Review on Smart in Situ Gels for Site Specific Delivery of Anti-Fungal: Opportunities and Challenges
DOI:
https://doi.org/10.63682/jns.v14i28S.8248Keywords:
In situ, ocular delivery, Anti-fungal, site specific, Sustained release, smart polymerAbstract
Aims: The aim of this study is to explore the potential of in situ gel systems as innovative drug delivery vehicles, particularly for the treatment of invasive fungal infections (IFIs) in patients undergoing hematopoietic cell transplantation. The study emphasizes the advantages of in situ gelling systems in delivering antifungal agents locally or systemically with improved therapeutic efficacy and prolonged residence time.
Methodology: The study involves the evaluation of in situ gel systems composed of synthetic, natural, or semi-synthetic polymers that exhibit a sol-to-gel transition in response to biological stimuli such as temperature, pH, or ionic strength. These gels can be formulated alone or in combination with mucoadhesive polymers to enhance site-specific drug retention. The potential of these gels as carriers for nanoparticles or microparticles is also considered. The clinical background includes the assessment of systemic Candida infections during the pre-engraftment phase in hematopoietic cell transplant patients and a comparison of the effectiveness of fluconazole, amphotericin B, and caspofungin as antifungal agents.
Conclusion: In situ gel systems offer a promising strategy for the delivery of antifungal agents in immunocompromised patients, particularly those undergoing hematopoietic cell transplantation. Their stimuli-responsive behavior, prolonged residence time, and compatibility with nanoparticle carriers make them highly suitable for improving antifungal therapy. Integration with mucoadhesive polymers may further enhance therapeutic efficacy by increasing localization and bioavailability at the site of infection.
Results: Systemic Candida infections were previously reported in 15–25% of cases during the pre-engraftment phase. The introduction of fluconazole prophylaxis has significantly reduced early infection rates. Caspofungin has emerged as a superior alternative due to its broad-spectrum activity and lower toxicity compared to amphotericin B. In situ gel systems have demonstrated the ability to respond to endogenous stimuli and effectively transition into gels post-injection, allowing for controlled and localized drug delivery
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Ameen, M. (2010). Epidemiology of superficial fungal infections. Clinics in dermatology, 28(2), 197-201.
Havlickova, B., Czaika, V. A., & Friedrich, M. (2008). Epidemiological trends in skin mycoses worldwide. Mycoses, 51, 2-15.
Zhang, A. Y., Camp, W. L., & Elewski, B. E. (2007). Advances in topical and systemic antifungals. Dermatologic clinics, 25(2), 165-183.
Goldstein, A. O., Smith, K. M., Ives, T. J., & Goldstein, B. (2000). Mycotic infections. Effective management of conditions involving the skin, hair, and nails. Geriatrics, 55(5), 40-2.
Zuber, T. J., & Baddam, K. (2001). Superficial fungal infection of the skin: where and how it appears help determine therapy. Postgraduate medicine, 109(1), 117-132.
Adams, B. B. (2002). Tinea corporis gladiatorum. Journal of the American Academy of Dermatology, 47(2), 286-290.
Queiroz-Telles, F., McGinnis, M. R., Salkin, I., & Graybill, J. R. (2003). Subcutaneous mycoses. Infectious Disease Clinics, 17(1), 59-85.
Bassetti, M., Peghin, M., & Timsit, J. F. (2016). The current treatment landscape: candidiasis. Journal of Antimicrobial Chemotherapy, 71(suppl_2), ii13-ii22.
Kullberg, B. J., & Arendrup, M. C. (2015). Invasive candidiasis. New England Journal of Medicine, 373(15), 1445-1456.
P.G. Pappas, Invasive candidiasis, Infect. Dis. Clin. N. Am. 20 (3) (2006) 485–506.
Garg, A., Sharma, G. S., Goyal, A. K., Ghosh, G., Si, S. C., & Rath, G. (2020). Recent advances in topical carriers of anti-fungal agents. Heliyon, 6(8).
Inchara, R., & Maheshwari, T. U. (2020). In situ gel treatment for oral mucosal lesions: A systematic review. Journal of International Oral Health, 12(6), 499-503.
Ulijn, R. V., Bibi, N., Jayawarna, V., Thornton, P. D., Todd, S. J., Mart, R. J., ... & Gough, J. E. (2007). Bioresponsive hydrogels. Materials today, 10(4), 40-48.
Miyata, T., Uragami, T., & Nakamae, K. (2002). Biomolecule-sensitive hydrogels. Advanced drug delivery reviews, 54(1), 79-98.
