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     

Interpenetrating polymeric network hydrogels for potential gastrointestinal drug release

New interpenetrating polymeric network (IPN) hydrogels based on chitosan (C), poly(N‐vinyl pyrrolidone) (PVP) and poly(acrylic acid) (PAAc), crosslinked with glutaraldehyde (G) and N,N‘‐methylenebisacrylamide (MBA), were prepared and investigated for potential gastrointestinal drug delivery vehicles utilizing a model drug, amoxicillin. IPN hydrogels were synthesized by simultaneous polymerization/crosslinking of acrylic acid monomer in the presence of another polymer (C) and crosslinker (G, MBA). Three different concentrations of glutaraldehyde were used (0.5, 1.0 and 2.0 w/w) to control the overall porosity of the hydrogels, named C‐P‐AAc/0.5, C‐P‐AAc/1.0 and C‐P‐AAc/2.0, respectively. Spectroscopic and thermal analyses such as Fourier transform infrared spectroscopy, thermogravimetric analysis and thermomechanical analysis were performed for IPN characterization. Equilibrium swelling studies were conducted for pH and temperature response behavior. Swelling studies were also carried out in simulated gastric fluid of pH = 1.1 and simulated intestinal fluid of pH = 7.4 to investigate possible site‐specific drug delivery. It was found that the release behavior of the drug from these IPN hydrogels was dependent on the pH of the medium and the proportion of crosslinker in the IPN. It was observed that amoxicillin release at pH = 7.4 was higher than at pH = 1.1. The analysis of the drug release showed that amoxicillin was released from these hydrogels through a non‐Fickian diffusion mechanism. Copyright © 2007 Society of Chemical Industry     

Gelatin based pH‐sensitive hydrogels for colon‐specific oral drug delivery: Synthesis,characterization, and in vitro release study

Based on gelatin (Gltn) and acrylic acid (AAc), biodegradable pH‐sensitive hydrogel was prepared using gamma radiation as super clean source for polymerization and crosslinking. Incorporation of PAAc in the prepared hydrogel was confirmed by Fourier transform infrared spectroscopy (FTIR). The effect of PAAc content on the morphological structure of the prepared hydrogel swollen at pH 1, 5, and 7 was examined using scanning electron microscopy (SEM). The results showed the dependence of the porous structure of the prepared hydrogels on AAc content and the pH of the swelling medium. Swelling properties of gelatin/acrylic acid copolymer hydrogels with different AAc contents were investigated at different pH values. Swelling data showed that the prepared hydrogels possessed pronounced pH sensitivity. In vitro release studies were performed to evaluate the hydrogel potential as drug carrier using ketoprofen as a model drug. Experimental data showed that the release profile depends on both hydrogel composition and pH of the releasing medium. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Simulation and experimental analysis of an intelligent tissue for controlled drug delivery

In this research, an antibiotic was loaded in the composites of polyethylene glycol (PEG), acrylamide (AAm) and acrylic acid (AAc) hydrogels matrices and their drug deliveries were tested. Effect of some parameters on the drug delivery was checked by UV‐spectrophotometer. Temperature enhancement considerably increased hydrogel swelling and the drug release in the AAc and AAm. A dynamic model based on the Maxwell–Stefan equation was developed to model the drug delivery of hydrogels. COMSOL software was also applied to simulate buffer diffusion inside the hydrogels.     

