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     

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

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

一种新型聚天冬氨酸水凝胶的制备及其药物缓释性能研究

介绍了一种新型羟化聚天冬氨酸-乙基纤维素(PASP-EC)互穿网络水凝胶的制备,研究了交联剂用量、乙醇胺用量及乙基纤维素(EC)用量对水凝胶溶胀性能的影响;同时,进行了水凝胶的pH敏感性测试,并以5-Fu为药物模型,研究其在肠液中(pH=7.4)的药物控释性能。实验结果表明,当己二胺、乙醇胺、EC的用量分别是聚琥珀酰亚胺(PSI)用量的3%、20%、30%时,水凝胶的溶胀性能最佳,达到290倍;且随着乙醇胺用量的增加,水凝胶在50%乙醇中的溶胀性能提高。pH敏感实验表明,羟化PASP-EC水凝胶具有pH敏感性。羟化PASP-EC水凝胶对5-Fu具有缓释效果,随着EC用量增加,缓释效果越明显。     

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     

Rheological properties and drug release characteristics of pH‐responsive hydrogels

Rheological properties, blend compatibility, and gel‐forming capacity of carbopol 940 (CP‐940), sodium alginate (NaAlg), and guar gum (GG) have been studied. These matrices have been used in delivery of timolol maleate for ophthalmic applications. Aqueous solutions of CP‐940, NaAlg, and GG in concentrations between 0.1 and 1% (wt/vol) and their blends have been prepared. In situ gel forming polymeric solutions have shown an increase in viscosity upon exposure to specific pH, ions, and temperature of the eyeball. Blend miscibility was studied by calculating polymer–polymer interaction parameters using viscosity data. Rheological properties viz., torque, viscosity, shear stress, and shear rate were obtained using a Brookfield rheometer. Viscosities of polymer solutions were obtained by a Schott Gerate viscometer. Rheological data were analyzed using Bingham, Casson Standard, and Casson Chocolate equations. The hydrogels were subjected to ex vivo release studies on timolol maleate through the excised bovine cornea using a modified Franz diffusion cell. Results were compared with the conventional drug solution. The release could be extended when the drug is incorporated into hydrogel‐forming solution. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 2057–2064, 2004     

聚天冬氨酸水凝胶合成及其应用于药物控释的研究进展

聚天冬氨酸是一种新型的聚合氨基酸材料,具有很好的生物相容性、生物降解性。本文综述了聚天冬氨酸及其衍生物水凝胶的研究现状,介绍了化学交联、光交联、γ射线交联3种交联方法合成的聚天冬氨酸及其衍生物水凝胶,以及近年来聚天冬氨酸基凝胶对大分子蛋白药物、小分子抗炎性药物、抗癌和基因药物控释的研究进展,并对该凝胶在药物控释领域的发展方向进行了预测。     

Preparation and application in drug controlled delivery of pH‐sensitive P(CE‐co‐DMAEMA‐co‐MEG) hydrogel

A pH‐sensitive hydrogel [P(CE‐co‐DMAEMA‐co‐MEG)] was synthesized by the free‐radical crosslinking polymerization of N,N‐dimethylaminoethyl methacrylate (DMAEMA), poly(ethylene glycol) methyl ether methacrylate(MPEG‐Mac) and methoxyl poly(ethylene glycol)‐poly(caprolactone)‐methacryloyl methchloride (PCE‐Mac). The effects of pH and monomer content on swelling property, swelling and deswelling kinetics of the hydrogels were examined and hydrogel microstructures were investigated by SEM. Sodium salicylate was chosen as a model drug and the controlled‐release properties of hydrogels were pilot studied. The results indicated that the swelling ratios of the gels in stimulated gastric fluids (SGF, pH = 1.4) were higher than those in stimulated intestinal fluids (SIF, pH = 7.4), and followed a non‐Fickian and a Fickian diffusion mechanism, respectively. In vitro release studies showed that its release rate depends on different swelling of the network as a function of the environmental pH and DMAEMA content. SEM micrographs showed homogenous pore structure of the hydrogel with open pores at pH 1.4. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40737.     

