Synthesis of chemically cross-linked polyvinyl alcohol-co-poly (methacrylic acid) hydrogels by copolymerization; a potential graft-polymeric carrier for oral delivery of 5-fluorouracil
© Minhas et al.; licensee BioMed Central Ltd. 2013
Received: 15 February 2013
Accepted: 28 May 2013
Published: 30 May 2013
Background of the Study
The propose of the present work was to develop chemically cross-linked polyvinyl alcohol-co-poly(methacrylic acid) hydrogel (PVA-MAA hydrogel) for pH responsive delivery of 5-Fluorouracil (5-FU).
PVA based hydrogels were prepared by free radical copolymerization. PVA has been cross-linked chemically with monomer (methacrylic acid) in aqueous medium, cross-linking agent was ethylene glycol di-methacrylate (EGDMA) and benzoyl peroxide was added as reaction initiator. 5-FU was loaded as model drug. FTIR, XRD, TGA and DSC were performed for characterization of copolymer. Surface morphology was studied by SEM. pH sensitive properties were evaluated by swelling dynamics and equilibrium swelling ratio at low and higher pH.
FTIR, XRD, TGA and DSC studies confirmed the formation of new copolymer. Formulations with higher MAA contents showed maximum swelling at 7.4 pH. High drug loading and higher drug release has been observed at pH 7.4.
The current study concludes that a stable copolymeric network of PVA was developed with MAA. The prepared hydrogels were highly pH responsive. This polymeric network could be a potential delivery system for colon targeting of 5-FU in colorectal cancers.
KeywordsPolyvinyl alcohol Methacrylic acid Hydrogel 5-Fluorouracil pH-responsive
The term “hydrogel” is being considered for water insoluble polymeric network that has capacity to absorb large amount of water [1–5]. Synthetic or natural polymers, homopolymer or copolymer, are used to make three dimensional networks by molecular entanglements or by chemical crosslinking . Physical or reversible hydrogels are synthesized by entanglements of polymer molecules or by hydrophobic interactions. Physical hydrogels can absorb the water but inhomogeneities or network defects may occur due to free chain ends or chain loops [7, 8]. The network defects or loose aggregates in physical gels may cause the problem in drug loading and release formed by covalent crosslinking of polymers . Chemical or permanent hydrogels are formed by covalent crosslinking of polymers . Chemically cross-linked hydrogels do not change the shape under the ordinary pressure and erratic movements in GIT do not break the drug carrier systems. Therefore such stable system could be effective in site specific delivery of various agents.
Chemical structures of Polymer, monomer and possible cross-linked structure of hydrogels
Ethylene glycol di-methacrylate
Cross-linked polyvinyl-co-poly(Methacrylic acid) hydrogels
Materials and methods
5-Fluorouracil was obtained as a kind gift from Pharmedic Laboratories (Pvt.) Ltd. Lahore, Pakistan. Polyvinyl alcohol (PVA), methacrylic acid (MAA), ethylene glycol dimethacrylate (EGDMA), benzoyl peroxide were purchased from Sigma Aldrich, UK., Deionized distilled water was obtained from our laboratory.
Synthesis of PVA-co-polyMAA hydrogels
Formulations of PVA-co-poly(MAA) hydrogels
Polyvinyl alcohol (g/100 g)
Methacrylic acid (g/100 g)
EGDMA mol% of monomer
The FT-IR spectra of pure PVA and MAA were recorded. Samples were thoroughly ground and analyzed by attenuated total reflectance ATR-FTIR (Shimadzu, Germany) in range of 4000–650 cm-1. All the hydrogel formulations were examined by FT-IR.
TGA and DSC
Thermal analysis was performed by thermogravimetric analysis (TGA) of TA instruments Q5000 series Thermal Analysis System (TA instruments,WestSussex, UK) and differential scanning calorimetry (DSC) of TA instruments Q2000 Series Thermal Analysis system (TA Instrument WestSussex, UK). The hydrogel samples were ground and passed through mesh 40. For TGA, amount between 0.5-5 mg was placed in an open pan (platinum 100 μl) attached to a microbalance .The samples were heated at 20°C/min from 25-500°C under dry nitrogen at standard mode with ramp test type. All the measurements were made in triplicate. For DSC, samples of PVA, MAA and formulations (0.5-3 mg) were precisely weighed into an aluminum pan onto which aluminum lid with a central pierced hole was crimped. The samples were then scanned under a stream of nitrogen gas from 0-400°C using heating rate 20°C/min.
Bruker D-8 powder diffractometer (Bruker Kahlsruhl, Germany) was used to record the XRD pattern, at room temperature. Powdered samples were filled on to plastic sample holder and smoothing the surface with a glass slide. Samples were scanned over range 5-50° 2θ at a rate of 1º 2θ/min using a copper Kα radiation source with a wavelength of 1.542 Å and 1 mm slits.
