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.     

Controlled release of aspirin from pH‐sensitive chitosan/poly(vinyl alcohol) hydrogel

The aim of this study was to develop a cheap, pH‐sensitive enteric coating of aspirin with biocompatible polymers. A novel approach was used to develop enteric coating from chitosan (CS) and poly(vinyl alcohol) (PVA). Solutions of CS and PVA (5 : 1 mol ratio) were mixed and selectively crosslinked with tetraethoxysilane. IR analysis confirmed the presence of the incorporated components and the existence of siloxane linkages between CS and PVA. The crosslinking percentage and thermal stability increased with increasing amount of crosslinker. The response of the developed coating in different media, such as water, pH (nonbuffer and buffer), and ionic media showed hydrogel properties. All hydrogels showed low swelling in acidic and basic pH media, whereas maximum swelling was exhibited at neutral pH. This pH sensitivity of the hydrogel has been exploited as enteric coating for commercial aspirin tablets. The dissolution test of enteric‐coated aspirin tablet in simulated gastric fluid (pH 1.2) showed 7.11% aspirin release over a period of 2 h, whereas a sustained release of remaining aspirin (83.25%) was observed in simulated intestinal fluid (pH 6.8). © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Synthesis and characterization of novel pH-, ionic strength and temperature- sensitive hydrogel for insulin delivery

A series of novel silane crosslinked hydrogel was prepared from kappa carrageenan (KC), acrylic acid (AA) using vinyltriethoxysilane (VTESi). Potassium persulphate initiated the grafting and copolymerization reactions between reactants. In addition, the condensation of the hydroxyl groups of KC and VTESi resulted into crosslinking. Novelty of this work is the use of VTESi as crosslinker for such a composition of hydrogel. The structure of prepared hydrogels was characterized by Fourier transform infrared spectroscopy. The analysis of spectra confirmed the presence of feed components in the prepared hydrogels. Thermogravimetric analysis showed an increase in the stability of the hydrogels either having high AA contents or crosslinker amount. The effect of feed components, pH (buffer, non-buffer), electrolytic media and temperature on the swelling behaviour of the hydrogels is reported here.Most promising results with high swelling ratio were observed in hydrogel having low monomeric ratio (KC:AA = 1:7). pH response of this hydrogel in acidic and neutral pH makes it suitable for drug delivery application. Insulin, a protein based drug was selected as a model drug. It requires its delivery in small intestine for proper action; therefore its release behaviour was studied in-vitro in simulated stomach and intestinal fluids. The release profile of insulin showed negligible release in simulated gastric fluid (SGF) and sustained release in simulated intestinal fluid (SIF). The obtained results are in good agreement with the swelling response of this hydrogel. The weak structure of this hydrogel makes it preferable for drug delivery, as it is able to get crumbled after releasing the drug for 6 h at neutral pH.     

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。     

Synthesis and characterization of a novel pH-responsive nanocomposite hydrogel based on chitosan for targeted drug release

Over the last decade, nanocomposite hydrogels have been provided a new approach for the biomedical field. In this work, a novel pH-responsive nanocomposite hydrogel was fabricated using simultaneous in situ formation of magnetite iron oxide nanoparticles and hydrogel networks of poly(acrylic acid) grafted onto chitosan. The effects of various types of precursor molecules, pH, salt, and loading pressure were examined on the swelling properties of resulting nanocomposite hydrogels. The synthesized nanocomposite hydrogel was well characterized using different instruments. In vitro drug releasing behavior of doxorubicin was studied at pH 5.4 and 7.4. The drug release mechanism was investigated through different kinetic models. These experimental results open a new opportunity to make pH-responsive nanocomposite hydrogel devices for controlled delivery of drug.     

