MAKSİLLOFASİYAL CERRAHİ UYGULAMALARINDA KEMİK REJENERASYONU İÇİN BİFOSFONAT YÜKLÜ PLGA MİKROKÜRELERİ İÇEREN İN SİTU JEL FORMÜLASYONLARININ GELİŞTİRİLMESİ; FORMÜLASYONLAR, İN VİTRO KARAKTERİZASYON VE SALIM KİNETİK ÇALIŞMALARI

Amaç: Bu çalışmada maksillofasiyal cerrahide implant bölgesinde kemik rejenerasyonunu artırmak için hazırlanan bifosfonat yüklü mikrosfer ilaç taşıyıcı sistemin in situ jel formülasyonu ile lokal olarak uygulanması amaçlanmıştır. Gereç ve Yöntem: Kombinasyon taşıyıcı sistemini tasarlamak için bifosfonat yüklü PLGA mikroküreleri, hazırlanan in situ jell formülasyonlarına yüklenmiştir. Geliştirilen formülasyonlar için in vitro ilaç salım, pH, berraklık, sol-jel geçiş sıcaklığı ve salım kinetik çalışmaları değerlendirilmiştir. Sonuç ve Tartışma: Üretilen formülasyonların yerinde jelleşme sıcaklıkları 33 ila 37°C arasında; pH değerleri 6 civarında ve bütün formülasyonlar 20 gauge’lik şırıngalardan uygulanabilir düzeydeydi. Preparatlar içerisinde yer alan, P407 ve kitosan miktarları arttıkça, in vitro patlama salınımını düşürürken aynı zamanda viskoziteyi yükselmiştir. Bununla birlikte, her bir in situ jel formülasyonu, 14 günlük bir süre içinde salım yapmıştır. Sonuç olarak, Bifosfonat yüklü PLGA mikroküreleri yüklü in situ jel formülasyonlarına ayrıntılı olarak değerlendirilmiş ve özellikle dental implant uygulamalarında maksillofasiyal cerrahide lokal olarak uygulanabilir bir ilaç taşıma sistemi olarak sunulmuştur.

Anahtar Kelimeler:

Bifosfonat, Kombinasyon Taşıma Sistemleri, PLGA Mikroküreler, Poloksamer, Kitosan

DEVELOPMENT OF IN SITU GEL FORMULATION CONTAINING BISPHOSPHONATE-LOADED PLGA MICROSPHERES FOR BONE REGENERATION IN MAXILLOFACIAL SURGERY APPLICATIONS; FORMULATIONS, IN VITRO CHARACTERIZATION AND RELEASE KINETIC STUDIES

Objective: In this study, it was aimed to locally apply the bisphosphonate-loaded microsphere drug delivery system with in situ gel formulation, which was prepared to increase bone regeneration in the implant area in maxillofacial surgery. Material and Method: In order to design the combination delivery system, bisphosphonate-loaded PLGA microspheres were embedded in the prepared in situ gel formulations. In vitro drug release, pH, clarity, sol-gel transition temperature and release kinetic studies were all assessed for the developed formulations. Result and Discussion: The produced formulations' in situ gelation temperatures ranged from 33 to 37°C; their pH values were in the range of 6; and they were all syringeable, which is defined as the force required to expel each formulation from a syringe equipped with a 20-gauge needle. With the preparations, the amounts of P407 and chitosan increased, lowering in vitro burst release while simultaneously raising viscosity. However, each in situ gel formulation releases over a period of 14 days. Consequently, Bisphosphonate loaded PLGA microspheres embedded in situ gel formulations were elucidated in detail and presented as a locally applicable drug delivery system in maxillofacial surgery, especially in dental implant applications

Keywords:

Bisphosphonate, Combination Delivery Systems, PLGA Microspheres, Poloxamer, Chitosan,