Bromberg, L. E., & Ron, E. S. (1998). Temperature-responsive gels and thermogelling polymer matrices for protein and peptide delivery. Advanced drug delivery reviews, 31(3), 197-221.
Qiu, Y., & Park, K. (2001). Environment-sensitive hydrogels for drug delivery. Advanced drug delivery reviews, 53(3), 321-339.
Ruel-Gariepy, E., & Leroux, J. C. (2004). In situ-forming hydrogels—review of temperature-sensitive systems. European Journal of Pharmaceutics and Biopharmaceutics, 58(2), 409-426.
Jeong, B., Kim, S. W., & Bae, Y. H. (2012). Thermosensitive sol–gel reversible hydrogels. Advanced drug delivery reviews, 64, 154-162.
Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in polymer science, 29(12), 1173-1222.
Agrawal, A. K., Das, M., & Jain, S. (2012). In situ gel systems as ‘smart’carriers for sustained ocular drug delivery. Expert opinion on drug delivery, 9(4), 383-402.
Klouda, L., & Mikos, A. G. (2008). Thermoresponsive hydrogels in biomedical applications. European journal of pharmaceutics and biopharmaceutics, 68(1), 34-45.
Nigam, P. K. (2015). Antifungal drugs and resistance: Current concepts. Our Dermatology Online, 6(2), 212.
Paolicelli, P., Corrente, F., Serricchio, D., Cerreto, F., Cesa, S., Tita, B., ... & Casadei, M. A. (2011). The system SLN-Dextran hydrogel: An application for the topical delivery of ketoconazole. J Chem Pharm Res, 3(4), 410-21.
Schaller, M., Preidel, H., Januschke, E., & Korting, H. C. (1999). Light and electron microscopic findings in a model of human cutaneous candidosis based on reconstructed human epidermis following the topical application of different econazole formulations. Journal of drug targeting, 6(5), 361-372.
Bachhav, Y. G., Mondon, K., Kalia, Y. N., Gurny, R., & Möller, M. (2011). Novel micelle formulations to increase cutaneous bioavailability of azole antifungals. Journal of controlled release, 153(2), 126-132.
Gupta, M., Vaidya, B., Mishra, N., & Vyas, S. P. (2011). Effect of surfactants on the characteristics of fluconazole niosomes for enhanced cutaneous delivery. Artificial Cells, Blood Substitutes, and Biotechnology, 39(6), 376-384.
Babu, V. B., & Vadivelu, J. K. (2022). Topical antifungals and systemic antifungals in the management of candidiasis. J Evid Based Med Healthc, 9, 29-35
Liang, K. L., Su, M. C., Shiao, J. Y., Tseng, H. C., Hsin, C. H., Lin, J. F., & Jiang, R. S. (2008). Amphotericin B irrigation for the treatment of chronic rhinosinusitis without nasal polyps: a randomized, placebo-controlled, double-blind study. American Journal of Rhinology, 22(1), 52-58.
Nanjawade, B. K., Manvi, F. V., & Manjappa, A. S. (2007). RETRACTED: In situ-forming hydrogels for sustained ophthalmic drug delivery. Journal of Controlled Release, 122(2), 119-134.
Schenker, H. I., Silver, L. H., & Timolol Gel-Forming Solution Study Group. (2000). Long-term intraocular pressure–lowering efficacy and safety of timolol maleate gel-forming solution 0.5% compared with timoptic XE 0.5% in a 12-month study. American journal of ophthalmology, 130(2), 145-150.
Choi, H. G., Jung, J. H., Ryu, J. M., Yoon, S. J., Oh, Y. K., & Kim, C. K. (1998). Development of in situ-gelling and mucoadhesive acetaminophen liquid suppository. International journal of pharmaceutics, 165(1), 33-44.
Singhare, D. S., Khan, S., & Yeole, P. G. (2005). Temperature induced In situ gel of lidocaine hydrochloride for periodontal anaesthsia. INDIAN DRUGS-BOMBAY-, 42(8), 519.
Shastri, D. H., Prajapati, S. T., & Patel, L. D. (2010). Thermoreversible mucoadhesive ophthalmic in situ hydrogel: Design and optimization using a combination of polymers. Acta pharmaceutica, 60(3), 349-360.
Hassan, E. E., & Gallo, J. M. (1990). A simple rheological method for the in vitro assessment of mucin-polymer bioadhesive bond strength. Pharmaceutical research, 7, 491-495.
