Preparation and release behavior of carboxymethylated chitosan/alginate microspheres encapsulating bovine serum albumin

Microspheres were prepared from carboxymethylated chitosan (CM‐chitosan) and alginate by emulsion phase separation. Their structure and morphology were characterized with IR spectroscopy and scanning electron microscopy. Bovine serum albumin (BSA) was encapsulated in the microspheres to test the release behavior. The swelling behavior, encapsulation efficiency, and release behavior of BSA from the microspheres at different pHs and with a pH‐gradient condition were investigated. The BSA encapsulation efficiency was calculated to be 80%. The degree of swelling of the microspheres without BSA loaded at pH 7.2 was much higher than that at pH 1.0. The encapsulated BSA was quickly released in a Tris–HCl buffer (pH 7.2), whereas a small amount of BSA was released under acid conditions (pH 1.0) because of the strong electrostatic interaction between ? NH₂ groups of CM‐chitosan and ? COOH groups of alginic acid and a dense structure caused by a Ca²⁺ crosslinked bridge. For the simulation of the processing of the drug under the conditions of the intestine, the microspheres were tested in a pH‐gradient medium, in which an acceleration of the release occurred at pH 7.4 after a lag time at a low pH (5.8–6.8). At pH 7.4, a large amount of BSA was released from the microspheres in a short time because of the rapid swelling of the microspheres. However, the release only depended on the diffusion of BSA at relatively low pHs, this resulted in a relatively low release. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 878–882, 2004     

Structure and control release of chitosan/carboxymethyl cellulose microcapsules

Microcapsules of chitosan/sodium carboxymethyl cellulose (NaCMC) were successfully prepared using a novel method of emulation phase separation. Their structure and morphology were characterized by infrared spectroscopy (IR), scanning electron microscopy (SEM), and X-ray diffraction. Bovine serum albumin (BSA) was encapsulated in the microcapsules to test their release behavior. The swelling behavior, encapsulation efficiency, and release behavior of the microcapsules with different chitosan contents and pH conditions were investigated. The results indicated that the microcapsules have a high encapsulation efficiency (75%) and a suitable size (20–50 μm). The BSA in the microcapsules was speedily released at pH 7.2, namely, in intestinal fluid. The BSA release was reduced with increase of the chitosan content from 17 to 38% in the microcapsules. Acid-treated microcapsules have a compact structure, owing to a strong electrostatic interaction caused by —NH₂ groups of chitosan and —COOH groups of CMC, and the encapsulated BSA was hardly released at pH 1.0, namely, in gastric juice. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 82: 584–592, 2001     

Alginate/carboxymethyl chitosan composite gel beads for oral drug delivery

This paper reports the synthesis of pH-sensitive gel beads derived from alginate (SA) and carboxymethyl chitosan (CMCS) for drug delivery. The composite SA/CMCS gel beads were prepared by dual ionic gelation: one ionic gelation between SA and Ca²⁺ and another one between CMCS and β-Sodium glycerophosphate (β-GP). The structure properties of hydrogel beads were characterized by SEM, IR and TG technique. The influence of the polymer composition and cross-linkers on the gel swelling property was investigated. When the concentration of CMCS and SA were 3 % and the volume ratio was 1:2, the swelling rate of gel beads crosslinked by β-GP and CaCl₂ solution can increase up to 31.2 and the swelling time can reach 10.5 h. In the drug release study, bovine serum albumin (BSA) was chosen as model drugs. The results indicated that BSA released slowly from the gel beads at pH 1.2 and the release ratio was about 10 %. At pH 7.4, the amounts of BSA released increased significantly as compared to those released at pH 1.2 and the total release time was extended to 11 h. The composite gel system demonstrates sustained release profile and pH sensitivity, which can be considered as good candidates for oral drug delivery systems.     

Chitosan/calcium–alginate beads for oral delivery of insulin

A mild chitosan/calcium alginate microencapsulation process, as applied to encapsulation of biological macromolecules such as albumin and insulin, was investigated. The microcapsules were derived by adding dropwise a protein-containing sodium alginate mixture into a chitosan–CaCl₂ system. The beads containing a high concentration of entrapped bovine serum albumin (BSA) as more than 70% of the initial concentration were achieved via varying chitosan coat. It was observed that approximately 70% of the content is being released into Tris-HCl buffer, pH 7.4 within 24 h and no significant release of BSA was observed during treatment with 0.1M HCl pH 1.2 for 4 h. But the acid-treated beads had released almost all the entrapped protein into Tris-HCl pH 7.4 media within 24 h. Instead of BSA, the insulin preload was found to be very low in the chitosan/calcium alginate system; the release characteristics were similar to that of BSA. From scanning electron microscopic studies, it appears that the chitosan modifies the alginate microspheres and subsequently the protein loading. The results indicate the possibility of modifying the formulation in order to obtain the desired controlled release of bioactive peptides (insulin), for a convenient gastrointestinal tract delivery system. © 1996 John Wiley & Sons, Inc.     

