由CPVA-g-PSSS功能接枝微球构建pH依赖型5-ASA结肠定位释药体系

采用铈盐-羟基氧化还原引发体系,在交联聚乙烯醇(CPVA)微球表面引发接枝聚合对苯乙烯磺酸钠(SSS),制备了接枝聚阴离子的功能接枝微球CPVA-g-PSSS,研究了其对5-氨基水杨酸(5-ASA)的吸附(载药)性能、机理和释放行为. 结果表明,在酸性介质中,受强静电相互作用驱动,CPVA-g-PSSS对5-ASA分子表现出很强的吸附能力,吸附容量达39.1 mg/g,可实现有效载药. 载药微球的释药行为具有强烈的pH值依赖性, 在pH=1的介质中基本不释药,而在pH=7.4的介质中发生突释,释放率可达86%,表现出良好的结肠定位释放行为.     

含5-氟尿嘧啶的聚乙二醇酯的制备与表征

采用氯乙酸与不同分子量的聚乙二醇进行酯化反应得到氯乙酸聚乙二醇酯,由于酯中的α-氯具有良好的反应活性,将它再与抗癌药物5-氟尿嘧啶结合制备了不同分子量的高分子前药,并对得到的产物进行表征。产物的体外降解实验表明,该产物具有长效缓释的功效,其中(PEG 2000)-5-FU的载药量为18.6%,随着聚乙二醇分子量的增加,产物水溶性提高,当聚乙二醇相对分子质量为2000时水解速率最大。     

含5-氟尿嘧啶的氨基甲酸聚乙二醇酯前药的合成与表征

采用异氰酸-α-氯乙酰酯与不同相对分子质量的聚乙二醇反应得到双氯乙酰氨基甲酸聚乙二醇酯,由于端基的α-氯具有良好的反应活性,将它与抗肿瘤药物5-氟尿嘧啶结合制备不同相对分子质量的高分子前药。对产物进行红外、核磁、紫外表征,证明5-氟尿嘧啶已经成功接到聚乙二醇链的末端,由紫外分光光度法测得最大载药量为22.6%。与5-氟尿嘧啶相比,前药的水溶性得到增强,而且具有长效缓释的功能。前药在不同pH的缓冲液中可以释放5-氟尿嘧啶或其衍生物,当聚乙二醇相对分子质量为2000时水解速度最快,20h的最大释药率为71.5%。     

新型负载5-氨基水杨酸微胶囊的制备及其载药效果

采用锐孔/聚合法制备了平均粒径为1.89 mm、负载5-氨基水杨酸(5-ASA)的纤维素硫酸钠(NaCS)-壳聚糖微胶囊,采用Box-Behnken响应面法进行实验设计和分析,考察了内、外水相pH值和NaCS浓度、多聚磷酸钠(PPS)浓度对微胶囊载药量和包封率的影响. 结果表明,内水相pH值对负载5-ASA微胶囊的载药量和包封率起关键作用. 最佳制备条件为内水相pH 4.25,外水相pH 6.0,NaCS浓度14 g/L, PPS浓度5 g/L,该条件下所制微胶囊最大载药量为59.02%,最大包封率为89.96%..     

自组装法制备CMCS/PEG纳米粒子及其pH值响应性研究

以壳聚糖(CS)为原料与氯乙酸反应制备羧甲基壳聚糖(CMCS),再将聚乙二醇(PEG)和CMCS以不同的质量比溶解在不同pH值的溶液中,通过氢键相互作用自组装形成CMCS/PEG纳米粒子,并研究其粒径大小与二者配比和溶液pH值之间的关系。结果表明,不同配比下的粒子粒径均随pH值的增大先增大后减小;当pH5时,在相同pH值溶液中,随着PEG比例的增加,粒子的粒径先减小后增大,在pH=1.22、PEG∶CMCS=4∶1时粒径最小,约为160nm;当pH≥5时,在相同pH值溶液中,粒径随PEG用量的增加而增大;通过自组装法制备的CMCS/PEG纳米粒子粒径大小具有pH值响应性。     