Costa, P., & Lobo, J. M. S. (2001). Modeling and comparison of dissolution profiles. European journal of pharmaceutical sciences, 13(2), 123-133.
US Food and Drug Administration. (2003). Q1A (R2) Stability testing of new drug substances and products. US Department of Health and Human Services.
Zhang, L., & Falla, T. J. (2006). Antimicrobial peptides: therapeutic potential. Expert opinion on pharmacotherapy, 7(6), 653-663.
solution Stoutamire, D. W. (2012). U.S. Patent No. 8,153,688. Washington, DC: U.S. Patent and Trademark Office.
Castelli, M. V., Butassi, E., Monteiro, M. C., Svetaz, L. A., Vicente, F., & Zacchino, S. A. (2014). Novel antifungal agents: a patent review (2011–present). Expert Opinion on Therapeutic Patents, 24(3), 323-338.
Bramhe, P., Waghmare, S., Rarokar, N., Sabale, P., Khedekar, P., Sabale, V., & Potey, L. (2025). Polymer blends innovation: Advancement in novel drug delivery. International Journal of Polymeric Materials and Polymeric Biomaterials, 74(10), 957-974.
Maddiboyina, B., Desu, P. K., Vasam, M., Challa, V. T., Surendra, A. V., Rao, R. S., ... & Jhawat, V. (2022). An insight of nanogels as novel drug delivery system with potential hybrid nanogel applications. Journal of Biomaterials Science, Polymer Edition, 33(2), 262-278.
Chaiwut, C., Tadtong, S., Akachaipaibul, P., Jiaranaikulwanitch, J., Singh, S., Okonogi, S., Syukri, D. M., & Chittasupho, C. (2025). Thermosensitive In Situ Ophthalmic Gel for Effective Local Delivery and Antifungal Activity of Ketoconazole Nanoparticles. Gels, 11(1),
Permana, A. D., Utami, R. N., Layadi, P., Himawan, A., Juniarti, N., Anjani, Q. K., ... & Donnelly, R. F. (2021). Thermosensitive and mucoadhesive in situ ocular gel for effective local delivery and antifungal activity of itraconazole nanocrystal in the treatment of fungal keratitis. International Journal of Pharmaceutics, 602, 120623.
Hsin YK, Thangarajoo T, Choudhury H, Pandey M, Meng LW, Gorain B. Stimuli-Responsive in situ Spray Gel of Miconazole Nitrate for Vaginal Candidiasis. J Pharm Sci. 2023 Feb;112(2):562-572.
Thermosensitive In Situ Vaginal Gel of the Gel Flake-Solid Dispersion of Itraconazole for Enhanced Antifungal Activity in the Treatment of Vaginal Candidiasis. ACS Appl Mater Interfaces. 2021 Apr 21;13(15):18128-18141
Ghimire, S., Wu, Y., Chug, M. K., Brisbois, E. J., Kim, K., & Mukhopadhyay, K. (2025). Engineered Zwitterion-Infused Clay Composites with Antibacterial and Antifungal Efficacy. arXiv preprint arXiv:2502.15645.
Fu, X., Tian, X., Lin, J., Wang, Q., Gu, L., Wang, Z., ... & Zhao, G. (2024). Zeolitic Imidazolate Framework-8 Offers an Anti-Inflammatory and Antifungal Method in the Treatment of Aspergillus Fungal Keratitis in vitro and in vivo. International Journal of Nanomedicine, 11163-11179.
Sandeep, D. S., Narayana, C. R., & Anoop, N. V. (2018). Smart in situ gels for Glaucoma-An Overview. Int J Pharm Sci Rev Res, 50(1), 94-100.
Kumaran, K. S. G. A., Karthika, K., & Padmapreetha, J. (2010). Comparative review on conventional and advanced ocular drug delivery formulations. Int J Pharm Pharm Sci, 2(4), 1-5.
Patel, H., Desai, D., Koradia, S., & Prajapati, D. (2021). Role of In-situ Gel in Drug Delivery System: A Comprehensive Review. Journal of Advancement in Pharmacology, 1(2), 1-16.
Pandey, M., Choudhury, H., Aziz, A. B. A., Bhattamisra, S. K., Gorain, B., Su, J. S. T., Tan, C. L., Chin, W. Y., & Yip, K. Y. (2021). Potential of Stimuli-Responsive in situ gel system for Sustained ocular drug Delivery: Recent progress and contemporary research. Polymers, 13(8), 1340. https://doi.org/10.3390/polym13081340
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