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     

Alginate/BSA/montmorillonite composites with enhanced protein entrapment and controlled release efficiency

Novel pH sensitive alginate–protein–clay composite beads were investigated for the in vitro oral delivery of the model protein, bovine serum albumin (BSA). X-ray diffraction (XRD) results revealed that BSA enter between layers of montmorillonite (MMT) by expanding interlayer distance and finally an exfoliated structure forms in the alginate hydrogel. MMT incorporation increases protein entrapment efficiency to 78%, compared to 40% of conventional alginate beads. The release ratio of BSA from composite beads is 9–13% depending on MMT contents after around a 2 h stay in gastric fluid. More importantly, no BSA release is detected until 60–90 min after the first contact time of beads with gastric solution. The presence of clay in alginate beads prevents burst release in higher pH of intestine by slowing release rate of BSA to 45–55% within around 9 h, resulting in a potential matrix for intestinal release of protein drugs.     

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.     

Dynamics of controlled release of potassium nitrate from a highly swelling binary polymeric blend of alginate and carboxymethyl cellulose

Highly water absorbing and homogeneous binary biopolymeric blends in bead form were prepared of calcium alginate and carboxymethyl cellulose by solution cast method. The prepared blends were evaluated for controlled delivery of KNO₃ taking it as a model agrochemical. The beads characterized by Fourier transform infrared spectroscopy (FTIR) and Scanning electron microscopy (SEM) were used to investigate the molecular structure and morphology of beads. The swelling experiments were performed for different compositions of beads and at varying pH and temperature of the aqueous media. The release experiments were performed under static and varying experimental conditions and the release data obtained were conductometrically fitted to Ficks equation to evaluate diffusion coefficients of released KNO₃. The release results were further analyzed by Ficks power law equation, and the possible mechanisms of KNO₃ release were explored at different experimental conditions. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007     

Mechanical and drug release properties of alginate beads reinforced with cellulose

The limited efficacy of alginate as a drug carrier is thought to be due to its poor mechanical stability and durability. In the present study, cellulose/alginate (C/Alg) beads were successfully fabricated by droplet extrusion/precipitation method for drug release of metformin hydrochloride (MH). To evaluate the effects of three different cellulose fibers, including cotton linter (CL), microcrystalline cellulose (MCC), and microfibrillated cellulose (MFC) on the stability and drug release property, the structure and properties of composite beads were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), and also mechanical properties, thermogravimetric analysis (TGA), swelling and in vitro drug release properties were assessed. The results indicated that the incorporation of cellulose enhances the mechanical properties and thermal stability of alginate matrix. The peak force values of the alginate beads increased from 4.07 ± 1.64 kg to 11.87 ± 2.61 kg with adding 30 wt % MFC. Cellulose with micro‐ and nanostructures improved the encapsulation efficiency and inhibited the rapid release of alginate in simulated intestinal fluid. It was suggested that cellulose could be an effective modifier to adjust the swelling property, mechanical property, and drug release behavior of alginate beads. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 44495.     

膨润土对海藻酸钠/壳聚糖凝胶微球性能的影响

为了得到一种对啶虫脒具有高负载率和良好的缓释性能的农药载体,以膨润土作为吸附剂,利用壳聚糖的成膜性,采用挤出外源凝胶法制备了啶虫脒凝胶微球。并通过FTIR、SEM、TG、溶胀实验和释药实验对其结构、形貌和性能进行表征。结果表明,所制得的凝胶微球的粒径为1.42～1.71 mm,膨润土可提高微球粒径与球形度,使啶虫脒的载药率和包封率分别由原来的4.16%和36.36%提升为4.91%和63.01%。壳聚糖与海藻酸钠通过静电作用形成了聚电解质复合物,辅助了钙离子交联,使啶虫脒的载药率和包封率分别由原来的4.16%和36.36%提升为5.23%和54.29%。膨润土表面含有大量的羟基,与海藻酸钠和壳聚糖形成氢键作用,可有效抑制海藻酸钙的大量溶胀,提高其缓释性能。     

