• Vol 11, No 3 (2020)
  • Chemical Engineering

Controlled Release of Metformin Hydrogen Chloride from Stimuli-responsive Hydrogel based on Poly(N- Isopropylacrylamide)/Chitosan/Polyvinyl Alcohol Composite

Dhena Ria Barleany, Claudia Vivi Ananta, Fistia Maulina, Agus Rochmat, Hafid Alwan, Erizal

Corresponding email: ria.barleany@untirta.ac.id


Cite this article as:
Barleany, D.R., Ananta, C.V., Maulina, F., Rochmat, A., Alwan, H., Erizal,  2020. Controlled Release of Metformin Hydrogen Chloride from Stimuli-responsive Hydrogel based on Poly(N- Isopropylacrylamide)/Chitosan/Polyvinyl Alcohol Composite. International Journal of Technology. Volume 11(3), pp. 511-521

77
Downloads
Dhena Ria Barleany Departement of Chemical Engineering, Faculty of Engineering, University of Sultan Ageng Tirtayasa, Jl. Jend. Sudirman Km. 03, Cilegon, Banten 42435, Indonesia
Claudia Vivi Ananta Departement of Chemical Engineering, Faculty of Engineering, University of Sultan Ageng Tirtayasa, Jl. Jend. Sudirman Km. 03, Cilegon, Banten 42435, Indonesia
Fistia Maulina Departement of Chemical Engineering, Faculty of Engineering, University of Sultan Ageng Tirtayasa, Jl. Jend. Sudirman Km. 03, Cilegon, Banten 42435, Indonesia
Agus Rochmat Departement of Chemical Engineering, Faculty of Engineering, University of Sultan Ageng Tirtayasa, Jl. Jend. Sudirman Km. 03, Cilegon, Banten 42435, Indonesia
Hafid Alwan Departement of Chemical Engineering, Faculty of Engineering, University of Sultan Ageng Tirtayasa, Jl. Jend. Sudirman Km. 03, Cilegon, Banten 42435, Indonesia
Erizal Centre for Application of Isotopes and Radiation, South Jakarta 7002, Indonesia
Email to Corresponding Author

Abstract
image

Hydrogels are ideal biomaterials owing to their unique network structure that facilitates considerable hydrophilicity and biocompatibility. At the same time, hydrogels also possess soft physical properties when combined with living tissue. In this study, metformin hydrogen chloride (metformin HCl)-loaded stimuli-responsive poly(N-isopropylacrylamide) (pNIPAAm)chitosanpolyvinyl alcohol (PVA) hydrogels were synthesized through a freezing and thawing procedure and subsequently subjected to gamma irradiation at room temperature. The gel content and the water absorption capacity of the synthesized hydrogels were analyzed. The polymer interaction in the matrix was observed by Fourier transform infrared spectroscopy, and the release of metformin HCl was studied in different pHs and temperatures. The hydrogels had 85% of the gel content and 373% of the water absorption capacity after 24 h of water immersion. The metformin HCl-loaded (pNIPAAmchitosanPVA) hydrogels demonstrated a sustained drug release profile over 7 h. The drug release exhibited pH-dependent and temperature-dependent behavior. The developed hydrogels showed good metformin HCl release ability at pH 3 and pH 6.86 at the temperature of 37oC. The results showed that pNIPAAmchitosanPVA hydrogels could be employed for controlled drug release of metformin HCl.

Controlled drug release; Hydrogel; Metformin HCl

Introduction

Diabetes mellitus is a disorder that can cause morbidity and mortality. It is considered a serious disease in countries across the world. It can increase susceptibility to infections and reduce life expectancy (Chacko, 2016). Metformin hydrogen chloride (metformin HCl) is one of the most commonly used drugs to manage some forms of diabetes mellitus. It acts as an antihyperglycemic agent for the treatment of insulin-resistant diabetes mellitus (Zhou et al., 2018). Metformin release kinetics have been reported to have slow and incomplete absorption (bioavailability 50%–60%); approximately 30% to 50% of an oral dose is excreted unchanged in urine within 24 h, and about 30% is excreted in feces (Patiño-Herrera et al., 2019).  Some of the symptoms that are often reported as the side effects of metformin HCl in the treatment of diabetes are mostly related to the gastrointestinal digestive  tract,  such  as  diarrhea,  nausea,  dyspepsia,  flatulence,  and  abdominal  pain (Zhou et al., 2018). To increase adherence and reduce the side effects, metformin formulations in a controlled drug system have been developed (Patiño-Herrera et al., 2019; Shariatinia and Zahraee, 2017).

