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     

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     

Preparation of poly(acrylic acid)–chitosan hydrogels by gamma irradiation and in vitro drug release

Biocompatible and biodegradable pH‐responsive hydrogels based on poly(acrylic acid) (AAc) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a gamma irradiation polymerization technique. The degree of gelation was over 96% and increased as the chitosan or acrylic acid content increased. The equilibrium swelling studies of hydrogels prepared in various conditions were carried out in an aqueous solution, and the pH sensitivity in the range of pH 1–12 was investigated. The AAc/chitosan hydrogels showed the highest water content when the 30 vol % AAc and 0.1 wt % chitosan were irradiated with a 30‐kGy radiation dose. Also, an increase of swelling degree with an increase in the pH was noticed and showed the highest value at pH 12. The drug, 5‐fluorouracil, was loaded into these hydrogels and the release studies were carried out in simulated gastric and intestinal fluids. The in vitro release profiles of the drugs showed that more than 90% of the loaded drugs were released in the first 1 h at the intestinal pH and the rest of the drug had been released slowly. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 3660–3667, 2003     

γ‐Irradiation preparation of poly(acrylic acid)–chitosan hydrogels for in vitro drug release

Biocompatible and biodegradable pH‐responsive hydrogels based on poly(acrylic acid) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a γ‐irradiation polymerization technique. The degree of gelation was over 96% and increased as the chitosan or acrylic acid (AAc) content increased. The equilibrium swelling studies of hydrogels prepared under various conditions were carried out in an aqueous solution, and the pH sensitivity in a range of pH 1–12 was investigated. The AAc/chitosan hydrogels showed the highest water content when 30 vol % AAc and 0.1 wt % chitosan were irradiated with a 30 kGy dose of radiation. In addition, an increase of the degree of swelling with an increase in the pH was noticed and it had the highest value at pH 12. The drug 5‐fluorouracil was loaded into these hydrogels and the release studies were carried out in simulated gastric and intestinal fluids. The in vitro release profiles of the drugs showed that more than 90% of the loaded drugs were released in the first 1 h at intestinal pH and the rest of the drug was released slowly. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 3270–3277, 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     

Study on Synthesis and Chloramphenicol Release of Poly（2-hydroxyethylmethacrylate-co-acrylamide） Hydrogels

In this article, poly（2-hydroxyethylmethacrylate-co-acrylamide） hydrogels were synthesized by bulk free-radical copolymerization of 2-hydroxyethylmethacrylate （HEMA） and acrylamide （AAm） for soft contact lens（SCL）-based ophthalmic drug delivery system. The copolymer was characterized with FT-IR and SEM, the swelling property of the hydrogels were studied by gravimetrical method, and chloramphenicol was used as a model drug to investigate drug release profile of the hydrogels. The results showed that poly（2-hydroxyethylmethacrylateco-acrylamide） hydrogels were transparent and useful SCL biomaterial, the water content increased as AAm content increase and pH decrease, and in the same way, hydrogel composition affected chloramphenicol release process too. Migration rate of chloramphenicol increased as the AAm content in the hydrogels increased in the first stage of diffusion process, whereas there was no significant difference thereafter.     

Preparation of pH‐sensitive poly(vinyl alcohol‐g‐methacrylic acid) and poly(vinyl alcohol‐g‐acrylic acid) hydrogels by gamma ray irradiation and their insulin release behavior

A series of pH‐responsive hydrogels were studied as potential drug carriers for the protection of insulin from the acidic environment of the stomach before releasing in the small intestine. Hydrogels based on poly(vinyl alcohol) networks grafted with acrylic acid or methacrylic acid were prepared by a two‐step process. Poly(vinyl alcohol) hydrogels were prepared by gamma ray irradiation (50 kGy) and then followed by grafting either acrylic acid or methacrylic acid onto these poly(vinyl alcohol) hydrogels with subsequent irradiation (5–20 kGy). These graft hydrogels showed pH‐sensitive swelling behavior and were used as carriers for the controlled release of insulin. The in vitro release of insulin was observed for the insulin‐loaded hydrogels in a simulated intestinal fluid (pH 6.8) but not in a simulated gastric fluid (pH 1.2). The release behavior of insulin in vivo in a rat model confirmed the effectiveness of the oral delivery of insulin to control the level of glucose. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 636–643, 2004     

