Design,Synthesis, Characterization,Swelling and in Vitro Drug Release Behavior of Composite Hydrogel Beads Based on Methotrexate and Chitosan Incorporating Antipyrine Moiety

Novel biodégradable pH and thermal-responsive hydrogels were prepared for controlled drug delivery studies via reaction of chitosan with 4-chloroacetylantipyrine in DMF/H₂O, followed by heating of the formed poly [acetylantipyrine-chitosan] with glutaraldehyde as a crosslinking agent to give the hydrogels. These hydrogels were subjected to equilibrium swelling studies at different temperatures (25°C, 37°C and 45°C) in solutions of pH 2.1 and 7.4. Methotrexate (MTX) was entrapped in the hydrogels, and drug release studies were carried out at 37 °C in solutions at pH 2.1 and 7.4.     

Preparation and Swelling Study of a pH-Dependent Interpolymeric Hydrogel Based on Chitosan for Controlled Drug Release

Novel pH-dependent, biodegradable interpolymeric network (IPN) hydrogels were prepared for controlled drug release investigations. The IPN hydrogels were prepared by irradiation of solutions of N-acryloyglycine (NAGly), polyethylene glycol diacrylate (PEGDA) mixed with chitosan, in the presence of a lower amount of glutaraldehyde as the crosslinker and using 2,2-dimethoxy-2-phenyl acetophenone as the photo-initiator. The equilibrium swelling studies were carried out for the gels at 37°C in buffer solutions of pH 2.1 and 7.4 (simulated gastric and intestinal fluids, respectively). 5-Fluorouracil (5-FU) was entrapped, as a model therapeutic agent, in the hydrogels and equilibrium-swelling studies were carried out for the drug-entrapped gels at 37°C. The in-vitro release profiles of the drug were established at 37°C in pH 2.1 and 7.4.     

pH- and thermo-sensitive semi-IPN hydrogels composed of chitosan, <Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide,and poly(ethylene glycol)-<Emphasis Type="Italic">co</Emphasis>-poly(ε-caprolactone) macromer for drug delivery

In this study, semi-IPN chitosan/poly(N-isopropylacrylamide) (PNIPAAm) hydrogels have been prepared via in situ UV-photo-crosslinking of N-isopropylacrylamide monomer using poly(ethylene glycol)-co-poly(ε-caprolactone) (PEG-co-PCL) macromer as a crosslinker in the presence of chitosan. Swelling properties of the resultant hydrogels were studied by investigating pH- and temperature dependence of equilibrium swelling ratio and oscillatory swelling–deswelling kinetics. It was found that semi-IPN hydrogels responded to both temperature and pH changes, and such stimuli-responsiveness was rapidly reversible. The rheological measurements demonstrated that the incorporation of chitosan greatly improved the mechanical strength of the hydrogels prepared. The release profiles of bovine serum albumin (BSA) from the hydrogels were also evaluated. The results showed that the release rate of BSA was higher in pH 2.0 buffer solution than in pH 7.4 buffer solution at 37 °C. Such double-sensitive hydrogels have the potential to use as smart carriers for drug delivery systems.     

Chitosan‐based interpolymeric pH‐responsive hydrogels for in vitro drug release

Two series of pH‐responsive biodegradable interpolymeric (IPN) hydrogels based on chitosan (Ch) and poly(vinyl alcohol) (PVA) were prepared for controlled drug release investigations. The first series was chemically crosslinked with different concentrations of glutaraldehyde and the second was crosslinked upon γ‐irradiation by different doses. The equilibrium swelling characteristics were investigated for the gels at 37°C in buffer solutions of pH 2.1 and 7.4 as simulated gastric and intestinal fluids, respectively. 5‐Fluorouracil (FU) was entrapped in the hydrogels, as a model therapeutic agent, and the in vitro release profiles of the drug were established at 37°C in pH 2.1 and 7.4. FTIR, SEM, and X‐ray diffraction analyses were used to characterize and investigate the structural changes of the gels with the variation of the blend composition and crosslinker content before and after the drug loading. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2864–2874, 2007     

