DESIGN AND CHARACTERIZATION OF IN-SITU HYDROGEL FORMULATIONS TO PREVENT DRY EYE AFTER CORNEAL SURGERIES

Year 2025, Volume: 49 Issue: 2, 382 - 401, 19.05.2025

Şevval Demir , Aylin Deljavan Ghodratı , Tansel Çomoğlu , Kader Çömlekçi

https://doi.org/10.33483/jfpau.1590625

Abstract

Objective: The short retention time of eye drops used to prevent dryness has necessitated the exploration of alternative dosage forms. İn-situ hydrogels remain in a sol phase during storage but transition to a gel phase under environmental conditions, allowing prolonged retention at the target site. In this study, in-situ hydrogel formulations capable of sol-gel transition at ocular temperature were developed using natural and biocompatible polymers, and their characterizations were performed.
Material and Method: HA, CMC, PAA, and citric acid were homogeneously dispersed in distilled water at 37°C by the physical mixing method. The suitability for ocular physiology was verified through characterization studies. pH measurement, swelling/erosion assessment, sol-gel transition temperature evaluation, and viscosity measurement were conducted as part of the characterization studies. Based on the evaluation of all data, the most suitable formulation(s) with optimal properties were selected, and accelerated stability studies were performed.
Result and Discussion: The combination of hyaluronic acid, polyacrylamide, and carboxymethyl cellulose was found suitable for in-situ hydrogel formulations with high water retention capacity, biocompatibility, and prolonged ocular residence time. During the 7-day accelerated in vitro stability study, no significant changes were observed in the pH and viscosity values of the formulations.

Keywords

Carboxymethyl cellulose, cornea, hyaluronic acid, in-situ hydrogel, polyacrylamide

Project Number

TÜBİTAK 2209-B projesi, 1139B412301841

KORNEA AMELİYATLARI SONRASINDA KULLANILABİLECEK GÖZ KURULUĞUNU ÖNLEYİCİ İN-SİTU HİDROJEL FORMÜLASYONLARININ TASARIMI VE İN VİTRO KARAKTERİZASYONU

Abstract

Amaç: Göz kuruluğunu önlemek için kullanılan göz damlalarının gözde kalış süresinin kısa olmasıyla alternatif dozaj şekillerinin araştırılmasını gerektirmiştir. İn-situ hidrojeller, saklama sırasında sol fazında olup çevresel koşullarda jel fazına geçerek hedef bölgede daha uzun süre kalabilmektedir. Bu çalışmada, doğal ve biyouyumu polimerler kullanılarak göz sıcaklığında sol-jel geçişi yapabilen in-situ hidrojel formülasyonları geliştirilmiş ve karakterizasyonları gerçekleştirilmiştir.
Gereç ve Yöntem: HA, CMC, PAA ve sitrik asit, fiziksel karıştırma yöntemi esas alınarak 37°C sıcaklıkta distile su içerisine serpilerek homojen dağılımı sağlanmıştır. Göz fizyolojisine uygunluğu karakterizasyon çalışmaları ile kontrol edilmiştir. pH ölçümü, şişme/erozyon ve sol-jel geçiş sıcaklığı değerlendirilmesi ve viskozite ölçümü karakterizsyon çalışmaları altında gerçekleştirilmiştir. Tüm veriler değerlendirilerek optimum özelliklere sahip en uygun formülasyon/lar seçilerek hızlandırılmış stabilite çalışmaları gerçekleştirilmiştir.
Sonuç ve Tartışma: Su tutma kapasitesi yüksek, biyouyumlu, gözde uzun süre kalabilen in-situ hidrojel formülasyonları için hyaluronik asit, poliakrilamid ve karboksimetil selüloz kombinasyonu uygun bulunmuştur. 7 günlük hızlandırılmış in vitro stabilite çalışmasında, formülasyonların pH ve viskozite değerlerinde önemli bir değişiklik gözlenmemiştir.

