pH-sensitive hydrogel based on carboxymethyl chitosan/sodium alginate and its application for drug delivery

Carboxymethyl chitosan sodium salt (CMCS)/sodium alginate (SA), a pH-sensitive hydrogel composed of CMCS and SA crosslinked by 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide, has been evaluated in vitro as a potential carrier for protein drug delivery of bovine serum albumin (BSA). The crosslinked structures, pore morphologies, and mechanical properties of the composite CMCS/SA hydrogel at different pH have been characterized by Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and dynamic mechanical analysis (DMA). The swelling behavior of the prepared hydrogel was assessed at different pH values, 1.2, 4.0, 6.86, 7.4, and 9.0. The in vitro slow release ability of the CMCS/SA hydrogel was assessed at 37°C and pH 1.2 or pH 7.4 to simulate gastrointestinal and mouth environments in vivo. The efficiency was found to be greater than 90% at pH 7.4. The composite CMCS/SA hydrogel showed no cytotoxic effect toward L-929 cells according to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. These findings demonstrate that the composite hydrogel has promising potential for drug delivery. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 46911.     

Graphene oxide/poly(<Emphasis Type="Italic">N</Emphasis>-isopropyl acrylamide)/sodium alginate-based dual responsive composite beads for controlled release characteristics of chemotherapeutic agent

In this work, graphene oxide (GO)-incorporated composite beads were developed from poly(N-isopropyl acrylamide)/sodium alginate (PNIPAM/NaAlg) using ionotropic gelation technique. The interaction between GO and PNIPAM/NaAlg with Ca²⁺ ions as a cross-linker was investigated by Fourier transform spectroscopy. X-Ray diffraction pattern showed that the GO was distributed uniformly in the PNIPAM/NaAlg with Ca²⁺ ions while scanning electron micrograph technique revealed that composite beads were formed in spherical shape. The controlled release characteristics of composite beads were studied using 5-fluorouracil (5-FU) as anti-cancer model drug. The encapsulation efficiencies were found to be between 90 and 92% in all formulations. Furthermore, the equilibrium swelling ratio (%) and in vitro release studies of the beads were carried out in two different pH values of 1.2 and 7.4 and at different temperature conditions of 25 and 37 °C. The obtained results showed that the swelling ratio decreased with an increase in GO concentration. In vitro release studies performed in response to both pH and temperature and they proved that the 5-FU drug was released from composite beads over 32 h without burst release. Cytotoxicity results showed pristine composite beads are good cytocompatible. In addition, the cytotoxicity of 5-FU was found to be improved when incorporated with composite beads than pure 5-FU. It is therefore concluded that the developed composite beads have dual response and can be used as controlling released carriers in cancer drug delivery applications.     

Calcium‐carboxymethyl chitosan hydrogel beads for protein drug delivery system

In this study, carboxymethyl chitosan (CMC) hydrogel beads were prepared by crosslinking with Ca²⁺. The pH‐sensitive characteristics of the beads were investigated by simulating gastrointestinal pH conditions. As a potential protein drug delivery system, the beads were loaded with a model protein (bovine serum albumin, BSA). To improve the entrapment efficiency of BSA, the beads were further coated with a chitosan/CMC polyelectrolyte complex (PEC) membrane by extruding a CMC/BSA solution into a CaCl₂/chitosan gelation medium. Finally, the release studies of BSA‐loaded beads were conducted. We found that, the maximum swelling ratios of the beads at pH 7.4 (17–21) were much higher than those at pH 1.2 (2–2.5). Higher entrapment efficiency (73.2%) was achieved in the chitosan‐coated calcium‐CMC beads, compared with that (44.4%) in the bare calcium‐CMC beads. The PEC membrane limited the BSA release, while the final disintegration of beads at pH 7.4 still leaded to a full BSA release. Therefore, the chitosan‐coated calcium‐CMC hydrogel beads with higher entrapment efficiency and proper protein release properties were a promising protein drug carrier for the site‐specific release in the intestine. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 3164–3168, 2007     

A Carbodiimide Cross-Linked Silk Fibroin/Sodium Alginate Composite Hydrogel with Tunable Properties for Sustained Drug Delivery

