ORAL MUKOZİT TEDAVİSİ İÇİN METRONİDAZOL İÇEREN MUKOADEZİF-TERMOSENSİTİF BUCCAL JELİN GELİŞTİRİLMESİ VE KARAKTERİZASYONU

Yıl 2020, Cilt: 44 Sayı: 3, 517 - 539, 30.09.2020

Melike Ongun Emre Tunçel , Esra Kodan , Fatma Nur Tuğcu Demiröz , Fahriye Figen Tırnaksız

https://doi.org/10.33483/jfpau.742957

Cited By: 3

Öz

Amaç: Bu çalışmada oral mukozit tedavisi için bukkal mukoza sıcaklığında hızla jelleşebilen, metronidazol içeren mukoadhesif-termosensitif jel formülasyonu hazırlanması ve karakterize edilmesi amaçlanmıştır.

Gereç ve Yöntem: Bu çalışmada, belirli konsantrasyonlarda poloksamer 407 (P407), poloksamer 188 (P188) ve hidroksipropil metilselüloz (HPMC) kombinasyonları, bukkal mukozada jel oluşturmak için kullanılmıştır. Optimum formülasyonlar hazırlanan formülasyonların jelleşme süresi ve jelleşme sıcaklığı ölçülerek seçilmiştir. Seçilen formülasyonların sertlik, adhezif, kohezif, esneklik, püskürtülebilirlik, mukoadhezif ve salım özellikleri değerlendirilmiştir.

Sonuç ve Tartışma: Sonuçlar, 33 °C'de hızla jel formuna dönüşen F1 ve F3 formülasyonunun optimum formülasyonlar olabileceğini göstermiştir. Bu iki formülasyon 8 saat boyunca kontrollü salım göstermiştir. Doku profili analizi (TPA), mukoadhezyon ve püskürtülebilirlik çalışmaları, F1 formülasyonun, P407 (% 15), P188 (% 20) ve HPMC (% 5) kombinasyonu, bukkal mukoza için optimum formülasyon olduğunu göstermiştir. Sonuç olarak, metronidazole içeren mukoadhezif-ısıya duyarlı jeller oral mukozit tedavisinde iyi bir alternatif olabilir.

Anahtar Kelimeler

Metronidazol, mukoadhezif-ısıya duyarlı jel, oral mukozit, poloksamer

DEVELOPMENT AND CHARACTERIZATION OF MUCOADHESIVE-THERMOSENSITIVE BUCCAL GEL CONTAINING METRONIDAZOLE FOR THE TREATMENT OF ORAL MUCOSITIS

Öz

Objective: This study was aimed to develop and characterize, mucoadhesive-thermosensitive gel formulation containing metronidazole that can quickly gel at the buccal mucosa temperature for treatment of oral mucositis.

Material and Method: In this study, the combinations Poloxamer 407 (P407), Poloxamer 188 (P188) and Hydroxypropyl methylcellulose (HPMC) were used in certain concentrations to form a gel in buccal mucosa. Optimum formulations were selected by measuring the gelling time and gelling temperature of the formulations prepared. The hardness, adhesiveness, cohesiveness, resilience, sprayability, mucoadhesion and release properties of selected formulations were evaluated.

Result and Discussion: The results showed that F1 and F3 formulations, which quickly turn into gel form at 33 °C, could be the optimum formulations. These two formulations showed controlled release for 8 hours. Texture profile analysis (TPA), mucoadhesion studies and sprayability studies have shown that F1 formulation which the mixture of P407 (15%), P188 (20%) and HPMC (5%) is the optimum formulation for the buccal mucosa. In conclusion, mucoadhesive-thermosensitive gels containing metronidazole may be a good alternative in the treatment of oral mucositis.

