Nafcillin release from poly(acrylic acid–co–methyl methacrylate) hydrogels

Summary Copolymeric poly(acrylic acid-co-methyl methacrylate) hydrogels for three different compositions: (90/10), (80/20) and (60/40), have been studied. Drug release has been examined as a function of the hydrogel composition by HPLC (High Pressure Liquid Cromatography). The release experiments were carried out at 37 °C. The fraction of available drug release was linear in t^1/2. The values of the diffusional coefficient (0.50<n<1.0) indicate that the nafcillin release mechanism from the hydrogels in study is non-Fickian. The diffusion coefficients for this drug release have been calculated. The molecular diffusion of nafcillin through hydrogels is controlled by the swelling.     

Preparation a novel pH‐sensitive blend hydrogel based on polyaspartic acid and ethylcellulose for controlled release of naproxen sodium

Hydrogels based on pH‐sensitive polymers are of great interest as potential biomaterials for the controlled delivery of drug molecules. In this study, a novel, pH‐sensitive hydrogel was synthesized by poly(aspartic acid) (PASP) crosslinked with 1,6‐hexanediamine and reinforced with ethylcellulose (EC). The loading and release characteristics of naproxen sodium (NS) were studied. The PASP–EC blend hydrogels had pH‐sensitive characteristics and were strongly dependent on the pH value. The release kinetics for NS from the PASP–EC blend hydrogels and PASP hydrogel were evaluated in simulated gastric fluid (pH = 1.05) and simulated intestinal fluid (pH = 6.8) at 37°C. The results showed that the drug‐loaded hydrogels were resistant to simulated gastric fluid, and hence, they could be useful for oral drug delivery. Compared with the PASP hydrogel, the PASP–EC blend hydrogels showed a lower release rate of NS in the same pH conditions. It was evident that the presence of hydrophobic groups (EC) retarded the release of NS and led to sustained release. The kinetics of NS release from the drug‐loaded hydrogels conformed to the Korsmeyer–Peppas model. The release exponent of the model was 0.7291, which indicated multiple drug release. The PASP–EC blend hydrogels were biodegradable and pH sensitive; there would be a wide range of applications for them in controlled drug‐delivery systems. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

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.     

Preparation and in vitro evaluation of new pH‐sensitive hydrogel beads for oral delivery of protein drugs

New biodegradable pH‐responsive hydrogel beads based on chemically modified chitosan and sodium alginate were prepared and characterized for the controlled release study of protein drugs in the small intestine. The ionotropic gelation reaction was carried out under mild aqueous conditions, which should be appropriate for the retention of the biological activity of an uploaded protein drug. The equilibrium swelling studies were carried out for the hydrogel beads at 37°C in simulated gastric (SGF) and simulated intestinal (SIF) fluids. Bovine serum albumin (BSA), a model for protein drugs was entrapped in the hydrogels and the in vitro drug release profiles were established at 37°C in SGF and SIF. The preliminary investigation of the hydrogel beads prepared in this study showed high entrapment efficiency (up to 97%) and promising release profiles of BSA. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Synthesis and Properties of Temperature-Sensitive Hydrogel Based on Hydroxyethyl Cellulose

Hydrogels were prepared from modified hydroxyethyl cellulose by copolymerization with N-isopropylacrylamide. The equilibrium swelling ratio of hydrogel was measured in buffer solution with pH 7.0 from 25.0 to 45.0°C and the data obtained showed that hydrogels exhibited temperature sensitivity. The results of DSC analysis revealed that the low critical solution temperature (LCST) of hydrogels was enhanced by the introduction of hydroxyethyl cellulose. SEM images suggested that the cross-section of freeze-dried hydrogels was porous. The data of adsorption and release experiments for two model drugs suggest that the controlled drug release can be achieved.     