Timolol‐imprinted soft contact lenses: Influence of the template: Functional monomer ratio and the hydrogel thickness

Isothermal titration calorimetry (ITC) was used to identify the optimal timolol:functional monomer ratio for preparing soft contact lenses (SCLs) able to sustain drug release. ITC profiles revealed that each timolol molecule required six to eight acrylic acid (AAc) monomers to saturate the binding and that these ratios could be the most suitable for creating imprinted cavities. Various poly(hydroxyethyl methacrylate‐co‐AAc) hydrogels 0.2 and 0.9 mm thick were prepared with timolol:AAc molar ratios ranging from 1 : 6 to 1 : 32 and also in the absence of timolol. The hydrogels were reloaded with timolol by immersion in 0.04, 0.06, 0.08, and 0.10 mM drug solutions. Both imprinted and nonimprinted hydrogels showed a high affinity for the drug because of the presence of AAc. Nevertheless, the 1 : 6 and 1 : 8 imprinted hydrogels loaded less timolol but sustained the release better than the other hydrogels. These differences were explained in terms of the different arrangement of the functional monomers along the network. The imprinting effect was more noticeable in the case of the thinnest hydrogels, where the contribution of the diffusion path to the release rate was smaller. The results obtained prove the interest of ITC for the rational design of drug‐imprinted networks to be used as medicated SCLs. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Design of a drug delivery system based on poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels

To obtain biodegradable materials for biomedical applications, new biopolymeric hydrogels based on blends of polyacrylamide nanoparticles and chitosan have been prepared. In this work, we have studied the behavior of the diffusion of ascorbic acid (V‐C) from poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels. The process involves the synthesis of nanoparticles of polyacrylamide by inverse microemulsion polymerization and their complexation with chitosan dissolved in an acrylic acid aqueous solution. We have studied the effect of the concentration of the polyacrylamide nanoparticles, which are crosslinked with N,N′‐methylenebisacrylamide, in the delivery of V‐C. The results indicate that the drug delivery operates by a non‐Fickian mechanism. Also, we have obtained the diffusion coefficient for V‐C in gels for different nanoparticle concentrations, using a modified form of Fick's second law that takes into account dimensional changes in the hydrogels during drug release. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Kinetic degradation and controlled drug delivery system studies for sensitive hydrogels prepared by gamma irradiation

Ternary mixtures of N‐vinyl‐2‐pyrrolidone/itaconic acid and gelatin were irradiated by gamma rays at 30 kGy/s and at ambient temperature to prepared poly (NVP/IA and G) hydrogels. Poly (NVP/IA) hydrogels were prepared in different compositions (NVP/IA) mole ratio, (100/0), (98/1.5), (96.5/3.5), and (93/7.0) at 30 kGy. Then adding gelatin at different content (5, 10, 15, 20) mg to the best composition (NVP/IA/H₂O) (93/7)% for the characterization of network structure of these hydrogels, kinetic swelling drug release behavior and Scan Electron Microscope was studied. The equilibrium degree of swelling for P(NVP/IA) and P(NVP/IA/G) copolymer and the swelling‐degradation kinetics were also studies. According to dynamic swelling studies, both the diffusion exponent and the diffusion coefficient increase with increasing content of (IA), whereas, the addition of gelatin to (NVP/IA) composition by different content did not lead to any significant change in swelling percent. Also, the swelling behavior of copolymer hydrogels in response to pH value of the external media was studied, it is noted that the highest swelling values were at pH 4. The in vitro drug release behavior of these hydrogels was examined by quantification analysis with a UV/VIS spectrophotometers. Chlorpromazine hydrochloride was loaded into dried hydrogels to investigate the stimuli‐sensitive property at the specific pH and the drug release profile of these pH‐sensitive hydrogels in vitro. The release studies show that the highest value of release was at pH 4 which can be used for drug delivery system. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Synthesis and Characterization of New Biodegradable Injectable Thermosensitive Smart Hydrogels for 5-Fluorouracil Delivery

