Preparation and characterization of chitosan based hydrogels containing cyclodextrin inclusion compounds or nanoemulsions of thyme oil

Hydrogels derived from natural polysaccharides are ideal scaffolds for use in biomedical applications. pH‐sensitive polyvinyl alcohol and chitosan hydrogels containing inclusion compounds of thyme oil (TM) with host methyl‐β‐cyclodextrin (MβCD) and hydroxypropyl‐β‐cyclodextrin (HβCD) and TM nanoemulsion (TM‐nano) were prepared via controlled, biocompatible and low cost freeze–thaw method. The structure of the hydrogels was characterized by Fourier transform IR spectroscopy and optical and scanning electron microscopy. The physicochemical properties of the hydrogels such as gel fraction, swelling ratio and tensile properties were measured. The water vapor transmission rate of the hydrogels indicated that they can maintain a moist environment over the wound bed. Encapsulation and release of antibacterial TM from the hydrogels were determined by UV spectroscopy. In all cases, hydrogels with lower amounts of TM evidenced slower and more controlled release. Different kinetic models were applied for evaluating the drug release mechanism. The antibacterial activity of the samples was studied by counting the number of both Gram‐negative and Gram‐positive bacteria surviving in a broth medium and the results proved the antibacterial activity of all prepared hydrogels. The results of an MTT (3‐(4,5‐dimethylthiazol‐2yl)‐2,5‐diphenyltetrazolium bromide) assay indicated more cell viability of TM‐nano hydrogels in comparison with those of TM‐βCD inclusion compounds. Cell attachment observations also showed great biocompatibility of TM‐nano hydrogels. The prepared hydrogels, especially those containing TM‐nano, might be used as potential wound dressings to improve the wound healing process. © 2019 Society of Chemical Industry     

Multifunctional mussel-inspired Gelatin and Tannic acid-based hydrogel with pH-controllable release of vitamin B12

Hydrogels have emerged to be an impeccable material for a large variety of applications over the past few decades. In the field of biomedical applications, remarkable progress has been observed in the effort of fabricating numerous hydrogel systems. In this work, gelatin and tannic acid-based stretchable and adhesive hydrogel has been synthesized to study the release behavior of vitamin B₁₂. Successful formation of the synthesized hydrogels was confirmed by Fourier transform infrared and X-ray diffraction analysis. The morphology of the surfaces and the cross section of such hydrogels were studied with Scanning electron microscopy analysis. Swelling behavior of our hydrogel was studied with Design Expert software. The maximum swelling of the hydrogel was found to be around 137 g/g. Adhesive property was demonstrated on various surfaces to observe the adhesiveness of the fabricated hydrogel. Blood compatibility study was also performed. The release behavior of vitamin B₁₂ was performed in two different pH media and it was found to have enhanced value in the fluid mimicking the intestine. This work provides a new prospect for designing hydrogels with stretchable and adhesive properties with pH-controllable drug delivery applications along with other promising applications in various fields of research.     

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.     

Effect of clinoptilolite on structure and drug release behavior of chitosan/thyme oil γ-Cyclodextrin inclusion compound hydrogels

Chitosan-based hydrogels involving γ-cyclodextrin inclusion compounds of thyme oil were prepared by freeze–thaw cycling method. Clinoptilolite as a natural zeolite was added to investigate its effects on the structural, mechanical, and drug release behaviors of the hydrogels. Zeolite compressed the structure and improved mechanical properties, which decreased swelling values. Release of thyme oil in prepared hydrogels were investigated by UV spectroscopy and drug release mechanism was evaluated by applying various mathematical methods. Rates of water vapor transmission of the samples were calculated as 2247–2998 g m⁻² day⁻¹ which are all in the range of an ideal wound dressing. Hydrogels with clinoptilolite had slower drug release (from 56% to 24% for hydrogels containing zeolite 1%) in comparison with that of without zeolite. Based on MTT assay, samples were low-toxic. Obtained results suggest that drug loaded hydrogels can be applied in biomedical field including drug delivery systems and wound dressings.     

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.     