壳聚糖改性蒙脱石作为药物控释载体的研究

采用壳聚糖(CS)对钠基蒙脱石(MMT)进行改性制备有机蒙脱石(CS-MMT),对改性后的蒙脱石进行红外光谱(FT-IR)和X射线衍射(XRD)等分析表征.以5-氟尿嘧啶(5-FU)为药物模型制备出壳聚糖改性蒙脱石载药复合物(5-FU/CS-MMT),并以钠基蒙脱石载药复合物(5-FU/MMT)作为对照,探究载药复合物在模拟人工胃液、人工小肠液和人工结肠液中的药物释放情况.结果 表明,当CS的用量是MMT的1.0倍阳离子交换容量时,形成的有机蒙脱石的层间距增大,且对5-FU的载药量达到393 mg/g,而同等情况下,MMT的载药量为239 mg/g.体外释放试验的结果表明,5-FU/CS-MMT中5-FU的体外释放能力主要受释放介质pH值的影响,当pH值为7.4时,5-FU的累积释放率最大,在pH值为1.5时的结果最小.     

聚乙二醇-壳聚糖两嵌段水溶性共聚物的pH值敏感性及其对辅酶A的控制释放的研究

利用官能团偶合的方法合成了一种新型的共聚物CS-TDI-PEGOMe,应用FTIR,1HNMR和UV对中间产物和最终产物的结构进行了表征.结果表明,单甲氧基聚乙二醇(PEGOMe)被成功地接枝到壳聚糖(CS)上,使不溶于水的壳聚糖改性为水溶性的PEG化的壳聚糖.还研究了该聚合物对辅酶A的控制释放,表明共聚物CS-TDI-PEGOMe在不同质量分数和不同pH值时对辅酶A具有良好的控制释放作用.     

水溶性聚氨酯热熔胶的合成

以聚乙二醇(PEG)和甲苯二异氰酸酯(TDI)为原料,合成水溶性聚氨酯热熔胶,考察了PEG脱水、PEG分子量、原料配比等因素的影响。结果表明,低分子量和高分子量的PEG相混合时产品性能较好,最适宜的合成条件是聚乙二醇(8000)与聚乙二醇(600)混合脱水后与TDI反应,摩尔比1∶1∶2.28,反应温度110~115℃,产品为黄色固体。     

5-氟脲嘧啶载O-羧甲基壳聚糖自组装pH敏感纳米粒的体外释放

为了提高抗癌药物5-氟脲嘧啶(5-FU)对肿瘤细胞的靶向性及选择性,采用超声-透析法制备了具有pH敏感性的纳米药物载体5β-胆烷酸/O-羧甲基壳聚糖/磺胺地托辛(5β-CHA/OCMC/SDM)自组装水凝胶纳米粒,并用同样的方法将5-FU包载于纳米载体中进行体外释放研究。利用紫外分光光度计于269nm波长下检测5-FU的载药量和包封率以及释放浓度。结果表明,对于5β-CHA/OCMC/SDM纳米粒,药载比(药物和载体的质量比)增加到0.6时,载药量和包封率分别高达51.3%和85.4%。体外释药结果表明,在pH=7.4(人体正常组织的pH值)的磷酸盐缓冲溶液中,接枝5β-CHA的OCMC水凝胶纳米粒对5-FU具有良好的缓释效果,且随接枝量的增加缓释效果增强。pH6.8(肿瘤组织的pH值)时,接枝SDM的载药纳米粒迅速聚集并强烈释放,表现出良好的pH敏感性。     

