Synthesis and Characterization of Alginate-Chitosan Nanocarrier System for Empagliflozin Delivery

Document Type : Research Article


Faculty of Sciences, Department of Organic Chemistry, University of Guilan, Rasht, I.R. IRAN


A biocompatible nanocarrier system was prepared by reacting Calcium Alginate (CA) with Chitosan (CS). The structure of synthesized nanocarrier chitosan-calcium alginate (CS-CA) was characterized using Thermo Gravimetric Analysis (TGA), Fourier Transforms InfraRed (FT-IR), Field Emission Scanning Electron Microscopy (FE-SEM), X-Ray Diffraction (XRD) Atomic Force Microscopy (AFM), and Transmission Electron Microscopy (TEM). Swellings of CS-CA and CA, and their ability for loading and in vitro release behavior of empagliflozin (EMP) were investigated. The results show that the capacity of loading on CS-CA is more than that of CA. For both nanocarriers, the release of the drug is higher in neutral pH (7.4 and 6.8) than in acidic pH (1.2). Although more release was observed for CA than CS-CA, the latter shows a favorable delay in the drug release in all pHs.  As a result, CS-CA nanocarrier is suggested as a new candidate for an EMP colon drug delivery.


[1] Mahmoodi N.O., Alavi, S.M., Yahyazadeh, A., Formulation and Therapeutic Efficacy of PEG-Liposomes of Sorafenib for the Production of NL-PEG-SOR FUM and NL-PEG-SOR TOS. Res. Chem. Intermed., 48: 3915–3935 (2022).
[2]  Zhu J., Zhong L., Chen W., Song Y., Qian Z., Cao X., Huang Q., Zhang B., Chen H., Chen W., Preparation and Characterization of Pectin/Chitosan Beads Containing Porous Starch Embedded with Doxorubicin Hydrochloride: A Novel and Simple Colon Targeted Drug Delivery System,  Food Hydrocolloids, 95:562-570 (2019).
[3]  Englert C., Brendel J.C., Majdanski T.C., Yildirim T., Schubert S., Gottschaldt M., Windhab N., Schubert U.S., Pharma Polymers in the 21st Century: Synthetic Polymers in Drug Delivery Applications, Prog. Polym. Sci., 87:107-164 (2018).
[4] Peng C., Huang Y., Zheng J., Renal Clearable Nanocarriers: Overcoming the Physiological Barriers for Precise Drug Delivery and Clearance, J. Controlled Release, 10(322):64-80 (2020).
[6] Bassas-Galia M., Follonier S., Pusnik M., Zinn M., Natural Polymers: A Source of Inspiration, in:  "Bioresorbable Polymers for Biomedical Applications", Elsevier, 31-64 (2017).
[7] Tong X., Pan W., Su T., Zhang M., Dong W., Qi X., Recent Advances in Natural Polymer-Based Drug Delivery Systems, React. Funct. Polym., 148: 104501 (2020).
[8] Prajapati S.K., Jain A., Jain A., Jain S., Biodegradable Polymers and Constructs: A Novel Approach in Drug Delivery, Eur. Polym. J., 1(120): 109191 (2019).
[9] Kumar S., Bhanjana G., Verma R.K., Dhingra D., Dilbaghi N., Kim K.H., Metformin‐Loaded Alginate Nanoparticles as an Effective Antidiabetic Agent for Controlled Drug Release, J. Pharm. Pharmacol., 69:143-15 (2017).
[10] Rani R., Dahiya S., Dhingra D., Dilbaghi N., Kim K.-H., Kumar S., Evaluation of Anti-Diabetic Activity of Glycyrrhizin-Loaded Nanoparticles in Nicotinamide-Streptozotocin-Induced Diabetic Rats, European Journal of Pharmaceutical Sciences, 106: 220-230 (2017).
[11] Chauhan P., Mahajan S., Prasad G., Preparation and Characterization of CS-ZnO-NC Nanoparticles for Imparting Anti-Diabetic Activities in Experimental Diabetes, Journal of Drug Delivery Science and Technology, 52: 738-747(2019).
[12] Amirmahani N., Mahmoodi N. O., Mohammadi Galangashd M., Ghavidasta A., Advances in Nanomicelles for Sustained Drug Delivery, J. Ind. Eng. Chem., 55(25): 21-34 (2017).
[15] Nesamony J., Singh P.R., Nada S.E., Shah Z.A., Kolling W.M., Calcium Alginate Nanoparticles Synthesized Through a Novel Interfacial Cross-Linking Method as a Potential Protein Drug Delivery System, J. Pharm. Sci., 101: 2177-2184 (2012).
[16] Zhang R., Lei L., Song Q., Li X., Calcium Ion Cross-Linking Alginate/Dexamethasone Sodium Phosphate Hybrid Hydrogel for Extended Drug Release, Colloids Surf. B. Biointerfaces, 175:569-575 (2019).
[17] Shafabakhsh R., Yousefi B., Asemi Z., Nikfar B., Mansournia M.A., Hallajzadeh J., Chitosan: A Compound for Drug Delivery System in Gastric Cancer-A Review, Carbohydr. Polym., 116403 (2020).