In this paper, injectable, thermosensitive smart hydrogel local drug delivery systems (LDDSs) releasing the model antitumour drug 5-fluorouracil (5-FU) were developed. The systems were based on biodegradable triblock copolymers synthesized via ring opening polymerization (ROP) of ε-caprolactone (CL) in the presence of poly(ethylene glycol) (PEG) and zirconium(IV) acetylacetonate (Zr(acac)₄), as co-initiator and catalyst, respectively. The structure, molecular weight (M_n) and molecular weight distribution (Đ) of the synthesized materials was studied in detail using nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques; the optimal synthesis conditions were determined. The structure corresponded well to the theoretical assumptions. The produced hydrogels demonstrated a sharp sol–gel transition at temperature close to physiological value, forming a stable gel with good mechanical properties at 37 °C. The kinetics and mechanism of in vitro 5-FU release were characterized by zero order, first order, Higuchi and Korsmeyer–Peppas mathematical models. The obtained results indicate good release control; the kinetics were generally defined as first order according to the predominant diffusion mechanism; and the total drug release time was approximately 12 h. The copolymers were considered to be biodegradable and non-toxic; the resulting hydrogels appear to be promising as short-term LDDSs, potentially useful in antitumor therapy.     

Effect of graphene oxide on the pH-responsive drug release from supramolecular hydrogels

Polypseudorotaxane (PPR) hydrogels formed by inclusion complexes between poly(ethylene glycol) (PEG) and α-cyclodextrin (α-CD) are highlighted as promising biomaterial for drug delivery. Here, we report a novel injectable PPR hydrogel containing graphene oxide (GO) for pH-responsive controlled release of doxorubicin hydrochloride (DOX). Our results showed that the gelation rates of the PEG/α-CD supramolecular structures could be tailored depending on the reagent concentrations. The formation of PEG/α-CD inclusion complexes was confirmed by TEM and XRD, the latter further confirming that GO restricts their formation. The supramolecular hydrogels were easily loaded with DOX by simple addition into the PEG solution before the complex formation with the α-CD solution. Noteworthy, disruption of ionic interactions between DOX and GO in the nanocomposite at pH = 5.5 resulted in higher DOX release than under physiological conditions (pH = 7.4). This pH dependence was barely observed in pure PPR hydrogel. These findings introduce DOX-loaded supramolecular hydrogels nanocomposites as promising carriers for pH-responsive and therefore localized, drug delivery systems.     

Thermally crosslinked anionic hydrogels composed of poly(vinyl alcohol) and poly(γ‐glutamic acid): Preparation,characterization, and drug permeation behavior

pH‐sensitive anionic hydrogels composed of poly(vinyl alcohol) (PVA) and poly(γ‐glutamic acid) (γ‐PGA) were prepared by the freeze drying method and thermally crosslinked to suppress hydrogel deformation in water. The physical properties, swelling, and drug‐diffusion behaviors were characterized for the hydrogels. In the equilibrium swelling study, PVA/γ‐PGA hydrogels shrunk in pH regions below the pK_a (2.27) of γ‐PGA, whereas they swelled above the pK_a. In the drug‐diffusion study, the drug permeation rates of the PVA/γ‐PGA hydrogels were directly proportional to their swelling behaviors. The cytocompatibility test showed no cytotoxicity of the PVA/γ‐PGA hydrogels for the 3T3 fibroblast cell lines. The results of these studies suggest that hydrogels prepared from PVA and γ‐PGA could be used as orally administrable drug‐delivery systems. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Dual pH‐ and thermal‐responsive nanocomposite hydrogels for controllable delivery of hydrophobic drug baicalein