PDF

___

1. Haynes, D.R., Crotti, T., Zreiqat, H. (2004). Regulation of osteoclast activity in peri-implant tissues, Biomaterials, 25, 4877-4885. [CrossRef] 2. Retzepi, M., Donos, N. (2010). Guided bone regeneration: biological principle and therapeutic applications, Clinical Oral Implants Research, 21, 567-576. [CrossRef]
3. Brown, J.E., Coleman, R.E. (2001). The role of bisphosphonates in breast cancer: the present and future role of bisphosphonates in the management of patients with breast cancer, Breast Cancer Research, 4, 1-6. [CrossRef]
4. Von Knoch, F., Jaquiery, C., Kowalsky, M., Schaeren, S., Alabre, C., Martin, I., Rubash, H.E., Shanbhag, A.S. (2005). Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells, Biomaterials, 26, 6941-6949. [CrossRef]
5. Miladi, K., Sfar, S., Fessi, H., Elaissari, A. (2015). Encapsulation of alendronate sodium by nanoprecipitation and double emulsion: From preparation to in vitro studies, Industrial Crops and Products, 72, 24-33. [CrossRef]
6. Carvalho, I., Marques, C., Oliveira, R., Coelho, P., Costa, P., Ferreira, D. (2015). Sustained drug release by contact lenses for glaucoma treatment—A review, Journal of Controlled Release, 202, 76-82. [CrossRef]
7. Öz, U.C., Toptaş, M., Küçüktürkmen, B., Devrim, B., Saka, O.M., Deveci, M.S., Bilgili, H., Ünsal, E., Bozkır, A. (2020). Guided bone regeneration by the development of alendronate sodium loaded in-situ gel and membrane formulations, European Journal of Pharmaceutical Sciences, 155, 105561. [CrossRef] 8. Wysowski, D.K., Chang, J.T. (2005). Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Archives of Internal Medicine, 165, 346-347. [CrossRef]
9. Ideguchi, H., Ohno, S., Hattori, H., Ishigatsubo, Y. (2007). Persistence with bisphosphonate therapy including treatment courses with multiple sequential bisphosphonates in the real world, Osteoporosis international, 18, 1421-1427. [CrossRef] 10. Dong, Y., Su, H., Jiang, H., Zheng, H., Du, Y., Wu, J., Li, D. (2017). Experimental study on the influence of low-frequency and low-intensity ultrasound on the permeability of the Mycobacterium smegmatis cytoderm and potentiation with levofloxacin, Ultrasonics Sonochemistry, 37, 1-8. [CrossRef]
11. Pardeshi, S.R., Nikam, A., Chandak, P., Mandale, V., Naik, J.B., Giram, P.S. (2021). Recent advances in PLGA based nanocarriers for drug delivery system: a state of the art review, International Journal of Polymeric Materials and Polymeric Biomaterials, 1-30. [CrossRef]
12. Ruhe,P., Boerman, O., Russel, F., Spauwen, P., Mikos, A., Jansen, J. (2005). Controlled release of rhBMP-2 loaded poly (dl-lactic-co-glycolic acid)/calcium phosphate cement composites in vivo. Journal of Controlled Release, 106, 162-171. [CrossRef] 13. Nasra, M.M., Khiri, H.M., Hazzah, H.A., Abdallah, O.Y. (2017). Formulation, in-vitro characterization and clinical evaluation of curcumin in-situ gel for treatment of periodontitis, Drug Delivery, 24, 133-142. [CrossRef]
14. Ünal, S., Aktaş, Y. (2022). Bisphosphonate-loaded PLGA microspheres for bone regeneration in dental surgery: formulation, characterization, stability, and comprehensive release kinetic studies. International Journal of Polymeric Materials and Polymeric Biomaterials, 1-12. [CrossRef] 15. El-Kamel, A. (2002), In vitro and in vivo evaluation of Pluronic F127-based ocular delivery system for timolol maleate. International Journal of Pharmaceutics, 241, 47-55. [CrossRef] 16. Polat, H.K. (2022). In situ gels triggered by temperature for ocular delivery of dexamethasone and dexamethasone/ SBE-β-CD complex., Journal of Research in Pharmacy, 26(4), 873-883. [CrossRef]
17. Maheshwari, M., Miglani, G., Mali, A., Paradkar, A., Yamamura, S., Kadam, S. (2006). Development of tetracycline-serratiopeptidase-containing periodontal gel: formulation and preliminary clinical study, AAPS PharmSciTech, 7, E162-E171. [CrossRef] 18. Qi, H., Chen, W., Huang, C., Li, L., Chen, C., Li, W., Wu, C. (2007). Development of a poloxamer analogs/carbopol-based in situ gelling and mucoadhesive ophthalmic delivery system for puerarin. International Journal of Pharmaceutics, 337(1-2), 178-187. [CrossRef]
19. Alexandridis, P., Hatton, T.A. (1995). Poly (ethylene oxide) poly (propylene oxide) poly (ethylene oxide) block copolymer surfactants in aqueous solutions and at interfaces: thermodynamics, structure, dynamics, and modeling, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 96, 1-46. [CrossRef]
