5-FU Drug Loading During the Production of Hydroxyapatite-Gelatin and Hydroxyapatite-Chitosan Biocomposites in the Simulated Body Fluid Medium and Drug Release Studies

Yıl 2018, Cilt: 11 Sayı: 3, 587 - 605, 30.12.2018

Nalan Erdöl Aydın

https://doi.org/10.18185/erzifbed.413332

Cited By: 2

Öz

Hydroxyapatite, (HAp,Ca₁₀(PO₄)₆(OH)₂) is a bioceramic applied in different biomedical areas. In
recent studies, it has been concluded that hydroxyapatite nanoparticles has
inhibition effect on different kind of tumors. Therefore, HAp or composite
materials including HAp have been preferred in controlled drug delivery studies
as a drug carrier. However, hard structure and highly fragile structure
of hydroxyapatite limited its usage in clinical applications. This mechanical
disadvantages can be overcomed by using a polymer to produce a
hydroxyapatite-polymer biocomposite.In this study, hydroxyapatite-gelatin
(HAp-GEL) and hydroxyapatite-chitosan (HAp-CTS) biocomposites were produced by
wet precipitation method at pH 7.4 and 37°C implementing glutaraldehyde (GA) as a
cross-linking agent in the SBF (Simulated Body Fluid) medium. Drug loading
process was performed during the production of biocomposites by wet
precipitation method. By running experiments with different amounts (2% and 5%)
of glutaraldehyde (GA) and different biocomposites, the effect of
glutaraldehyde and type of composite on drug loading efficiency and drug
release profiles were investigated. All experiments were performed with
5-Fluorouracil (5-FU) drug. Drug loading performance of 5-FU at the HAp-GEL and
Hap-CTS biocomposites were determined in deionized water, phosphate buffer
solution (PBS) and HCl solution. To determine of drug loading and drug release
performace of the samples, UV spectrophotometer was used. Fourier transform
infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron
microscopy (SEM), thermogravimetric analysis (TGA) and particle size analyses were performed to
characterize the produced biocomposites.

Anahtar Kelimeler

Biocomposite, Hydroxyapatite, Drug Release, Drug Loading, Gelatin, Chitosan

Hidroksiapatit-Jelatin ve Hidroksiapatit-Kitosan Biyokompozitlerin Yapay Vücut Sıvısı Ortamında Üretimi Sırasında 5-FU İlacının Yüklenmesi ve İlaç Salım Çalışmaları

Öz

Hidroksiapatit,
(HAp,Ca₁₀(PO₄)₆(OH)₂) farklı medikal alanlarda uygulaması olan bir
biyoseramiktir. Son yapılan çalışmalarda,
nanoboyutlu HAp parçacıklarının farklı tümör türleri üzerinde gelişimi önleyici
etki gösterdiği görülmüştür. Bu nedenle, HAp veya HAp içeren kompozit
malzemeler kontrollü ilaç salımı uygulamalarında ilaç taşıyıcı ortam olarak
tercih edilmiştir. Ancak, sert yapısı ve yüksek kırılganlığı klinik
uygulamalarda kullanımını sınırlamaktadır. Bu mekanik dezavantajlar, polimer
kullanılarak hidroksiapatit-polimer biyokompozit üretilmesiyle aşılabilmektedir.Bu
çalışmada, hidroksiapatit-jelatin
(HAp-GEL) ve hidroksiapatit-kitosan (HAp-CTS) biyokompozitler, pH 7.4 ve 37°C’
de yaş çöktürme yöntemiyle, çapraz bağlama ajanı olarak gluteraldehitin (GA)
kullanıldığı SBF (Yapay Vücut Sıvısı) ortamında üretilmiştir. İlaç yüklemi
işlemi, biyokompozitlerin yaş çöktürme yöntemi ile üretimi sırasında
gerçekleştirilmiştir. Farklı miktarlarda (%2 ve %5) gluteraldehit (GA) ve
farklı biyokompozitler ile yürütülen deneylerde gluteraldehitin ve biyokompozit
türünün ilaç yükleme verimi ve ilaç salım profili üzerine etkisi incelenmiştir.
Tüm deneyler 5-Fluorouracil (5-FU) ilacı ile gerçekleştirilmiştir. HAp-GEL ve
Hap-CTS biyokompozitlerde 5-FU ilacının yüklenme performansı deiyonize su,
fosfat tampon çözelti (PBS) ve HCl çözelti ortamında incelenmiştir. Numunelerin
5-FU ilaç yükleme ve ilaç salımı performansının belirlenmesinde UV
spektrofotometre kullanılmıştır. Üretilen biyokompozitleri karakterize etmek
için, Fourier dönüşümlü kızılötesi spektroskopi (FTIR), X-ışını kırınımı (XRD),
taramalı elektron mikroskobu (SEM), termogravimetrik analiz (TGA) ve partikül
boyut analizleri yapılmıştır.

