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

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) –chitosan–polyvinyl 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 (pNIPAAm–chitosan–PVA) 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 37^oC. The results showed that pNIPAAm–chitosan–PVA hydrogels could be employed for controlled drug release of metformin HCl.

Controlled drug release; Hydrogel; Metformin HCl

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).

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 37^oC. The results showed that pNIPAAm–chitosan–PVA hydrogel hydrogels could be employed for controlled drug release of metformin HCl.

    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).

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