Morphology of networks
Surface morphology of hydrogels was investigated using scanning electron microscopy (SEM) by a Quanta 400 SEM (FEI Company, Cambridge, UK). Completely dried discs of hydrogels were cut to optimum sizes to fix on a double-adhesive tape stuck to an aluminum stub. The stubs were coated with gold to a thickness of ~300 Å under an argon atmosphere using a gold sputter module in a high-vacuum evaporator. The coated samples were randomly scanned and photomicrographs were recorded to reveal surface morphology.
Equilibrium swelling ratio
Where M s indicates mass of swelling at predetermined time interval, M eq is weight at equilibrium swelling and M d represents the weight of dry gel before initiation of swelling experiments.
Drug loading and release studies
5-Fluorouracil (5-FU) was loaded in hydrogels by absorption method [17, 19, 20] as model drug by diffusion method. Dried circle PVA-co-MAA hydrogels discs (8 mm) were immersed into 100 ml 5-FU solution (1.0%) in phosphate buffer of pH 7.4 for 72 hours at room temperature. Higher pH and solvent was selected in which drug showed maximum solubility and higher swelling. The discs were immediately washed with distilled water and first dried at room temperature and then placed in oven at 40°C.
Percentage of drug loading was assessed by extracting the weighed amount of polymer with same solvent used for drug loading. Each time 25 ml of fresh buffer solution was used to extract the drug from discs. Extraction was repeated until no drug found in solution. Drug contents were determined by preparing calibration curve of 5-FU dilutions in phosphate buffer using UV–vis-spectrophotometer (UV-1601Shimadzu). The sample was scanned first to determine the λ max that was found 266 nm.
Drug release was investigated at low and high pH values to confirm the pH dependant delivery of 5-FU from PVA/MAA hydrogel network. Drug loaded disks were evaluated for 5-FU release in 900 ml solutions of pH 1.2 and 7.4 in USP dissolution apparatus-II at 37 ± 0.5°C. These samples were analysed at 266 nm using UV–vis-spectrophotometer (UV-1601Shimadzu).
Results and discussion
Physical appearance of hydrogels
The spectrum from cross-linked hydrogel formulations showed different peaks from the parent components (polyvinyl alcohol and methacrylic acid). Broad absorption at 3467 cm-1 showed –OH stretching and a absorption at region of 1700 cm-1 revealed the presence of carbonyl group that was not present in pure PVA spectrum which indicates the esterification between PVA and MAA.
DSC endothermic peaks of pure PVA and MAA were different from the cross-linked PVA-MAA macromolecule. The DSC endothermic peak of PVA at 85°C can be attributed as Tg and decomposition start at 200°C that is melting temperature. Complete mass loss was observed for MAA at 25°C. DSC thermograms of PVA-MAA hydrogel formulations showed two major endothermic peaks, mass loss at 100°C could be attributed to water loss from preparation. However peak at 240°C showed the decomposition of cross-linked polymer-monomer networks, similar reponse by TGA thermogram has been recorded that indicates the decomposition range from 180 to 325°C. TGA and DSC thermograms indicate different thermal pattern of pure PVA and MAA from prepared hydrogels. Cross-linking between PVA and MAA increases the thermal stability and these cross-linked matrices could provide a good delivering capacity for various types of drug molecules.
Effect of polymer, monomer and cross-linker on swelling
Drug loading and release studies
Effect of reaction variables on drug loading and percent release
5FU loading mg/0.5 g of dry gel
% release of 5FU up to 24 hrs.
Chemical cross-linking between polyvinyl alcohol and methacrylic acid modified the characteristics of individual components and formed a pH responsive co-polymeric matrix system. The chemical cross-linking of PVA by EGDMA impart a good strength, very low water absorption at low pH and high at high pH. The prepared hydrogels showed a pH responsive behavior as well as higher drug release at high pH. 5-FU has been loaded as model drug that is being used in cancer chemotherapy but intravenously. It can be concluded that a promising chemically cross-linked pH responsive co-polymeric matrix delivery would be highly effective in colorectal cancer therapies.
Authors are thankful to Higher Education Commission of Pakistan to finance the study.
