KGM and PMAA based pH-sensitive interpenetrating polymer network hydrogel for controlled drug release
Introduction
Many scientific works in recent years have been dealing with hydrogels that are able to alter their volume and properties in response to environmental stimuli such as pH, temperature, ionic strength and electric field (Li et al., 2008, Qiu and Park, 2012, Vashist et al., 2012, Wang and Wang, 2010, Zhang and Peppas, 2000). Because of their drastic swelling and syneresis in response to environmental stimuli, these polymeric hydrogels have been investigated for many biomedical and pharmaceutical applications, including controlled drug delivery (Liu et al., 2010, Ramkissoon-Ganorkar et al., 1999, Yang et al., 2012), molecular separation (Feil et al., 1991, Gunavadhi et al., 2012, Tokarev and Minko, 2010), artificial muscles (Peppas & Langer, 1994), sensors (Lin et al., 2009, Monleón Pradas et al., 2001, Riedinger et al., 2011), etc. Among these “intelligent” polymers, pH-sensitive hydrogels have been widely studied to develop oral drug delivery system. The pH of physiological media is very precisely controlled because of its crucial importance in all functions of the human body. One example is the change of pH through the gastrointestinal tract, from the acidic pH of the stomach, namely, pH from 2 to 4, increasing progressively in the small intestine to neutral or slightly basic pH (Mc Gann et al., 2009, Nguyen et al., 2009, Zhang et al., 2012). Hydrogels containing ionizable groups can take advantage of their ability to volume changes depending on the pH of the physiological medium. Poly(methacrylic acid) (PMAA) is an ionizable hydrophilic polymer (Fernyhough et al., 2009, Solhi et al., 2012). Cross-linked PMAA is able to swell in water. Its swelling behavior is greatly pH-dependent due to the ionization/deionization of the carboxylic acid groups. At low pH, usually pH value less than 5.5, the COOH groups are not ionized and keep the PMAA network at its collapsed state. At high pH values, usually pH value 5.5–7.4, the COOH groups are ionized, and the charged COO− groups repel each other, leading to PMAA swelling (Andersson Trojer et al., 2012, Shalviri et al., 2012, Zhang et al., 2013). Hydrogel made of PMAA swells least in the stomach and the drug release is minimal. The extent of drug release increases due to the increasing swelling of hydrogel as it passes down the intestinal tract. Consequently, they can be used to release drugs in a neutral pH environment.
Konjac glucomannan (KGM) is a neutral polysaccharide isolated from the konjac tuber. It consists primarily of a linear chain of β-1,4 linked d-glucose and d-mannose units with a glucose to mannose ratio of approximately 1:1.6 (Kato and Matsuda, 1969, Lin et al., 2013). There has been a suggestion that there are some branches on the C3 on mannose; the length of the branched chains being in the range of 11–16 mannose units and 5–10% of the backbone residues being acetylated (Dea et al., 1977). In the presence of alkali, konjac glucomannan will deacetylate and form a heat stable gel. Alkali gelation is considered as a consequence of the formation of associations between acetyl free regions of the backbone (Gao and Nishinari, 2004, Penroj et al., 2005). It is worth noting that KGM can be used as a colon-targeting drug-delivery system because it can only be degraded by colonic bacterial enzymes (β-mannase or β-glycosidases) and not be degraded in the stomach and small intestine (He et al., 2001, Liu et al., 2010, Liu et al., 2012). In order to improve and exploit the properties of KGM and PMAA for colon-targeting delivery, the interpenetrating polymer networks (IPN) are utilized instead of synthesizing new types of polymers. IPN is defined as a mixture of two or more cross-linked networks which are dispersed within each other at a molecular segmental level. In general, no significant degree of covalent bonds exists between the constituent networks (Klempner, Frisch, & Frisch, 1970). Since there is no chemical bonding between them, each polymer network may retain its own property like its homopolymer. Meanwhile, because of IPN physically interlocked structure, when one component swells or shrinks, the other component can be enforced to cooperate by attractive and repulsive interactions of whole network (Liu et al., 2006). Interpenetration of the two networks may lead to an enhanced mechanical strength due to the physical entanglements and network interaction (Chivukula et al., 2006). There are two basic synthetic routes for IPN: sequential and simultaneous IPN. When the second network formation proceeds in the presence of the already formed network, the IPN is called sequential networks; the both polymers grow simultaneously with non-interfering modes, the IPN is known as a simultaneous IPN (Ilavský, Mamytbekov, Hanyková, & Dušek, 2002).
In this paper, we synthesized sequential IPN based on KGM and PMAA. It is expected that these IPN hydrogels will exhibit good pH-dependent swelling behavior and biodegradability. The enzymatic degradation and drug release experiments were carried out to test whether the IPN hydrogels can be used for colon specific controlled drug delivery.
Section snippets
Materials
Konjac glucomannan (KGM) (purity of 95%) was supplied by Shiyan Huaxianzi Konjac productions Co. Ltd., Hubei, China. Methacrylic acid (MAA) purchased from Fuchen Shiji Co. Ltd., China was purified by vacuum distillation before use. N,N′-methylenebisacrylamide (MBAAm), ammonium persulfate (APS) and other chemicals bought from Shanghai Chemical Group, China were of analytical reagent grade and used without any further purification. Mannaway25L (endo-1,4-β-mannanase, CAS number: 37288-54-3) was
FT-IR characterization of the IPN hydrogels
Fig. 1 shows the FT-IR spectra of PMAA, KGM gels and the IPN hydrogels. For the IR spectra of the IPN hydrogels, new peaks appeared and some peaks became stronger due to interaction or superposition of peaks among groups of MBAAm, MAA and KGM moieties. The band at 1635 cm−1 is the intramolecular hydrogen bonds of KGM. The peaks at 808 cm−1 and 871 cm−1 are the absorption of pyran ring and β-d glucosidic bond. The peaks at 1715, 1390 and 966 cm−1 were assigned as absorption bands of PMAA moieties.
Conclusion
A novel biodegradable and pH-sensitive IPN hydrogels of KGM and PMAA were synthesized by polymerization of MAA in the KGM network. The mass ratio of KGM to PMAA has significant influence on the properties of resultant IPN hydrogels. The studies on the swelling behavior of hydrogels reveal their sensitive response to pH change. The equilibrium swelling ratios increase with increasing PMAA content. KGM network in the IPN hydrogels can be degraded under the action of β-glycosidase, such as
Acknowledgment
This project was funded by the Fundamental Research Funds for the Central Universities of China (No. 52902-0900202208).
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