Journal of Food and Bioprocess Engineering

Optimization and development of insulin nanoparticles by new thiolated chitosan derivative with ionic gelation method using a model-based methodology

Document Type : Original research

Authors

1 Transfer Phenomena Laboratory (TPL), Department of Food Science, Technology and Engineering, Faculty of Agricultural Engineering and Technology,College of Agriculture and Natural Resources, University of Tehran, PO Box: 4111, 31587-11167 Karaj, Iran

2 Faculty of food industry and agriculture , Standard Research Institute (SRI), Karaj, Iran

3 Center of Excellence for Application of Modern Technologies for Producing Functional Foods and Drinks

4 Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

5 Institute of Biochemistry & Biophysics (IBB), University of Tehran, Tehran, Iran

Abstract

Insulin therapy has been the best choice for the clinical management of diabetes mellitus. The current insulin therapy is via subcutaneous injection, which often fails to mimic the glucose homeostasis that occurs in normal individuals. Oral delivery is the most convenient administration route. However, insulin cannot be well absorbed orally because of its rapid enzymatic degradation in the gastrointestinal tract. Therefore, nanoparticulate carriers such as polymeric nanoparticles are employed for the oral delivery of insulin. This study aims at the statistical optimization by Box-Behnken statistical design, fabrication by ionic gelation technique and in vitro characterization of insulin nanoparticles containing thiolated N- dimethyl ethyl chitosan (DMEC-Cys) conjugate. Independent variables such as the concentrations of polymer, TPP and insulin were optimized using a 3-factor, 3-level Box–Behnken statistical design. The selected dependent variables were size, zeta potential, PdI and associated efficiency of nanoparticles. The optimized nanoparticles were shown to have mean particle size diameter of 148 nm, zeta potential of 15.5 mV, PdI of 0.26 and AE of 97.56%. In vitro release study, FTIR, FE-SEM and cytotoxicity also indicated that nanoparticles made of this thiolated polymer are good candidate for oral insulin delivery.