[18] Nalinbenjapun S., Ovatlarnporn C., Chitosan-5-Aminosalicylic Acid Conjugates for Colon-Specific Drug Delivery: Methods of Preparation and in Vitro Evaluations, Journal of Drug Delivery Science and Technology, 57: 101397(2019).
[19] Ren G., Clancy C., Tamer T.M., Schaller B., Walker G.M., Collins M.N., Cinnamyl O-amine Functionalized Chitosan as a New Excipient in Direct Compressed Tablets with Improved Drug Delivery, Int. J. Biol. Macromol., 141:  936-946 (2019).
[20] Berger J., Reist M., Mayer J.M., Felt O., Peppas N., Gurny R., Structure And Interactions in Covalently and Ionically Crosslinked Chitosan Hydrogels for Biomedical Applications, European Journal of Pharmaceutics and Biopharmaceutics, 57:19-34 (2004).
[21] Nalini T., Basha S.K., Sadiq A.M.M., Kumari V.S., Kaviyarasu K., Development and Characterization of Alginate/Chitosan Nanoparticulate System for Hydrophobic Drug Encapsulation, Journal of Drug Delivery Science and Technology, 52: 65-72 (2019).
[22] Zelniker T.A., Wiviott S.D., Raz I., Im K., Goodrich E.L., Bonaca M.P., Mosenzon O., Kato E.T, Cahn A., Furtado R.H., Bhatt D.L., Leiter L.A., McGuire D.K., Wilding J.P., Sabatine M.S., SGLT2 Inhibitors for Primary and Secondary Prevention of Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Cardiovascular Outcome Trials, Lancet, 393(10166): 31–39 (2019)
[23] Peniche C., Howland I., Carrillo O., Zaldıvar C., Argüelles-Monal W., Formation and Stability of Shark Liver Oil Loaded Chitosan/Calcium Alginate Capsules, Food Hydrocolloids, 18: 865-871(2004).
[24] Amir Mahani N, Mahmoodi N.O., Ghavidast A., A Comparative Study on the Nanoparticles for Improved Drug Delivery Systems, J. Photochem. Photobiol. B, Biol., 152(12): 681-693 (2016).
[26] Nunthanid J., Puttipipatkhachorn S., Yamamoto K., Peck G.E., Physical Properties and Molecular Behavior of Chitosan Films, Drug Dev. Ind. Pharm., 27:143-157 (2001).
[28] Soulairol I., Sanchez N., -Ballester M., Aubert A., Tarlier N., Bataille B., Quignard F., Sharkawi T., Evaluation of the Super Disintegrant Functionnalities of Alginic Acid and Calcium Alginate for the Design of Orodispersible Mini Tablets, Carbohydr. Polym., 197:576-585(2018).
[29] Tripathi S., Mehrotra G., Dutta P., Physicochemical and Bioactivity of Cross-Linked Chitosan–PVA Film for Food Packaging Applications, Int. J. Biol. Macromol., 45:372-376 (2009).
[30] Wu T., Li Y., Shen N., Yuan C., Hu Y., Preparation and Characterization of Calcium Alginate-Chitosan Complexes Loaded with Lysozyme, J. Food Eng., 233: 09-116 (2018).
[32] Mahmoodi N.O., Parvizi J., Sharifzadeh B., Rassa M., Facile Regioselective Synthesis of Novel Bis‐Thiazole Derivatives and Their Antimicrobial Activity, Arch. Pharm., 346:860-864 (2013).
[33] Rineh A., Mahmoodi N., Abdollahi M., Foroumadi A., Sorkhi M., Shafiee A., Synthesis, Analgesic and Anti‐Inflammatory Activity of 4‐(2‐phenoxyphenyl) Semicarbazones, Archiv Der Pharmazie, An International Journal Pharmaceutical and Medicinal Chemistry, 340:409-415 (2007).
[34] Mollayousefi Samadi H., Fallah Shojaei  A., Mahmoodi N.O., Preparation, Characterization, and Performance Study of PVDF Nanocomposite Contained Hybrid Nanostructure TiO2-POM Used as a Photocatalytic Membrane, Iran. J. Chem. Chem. Eng.  (IJCCE), 40(1): 35-47 (2021).
[35] Chen S.-C., Wu Y.-C., Mi F.-L., Lin Y.-H., Yu L.-C., Sung H.-W., A Novel pH-Sensitive Hydrogel Composed of N, O-Carboxymethyl Chitosan and Alginate Cross-Linked By Genipin for Protein Drug Delivery, J. Controlled Release, 96:285-300 (2004).
[36] Basu S.K., Rajendran A., Studies in the Development of Nateglinide Loaded Calcium Alginate and Chitosan Coated Calcium Alginate Beads, Chem. Pharm. Bull., 56:1077-1084 (2008).
[37] Irfan A., Imran M., Waseem Mumtaz A., Asim Raza Basra M., Molecular Docking and Computational Exploration of Isolated Drugs from Daphne Species Against COVID-19, Iran. J. Chem. Chem. Eng. (IJCCE), 40(6): 2019-2027 (2021).
[39] Belletire J.L., Mahmoodi N.O., γ-Butyrolactone Natural Products via Tributyltin-Hydride-Mediated Radical Cyclizations, Journal of Natural Products, 55(2):194-206 (1992).