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     

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     

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/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.     

Effect of preparation method on the capture and release of biologically active molecules in chitosan gel beads

Model bioactive compounds with different molecular and functional characteristics were entrapped in gel beads prepared by polyelectrolyte complexation of chitosan and pentasodium tripolyphosphate (TPP). Three compounds of interest to the food and biomedical industries were tested: (1) lysine, (2) bovine serum albumin (BSA), and (3) β‐galactosidase. Effects of the compound concentration in the initial chitosan solution, pH of the curing solution, and length of the curing phase on the capture efficiency were evaluated. Release rates for lysine and BSA into a phosphate buffer, distilled water, and a synthetic ocean solution were observed, and the activity of the entrapped β‐galactosidase was determined. The capture efficiencies for lysine and BSA decreased as the concentration increased. The capture efficiency for lysine ranged from 90% at pH 5 to 20% at pH 8.6. There was no significant effect of the release media on the rate of release. BSA and lysine release reached 90% of the maximum after 100 and 50 min, respectively. The capture efficiency of β‐galactosidase was not affected by the pH of TPP; however, enzyme activity in the beads decreased as the pH increased. Beads prepared in the pH 8.6 TPP solution had significantly higher rates of enzyme release over time. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 84: 405–413, 2002; DOI 10.1002/app.10393     

Beta cyclodextrin–insulin‐encapsulated chitosan/alginate matrix: Oral delivery system

Cyclodextrins (CD) form inclusion complexes with many drug molecules. The complexed drugs have increased bioabsorption in in vivo system. We have attempted to complex insulin with β‐Cyclodextrin (BCD) and encapsulate in the chitosan/calcium alginate matrix. For drug release studies insulin complexed with BCD for 20 min and that complexed with BCD for 150 min have been used for encapsulation in the chitosan/calcium alginate matrix. The two matrices seem to have different drug release profiles in simulated intestinal medium (pH 7.4) It appears that drug release from the 20‐min BCD complexed system encapsulated in the chitosan/calcium alginate matrix begins only after an hour, where, being released from the 150‐min BCD complexed system it begins in the first hour itself. Also, aggregation of the insulin molecules seems to be reduced by the complexation of the drug with BCD. Another noticeable fact is the change in the loading character, which is found to be inversely related to the concentration of BCD when it is above the stoichiometric equivalent of the drug. In an attempt to increase the payload of the drug in the matrix, the pH of the processing medium consisting of calcium chloride and chitosan is varied. It is found that the encapsulation efficiency increases as the pH is decreased from 6.0 to 4.0. Another way of increasing the loading is studied by decreasing the concentration gradient of insulin in the processing alginate solution and the crosslinking medium consisting of chitosan/calcium chloride. Preliminary animal studies on rabbits seem to be promising. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 75: 1089–1096, 2000     

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     

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     

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.     

Dual crosslinked carboxymethyl sago pulp/pectin hydrogel beads as potential carrier for colon‐targeted drug delivery

Carboxymethyl sago pulp (CMSP)/pectin hydrogel beads were synthesized by calcium crosslinking and further crosslinked by electron beam irradiation to form drug carrier for colon‐targeted drug. Sphere‐shaped CMSP/pectin 15%/5% hydrogel beads is able to stay intact for 24 h in swelling medium at pH 7.4. It shows pH‐sensitive behavior as the swelling degree increases as pH increases. Fourier transform infrared spectroscopy analysis confirmed the absence of chemical interaction between hydrogel beads and diclofenac sodium. Differential scanning calorimetric and X‐ray diffraction studies indicate the amorphous nature of entrapped diclofenac sodium. The drug encapsulation efficiency is up to about 50%. Less than 9% of drug has been released at pH 1.2 and the hydrogel beads sustain the drug release at pH 7.4 over 30 h. This shows the potential of CMSP/pectin hydrogel beads as carrier for colon‐targeted drug. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43416.     

Hemolglobin encapsulation in chitosan/calcium alginate beads

A mild chitosan/calcium alginate encapsulation process, as applied to encapsulation of hemoglobin, was investigated. The first procedure consisted of adding dropwise a hemoglobin-containing sodium alginate mixture in a chitosan solution, then hardening the interior of capsules thus formed, in the presence of CaCl₂. In the second method, the droplets were directly pulled off in a chitosan–CaCl₂ mixture. Both procedures led to beads containing a high concentration in entrapped hemoglobin as more than 90% of the initial concentration (150 g/L) were retained inside the beads provided that the chitosan concentration was great enough. The molecular weight of chitosan (M?_u 245,000 or 390,000) and the pH of its solution (2, 4, or 5.4) had only a slight effect, the best retention being obtained with beads prepared at pH 5.4. The hemoglobin release during the bead storage in water was found to depend on the conditions of their formation and especially on the chitosan molecular weight. The best retention during storage in water was obtained with beads prepared with the high M?_u chitosan solution at pH 2. Considering the total loss in hemoglobin during the bead formation and after 1 month of storage in water, the best results were obtained by preparing the beads in an 8 g/L solution of a 390,000 chitosan at pH 4 (less than 7% of loss with regard to the 150 mg/L initial concentration). © 1994 John Wiley & Sons, Inc.     