Properties of hydrogels of atactic poly(vinyl alcohol)/NaCl/H2O system and their application to drug release

In order to prepare cost‐effective physically cross‐linked hydrogels including food salt sodium chloride, samples, were prepared with various concentrations of NaCl and respective atactic poly(vinyl alcohol) (a‐PVA), and were evaluated. It had been observed that hydrogels containing NaCl concentration (9–11 wt%) along with a‐PVA concentration 9–5% respectively exhibited higher melting points (91.5–95.1 °C). A higher melting point characterizes the hydrogel composition of a system like a‐PVA(7%)/NaCl(11%)/H₂O. The swelling degree of this hydrogel was found to be comparatively better at 37 °C than at any other temperature studied here. However, irregular Fickian swelling was found at this temperature. The UV light absorption maximum at 362–364 nm and minimum at 351 nm for this hydrogel had been found as evidence of physical cross‐linking. A drug, theophylline was loaded by solvent‐sorption and feed‐mixture dissolving methods. The feed‐mixture dissolving method is better than solvent sorption because of high drug loading, comparatively low fraction release rate and more sustained‐release of drug than that of solvent‐sorption. Theophylline was released twice as fast from the hydrogel after solvent‐sorption drug loading (3 h) than from that which used the feed‐mixture dissolving method (6.5 h). Theophylline‐loaded hydrogels of this system (feed‐mixture dissolving) were then prepared at high temperature (60 °C) thawing for 6 h followed by chilling at 0.4 °C for 3 h as one cycle. And the drug release behaviour and mass transfer were found almost the same as for chilling (24 h at 0.4 °C)–thawing (48 h at room temperature). Drug release behaviour was studied as apparently irregular Fickian diffusion (Higuchi Matrix Dissolution Model). © 2002 Society of Chemical Industry     

A new photocrosslinkable hydrogel based on a derivative of polyaspartic acid for the controlled release of ketoprofen

A novel photocrosslinkable and pH-sensitive hydrogel used for drug delivery was developed based on polyaspartic acid. Polysuccinimide (PSI) was modified by hydrazine and acryloyl chloride. The unreacted imide rings of PSI were hydrolyzed. Hydrogels were formed by photocrosslinking without any crosslinker or photoinitiator. Products were characterized by FT-IR and solid-state ¹³CNMR analysis. The swelling behaviors of hydrogel in various pH values were studied. Ketoprofen (KP) was chosen as a model drug. Two drug loading methods were compared. The release kinetics of KP was evaluated in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) at 37 °C. The results showed that drug-loaded hydrogels were resistant to SGF, and hence they could be useful for oral drug delivery. There would be a wide range of applications for controlled drug delivering system.     

Injectable and thermosensitive poly(organophosphazene) hydrogels for a 5‐fluorouracil delivery

The drug solubility and its release profiles of an anticancer drug from an injectable thermosensitive poly(organophosphazene) hydrogel bearing hydrophobic L ‐isoleucine ethyl ester and hydrophilic α‐amino‐ω‐methoxy‐poly(ethylene glycol) with and without hydrolysis‐sensitive glycyl lactate ethyl ester or functional glycyl glycine have been investigated. 5‐Fluorouracil (5‐FU) was used as a model anticancer drug. The aqueous solutions of 5‐FU incorporated poly(organophosphazenes) were an injectable fluid state at room temperature and formed a transparent gel at body temperature. The poly(organophosphazene) solution could enhance the solubility of 5‐FU and its solubility (34.26 mg/mL) was increased up to 10‐fold compared to that in phosphate‐buffered saline (3.39 mg/mL, pH 7.4, 4°C). The in vitro drug release profiles from poly(organophosphazene) hydrogels were established in phosphate‐buffered saline at pH 7.4 at 37°C and the release of 5‐FU was significantly affected by the diffusion‐controlled stage. The results suggest that the injectable and thermosensitive poly(organophosphazene) hydrogel is a potential carrier for 5‐FU to increase its solubility, control a relatively sustained and localized release at target sites and thus decrease systemic side effects. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

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.     

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.     