Anahtar Kelimeler

Metronidazole, mucoadhesive-thermosensitive gel, oral mucositis, poloxamer

Kaynakça

• 1. Lalla, R. V., Peterson, D. E. (2005). Oral mucositis. Dental Clinics of North America, 49 (1 SPEC.ISS.), 167–184.
• 2. Trotti, A., Bellm, L.A., Epstein, J. B., Frame, D., Fuchs, H. J., Gwede, C. K., Komaroff, E., Nalysnyk, L., Zilberberg, M.D. (2003). Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: A systematic literature review. Radiotherapy and Oncology, 66 (3), 253-62.
• 3. Itoh, Y., Kubota, S., Kawamura, M., Nomoto, Y., Murao, T., Yamakawa, K., Ishihara, S., Hirasawa, N., Asano, A., Yanagawa, S., Naganawa, S. (2016). A multicenter survey of stage T1 glottic cancer treated with radiotherapy delivered in 2.25-Gy fractions in clinical practice: An initial 5-year analysis. Nagoya Journal of Medical Science, 78 (4), 399–406.
• 4. Donnelly, J. P., Bellm, L. A., Epstein, J. B., Sonis, S. T., Symonds, R. P. (2003). Antimicrobial therapy to prevent or treat oral mucositis. Lancet Infectious Diseases, 3 (7), 405–412.
• 5. Mosel, D. D., Bauer, R. L., Lynch, D. P., Hwang, S. T. (2011). Oral complications in the treatment of cancer patients. Oral Diseases, 17 (6), 550–559.
• 6. Villa, A., Sonis, S. T. (2015). Mucositis: Pathobiology and management. Current Opinion in Oncology, 27 (3), 159–164.
• 7. Chan, A., Ignoffo, R.J. (2005). Survey of topical oral solutions for the treatment of chemo-induced oral mucositis. Journal of Oncology Pharmacy Practice, 11 (4), 139–143.
• 8. Buchsel, P. C. (2008). Polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®): A bioadherent oral gel for the treatment of oral mucositis and other painful oral lesions. Expert Opinion on Drug Metabolism and Toxicology, 4 (11), 1449–1454.
• 9. Carl, W., Emrich, L. S. (1991). Management of oral mucositis during local radiation and systemic chemotherapy: A study of 98 patients. The Journal of Prosthetic Dentistry, 66 (3), 361–369.
• 10. Leiknes, T., Leknes, K. N., Böe, O. E., Skavland, R. J., Lie, T. (2007). Topical use of a metronidazole gel in the treatment of sites with symptoms of recurring chronic inflammation. Journal of Periodontology, 78 (8), 1538–1544.
• 11. Jones, D. S., Woolfson, A. D., Brown, A. F., Coulter, W. A., McClelland, C., Irwin, C. R. (2000). Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease. Journal of Controlled Release, 67 (2–3), 357–368.
• 12. Kaur, J., Kaur, J., Jaiswal, S., Gupta, G. (2016). Recent advances in topical drug delivery system. Pharmaceutical Research, 6 (07), 6353-6369.
• 13. Patil, P. B., Datir, S. K., Saudagar, R. B. (2019). A review on topical gels as drug delivery system P.B. Journal of Drug Delivery and Therapeutics, 3 (3-s), 989–994.
• 14. Agrawal, A. K., Das, M., and Jain, S. (2012). In situ gel systems as “smart” carriers for sustained ocular drug delivery. Expert Opinion on Drug Delivery, 9 (4), 383–402.
• 15. Baloglu, E., Karavana, S. Y., Senyigit, Z. A., Guneri, T. (2011). Rheological and mechanical properties of poloxamer mixtures as a mucoadhesive gel base. Pharmaceutical Development and Technology, 16 (6), 627–636.
• 16. Kabanov, A. V., Batrakova, E. V., Miller, D. W. (2003). Pluronic® block copolymers as modulators of drug efflux transporter activity in the blood-brain barrier. Advanced Drug Delivery Reviews, 55 (1), 151–164.
• 17. Maynard, C., Swenson, R., Paris, J. A., Martin, J. S., Hallstrom, A. P., Cerqueira, M. D., Weaver, W. D. (1998). Randomized, controlled trial of RheothRx (poloxamer 188) in patients with suspected acute myocardial infarction. American Heart Journal, 135(5 I), 797–804.
• 18. Singh, S., Parhi, R., Garg, A. (2011). Formulation of topical bioadhesive gel of aceclofenac using 3-level factorial design. Iranian Journal of Pharmaceutical Research, 10 (3), 435-45.