采用DoE设计方法优化可溶性肿瘤坏死因子I型受体蛋白的聚乙二醇修饰工艺

目的采用DoE设计方法对人可溶性肿瘤坏死因子I型受体(soluble tumour necrosis factorαreceptors I,sTNFα-RⅠ)的聚乙二醇(PEG)修饰工艺参数进行优化,以期获得稳定、可控的工艺参数。方法采用UNICORN(DoE)软件中Central Composite Face Centered(CCF)模型对sTNFα-RⅠ的3个PEG修饰工艺参数,即溶液pH值(pH)、反应时间(Time)和PEG与蛋白质量比(PEGrate)进行优化,设置4个响应值(多PEG修饰蛋白峰面积、单PEG修饰蛋白峰面积、未修饰蛋白峰面积及单PEG修饰蛋白峰面积与多PEG修饰蛋白峰面积比值)揭示其化学反应过程,确定参数操作空间;应用蒙特-卡罗模拟法(Monte-Carlo Simulation)对优化参数进行风险评估。结果 3因子17组试验结果的重复性较好,中心点重复组响应值介于最低值和最高值之间,且随机分布,符合DoE试验设计的要求;4个响应值所对应的回归系数(R2)均>0.75,预测准确性(Q2)>0.5,模型有效性(Model Validity)>0.25,重复性(Reproducibility)>0.5,模型预测与实验值之间偏差较小,具有可靠的预测准确性;17组试验结果标准残差在允许范围(-4⁴)之间,线性较好,预测值与观测值之间相关性较好,建立的模型拟合度高,可较为准确地预测试验结果。溶液pH值对多PEG修饰产量影响较小,随着Time和PEGrate的升高,多PEG修饰产物增加,单PEG修饰产物经二次或多次修饰形成多PEG修饰产物,减少Time和PEG用量可减少多PEG修饰产物;单PEG修饰产物随着pH上升,产量有所增加,与Time呈二次项关系,在Time·PEGrate交互作用中,减少PEG用量可增加单PEG修饰产物量;减少Time和降低PEG用量可提高单PEG修饰产物与多PEG修饰产物的比值,有利于下游纯化。确定了工艺参数的操作空间,当pH为5.5时,反应时间控制在30 h以上,PEG与蛋白质量比控制在3.7以下,符合预设值;pH在6.5时,反应时间控制在224)之间,线性较好,预测值与观测值之间相关性较好,建立的模型拟合度高,可较为准确地预测试验结果。溶液pH值对多PEG修饰产量影响较小,随着Time和PEGrate的升高,多PEG修饰产物增加,单PEG修饰产物经二次或多次修饰形成多PEG修饰产物,减少Time和PEG用量可减少多PEG修饰产物;单PEG修饰产物随着pH上升,产量有所增加,与Time呈二次项关系,在Time·PEGrate交互作用中,减少PEG用量可增加单PEG修饰产物量;减少Time和降低PEG用量可提高单PEG修饰产物与多PEG修饰产物的比值,有利于下游纯化。确定了工艺参数的操作空间,当pH为5.5时,反应时间控制在30 h以上,PEG与蛋白质量比控制在3.7以下,符合预设值;pH在6.5时,反应时间控制在22³5 h之间,PEG与蛋白质量比控制在2.535 h之间,PEG与蛋白质量比控制在2.5⁴.0之间,符合预设值;蒙特-卡罗模拟法对在最佳操作参数(反应时间34.1 h,溶液pH值6.5,PEG与蛋白质量比2.5)时模型预测的响应值(单PEG修饰产物峰面积值5 635.82和单PEG修饰产物与多PEG修饰产物比值3.226 5)的风险评估,10万次模拟试验可信度分别为99.825%和99.982%,试验风险较小,工艺可控。结论确定了sTNFα-RⅠ蛋白PEG修饰稳健的工艺参数。     

Complexation of pepsin poly(ethylene glycol)

Summary Complexation of porcine pepsin (or pepsin A) (EC.3.4.23.1) with poly(ethylene glycol) (PEG) in an aqueous solution was studied as a function of pH and PEG concentration. The addition of PEG increased the reduced viscosity of the enzyme solution at pH 3 but not at pH 4.5. An increase in pH was observed by mixing both PEG and enzyme solutions which were previously adjusted to pH 3. Under conditions of pH 2.5–3 and 50°C, PEG contributed to an increase in the hydrolyzing activity of pepsin towardN-acetyl-l-phenylalanyl-3,5-diiodo-l-tyrosine. These results indicate that pepsin forms a water-soluble complex with PEG mainly through hydrogen bonds between the carboxyl groups in the enzyme and the ether groups in PEG.     

Degradability of the linear azo polymer conjugated 5,5′-azodisalicylic acid segment in the main chain for colon-specific drug delivery

A novel type of linear copolymer composed of poly(ethylene glycol) (PEG) with 5,5′-azodisalicylic acid [olsalazine (OLZ)] was developed for colon-specific drug delivery. These copolymers contained azo bonds that would be degraded by the azoreductase activities in the colon. The resultant condensation polymers were characterized with Fourier transform infrared, nuclear magnetic resonance, and gel permeation chromatography. The degradation behavior of the polymer was evaluated in vitro and in vivo. The in vitro results indicated that the active 5-aminosalicylic acid (5-ASA), one of the degradation products, could be released in the medium of the cecum contents specifically. In an in vivo test, there was a 8-h lag time before 5-ASA could be detected in urine samples, and this indicated that the conjugate could remain intact in the upper part of the gastrointestinal tract. In comparison with OLZ, the release profiles of 5-ASA from PEG–OLZ copolymers were significantly prolonged. In addition, the release profiles of 5-ASA from PEG–OLZ copolymers could be adjusted by changes in the molecular weight of the PEG segment. Because of these advantages of PEG–OLZ copolymers, it could be concluded that PEG–OLZ copolymers could be promising candidates for colon-specific polymeric prodrugs of 5-ASA. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

pH-sensitive nanogels based on Boltorn H40 and poly(vinylpyridine) using mini-emulsion polymerization for delivery of hydrophobic anticancer drugs