Anahtar Kelimeler

Hidroksiapatit, Biyokompozit, İlaç Salım, İlaç Yükleme, Jelatin, Kitosan

Kaynakça

• Afshar, A, Ghorbani, M., Ehsani, N., Saeri, M.R., Sorrell, C.C. 2002. Some Important Factors in the Wet Precipitation Process of Hydroxyapatite. Materials and Design, 24, 197–202.
• Alhalafi, A.M. 2017. Applications of Polymers in Intraocular Drug Delivery Systems. Oman Journal of Ophthalmology, 10(1), 3-8.
• Arami, H., Mohajerani, M., Mazloumia, M., Khalifehzadeh, R., Laka, A. Sadrnezhaad, S.K. 2008. Rapid Formation of Hydroxyapatite Nanostrips Via Microwave Irradiation. Journal of Alloys and Compounds, 469, 391–394.
• Ashwanikumar, N., Kumar, N.A., Nair, S.A. ve Kumar, G.S.V. 2014. Dual Drug Delivery of 5-Fluorouracil (5-FU) and Methotrexate (MTX) through Random Copolymeric Nanomicelles of PLGA and Polyethylenimine Demonstrating Enhanced Cell Uptake and Cytotoxicity. Colloids and surfaces B: Biointerfaces, 122, 520–528.
• Azami, M., Rabiee, M., Mostarzadeh, F. 2010. Glutaraldehyde Crosslinked Gelatin/hydroxyapatite Nanocomposite Scaffold, Engineered Via Compound Techniques. Polymer Composites, 31 (12), 2112-2120.
• Başargan, T., Erdol Aydin, N., Nasun-Saygılı, G. 2017. Hydroxyapatite-chitosan Biocomposites Synthesized in the Simulated Body Fluid and Their Drug Loading Studies. Journal of Material Science: Materials in Medicine, 28, 180 (10).
• Başargan, T., Erdol Aydin, N., Nasun-Saygılı, G. 2016a. In Situ Biomimetic Synthesis to Produce Hydroxyapatite-polyvinyl Alcohol Biocomposites: Precipitation and Spray Drying Methods. Polymer-plastic Technology and Engineering, 55 (5), 447-452.
• Başargan, T., Erdol-Aydin, N., Nasun-Saygili, G. 2016b. Spray Dried Hydroxyapatite-polyvinyl Alcohol Biocomposites, De Gruyter. Journal of Polymer Engineering, 36 (8), 795-804.
• Bera, T., Vivek, A.N., Saraf, S.K., Ramachandrarao, P. 2008. Characterization of Biomimetically Synthesized Hap-Gel Nanocomposites as Bone Substitute. Biomedical Materials, 3.
• Best, S.M., Porter,A. E., Thian E.S. ve Huang, J. 2008. Bioceramics : Past, Present and for the Future. Journal of the European Ceramic Society, 28 (7), 1319-1327.
• Chang, M.C., Douglas, W.H. ve Tanaka, J. 2006. Organic-inorganic Interaction and the Growth Mechanism of Hydroxyapatite Crystals in Gelatin Matrices between 37 and 80°C. Journal of Materials Science, 17, 387-396.
• Çakmak, S. 2015. Kemik Doku Onarımı için Hidroksiapatit/Peptit Amfifil Bazlı Nanokompozit Doku İskelelerinin Geliştirilmesi. Doktora Tezi, Hacettepe Üniversitesi Nanoteknoloji ve Nanotıp Anabilimdalı, Ankara, 4-34.
• Dutta, R.K., Sahu, S. 2012. Development of a Novel Probe Sonication Assisted Enhanced Loading of 5-FU in SPION Encapsulated Pectin Nanocarriers for Magnetic Targeted Drug Delivery System. European Journal of Pharmaceutics and Biopharmaceutics, 82, 58–65.
• Elhassan, G.O. 2017. Design and Evaluation of Controlled Release Matrix Tablet of Aspirin by Using Hydrophobic Polymer. International Journal of Pharmaceutical Research and Allied Sciences, 6(4), 32-41.