Preparation of acrylated agarose‐based hydrogels and investigation of their application as fertilizing systems

In this study, we attempt to synthesize novel acrylated agarose (ACAG)‐based hydrogels with three different crosslinking densities. Acrylate groups were inserted onto agarose (AG) backbone through homogeneous reaction of acrylic monomers with AG backbone. Hydrogels were synthesized through radical copolymerization of a mixture of acrylic acid and 2‐hydroxyethyl acrylate with ACAG in aqueous solution using ammonium persulfate as an initiator. Infrared spectroscopy (FTIR) was carried out to confirm the chemical structure of the hydrogel. Moreover, morphology of the samples was assessed by scanning electron microscopy. The equilibrium swelling capacities of synthesized hydrogels were evaluated in various conditions. The absorbency under load and dynamic swelling kinetics of the hydrogels were also studied. Finally, the hydrogels were loaded with potassium nitrate and their potential for controlled release of this salt was investigated by conductimetry. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011.     

Preparation of a novel pH-sensitive hydrogel based on acrylic acid and polyhedral oligomeric silsesquioxane for controlled drug release of theophylline

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 copolymer hydrogel based on acrylic acid (AA) monomer by free-radical solution polymerization were synthesized with organic–inorganic cross-linking agent of octavinyl polyhedral oligomeric silsesquioxane (OVPOSS). And its properties were compared with conventional hydrogels using N,N′-methylenebisacrylamide (MBA) as cross-linking agent. The copolymers were characterized by Fourier transform infrared spectra and differential scanning calorimetry. The morphology after swelling was presented by scanning electron microscopy. Swelling behaviors in different pH and potential applications in controlled drug delivery of the hydrogels were also examined. The results showed that both hydrogels were pH sensitive. However, as the addition of OVPOSS limited the movement of the molecular chain segment, the swelling ratio and the drug-release rate of theophylline in SGF decreased obviously when using OVPOSS as cross-linking agent, comparing with P(MBA-co-AA) hydrogels. The results in this study suggested that P(OVPOSS-co-AA) could serve as potential candidate for theophylline drug delivery.     

Preparation of novel bilayer hydrogels by combination of irradiation and freeze–thawing and their physical and biological properties

BACKGROUND: Hydrogels made by irradiation or freeze–thawing often exhibit poor mechanical strength; therefore we investigated a novel synthetic method to circumvent this detrimental effect. We report a series of novel bilayer poly(vinyl alcohol) (PVA)/water‐soluble chitosan (ws‐chitosan)/glycerol hydrogels prepared by a combination of irradiation and freeze–thawing. Scanning electron microscopy morphology, swelling behavior, mechanical strength, elongation at break, PVA dissolution behavior and bovine serum albumin (BSA) release profile of the bilayer hydrogels were compared with those of hydrogels made by irradiation and freeze–thawing followed by irradiation. The cytotoxicity of the bilayer hydrogels was studied using a tetrazolium salt (MTT) assay. RESULTS: The novel bilayer hydrogels contain one layer made by freeze–thawing followed by irradiation and the other layer made by irradiation. The preparation method provides the two layers with good combination force in the wet state. However, the two layers are not combined very well in the freeze‐dried state due to the difference in microstructure. The bilayer hydrogels have large swelling capacity and good mechanical strength, and these properties can be varied by changing freeze–thawing cycles, irradiation doses and the relative thickness of the two layers. The PVA and BSA release behaviors show that the bilayer hydrogels have a small amount of dissolved PVA and can prolong the BSA release time. The MTT assay shows that extracts of the bilayer hydrogels are non‐toxic towards L929 mouse fibroblasts. CONCLUSION: The novel bilayer hydrogels prepared in this study show good physical properties with no cytotoxicity, indicating that they are suitable for biomedical applications, such as in wound dressings and drug delivery devices. Copyright © 2009 Society of Chemical Industry     

Thermal and pH dual‐responsive hydrogels based on semi‐interpenetrating network of poly(N‐isopropylacrylamide) and collagen nanofibrils

Hydrogels with environment‐sensitive properties have great potential applications in the controlled drug release field. In this paper, hybrid hydrogels with semi‐interpenetrating polymer networks (semi‐IPNs), composed of poly(N‐isopropylacrylamide) (PNIPAM) as the thermo‐sensitive component by in situ polymerization and self‐assembled collagen nanofibrils as the pH‐sensitive framework, were prepared for controlled release of methyl violet as a model drug. From Fourier transform infrared spectroscopy and scanning electron microscopy, it was indicated that the crosslinking of PNIPAM in the presence of collagen nanofibrils led to the formation of semi‐IPNs with homogeneous porous structure, and the semi‐IPNs showed improved thermal stability and elastic properties compared with the native collagen as determined using differential scanning calorimetry and rheologic measurements. Furthermore, the semi‐IPNs possessed swelling behaviors quite different from those of neat collagen or PNIPAM hydrogel under various pH values and temperatures. Correspondingly, as expected, the drug release behavior in vitro for semi‐IPNs performed variously compared with that for single‐component semi‐IPNs, which revealed the tunable performance of semi‐IPNs for release ability. Finally the thermo‐ and pH‐responsive mechanism of the semi‐IPNs was illuminated to provide guidance for the application of the thermo‐ and pH‐sensitive collagen‐based hybrid hydrogels in controlled drug delivery systems. © 2019 Society of Chemical Industry     