Keywords

Hyaluronik asit, in-situ hidrojel, karboksimetil selüloz, kornea, poliakrilamid

Project Number

TÜBİTAK 2209-B projesi, 1139B412301841

References

• 1. Volatier, T., Cursiefen, C., Notara, M. (2024). Current advances in corneal stromal stem cell biology and therapeutic applications. Cells, 13(2), 163. [CrossRef]
• 2. Lv, Z., Li, S., Zeng, G., Yao, K., Han, H. (2024). Recent progress of nanomedicine in managing dry eye disease. Advances in Ophthalmology Practice and Research. 4(1), 23-31. [CrossRef]
• 3. Yusufoğlu, E., Keser, S. (2024). The effect of sodium hyaluronate on dry eye and corneal epithelial thickness following cataract surgery. International Ophthalmology, 44(1), 211. [CrossRef]
• 4. Ch, S., Mishra, P., Bhatt, H., Ghosh, B., Roy, S., Biswas, S. (2021). Hydroxypropyl methacrylamide-based copolymeric nanoparticles loaded with moxifloxacin as a mucoadhesive, cornea-penetrating nanomedicine eye drop with enhanced therapeutic benefits in bacterial keratitis. Colloids and Surfaces B: Biointerfaces, 208, 112113. [CrossRef]
• 5. Ammar, N.E.B., Barbouche, M., Hamzaoui, A.H. (2020). Historical view of hydrogel characterization. Hydrogels Based on Natural Polymers, (pp. 459-479). Elsevier. [CrossRef]
• 6. Kaczmarek, B., Nadolna, K., Owczarek, A. (2020). The physical and chemical properties of hydrogels based on natural polymers. Hydrogels based on natural polymers, 151-172. [CrossRef]
• 7. Mutlu, D., Karagöz, İ. (2023). Akıllı malzeme olarak polimerler ve uygulamaları. Konya Journal of Engineering Sciences, 11(1), 274-299. [CrossRef]
• 8. Parhi, R. (2017). Cross-linked hydrogel for pharmaceutical applications: A review. Advanced Pharmaceutical Bulletin, 7(4), 515-530. [CrossRef]
• 9. Hoffman, A.S. (2012). Hydrogels for biomedical applications. Advanced drug delivery reviews, 64, 18-23. [CrossRef]
• 10. Chai, Q., Jiao, Y., Yu, X. (2017). Hydrogels for biomedical applications: Their characteristics and the mechanisms behind them. Gels, 3(1), 6. [CrossRef]
• 11. Vigani, B., Rossi, S., Sandri, G., Bonferoni, M.C., Caramella, C.M., Ferrari, F. (2020). Recent advances in the development of in situ gelling drug delivery systems for non-parenteral administration routes. Pharmaceutics, 12(9), 859. [CrossRef]
• 12. Tsung, J., Burgess, D.J. (2012). Biodegradable polymers in drug delivery systems. Fundamentals and Applications of Controlled Release Drug Delivery (pp. 107-123). Boston, MA: Springer US. [CrossRef]
• 13. Lev, R., Seliktar, D. (2018). Hydrogel biomaterials and their therapeutic potential for muscle injuries and muscular dystrophies. Journal of the Royal Society Interface, 15(138), 20170380. [CrossRef]
• 14. Chowhan, A., Giri, T.K. (2020). Polysaccharide as renewable responsive biopolymer for in situ gel in the delivery of drug through ocular route. International Journal Of Biological Macromolecules, 150, 559-572. [CrossRef]
• 15. Kulbay, M., Wu, K.Y., Truong, D., Tran, S.D. (2024). Smart molecules in ophthalmology: Hydrogels as responsive systems for ophthalmic applications. Smart Molecules, e20230021. [CrossRef]
• 16. Dubald, M., Bourgeois, S., Andrieu, V., Fessi, H. (2018). Ophthalmic drug delivery systems for antibiotherapy- a review. Pharmaceutics, 10(1), 10. [CrossRef]
• 17. Huang, J., Wang, W., Yu, J., Yu, X., Zheng, Q., Peng, F., He, Z., Zhao, W., Zhang, Z., Li, X., Wang, Q. (2017). Combination of dexamethasone and Avastin® by supramolecular hydrogel attenuates the inflammatory corneal neovascularization in rat alkali burn model. Colloids and Surfaces B: Biointerfaces, 159, 241-250. [CrossRef]
• 18. Mandal, A., Clegg, J.R., Anselmo, A.C., Mitragotri, S. (2020). Hydrogels in the clinic. Bioengineering & Translational Medicine, 5(2), e10158. [CrossRef]
• 19. Ahsan, A., Farooq, M.A., Parveen, A. (2020). Thermosensitive chitosan-based injectable hydrogel as an efficient anticancer drug carrier. ACS omega, 5(32), 20450-20460. [CrossRef]
• 20. Selvaraj, S., Chauhan, A., Verma, R., Dutta, V., Rana, G., Duglet, R., Subbarayan, R., Batoo, K.M. (2024). Role of degrading hydrogels in hepatocellular carcinoma drug delivery applications: A review. Journal of Drug Delivery Science and Technology, 105628. [CrossRef]
• 21. Fathi, M., Alami-Milani, M., Geranmayeh, M. H., Barar, J., Erfan-Niya, H., Omidi, Y. (2019). Dual thermo-and pH-sensitive injectable hydrogels of chitosan/(poly (N-isopropylacrylamide-co-itaconic acid)) for doxorubicin delivery in breast cancer. International Journal Of Biological Macromolecules, 128, 957-964. [CrossRef]