• El-Tahlawy, K.F., El-bendary, M.A., Elhendawy, A.G., Hudson, S.M. 2005. The Antimicrobial Activity of Cotton Fabrics Treated with Different Crosslinking Agents and Chitosan. Carbohydrate Polymers, 60, 421-430.
• Fomin, A.S., Barinov, S., Ievlev, V.M., Smirnov, V.V., Mikhailov, B.P., Belonogov, E.K., Drozdova, N.A. 2008. Nanocrystalline Hydroxyapatite Ceramics Produced by Low-Temperature Sintering After High-pressure Treatment. Chemical Technology, 418 (3), 352–355.
• Fournier, E., Passirani, C., Colin,N., Breton, P., Sagodira, S., Benoit, J. 2004. Development of Novel 5-FU-loaded Poly(methylidene malonate 2.1.2)-based Microspheres for the Treatment of Brain Cancers. European Journal of Pharmaceutics and Biopharmaceutics, 57, 189–197.
• Ganguly, K., Aminabhavi, T.M., Kulkarni, A.R. 2011. Colon targeting of 5-Fluorouracil Using Polyethylene Glycol Cross-linked chitosan Microspheres Enteric Coated with Cellulose Acetate Phthalate, Industrial & Engineering Chemistry Research, 50, 11797–11807.
• Gomez-Guillen, M.C., Gimenez, B., Caballero, M., Montero, M.P. 2011. Functional and Bioactive Properties of Collagen and Gelatin from Alternative Sources: A Review, Biochemical Journal, 25(8), 1813-1827.
• Gouda, R., Baishya, H., Qing, Zhao 2017. Application of Mathematical Models in Drug Release Kinetics of Carbidopa and Levodopa ER Tablets. Journal of Developing Drugs, 6(2).
• Guang, W.Y. 2002. The effect of Chitosan and Its Derivatives on the Dyeability of Silk. Ph.D. Thesis, Hong Kong Polytechnic University. Hasret, E. 2010. Hidroksiapatit Sentezi, Karakterizasyonu ve Adsorban Özelliğinin İncelenmesi. Yüksek Lisans Tezi, İTÜ Fen Bilimleri Enstitüsü, İstanbul, 10-22.
• Hench, L. 1991.Bioceramics from Concept to Clinic. Journal of the American Ceramic Society, 74 (7), 1487-1510.
• Jain, A., Jain, S.K. 2016. In vitro release kinetics model fitting of liposomes: An insight. Chemistry and Physics of Lipids, 201, 28-40.
• Janes, K.A., Calvo, P., Alonso, M.J. 2001. Polysaccharide Colloidal Particles as Delivery Systems for Macromoleculs. Advanced Drug Delivery Reviews, 47, 83- 97.
• Kahraman, E. 2017. SBF Ortamında Üretilen Hidroksiapatit-Jelatin Kompozit Malzemelerin İlaç Salım Performansının İncelenmesi, Yüksek Lisans Tezi, İTÜ-Fen Bilimleri Enstitüsü, İstanbul.
• Kalita, S.J., Bhardwaja, A. 2007. Nanocrystalline Calcium Phosphate Ceramics in Biomedical Enginering. Material Science Engineeering: C, 27(3), 441-449.
• Kim, H.W., Knowles, J.C., Kim, H.E. 2005. Porous Scaffolds of Gelatin-Hydroxyapatite Nanocomposites Obtained by biomimetic approach: Characterization and Antibiotic Drug Release. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 74 (2) 686-698.
• Kumar, S., Koh, J. 2012. Physiochemical, Optical and Biological Activity of Chitosan-Chromone Derivative for Biomedical Applications. International Journal of Molecular Sciences, 13, 6102-6116.