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     

Synthesis and properties of hydrogels of poly(acrylic‐co‐acroloyl β‐cyclodextrin)

Novel acrylic monomers (β‐CD‐A and β‐CD‐6‐EA) containing β‐cyclodextrin (β‐CD) with different extent of substitution were prepared by using dicyclohexylcarbodiimide (DCC) as a condensation agent at room temperature. Two kinds of functional hydrogels were also synthesized by copolymerization of β‐CD‐A and β‐CD‐6‐EA with acrylic acid (AAc) using a redox initiator system in aqueous solution. The nuclear magnetic resonance (¹H NMR), infrared spectroscopy (IR), thermogravimetric analysis (TGA) were employed to character the molecular structures of β‐CD modified monomers and their copolymers. The swelling experiments indicate that the hydrogels with different equilibrium swelling ratio (ESR) possess obvious pH‐sensitivity and distinct dynamic swelling behavior. Using an anti‐cancer drug, chlorambucil (CHL), able to form complexes with β‐CD in water, as a model compound, the controlled drug release behaviors of these hydrogels were investigated. The release behavior of CHL from two kinds of hydrogels synthesized reveals that the release rate of CHL can be effectively controlled by pH values, cross‐linking density, and β‐CD content. In addition, it is found that the β‐CD with the proper frame and concentration can increase release efficiency of CHL from the hydrogels. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Equilibrium adsorption isotherm and controlled release of antibiotic drug chloroamphenicol from poly(2‐vinyl pyridine/acrylic acid) hydrogels prepared by gamma radiation

High water sorption of 2‐vinyl pyridine (2‐VP)/acrylic acid (AAc) hydrogel were prepared by free‐radical polymerization in aqueous solution of 2‐VP with AAc as comonomer. The amount of ionic monomer (AAc), the irradiation dose of prepared hydrogel, the pH, and the concentration of drug play an important factor on loading, adsorption, and releasing of water‐soluble chloroamphenicol drug. As a result of dynamic swilling tests, the effect of relative content of AAc on the swelling showed that it allowed a non‐Fickian type of water diffusion. The adsorption of the drug onto (2‐VP/AAc) hydrogels was studied by Freundlish adsorption isotherm. The drug concentrations showed an influence on the adsorption of drug which increased with increasing AAc content. From Freundlish adsorption isotherm, the empirical constants, k and n, can be evaluated and showed the ability of hydrogel to be loaded by the drug and the affinity of the drug to be uptake onto the hydrogel respectively. FTIR, TGA, and SEM techniques were used to study the characterization of hydrogel (2‐VP/AAc). Additionally, the release of the drug loaded from hydrogel discs was studied microbiologically to show that hydrophilic structure of the hydrogel has an antimicrobial effect as a dehydration of cytoplasm and unbalance of the cell wall functions. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Preparation and characteristics of pH‐sensitive derivated dextran hydrogel nanoparticles

An optimized procedure was used to prepare erythromycin (EM)‐loaded pH‐sensitive glycidyl methacrylate derivatized dextran (dex‐GMA)/acrylic acid (AAc) nanoparticles. The size distribution and drug release profile at different pH demonstrated that poly(dex‐GMA/AAc) nanoparticles possessed pH‐sensitivity. At pH 1.2, the mean diameter of nanoparticles was about 60 nm. While at pH 7.4 it increased approximately to 250 nm. The release of EM was about 7% of initial loading after 2 h at pH 1.2. However, at pH 7.4 it reached to 17.8%, 30.9% after 2 and 6 h, respectively. The results demonstrated that poly(dex‐GMA/AAc) nanoparticles could release EM slightly while passing through acerbic stomach, whereas in the alkaline intestine the drug is released considerably. The prepared nanoparticles were partially degradable and also had satisfactory biocompatibility. This study suggests that the poly(dex‐GMA/AAc) nanoparticles are potential colon‐specific targeting carriers, which can keep promising pharmaceutical dosage form of EM. POLYM. COMPOS., 2009. © 2008 Society of Plastics Engineers     

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 and drug‐release behavior of the poly(AA‐co‐N‐vinyl pyrrolidone)/chitosan interpenetrating polymer network hydrogels