Fluconazole release through semi‐interpenetrating polymer network hydrogels based on chitosan,acrylic acid,and citraconic acid

Semi‐interpenetrating polymer network hydrogels with different compositions of chitosan (Cs), acrylic acid, and citraconic acid were synthesized via free‐radical polymerization with ethylene glycol dimethacrylate as a crosslinker. The variations of the swelling percentages of the hydrogels with time, temperature, and pH were determined, and Cs–poly(acrylic acid) (PAA) hydrogels were found to be most swollen at pH 7.4 and 37°C. Scanning electron micrographs of Cs–PAA and Cs–P(AA‐co‐CA)‐1 (Cs‐poly(acrylicacid‐co‐citraconir acid)^?1) were taken to observe the morphological differences in the hydrogels. Although the less swollen hydrogel, Cs–P(AA‐co‐CA)‐1, had a sponge‐type structure, the most swollen hydrogel, Cs–PAA, displayed a uniform porous appearance. Fluconazole was entrapped in Cs–P(AA‐co‐CA)‐1 and Cs–PAA hydrogels, and the release was investigated at pH 4.0 and 37°C. The kinetic release parameters of the hydrogels (the gel characteristic constant and the swelling exponent) were calculated, and non‐Fickian diffusion was established for Cs–PAA, which released fluconazole much more slowly than the Cs–P(AA‐co‐CA)‐1 hydrogel. A therapeutic range was reached at close to 1 h for both hydrogels. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Temperature‐responsiveness and sustained delivery properties of macroporous PEG‐co‐PNIPAAm‐co‐PCL hydrogels

A series of novel thermosensitive macroporous poly (ethylene glycol) (PEG)‐co‐poly(N‐isopropylacrylamide) (PNIPAAm)‐co‐poly (ε‐caprolactone) (PCL) hydrogels were synthesized via in situ free radical polymerization. Poly(ethylene glycol diacrylate) (PEGDAc) and poly(ε‐caprolactone diacrylate) (PCLDAc) were prepared as macrocrosslinkers. All compounds were investigated by Nuclear Magnetic Resonance (NMR) and Fourier transform‐infrared spectroscopy (FT‐IR). Differential Scanning Calorimetry (DSC) results showed the lower critical solution temperatures (LCSTs) of the gels were at around 31°C. The macroporous gels not only had considerable swelling ratios, but also exhibited rapid swelling kinetics and response sensitivity. Above mentioned hydrogels showed a remarkable oscillatory swelling–deswelling transition, making them have potential application in long‐term drug delivery. POLYM. ENG. SCI., 55:223–230, 2015. © 2014 Society of Plastics Engineers     

Novel temperature and pH dual-sensitive PNIPAM/CMCS/MWCNT semi-IPN nanohybrid hydrogels: Synthesis,characterization, and DOX drug release

Novel poly(N-isopropylacrylamide)/carboxymethyl chitosan/multiwalled carbon nanotube semi-interpenetrating nanohybrid hydrogels were prepared, and the chemical structure and morphology were characterized. The prepared hydrogels showed temperature and pH dual-responsiveness, and the one containing multiwalled carbon nanotubes (MWCNTs)–COOH possessed high maximal swelling ratios. The phase transition produced at pH of 6.8–7.4 and temperature of 35–40°C, hinging on the system compositions and charge ratios. The hydrogels were used to load hydrophilic anticancer drug, with high entrapped efficiency of about 44%. The drug release changed with temperature, pH, and MWCNTs–COOH contents. The designed hydrogels can be used for site-specific target delivery of protein or hydrophilic anticancer drug.     

UV photopolymerized hydrogels with β-cyclodextrin moieties

Hydrophilic hydrogels based on poly(ethylene glycol)–poly(propylene glycol)–poly(ethylene glycol) block copolymers have potential applications in drug delivery, tissue engineering and other biomedical devices due to their excellent biocompatibility and environmental sensitivity. However, they also exhibit some shortcomings in terms of swelling and mechanical properties as well as affinity for water-insoluble or hydrophobic drug molecules. To address these limitations, new polymeric hydrogels with β-cyclodextrin moieties were prepared by UV photo-polymerization of maleic anhydride-substituted β-CD (MAH-CD) and the block copolymer macromer from Pluronic F68 and poly(ɛ-caprolactone). Their swelling and dynamic rheological properties were investigated with respect to the effects of feed compositions. It was found that the swelling ratio, storage modulus and loss modulus of the resulting hydrogel increased with the increase of MAH-CD amount. Incorporation of MAH-CD resulted in strong viscoelastic system with dominating elastic behavior.     