• Kumari, S., Rath, P., Kumar, A.S.H., Tiwari, T.N. 2015. Extraction and characterization of chitin and chitosan from fishery waste by chemical method. Environmental Technology & Innovation, 3, 77-85.
• Li, Y., Liu, T., Zheng, J., Xu, X. 2013. Glutaraldehyde-crosslinked Chitosan/hydroxyapatite Bone Repair Scaffold and Its Application as Drug Carrier for Icariin. Journal of Applied Polymer Science, 130 (3), 1539-1547.
• Lin, Y., Li, Y., Ooi, C.P. 2012. 5-Fluorouracil Encapsulated HA/PLGA Composite Microspheres for Cancer Therapy. Journal of Materials Science: Materials in Medicine, 23, 2453–2460.
• Liu, Y., Hou, D., Wang, G., 2004. A Simple Wet Chemical Synthesis and Characterization of Hydroxyapatite Nanorods. Materials Chemistry and Physics, 86, 69–73.
• Lopez-Macipe, A., Rodriguez-Clemente, R., Hidalgo-Lopez, A., Arita, I., Garcia-Garduno, M.V., Rivera, E. ve Castano, V.M. 1998. Wet Chemical Synthesis of Hydroxyapatite Particles from Nonstoichiometric Solutions. Journal of Materials Synthesis and Processing, 6(1), 21-26.
• Misra, A., Shahiwala, A. 2014. Applications of Polymers in Drug Delivery, Smithers Rapra, US, Ch.2, 1-38.
• Mobasherpour, I., Soulati Heshajin, M., Kazemzadeh, A., Zakeri, M. 2007. Synthesis of Nanocrystalline Hydroxyapatite by Using Precipitation Method. Journal of Alloys and Compounds, 430(1-2), 330–333.
• Murugan R. ve Ramakrishna, S.2005. Development of Nanocomposites for Bone Grafting. Composites Science and Technology, 65, 2385-2406.
• Narbat, M.K., Orang, F., Hashtjin, M.S., Goudarzi, A. 2006. Fabrication of Porous Hydroxyapatite-gelatin Composite Scaffolds for Bone Tissue Engineering. Journal of Iranian Biomedical, 10 (4), 215-223.
• Olukman, M., Şanlı, O., Solak, E.K. 2012. Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads. Journal of Biomaterials and Nanobiotechnology, 3, 469-479.
• Özbaş, Z., Gürdağ, G. 2016. Synthesis and Characterization of 5‐Fluorouracil‐loaded Glutaraldehyde Crosslinked Chitosan Hydrogels. Journal of Natural and Applied Sciences, 20(3), 460-467.
• Parhi, P., Ramanan, A., Ray, R. 2004. A Convenient Route for the Synthesis of Hydroxyapatite through a Novel Microwave-mediated Metathesis Reaction. Materials Letters, 58, 3610-3612.
• Peng, Z., Li, Z., Shen, Y., 2012, Preparation and in Vitro Characterization of Gelatin Microspheres Containing 5-Fluorouracil. Journal of Macromolecular Science, Part B, 51 (6), 1117-1124.
• Rampine, A., Borgogno, M., Blasi, P., Bellich, B., Cesaro, A. 2013. Chitosan Nanoparticles: Preperation, Size Evolution and Stability. International Journal of Pharmaceutics, 455 (1-2), 219-228.
• Rehman, I., Bonfield, W. 1997. Characterization of Hydroxyapatite and Carbonated Apatite by Photo Acoustic FTIR Spectroscopy. Journal of Materials Science: Materials in Medicine, 8, 1-4.
• Sahoo, R., Sahoo, S., Lochan, P. 2013. Synthesis and Characterization of Gelatin-chitosan Nanocomposite to Explore the Possible Use as Drug Delivery Vehicle. European Scientific Journal, 9 (18), 134-141.