聚天冬氨酸凝胶的制备及生物降解性

以丙三醇三缩水甘油醚为交联剂制备聚天冬氨酸凝胶,考察了凝胶的热性能和黏弹性,并采用平板培养和液体培养法考察了凝胶的生物降解性。结果表明:丙三醇三缩水甘油醚交联凝胶具有良好的吸水保水性,且耐热性和黏弹性更优,平板试验证明凝胶也具有良好的生物降解性,液体培养法证明交联剂的种类和用量对凝胶的降解有较大影响,交联度均为60%的凝胶,交联剂为丙三醇三缩水甘油醚时第9天降解率为49.3%,较交联剂为乙二醇二缩水甘油醚制备的凝胶低9.2%,说明在相同交联度下丙三醇三缩水甘油醚形成的网络结构更致密;交联剂均为丙三醇三缩水甘油醚时,交联度为40%的第9天降解率为59.8%,较交联度为60%的凝胶提高了17.5%,交联度增加,降解速率降低。     

Fluconazole release through semi‐interpenetrating polymer network hydrogels based on chitosan,acrylic acid,and citraconic acid

Semi‐interpenetrating polymer network hydrogels with different compositions of chitosan (Cs), acrylic acid, and citraconic acid were synthesized via free‐radical polymerization with ethylene glycol dimethacrylate as a crosslinker. The variations of the swelling percentages of the hydrogels with time, temperature, and pH were determined, and Cs–poly(acrylic acid) (PAA) hydrogels were found to be most swollen at pH 7.4 and 37°C. Scanning electron micrographs of Cs–PAA and Cs–P(AA‐co‐CA)‐1 (Cs‐poly(acrylicacid‐co‐citraconir acid)^?1) were taken to observe the morphological differences in the hydrogels. Although the less swollen hydrogel, Cs–P(AA‐co‐CA)‐1, had a sponge‐type structure, the most swollen hydrogel, Cs–PAA, displayed a uniform porous appearance. Fluconazole was entrapped in Cs–P(AA‐co‐CA)‐1 and Cs–PAA hydrogels, and the release was investigated at pH 4.0 and 37°C. The kinetic release parameters of the hydrogels (the gel characteristic constant and the swelling exponent) were calculated, and non‐Fickian diffusion was established for Cs–PAA, which released fluconazole much more slowly than the Cs–P(AA‐co‐CA)‐1 hydrogel. A therapeutic range was reached at close to 1 h for both hydrogels. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Preparation and characterization of a novel thermosensitive hydrogel based on chitosan and gelatin blends

In this study, a novel injectable in situ gelling thermosensitive hydrogel system based on chitosan and gelatin blends was designed and investigated. The addition of gelatin provides the correct buffering and other physicochemical conditions including control of hydrophobic interactions and hydrogen bonding, which are necessary to retain chitosan in solution at neutral pH near 4°C and furthermore to allow gel formation upon heating to body temperature. The chitosan/gelatin hydrogels were studied by FTIR, swelling, and rheological analysis. The rheological analysis evidenced the endothermic gelation of chitosan/gelatin solutions, which indicated their gelation temperatures and reflected the effect of gelatin concentration on the thermosensitive properties of gels. The morphology of this system was examined with laser scanning confocal microscopy and scanning electron microscopy. The images indicated that the gels were quite heterogeneous and porous. The investigation of these gels as vehicles for delivering bovine serum albumin as a model drug of protein showed that the system could sustain the release of the protein drug. These results show that chitosan/gelatin solutions can form gels rapidly at body temperature and have promising perspective for their use in local and sustained delivery of protein drug. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Preparation and characterization of pH‐sensitive hydrogels based on chitosan,itaconic acid and methacrylic acid

Novel pH‐sensitive hydrogels based on chitosan, itaconic acid and methacrylic acid were prepared in two steps. Chitosan was first ionically crosslinked with itaconic acid, after which a free radical polymerization and crosslinking of the chitosan/itaconic acid network was performed by adding methacrylic acid and a crosslinker in order to achieve better mechanical properties and tunable swelling. The samples were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, thermogravimetric analysis, X‐ray diffraction, dynamic mechanical analysis and the swelling ratios of the hydrogels at various pH values (2.0–8.0). The hydrogel composition is found to have a great impact on the hydrogel structure, mechanical and thermal properties, morphology and swelling kinetics. The highly porous morphology of the gels is probably connected with the bulky chitosan/itaconic acid network which reduces the degree of crosslinking in the second step of the synthesis due to steric hindrances. The gels demonstrate substantial change in buffer absorbency with change of pH, low for acid buffers and the higher for pH values above 6 where the swelling is considerably slow, thus suggesting their strong candidature for use as oral drug‐delivery systems in the lower parts of the gastrointestinal tract and for drugs that require longer release times. Copyright © 2010 Society of Chemical Industry     

