Influence of coating on the triamcinolone release of alginate chitosan beads for colonic drug delivery

The aim of this study was to evaluate the effect of coating of alginate-chitosan (AL:CS) beads on the colonic drug delivery. The AL:CS systems containing triamcinolone (TC) were coated with the HPMCP and Eudragit? L100 by immersion and by spraying methods. The drug release profile in simulated colonic medium was determined using 5% human fecal content suspension in 0.01 N buffer solution, pH 6.8. The systems coated with HPMCP showed a lower rate of drug delivery in simulated enteric medium. The delivery profile in simulated colonic medium followed zero-order kinetic. The coated systems provided a promising drug-delivery profile for application in colonic drug delivery.

Formulation and evaluation of Albendazole microcapsules for colon delivery using chitosan

Objective:To formulate and evaluate Albendazole microcapsules using chitosan,a natural polymer for colon-specific delivery for better treatment of helminthiasis,filariasis,colorectal cancer,avoiding the side effects.Methods:The Albendazole microcapsules were prepared by the use of different concentrations of sodium alginate,chitosan and hydroxypropyl methylcellulose(HPMC).The polysaccharides chitosan reacted with sodium alginate in the presence of calcium chloride to form microcapsules with a polyelectrolyte complex membrane by electrostatic interactions between the two oppositely charged polymers.The microcapsules were then studied for entrapment efficiency,drug-polymer compatibility and surface morphology. In vitro drug release study in presence and absence of cecal content were also studied.Further, kinetic modellings were employed to find out release mechanisms.Results:Albendazole loaded microspheres showd high entrapment efficiency(72.8%) and the microcapsules were free flowing,non aggregated and spherical,between 600 and 1 000μm in diameter.The surface of microcapsules were found to be porous and wavy.The FT-IR spectrum showed that there is no interaction between the polymer and the drug.The in vitro drug release study found to be affected by change in chitosan,sodium alginate and HPMC concentration.The microcapsules with 2.5% sodium alginate and 0.4% chitosan shown minimum release in gastrointestinal simulated condition but shows maximum drug release at the end of 24th hour in presence of cecal content.The rate of drug release follows Korsmeyer-peppas model that was the drug release is by diffusion and erosion.Conclusions:The study reveals that Albendazole loaded chitosanalginate based microsphere can be used effectively for the colon targeting.

Optimizing pH-sensitive and time-dependent polymer formula of colonic pH-responsive pellets to achieve precise drug release

Time-sensitive and pH-dependent polymers are generally employed to prepare colon-site delivery system, and their coating thickness and order are very important in controlling the drug release. The traditional colon-site delivery systems consist of time-dependent polymers as inner layer and pH-sensitive polymers as outer layer. However, they suffer from low drug-loading rate and immature drug release. In this study, total alkaloids of sophora alopecuroides(TASA)-loaded pellets were prepared by extrusion-spheronization method and coated with Eudragit RS30D and Eudragit S100. Pellets using Eudragit RS30D as inner layer and Eudragit S100 as outer layer were named as ERS-ES100 TCO, while pellets with Eudragit S100 as inner layer and Eudragit RS30D as outer layer were ES100-ERS NCO. Both types of formulations with varying coating ratios and orders of Eudragit S100 and Eudragit RS30D were designed and prepared. The following in vitro drug release and SEM studies indicated that ERS-ES100 TCO(F2) with 12.8% Eudragit RS30D as inner layer and 21% Eudragit S100 as outer layer released up to 42% drug in 5 h. Interestingly, ES100-ERS NCO(F4) coated with 12.8% Eudragit S100 and 14.8% Eudragit RS30D showed optimal drug release in colon. In conclusion, ES100-ERS NCO colonic delivery system achieved reduced coating thickness and improved colonic targeting compared with traditional delivery system(ERS-ES100 TCO). In addition, the similarity factors( f 2) value of sophoridine and matrine for investigated formulation were within 50–100 and > 80, demonstrating that sophoridine and matrine in all formulations achieved a synchronous release.