• 19. Shin, S. C., Kim, J. Y., Oh, I. J. (2000). Mucoadhesive and physicochemical characterization of Carbopol-poloxamer gels containing triamcinolone acetonide. Drug Development and Industrial Pharmacy, 26 (3), 307–312.
• 20. BASF Web site. (2017). Retrieved May 22, 2020, from https://pharmaceutical.basf.com/
• 21. Valenta, C. (2005). The use of mucoadhesive polymers in vaginal delivery. Advanced Drug Delivery Reviews, 57 (11), 1692-712.
• 22. Tuğcu-Demiröz, F. (2017). Development of in situ poloxamer-chitosan hydrogels for vaginal drug delivery of benzydamine hydrochloride: Textural, mucoadhesive and in vitro release properties. Marmara Pharmaceutical Journal, 21 (4), 762–770.
• 23. Marques, M. R. C., Loebenberg, R., Almukainzi, M. (2011). Simulated biological fluids with possible application in dissolution testing. Dissolution Technologies, 18 (3), 15-27.
• 24. Tuğcu-Demiröz, F., Acartürk, F., Özkul, A. (2015). Preparation and characterization of bioadhesive controlled-release gels of cidofovir for vaginal delivery. Journal of Biomaterials Science, Polymer Edition, 26 (17), 1237-1255.
• 25. Tuǧcu-Demiröz, F., Acartürk, F., Erdoǧan, D. (2013). Development of long-acting bioadhesive vaginal gels of oxybutynin: Formulation, in vitro and in vivo evaluations. International Journal of Pharmaceutics, 457 (1), 25-39.
• 26. Patel, P., Varshney, P., Rohit, M. (2014). Analytical method development and validation for simultaneous estimation of metronidazole and amoxicillin in synthetic mixture by UV- visible spectroscopy. International Journal of Pharmacy and Pharmaceutical Sciences, 6 (SUPPL. 2), 317–319.
• 27. de Francisco, L. M. B., Rosseto, H. C., de Alcântara Sica de Toledo, L., dos Santos, R.S., de Souza Ferreira, S. B., Bruschi, M. L. (2019). Organogel composed of poloxamer 188 and passion fruit oil: Sol-gel transition, rheology, and mechanical properties. Journal of Molecular Liquids, 289, 111170.
• 28. Jones, D.S., Woolfson, A. D., Brown, A. F. (1997). Textural, viscoelastic and mucoadhesive properties of pharmaceutical gels composed of cellulose polymers. International Journal of Pharmaceutics, 151 (2), 223–233.
• 29. Amasya, G., Karavana, S. Y., Şen, T., Baloǧlu, E., Tarimci, N. (2012). Bioadhesive and mechanical properties of triamcinolone acetonide buccal gels. Turkish Journal of Pharmaceutical Sciences, 9 (1), 1–11.
• 30. Cevher, E., Taha, M. A. M., Orlu, M., Araman, A. (2008). Evaluation of mechanical and mucoadhesive properties of clomiphene citrate gel formulations containing carbomers and their thiolated derivatives. Drug Delivery, 15 (1), 57–67
• 31. Sorasitthiyanukarn, F. N., Rojsitthisak, P., Rojsitthisak, P. (2017). Kinetic study of chitosan-alginate biopolymeric nanoparticles for the controlled release of curcumin diethyl disuccinate. Journal of Metals, Materials and Minerals, 27 (2), 17–22.
• 32. Mehravaran, N., Moghimi, H., Mortazavi, S. A. (2009). The influence of various mucoadhesive polymers on in vitro performance of the resulting artificial saliva pump spray formulations. Iranian Journal of Pharmaceutical Research, 8 (1), 3–13.
• 33. Lapum, J., Verkuyl, M., Garcia, W., St-Amant, O., Tan, A. (2018). Vital Sign Measurement Across the Lifespan, 1st Canadian edition, Springer, Toronto, p. 26.
• 34. Moore, R. J., Watts, J. T. F., Hood, J. A. A., Burritt, D. J. (1999). Intra-oral temperature variation over 24 hours. European Journal of Orthodontics, 21(3), 249–261.
• 35. Ban, E., Park, M., Jeong, S., Kwon, T., Kim, E. H., Jung, K., Kim, A. (2017). Poloxamer-based thermoreversible gel for topical delivery of emodin: Influence of P407 and P188 on solubility of emodin and its application in cellular activity screening. Molecules, 22 (2), 246.