• Santos, C., Rovath, C.F., Franke, R.P., Almeida, M.M., Costa, M.E.V. 2009. Spray-Dried Hydroxyapatite-5-Fluorouracil Granules as a Chemotherapeutic Delivery System. Ceramics International, 35, 509-513.
• Santos, M.H., Oliveira, M., Souza, L.F., Mansur, H.S., Vasconcelos, W.L. 2004. Synthesis Control and Characterization of Hydroxyapatite Prepared by Wet Precipitation Process. Materials Research, 7(4), 625-630.
• Sastre, R.L., Olmo, R., Teijon, C., Muniz, E., Teijon, J.M. ve Blanco, M.D. 2007. 5-Fluorouracil Plasma Levels and Biodegradation of Subcutaneouslyinjected Drug-loaded Microspheres Prepared by Spray-drying Poly(d,l-lactide) and Poly(d,l-lactide-co-glycolide) Polymers. International Journal of Pharmaceutics, 338, 180–190.
• Siddharthan, A., Seshadri S.K., Sampath Kumar, T.S. 2006 . Influence of Microwave Power on Nanosized Hydroxyapatite Particles. Scripta Materialia, 55, 175–178.
• Singhvi, G., Singh, M. 2011. Revıew: In-vitro Drug Release Characterization Models. International Journal of Pharmaceutical Studies and Research, 2(1), 77-84.
• Sionkowska, A., Wisniewski, M., Skopinska, J., Vicini, S., Marsano, E. 2005. The Influence of UV Irradiation on the Mechanical Properties of Chitosan/poly(vinyl pyrrolidone) Blends. Polymer Degradation and Stability, 88 (2) 261-267.
• Stigter, M., Bezemer, J., Groot, K. ve Layrolle, P. 2004. Incorporation of Different Antibiotics into carbonated Hydroxyapatite Coatings on Titanium Implants, Release and Antibiotic Efficacy. Journal of Controlled Release, 99, 127–137.
• Suvakanta, D., Murthy, P.N. Nath, L., Chowdhury, P. 2010. Kinetic Model on Drug Release from Controlled drug delivery systems, Acta Poloniae Pharmaceutica in Drug Research, 67(3) 217-223.
• Teseng, C., Chen, J., Wu, Y., Fang, H., Lin, F., Tang, T. 2015. Development of Lattice-Inserted5-Fluorouracil-Hydroxyapatite Nanoparticles as a Chemotherapeutic Delivery. Journal of Biomaterials Applications, 30(4), 388-397.
• Wang, S.F., Shen, L., Tong, Y.J., Chen, L., Phang, I.Y., Lim, P.Q., Liu, T.X. 2005. Biopolimer Chitosan/Montmorillonite Nanocomposite: Preparation and Characterization. Polimer Degredation and Stability, 9 (1), 123-131.
• Verwilghen, C., Chkir, M., Rio, S., Nzihou, A., Sharrock, P., Depelsenaire, G. 2008. Convenient Conversion of Calcium Carbonate to Hydroxyapatite at Ambient Pressure. Materials Science and Eengineering C, 29, 771-773.
• Xiao, J., Zhu, Y., Liu, Y., Zeng, Y. ve Xu, F. 2009, An asymmetric Coating Composed of Gelatin and Hydroxyapatite for the Delivery of Water Insoluble Drug. Journal of Materials Science: Materials in Medicine, 20, 889–896.
• Yanga, Z., Jianga, Y., Wangb, Y., Maa, L., Lia, F. 2004. Preparation and Thermal Stability Analysis of Hydroxyapatite Derived from the Precipitation Process and Microwave Irradiation Method. Materials Letters, 58, 3586-3590.
• Zhou, Z., Liu, L., Liu, Q., Zhao, Y., Xu,G., Tang, A., Zeng, W., Yi, Q. and Zhou, J. 2012, Study on Controlled Release of 5-Fluorouracil from Gelatin/Chitosan Microspheres. Journal of Macromolecular Science, Part A: Pure and Applied Chemistry, 49 (12), 1030-1034.