Chitosan-g-PAA Hydrogels for Colon-Specific Drug Delivery: Preparation, Swelling Behavior and in vitro Degradability

A series of cross-linked hydrogels for colon-specific drug delivery were synthesized by graft copolymerization of Chitosan and acrylic acid using N, N＇-methylene-bis-（acrylamide） as a cross-linker. Their swelling behavior in different pH buffer solutions and colonic enzymatic degradability were studied. The obtained results show that these hydrogels have good pH sensitivity which can avoid drug release in stomach, and their swelling kinetics in stimulant intestinal environment follow second-order swelling kinetics equation. The factors influencing the swelling kinetics include the degree of cross-linking and the composition, which may control no release or a little amount release of drug inside the hydrogels in the small intestine by tailoring these factors. The gels are degradable by colonic enzymes and there is a correlativity between the degradation of networks and the swelling degree of the gels, which may trigger the release of drug in the colon. The hydrogels show a great potential for their application in oral colon-specific drug delivery system.

5-氨基水杨酸口服制剂及联合中药在炎症性肠病治疗中的应用

5-氨基水杨酸(5-ASA)是1种从中药柳树皮中分离提纯得到的天然抗炎活性成分水杨酸的衍生物,别名阿米诺水杨酸、美沙拉嗪,是临床治疗炎症性肠病(IBD)并预防其复发的一线药物。尽管目前莎尔福(Salofalk)、亚沙可(Asacol)和潘他沙(Pentasa)等5-ASA口服结肠靶向制剂已广泛用于IBD的临床治疗,但仍存在在小肠提前释药和受胃肠道生理状态影响显著等制剂缺陷、对克罗恩病和重度溃疡性结肠炎(UC)治疗效果不佳等临床未满足的需求,以及减少UC患者黏膜菌群多样性、长期使用增加用药风险和降低患者服药依从性等问题。开发硅胶纳米粒、水凝胶等新型递药载体,基于pH依赖、时滞控制和菌群/酶触发等多机制结合释药原理设计新型口服结肠靶向制剂从而解决制剂缺陷问题,提高5-ASA疗效和患者服药耐受性、依从性是目前制剂研究的重点。此外,5-ASA口服制剂联合中药保留灌肠、中药口服制剂和注射液等治疗IBD可发挥协同抗炎作用,实现增效减毒目的。对5-ASA口服制剂品种、近年来新型制剂和递药载体的研究进展,以及与中药联用的临床应用和研究现状等进行综述,为5-ASA口服制剂的剂型改造、载体材料研究和临床用药等提供参考。

卵清蛋白-羧甲基魔芋葡甘聚糖复合物稳定的姜黄素Pickering乳液及其肠道递送性能

为探究羧甲基魔芋葡甘聚糖(carboxymethyl konjac glucomannan,CMKGM)在姜黄素结肠靶向递送体系构建中的应用潜力,以CMKGM与卵清蛋白(ovalbumin,OVA)形成的聚电解质复合物为稳定剂制备姜黄素Pickering乳液,研究两者质量比和总聚合物浓度对所得Pickering乳液稳定性、外观结构、姜黄素包封率和载药量的影响,并对最佳乳液在模拟胃肠液消化过程中姜黄素释放率、乳滴粒径和形态的变化规律进行跟踪。结果表明,当OVA与CMKGM质量比为1∶1、总聚合物浓度为0.4%时所得Pickering乳液的稳定性最好且姜黄素的包封率和载药量最高,分别达到了91.79%和1.05 mg/g。体外模拟消化研究表明,与OVA稳定的姜黄素乳液相比,该Pickering乳液在模拟胃液中具有更好的稳定性,且在模拟结肠液中的姜黄素释放率高达22.78%,远高于OVA稳定乳液的5.35%,表现出了良好的结肠靶向递送性能。

纳米制剂靶向治疗炎症性肠病的研究进展

炎症性肠病是一种长期反复发作的非特异性疾病,对生活影响严重,目前无法完全治愈。结肠靶向给药系统可以将药物直接送达到结肠病变部位,提高治疗效果及药物的利用率,减少全身不良反应,对治疗炎症性肠病非常有帮助。纳米颗粒小且具有强大的吸附能力,可以特异性地聚集在结肠上,缓慢释放药物,并增加局部药物浓度,提高患者的依从性,发挥药物的长效作用。本文讨论了炎症性肠病患者肠道生理变化对传统结肠靶向药物输送系统的影响,并探讨了纳米颗粒作为治疗炎症性肠病的药物输送载体的最新研究。