Hydrogels have been widely used as mild biomaterials due to their bio‐affinity, high drug loading capability and controllable release profiles. However, hydrogel‐based carriers are greatly limited for the delivery of hydrophobic payloads due to the lack of hydrophobic binding sites. Herein, nano‐liposome micelles were embedded in semi‐interpenetrating poly[(N‐isopropylacrylamide)‐co‐chitosan] (PNIPAAm‐co‐CS) and poly[(N‐isopropylacrylamide)‐co‐(sodium alginate)] (PNIPAAm‐co‐SA) hydrogels which were responsive to both temperature and pH, thereby establishing tunable nanocomposite hydrogel delivery systems. Nano‐micelles formed via the self‐assembly of phospholipid could serve as the link between hydrophobic drug and hydrophilic hydrogel due to their special amphiphilic structure. The results of transmission and scanning electron microscopies and infrared spectroscopy showed that the porous hydrogels were successfully fabricated and the liposomes encapsulated with baicalein could be well contained in the network. In addition, the experimental results of response release in vitro revealed that the smart hydrogels showed different degree of sensitiveness under different pH and temperature stimuli. The results of the study demonstrate that combining PNIPAAm‐co‐SA and PNIPAAm‐co‐CS hydrogels with liposomes encapsulated with hydrophobic drugs is a feasible method for hydrophobic drug delivery and have potential application prospects in the medical field. © 2018 Society of Chemical Industry     

Dynamic swelling behavior of pH‐sensitive anionic hydrogels used for protein delivery

There have been many attempts to use anionic hydrogels as oral protein delivery carriers because of their pH‐responsive swelling behavior. The dynamic swelling behavior of poly(methacrylic acid‐co‐methacryloxyethyl glucoside) and poly(methacrylic acid‐g‐ethylene glycol) hydrogels was investigated to determine the mechanism of water transport through these anionic hydrogels. The exponential relation M_t/M_∞ = ktⁿ (where M_t is the mass of water absorbed at time t and M_∞ is the mass of water absorbed at equilibrium) was used to calculate the exponent (n) describing the Fickian or non‐Fickian behavior of swelling polymer networks. The mechanism of water transport through these gels was significantly affected by the pH of the swelling medium. The mechanism of water transport became more relaxation‐controlled in a swelling medium of pH 7.0, which was higher than pK_a of the gels. The experimental results of the time‐dependent swelling behaviors of the gels were analyzed with several mathematical models. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 1606–1613, 2003     

Preparation and properties of crosslinked chitosan thermosensitive hydrogel for injectable drug delivery systems

The aim of this study was to prepare and investigate the physical properties of a thermosensitive crosslinked chitosan pregel solution, and evaluate the in vitro release profiles of macromolecules from this sol–gel transition system. Chitosan and poly (vinyl alcohol) were used to form an interpenetrating polymeric network with glutaraldehyde as the crosslinker, and glycerophosphate (GP) was added to transform the pH‐dependent solutions into thermosensitive pH‐dependent solutions. Rheological study showed that the gelation was dependent on the crosslink degree and GP concentration of the solution. The crosslinked gel had excellent mechanic properties and no apparent “pores” and formed an integrated hydrogel texture according to scanning electronic micrograph. Gas chromatography test guaranteed the medication safety with no detection of glutaraldehyde remnants in the hydrogels. In vitro release study showed that the gelation does not significantly affect the macromolecules diffusion but the crosslinking degree does. These results indicated that the hydrogel formed an intensified three‐dimensional hybrid network with interpenetrating molecules, which effectively buffered or delayed the macromolecules diffusion. The hydrogels sustained the drug release over 30 days and could be potentially used as in situ gelling implants. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 1892–1898, 2006     

Photopolymerized hydrogel composites from poly(ethylene glycol) and hydroxyapatite for controlled protein delivery in vitro

