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.     

Polyelectrolyte complexes of sodium alginate with chitosan or its derivatives for microcapsules

Chitosan, a cationic polysaccharide, was heterogeneously deacetylated with a 47% sodium hydroxide solution and followed by a homogeneous reacetylation with acetic anhydrides to control the N-acetyl content of the chitosan having a similar molecular weight. The chitosans having different degrees of N-acetylation were complexed with sodium alginate, an anionic polysaccharide, and the formation behavior of polyelectrolyte complexes (PECs) was examined by the viscometry in various pH ranges. The maximum mixing ratio (R_max) increased with a decrease in the degree of N-acetylation of the chitosan at the same pH, and with a decrease in pH at the same degree of N-acetylation. Similarly, N-acylated chitosans were also prepared. The N-acyl chitosans scarcely affected the formation behavior of PECs with sodium alginates. For the application of the PECs produced, the microencapsulation of a drug was performed and the release property of drug was tested. The microcapsules were prepared in one step by the extrusion of a solution of guaifenesin and sodium alginate into a solution containing calcium chloride and chitosan through interpolymeric ionic interactions. The drug release during the drug-loaded microcapsules storage in saline was found to depend on the pH where the microcapsules were formed and the kind of N-acyl groups introduced to the chitosan. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 63: 425–432, 1997     

重组人粒细胞-巨噬细胞集落刺激因子壳聚糖-海藻酸钠微囊的制备

目的以壳聚糖和海藻酸钠为原料,制备重组人粒细胞-巨噬细胞集落刺激因子(rhGM-CSF)微囊,探讨开发口服蛋白多肽类药物的可行性。方法以rhGM-CSF为药物模型,通过壳聚糖与海藻酸钠聚电解质的络合反应制备rhGM-CSF壳聚糖-海藻酸钠微囊,观察微囊的形态大小,测定其包封率,不同pH值下的膨胀度和体外释放率。结果制备的rhGM-CSF壳聚糖-海藻酸钠微囊呈均匀、完整的圆球形,平均直径1mm左右;包封率达80%以上;在模拟肠液(磷酸盐缓冲液,pH7.4)中浸泡3h,膨胀度可达600%,药物释放率达85%以上。结论壳聚糖-海藻酸钠微囊具有肠溶控释作用,有望成为rhGM-CSF等蛋白类口服药物的控释载体。     

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     

干扰素壳聚糖/海藻酸钠微囊控释制剂载体的初步研究

目的研究蛋白质类药物口服控释给药的可行性。方法壳聚糖与海藻酸钠通过聚电解质络合反应制备成壳聚糖/海藻酸钠微囊,以干扰素为模型药物,研究不同pH条件下,药物的控制释放情况。结果微囊的粒径为1 mm左右,其干扰素的包封率达90.0%以上,微囊在模拟胃液(pH1.0)中,3h药物释放不到5%;在模拟肠液(pH7.4)中,3h药物释放近100%。结论壳聚糖/海藻酸钠微囊有可能成为蛋白质类药物口服控释制剂的载体。     

制备CS-Ca2+-SAL中空凝胶球及其对碳纳米的缓释行为

将海藻酸钠溶液(SAL)滴入壳聚糖-钙(CS-Ca2+)分散溶液中，海藻酸钠与壳聚糖分子链之间发生物理交联的同时，也与钙离子进行同步交联，可一步制备毫米级壳聚糖-钙-海藻酸钠(CS-Ca2+-SAL) 水凝胶球。通过调控原料用量比例、滴加速度和方式，成功制备内部中空，球壁均匀，表面致密的凝胶球。以荧光性碳纳米点为标记物，考察凝胶球的溶胀性能和缓释性能。结果表明，凝胶球在中性水溶液中12h溶胀率可达26.09%，并能保持完整球形结构。溶胀性能受到pH的影响显著，处于pH=1.2的溶液体系中溶胀率最小，处于pH =6.8溶液环境中溶胀率最大。荧光凝胶球在pH=7.1的Tris-HCl缓冲液中的释放率实验结果表明，对碳纳米的释放模型最符合Hixon-crowell溶蚀方程，说明凝胶球的缓释机制以溶蚀为主，扩散为辅。     