A series of novel hydrogels were prepared from acrylic acid (AA), N‐vinyl pyrrolidone (NVP), and chitosan by photopolymerization. The swelling behavior, gel strength, and drug release behavior of the poly(AA/NVP) copolymeric hydrogels and corresponding interpenetrating polymer network hydrogels were investigated. Results showed that the swelling ratios for the present hydrogels decreased with an increase of NVP content in the gel, but the gel strength increased with an increase of NVP content in the gel. Results also showed that the drug‐release behavior for the gels is related to the ionicity of drug and the swelling ratio of the gel. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 2135–2142, 2004     

Swelling behaviour of a new kind of polyampholyte hydrogel composed of dimethylaminoethyl methacrylate and acrylic acid

Poly[(dimethylaminoethyl methacrylate)‐co‐(acrylic acid)] [poly(DMAEMA‐co‐AAc)] hydrogels have been synthesized by UV‐induced copolymerization of dimethylaminoethyl methacrylate (DMAEMA) and acrylic acid monomer. The effects of pH and ionic strength on the swelling behaviour of poly(DMAEMA‐co‐AAc) hydrogels were investigated in detail. It was found that there is minimal equilibrium swelling ratio (ESR) for the hydrogels with the change of pH, and the pH at minimal ESR of the hydrogels was defined by the isoelectric points (IEP), similar to the situation with protein molecules. The IEP of the hydrogels shifted to higher values with increase in the DMAEMA content in the hydrogels. Antipolyelectrolyte behaviour of the hydrogels at a pH near the IEP was observed as well, and the ESR increased with increasing ionic strength. The study of swelling kinetics of the hydrogels showed that the swelling process was Fickian at the IEP and non‐Fickian when the pH deviated from the IEP. Copyright © 2003 Society of Chemical Industry     

Synthesis and properties of radiation‐induced acrylamide–acrylic acid hydrogels

Acrylamide (AAm)/acrylic acid (AAc) hydrogels in the cylindirical form were prepared by γ‐irradiating binary systems of AAm/AAc with 2.6–20.0 kGy γ‐rays. The effect of the dose and relative amounts of AAc and pH on the swelling properties, diffusion behavior of water, diffusion coefficients, and network properties of hydrogel systems was investigated. The swelling capacities of AAm/AAc hydrogels were in the range of 1000–3000%, while poly(acrylamide) (PAAm) hydrogels swelled in the range of 450–700%. Water diffusion into hydrogels was found to be non‐Fickian‐type diffusion. Diffusion coefficients of AAm/AAc hydrogels were found between 0.79 × 10^?5 and 2.78 × 10^?5 cm² min^?1. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 3570–3580, 2002     

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.     

Release of vitamin B12 from poly(N‐vinyl‐2‐pyrrolidone)‐crosslinked polyacrylamide hydrogels: A kinetic study

Hydrogels, composed of poly(N‐vinyl‐2‐pyrrolidone) and crosslinked polyacrylamide, were synthesized and the release of vitamin B₁₂ from these hydrogels was studied as a function of the degree of crosslinking and pH of the external swelling media. The three drug‐loaded hydrogel samples synthesized with different crosslinking ratios of 0.3, 0.7, and 1.2 (in mol %) follow different drug‐release mechanisms, that is, chain relaxation with zero‐order, non‐Fickian and Fickian, or diffusion‐controlled mechanisms. To establish a correlation between their swelling behavior and drug‐release mechanism, the former was studied by the weight‐gain method and, at the same time, the concentration of the drug released was studied colorimetrically. Various swelling parameters such as the swelling exponent n, gel‐characteristic constant k, penetration velocity v, and diffusion coefficient D were evaluated to reflect the quantitative aspect of the swelling behavior of these hydrogels. Finally, the drug‐release behavior of the hydrogels was explained by proposing the swelling‐dependent mechanism. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 76: 1706–1714, 2000     

Temperature‐responsive properties of poly(acrylic acid‐co‐acrylamide)‐graft‐oligo(ethylene glycol) hydrogels