Irradiated Ch/GG/PVP-based stimuli-responsive hydrogels for controlled drug release

Hydrogels based on gamma (γ) irradiated chitosan (pre-irradiated), guar gum, and polyvinyl pyrrolidone were crosslinked with various concentrations of (3-mercapto propyl)trimethoxysilane and fabricated by solution casting technique for the drug delivery applications. High molecular weight chitosan (Ch) possesses lower solubility and higher viscosity, these problems overcame by γ irradiation, which also generated hydrophilicity and effect of irradiated Ch on controlled drug release was assessed. FTIR analysis showed the development of chemical and physical interactions and confirmed the incorporation of characteristic peaks. SEM micrographs revealed porous structure of the prepared hydrogels. Swelling analysis of the hydrogels was performed in distilled water, buffer, and electrolyte mediums. All the hydrogel samples showed higher swelling at acidic pH and lower swelling at neutral and basic pH. These pH-responsive characteristics made these RCGP hydrogels an important contender for injectable controlled drug release. The ampicillin sodium drug was loaded and in vitro controlled release mechanism was evaluated in the PBS, SIF, and SGF which shown out of all prepared hydrogels (RCGP-1, RCGP-2, and RCGP-3), RCGP-1 has exhibited 87.4% release in PBS and 81.3% in SIF in 180 min.     

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.     

Rapid swelling and deswelling of semi‐interpenetrating network poly(acrylic acid)/poly(aspartic acid) hydrogels prepared by freezing polymerization

Hydrogels with semi‐interpenetrating networks composed of poly(acrylic acid) (PAAc) and poly(aspartic acid) (PASP) have great potential for pharmaceutical and biomedical applications. In this study, we aimed to synthesize semi‐interpenetrating PAAc/PASP hydrogels with improved swelling–deswelling properties via two‐step polymerization, in which the first step of polymerization was performed at 37 °C for 15 min and the second step, the freezing polymerization, was performed at ?20 °C for 24 h. The synthesized hydrogels were characterized with field emission scanning electron microscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis. The swelling and deswelling behaviors of the hydrogels in response to the ionic strength of the buffer solution were investigated. The Schott's swelling kinetic model was used to elucidate the swelling behavior of the hydrogels. The swelling and deswelling rates of the hydrogels prepared via freezing polymerization were faster than those of the hydrogels prepared via conventional polymerization. This was attributed to the large mean pore size of the freeze‐polymerized hydrogels. The PAAc/PASP hydrogels that underwent freezing polymerization had better swelling–deswelling characteristics than the PAAc hydrogels. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43515.     

Construction and evaluation of the hydroxypropyl methyl cellulose-sodium alginate composite hydrogel system for sustained drug release

We prepared a hydroxypropyl methyl cellulose-sodium alginate (HPMC-SA) composite hydrogel with a membrane covering the semi-interpenetrating network based on a semi-synthetic polymer hydroxypropyl methyl cellulose (HPMC) and a natural polymer sodium alginate (SA) by Ca²⁺ crosslinking and polyelectrolyte complexation with chitosan (CS) covering the hydrogel surface. The physiochemical properties of HPMC-SA hydrogels were evaluated by scanning electron microscopy, infrared spectrum, X-ray diffraction, and thermogravimetric analysis. The swelling ratio of the HPMC-SA composite hydrogel in simulated gastrointestinal fluid was measured. The drug release behavior of the HPMC-SA composite hydrogel for macro-molecular and small-molecule drugs was evaluated by using bovine serum albumin, metformin hydrochloride, and indomethacin as model drugs. The results showed that the HPMC-SA hydrogel had good water absorption and degradability, an increased swelling ratio of 55, and a prolonged time for maximum swelling degree of 50 h. Moreover, the hydrogel exhibited higher drug-loading capacity and improvements in the sustained release of bio-macromolecules, demonstrating its potential as a drug carrier for biomedical applications.     