Drug delivery systems can increase the therapeutic effect of the drug at the target site by protecting the drug under physiological conditions, controlling its release, increasing or reducing its systemic circulation, and helping it reach the site of action (Khors et al., 2019). For these purposes, drugs are encapsulated in responsive materials that release their drug payloads under varying external triggers, such as pH, temperature, enzymes, reduction, diol moieties, reactive oxygen species, shear stress, ionic strength, and light (Fu et al., 2018).

Natural polymers are potential candidates to form hydrogels for drug delivery applications because of their biodegradability, high biocompatibility, and low toxicity. Among natural polymers, chitosan has recently attracted growing consideration (Usman et al., 2018) owing to its cationic nature and the presence of primary amino groups in its structure, which are responsible for its many useful properties. It also possesses pH- and temperature-responsive properties. These responsive properties of chitosan have led to it becoming an advanced biopolymer in the development of smart polymeric systems for delivery of numerous drugs (Muharam et al., 2015; Hasnain and Nayak, 2018; Krisanti et al., 2019). Chitosan can be modified with other substances to broaden the scope of its role as a drug carrier (Kusrini et al., 2014; Shariatinia and Zahraee, 2017).

Chitosan is a unique cationic polysaccharide that can be easily functionalized into different derivatives through chemical, radiation, and enzymatic procedures (Mittal et al., 2018). Chitosan can be used as a protective material for active substances (Usman et al., 2018). An emerging technique to improve its performance and expand its potential applications uses chemical modification to graft it to a vinyl monomer(s) and then cross-link the material. For enhancing chitosan’s performance, one of the more intensively studied monomers is poly(N-isopropylacrylamide) (pNIPAAm) (Zhang et al., 2009; Carreira et al., 2010; Rasib et al., 2018). pNIPAAm is one of the most studied thermally-sensitive (thermoresponsive) polymers. It has a low critical solution temperature (LCST) of 32°C, which is a useful temperature for biomedical applications since it is close to body temperature (Carreira et al., 2010). Grafting pNIPPAm onto chitosan enables an increase in the water content of the graft following exposure to aqueous media along with improved mechanical and temperature-responsive properties (Zhang et al., 2009).

Polyvinyl alcohol (PVA) is a water-soluble synthetic polymer that has several desirable physical properties, such as elasticity and high hydrophilicity. It is cheap, non-toxic, and non-carcinogenic. It has good biocompatibility and a high degree of swelling in aqueous solutions, which make it suitable for blending with chitosan in order to produce biodegradable blend hydrogels for controlled drug release systems (Abdel-Mohsen et al., 2011).

In this article, we report a model drug delivery system for the release of metformin HCl based on cross-linked PVA–chitosan blended hydrogels and pNIPAAm. We used metformin HCl as the drug because it is a type 2 diabetes drug that needs a controlled delivery system to ensure that the release occurs at the target site. The hydrogels were prepared through a procedure that combined physical freezing-thawing and gamma-ray irradiation. The release behaviors of metformin HCl from the hydrogel matrix at various pHs and temperatures were investigated. The use of the freezing-thawing method followed by gamma irradiation produced hydrogels with good mechanical properties, compact network structures, high porosity, and high absorption capacity without any hazardous initiators or cross-linking agents (Hamedi et al., 2018).

Conclusion

From this study, it can be concluded that a pH- and temperature-responsive pNIPAAm–chitosan–PVA hydrogel can be synthesized through a combination of physical and chemical crosslinking by freezing and thawing followed by gamma irradiation. A dose of 20 kGy gamma-ray irradiation can produce a hydrogel with a gel fraction of 85% and water absorption capacity of 373% after 24 h of immersion. The developed hydrogels showed good metformin HCl release ability at the temperature of 37oC. The results showed that pNIPAAm–chitosan–PVA hydrogel hydrogels could be employed for controlled drug release of metformin HCl.

Acknowledgement

    We highly appreciate the financial support from the University of Sultan Ageng Tirtayasa (UNTIRTA) through the “Competency Based Research Grant Program” for fiscal year 2018 (contract number: 667/UN43.9/PP/KT/2018).