• 36. Zhang, K., Shi, X., Lin, X., Yao, C., Shen, L., Feng, Y. (2015). Poloxamer-based in situ hydrogels for controlled delivery of hydrophilic macromolecules after intramuscular injection in rats. Drug Delivery, 22 (3), 375–382.
• 37. Inal, O., Yapar, E. A. (2013). Effect of mechanical properties on the release of meloxicam from poloxamer gel bases. Indian Journal of Pharmaceutical Sciences, 75 (6), 700–706.
• 38. Koffi, A. A., Agnely, F., Ponchel, G., Grossiord, J. L. (2006). Modulation of the rheological and mucoadhesive properties of thermosensitive poloxamer-based hydrogels intended for the rectal administration of quinine. European Journal of Pharmaceutical Sciences, 27 (4), 328–335.
• 39. Ibrahim, E. S. A., Ismail, S., Fetih, G., Shaaban, O., Hassanein, K., Abdellah, N. H. (2012). Development and characterization of thermosensitive pluronic-based metronidazole in situ gelling formulations for vaginal application. Acta Pharmaceutica, 62 (1), 59–70.
• 40. Tirnaksiz, F., Robinson, J. R. (2005). Rheological, mucoadhesive and release properties of Pluronic F-127 gel and Pluronic F-127/polycarbophil mixed gel systems. Pharmazie, 60 (7), 518-23.
• 41. Todica, M., Pop, C. V., Udrescu, L., Pop, M. (2010). Rheological behavior of some aqueous gels of carbopol with pharmaceutical applications. Chinese Physics Letters, 27 (1), 018301.
• 42. Rahimi, S., Natan, B. (2000). Numerical solution of the flow of power-law gel propellants in converging injectors. Propellants, Explosives, Pyrotechnics, 25 (4), 203-212.
• 43. Franzén, H. M., Draget, K. I., Langebäck, J., Nilsen-Nygaard, J. (2015). Characterization and properties of hydrogels made from neutral soluble chitosans. Polymers, 7, 373-389.
• 44. Liu, W.H., Yu, T.L., Lin, H.L. (2007). Shear thickening behavior of dilute poly(diallyl dimethyl ammonium chloride) aqueous solutions. Polymer, 48 (14), 4152–4165.
• 45. Jones, D. S., Woolfson, A. D., Djokic, J. (1996). Texture profile analysis of bioadhesive polymeric semisolids: Mechanical characterization and investigation of interactions between formulation components. Journal of Applied Polymer Science, 61 (12), 2229–2234.
• 46. Tan, Y. T. F., Peh, K. K., Al-Hanbali, O. (2000). Effect of carbopol and polyvinylpyrrolidone on the mechanical, rheological, and release properties of bioadhesive polyethylene glycol gels. AAPS PharmSciTech, 1 (3), E24.
• 47. Cevher, E., Sensoy, D., Taha, M. A. M., Araman, A. (2008). Effect of thiolated polymers to textural and mucoadhesive properties of vaginal gel formulations prepared with polycarbophil and chitosan. AAPS PharmSciTech, 9 (3), 953-65.
• 48. Sarkar, U., Raha, A., Mukherjee, P., Paul, M., Bagchi, A. (2018). Development and evaluation of Metronidazole containing topical gel using different gelling agents. Asian Journal of Pharmacy and Pharmacology, 4 (6), 785–789.
• 49. Zhang, Y., Huo, M., Zhou, J., Zou, A., Li, W., Yao, C., Xie, S. (2010). DDsolver: An add-in program for modeling and comparison of drug dissolution profiles. The AAPS Journal, 12 (3), 263–271.
• 50. Soares, P. I. P., Sousa, A. I., Silva, J. C., Ferreira, I. M. M., Novo, C. M. M., Borges, J. P. (2016). Chitosan-based nanoparticles as drug delivery systems for doxorubicin: Optimization and modelling. Carbohydrate Polymers, 147 304–312.
• 51. Wang, Y., Jiang, S., Wang, H., Bie, H. (2017). A mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases. PLoS ONE, 12 (12), e0189478.
• 52. Parhi, R. Suresh, P. (2015). Alginate-poloxamer beads for controlled release of metoprolol succinate. Turkish Journal of Pharmaceutical Sciences, 12 (1), 59–66.
• 53. Mori, N. M., Patel, P., Sheth, N. R., Rathod, L. V., Ashara, K.C. (2017). Fabrication and characterization of film-forming voriconazole transdermal spray for the treatment of fungal infection. Bulletin of Faculty of Pharmacy, Cairo University, 55 (1), 41–51.