Design and <i>in Vitro</i>Evaluation of Eudragit^®S100/Lipid Based Simvastatin Chronotherapeutic Drug Delivery System

The present study was undertaken to 1) formulate a pulsatile colonic delivery of simvastatin (SIM) as chronotherapy for treatment of hypercholesterolemia, and 2) enhance the dissolution profile of the prepared SIM chronotherapeutic system. Lipid based formulations were utilized to formulate SIM in capsule dosage form coated with Eudragit&reg S100. SIM was formulated using different percentages of Cremophor EL40, Capmul MCM EP and PEG 400. SIM coated capsules (SIMcc) were evaluated for drug release in different pH media. The results showed that SIMcc were able to withstand the acidic pH for 2 hours. Drug release rate was higher (88%) from SIMcc containing 10% polyethylene glycol (PEG) 400. In conclusion, Eudragit&reg S100 as time-dependent and site specific polymer retards SIM release from coated capsules;hence SIMcc could be considered as successful pulsatile treatment of hypercholesterolemia. Also, dissolution profile of lipid based SIMcc was enhanced in comparison with that of SIM filled capsules.

提高益生菌耐加工贮藏稳定性和体内存活率的递送系统研究进展

益生菌对人体健康发挥诸多积极作用,但由于益生菌在加工贮藏和消化过程中会发生活性损失,直接口服益生菌很难达到预期的益生效果。递送载体是一种能够提高益生菌加工贮藏稳定性、胃酸胆盐耐受性以及肠道黏附定植能力的有效方法。本综述关注益生菌口服递送的最新研究进展,总结了益生菌制剂中常用的益生菌种类及其功能特性;分析了湿度、温度、pH值、氧气等体外环境及口腔、胃、小肠等体内环境对益生菌存活率的影响;比较了微胶囊、水凝胶、油凝胶、纳米涂层、乳液、纳米纤维等不同递送载体的特点和应用情况;并对未来益生菌递送系统在降低成本、智能封装、共封装和人群实验中的应用做出展望,以期为开发贮藏稳定性高、肠道靶向递送和高活性的益生菌制剂提供技术支持。

多尺度蛋白质-多糖基益生菌递送体系研究进展

益生菌在食品加工过程、贮存和胃肠消化等不良环境中易大量失活,导致缺乏足够的活菌量能够顺利到达人体结肠并发挥其益生作用。作为食品中常用的天然生物聚合物材料,蛋白质和多糖可以通过非共价或共价作用组装形成宏观级-微米级-纳米级三种尺度结构的益生菌递送体系。其中,水凝胶、微粒、纳米颗粒等体系均已展现出优异的结肠靶向传输功效,但更多关于益生菌活性保持的方法和材料仍待进一步探索。蛋白质-多糖基递送体系已在酸奶、奶酪、饮料等食品中成功运用,其尺度结构决定了益生菌的靶向递送效果和发酵程度对产品品质的改善情况。未来,蛋白质-多糖基递送体系可在设计高效传输的纳米级结构、与其他生物活性物质共包埋的多功能食品、含活性益生菌的包装材料及新型健康食品等方面继续深入研究。本文以蛋白质-多糖基体系的形成机制为出发点,对常用于递送益生菌的蛋白质-多糖基体系的多尺度结构及在食品中的最新研究应用进展进行论述,以期为开发含活性益生菌的蛋白质-多糖基食品体系提供参考。

w/o/w双乳结构调控及在益生菌递送中的应用进展

为了改善双重乳液的稳定性及对生物活性物质的递送效果,水包油包水(w/o/w)双重乳液可以通过现代加工技术和结构组成设计形成多元化结构,包括液体、水凝胶、油凝胶、微胶囊等多种形式。w/o/w双重乳液的结构调控可以将益生菌包覆在内层水相内,提高益生菌对不良环境的抵抗力,从而实现益生菌在结肠靶向递送以及酸奶、奶酪、果蔬等食品制作方面的应用。该文以w/o/w双重乳液结构的优缺点和制备方法为出发点,对w/o/w双重乳液体系多元化结构的最新研究及在益生菌递送中的应用进展进行综述,以期为设计和开发含活性益生菌的新型减脂食品提供参考。