Swelling behaviour and paracetamol release from poly(<Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide-itaconic acid) hydrogels

Copolymer hydrogels of N-isopropylacrylamide and itaconic acid (IA), crosslinked with N,N′-methylenebisacrylamide, were prepared by radical copolymerization. These hydrogels were investigated with regard to their composition to find materials with satisfactory swelling and drug release properties. A paracetamol is used as a model drug to investigate drug release profile of the hydrogels. It was found that the investigated hydrogels exhibited pH- and temperature-dependent swelling behaviour with restricted swelling and lower equilibrium degree of swelling at lower pH values and temperatures above the LCST value of PNIPAM (around 34 °C). The diffusion exponent for paracetamol release indicate that the mechanism of paracetamol release are governed by Fickian diffusion, while in all release media initial diffusion coefficient was lower than late time diffusion coefficient. Furthermore, the paracetamol release rate depends on the hydrogel degree of swelling and it increased in the first stage of diffusion process, whereas was no significant difference thereafter. The presence of the IA moieties incorporated into the network weakened the shear resistance of the hydrogels. In order to calculate the pore size the characteristic ratio for PNIPAM, C _n  = 11.7, was calculated. Based on the pore size, the investigated hydrogels can be regarded as microporous. According to the obtained results swelling behaviour, mechanical properties, drug-loading capacity and the drug release rate could be controlled by hydrogel composition and crosslinking density, which is important for application of the investigated hydrogels as drug delivery systems.     

Controlled release of Montelukast Sodium from pH-sensitive injectable hydrogels

pH sensitive hydrogels showed excellent drug release properties, with promise for other biomedical applications. Also, the impact of molecular weight (MW) and degree of deacetylation (DDA) of chitosan on the fabricated chitosan/poly (vinyl alcohol) (3:1 mol ratio) hydrogel with selective silane crosslinker amount was evaluated for controlled drug delivery. The FTIR spectroscopy confirmed the incorporated components and the developed interactions among the polymer chains. The hydrogel characteristics were expressed by their responsive behaviour in different environments (water, ionic media and pH). The hydrogel sample (CH1000) having chitosan with higher MW and DDA exhibited more thermal stability and bacterial growth inhibition against E.coli. All hydrogels exhibited maximum swelling at basic and neutral pH and less swelling was observed in acidic media. For drug release analysis performed in simulated gastric fluid, hydrogel showed controlled drug release in 2 h but it was more than 10%, consequently cannot be used for oral purpose. In simulated intestinal fluid, hydrogels exhibited more than 80% release within 90 min. This characteristic phenomenon at neutral pH empowered hydrogel appropriate towards injectable and targeted controlled release of applicable drug. It was concluded that the prepared hydrogel can be administered directly into the venous circulation through syringe and can be used with better results for biomedical applications.     

Synthesis and characterization of poly{N‐[3‐(dimethylamino) propyl] methacrylamide‐co‐itaconic acid} hydrogels for drug delivery

A novel pH‐sensitive hydrogel system composed of itaconic acid (IA) and N‐[3‐(dimethylamino) propyl] methacrylamide was designed. This system was prepared by aqueous copolymerization with N,N‐methylene bisacrylamide as a chemical crosslinker. The chemical structure of the hydrogels was characterized by Fourier transform infrared (FTIR) spectroscopy. The microstructure and morphology of the hydrogels were evaluated by X‐ray diffraction (XRD) and scanning electron microscopy (SEM). The SEM study of hydrogels on higher magnification revealed a highly porous morphology with uniformly arranged pores ranging from 40 to 200 μm in size. XRD analysis revealed the amorphous nature of the hydrogels, and it was found that an increase in the IA content in the monomer feed greatly reduced the crystallinity of the hydrogels. Swelling experiments were carried out in buffer solutions at different pH values (1.2–10) at 37°C ± 1°C to investigate their pH‐dependent swelling behavior and dimensional stability. An increase in the acid part (IA) increased the swelling ratio of the hydrogels. Temperature‐sensitive swelling of the hydrogels was investigated at 20–70°C in simulated intestinal fluid. The hydrogels swelled at higher temperatures and shrank at lower temperatures. 5‐Aminosalicylic acid (5‐ASA) was selected as a model drug, and release experiments were carried out under simulated intestinal and gastric conditions. 5‐ASA release from the poly N‐[3‐(dimethylamino) propyl] methacrylamide‐co‐itaconic acid‐80 (PDMAPMAIA‐80) hydrogel was found to follow non‐Fickian diffusion mechanism under gastric conditions, and a super case II transport mechanism was found under intestinal conditions. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

