Modified curdlan-based hydrogels containing ornidazole for vaginal delivery

Abstract

Background and Aims: This study aimed to prepare and characterize, as well as compare the potential of biopolymer-based hydrogels for topical administration of ornidazole, a commonly used drug against vaginal infections. Hydrogels were successfully prepared using curdlan (Crd), carboxymethyl curdlan (CMCrd), hydroxypropyl methyl cellulose (HPMC), and xanthan gum (XG) as biopolymers, which were used alone or blended. In addition, carboxymethylation of Crd, a natural polysaccharide polymer that is attractive in the pharmaceutical field, was carried out in-house. Methods: The structure of the synthesised CMCrd was analysed by Fourier-transform infrared spectroscopy(FT-IR). The physicochemical, mechanical, and mucoadhesive properties of hydrogels were evaluated, then the drug release patterns from the hydrogels were examined in a simulated vaginal environment. Results: The hydrogels exhibited a uniform appearance and were pH-compatible with the vaginal environment. The viscosity, spreadability, and drug release characteristics were dependent on the polymer type and total amount of polymer present in the hydrogels. The texture profile analysis results indicated that all formulations exhibited appropriate mechanical characteristics (hardness, compressibility, cohesiveness, and elasticity) for vaginal administration, while also demonstrating mucoadhesive properties and good stability. Carboxymethylation improved mucoadhesion of Crd. Conclusion: The results obtained indicate that the hydrogels developed in this study can be considered promising candidates for the local treatment of vaginal infections.

Keywords

• Hydrogel
• Polymer
• Curdlan
• Ornidazole
• Vaginal infection
• Texture analysis

References

1. Ahmad, F., Alam, M., Khan, Z., Khar, R., & Ali, M. (2008). Devel-opment and in vitro evaluation of an acid buffering bioadhesive vaginal gel for mixed vaginal infections. Acta Pharmaceutica, 58(4), 407-419. https://doi.org/10.2478/v10007-008-0023-2 google scholar
2. Ahuja, M., Singh, S., & Kumar, A. (2013). Evaluation of car-boxymethyl gellan gum as a mucoadhesive polymer. Interna-tional Journal of Biological Macromolecules, 53, 114-121. https: //doi.org/10.1016/j.ijbiomac.2012.10.033 google scholar
3. Al-barudi, A., Sinani, G., & Ulker, Z. (2024). Biodegradable polysac-charide aerogels based on tragacanth and alginate as novel drug delivery systems. Journal of Sol-Gel Science and Technology, 109(3), 748-756. https://doi.org/10.1007/s10971-024-06312-0 google scholar
4. Antonietti, M., Caruso, R. A., Göltner, C. G., & Weissenberger, M. C. (1999). Morphology Variation of Porous Polymer Gels by Polymerization in Lyotropic Surfactant Phases. Macromolecules, 32(5), 1383-1389. https://doi.org/10.1021/ma9812478 google scholar
5. Arpa, M. D., Yoltaş, A., Onay Tarlan, E., Şenyüz, C. Ş., Sipahi, H., Aydın, A., & Üstündağ Okur, N. (2020). New therapeutic sys-tem based on hydrogels for vaginal candidiasis management: formulation-characterization and in vitro evaluation based on vaginal irritation and direct contact test. Pharmaceutical Devel-opment and Technology, 25(10), 1238-1248. https://doi.org/10. 1080/10837450.2020.1809457 google scholar
6. Bachhav, Y. G., & Patravale, V. B. (2009). Microemulsion-Based Vaginal Gel of Clotrimazole: Formulation, In Vitro Evalua-tion, and Stability Studies. AAPS PharmSciTech, 10(2), 476. https://doi.org/10.1208/s12249-009-9233-2 google scholar
7. Baloğlu, E., Özyazıcı, M., Yaprak Hızarcıoğlu, S., Şenyiğit, T., Özyurt, D., & Pekçetin, C. (2006). Bioadhesive Controlled Release Sys-tems of Ornidazole for Vaginal Delivery. Pharmaceutical Devel-opment and Technology, 11(4), 477-484. https://doi.org/10.1080/ 10837450600939784 google scholar
8. Barradas, T. N., Senna, J. P., Cardoso, S. A., de Holanda e Silva, K. G., & Elias Mansur, C. R. (2018). Formulation characterization and in vitro drug release of hydrogel-thickened nanoemulsions for topical delivery of 8-methoxypsoralen. Materials Science and Engineer-ing: C, 92, 245-253. https://doi.org/10.1016/j.msec.2018.06.049 google scholar