References

Abdel-Mohsen, A.M., Aly, A.S., Hrdina, R., Montaser, A.S., Hebeish, A., 2011. Eco-synthesis of PVA/Chitosan Hydrogels for Biomedical Application. Journal of Polymers and Environment, Volume 19(4), pp. 1005–1012

Afshari, M.J., Sheik, N., Afarideh, H., 2015. PVA/CM-chitosan/honey Hydrogels Prepared by using the Combined Technique of Irradiation Followed by Freezing-thawing. Radiation Physics and Chemistry, Volume 113, pp. 28–35

Alcântara, M.T.S., Brant, A.J.C., Giannini, D.R., Pessoa, J.O.C.P., Andrade, A.B., Riella, H.G., Lugão, A.B., 2012. Influence of Dissolution Processing of PVA Blends on the Characteristics of their Hydrogels Synthesized by Radiation-Part I: Gel Fraction, Swelling, and Mechanical Properties. Radiation Physics and Chemistry, Volume 81(9), pp. 1465–1470

Awada, H., Daneault, C., 2015. Chemical Modification of Poly(Vinyl Alcohol) in Water. Applied Sciences, Volume 5(4), pp. 840–850

Carreira, A.S., Gonçalves, F.A.M.M., Mendonça, P.V., Gil, M.H., Coelho, J.F.J., 2010. Temperature and pH Responsive Polymers based on Chitosan: Applications and New Graft Copolymerization Strategies based on Living Radical Polymerization. Carbohydrate Polymers, Volume 80(3), pp. 618–630

Chacko, E., 2016. Blunting Post-meal Glucose Surges in People with Diabetes. World Journal Diabetes, Volume 7(11), pp. 239–242

Erizal, Abbas, B., Sukaryo, S.G., Barleany, D.R., 2015. Synthesis and Characterization Superabsorbent Hydrogels of Partially Neutralized Acrylic Acid Prepared using Gamma Irradiation: Swelling and Thermal Behavior. Indonesian Journal of Chemistry, Volume 15(3), pp. 281–287

Fu, X., Hosta-Rigau, L., Chandrawati, R., Cui, J., 2018. Multi-Stimuli-Responsive Polymer Particles, Film, and Hydrogels for Drug Delivery. Chem, Volume 4(9), pp. 2084–2107

Ghazaie, M., Ghiaci, P., Ghiaci, M. 2017. Study on Release of Naproxen and Metformin Encapsulated in Biopolymer-Inorganic Mesoporous Matrices as Controlled Drug-Delivery Systems. Microporous and Mesoporous Materials, Volume 244, pp. 291–300

Hamedi, H., Moradi, S., Hudson, S.M., Tonelli, A.E. 2018. Chitosan Based Hydrogels and Their Applications for Drug Delivery in Wound Dressings: A Review. Carbohydrate Polymers, Volume 199, pp. 445–460

Hasnain, M.S., Nayak, A.K., 2018. Chitosan as Responsive Polymer for Drug Delivery Applications. Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications, Types and Triggers, Volume 1, pp. 581–605

Kakar, S., Singh, R., Semwal, A., 2014. Drug Release Characteristics of Dosage Form: A Review. Journal of Coastal Life Medicine, Volume 2(4), pp. 332–336

Kalhapure, A., Kumar, R., Singh, V.P., Pandey, D.S., 2016. Hydrogels: A Boon for Increasing Agricultural Productivity in Water-Stressed Environment. Current Science, Volume 3(11), pp. 1773–1779

Khors, N.J., Liyanage, T., Venkatesan, N., Najarzadeh, A., Puleo, D.A., 2019. Drug Delivery Systems and Controlled Release. Reference Module in Biological Sciences: Encyclopedia of Biomedical Engineering, pp. 316–329

Krisanti, E.A., Hijrianti, N., Mulia, K., 2019. Preparation and Evaluation of Alginate-Chitosan Matrices Loaded with Red Ginger Oleoresin using the Ionotropic Gelation Method. International Journal of Technology, Volume 10(8), pp. 1513–1522

Kusrini, E., Arbianti, R., Sofyan, N., Abdullah, M.A.A., Andriani, F., 2014. Modification of Chitosan by using Samarium for Potential use in Drug Delivery System. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Volume 120, pp. 77–83