Carbodiimide cross-linked silk fibroin (SF)/sodium alginate (SA) composite hydrogels with superior stability and tunable properties are developed by varying preparation parameters. SF/SA blend ratio modulation allows to achieve composite hydrogel gelation times of 18–65 min, and rheological analysis shows that the speed of gel formation, the hydrogel network's density, and the hydrogels’ compressive properties are closely related to the blend ratio. The G′ of different hydrogels varies substantially from 28 to 413 Pa, and the hydrogel with higher SF content has a greater stiffness. The composite hydrogels present appropriate porosity of 76.63–85.09% and pore size of 316–603 µm. Hydrogel stability improves significantly after cross-linking, and substantial swelling occurs due to the hydrophilicity of SA. The 7/3 and 6/4 SF/SA hydrogels are more resistant to degradation in PBS, and cytotoxicity testing confirmed their biocompatibility. For release studies in vitro, two model compounds are used as drug models, tetracycline hydrochloride, and bovine serum albumin (BSA). Different ratios of SF/SA have a greater influence on the release of BSA. This study provides a practical preparation method for flexible SF/SA composite hydrogels, which can help design hydrogels with specific physicochemical properties for different applications, especially drug delivery.     

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.     

壳聚糖基可注射温敏凝胶的制备及其药物缓释性能研究

研究不同浓度的壳聚糖、不同质量配比的α-甘油磷酸钠和β-甘油磷酸钠混合盐和混合溶液的pH等因素对CS/GP溶液凝胶化性能的影响,在37℃形成凝胶体系负载模型药物依诺沙星考察该凝胶的释药性能。结果表明:壳聚糖浓度为100 mg,α-甘油磷酸钠和β-甘油磷酸钠按质量比为1∶4混合,控制凝胶体系pH为7.2,凝胶体系IGT可由45℃降至32℃;37℃下,可在3.5 min快速凝胶,凝胶强度达到约0.48 kPa。以依诺沙星为模型药物,载药凝胶体系可持续释放药物10 d左右,有很好的药物缓释作用。     

Effect of attapulgite contents on release behaviors of a pH sensitive carboxymethyl cellulose‐g‐poly(acrylic acid)/attapulgite/sodium alginate composite hydrogel bead containing diclofenac

A series of pH‐sensitive composite hydrogel beads, carboxymethyl cellulose‐g‐poly(acrylic acid)/attapulgite/sodium alginate (CMC‐g‐PAA/APT/SA), were prepared by combining CMC‐g‐PAA/APT composite and SA, using Ca²⁺ as the ionic crosslinking agent and diclofenac sodium (DS) as the model drug. The effects of APT content and external pH on the swelling properties and release behaviors of DS from the composite hydrogel beads were investigated. The results showed that the composite hydrogel beads exhibited good pH‐sensitivity. Introducing 20% APT into CMC‐g‐PAA hydrogel could change the surface structure of the composite hydrogel beads, decrease the swelling ability, and relieve the burst release effect of DS. The drug cumulative release ratio of DS from the hydrogel beads in simulated gastric fluid was only 3.71% within 3 hour, but in simulated intestinal fluid about 50% for 3 hour, 85% for 12 hour, up to 90% after 24 hour. The obtained results indicated that the CMC‐g‐PAA/APT/SA hydrogel beads could be applied to the drug delivery system as drug carriers in the intestinal tract. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Preparation,Characterization, and Drug-Release Behaviors of a pH-Sensitive Composite Hydrogel Bead Based on Guar Gum,Attapulgite, and Sodium Alginate

A novel guar gum-g-poly (acrylic acid)/attapulgite/sodium alginate (GG-g-PAA/APT/SA) composite hydrogel bead with excellent pH sensitivity was prepared via a facile ionic gelation approach and characterized by FTIR and SEM techniques. The effect of APT content on the encapsulation efficiency (EE), swelling ratio, and drug release behaviors of the beads was investigated and the in-vitro release kinetics were also evaluated using diclofenac sodium (DS) as the model drug. The results indicate that the burst release effect of DS drug was eliminated due to the incorporation of APT, and the DS cumulative release was clearly decreased with increasing the APT content.     