Poly(L‐histidine)‐chitosan/alginate complex microcapsule as a novel drug delivery agent

Novel poly(L ‐histidine)‐chitosan/alginate complex microcapsules were prepared from biodegradable polymers poly(L ‐histidine) (PLHis) in the presence of chitosan at acetate buffer solution pH 4.6. Microcapsules obtained are spherical and well‐dispersed with a smooth surface and a narrow size distribution. The microcapsules can encapsulate the protein model drug hemoglobin (Hb) efficiently. The results show that the complex microcapsules with low, medium, or high molecular weight of chitosan (0.05%, w/v), the highest encapsulation efficiencies obtained are 91.3%, 85.9%, and 94.2% with loading efficiencies of 47.8%, 44.3%, and 39.7%, respectively. The release profiles indicate that Hb‐loaded microcapsules conform to first‐order release kinetic in whole procedure, and 84.8%, 71.4%, and 87.3% of Hb were released during 72‐h incubation in PBS pH6.8 for microcapsules with low, medium, and high molecular weight chitosan (0.05%, w/v), respectively. The results also indicate that particle size and drug loading efficiency have a significant influence on the release profile and encapsulation efficiency. Our results reveal that the PLHis‐chitosan/alginate complex microcapsules are able to encapsulate and release Hb and are potential carriers for protein drugs. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

二甲酸钾微胶囊的构建与缓释抑菌性

以自制沸石分子筛为载体,通过水热法将二甲酸钾负载形成芯材,海藻酸钠、壳聚糖为壳材,以复凝聚法制备出缓释微胶囊。通过FTIR、XPS对微胶囊进行了结构表征,通过缓释及抑菌率测试对其性能进行表征。结果表明:沸石分子筛与二甲酸钾之间可形成复配效应,构成微胶囊的芯材;壳聚糖和海藻酸钠发生静电作用,形成聚电解质膜,构成微胶囊的壳材;制备的微胶囊在pH=2.0的模拟胃环境中稳定,在pH=7.2的模拟肠道环境中二甲酸钾得到了释放,并在3 h内可释放完全;微胶囊包封率为68.33%,二甲酸钾的释放量为137.50 mg/g。微胶囊对大肠杆菌的生长具有一定的抑制作用,并随着微胶囊浓度的增大对大肠杆菌的抑制率呈现增长的趋势,最高抑菌率可以达到85%。     

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.     

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     

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     

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     

海藻酸钙/聚精氨酸微胶囊的载药和缓释性能

采用乳化-固化法,制备海藻酸钙/聚精氨酸微胶囊。分别考察不同聚精氨酸相对分子质量、海藻酸钠浓度、氯化钙浓度对海藻酸钙-聚精氨酸微胶囊载药量以及牛血红蛋白缓释性能的影响。实验结果表明,中相对分子质量聚精氨酸制备的海藻酸钙/聚精氨微胶囊的载药量较高并且具有更好的缓释效果。随着海藻酸钠浓度的升高,海藻酸钙/聚精氨微胶囊的载药量降低;随着氯化钙浓度的升高,海藻酸钙/聚精氨微胶囊的载药量先升高后略有降低;然而,以上因素对海藻酸钙/聚精氨微胶囊的缓释性能均无明显影响。     

Preparation of polyethersulfone–alginate microcapsules for controlled release

In this study, polyethersulfone (PES)–alginate microcapsules were prepared for drug‐controlled release, and vitamin B₁₂ (VB₁₂), rifampicin (RFP), and bovine serum albumin (BSA) were used as model drugs. Different microcapsules were prepared by the variation of the crosslinking degree of alginate and the variation of the chemical components of the microcapsule membrane, including the PES and polyethylene glycol (PEG) contents. Systematic experiments were carried out to study their influences on the release profile of the model drugs. The results showed that with the increase of the crosslinking degree of the alginate, the drug release rate increased; whereas with the increase of the PES concentration used to prepare the microcapsule membrane, the drug release rate decreased. The contents of the PEG in the microcapsule membrane also affected the drug release. This study enriched the methodology of the fabrication of the microcapsules, and the microcapsules may have a potential use for controlled release. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