The incorporation of hard particles into soft hydrogels can improve the mechanical properties and provide necessary bioactivity to the hydrogels for desired biomedical applications. Hydrogel composites containing hydroxyapatite (HA) are promising materials for orthopedic applications. In this study, injectable poly(ethylene glycol) (PEG) hydrogel precursor solutions containing HA particles and model protein bovine serum albumin (BSA) were synthesized in situ by photopolymerization. In vitro BSA release properties from the hydrogel composites containing various amounts of HA were investigated and discussed. Fourier transform infrared spectroscopy and scanning electron microscopy were employed to investigate the interaction between HA and the hydrogel network and the morphology of the hydrogel composites. It is found that PEG hydrogel composites containing HA sustained the release of BSA for at least 5 days and the presence of HA slowed down BSA release. Photopolymerized hydrogel composites containing HA may find potential use as a drug delivery matrix for orthopedic tissue engineering. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Controlled release of prednisolone acetate from molecularly imprinted hydrogel contact lenses

The aim of this work was to study the influence of methacrylic acid (MAA) as a comonomer and the application of a molecular imprinting technique on the loading and release properties of weakly crosslinked 2‐hydroxyethyl methacrylate (HEMA) hydrogels, with a view toward their use as reloadable soft contact lenses for the administration of prednisolone acetate (PA). The hydrogels were prepared with HEMA (95.90–98.30 mol %) as a backbone monomer, ethylene glycol dimethacrylate (140 mM) as a crosslinker, and MAA (0, 50, 100, or 200 mM) as a functional monomer. Different PA/MAA molar ratios (0, 1 : 8, 1 : 6, and 1 : 4) in the feed composition of the hydrogels were also applied to study the influence of the molecular imprinting technique on their binding properties. The hydrogels (0.4 mm thick) were synthesized by thermal polymerization at 60°C for 24 h in a polypropylene mold. The hydrogels were then characterized by the determination of their swelling and binding properties in water. Their loading and release properties were also studied in 0.9% NaCl and artificial lachrymal fluid. Increasing the MAA content of the hydrogel and applying the molecular imprinting technique led to an increase in the loading capacity of the hydrogel. The optimized imprinted hydrogel showed the highest affinity for PA and the greatest ability to control the release process, sustaining it for 48 h. The results obtained clearly indicate that the incorporation of MAA as a comonomer increased the PA loading capacity of hydrogel. Our data showed that the molecular imprinting technique also had a significant effect on the loading and release properties of the hydrogels. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Cephazoline sodium release from poly(N‐isopropyl acrylamide‐co‐N,N‐dimethylacrylamide) hydrogels

Hydrogels are hydrophilic polymers that swell to an equilibrium volume in the presence of water, preserving their shape. The dynamic swelling behavior of poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide) [poly(NIPA‐co‐DMA)] copolymers at 37°C was investigated. It was observed that the swelling degree in the copolymers decreases with the N‐isopropylacrylamide content. In addition, the liberation mechanism was found to be Fickian. Diffusion coefficients according to Fick′s law as a function of the N‐isopropylacrylamide concentration and results of the release process are reported. The kinetics of cephazoline sodium release from poly(NIPA‐co‐DMA) hydrogels with different compositions was studied. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 91: 3433–3437, 2004     

Investigation of loading and release in PVA‐based hydrogels

We used Methylene Blue (MB) and Methyl Orange (MO) as model drugs to investigate the controlled release behavior of hydrogels from poly(vinyl alcohol) crosslinked with ethylenediaminetetraacetic dianhydride. The cationic or anionic character of these compounds and the molecular weight between crosslinks of the hydrogel and the concentration of ionizable groups in the hydrogel greatly affected the loading and release of the drugs. MB loading was favored, therefore, by a higher content of negative charges in the hydrogel, although this implied a greater degree of crosslinking and, therefore, a lower mesh size. On the other hand, the overall loading of negative MO, favored by a higher mesh size, was very low because of unfavorable interactions with the electrolyte charges. Release studies showed that one of the parameters that most affected the drug release behavior of these hydrogels was the pH of the solution. MB and MO were not completely released, even at pH 1. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 85: 1644– 1651, 2002.