pH-/temperature-sensitive carboxymethyl chitosan/poly(N-isopropylacrylamide-co-methacrylic acid) IPN: preparation,characterization and sustained release of riboflavin

Dual crosslinked pH-/temperature-sensitive interpenetrating polymer networks (IPN) were prepared by free-radical copolymerization of N-isopropylacrylamide and methylacrylic acid (MAA) using N,N′-methylenebisacrylamide as a crosslinker in carboxymethyl chitosan (which was crosslinked by Ca²⁺) aqueous solution. Scanning electron microscopy was used to observe the morphologies of the IPN at different pH values and temperatures. The effects of MAA content and environmental pH on the “pH-/temperature-induced” phase transition behavior of the IPN hydrogels were investigated. The phase transition temperature was adjusted to 37 °C by changing the MAA content. The effects of drug-loaded content, crosslinking density, environmental pH, and temperature on the drug release behavior of the drug-loaded IPN hydrogel were also explored. Based on results, the hydrogel possessed pH/temperature sensitivity. The swelling ratio and phase translation temperature of the hydrogel were lower at lower pH. These values were lowest at pH 3.0. The release behavior of riboflavin was dependent on preparation condition, environmental pH, and temperature. Drug cumulative release was only 6 % at pH 1.8 for 2 h. The drug cumulative release was 13 % before the drug-loaded hydrogel reached the position with pH 6.8. The drug release rate was higher at lower temperature. Therefore, dual-crosslinked hydrogel holds much potential as a drug site-specific carrier.     

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.

     

Theophylline‐loaded pectin‐based hydrogels. I. Effect of medium pH and preparation conditions on drug release profile

In this study, a series of theophylline‐loaded calcium pectin gel films were prepared in three different Ca⁺² concentrations with three different methods for wound dressing applications. Drug release performance of the films were investigated in four different medium pH in order to mimic wound healing pH conditions. Hydrogel films were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy and atomic force microscopy. Their absorbency (fluid handling), swelling behavior, dehydration rate, dispersion characteristic, dressing pH determination, water vapor permeability, oxygen permeability, surface contact angle, flexibility, Shore A hardness, mean mass per unit area and thickness were determined. The effect of the hydrogels on wound healing was evaluated with an in vitro wound healing assay. After evaluating all data, we suggested that the hydrogel film prepared with swelling method using 7% or 10% crosslinker and dried at 26 °C is more suitable for controlled drug release process. We showed that between pH 3.25 and 7.12 the form of the hydrogel did not change, and drug release was continuous. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46731.     

Diffusion and controlled release characteristics of pH-sensitive poly(2-(dimethyl amino)ethyl methacrylate-co-2-hydroxyethylacrylate) hydrogels

The authors describe a facial development of pH-responsive hydrogels composed of 2-(dimethylamino)ethylmethacrylate and 2-hydroxyethylacrylate via free-radical polymerization at 29°C. The hydrogels were characterized by FTIR, SEM, and XRD studies. The diffusional exponent (n), hydrogel network parameters such as average molecular weight between crosslinks (M_c), and polymer-solvent interaction (χ) were calculated by using swelling data. The hydrogels were encapsulated with 5-fluorouracil, the in vitro release data indicated that the maximum drug release was significantly achieved in pH 1.2 rather than in pH 7.4 and it was enhanced up to 30 h. These results suggested that the gels are highly useful for anticancer drug delivery applications.     