A series of temperature‐ and pH‐responsive hydrogels were prepared from acrylic acid (AAc), acrylamide (AAm), oligo(ethylene glycol)monoacrylate (OEGMA), and oligo(ethylene glycol)diacrylate by varying the AAc:AAm molar ratio and the OEGMA content. Phase‐transition temperatures and swelling ratios of the obtained poly(AAc‐co‐AAm)‐graft‐OEG gels were measured as a function of temperature and pH. At pH < 5, the obvious transition temperatures ranging from 5 to 35°C were obtained as the AAc : AAm molar ratio was varied. The highest transition temperature was obtained at the AAc : AAm ratios of 5 : 5 and 6 : 4, and the sharp transition curves were observed at the AAc : AAm ratios from 5 : 5 to 8 : 2. The transition temperature further increased with increasing OEGMA content. It was suggested that OEG graft chains with a large mobility played an important role for the formation of hydrogen bonding in the hydrogels. The gels prepared here showed obvious reproducibility of the phase transition in response to temperature changes, which suggests the feasibility of their practical applications. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 80: 798–805, 2001     

Prolonged zero‐order BSA release from pH‐sensitive hydrogels of poly(AAc‐co‐DMAPMA) having rich nano through micro scale morphology

New variety of pH‐sensitive hydrogels, having macroporous interior with honey‐comb type architecture and continuous skin at the surface, have been developed by single step aqueous copolymerization of acrylic acid (AAc) and N‐[3‐(dimethylamino)propyl]‐methacrylamide (DMAPMA) in different feed ratios at 41 ± 1°C. Interlocked nanogels of ～ 300 nm were identified as the building blocks in all of these cylindrical poly(AAc‐co‐DMAPMA) matrices (PDMAAc). The gels showed good compressive strength even at a swelling as high as 4330% (mass) at pH 7.0. Morphology of McCoy fibroblast cell line remained unchanged in direct contact with different PDMAAc gels, and cell viability (±SD) was recorded to be in the range of 105 (±3)% to 87 (±8)% after 72 h. Bovine serum albumin (BSA) loaded gels were prepared by means of equilibrium partitioning. Loading efficiency of PDMAAc gels has been found to be in the range of 210–277 mg/g dry gel. BSA release from PDMAAc gels at 37°C has been found to follow non‐Fickian diffusion mechanism in simulated gastric juice (pH 1.2), and Case II transport in simulated intestinal juice (pH 7.4). In vitro study showed that the gels are capable of retaining >95% of the loaded BSA in gastric medium through average gastric emptying period. Again, ～ 56% BSA release was recorded in 24 h at pH 7.4, indicating prolonged BSA diffusion in intestinal condition. Constant rate of BSA diffusion was reflected from the release profiles at both the pH. Diffusion exponents also supported the same and indicated for absolute zero‐order kinetics at pH 7.4. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

京尼平交联大豆蛋白/壳聚糖复合凝胶的控释

利用天然无毒的京尼平交联大豆蛋白(SB)和壳聚糖(CS)制备复合水凝胶(HD)并用作茶碱的控释载体。同时对其在模拟胃肠液和pH7.4缓冲液（PBS）中的控释特性进行了研究。结合扫描电镜和红外光谱以及核磁共振表征了复合凝胶的表观形态和结构。结果表明,复合水凝胶中大豆蛋白和壳聚糖通过京尼平发生了明显的交联作用,并呈现致密的片层结构。复合凝胶在模拟胃肠液和pH7.4PBS中均呈现溶胀现象,在模拟胃液中的溶胀度较低。而且凝胶在pH1.2模拟胃液中的释放量比模拟肠液和pH7.4PBS液中的低,并发现该凝胶具有pH响应,在120 h内可实现对茶碱的可控释放。因此,这种京尼平交联的复合凝胶具有作为药物在胃肠道中定向运送载体的潜力。     

Preparation and properties of core–shell alginate–carboxymethylchitosan hydrogels