- Nguyen KT, West JL: Photopolymerizable hydrogels for tissue engineering applications. Biomater. 2002, 23: 4307-4314. 10.1016/S0142-9612(02)00175-8.View ArticleGoogle Scholar
- Peppas NA, Bures P, Leobandung W, Ichikawa H: Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm. 2000, 50: 27-46. 10.1016/S0939-6411(00)00090-4.View ArticlePubMedGoogle Scholar
- Sawhney AS, Pathak CP, van Rensburg JJ, Dunn RC, Hubbell JA: Optimization of photopolymerized bioerodible hydrogel properties for adhesion prevention. J Biomed Mat Res. 1994, 28: 831-838. 10.1002/jbm.820280710.View ArticleGoogle Scholar
- Miyata T, Uragami T, Nakamae K: Biomolecule-sensitive hydrogels. Adv Drug Deliv Rev. 2002, 54: 79-98. 10.1016/S0169-409X(01)00241-1.View ArticlePubMedGoogle Scholar
- Chang C, Duan B, Cai J, Zhang L: Superabsorbent hydrogels based on cellulose for smart swelling and controllable delivery. Eur Polym J. 2010, 46: 92-100. 10.1016/j.eurpolymj.2009.04.033.View ArticleGoogle Scholar
- Langer R, Peppas NA: Advances in biomaterials, drug delivery, and biotechnology. Bioeng Food & Nat Prod. 2003, 49: 2990-3006.Google Scholar
- Campoccia D, Doherty P, Radice M, Brun P, Abatangelo G, Williams DF: Semisynthetic resorbable materials from hyaluronan esterification. Biomater. 1998, 19: 2101-2127. 10.1016/S0142-9612(98)00042-8.View ArticleGoogle Scholar
- Prestwich GD, Marecak DM, Marecak JF, Vercruysse KP, Ziebell MR: Controlled chemical modification of hyaluronic acid. J Cont Rel. 1998, 53: 93-103. 10.1016/S0168-3659(97)00242-3.View ArticleGoogle Scholar
- Hoffman AS: Hydrogels for biomedical applications. Adv Drug Deliv Rev. 2002, 43: 3-12.View ArticleGoogle Scholar
- Wichterle O, Lim D: Hydrophilic gels in biologic use. Nature. 1960, 185: 117-118. 10.1038/185117a0.View ArticleGoogle Scholar
- Gibas I, Janik H: Review: synthetic polymer hydrogels for biomedical applications. Chemistry Chemical technol. 2010, 4: 297-304.Google Scholar
- Liu Y, Vrana NE, Cahill PA, McGuinness GB: Physically crosslinked composite hydrogels of pva with natural macromolecules: structure, mechanical properties, and endothelial cell compatibility. J Biomed Mater Res B Appl Biomater. 2009, 90: 492-502.View ArticlePubMedGoogle Scholar
- Wu M, Bao B, Yoshii F, Makuuchi K: Irradiation of crosslinked, Poly(Vinyl Alcohol) blended hydrogel for wound dressing. J Radioanal Nuclear Chem. 2001, 250: 391-395. 10.1023/A:1017988822121.View ArticleGoogle Scholar
- Yusong P, Dangsheng X, Xiaolin C: Mechanical properties of nanohydroxyapatite reinforced poly(vinyl alcohol) gel composites as biomaterial. J Mater Sci. 2007, 42: 5129-5134. 10.1007/s10853-006-1264-4.View ArticleGoogle Scholar
- Fenglan X, Yubao L, Jiang WX: Preparation and characterization of nano- hydroxyl apatite polyvinyl alcohol hydrogel biocomposite. J Mater Sci. 2004, 39: 5669-5672.View ArticleGoogle Scholar
- Cascone MG, Lazzeri L, Sparvoli E, Scatena M, Serino LP, Danti S: Morphological evaluation of bioartificial hydrogels as potential tissue engineering scaffolds. J Mater Sci: Mater In Medicine. 2004, 15: 1309-1313. 10.1007/s10856-004-5739-z.Google Scholar
- Alemzadeh I, Vossoughi M: Controlled release of paraquat from poly vinyl alcohol hydrogel. Chem Eng Process. 2002, 41: 707-710. 10.1016/S0255-2701(01)00190-8.View ArticleGoogle Scholar
- Peppas NA, Barr-Howell BD: Characterization of the crosslinked structures of hydrogels. Hydrogels in medicine and pharmacy, Fundamentals. Edited by: Pappas NA. 1986, Boca Raton, Florida: CRC Press, 27-57.Google Scholar
- Bettini R, Colombo P, Peppas NA: Solubility effects on drug transport through pH-sensitive, swelling-controlled release systems: transport of theophylline and metoclopramide monohydrochloride. J Cont Rel. 1995, 37: 105-111. 10.1016/0168-3659(95)00069-K.View ArticleGoogle Scholar
- Chen J, Rong L, Lin H, Xiao R, Wu H: Radiation synthesis of pH-sensitive hydrogels from β-cyclodextrin-grafted PEG and acrylic acid for drug delivery. Mater Chem Phys. 2009, 116: 148-152. 10.1016/j.matchemphys.2009.03.005.View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.