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

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

Preparation of phycocyanin microcapsules and its properties

Phycocyanin was microencapsulated by an extrusion method using alginate and chitosan as coating materials. This work was aimed to optimize the encapsulation process, characterize the physicochemical properties of microcapsules, and evaluate the storage stability and in vitro release performance. The optimum process conditions for preparing microcapsule gained from the single factor experiments were as follows: alginate content 2.5%, ratio of phycocyanin to alginate 1.5:1, content of calcium chloride 2.5%, and chitosan content 2.0%. Phycocyanin/alginate/chitosan microcapsules (PACM) were found to have compact spherical shape with mean diameters of 1.03 mm, whereas phycocyanin/alginate microspheres (PAM) were internal porous spherical appearances with mean diameters of 1.81 mm. Storage stability study showed that encapsulation by alginate and chitosan conferred greater ability to phycocyanin against temperature during storage. In vitro release study revealed that both PAM and PACM could be resistant against acidic environment, and would rapidly release phycocyanin under mild alkali condition. The sustained-release profile of phycocyanin from PACM was superior to that from PAM.     

高压静电法制备载阿糖胞苷海藻酸钙-几丁聚糖微胶囊

采用海藻硅酸钠和几丁聚糖为原料制备海藻酸钙-几丁聚糖药物缓释微胶囊,初步考察了载阿糖胞苷微胶囊的制备以及不同分子量几丁聚糖、静/动态载药方式对阿糖胞苷释放性能的影响。     

Fabrication of sustained‐release and antibacterial citronella oil‐loaded composite microcapsules based on Pickering emulsion templates

In this work, the citronella oil (CTO)‐loaded composite microcapsules with hydroxyapatite (HAp)/quaternary ammonium salt of chitosan (HACC)/sodium alginate (SA) shells are facilely and effectively fabricated by templating citronella oil‐in‐water Pickering emulsions, which are stabilized with HAp nanoparticles. The microcapsule composite shells are prepared by the electrostatic adsorption of HACC and SA, and then chelation interaction of alginate and Ca²⁺ ions released from HAp nanoparticles. Scanning electronic microscope observation shows that the microcapsules have a spherical shape. Thereafter, Fourier transform infrared spectroscopy and thermal gravimetric analysis results indicate that CTO is successfully loaded into the microcapsules, and the related CTO‐loaded microcapsules possess the thermal stability. Moreover, the in vitro release study of CTO shows that the microcapsules have sustained release activity, and the related CTO release profiles can be well described by Rigter–Peppas model. The antimicrobial assays of microcapsules display the antibacterial effect of CTO‐loaded microcapsules against Staphylococcus aureus and Escherichia coli. Overall, this study opens up new potentiality for unstable active ingredient as an environmental friendly and ingenious microencapsulation in food and agriculture applications. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46386.     

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     

载牛血清白蛋白凝胶微球体液环境下释药性能的研究

研究可在体内缓释并口服的蛋白多肽类药物是国内外医药界目前广泛关注的问题。利用毒性较低但力学性能差的海藻酸钠和水溶性较低但机械性能良好的聚乙烯醇共混制备凝胶微球,在模拟体液环境(p H=7.4),以空白微球作对照,来对载牛血清白蛋白凝胶微球进行释药性能研究,可看到凝胶微球在白蛋白药物的控释方面是有良好效果的,4 h时可达到牛血清白蛋白药物释放增速最快,12 h时牛血清白蛋白药物累计释放达到55%,这可以为可口服的蛋白多肽类药物口服体内靶向缓释的临床应用提供相关的参考依据,具有重大意义。