Theophylline-loaded pectin-based hydrogels. II. Effect of concentration of initial pectin solution,crosslinker type and cation concentration of external solution on drug release profile

A series of drug-loaded pectin hydrogels were prepared by mixing method in two ion types, Ca⁺² or Zn⁺², for wound dressing applications and their drug release performances were investigated at pH 6.4 in four different calcium ion concentrations of external solution. Pectin hydrogels were synthesized in three different concentrations of initial pectin solution and theophylline was used as a model drug. Fourier transform infrared spectroscopy, scanning electron microscopy, and atomic force microscopy were used for hydrogel characterization. Additionally, fluid handling capacity, swelling behavior, dehydration rate, dispersion characteristic, dressing pH determination, water vapor permeability, oxygen permeability, surface contact angle, flexibility, mass per unit area, and thickness were determined for selected hydrogels. One of the most valuable contributions of our study is that the concentration of initial pectin solution and calcium ion concentration of external solution are very important parameters to obtain an effective drug release. After evaluating all data, we have shown that flexible and transparent pectin-based wound dressings can be synthesized as a controlled drug release system. Zinc-containing hydrogel was antibacterial against Staphylococcus aureus and Escherichia coli but not suitable for cell migration. On the other hand, calcium-based hydrogel was nontoxic on the fibroblast cells and it had no negative effect on cell migration. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 48155.     

Drug diffusion in hydrophobically modified N,N-dimethylacrylamide hydrogels

The use of hydrophobically modified hydrogels for drug release was investigated. Copolymers of N,N-dimethylacrylamide and 2-(N-ethyl-perfluorooctanesulfonamido) ethyl acrylate (FOSA) were prepared by free-radical polymerization. The drug release rates, dynamic swelling behavior, and pH sensitivities of copolymers ranging in composition from 0 to 30 mol% FOSA were studied. Pheniramine maleate, an ocular antihistamine, was used as the model drug substance. Hydrogels of DMA produced with increasing amounts of FOSA had a decreased equilibrium media content and exhibited a slower drug release rate. Early-time, late-time and Etters approximation drug diffusion coefficients ranged from 0.4×10⁻³ to 12.3×10⁻³ mm²/min. The diffusion of the drug model was less sensitive to pH of the buffered media over the range of pH 4-8, but increasing the media pH slowed the permeability slightly by decreasing the swellability of the hydrogel. The power law exponent (n≈0.5) and the swelling interface number (Sw?1) suggested that the drug release mechanism from these hydrogels was Fickian and not swelling controlled. These novel thermoprocessible hydrogels have potential to be used as controlled ocular drug delivery devices (e.g. contact lenses or ocular inserts).     

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.     

pH‐ and temperature‐responsive IPN hydrogels based on soy protein and poly(N‐isopropylacrylamide‐co‐sodium acrylate)

pH‐ and temperature‐responsive interpenetrating polymer network (IPN) hydrogels based on soy protein and poly(N‐isopropylacrylamide‐co‐sodium acrylate) were successfully prepared. The structure and properties of the hydrogels were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, differential scanning calorimetry, and thermogravimetric analyzer. The equilibrium and dynamic swelling/deswelling behaviors and the drug release properties of the hydrogels responding to pH and/or temperature were also studied in detail. The hydrogels have the porous honeycomb structures, good miscibility and thermal stability, and good pH‐ and temperature‐responsivity. The volume phase transition temperature of the hydrogels is ca. 40°C. Changing the soy protein or crosslinker content could be used to control the swelling behavior and water retention, and the hydrogels have the fastest deswelling rate in pH 1.2 buffer solutions at 45°C. Bovine serum albumin release from the hydrogels has the good pH and temperature dependence. The results show that the proposed IPN hydrogels may have potential applications in the field of biomedical materials such as in drug delivery systems. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39781.     

Novel physically crosslinked hydrogels of carboxymethyl chitosan and cellulose ethers: Structure and controlled drug release behavior

Novel hydrogels, physically crosslinked by hydrogen bonding of component polymers, were obtained by mixing aqueous solutions of carboxymethylchitosan (CMCS) with cellulose ethers including hydroxyethylcellulose (HEC) and methylcellulose (MC). The hydrogels were characterized by IR, XPS, WAXD, and SEM. The swelling and controlled drug release behaviors of hydrogels were also studied. The results indicate that intermacromolecular hydrogen bonding in CMCS/HEC is stronger than that in CMCS/MC. The swelling and drug release rate of hydrogels decrease as the interaction of component polymers increases. Both the swelling and drug release from hydrogels can be controlled by component polymer ratio. The hydrogels may be potential candidates for biomedical applications. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

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     

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