结肠靶向给药系统在粪菌移植中的应用

粪菌移植(FMT)对多种疾病有独特的疗效,其常见的治疗途径主要有口服、鼻肠管、结肠镜、灌肠等。其中口服服用方便,多次服用相对损伤小,但是口服粪菌如果在胃或小肠中崩解会影响FMT效果。结肠靶向给药系统(CTDDS)使药物更准确地作用于结肠,能提高治疗效果,减少毒副作用。CTDDS除了传统的pH敏感型、时滞型、酶触发型、压力依赖型等外,随着研究的深入还发展出了磁驱动型、配(受)体介导型、纳米药物型等。近年来一些研究将二者结合,使用CTDDS进行FMT,取得了一定的疗效,该文系统介绍了CTDDS在FMT中的应用。

Micro-ecology restoration of colonic inflammation by in-Situ oral delivery of antibody-laden hydrogel microcapsules

In-situ oral delivery of therapeutic antibodies,like monoclonal antibody,for chronic inflammation treatment is the most convenient approach compared with other administration routes.Moreover,the abundant links between the gut microbiota and colonic inflammation indicate that the synergistic or antagonistic effect of gut microbiota to colonic inflammation.However,the antibody activity would be significantly affected while transferring through the gastrointestinal tract due to hostile conditions.Moreover,these antibodies have short serum half-lives,thus,require to be frequently administered with high doses to be effective,leading to low patient tolerance.Here,we develop a strategy utilizing thin shell hydrogel microcapsule fabricated by microfluidic technique as the oral delivering carrier.By encapsulating antibodies in these microcapsules,antibodies survive in the hostile gastrointestinal environment and rapidly release into the small intestine through oral administration route,achieving the same therapeutic effect as the intravenous injection evaluated by a colonic inflammation disease model.Moreover,the abundance of some intestinal microorganisms as the indication of the improvement of inflammation has remarkably altered after in-situ antibody-laden microcapsules delivery,implying the restoration of micro-ecology of the intestine.These findings prove our microcapsules are exploited as an efficient oral delivery agent for antibodies with programmable function in clinical application.

载奥沙利铂类弹性蛋白多肽水凝胶的制备及其对小鼠结肠癌CT26细胞的杀伤作用

目的:制备担载奥沙利铂(OXA)的类弹性蛋白多肽(ELPs)水凝胶,研究其体外药物释放情况及对小鼠结肠癌CT26细胞的杀伤作用。方法:利用大肠杆菌(E.coli)系统表达ELPs原核蛋白,利用可逆相变循环法(ITC)进行蛋白纯化,将ELPs蛋白溶液与交联剂四羟甲基氯化磷(THPC)混匀制备水凝胶,扫描电子显微镜(SEM)观察水凝胶的超微结构,CCK-8法检测不同浓度ELPs水凝胶处理后CT26细胞和小鼠成纤维NIH3T3细胞存活率,活/死细胞染色法观察30和40 g∙L-1 ELPs水凝胶作用48 h后CT26细胞存活情况。制备载OXA的ELPs水凝胶,检测其在不同pH值(6.5和7.4)缓冲液中的药物释放情况,CCK-8法检测加入载不同浓度(0.25、1.00、4.00、16.00和64.00 mg∙L-1)OXA的ELPs水凝胶浸泡液后各组CT26细胞存活率和处理不同时间各组CT26细胞存活率。结果:凝胶电泳分析,E.coli诱导后在预计相对分子质量38000附近出现明显加粗的蛋白条带,ITC纯化后泳道中无明显杂蛋白存在。ELPs蛋白溶液中加入THPC后由透明液体状态转变为不透明的白色水凝胶,SEM观察显示出排列整齐的孔隙和三维结构;CCK-8法检测,经不同浓度ELPs蛋白处理后CT26细胞和NIH3T3细胞存活率仍接近100%;活/死细胞染色,ELPs水凝胶处理后的CT26细胞在荧光显微镜下呈现明亮的绿色荧光。载OXA的ELPs水凝胶能在体外持续释放OXA,在pH值6.5条件下OXA的释放速度较pH值7.4条件下稍快;CCK-8法检测,载不同浓度OXA的ELPs水凝胶浸泡液呈剂量依赖性抑制CT26细胞增殖,且随孵育时间的延长CT26细胞存活率逐渐降低。结论:载OXA的ELPs水凝胶具有持续释放OXA的特性,能够高效且持续地杀伤小鼠结肠癌CT26细胞,可作为一种安全有效的药物递送载体用于抗肿瘤研究。