Preparation of new dendrimer‐like star‐shaped amphiphilic poly(ethylene glycol)–poly(ϵ‐caprolactone) copolymers for biocompatible and high‐efficiency curcumin delivery

Novel amphiphilic star‐shaped terpolymers comprised of hydrophobic poly(?‐caprolactone), pH‐sensitive polyaminoester block and hydrophilic poly(ethylene glycol) (M_n = 1100, 2000 g mol^?1) were synthesized using symmetric pentaerythritol as the core initiator for ring‐opening polymerization (ROP) reaction of ?‐caprolactone functionalized with amino ester dendrimer structure at all chain ends. Subsequently, a second ROP reaction was performed by means of four‐arm star‐shaped poly(?‐caprolactone) macromer with eight ‐OH end groups as the macro‐initiator followed by the attachment of a poly(ethylene glycol) block at the end of each chain via a macromolecular coupling reaction. The molecular structures were verified using Fourier transform infrared and ¹H NMR spectroscopies and gel permeation chromatography. The terpolymers easily formed core–shell structural nanoparticles as micelles in aqueous solution which enhanced drug solubility. The hydrodynamic diameter of these agglomerates was found to be 91–104 nm, as measured using dynamic light scattering. The hydrophobic anticancer drug curcumin was loaded effectively into the polymeric micelles. The drug‐loaded nanoparticles were characterized for drug loading content, encapsulation efficiency, drug–polymer interaction and in vitro drug release profiles. Drug release studies showed an initial burst followed by a sustained release of the entrapped drug over a period of 7days at pH = 7.4 and 5.5. The release behaviours from the obtained drug‐loaded nanoparticles indicated that the rate of drug release could be effectively controlled by pH value. Altogether, these results demonstrate that the designed nanoparticles have great potential as hydrophobic drug delivery carriers for cancer therapy. © 2015 Society of Chemical Industry     

Preparation and application in drug controlled delivery of pH‐sensitive P(CE‐co‐DMAEMA‐co‐MEG) hydrogel

A pH‐sensitive hydrogel [P(CE‐co‐DMAEMA‐co‐MEG)] was synthesized by the free‐radical crosslinking polymerization of N,N‐dimethylaminoethyl methacrylate (DMAEMA), poly(ethylene glycol) methyl ether methacrylate(MPEG‐Mac) and methoxyl poly(ethylene glycol)‐poly(caprolactone)‐methacryloyl methchloride (PCE‐Mac). The effects of pH and monomer content on swelling property, swelling and deswelling kinetics of the hydrogels were examined and hydrogel microstructures were investigated by SEM. Sodium salicylate was chosen as a model drug and the controlled‐release properties of hydrogels were pilot studied. The results indicated that the swelling ratios of the gels in stimulated gastric fluids (SGF, pH = 1.4) were higher than those in stimulated intestinal fluids (SIF, pH = 7.4), and followed a non‐Fickian and a Fickian diffusion mechanism, respectively. In vitro release studies showed that its release rate depends on different swelling of the network as a function of the environmental pH and DMAEMA content. SEM micrographs showed homogenous pore structure of the hydrogel with open pores at pH 1.4. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40737.     