Modulation of dynamic release of vitamin B2 from a model pH‐sensitive terpolymeric hydrogel system

Terpolymeric devices consisting of acrylamide, methacrylamide and acrylic acid were synthesized and the release of the model drug riboflavin from these devices was studied at the physiological temperature 37°C. The gels exhibit a sharp pH‐dependent release behavior. The devices released nearly 42.2 ± 2.6% drug at pH 1.0 while nearly 95.3 ± 3.2% drug was released at pH 7.4. With increasing concentration of cross‐linker in the gel, the drug released was found to decrease. Moreover, with low content of cross‐linker a nearly zero‐order profile was obtained. The size of the cylindrical devices also affected the release kinetics and a linear dependency was observed between t_1/2 (ie, the time required for 50 % release) and the square of the diameter, thus supporting the Tanaka–Fillmore theory. The molar ratio of acrylamide and methacrylamide also affected the dynamic release of riboflavin. It was found that variation in transit time could also affect the drug‐releasing capacity of the devices. Finally, the average and ‘late‐time’ diffusion coefficients for the gels having different initial loads were also evaluated. Copyright © 2004 Society of Chemical Industry     

Glucose‐sensitive and blood‐compatible nanogels for insulin controlled release

For insulin delivery, many reported glucose‐sensitive materials are designed to response to the glucose in the blood. However, few particular studies on their blood compatibility have been reported. In this article, for controlled insulin release in diabetes therapy, a glucose‐sensitive nanogel was prepared through thermally initiated precipitation polymerization using the aminophenylboronic acid‐containing monomer to copolymerize with methacrylic acid. The obtained nanogels showed the uniform and spheroidal morphology as observed by SEM, and their sizes in aqueous solution are dependent on the concentration of glucose. Through in vitro and in vivo insulin release tests, it was found that nanogels showed the glucose‐dependent insulin release and prolonged effect of lowing blood glucose level. The blood compatibility of nanogels has also been explored through various assays including the hemolysis, activated partial thromboplastin time, prothrombin time as well as the thromboelastography. All results indicated that the obtained glucose‐sensitive nanogels showed good blood safety. Moreover, their low cytotoxicity suggested a potential application in diabetes therapy. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43504.     

pH sensitive interpenetrating network microgels of sodium alginate‐acrylic acid for the controlled release of ibuprofen

pH‐Sensitive interpenetrating network (IPN) microgels (MGs) of sodium alginate (NaAlg) and acrylic acid have been prepared by using water‐in‐oil (W/O) emulsion technique. The MGs were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X‐ray diffractometer (X‐RD). The release of ibuprofen (IB), an anti‐inflammatory drug, from these MGs was studied in pH 1.2 and 7.4 media. MG network consists of NaAlg, which disintegrates in the intestinal fluid, while poly(acrylic acid) provides pH‐sensitivity to the microgel network. The system developed in this study showed a pH‐sensitivity for the release of IB, which was attributed to the diffusion controlled release of the drug through the surfaces of MGs that undergo disintegration after swelling, depending upon the chemical composition of MGs and pH of the medium. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006     

pH‐Sensitive pectin polymeric rafts for controlled‐release delivery of pantoprazole sodium sesquihydrate

The aim of the present work was to develop pectin raft‐forming tablets for controlled‐release delivery of pantoprazole sodium sesquihydrate (PSS). A Box–Behnken design was used to optimize 15 formulations with three independent and three dependent variables. The physical tests of all compressed formulations were within pharmacopoeial limits. The rafts were characterized by their strength, thickness, resilience, reflux resistance, acid‐neutralizing capacity, floating lag time, and total floating time. The raft strength, thickness, resilience, and reflux resistance through a 10‐mm orifice of optimized formulation PR9 were 7.43 ± 0.019 g, 5.8 ± 0.245 cm, greater than 480 min, and 2490 ± 0.004 g, respectively. The buffering and neutralizing capacity was 11.2 ± 1.01 meq and 6.5 ± 0.56 meq, respectively. Dissolution studies were performed by using simulated gastric fluid at pH 1.2, and the cumulative percentage release of PR9 was found to be 97%. First‐order release kinetics were followed, and non‐Fickian diffusion was observed as the value of n was greater than 0.45 in the Korsmeyer–Peppas model. The Fourier transform infrared spectra of the PSS, polymers, and optimized raft formulation PR9 showed peaks at 3223.09 cm^?1, 1688.17 cm^?1, 1586.67 cm^?1, 1302.64 cm^?1, and 1027.74 cm^?1 that are due to ? OH stretching, ester carbonyl group (C?O) stretching, the existence of water and carboxylic groups in the raft, C? N stretching, and ? OH bending vibrations and showed no interaction between them. The developed raft was suitable for sustained‐release delivery of PSS. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134 , 44442.     