Konjac glucomannan and xanthan gum as compression coat for colonic drug delivery:experimental and theoretical evaluations

Compression coated tablets for oral colon specific delivery systems were developed with a mixture polysaccharide of konjac glucomannan(KGM)and xanthan gum(XG)as the compression coat.Diffusion of cimetidine from compression coated tablets was investigated by release experiment in Vitro.0.22U/mLβ-mannanase was applied in the mimic colon solution.The structure of the mixture polysaccharide was studied by an atomic force microscope(AFM).The experimental results indicate that a KGM70 tablet with a 0.4 g coat is of good design,due to a less than 5%drug loss in the mimic upper gastrointestinal solution by the synergistic interaction between XG and KGM,and due to about 50%cumulative release in the mimic colon solution by degradation after 24 hours.The release mechanism and model are discussed based on different periods of drug release including the delay of the drug,the constant release without an enzyme and the delay of degradation.Under hydrolysis byβ-mannanase,drug release from the tablet with KGM coat shows an exponential increase,while that from the dosage with the mixture polysaccharide coat is an approximately zero-order process in which the constant release rate relates to the release velocity of a non-degraded system,the content of KGM within the coat and the average molecular weight ratio of KGM to XG.It was found that XG was the framework of the polysaccharide mixtures by AFM,which is similar to the analysis results from experiments on drug release.

左氧氟沙星羧甲基壳聚糖微球结肠靶向释药的实验研究

目的:检测所制备的左氧氟沙星羧甲基壳聚糖(LVFX/CMC)微球在人工消化液中和大鼠体内结肠靶向释药的性能。方法:以分光光度仪测定微球在人工消化液中的累积释放量,电镜观察微球在人工消化液中形态的改变。SD大鼠60只,随机分为两组,分别以LVFX/CMC微球(含40 mg左氧氟沙星)及等量左氧氟沙星溶剂灌胃,以高效液相色谱法对LVFX/CMC微球和左氧氟沙星(LVFX)灌胃后大鼠盲肠、结肠中药物浓度进行定量检测。结果:左氧氟沙星壳聚糖微球在人工胃液介质中溶解缓慢,2 h仅释药8.62%;在人工小肠液介质中溶解速度稍见加快,6 h释药29.39%,但表现为药物缓释曲线,24 h仅释药42.13%;在人工结肠液中,4 h后释药84.56%,24 h内累积释药量为93%。扫描电镜观察人工胃液中的微球明显溶胀,稍见变形;人工结肠液中的微球溶解,粒径明显减小。灌胃后LVFX/CMC微球组5和9 h时段盲肠、结肠药量明显高于LVFX组。结论:左氧氟沙星羧甲基壳聚糖微球在体外、体内实验中的释放符合结肠靶向释药的特点。