9. Bayer, I. S. (2022). Recent Advances in Mucoadhesive Interface Ma-terials, Mucoadhesion Characterization, and Technologies. Ad-vanced Materials Interfaces, 9(18). https://doi.org/10.1002/admi. 202200211 google scholar
10. Brookfield. (2015). Brookfield DV-I PRIME Digital Viscometer Op-erating Instructions. google scholar
11. Caccavo, D. (2019). An overview on the mathematical modeling of hydrogels’ behavior for drug delivery systems. International Jour-nal of Pharmaceutics, 560, 175-190. https://doi.org/10.1016/j. ijpharm.2019.01.076 google scholar
12. Caramella, C. M., Rossi, S., Ferrari, F., Bonferoni, M. C., & Sandri, G. (2015). Mucoadhesive and thermogelling systems for vaginal drug delivery. Advanced Drug Delivery Reviews, 92, 39-52. https: //doi.org/10.1016/j.addr.2015.02.001 google scholar
13. Cevher, E., Açma, A., Sinani, G., Aksu, B., Zloh, M., & Mülazımoğlu, L. (2014). Bioadhesive tablets containing cyclodextrin complex of itraconazole for the treatment of vaginal candidiasis. International Journal of Biological Macromolecules, 69, 124-136. https://doi. org/10.1016/j.ijbiomac.2014.05.033 google scholar
14. Cevher, E., Taha, M. A. M., Orlu, M., & Araman, A. (2008). Evalua-tion of Mechanical and Mucoadhesive Properties of Clomiphene Citrate Gel Formulations Containing Carbomers and Their Thi-olated Derivatives. Drug Delivery, 15(1), 57-67. https://doi.org/ 10.1080/10717540701829234 google scholar
15. Chen, Y., & Wang, F. (2020). Review on the preparation, biologi-cal activities and applications of curdlan and its derivatives. Eu-ropean Polymer Journal, 141, 110096. https://doi.org/10.1016/j. eurpolymj.2020.110096 google scholar
16. Cook, M. T., & Brown, M. B. (2018). Polymeric gels for intravaginal drug delivery. Journal of Controlled Release, 270, 145-157. https: //doi.org/10.1016/j.jconrel.2017.12.004 google scholar
17. de Araujo, P. R., Calixto, G. M. F., da Silva, I. C., de Paula Zago, L. H., Oshiro Junior, J. A., Pavan, F. R., Ribeiro, A. O., Fontana, C. R., & Chorilli, M. (2019). Mucoadhesive In Situ Gelling Liquid Crystalline Precursor System to Improve the Vaginal Administration of Drugs. AAPS PharmSciTech, 20(6). https://doi.org/10.1208/s12249-019-1439-3 google scholar
18. Enggi, C. K., Isa, H. T., Sulistiawati, S., Ardika, K. A. R., Wijaya, S., Asri, R. M., Mardikasari, S. A., Donnelly, R. F., & Permana, A. D. (2021). Development of thermosensitive and mu-coadhesive gels of cabotegravir for enhanced permeation and retention profiles in vaginal tissue: A proof of concept study. International Journal of Pharmaceutics, 609, 121182. https: //doi.org/10.1016/j.ijpharm.2021.121182 google scholar
19. Giri, P., & Singh, I. (2020). Development and Evaluation of Mu-coadhesive Tablets of Cinnarizine Using Carboxymethylated Guar Gum by Compression Coating Technique. Biointerface Re-search in Applied Chemistry, 10(5), 6365-6376. https://doi.org/ 10.33263/BRIAC105.63656376 google scholar
20. Gosecka, M., & Gosecki, M. (2021). Antimicrobial Polymer-Based Hydrogels for the Intravaginal Therapies—Engineering Consid-erations. Pharmaceutics, 13(9), 1393. https://doi.org/10.3390/ pharmaceutics13091393 google scholar
21. International Conference on Harmonisation (ICH). (2003). Stability testing of new drug substances and drug products Q1A (R2). google scholar
22. Jadav, M., Pooja, D., Adams, D. J., & Kulhari, H. (2023). Advances in Xanthan Gum-Based Systems for the Delivery of Therapeu-tic Agents. Pharmaceutics, 15(2), 402. https://doi.org/10.3390/ pharmaceutics15020402 google scholar
23. Jin, Y., Zhang, H., Yin, Y., & Nishinari, K. (2006). Comparison of curdlan and its carboxymethylated derivative by means of Rhe-ology, DSC, and AFM. Carbohydrate Research, 341(1), 90-99. https://doi.org/10.1016/j.carres.2005.11.003 google scholar