Design and fabrication of a triple-responsive chitosan-based hydrogel with excellent mechanical properties for controlled drug delivery

A pH-, temperature- and salinity responsive hydrogel with enhanced mechanical performance was developed based on semi interpenetrating network that was formed as a result of concurrent free radical polymerization of acrylic acid (AA), oligo(ethylene glycol) methacrylate (OEGMA) and 2-(2-methoxyethoxy) ethyl methacrylate (MEO₂MA) along with chitosan (CS) for controlled drug delivery. The mechanical behaviors and swelling properties of these hydrogels were systematically investigated, and the results indicated that they were strongly affected by the content of AA and MEO₂MA and exhibited strong pH-, temperature and salinity sensitivity. Bovine serum albumin (BSA) and 5-Fluorouracil (5-Fu) were used as the model drugs to evaluate the sustained release of the hydrogel. The result indicated that the amount of both drugs released was relatively low in acidic condition (pH 1.2) but high in neutral environment (pH 7.4), and the release rate of the drugs was slower at 37 °C than that at 25 °C. Cytotoxicity results suggested that the blank hydrogels had negligible toxicity to normal cells, whereas the 5-Fu-loaded hydrogels remained high in cytotoxicity for LO2 and HepG2 cancer cells. These results suggest that the synthesized hydrogels have the potential to be used as an effective pH/temperature sustainable site-specific oral drug delivery in intestine and colon.     

Preparation and 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     

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.     

印迹水凝胶作为氟尿嘧啶载体的药物缓释性能

以氟尿嘧啶为模板药物,以甲基丙烯酸羟乙酯为骨架单体,以甲基丙烯酸为功能单体,乙二醇二甲基丙烯酸酯为交联剂,偶氮二异丁腈为引发剂合成印迹水凝胶,并通过扫描电镜、红外光谱及差示热量扫描等测试手段对凝胶进行了表征,结果表明：制备的印迹水凝胶表面无孔、光滑,氟尿嘧啶与其中的单体通过氢键结合成了复合物,同时经处理后凝胶中已不再残留未反应的单体。印迹水凝胶的吸水溶胀性能实验结果显示其吸水溶胀性能随制备中模板药物的含量的增加而增强,同时同一凝胶的溶胀速度与溶胀率随体系pH值的升高而增强。在氟尿嘧啶溶液中测定水凝胶的药物负载量,结果显示：印迹水凝胶的药物负载能力明显强于非印迹水凝胶,同时印迹水凝胶（8∶1）对药物的负载能力强于印迹水凝胶（4∶1）,药物负载量高达0.0914 mg/g。在模拟体液中测试水凝胶对药物的释放效果结果显示：印迹水凝胶对药物的缓释作用明显优于非印迹水凝胶,并且印迹水凝胶（8∶1）对药物的缓释效果优于印迹水凝胶（4∶1）,对药物的释放平缓,同时,释放体系pH值的升高不利于印迹水凝胶的药物缓释效果。     

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     

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     

Dual‐responsive semi‐interpenetrating network beads based on calcium alginate/poly(N‐isopropylacrylamide)/poly(sodium acrylate) for sustained drug release

To improve the mechanical strength of natural hydrogels and to obtain a sustained drug‐delivery device, temperature‐/pH‐sensitive hydrogel beads composed of calcium alginate (Ca‐alginate) and poly(N‐isopropylacrylamide) (PNIPAAm) were prepared in the presence of poly(sodium acrylate) (PAANa) with ultrahigh molecular weight (M_η ≥ 1.0 × 10⁷) as a strengthening agent. The influence of PAANa content on the properties, including the beads stability, swelling, and drug‐release behaviors, of the hydrogels was evaluated. Scanning electron microscopy and oscillation experiments were used to analyze the structure and mechanical stability of the hydrogel beads, respectively. The results show that stability of the obtained Ca‐alginate/PNIPAAm hydrogel beads strengthened by PAANa the alginate/poly(N‐isopropyl acrylamide) hydrogel bead (SANBs) was significantly improved compared to that of the beads without PAANa (NANBs) at pH 7.4. The swelling behavior and drug‐release capability of the SANBs were markedly dependent on the PAANa content and on the environmental temperature and pH. The bead sample with a higher percentage of PAANa exhibited a lower swelling rate and slower drug release. The drug release profiles from SANBs were further studied in simulated intestinal fluid, and the results demonstrated here suggest that SANBs could serve as a potential candidate for controlled drug delivery in vivo. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Enhancing the crystallization and orientation of electrospinning poly (lactic acid) (PLLA) by combining with additives