双乳化-凝胶法制备单分散海藻酸钙微球及其载BSA研究

采用双乳化-凝胶法制备了单分散的海藻酸钙凝胶微球,并通过正交试验系统考察了海藻酸钠浓度、氯化钙浓度、表面活性剂浓度、搅拌速度和油水比对海藻酸钙凝胶微球粒径及形貌的影响。在优化的条件下,制备出了平均粒径为4μm、单分散和球形度好的海藻酸钙凝胶微球。包埋模型药物牛血清白蛋白(BSA)的过程中,以去离子水作为洗涤液洗涤海藻酸钙微球时,BSA的包封率仅为13%左右;当水洗液的pH值为3.2时,BSA的包封率提高到66%左右,载药率可达16%,这是海藻酸钙pH值响应溶胀和BSA与海藻酸盐之间静电作用的结果。微球中BSA的体外释放曲线表明,该系统具有在模拟胃液中释药速率慢、释药量低、模拟肠液中释药迅速的特性。因此,双乳化-凝胶法制备海藻酸钙微球有望成为制备蛋白类药物控释制剂的一种新方法,以达到靶向快速给药的目的。     

Chitosan/polyethylene glycol–alginate microcapsules for oral delivery of hirudin

A mild chitosan/calcium alginate microencapsulation process, as applied to encapsulation of biological macromolecules such as albumin and hirudin, was investigated. The polysaccharide chitosan was reacted with sodium alginate in the presence of calcium chloride to form microcapsules with a polyelectrolyte complex membrane. Hirudin-entrapped alginate beads were further surface coated with polyethylene glycol (PEG) via glutaraldehyde functionalities. It was observed that approximately 70% of the content is being released into Tris-HCl buffer, pH 7.4 within the initial 6 h and about 35% release of hirudin was also observed during treatment with 0.1 M HCl, pH 1.2 for 4 h. But acid-treated capsules had released almost all the entrapped hirudin into Tris-HCl, pH 7.4 media within 6 h. From scanning electron microscopic and swelling studies, it appears that the chitosan and PEG have modified the alginate microcapsules and subsequently the protein release. The microcapsules were also prepared by adding dropwise albumin-containing sodium alginate mixture into a PEG– CaCl₂ system. Increasing the PEG concentration resulted in a decrease rate of albumin release. The results indicate the possibility of modifying the formulation to obtain the desired controlled release of bioactive peptides (hirudin), for a convenient gastrointestinal tract delivery system. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 70: 2143–2153, 1998     

Antibacterial activity of chitosan–alginate sponges incorporating silver sulfadiazine: Effect of ladder‐loop transition of interpolyelectrolyte complex and ionic crosslinking on the antibiotic release

Hydrogel membranes prepared from polyelectrolyte complex (PEC) have been used for repair of wounds and controlled antibacterial release. A simple method, based on homogenizing interpolyelectrolyte complex, has been developed to prepare a chitosan–alginate sponge with high stability. The spongelike chitosan–alginate hydrogel can be used as a wound dressing for the sustained release of silver sulfadiazine (AgSD) in a controlled way. In this study, we evaluated the effect of electrolyteic properties of chitosan and alginate on the characteristics of the prepared chitosan–alginate PEC. All types of the spongelike chitosan–alginate hydrogels exhibited superabsorbent properties. However, only the chitosan–alginate hydrogel prepared by the interpolyelectrolyte complex of alginate with low pH of chitosan, and that prepared by the interpolyelectrolyte complex of chitosan with high pH of alginate, can keep their stability after swelling in PBS solution. FTIR analysis suggests that the protonated amino groups on chitosan and the ionized carboxylic groups on alginate should be responsible for the formation of a stable ladder‐type of chitosan–alginate PEC. Ionic crosslinking is helpful to increase the stability of the loop‐type of chitosan–alginate PEC. The release of AgSD from chitosan–alginate PEC sponges could be controlled by the variation of ladder‐loop structural transition of chitosan–alginate PEC and the ionic crosslinking of the chitosan–alginate complex. The antibacterial ability of AgSD‐incorporated PEC sponges was examined in agar plate against Pseudomonas aeruginosa and Staphylococcus aureus. The result suggests that the PEC sponges containing antimicrobial agents should effectively suppress bacterial proliferation to protect the wound from bacterial invasion. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 538–549, 2005     

Controlled delivery of diclofenac sodium from calcium alginate beads loaded with a drug–resin complex

This study focused on a detailed investigation of the release of the nonsteroidal anti‐inflammatory drug diclofenac sodium from strong anion resin particles, entrapped in ionotropically crosslinked alginate beads, in simulated gastric and intestinal fluids at 37°C. The percentage drug released from the beads in media of various pH values in 6 h was nearly 68.8 ± 2.6%, whereas, for the same duration, the drug–resin complex particles released 87.6 ± 3.2% drug. The amount of drug released from the beads depended on the composition of the beads, their degree of crosslinking, and the size of the crosslinker ions. Finally, the value of the release exponent was found to be 0.56, which thus indicated the diffusion‐controlled mechanism of drug release from the alginate beads © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Controlled release formulations of carbaryl based on copper alginate,barium alginate,and alginic acid beads