20. Karataş, A., Sonakin, O., Kiliçarslan, M., Baykara, T. (2009). Poly (ε-caprolactone) microparticles containing Levobunolol HCl prepared by a multiple emulsion (W/O/W) solvent evaporation technique: Effects of some formulation parameters on microparticle characteristics, Journal of Microencapsulation, 26 63-74. [CrossRef] 21. 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, 263-271. [CrossRef]
22. Pham, D.T., Phewchan, P., Navesit, K., Chokamonsirikun, A., Khemwong, T., Tiyaboonchai, W. (2021). Development of metronidazole-loaded in situ thermosensitive hydrogel for periodontitis treatment, Turkish Journal of Pharmaceutical Sciences, 18, 510. [CrossRef]
23. Bohorquez, M., Koch, C., Trygstad, Pandit, N. (1999). A study of the temperature-dependent micellization of pluronic F12, Journal of Colloid and Interface Science, 216, 34-40. [CrossRef]
24. Okur, N., Yozgatli, V., Okur, M.E., (2020). In vitro–in vivo evaluation of tetrahydrozoline‐loaded ocular in situ gels on rabbits for allergic conjunctivitis management, Drug Development Research, 81, 716-727. [CrossRef]
25. Karatas, A., Boluk, A., Hilal Algan, A. (2014). Poloxamer/Chitosan in situ gelling system for ocular delivery of ofloxacin. Current Drug Therapy, 9(4), 219-225. [CrossRef]
26. Gilbert, J. C., Richardson, J. L., Davies, M. C., Palin, K. J., Hadgraft, J. (1987). The effect of solutes and polymers on the gelation properties of pluronic F-127 solutions for controlled drug delivery. Journal of Controlled Release, 5(2), 113-118. [CrossRef] 27. Edsman, K., Carlfors, J., Petersson, R. (1998). Rheological evaluation of poloxamer as an in situ gel for ophthalmic use, European Journal of Pharmaceutical Sciences, 6, 105-112. [CrossRef]
28. Bansal, M., Mittal, N., Yadav, S.K., Khan, G., Gupta, P., Mishra, B., Nath, G.Ç (2018). Periodontal thermoresponsive, mucoadhesive dual antimicrobial loaded in-situ gel for the treatment of periodontal disease: Preparation, in-vitro characterization and antimicrobial study, Journal of Oral Biology and Craniofacial Research, 8, 126-133. [CrossRef] 29. Du, L., Tong, L., Jin, Y., Jia, J., Liu, Y., Su, C., Li, X. (2012). A multifunctional in situ–forming hydrogel for wound healing. Wound Repair and Regeneration, 20(6), 904-910. [CrossRef]
30. Fathalla, Z.M., Vangala, A., Longman, M., Khaled, K.A., Hussein, A.K., El-Garhy, O.H., Alany, R.G. (2017). Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies, European Journal of Pharmaceutics and Biopharmaceutics, 114, 119-134. [CrossRef]
31. Chu, K., Chen, L., Xu, W., Li, H., Zhang, Y., Xie, W., Zheng, J. (2013). Preparation of a paeonol-containing temperature-sensitive in situ gel and its preliminary efficacy on allergic rhinitis. International Journal of Molecular Sciences, 14(3), 6499-6515. [CrossRef]
32. Munot, N.M., Kishore, G., Mithila, K. (2014). Development and evaluation of biodegradable microspheres embedded in in situ gel for controlled delivery of hydrophilic drug for treating oral infections: In vitro and in vivo studies, Asian Journal of Pharmaceutics (AJP), 8, 3. [CrossRef] 33. Morsi, N., Ghorab, D., Refai, H., Teba, H. (2016). Ketoroloac tromethamine loaded nanodispersion incorporated into thermosensitive in situ gel for prolonged ocular delivery. International Journal of Pharmaceutics, 506(1-2), 57-67. [CrossRef]
34. Beg, S., Dhiman, S., Sharma, T., Jain, A., Sharma, R. K., Jain, A., Singh, B. (2020). Stimuli responsive in situ gelling systems loaded with PLGA nanoparticles of moxifloxacin hydrochloride for effective treatment of periodontitis. AAPS PharmSciTech, 21(3), 1-18. [CrossRef]
35. Hu, C., Feng, H., Zhu, C. (2012). Preparation and characterization of rifampicin-PLGA microspheres/sodium alginate in situ gel combination delivery system, Colloids and Surfaces B: Biointerfaces, 95,162-169. [CrossRef]
36. Yang, H., Li, J., Patel, S.K., Palmer, K.E., Devlin, B., Rohan, L.C. (2019). Design of poly (lactic-co-glycolic acid)(PLGA) nanoparticles for vaginal co-delivery of griffithsin and dapivirine and their synergistic effect for HIV prophylaxis, Pharmaceutics, 11, 184. [CrossRef]
37. Papadopoulou, V., Kosmidis, K., Vlachou, M., Macheras, P. (2006). On the use of the Weibull function for the discernment of drug release mechanisms, International Journal of Pharmaceutics, 309, 44-50. [CrossRef]
38. Sanchez, L.T., Pinzon, M.L., Villa, C.C. (2022). Development of active edible films made from banana starch and curcumin-loaded nanoemulsions, Food Chemistry, 371, 131121. [CrossRef]