Novel hydrogel films composed of hydroxyethylacryl chitosan (HC) and sodium alginate (SA) were prepared for biomedical application by using calcium chloride (CaCl₂) as a nontoxic ionic crosslinker to form a semi-interpenetrating polymer network (semi-IPN). HC was successfully prepared by following a Michael addition reaction of chitosan (CS) and hydroxyethylacrylate completely dissolved in distilled water at 70 °C. The distribution pattern of Ca²⁺ ions were well-dispersed within the hydrogel films examined by scanning electron microscope-energy dispersive spectrometry (SEM-EDS), implying uniformity of crosslinking. The swelling behavior of the hydrogel films in distilled water, simulated gastric fluid (SGF, pH?=?1.2) and phosphate buffer solution (PBS, pH?=?7.4) were investigated. The equilibrium swelling degree of the hydrogel films in distilled water increased with a decreas of either the SA content or the concentration of CaCl₂. The hydrogel films showed pH-dependent behavior in that the shapes of the hydrogel films were stable in SGF while they degraded in PBS. The tensile strength and elongation of the hydrogel films reached 12.1 MPa and 162%, respectively, which presented reasonable mechanical properties during use and enough flexibility to follow skin movement. Cell viability of the hydrogels was measured using a methylthiazol tetrazolium (MTT) assay. The results indicated that the hydrogel films are not cytotoxic.     

Photo‐cross‐linked biodegradable thermo‐ and pH‐responsive hydrogels for controlled drug release

A new strategy was developed to prepare thermo‐ and pH‐sensitive hydrogels by the crosslinking of poly(N‐isopropylacrylamide) with a biodegradable crosslinker derived from poly(L ‐glutamic acid). Hydrogels were fabricated by exposing aqueous solutions of precursor containing photoinitiator to UV light irradiation. The swelling behaviors of hydrogels at different temperatures, pHs, and ionic strengths were examined. The hydrogels shrank under acidic condition or at temperature above their collapse temperature and would swell in neutral or basic media or at lower temperature. These processes were reversible as the pH or temperature changed. All hydrogels exhibited no weight loss in the simulated gastric fluid but degraded rapidly in the simulated intestinal condition. Bovine serum albumin were used as a model protein drug and loaded into the hydrogels. The in vitro drug release experiment was carried out at different pH values and temperatures. The pH and temperature dependent release behaviors indicated the promising application of these materials as stimuli‐responsive drug delivery vehicles. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

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.     

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.     

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.     

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

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

Hollow,pH‐sensitive calcium–alginate/poly(acrylic acid) hydrogel beads as drug carriers for vancomycin release

In this study, hollow calcium–alginate/poly(acrylic acid) (PAA) hydrogel beads were prepared by UV polymerization for use as drug carriers. The hollow structure of the beads was fortified by the incorporation of PAA. The beads exhibited different swelling ratios when immersed in media at different pH values; this demonstrated that the prepared hydrogel beads were pH sensitive. A small amount (<9%) of vancomycin that had been incorporated into the beads was released in simulated gastric fluid, whereas a large amount (≤67%) was released in a sustained manner in simulated intestinal fluid. The observed drug‐release profiles demonstrated that the prepared hydrogel beads are ideal candidate carriers for vancomycin delivery into the gastrointestinal tract. Furthermore, the biological response of cells to these hydrogel beads indicated that they exhibited good biological safety and may have additional applications in tissue engineering. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

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).