Lin, D.M., Kalachandra, S., Valiyaparambil, J., Offenbacher S., 2003. A Polymeric Device for Delivery of Anti-Microbial and Anti-fungal Drugs in the Oral Environment: Effect of Temperature and Medium on the Rate of Drug Release. Dental Materials, Volume 19, pp. 589–596

Mittal, H., Ray, S.S., Kaith, B.S., Bhatia, J.K., Sukriti, Sharma, J., Alhassan, S.M., 2018. Recent Progress in the Structural Modification of Chitosan for Applications in Diversified Biomedical Fields. European Polymer Journal, Volume 109, pp. 402–434

Muharam, Y, Purwanto, W.W., Mulia, K., Wulan, P.P.D.K., Marzuki, I., Dewi, M.N., 2015. Mathematical Model Controlled Potassium Chloride Release Systems from Chitosan Microspheres. International Journal of Technology, Volume 6(7), pp. 1228–1237

Patiño-Herrera, R., Louvier-Hernández, J.F., Escamilla-Silva, E.M., Chaumel, J., Escobedo, A.G.P., Pérez, E., 2019. Prolonged Release of Metformin by Sio2 Nanoparticles Pellets for Type II Diabetes Control. European Journal of Pharmaceutical Sciences, Volume 131, pp. 1–8

Queiroz, M.F., Melo, K.R.T., Sabry, D.A., Sassaki, G.L., Rocha, H.A.O., 2015. Does the Use of Chitosan Contribute to Oxalate Kidney Stone Formation?. Marine Drugs, Volume 13(1), pp. 141–158

Rasib, S.Z.M., Ahmad, Z., Khan, A., Akil, H.M., Othman, M.B.H., Hamid, Z.A.A., Ullah, F., 2018. Synthesis and Evaluation on pH- and Temperature-responsive Chitosan-p(MAA-co-NIPAM) Hydrogels. International Journal of Biological Macromolecules, Volume 108, pp. 367–375

Rizi, K., Green, R.J., Khutoryanskaya, O., Donaldson, M., Williams, A.C., 2011. Mechanism of Burst Release from pH-responsive Polymeric Microparticles. Journal Pharmacy and Pharmacology, Volume 63(9), pp. 1141–1155

Seddiki, N., Aliouche, D., 2013. Synthesis, Rheological Behavior and Swelling Properties of Copolymer Hydrogels based on Poly(N-Isopropylacrylamide) with Hydrophilic Monomers. Bulletin of the Chemical Society of Ethiopia, Volume 27(3), pp. 447–457

Shariatinia, Z., Zahraee, Z., 2017. Controlled Release of Metformin from Chitosan–based Nanocomposite Films Containing Mesoporous MCM-41 Nanoparticles as Novel Drug Delivery Systems. Journal of Colloid and Interface Science, Volume 501, pp. 60–76

The United States Pharmacopeial Convention, 2018. Metformin Hydrochloride Extended-Release Tablets. USP-NF Monograph (Revision Bulletin)

Usman, A., Kusrini, E., Widiantoro, A.B., Hardiya, E., Abdullah, N.A., Yulizar, Y., 2018. Fabrication of Chitosan Nanoparticles Containing Samarium Ion Potentially Applicable for Fluorescence Detection and Energy Transfer. International Journal of Technology, Volume 9(6), pp. 1112–1120

Wang, L., Zhao, X., Zhang, Y., Zhang, W., Ren, T., Chen, Z., Wang, F., Yang, H., 2015. Fabrication of Intelligent Poly(N-Isopropylacrylamide)/Silver Nanoparticle Composite Films with Dynamic Surface-Enhanced Raman Scattering Effect. RSC Advances, Volume 5(50), pp. 40437–40443

Zhang, H.F., Zhong, H., Zhang, L.L., Chen, S.B., Zhao, Y.J., Zhu, Y.L., 2009. Synthesis and Characterization of Thermosensitive Graft Copolymer of N-Isopropylacrylamide with Biodegradable Carboxymethylchitosan. Carbohydrate Polymers, Volume 77(4), pp. 785–790

Zhou, T., Xu, X., Du, M., Zhao, T., Wang, J., 2018. A Preclinical Overview of Metformin for the Treatment of Type 2 Diabetes. Biomedicine and Pharmacotherapy, Volume 106, pp. 1227–1235