BACKGROUND: Hydrogels of alginate (ALG) with partially carboxymethylated chitosan (CMCHI) have been produced for drug delivery, based on the interactions between the negative groups and an ionic crosslinker. In the present work, CMCHI was used to evaluate the influence of amino groups that are positively charged at pH = 4 and 6 on the ALG–CMCHI core–shell hydrogel preparation. An ANOVA statistics tool was used to evaluate the effect of composition, pH and chitosan chemical nature on the morphology and swelling properties of the hydrogels in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). RESULTS: The ALG–CMCHI core–shell hydrogels presented smaller (ca 2.3 µm) and more homogeneous microparticles than those with unmodified chitosan (ca 5.5 µm). The ALG–CMCHI hydrogels showed higher thermal stability and lower degree of swelling in SGF (314%) compared to those with chitosan (708%), since in the former hydrogels the protective layers that surround the particles are negatively charged. CONCLUSION: CMCHI can replace chitosan in the production of core–shell hydrogels with improved properties since the negative charge surrounding the ALG–CMCHI particles favours a lower degree of swelling. The results point out a possible prevention of burst release in SGF, sustaining the swelling ability of the ALG–CMCHI core–shell hydrogels in SIF, promising appropriate drug release. Copyright © 2009 Society of Chemical Industry     

β‐cyclodextrin/poly(vinyl alcohol) hydrogels containing phenylpropionic acid and naphthylamine: dual pH‐sensitive release

Hydrogel composed of β‐cyclodextrin (β‐CD) and poly(vinyl alcohol) was prepared in a strong alkaline condition using epichlorohydrin as a crosslinker. Phenylpropionic acid (PPA) and naphthylamine (NA) were loaded in the cavities of β‐CD residues to endow the hydrogel with a dual pH‐sensitive characteristic. In release experiments using fluorescein isothiocyanate‐dextran (FITC‐dextran) as a dye, PPA/NA‐loaded hydrogel exhibited an extensive release not only in acidic conditions (e.g. pH 3.0) but also in alkaline conditions (e.g. pH 9.0). PPA and NA will be highly ionized at the alkaline and the acidic pH and they could promote swelling of the hydrogel, causing an extensive release at those pH values. However, the release was suppressed at mid pH values (e.g. pH 5.0 and pH 7.4), possibly due to the formation of salt bridges between PPA^? and NA⁺. In fact, the degree of swelling at mid pH was lower than that observed at strong acidic pH and alkaline pH. According to SEM images, the pore size and the texture compactness of hydrogels which had been subjected to swelling at different pH values could also account for the dual pH‐sensitive releases. The hydrogels exhibited dual pH sensitivities in terms of FITC‐dextran release and swelling. These hydrogels might be used as a pH‐sensitive vehicle for water‐soluble drugs. © 2013 Society of Chemical Industry     

pH‐sensitive hydrogels based on bovine serum albumin for anticancer drug delivery

Protein conjugates consisting of hydroxyethyl methacrylate and acrylic acid monomers in the presence of bovine serum albumin (BSA) were prepared by gamma irradiation to examine the potential use of these hydrogels in the controlled drug release systems. The study parameter was the BSA content in the as‐prepared conjugates. Polymers were characterized with FTIR, scanning electron microscopy (SEM), and swelling studies. The polymerization reaction caused the rearrangement of the BSA carbonyl hydrogen bonding and finally led to the modification of the BSA secondary structure as proved by FTIR. SEM proved that the prepared conjugates matrices are porous, with a three‐dimensional interconnected microstructure. The swelling kinetics of the hydrogels and the release dynamics of an anticancer model drug (flutamide) have been studied. High equilibrium swelling values, up to 1550%, could be observed and were correlated with the increase in pH, temperature, and BSA content. The mechanism of swelling changed from Fickian to non‐Fickian by reducing the acidity of the medium. This study proved that there is a direct relationship between the protein content in the conjugates and both the loaded and the released drug. These pH responsive conjugates may be exploited for the delivery of flutamide. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010