Polyelectrolyte complex beads composed of water‐soluble chitosan/alginate: Characterization and their protein release behavior

Polyelectrolyte complex (PEC) beads were prepared from water‐soluble chitosan (WSC) and alginate complex solution with different ratios by dropping method, and all procedures used were performed in aqueous medium at neutral environment. The structure and morphology of the beads were characterized by IR spectroscopy and scanning electron microscopy (SEM). IR spectroscopy confirmed the electrostatic interactions between amino groups of WSC and carboxyl groups of alginate. SEM showed internal section of the PEC bead, which had porous structure compared with compact structure of alginate beads. The swelling behavior, encapsulation efficiency, and release behavior of bovine serum albumin (BSA) from the beads at different pHs were investigated. PEC beads demonstrated different responses to pH from alginate beads. The ratio of WSC to alginate influenced the encapsulation and release of BSA. At pH 1.2, small amount (< 15%) of BSA was released from the PEC beads except AC12. However, at pH 7.4, a large amount (> 80%) of BSA was released from AL in the first 3 h due to the rapid disintegration of the beads, whereas BSA release was retarded from complex beads due to the forming of PEC. The results suggested that the WSC/alginate beads could be a suitable polymeric carrier for site‐specific protein drug delivery in the intestine. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 4614–4622, 2006     

Synthesis of pH-responsive cellulose-g-P4VP by atom transfer radical polymerization in ionic liquid,loading, and controlled release of aspirin

A pH-responsive cellulose-g-P4VP copolymer was synthesized by atom transfer radical polymerization (ATRP) in ionic liquid 1-allyl-3-methylimidazolium chloride [AMIM]Cl. The polymer structure was characterized by Fourier transform infrared (FT-IR), ¹H nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC). The P4VP brushes that were covalently bonded to the cellulose backbone had a narrow molecular weight distribution, which was helpful for use in drug loading. The loading and controlled release of drug using aspirin as model drug in the micelles obtained the cellulose-g-P4VP copolymer was investigated. The structure and size of the copolymeric micelles were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and ultraviolet–visible (UV-Vis) spectroscopy, respectively. Blank micelles presented a stably spherical morphology with dimeter about 90 nm in aqueous solution. The resultant micelles had clear pH-sensitivity with a pH-dependent phase transition point at a pH of about 5.7. Drug-loaded micelles had a spherical, core–shell structure with dimeter about 150 nm. The polymeric micelles revealed an excellent controlled drug release at different pH values and the cumulative release of aspirin in phosphate buffer reached to 86.4% at pH 5.8, 60.9% at pH 7.4 and 42.2% at pH 8.0.at 50 h. The pH-sensitive cellulose-g-P4VP copolymer had an enormous potential as carriers for released drug delivery.     

On physical and antibacterial properties and drug release behavior of poly(vinyl alcohol) hydrogels: effect of drug loaded chitosan nanoparticles

This paper deals with influence of chitosan nanoparticles (CNPs) loaded by tetracycline, as a drug, on the physico-mechanical and antibacterial properties as well as drug release behavior of poly(vinyl alcohol), PVA, hydrogels prepared by electron beam irradiation. The formation of spherical chitosan particles in nanoscale size prepared by an ionic gelation method was confirmed by FTIR and UV spectroscopy, and scanning electron microscopy analyses. The drug release kinetic studies from drug loaded chitosan nanoparticles (DLCNPs) at pH = 7.4 revealed a linear and steady release behavior over long period of time. The theoretical analysis of the swelling kinetic data, using Peppas’s model showed that the swelling kinetic is governed by Fickian diffusion for all the prepared hydrogels, however, the water diffusion coefficient, and therefore, the swelling content were lower for the hydrogels loaded with DLCNPs as compared to the ones with the neat drug. In agreement with these results, the hydrogels containing DLCNPs exhibited a more controlled drug release behavior with significantly stronger antibacterial activity. The tensile mechanical properties of the hydrogels not affected by the DLCNPs were found to be suitable for wound dressing applications.     

Swelling and drug release behavior of calcium alginate/poly (sodium acrylate) hydrogel beads

In the present work calcium alginate/poly (sodium acrylate) composite beads have been prepared by in situ formation of cross-linked poly (sodium acrylate) network, within the calcium alginate (CA) beads. The CA/poly (SA) beads have been found to be stable for more than 48 h, in the physiological fluid (PF) of pH 7.4, while the plain alginate beads disintegrated within a couple of hours. The water uptake of beads was investigated under various composition parameters such as the amount of alginate, concentration of ionic cross-linker Ca⁺⁺ ions, monomer sodium acrylate (SA) contents, and degree of cross-linking. The beads also exhibited fair stability in the media of varying pH. Finally the release of model drug methylene blue (MB) was investigated. It was found that plain CA and CA/poly (SA) composite beads exhibited different release mechanisms.     