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.     

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.     

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     

包埋紫草细胞的海藻酸钙凝胶扩散性能

用非稳态法测定了充分搅拌条件下在未包埋紫草细胞和包埋紫草细胞的海藻酸钙凝胶珠粒体系内蔗糖溶液浓度的瞬间变化情况。结果表明，海藻酸钠浓度、氯化钙浓度和紫草细胞包埋量对蔗糖扩散有明显影响，有效扩散系数Ｄｅ随着海藻酸钠浓度、氯化钙浓度和紫草细胞包埋量的提高而下降．     

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。     

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.     

Controlled release of berberine hydrochloride from alginate microspheres embedded within carboxymethyl chitosan hydrogels

Berberine hydrochloride is a natural medicine with wide clinical application. In this article, berberine hydrochloride was entrapped into alginate microspheres via an emulsification/gelation method. The size distribution of the microspheres was determined by a laser particle sizer. Drug distribution within the microspheres was determined by confocal laser scanning microscopy. Those drug‐loaded microspheres were further entrapped into carboxymethyl chitosan (CMC) hydrogel to form a new drug‐delivery system (DDS). The surface morphology of the DDS was observed using metallographic microscopy and scanning electron microscopy (SEM). The compression strength of the DDSs with alginate microspheres was found significantly higher than that of the pure hydrogel. The drug‐release performances of the DDS in phosphate buffer solution (PBS, pH 7.4), saline solution (pH 6.3), and hydrochloric acid solution (HAS, pH 1.2) were also studied. Decay of the DDS in PBS within 72–80 h results in a faster release; however, the steady release in saline solution could last for all the testing period without cleavage of the DDS. In HAS, because of the shrinkage of the DDS, release is fast in the first period and remains steady later. The DDS exhibits prospective in controlled steady release of drugs. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Combined method of complex coacervation and electrospray for encapsulate preparation

Encapsulate beads composed of alginate and chitosan as shell and bovine serum albumin (BSA) as core were prepared by combined method of complex coacervation and electrospray. The main objective of this work was to produce mono‐sized and spherical capsule of chitosan‐alginate with controlled sizes of capsules and shell. However, the effects of applied voltage, flow rate, and molecular weight of chitosan were investigated on the size, size distribution, membrane thickness of the prepared capsules, as well as the release rate of BSA. The results revealed that by the method developed in this study, it was possible to produce spherical capsules with controlled size and narrow size distribution. Increasing the voltage and decreasing the flow rate reduced the radius of capsule and its shell thickness from 2.09 mm to 750 μm and from 1.31 mm to 490 μm, respectively. Furthermore, the molecular weight of chitosan had no significant effect on the capsules' size and the release rate of BSA, whereas the rate of BSA release was increased with increase of the voltage. The later effect would be due to the increase of shell porosity at the higher voltages. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Optimization of lactic acid production from whey by L casei NRRL B‐441 immobilized in chitosan stabilized Ca‐alginate beads

The production of lactic acid from whey by Lactobacillus casei NRRL B‐441 immobilized in chitosan‐stabilized Ca‐alginate beads was investigated. Higher lactic acid production and lower cell leakage were observed with alginate–chitosan beads compared with Ca‐alginate beads. The highest lactic acid concentration (131.2 g dm^?3) was obtained with cells entrapped in 1.3–1.7 mm alginate–chitosan beads prepared from 2% (w/v) Na‐alginate. The gel beads produced lactic acid for five consecutive batch fermentations without marked activity loss and deformation. Response surface methodology was used to investigate the effects of three fermentation parameters (initial sugar, yeast extract and calcium carbonate concentrations) on the concentration of lactic acid. Results of the statistical analysis showed that the fit of the model was good in all cases. Initial sugar, yeast extract and calcium carbonate concentrations had a strong linear effect on lactic acid production. The maximum lactic acid concentration of 136.3 g dm^?3 was obtained at the optimum concentrations of process variables (initial sugar 147.35 g dm^?3, yeast extract 28.81 g dm^?3, CaCO₃ 97.55 g dm^?3). These values were obtained by fitting of the experimental data to the model equation. The response surface methodology was found to be useful in optimizing and determining the interactions among process variables in lactic acid production using alginate–chitosan‐immobilized cells. Copyright © 2005 Society of Chemical Industry