Preparation and characterization of a positive thermoresponsive hydrogel for drug loading and release

A positive thermoresponsive hydrogel composed of poly(acrylic acid)‐graft‐β‐cyclodextrin (PAAc‐g‐β‐CD) and polyacrylamide (PAAm) was synthesized with the sequential interpenetrating polymer network (IPN) method for the purpose of improving its loading and release of drugs. The structure and properties of the PAAc‐g‐β‐CD/PAAm hydrogel (IPN hydrogel) were characterized with Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and swelling measurements. FTIR studies showed that the IPN hydrogel was primarily composed of an IPN of PAAc‐g‐β‐CD and PAAm. The data from DSC and swelling measurements indicated that the phase‐transition temperature or upper critical solution temperature (UCST) of the IPN hydrogel was approximately 35°C. Through the measurement of the temperature dependence of the swelling, increases in the UCST and non‐sensitivity to changes in the salt concentration were observed for the IPN hydrogel versus the normal IPN hydrogel poly(acrylic acid)/PAAm (without β‐cyclodextrin). Furthermore, the swelling/deswelling kinetics of the IPN hydrogel also exhibited an improved controllable response rate versus the normal IPN hydrogel. Ibuprofen (IBU) was chosen as the model drug for examining loading and release from the IPN hydrogel. The experimental data proved that the IPN hydrogel provided a positive drug release pattern; the IBU released faster at 37°C than at 25°C, and improved drug loading and controlled release were achieved by the IPN hydrogel versus the normal IPN hydrogel. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Kinetics study of isothermal nicotine release from poly(acrylic acid) hydrogel

The isothermal kinetic of the release of nicotine from a poly(acrylic acid) (PAA) hydrogel was investigated at temperature range from 26°C to 45°C. Specific shape parameters of the kinetic curves, the period of linearity and saturation time were determined. The change in the specific shape parameters of the kinetic curves with temperature and the kinetic parameters of release of nicotine E_a and ln A were determined. By applying the “model fitting” method it was established that the kinetic model of release of nicotine from the PAA hydrogel was [1 − (1 − α)^1/3] = k_Mt. The limiting stage of the kinetics release of nicotine was found to be the contracting volume of the interaction interface. The distribution function of the activation energy was determined and the most probable values of activation energies of 25.5 kJ mol⁻¹ and 35 kJ mol⁻¹ were obtained. Energetically heterogeneity of the interaction interface was explained by the existence of the two different modes of bonding the nicotine molecules onto the hydrogel network by hydrogen bond and electrostatic forces. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

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

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

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.     

Sustained release of potassium diclofenac from a pH‐responsive hydrogel based on gum arabic conjugates into simulated intestinal fluid

This work describes the preparation, the swelling properties and the potassium diclofenac (KDF) release profile of hydrogels of gum arabic (GA), N′,N′‐dimethylacrylamide, and methacrylic acid. In order to convert GA into a hydrogel, the polysaccharide was vinyl‐modified with glycidyl methacrylate. The hydrogels showed pH‐responsive swelling changes, which were more expressive in the basic environment. Release data of KDF were adjusted to a diffusion‐based kinetic model that provides an important insight on affinity of the drug for hydrogel and solvent, which may be the leading parameter for release of guest molecules from polymers. The KDF release from the hydrogels into simulated intestinal fluid decreases when the amount of modified GA increases. This was demonstrated to be due to the higher affinity of KDF for GA‐richer hydrogel, which makes the anti‐inflammatory release less favorable. The analysis of released drug half‐time (t_1/2 = 16.10 and 21.51 h) indicated sustained release characteristics. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43319.