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     

The preparation of pH-sensitive hydrogel based on host-guest and electrostatic interactions and its drug release studies in vitro

A new self-assembly strategy called the synthesis of an amphiphilic crosslinking agent for electrostatic and host-guest is used to prepare a new cellulose-based pH-responsive hydrogel. The amphiphilic crosslinking agent could be encapsulated by poly β-cyclodextrin (β-CDP) through host-guest interaction and be meanwhile attracted by carboxyl groups through electrostatic interaction, then, forming a three-dimensional (3D) gel network structure. Additionally, the linear β-CDP part of the remaining hydrophobic cavity can be equipped with hydrophobic drug molecules to achieve the function of hydrogel expansion. ¹H NMR was used to characterize the synthesized amphiphilic crosslinking agent N,N-dimethyl-1-adamantanamine (DM-AD). FTIR, SEM to characterize the synthesized β-CDP. SEM was used to observe the surface to characterize the prepared hydrogel. The swelling of the gel was measured in aqueous solution, and the swelling kinetic equation was fitted. Meanwhile, the in vitro release of ibuprofen (IBU) in hydrogels was studied. The gel showed a sustained release effect in drug release, and the IBU is hardly released in the gastric juice but is easily released in the intestines. Within 240–1350 min, the release of the drug from the hydrogel conforms to the Korsmeyer and Peppas model, which is a non-Fickian diffusion mechanism. Within 240–1350 min, the drug is released from the hydrogel conforms to the Higuchi model. Furthermore, the gel has the ability of self-healing and self-degradation under acid conditions.     

Synthesis of a novel pH‐sensitive polyurethane–alginate blend with poly(ethylene terephthalate) waste for the oral delivery of protein

With the aim of using poly(ethylene terephthalate) (PET) waste for the synthesis of a value added product, we prepared polyurethane (PU) from bishydrohxyethylene terephthalate (BHET), a byproduct obtained from the glycolysis of PET. Biodegradable, water‐swelling PU was synthesized by the reaction of BHET, hexamethylene diisocyanate, and poly(ethylene glycol) (PEG). Both BHET and PU were characterized by Fourier transform infrared spectroscopy, and the formation of PU was further confirmed by NMR analysis. The swelling behavior of PU in water was examined in terms of the various molecular weights of PEG. Semi‐interpenetrating network beads of PU and sodium alginate were prepared with calcium chloride (CaCl₂) as a crosslinker to attain a pH sensitivity for successful oral protein/drug delivery. Bovine serum albumin (BSA) was used as a model protein. The pH‐responsive swelling behavior and protein (BSA) release kinetics in different pH media corresponding to the gastrointestinal tract (pH 1.2 and 7.4) were investigated. The degree of swelling in the case of the PU–alginate beads at pH 1.2 was found to be at a minimum, whereas the degree of swelling was significantly elevated (1080%) at pH 7.4. This substantiated the pH sensitivity of the polymeric beads with a minimum loss of encapsulated protein in the stomach and the almost complete release of encapsulated protein in the intestine. This revealed good opportunities for oral protein/drug delivery with a polymer derived from waste PET. Moreover, the fungal biodegradation study confirmed its compatibility with the ecological system. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40650.     

Development of pH-sensitive and antibacterial gelatin/citric acid/Ag nanocomposite hydrogels with potential for biomedical applications

This work aimed to prepare pH-sensitive and antibacterial drug releasing systems through a completely green route. To achieve this, the gelatin natural biopolymer was crosslinked with citric acid in the presence of Ag nanoparticles (NPs). Interestingly, Ag NPs formation and gelatin crosslinking were simultaneously occurred during annealing of samples without need for any toxic chemicals, which were confirmed by FTIR, UV-vis spectra, SEM and TEM observations. In addition, potential of the citric acid crosslinked-gelatin/Ag nanocomposite hydrogels was successfully explored for drug delivery applications using cefixime as a model drug. It was found that these hydrogels have pH-dependent swelling and drug release behavior with higher drug release at pH 7.4 compared to pH 1.2. Also, an antibacterial effect against the E. coli and S. aureus microorganisms was achieved by incorporation of Ag NPs into hydrogels. These hydrogels can be considered as stimuli responsive materials for oral drug delivery and wound dressing applications.     

