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Formulation Development of Dual Drug-Loaded Thermosensitive Ocular In Situ Gel Using Factorial Design

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Abstract

Purpose

To overcome the problems of low bioavailability of the drug associated with the short pre-corneal residence time, a thermoresponsive in situ gel system containing poloxamer P407, hydroxypropyl methylcellulose, and chitosan was developed to prolong the pre-corneal residence time of the drug.

Methods

The central composite design was utilized to assess the effects of the concentration of poloxamer 407 hydroxypropyl methylcellulose and chitosan, the concentration of polymer, and the polymer type on the viscosity, pH, and gelation temperature, which were considered indicators of optimum formulations.

Results

After model selection for response analysis, the quadratic model was found to be the best-fitting model for the relationship between independent factors and response variables. As a result of the central composite design, the optimized formulation contained 15.17% poloxamer 407 and 2.141% chitosan. Viscosity 25 °C = 2199.4 ± 26.2, viscosity 35 °C = 15,487.2 ± 117.4, pH = 6.5 ± 0.01, and gelation temperature °C = 33.3 ± 0.47 were obtained. The ex-vivo study revealed that the BRN formulation containing flurbiprofen-cyclodextrin inclusion complex has higher corneal penetration (P < 0.01). The cytotoxicity of ARPE-19 cells and irritation studies, as measured by in situ gel, was found to be acceptable. In lipoxygenase studies, the effectiveness of the BRN formulation was found to be significantly higher than other formulations (P < 0.01).

Conclusions

It is thought that the BRN formulation may be an alternative to the treatment of ocular allergic disease.

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Authors and Affiliations

  1. Turkish Medicines and Medical Devices Agency, Republic of Turkey Ministry of Health, Ankara, 06100, Turkey

    Heybet Kerem Polat

  2. Elixir Pharmaceutical Research and Development Corporation, Ankara, 06100, Turkey

    Aslıhan Arslan

  3. Department of Pharmaceutical Technology, Faculty of Pharmacy, Erciyes University, Kayseri, 38280, Turkey

    Sedat Ünal

  4. Department of Pharmaceutical Technology, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, 06100, Turkey

    Heybet Kerem Polat & Muhammet Kerim Haydar

  5. Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, 06100, Turkey

    Eren Aytekin

  6. Department of Pharmacognosy, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, 06100, Turkey

    Sefa Gözcü

  7. Department of Pharmacology, Faculty of Pharmacy, Suleyman Demirel University, Isparta, 32200, Turkey

    Nasıf Fatih Karakuyu

  8. Department of Pathology, Faculty of Veterinary Medicine, Dicle University, Diyarbakır, 21200, Turkey

    Behzad Mokhtare

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Contributions

H.K.P., A.A., S.Ü., and E.A. approved the idea/concept and design. H.K.P. and A.A. contributed to the supervision/consultancy. H.K.P., A.A., S.Ü., E.A., M.K.H., S.G., N.F.K., and B.M. contributed to the data collection and/or processing and writing of the article. H.K.P., A.A., S.Ü., E.A., M.K.H., and S.G. performed the analysis and/or comment. H.K.P., A.A., S.Ü., E.A., M.K.H., S.G., N.F.K., and B.M. performed the source scan. H.K.P., A.A., S.Ü., E.A., M.K.H., S.G., N.F.K., and B.M. contributed to the critical review, resources, and funding.

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Correspondence to Heybet Kerem Polat.

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Polat, H.K., Arslan, A., Ünal, S. et al. Formulation Development of Dual Drug-Loaded Thermosensitive Ocular In Situ Gel Using Factorial Design. J Pharm Innov 18, 768–788 (2023). https://doi.org/10.1007/s12247-023-09762-1

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