Effect of poly(ethylene glycol)-derived crosslinkers on the properties of thermosensitive hydrogels

Three crosslinkers, poly(ethylene glycol) diacrylate (PEGDA), glycerol ethoxylate triacrylate (GETA) and citric acid-(PEG acrylate)₃ (CA-PEGTA) derived from poly(ethylene glycol) (PEG) were synthesized at first. The three series of poly (N-isopropylacrylamide) (PNIPAAm) hydrogels were prepared by photopolymerization with the crosslinkers and compared with a hydrogel based on commercial crosslinker, N,N′-methylene bis-acrylamide (NMBA). The influence of the crosslinker structures and contents on the swelling behaviour, mechanical properties, and drug release of the hydrogels was investigated. The results showed that the hydrogels based on PEGDA and NMBA exhibited the highest and the lowest swelling ratio, respectively. The content of crosslinker of all hydrogel series showed good thermosensitivity and thermo-reversibility. The critical gel transition temperature (CGTT) appeared at 32 °C for the hydrogel based on NMBA, but appeared at about 34 °C for other hydrogels due to higher hydrophilicity of the crosslinker. In the mechanical properties, three-arms crosslinker GETA and CA-PEGTA led to higher mechanical strength than a linear crosslinker PEGDA. A hydrogel based on GETA (NG6) showed the highest shear modulus of 656.9 kPa and Young’s modulus of 1655.0 kPa. The hydrogels containing higher content of crosslinker revealed lower swelling ratio and higher mechanical strength. In the drug release, the hydrogels with higher swelling ratios showed higher drug absorbed. The highest release percentage of caffeine and vitamin B12 for hydrogel based on PEGDA (NP6) could reach 68.3% and 75.4%, respectively. In addition, the bound water and toxicity of the hydrogels were also investigated.

     

Relaxational behavior and swelling‐pH master curves of poly[(diethylaminoethyl methacrylate)‐graft‐(ethylene glycol)] hydrogels

Poly[(diethylaminoethyl methacrylate)‐graft‐(ethylene glycol)] hydrogels were prepared with a molar ratio of 10:1 of diethylaminoethyl methacrylate to poly(ethylene glycol) of number‐average molecular weights (M_n) 200, 400 and 1000 g mol^?1 using tetra(ethylene glycol) dimethacrylate to give a crosslinking ratio between 0.5 and 4.0 %. Glucose oxidase and catalase were immobilized in the matrix during polymerization. The maximum enzyme loading used was 6.6 × 10^?4 g of glucose oxidase per g of polymer. The equilibrium and dynamic swelling properties of these hydrogels were investigated. The pH‐dependent equilibrium swelling characteristics showed a sharp transition between the swollen and the collapsed state at pH 7.0. The dynamic response of the hydrogel discs to pH was analyzed in pulsatile pH conditions. The effects of particle size, crosslinking and molecular weight of poly(ethylene glycol) (PEG) on the dynamic swelling response were investigated. The pulsatile nature of the response was analyzed using Boltzmann superposition. Swelling–pH master curves were obtained. Copyright © 2004 Society of Chemical Industry     

Temperature and pH sensitive hydrogels composed of chitosan and poly(ethylene glycol)

Summary Chitosan based semi-interpenetrating polymer network (semi-IPN) hydrogels containing different amounts of poly(ethylene glycol) (PEG) were prepared. The crosslinking of the hydrogels was achieved by using a naturally occurring nontoxic cross-linking agent genipin. The swelling behaviour of these hydrogels was studied by immersing the films in deionized water at 25, 37 and 45 °C and in media of different pHs at 37 °C. Swelling was found to be dependent on temperature, pH of the medium and the amount of PEG in the gel. States of water in the hydrogels swollen in deionized water at 37 °C were determined using Differential Scanning Calorimetry (DSC). The equilibrium water content and the amount of freezing water in the swollen hydrogels increased with the increase in PEG concentration in the gels.     