A controlled release system for reducing environmental impact was produced by encapsulating the pesticide carbaryl (Carb) in the alginate beads. The various bead formulations were prepared by using sodium alginate (NaAlg) as a polymer, CuCl₂, BaCl₂ as a crosslinking agent, and HCl as a linking agent. The surface morphology of prepared beads was characterized with scanning electron microscopy (SEM). SEM confirmed the spherical nature and surface morphology of the particles. Bead characteristics, such as Carb entrapment efficiency, particle size, swelling degree, and Carb release kinetics, were determined. The effects of crosslinker or linker concentration, type, and carbaryl/sodium alginate (Carb/NaAlg) ratio on Carb release from the beads were investigated for 20 days at 25°C. It was observed that Carb release from the beads increased with the increase of Carb/NaAlg ratio whereas decreased with the increase of crosslinker concentration. At the end of 20 days, the Carb release from alginic acid beads was found to be higher than that of copper alginate (Cu‐Alg) and barium alginate (Ba‐Alg) beads. The swelling measurements of the beads supported the release results. Release kinetics were described by Fickian and non‐Fickian approaches. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 4245–4253, 2006     

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.     

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     

海藻酸钙/埃洛石载药微球的制备与缓释盐酸二甲双胍性能

缓释可提高药物利用率,降低其毒副作用。采用交联法制备了海藻酸钙/埃洛石载药微球,以载药微球对盐酸二甲双胍（MH）药物的包封率和缓释效果为考察对象,研究了载药微球的制备工艺和缓释性能,并通过SEM、FTIR和TGA对其结构进行了表征。结果表明：在交联温度为0℃、海藻酸钠用量为1g、埃洛石添加量为2g时,能得到较优的载药微球包封率（79.23%）。上述条件下制得的复合载药微球在pH=6.8的磷酸盐缓冲液中能有效缓释,且720min后缓释度可达85.83%,说明其具有较好的pH敏感性和缓释效果。SEM表明海藻酸钙颗粒与埃洛石在载药微球内部形成复合结构,FTIR表明MH主要以物理包埋的形式于载药微球中,TGA表明添加埃洛石可以提高复合材料在200℃以上的热稳定性。     

Tunable transport of glucose through ionically‐crosslinked alginate gels: Effect of alginate and calcium concentration

Alginate beads have numerous biomedical applications, ranging from cell encapsulation to drug release. The present study focuses on the controlled release of glucose from calcium‐alginate beads. The effects of alginate concentrations (1–6 wt %) and calcium chloride concentrations (0.1–1.0M) on glucose release from beads were examined. It was found that the time required for complete glucose release from beads could be tuned from 15 min to over 2 h, simply by varying alginate and calcium chloride concentrations in beads. For calcium‐alginate beads with sodium alginate concentrations of 1–4 wt %, higher sodium alginate concentrations lead to more prolonged release of glucose and thus a smaller value of a rate constant k, a parameter shown to be proportional to the diffusion coefficient of glucose in the alginate gel. For beads with sodium alginate concentrations of 4–6 wt %, there was no statistically significant difference in k values, indicating a lower limit for glucose release from calcium‐alginate beads. Similarly, higher calcium chloride concentrations appear to extend glucose release, however, no conclusive trend can be drawn from the data. In a 50 : 50 mixture of calcium‐alginate beads of two different alginate concentrations (1 and 4 wt %), glucose release showed a two‐step profile over the time range of 20–50 min, indicating that the pattern and time of glucose release from beads can be tuned by making combinations of beads with varying alginate and/or calcium chloride concentrations. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

复相乳化法制备海藻酸钙微球及其释放行为

采用复相乳化法制备了载牛血清白蛋白(BSA)的海藻酸钙微球,通过正交实验和单因素分析,以BSA包埋率、微球的载药率和平均粒径为考察指标,优化了该方法的制备参数,使最终制备的微球平均粒径小于10 mm,球形度较好,包埋率约70%,载药率达4%. 随着海藻酸钠质量分数的降低和BSA质量的增大,微球的包埋率下降、载药率升高、平均粒径减小. 微囊化BSA的体外释放曲线表明,该系统存在pH响应特性,尤其在磷酸缓冲液中,被包埋BSA的释放速率较快. 电泳结果表明,BSA的分子结构并未受制备过程的影响. 因此,该微囊化方法有望用于蛋白类药物的控释制剂,使其免受胃酸等的破坏,达到肠部释药的目的.