果胶钙胶囊结肠定位释放介质的确定

目的 确定以果胶钙为代表的多糖类结肠定位制剂的结肠释放介质。方法 采用蘸胶法制备 5-Fu果胶钙胶囊 ;测定不同温度、pH值时的国产复合果胶酶 (FLW型 )、进口果胶酶PectinexUltraSP L的活性 ;考察 5 -Fu果胶钙胶囊在含大鼠盲肠内容物和不同浓度的果胶酶的结肠介质中的释放情况。结果 国产复合果胶酶 (FLW型 )随pH值的升高而活性下降 ,在pH 6 .0以上失活 ,进口果胶酶PectinexUltraSP L的活性在pH 5 .0最强 ,在pH 7.0以上失活 ;在 37℃时PectinexUltraSP L 3ml/L (pH 6 .0 )与复合果胶酶 (FLW型 ) 6g/L (pH 5 .0 )的活性比较接近 ;溶出试验表明 ,果胶酶对果胶钙胶囊确有降解作用 ,且随酶量增加释放加快 ,并且PectinexUltraSP L 3ml/L (pH 6 .0 )与复合果胶酶 (FLW型 ) 6g/L (pH 5 .0 )的释放情况比较接近 ;大鼠盲肠内容物也可有效降解果胶钙。结论 试验初步确定以含PectinexUltraSP L 3ml/L (pH 6 .0 )或复合果胶酶 (FLW型 ) 6g/L (pH 5 .0 )

魔芋胶为载体的结肠定位给药系统体外释放介质研究

目的 筛选合适的释放介质,用于魔芋胶为载体结肠定位给药系统的体外评价.方法 采用压制包衣法制备魔芋胶包衣片;制备含大鼠盲、结肠内容物,内容物降解酶和β-甘露聚糖酶的3种体外释放介质;通过测定不同pH、温度条件下酶的活性,比较魔芋胶包衣片在不同介质中的药物释放及衣膜溶蚀情况,筛选合适的体外释放介质.结果 酶的活性研究表明,在体外释放37℃,pH 6.8介质条件下,内容物降解酶和β-甘露聚糖酶可保持较高活性（为最大酶活性的80%～90%）;体外药物释放及衣膜溶蚀研究表明,在含酶介质中,魔芋胶包衣片的药物释放及衣膜溶蚀随酶浓度增加而加快（P＜0.05）,具有结肠定位释放特性;在含0.1 g·L^-1（酶活性6.27U·mL^-1）β-甘露聚糖酶、1.0 g·L^-1（酶活性7.32 U·mL^-1）盲结肠内容物降解酶、50 g·L^-1大鼠盲结肠内容物的3种介质中,包衣片药物释放及衣膜溶蚀情况相似.结论 含0.1 g·L^-1（酶活性6.27 U·mL^-1）β-甘露聚糖酶的pH 6.8磷酸盐缓冲液可有效模拟体内结肠环境,用于魔芋胶为载体结肠定位给药系统的体外评价.

香草醛交联的壳聚糖微囊的制备及表征

将壳聚糖溶液分散于葵花籽油中,以Span-80为乳化剂,搅拌形成油包水乳液,加入香草醛的丙酮溶液进行交联,得到微囊.扫描电镜显示微囊呈圆整的球形,表面致密,内部有空隙.FT-IR光谱和XRD光谱证实壳聚糖的氨基与香草醛的醛基的交联作用和丙酮的脱水作用是壳聚糖液滴固化成形的原因.以萘普生为模型药物制备了载药微囊.结果表明,壳聚糖的脱乙酰度增加,粘均分子量减小,香草醛的用量增加,则微囊的产量、包封率和载药率增加,而药物的释放速率减小.脱乙酰度为96.3%、粘均分子量60.5万的壳聚糖,以醛基/氨基为3.75:1(摩尔比)与香草醛交联制得的载有萘普生的微囊,在含有0.5g/L溶菌酶的模拟结肠环境的释放介质中在10h内可完全释放药物.

替硝唑结肠给药系统的研制

依据时控型结肠给药系统原理 ,以替硝唑为模型药物 ,利用干压包衣和薄膜包衣双层包衣的方法制备了结肠给药系统 ,并对影响药物释放的因素 (如 EC粒度 ,HPMC粘度 ,时控层厚度 ,片剂硬度等 )、肠衣层性能和药物释放稳定性等进行了考查。结果表明 ,HPMC粘度增加使药物释放滞后时间延长 ,但高粘度 HPMC会导致药物释放无明显突跃点 ;包芯片硬度 40～ 6 0 N、片重 0 .2 6～ 0 .2 8g的片剂药物释放较稳定。加速试验 ( 3个月 )结果表明 ,药物释放稳定性良好。