24. Karavana, S. Y., Güneri, P., & Ertan, G. (2009). Benzydamine hydrochloride buccal bioadhesive gels designed for oral ul-cers: Preparation, rheological, textural, mucoadhesive and release properties. Pharmaceutical Development and Technology, 14(6), 623-631. https://doi.org/10.3109/10837450902882351 google scholar
25. Khan, S., & Ranjha, N. M. (2014). Effect of degree of cross-linking on swelling and on drug release of low viscous chitosan/poly(vinyl alcohol) hydrogels. Polymer Bulletin, 71(8), 2133-2158. https: //doi.org/10.1007/s00289-014- 1178-2 google scholar
26. Khanum, H., Ullah, K., Murtaza, G., & Khan, S. A. (2018). Fabrication and in vitro characterization of HPMC-g-poly(AMPS) hydrogels loaded with loxoprofen sodium. International Journal of Biolog-ical Macromolecules, 120, 1624-1631. https://doi.org/10.1016/j. ijbiomac.2018.09.184 google scholar
27. Lin, M., Long, H., Liang, M., Chu, B., Ren, Z., Zhou, P., Wu, C., Liu, Z., & Wang, Y. (2021). Antifracture, Antibacterial, and Anti-inflammatory Hydrogels Consisting of Silver-Embedded Curd-lan Nanofibrils. ACS Applied Materials & Interfaces, 13(31), 36747-36756. https://doi.org/10.1021/acsami.1c06603 google scholar
28. Machado, R. M., Palmeira-de-Oliveira, A., Martinez-de-Oliveira, J., & Palmeira-de-Oliveira, R. (2017). Vaginal semisolid products: Technological performance considering physiologic parameters. European Journal of Pharmaceutical Sciences, 109, 556-568. https://doi.org/10.1016/j.ejps.2017.09.009 google scholar
29. Malyarenko, O. S., Usoltseva, R. V., Rasin, A. B., & Ermakova, S. P. (2023). The carboxymethylated derivative of laminaran from brown alga Saccharina cichorioides: Structure, anticancer and anti-invasive activities in 3D cell culture. International Journal of Biological Macromolecules, 226, 803-812. https://doi.org/10. 1016/j.ijbiomac.2022.11.247 google scholar
30. Mikusova, V., Ferkova, J., Zigrayova, D., Krchnak, D., & Mikus, P. (2022). Comparative Study of Polysaccharide-Based Hydrogels: Rheological and Texture Properties and Ibuprofen Release. Gels, 8(3), 168. https://doi.org/10.3390/gels8030168 google scholar
31. Osmalek, T., Froelich, A., Jadach, B., Tatarek, A., Gadzinski, P., Falana, A., Gralinska, K., Ekert, M., Puri, V., Wrotynska-Barczynska, J., & Michniak-Kohn, B. (2021). Recent Advances in Polymer-Based Vaginal Drug Delivery Systems. Pharmaceutics, 13(6), 884. https://doi.org/10.3390/pharmaceutics13060884 google scholar
32. Palmeira-de-Oliveira, R., Palmeira-de-Oliveira, A., & Martinez-de-Oliveira, J. (2015). New strategies for local treatment of vaginal infections. Advanced Drug Delivery Reviews, 92, 105-122. https: //doi.org/10.1016/j.addr.2015.06.008 google scholar
33. Pyka-Paj^k, A. (2023). TLC-Densitometric Analysis of Selected 5-Nitroimidazoles. Processes, 11(1), 170. https://doi.org/10.3390/ pr11010170 google scholar
34. Rafigh, S. M., Vaziri Yazdi, A., Safekordi, A. A., Heydari Nasab, A., Ardjmand, M., Naderi, F., & Mozafari, H. (2016). Protein adsorption using novel carboxymethyl-curdlan microspheres. In-ternational Journal of Biological Macromolecules, 87, 603-610. https://doi.org/10.1016/j.ijbiomac.2016.03.008 google scholar
35. Ravel, J., Moreno, I., & Simon, C. (2021). Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease. American Journal of Obstetrics and Gynecology, 224(3), 251-257. https://doi.org/10.1016/j.ajog.2020.10.019 google scholar
36. Rençber, S., Karavana, S. Y., Şenyiğit, Z. A., Eraç, B., Limoncu, M. H., & Baloğlu, E. (2017). Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole: formulation, preparation, and in vitro/in vivo evaluation. Pharmaceutical Development and Tech-nology, 22(4), 551-561. https://doi.org/10.3109/10837450.2016. 1163385 google scholar
