Document Type : Full Research Paper


1 Associate Professor, Faculty of Chemical Engineering, Urmia University of Technology, Urmia, Iran

2 M.Sc. Graduate, Faculty of Chemical Engineering, Urmia University of Technology, Urmia, Iran

3 Assistant Professor, Faculty of Chemical Engineering, Urmia University of Technology, Urmia, Iran


In this research, the response of a novel drug delivery system responsive to the temperature, as a unique stimulus, was studied. The performance of the system was modeled at the unsteady state, using the numerical method. The system has three individual layers, containing a drug core, a phase-transient intermediate layer and an external protective layer. The system has the ability to start and stop the release of the drug, according to the On-Off mechanism, by exerting any changes in the temperature of the release medium. Mathematical modeling was performed by solving the heat and mass transfer equations governing the layers of the system at the unsteady state. The lag time of system at On state, the drug release kinetics at On state and undesired drug release kinetics at Off state were determined as functions of the parameters of the system. The results obtained from the modeling showed that response of the system was under the influence of different parameters, such as the geometry of the system, the kind of constituents of the intermediate and protective layers and the ratio of the thermal conductivity of the intermediate layer at molten state to the thermal conductivity of the protective layer. It was shown that a reduced lag time for the system could be achieved by manipulating these parameters. From the viewpoint of the drug release kinetics at On state, it could be declared that the amount of the released drug is a function of the time constant of the system and the drug release could be increased by decreasing the time constant value. The results also showed that the undesired release of the drug could be accelerated by adjusting the parameters of the protective layer, such as the kind of constituents and the thickness of the layer. Using the obtained results from the numerical modeling, one can design and produce the temperature-responsive smart drug delivery systems with desired characteristics for practical applications.


[1]   Bandawane A., Saudagar R., A Review on Novel Drug Delivery System: A Recent Trend, J. Drug Deliv. Ther., 9, 517-521, 2019.
[2]   Villa C.H., Anselmo A.C., Mitragotri S., Muzykantov V., Red Blood Cells: Supercarriers for Drugs, Biologicals, and Nanoparticles and Inspiration for Advanced Delivery Systems, Adv. Drug Deliv. Rev., 106, 88-103, 2016.
[3]   Sirousazar M., Shabani Y., Modeling of Drug Release from a Novel Temperature-Responsive Phase-Transient Drug Delivery System in Cylindrical Coordinates, J. Macromol. Sci. B, 54, 450-468, 2015.
[4]   Sirousazar M., Mechanism of Gentamicin Sulphate Release in Nanocomposite Hydrogel Drug Delivery Systems, J. Drug Deliv. Sci. Technol., 23, 619-621, 2013.
[5]   Dams E.T.M., Laverman P., Oyen W.J.G., Storm G., Scherphof G.L., van der Meer J.W.M., Corstens F.H.M., Boerman O.C., Accelerated Blood Clearance and Altered Biodistribution of Repeated Injections of Sterically Stabilized Liposomes, J. Pharmacol. Exp. Ther., 292, 1071-1079, 2000.
[6]   Lavrador P., Gaspar V. M., Mano J.F., Stimuli-Responsive Nanocarriers for Delivery of Bone Therapeutics – Barriers and Progresses. J. Control. Release, 273, 51-67, 2018.
[7]   Fenton O.S., Olafson K.N., Pillai P.S., Mitchell M.J., Langer R., Advances in Biomaterials for Drug Delivery. Adv. Mater., 30, 1705328, 2018.
[8]   Li Y., Bui Q.N., Duy L.T.M., Yang H.Y., Lee D.S., One-Step Preparation of pH-Responsive Polymeric Nanogels as Intelligent Drug Delivery Systems for Tumor Therapy, Biomacromolecules,19, 2062-2070, 2018.
[9]   Sanchez-Moreno P., Ortega-Vinuesa J.L., Peula-Garcia J.M., Marchal J.A., Boulaiz H., Smart DrugDelivery Systems for Cancer Nanotherapy, Curr. Drug Targets, 19, 339-359, 2018.
[10]Okano T., Biorelated Polymers and Gels: Controlled Release and Applications in Biomedical Engineering, Academic Press, 1998.
[11]Jin Z., Wu K., Hou J., Yu K., Shen Y., Guo S., A PTX/nitinol Stent Combination with Remperature-Responsive Phase-Change 1-Hexadecanol for Magnetocaloric Drug Delivery: Magnetocaloric Drug Release and Esophagus Tissue Penetration, Biomaterials, 153, 49-58, 2018.
[12]Zhang G., Jiang X., Temperature Responsive Nanoparticles Based on PEGylated Polyaspartamide Derivatives for Drug Delivery, Polymers, 11, 316, 2019.
[13]Matsumoto K., Kimura S., Noguchi S., Itai S., Kondo H., Iwao Y., Mechanism of Drug Release From Temperature-Sensitive Formulations Composed of Low-Melting-Point Microcrystalline Wax, J. Pharm. Sci., 108, 2086-2093, 2019.
[14]Pourabdollah K., Rashedi H., Golzar H., Garshasbi M., Numerical Analysis of Temperature-Sensitive Hydrogels for Controlled Drug Release, J. Appl. Biotechnol. Rep., 3, 365-372, 2016.
[15]Brahima S., Boztepe C., Kunkul A., Yuceer M., Modeling of Drug Release Behavior of pH and Temperature Sensitive Poly(NIPAAm-co-AAc) IPN Hydrogels Using Response Surface Methodology and Artificial Neural Networks, Mater. Sci. Eng. C, 75, 425-432, 2017.
[16]Lucero-Acuna A., Gutierrez-Valenzuela C.A., Esquivel R., Guzman-Zamudio R., Mathematical Modeling and Parametrical Analysis of the Temperature Dependency of Control Drug Release from Biodegradable Nanoparticles, RSC Adv., 9, 8728-8739, 2019.
[17]Bai X., Bao Z., Bi S., Li Y., Yu X., Hu S., Tian M., Zhang X., Cheng X., Chen X., Chitosan-Based Thermo/pH Double Sensitive Hydrogel for Controlled Drug Delivery, Macromol. Biosci., 18, 1700305, 2018.
[18]Kim A.R., Lee S.L., Park S.N., Properties and In Vitro Drug Release of pH- and Temperature Sensitive Double Cross-Linked Interpenetrating Polymer Network Hydrogels Based on Hyaluronic Acid/Poly (N-isopropylacrylamide) for Transdermal Delivery of Luteolin, Int. J. Biol. Macromol., 118, 731-740, 2018.
[19]Zhang W., Jin X., Li H., Zhang R.R., Wu C.W., Injectable and Body Temperature Sensitive Hydrogels Based on Chitosan and Hyaluronic Acid for pH Sensitive Drug Release, Carbohydr. Polym., 186, 82-90, 2018.
[20]Sirousazar M., Onsorrudi H.J., Kokabi M., Drug Release Modeling from a Novel Temperature-Responsive Polymeric System, Iran. J. Polym. Sci. Technol. (Persian), 20, 257-269, 2007.