Thermosensitive chitosan hydrogel for implantable drug delivery: Blending PVA to mitigate body response and promote bioavailability

Thermosensitive hydrogels promise to be the injectable implants for long-term controlled drug release; however, body response to the implanted hydrogels and its unpredictable impacts on drug release complicates their applications. In the present study, hydrophilic polymer poly(vinyl alcohol) (PVA) was blended into the thermosensitive hydrogel composed of chitosan and glycerophosphate to mitigate the body responses and promote the drug bioavailability. The effects of PVA on the surface properties of the hydrogel were evaluated by zeta-potential, water contact angle, and cell attachment. Body responses were explored by histological examination via subcutaneously implanting the hydrogels into Sprague-Dawley rats. Drug release in vivo and bioavailability were determined with cyclosporine A (CsA) employed as the model drug. The results showed that, on one hand, the presence of PVA improved the surface hydrophilicity of the hydrogel and inhibited the cell attachment on the hydrogel, which alleviated the further cell infiltration and tissue integration in body; and on the other hand, blending of PVA led to the more rapid gel formation and more compact network, which resisted the dehydration and survived the hydrogel from cell division. These advantages benefited the controlled release and absorption of CsA, and contributed to the higher drug bioavailability. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Thermosensitive poly(n‐isopropylacrylamide) hydrogels bonded on cellulose supports

A two‐step initiation and polymerization process was developed for the preparation of two series of hydrogel–cellulose composites with distinctively different morphologies and swelling behaviors. Hydroentangled cotton cellulose fibers were optimally initiated in 20 mM aqueous ammonium cerium(IV) nitrate for 15 min and then polymerized in aqueous solutions of N‐isopropylacrylamide (NIPAAm) monomer and N,N′‐methylene bisacrylamide (BisA) crosslinker. The extents of hydrogels on the cellulose solids could be controlled by variations in the concentrations of the monomer and crosslinker as well as the NIPAAm/BisA solution‐to‐solid ratios. The two series of hydrogel–cellulose composites formed were hydrogel‐covered/filled cellulose (I) and cellulose‐reinforced hydrogel (II) composites. Series I composites were synthesized with NIPAAm/BisA solutions below the liquid saturation level of the cellulose; this led to pore structures (size and porosity) that depended on both the extent and swelling of the grafted hydrogels. Series II composites were polymerized in the presence of excessive NIPAAm/BisA solutions to produce cellulose solids completely encapsulated in the hydrogels. All the cellulose‐supported hydrogels exhibited lower extents of phase transition over a wider temperature range (28–40°C) than the free poly(N‐isopropylacrylamide) hydrogels (32°C). These findings demonstrate that hydrogels can be used to control the pore structure of cellulose and can be supported with cellulose fibers. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 999–1006, 2003     

Sustained release behavior of pH‐responsive poly(vinyl alcohol)/poly(acrylic acid) hydrogels containing activated carbon fibers

The composites of pH‐responsive poly(vinyl alcohol)/poly(acrylic acid) hydrogel and activated carbon fibers (ACFs) were prepared as sustained drug release system with excellent mechanical properties. The mechanical properties of hydrogels were improved greatly by addition of ACFs. The thinner ACFs were more effective in increasing the mechanical properties of composite hydrogels. The cumulative amount of release and the release period were dependent on the surface area and the pore volume of ACFs. The drug release was maximized at basic condition due to the pH‐sensitive hydrogel matrices and the initial bust phenomenon was alleviated by incorporating ACFs in the hydrogels. The drug release was sustained about four times longer and the mechanical property was increased about 2.6 times higher because ACFs worked as drug reservoir and reinforcement. Cytotoxicity evaluation confirmed the biocompatible characteristics of the ACFs‐containing hydrogels. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011