37. Şenyigit, Z. A., Karavana, S. Y., Eraç, B., Gürsel, Ö., Limoncu, M. H., & Baloglu, E. (2014). Evaluation of chitosan based vaginal bioad-hesive gel formulations for antifungal drugs. Acta Pharmaceutica, 64(2), 139-156. https://doi.org/10.2478/acph-2014-0013 google scholar
38. Sessevmez, M., Sinani, G., Okyar, A., Alpar, H. O., & Cevher, E. (2023). Induction of humoral and cell-mediated immunity in mice by chitosan-curdlan composite nanoparticles administered intranasally and subcutaneously. Journal of Drug Delivery Sci-ence and Technology, 86, 104704. https://doi.org/10.1016/j.jddst. 2023.104704 google scholar
39. Sethi, S., Saruchi, Kaith, B. S., Kaur, M., Sharma, N., & Kumar, V. (2020). Cross-linked xanthan gum-starch hydrogels as promising materials for controlled drug delivery. Cellulose, 27(8), 4565-4589. https://doi.org/10.1007/s10570-020-03082-0 google scholar
40. Sinani, G., Durgun, M. E., Cevher, E., & Özsoy, Y. (2023). Polymeric-Micelle-Based Delivery Systems for Nu-cleic Acids. Pharmaceutics, 15(8), 2021. https://doi.org/10.3390/ pharmaceutics15082021 google scholar
41. Singh, S., Verma, D., Mirza, Mohd. A., Das, A. K., dudeja, M., An-wer, Md. K., Sultana, Y., Talegaonkar, S., & Iqbal, Z. (2017). Development and optimization of ketoconazole loaded nano-transfersomal gel for vaginal delivery using Box-Behnken design: In vitro, ex vivo characterization and antimicrobial evaluation. Journal of Drug Delivery Science and Technology, 39, 95-103. https://doi.org/10.1016/j.jddst.2017.03.007 google scholar
42. Suflet, D. M., Popescu, I., Prisacaru, A. I., & Pelin, I. M. (2021). Syn-thesis and characterization of curdlan - phosphorylated curdlan based hydrogels for drug release. International Journal of Poly-meric Materials and Polymeric Biomaterials, 70(12), 870-879. https://doi.org/10.1080/00914037.2020.1765360 google scholar
43. Swingle, K. L., Riccardi, A. S., Peranteau, W. H., & Mitchell, M. J. (2023). Delivery technologies for women’s health applications. Nature Reviews Bioengineering, 1(6), 408-425. https://doi.org/ 10.1038/s44222-023-00040-w google scholar
44. Tao, H., Wang, B., Wen, H., Cui, B., Zhang, Z., Kong, X., & Wang, Y. (2021). Improvement of the textural characteristics of curdlan gel by the formation of hydrogen bonds with erythritol. Food Hy-drocolloids, 117, 106648. https://doi.org/10.1016/j.foodhyd.2021.106648 google scholar
45. Vaghani, S. S., Patel, M. M., & Satish, C. S. (2012). Synthesis and char-acterization of pH-sensitive hydrogel composed of carboxymethyl chitosan for colon targeted delivery of ornidazole. Carbohydrate Research, 347(1), 76-82. https://doi.org/10.1016/j.carres.2011. 04.048 google scholar
46. Zhang, F., Zhang, S., Lin, R., Cui, S., Jing, X., & Coseri, S. (2023). In-jectable multifunctional carboxymethyl chitosan/hyaluronic acid hydrogel for drug delivery systems. International Journal of Bio-logical Macromolecules, 249, 125801. https://doi.org/10.1016/j. ijbiomac.2023.125801 google scholar
47. Zhang, H., Nishinari, K., Williams, M. A. K., Foster, T. J., & Norton, I. T. (2002). A molecular description of the gelation mechanism of curdlan. International Journal of Biological Macromolecules, 30(1), 7-16. https://doi.org/10.1016/S0141-8130(01)00187-8 google scholar
48. Zhang, S., Huang, S., Lu, L., Song, X., Li, P., & Wang, F. (2018). Curdlan sulfate- O-linked quaternized chitosan nanoparticles: potential adjuvants to improve the immunogenicity of exoge-nous antigens via intranasal vaccination. International Journal of Nanomedicine, 13, 2377-2394. https://doi.org/10.2147/IJN. S158536 google scholar