Hydrogels based on poly(ethylene oxide) and poly(tetramethylene oxide) or poly(dimethyl siloxane). II. Physical properties and bacterial adhesion

To investigate the effects of polymer chemistry and topology on physical properties and bacterial adhesion, various hydrogels composed of short hydrophilic [poly(ethylene oxide) (PEO)] and hydrophobic blocks were synthesized by polycondensation reactions. Differential scanning calorimetry and X‐ray diffraction analysis confirmed that all of the hydrogels were strongly phase‐separated due to incompatibility between PEO and hydrophobic blocks such as poly(tetramethylene oxide) (PTMO) and poly(dimethyl siloxane) (PDMS). The crystallization of PEO in the hydrogels was enhanced by the incorporation of longer PEO chains, the adoption of PDMS as a hydrophobic block, and the grafting of monomethoxy poly(ethylene oxide) (MPEO). Compared to Pellethane, the control polymer, the hydrogels exhibited higher Young's moduli and elongations at break, which was attributed to the crystalline domains of PEO and the flexible characteristics of the hydrophobic blocks. The mechanical properties of the hydrogels, however, significantly deteriorated when they were hydrated in distilled water; this was primarily ascribed to the disappearance of PEO crystallity. The water capacity of hydrogels at 37°C in phosphate‐buffered saline (PBS) (pH = 7.4) was dominantly dependant on PEO content, which also influenced the thermonegative swelling behavior. From the bacterial adhesion tests, it was evident that both S. epidermidis and E. coli adhered to Pellethane much greater than to the hydrogels, regardless of the preadsorption of albumin. Better resistance to bacterial adhesion was observed in hydrogels with longer PEO chains, with PTMO as a hydrophobic block, and with MPEO grafts. The least bacterial adhesion for both species was achieved on MPEO_2k–PTMO, a hydrogel with MPEO grafts. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 1505–1514, 2003     

Swelling behavior of thermoreversible poly(N‐isopropylacrylamide‐co‐N‐vinylimidazole) hydrogels

Thermoresponsive hydrogels based on N‐isopropylacrylamide and N‐vinylimidazole were synthesized, and their swelling–deswelling behavior was studied as a function of the total monomer concentration. For copolymeric structures with better thermoresponsive properties with respect to poly(N‐isopropylacrylamide‐co‐N‐vinylimidazole) hydrogels, these hydrogels were protonated with HCl and HNO₃, and the copolymer behaviors were compared with those of the unprotonated hydrogels. The temperature was changed from 4 to 70°C at fixed pHs and total ionic strengths. The equilibrium swelling ratio, dynamic swelling ratio, and dynamic deswelling ratio were evaluated for all the hydrogels. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 1619–1624, 2004     

Photopolymerized pH‐sensitive semi‐IPN: Synthesis,water uptake analysis,and preliminary drug release study

A series of pH‐sensitive semi‐IPN hydrogels, composed of varying amounts of monomer acrylic acid(AAc), crosslinker N,N′ methylene bisacrylamide, polymer cellulose acetate (CA) were synthesized via photoinitiated polymerization in dimethyl formamide (DMF) medium. The CA/P (AAc) hydrogels were characterized by FTIR, and TG analysis. The equilibrium water uptake data was used to determine various network parameters. For all the samples synthesized, the swelling exponent “n,” initial diffusion coefficient D and average diffusion coefficient D_ave were found to be in the range of 0.51–0.72, 3.16 to 7.14 × 10^?6 cm² min^?1 and 94.16–120.56 cm² min^?1, respectively. The hydrogel demonstrated fair pH‐dependent swelling behavior, with nearly 20% swelling in the medium of pH 1.0 and 615% in the medium of pH 7.4 at 37°C, respectively. The gel showed excellent swelling–deswelling cycles which were interpreted quantitatively by first order kinetic swelling and deswelling models. Finally, the preliminary insulin release study, carried out in the media of varying pH, observed almost 16% release of entrapped drug in the simulating gastric fluid (SGF) of pH 1.0 in first 2 h and nearly 51% in next 6 h in simulating intestinal fluid(SIF) of pH 7.4 at 37°C. POLYM. ENG. SCI., 53:2129–2140, 2013. © 2013 Society of Plastics Engineers     

Swelling–deswelling kinetics of poly(N‐isopropylacrylamide) hydrogels formed in PEG solutions

