeation, capable to slip through the mucus barrier and adhere to the epithelial ocular surface, may be used to tackle both challenges. The aggregation behaviour of the block-copolymers in the presence of different additives will dramatically influence the quality attributes like particle size, particle size distribution, drug-polymer interaction, zeta potential, drug incorporation, important for the delicate balance among mucoadhesion and permeation, as well as safety and efficacy of the ophthalmic micelles. Therefore, quality by design approach and D-optimal experimental design model were used to create a pool of useful data for the influence of chitosan and the formulation factors on the block copolymer’s aggregation behaviour during the development and optimization of Diclofenac loaded Chitosan/Lutrol F127 or F68 micelles. Particle size, polydispersity index, dissolution rate, FTIR and DSC studies, NMR spectroscopy, cytotoxicity, mucoadhesivity, mucus permeation studies, and bioadhesivity were assessed as critical quality attributes. FTIR and DSC studies pointed to the chaotropic effect of chitosan during the micelle aggregation. Mainly, Pluronic F68 micellization behaviour was more dramatically affected by the presence of chitosan, and self-aggregation into larger micelles with high polydispersity index was favoured at higher chitosan concentration. The optimized formulation with highest potential for ophthalmic delivery of diclofenac sodium, good cytotoxicity profile, delicate balance of the mucoadhesivity, and mucus permeation was in the design space of Chitosan/Lutrol F127 micelles.

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Acknowledgements

The authors would like to acknowledge the Central Laboratory Unit, Qatar University, for providing resources for transmission electron microscopy studies, NMR, FTIR, and DSC studies.

Funding

The authors received financial support from the project Drug delivery systems for improved ophthalmic delivery, QUST-1-CPH2020-8, Qatar University.

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Authors and Affiliations

  1. College of Pharmacy, Qatar University, PO Box 2713, Doha, Qatar

    Sarra Aicha Koummich, Ikram Mustapha Zoukh & Katerina Goracinova

  2. Institute of Pharmaceutical Technology, Ss. Cyril and Methodius University in Skopje, Majka Tereza 47, 1000, Skopje, North Macedonia

    Filip Gorachinov, Nikola Geskovski, Marija Glavas Dodov & Katerina Goracinova

  3. Faculty of Natural Sciences and Mathematics, Institute of Chemistry, Ss. Cyril and Methodius University in Skopje, Arhimedova 5, 1000, Skopje, North Macedonia

    Petre Makreski

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  6. Marija Glavas Dodov
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  7. Katerina Goracinova
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Contributions

SAK: Investigation; IMZ: Investigation; FG: Investigation and formal analysis; NG: Formal analysis, writing—original draft, review and editing, and visualization; PM: Formal analysis, writing—original draft; MGD: Writing—review and editing; KG: Conceptualization and methodology, formal analysis, writing—original draft, visualization, supervision, project administration, and funding acquisition.

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Correspondence to Katerina Goracinova.

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Koummich, S.A., Zoukh, I.M., Gorachinov, F. et al. Design of ophthalmic micelles loaded with diclofenac sodium: effect of chitosan and temperature on the block-copolymer micellization behaviour. Drug Deliv. and Transl. Res. 12, 1488–1507 (2022). https://doi.org/10.1007/s13346-021-01030-4

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