Preparation and properties of a novel thermosensitive <Emphasis Type="Italic">N</Emphasis>-trimethyl chitosan hydrogel

A novel injectable thermosensitive hydrogel system composed of N-trimethyl chitosan chloride (TMC) and β-glycerophosphate (β-GP), coded as TMC/β-GP, was designed. The morphology and rheological behavior of hydrogels were characterized by scanning electron microscopy and rheometer, respectively. Their swelling properties were carefully studied. The results revealed that the TMC/β-GP system was liquid with low viscosity at low temperature, which allowed it to be an ideal injectable material for biomedical applications. It was interesting that the system kept in liquid status for a long time near 4 °C and transformed rapidly to gel status within 1 min upon heating to 37 °C. The hydrogel could be dissolved at acid pH, while it absorbed water at neutral and basic conditions. The release of BSA from TMC/β-GP gels was slow at neutral pH. The TMC/β-GP hydrogel is a promising vehicle for the drug release, tissue repairing and regeneration.     

Barium Ions Crosslinked Alginate and Sterculia Gum-Based Gastroretentive Floating Drug Delivery System for Use in Peptic Ulcers

The gastro-retentive drug delivery system is required to improve the bioavailability and therapeutic efficacy of the drugs used for the diseases associated with the stomach. Both sterculia gum and alginate enhance the repair of mucosal damage in the GI tract and pantoprazole is a therapeutic agent for GI tract ulcers. Ionotropic gelation of these polysaccharides for the release of pantoprazole will develop the double potential drug delivery systems. Therefore, in the present study, an attempt has been made to synthesize a gastro-retentive floating drug delivery system by simultaneous ionotropic gelation of alginate and sterculia gum using BaCl₂ as a crosslinker. The beads have been characterized by SEMs, EDAX, and FTIR analysis. The swelling of beads has been carried out as a function of pH of the swelling media. In addition, in vitro release dynamics of an anti-ulcer model drug pantoprazole from drug-loaded beads in different release media have been carried out for the evaluation of the drug release mechanism and diffusion coefficients. Release of drug from beads occurred through a Fickian-type diffusion mechanism. The present drug delivery sytem may have a double potential, first due to the therapeutic importance of the sterculia–alginate-based polymer matrix and second, release of pantoprazole in a controlled and sustained manner.     

A novel pH‐sensitive and freeze‐thawed carboxymethyl chitosan/poly(vinyl alcohol) blended hydrogel for protein delivery

BACKGROUND: Blended hydrogels are widely applied in medical fields. They can provide many advantages, such as biocompatibility and biodegradability. Many materials and methods are used to obtain blended hydrogels. In this work, carboxymethyl chitosan (CMCS) and poly(vinyl alcohol) (PVA) blended hydrogels were prepared using the freezing and thawing technique. The properties of the hydrogels prepared, i.e. gel fraction, swelling and pH‐responsive behaviors, were investigated. RESULTS: The gel fraction increased with increasing time of freezing and thawing as determined through gravimetric analysis. It was also found that the equilibrium degree of swelling improved obviously due to the addition of CMCS compared to pure PVA hydrogel. The blended hydrogel with composition CMCS/PVA 80/20 (by weight) possessed the highest swelling ratio. The results of the influence of pH values on the swelling behavior showed that minimum swelling ratios of the hydrogels occurred near the isoelectric point of CMCS. Protein release studies were performed under various pH conditions: the release was much slower under acid than under basic conditions. The release showed a burst in the first 15 h and then steadily increased. CONCLUSION: The addition of CMCS can improve the physical properties of pure PVA hydrogels and provide pH sensitivity. It is concluded that PVA hydrogels containing CMCS could be potentially applied as oral delivery systems for protein drugs. Copyright © 2009 Society of Chemical Industry     

Gastroretentive floating sterculia–alginate beads for use in antiulcer drug delivery

To improve the bioavailability and therapeutic efficacy of the drugs used for the diseases associated with the stomach, the retention of drug delivery systems in the stomach for longer time is requred. Therefore, in the present study, an attempt has been made to synthesize gastro-retentive floating drug delivery system by simultaneously ionotropic gelation of alginate and sterculia gum by using CaCl₂ as crosslinker. The beads thus formed have been characterized by scanning electron micrographs (SEMs), electron dispersion X-ray analysis (EDAX), Fourier transform infrared spectroscopy (FTIR) analysis. The swelling of beads has been carried out as a function of various reaction parameters and pH of the swelling media. In addition, in vitro release dynamics of anti-ulcer model drug pantoprazole from drug loaded beads in different release media has been carried out for the evaluation of the drug release mechanism and diffusion coefficients. Release of drug from beads occurred through Fickian type diffusion mechanism.