Keywords

Adlin, J., Gowthamarajan, K., & Somashekhara, C. (2009). Formulation and evaluation of nanoparticles containing flutamide. Interernational journal of ChemTech research, 1(4), 1331-1334.
Avadi, M. R., Sadeghi, A. M. M., Mohammadpour, N., Abedin, S., Atyabi, F., Dinarvand, R., & Rafiee-Tehrani, M. (2010). Preparation and characterization of insulin nanoparticles using chitosan and Arabic gum with ionic gelation method. Nanomedicine: Nanotechnology, Biology and Medicine, 6(1), 58-63.
Bayat, A., Larijani, B., Ahmadian, S., Junginger, H. E., & Rafiee-Tehrani, M. (2008). Preparation and characterization of insulin nanoparticles using chitosan and its quaternized derivatives. Nanomedicine: Nanotechnology, Biology and Medicine, 4(2), 115-120.
Calvo, P., Remunan‐Lopez, C., Vila‐Jato, J. L., & Alonso, M. J. (1997). Novel hydrophilic chitosan‐polyethylene oxide nanoparticles as protein carriers. Journal of Applied Polymer Science, 63(1), 125-132.
Calvo, P., Vila-Jato, J. L., & Alonso, M. J. (1997). Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers. International Journal of Pharmaceutics, 153(1), 41-50.
Castrignanò, S., Sadeghi, S. J., & Gilardi, G. (2012). Entrapment of human flavin-containing monooxygenase 3 in the presence of gold nanoparticles: TEM, FTIR and electrocatalysis. Biochimica et Biophysica Acta (BBA)-General Subjects, 1820(12), 2072-2078.
Chopra, S., Patil, G. V., & Motwani, S. K. (2006). Response surface methodology for optimization of losartan potassium controlled release tablets. Journal of Controlled Release, 2(116), e102-e104.
Couvreur, P. (2013). Nanoparticles in drug delivery: past, present and future. Advanced drug delivery reviews, 65(1), 21-23.
Dong, Y., Ng, W. K., Shen, S., Kim, S., & Tan, R. B. (2013). Scalable ionic gelation synthesis of chitosan nanoparticles for drug delivery in static mixers. Carbohydrate polymers, 94(2), 940-945.
Dorkoosh, F. A., Verhoef, J. C., Ambagts, M. H., Rafiee-Tehrani, M., Borchard, G., & Junginger, H. E. (2002). Peroral delivery systems based on superporous hydrogel polymers: release characteristics for the peptide drugs buserelin, octreotide and insulin. European journal of pharmaceutical sciences, 15(5), 433-439.
Fàbregas, A., Miñarro, M., García-Montoya, E., Pérez-Lozano, P., Carrillo, C., Sarrate, R., ... & Suñé-Negre, J. M. (2013). Impact of physical parameters on particle size and reaction yield when using the ionic gelation method to obtain cationic polymeric chitosan–tripolyphosphate nanoparticles. International journal of pharmaceutics, 446(1-2), 199-204.
Fan, W., Yan, W., Xu, Z., & Ni, H. (2012). Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique. Colloids and Surfaces B: Biointerfaces, 90, 21-27.
Hu, B., Pan, C., Sun, Y., Hou, Z., Ye, H., Hu, B., & Zeng, X. (2008). Optimization of fabrication parameters to produce chitosan− tripolyphosphate nanoparticles for delivery of tea catechins. Journal of Agricultural and Food Chemistry, 56(16), 7451-7458.
Jamshidi, L. (2012). Educational needs of diabetic patients whom referred to the diabetes center. Procedia-Social and Behavioral Sciences, 31, 450-453.
Khafagy, E. S., Morishita, M., Onuki, Y., & Takayama, K. (2007). Current challenges in non-invasive insulin delivery systems: a comparative review. Advanced drug delivery reviews, 59(15), 1521-1546.
Lin, Y. H., Mi, F. L., Chen, C. T., Chang, W. C., Peng, S. F., Liang, H. F., & Sung, H. W. (2007). Preparation and characterization of nanoparticles shelled with chitosan for oral insulin delivery. Biomacromolecules, 8(1), 146-152.
Manivasagan, P., Venkatesan, J., Senthilkumar, K., Sivakumar, K., & Kim, S. K. (2013). Biosynthesis, antimicrobial and cytotoxic effect of silver nanoparticles using a novel Nocardiopsis sp. MBRC-1. BioMed research international, 2013.
Mohammadpourdounighi, N., Behfar, A., Ezabadi, A., Zolfagharian, H., & Heydari, M. (2010). Preparation of chitosan nanoparticles containing Naja naja oxiana snake venom. Nanomedicine: Nanotechnology, Biology and Medicine, 6(1), 137-143.
Morishita, M., Goto, T., Nakamura, K., Lowman, A. M., Takayama, K., & Peppas, N. A. (2006). Novel oral insulin delivery systems based on complexation polymer hydrogels: single and multiple administration studies in type 1 and 2 diabetic rats. Journal of Controlled Release, 110(3), 587-594.
Mortazavian, E., Amini, M., Dorkoosh, F. A., Amini, H., Khoshayand, M. R., Amini, T., & Rafiee-Tehrani, M. (2014). Preparation, design for optimization and in vitro evaluation of insulin nanoparticles integrating thiolated chitosan derivatives. Journal of Drug Delivery Science and Technology, 24(1), 40-49.
Motwani, S. K., Chopra, S., Talegaonkar, S., Kohli, K., Ahmad, F. J., & Khar, R. K. (2008). Chitosan–sodium alginate nanoparticles as submicroscopic reservoirs for ocular delivery: Formulation, optimisation and in vitro characterisation. European Journal of Pharmaceutics and Biopharmaceutics, 68(3), 513-525.
Nagavarma, B. V. N., Yadav, H. K., Ayaz, A. V. L. S., Vasudha, L. S., & Shivakumar, H. G. (2012). Different techniques for preparation of polymeric nanoparticles-a review. Asian journal of pharmaceutical and clinical research, 5(3), 16-23.
Nasti, A., Zaki, N. M., de Leonardis, P., Ungphaiboon, S., Sansongsak, P., Rimoli, M. G., & Tirelli, N. (2009). Chitosan/TPP and chitosan/TPP-hyaluronic acid nanoparticles: systematic optimisation of the preparative process and preliminary biological evaluation. Pharmaceutical research, 26(8), 1918-1930.
Paul, S., Jayan, A., & Sasikumar, C. S. (2015). Physical, chemical and biological studies of gelatin/chitosan based transdermal films with embedded silver nanoparticles. Asian Pacific Journal of Tropical Disease, 5(12), 975-986.
Peng, Q., Zhang, Z. R., Gong, T., Chen, G. Q., & Sun, X. (2012). A rapid-acting, long-acting insulin formulation based on a phospholipid complex loaded PHBHHx nanoparticles. Biomaterials, 33(5), 1583-1588.
Sadeghi, A. M. M., Dorkoosh, F. A., Avadi, M. R., Saadat, P., Rafiee-Tehrani, M., & Junginger, H. E. (2008). Preparation, characterization and antibacterial activities of chitosan, N-trimethyl chitosan (TMC) and N-diethylmethyl chitosan (DEMC) nanoparticles loaded with insulin using both the ionotropic gelation and polyelectrolyte complexation methods. International Journal of Pharmaceutics, 355(1-2), 299-306.
Journal of Food and Bioprocess Engineering
Volume 2, Issue 1
June 2019
Pages 25-34