A series of poly(N‐isopropylacrylamide) (PNIPA) hydrogels was prepared by free‐radical crosslinking copolymerization of N‐isopropylacrylamide (NIPA) and N,N′‐methylenebisacrylamide (BAAm) in aqueous solutions of poly(ethylene glycol) of molecular weight 300 g/mol (PEG). The amount of PEG in the polymerization solvent, the crosslinker (BAAm) content, and the gel preparation temperature (T_prep) were varied in the gelation experiments. The hydrogels were characterized by the equilibrium swelling and elasticity tests as well as by the measurements of the deswelling–reswelling kinetics of the hydrogels in response to a temperature change between 25 and 48°C. The rate of deswelling of the swollen gel increases while the rate of reswelling of the collapsed gel decreases as the amount of PEG in the polymerization solvent is increased or as the crosslinker content is decreased. The T_prep effect on the swelling kinetics of the hydrogels was only observed if the PEG content of the polymerization solvent is less than 20%, which is explained with the screening of H‐bonding interactions in concentrated PEG solution. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 99: 37–44, 2006     

Swelling kinetics,mechanical properties,and release characteristics of chitosan‐based semi‐IPN hydrogels

Two series of pH‐sensitive semi‐interpenetrating network hydrogels (semi‐IPN) based on chitosan (CS) natural polymer and acrylamide (AAm) and/or N‐hydroxymethyl acrylamide (HMA) monomers by varying the monomer and CS ratios were synthesized by free radical chain polymerization. 5‐Fluorouracil (5‐FU), a model anticancer drug, has been added to the feed composition before the polymerization. The characterization of gels indicated that the drug is molecularly dispersed in the polymer matrix. The swelling kinetics of drug‐loaded gels have decreased with increased HMA content at 37°C in both distilled water and buffer solutions with a pH of 2.1 or 7.4. Elastic modulus of the gels increased with the increase in HMA content and higher CS concentration enhanced the elastic modulus positively. Moreover, cumulative release percentages of the gels for 5‐FU were ca. 10% higher in pH 2.1 than those in pH 7.4 media. It was determined that they can be suitable for the use in both gastric and colon environments. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41886.     

Preparation and characterization of pH responsive poly(methacrylic acid‐acrylamide‐N‐hydroxyethyl acrylamide) hydrogels for drug delivery systems

In this study, pH responsive polymers composed of methacrylic acid, acrylamide, and N‐hydroxyethyl acrylamide were synthesized by free radical polymerization technique. The characterization was done with Fourier transform infrared spectroscopy and scanning electron microscopy. The swelling and drug release behavior of the hydrogels was determined as a function of time at 37°C in pH 2.1 and 7.4. The swelling and drug release studies showed that increased methacrylic acid amount caused a higher increase in swelling and drug release values at pH 7.4 than those at pH 2.1. In addition, the drug release data were applied to kinetic models such as zero order, first order, and Higuchi equations, and it fit well in the Higuchi model of the hydrogel. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43226.     

Design and fabrication of a triple-responsive chitosan-based hydrogel with excellent mechanical properties for controlled drug delivery

A pH-, temperature- and salinity responsive hydrogel with enhanced mechanical performance was developed based on semi interpenetrating network that was formed as a result of concurrent free radical polymerization of acrylic acid (AA), oligo(ethylene glycol) methacrylate (OEGMA) and 2-(2-methoxyethoxy) ethyl methacrylate (MEO₂MA) along with chitosan (CS) for controlled drug delivery. The mechanical behaviors and swelling properties of these hydrogels were systematically investigated, and the results indicated that they were strongly affected by the content of AA and MEO₂MA and exhibited strong pH-, temperature and salinity sensitivity. Bovine serum albumin (BSA) and 5-Fluorouracil (5-Fu) were used as the model drugs to evaluate the sustained release of the hydrogel. The result indicated that the amount of both drugs released was relatively low in acidic condition (pH 1.2) but high in neutral environment (pH 7.4), and the release rate of the drugs was slower at 37 °C than that at 25 °C. Cytotoxicity results suggested that the blank hydrogels had negligible toxicity to normal cells, whereas the 5-Fu-loaded hydrogels remained high in cytotoxicity for LO2 and HepG2 cancer cells. These results suggest that the synthesized hydrogels have the potential to be used as an effective pH/temperature sustainable site-specific oral drug delivery in intestine and colon.