• 22. Ren, Y., Zhao, X., Liang, X., Ma, P.X., Guo, B. (2017). Injectable hydrogel based on quaternized chitosan, gelatin and dopamine as localized drug delivery system to treat parkinson’s disease. International Journal Of Biological Macromolecules, 105, 1079-1087. [CrossRef]
• 23. Wu, Y., Liu, Y., Li, X., Kebebe, D., Zhang, B., Ren, J., Lu, J., Li, J., Du, S., Liu, Z. (2019). Research progress of in-situ gelling ophthalmic drug delivery system. Asian Journal Of Pharmaceutical Sciences, 14(1), 1-15. [CrossRef]
• 24. Nitti, P., Demitri, C., Sannino, A., Ambrosio, L. (2024). Fundamentals of hydrogels II-architecture and biodegradability. Hydrogels for Tissue Engineering and Regenerative Medicine (pp. 13-28). [CrossRef]
• 25. Nguyen, L.T., Hsu, C.C., Ye, H., Cui, Z. (2020). Development of an in situ injectable hydrogel containing hyaluronic acid for neural regeneration. Biomedical Materials, 15(5), 055005. [CrossRef]
• 26. Sayıner, Ö. (2019). Master’s Thesis. Development of hydrogel formulations of brain-targeted active substance-loaded nanoparticles. Department of Pharmaceutical Technology, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
• 27. Başaran, B. (2008). Master’s Thesis. The development and evaluation of the ophthalmic in-situ gel formulations containing Ciprofloxacin and Hydroxypropyl-beta-cyclodextrin complex. Department of Pharmaceutical Technology, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
• 28. Khodaverdi, E., Ganji, F., Tafaghodi, M., Sadoogh, M. (2013). Effects of formulation properties on sol-gel behavior of chitosan/glycerolphosphate hydrogel. Iranian Polymer Journal, 22, 785-790. [CrossRef]
• 29. Chung, Y.M., Simmons, K.L., Gutowska, A., Jeong, B. (2002). Sol-gel transition temperature of PLGA-g-PEG aqueous solutions. Biomacromolecules, 3(3), 511-516. [CrossRef]
• 30. Villapiano, F., Silvestri, T., Lo Gatto, C., Aleo, D., Campani, V., Graziano, S. F., Giancola, C., D’Aria, F., De Rosa, G., Biondi, M., Mayol, L. (2024). Thermosensitive in situ gelling poloxamers/hyaluronic acid gels for hydrocortisone ocular delivery. Gels, 10(3), 193. [CrossRef]
• 31. Fernandes-Cunha, G.M., Chen, K.M., Chen, F., Le, P., Han, J.H., Mahajan, L.A., Lee, H.J., Na, K.S., Myung, D. (2020). In situ-forming collagen hydrogel crosslinked via multi-functional PEG as a matrix therapy for corneal defects. Scientific Reports, 10(1), 16671. [CrossRef]
• 32. Lee, Y., Chung, H.J., Yeo, S., Ahn, C.H., Lee, H., Messersmith, P.B., Park, T.G. (2010). Thermo-sensitive, injectable, and tissue adhesive sol–gel transition hyaluronic acid/pluronic composite hydrogels prepared from bio-inspired catechol-thiol reaction. Soft Matter, 6(5), 977-983. [CrossRef]
• 33. Liu, Y., Yang, F., Feng, L., Yang, L., Chen, L., Wei, G., Lu, W. (2017). In vivo retention of poloxamer-based in situ hydrogels for vaginal application in mouse and rat models. Acta Pharmaceutica Sinica B, 7(4), 502-509. [CrossRef]
• 34. Tan, H., Chu, C.R., Payne, K.A., Marra, K.G. (2009). Injectable in situ forming biodegradable chitosan-hyaluronic acid based hydrogels for cartilage tissue engineering. Biomaterials, 30(13), 2499-2506. [CrossRef]
• 35. Azari, Z., (2023). Master’s Thesis. Preparation and evaluation of metronidazole containing hydrogel formulation. Department of Pharmaceutical Technology, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
• 36. Guo, C., Jiang, G., Guan, J., Huang, S., Guo, Y., He, Y., Yang, L., Dong, T. (2024). Preparation and performance evaluation of a thixotropic polymer gel for loss circulation control. Fuel, 371, 132148. [CrossRef]
• 37. Sağlanmak, Ş. (2015). Master’s Thesis. Investigation of the viscosity of nanofluids. Department of Mechanical Engineering, Graduate School of Natural and Applied Sciences, Dokuz Eylül University, İzmir, Turkey.
• 38. Sheng, D., Yu, H., Li, H., Zhou, J., Zhang, H., Wang, W. (2022). Friction reduction mechanism of aqueous hydroxyethyl cellulose solution enhanced by synergistic effect of APTES. Tribology Letters, 70, 1-16. [CrossRef]
• 39. Balasubramaniam, J., Pandit, J.K. (2003). Ion-activated in situ gelling systems for sustained ophthalmic delivery of ciprofloxacin hydrochloride. Drug Delivery, 10(3), 185-191. [CrossRef]
• 40. Peppas, N.A., Bures, P., Leobandung, W., Ichikawa, H. (2000). Hydrogels in pharmaceutical formulations. European Journal of Pharmaceutics and Biopharmaceutics, 50(1), 27-46. [CrossRef]