In this study, we describe the synthesis of a new structure of pH-sensitive H40 based nanogel by click reaction through mini-emulsion polymerization. The nanogels were synthesized by cross coupling of H40-poly(ε-caprolactone) (H40-PCL) dendrimers as cores and poly(vinylpyridine) (PVP) as a pH sensitive crosslinker. The poly(ethylene glycol) (PEG) pendant group was introduced at the middle of PVP chains as hydrophilic segment to act as hydrophilic shell at final nanogel for better dispersity. Folic acid that is conjugated at the end of some of PEG through the free carboxyl group was used for targeting cancer cells that overexpress folate receptors.     

Preparation and in vitro controlled release behavior of a novel pH-sensitive drug carrier for colon delivery

The synthesis of a novel complex system designed for colon-targeting drug delivery was reported. The complex was prepared by dialdehyde konjac glucomannan and adipic dihydrazides to form steady Schiff base, and crosslinking with 5-aminosalicylic acid (5-ASA) through glutaraldehyde as a cross-linking agent. The structure was characterized by Fourier transform infrared (FTIR) spectroscopy, ¹³C NMR, wide angle X-ray diffraction (WAXRD) and thermogravimetric analysis. In vitro release of 5-ASA from the complex showed that the total released 5-ASA after 24 h in buffer solution at pH 1.2, 6.8, and 7.4 were 4, 59, and 21%, respectively. The release rate of 5-ASA can be controlled by tuning the pH value more effectively. The results indicated that the novel pH-sensitive complex could be potentially useful for colon-targeting drug delivery system.     

A mucoadhesive polymer prepared by template polymerization of acrylic acid in the presence of poly(ethylene glycol) macromer

A new mucoadhesive polymer complex was prepared by the template polymerization of acrylic acid with poly(ethylene glycol) macromer (PEGM) as a template polymer. Fourier transform infrared results showed that the poly(acrylic acid) (PAA)/PEGM mucoadhesive polymer complex was formed by hydrogen bonding between the carboxyl groups of PAA and the ether groups of PEGM. The glass‐transition temperature of the PAA/PEGM mucoadhesive polymer complexes was shifted to a lower temperature as the repeating unit ratio of PAA/PEGM in the complex decreased. The dissolution rate of the PAA/PEGM mucoadhesive polymer complex was much slower than that of the PAA/poly(ethylene glycol) (PEG) mucoadhesive polymer complex and was dependent on the pH and molecular weight of PEGM. The mucoadhesive force of the PAA/PEGM mucoadhesive polymer complexes was stronger than that of commercial Carbopol 971P NF and almost the same as that of the PAA/PEG mucoadhesive polymer complex. The PAA/PEGM interpolymer complex seemed to be a better mucoadhesive polymer matrix than the PAA/PEG interpolymer complex. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 1904–1910, 2002     

Synthesis and characterization of complexes between poly(itaconic acid) and poly(ethylene glycol)

Summary Interpolymer complexes of poly(itaconic acid) and poly(ethylene glycol) (PIA/PEG) were prepared by two different procedures: simple mixing of preformed PIA and PEG and by polymerization of itaconic acid on poly(ethylene glycol) as a template. Complex formation was attributed to hydrogen bond formation between the carboxyl group of PIA and the ether group of PEG. The two types of complexes were characterized by viscometric measurements, thermogravimetric analysis (TGA), Fourier-transform infrared (FTIR) spectroscopy and adhesive force measurements. The results indicate that complexes prepared by template polymerization have a stronger hydrogen bonding and hence more ordered structure and better mucoadhesive properties.     

Drug release from poly(ortho esters)–poly(ethylene glycol) polyblend

A polyblend of poly(ortho esters)–poly(ethylene glycol) (POE–PEG) was prepared. The release behavior of the acetanilide‐loaded film of the POE–PEG polyblend was studied. Blending POE with water‐soluble PEG can promote the release of drug in pH 7.4 PBS buffer at 37°C, while POE has plasticizing effect on PEG. Infrared and X‐ray diffraction studies reveal that there is some interaction between POE and acetanilide. The SEM micrographs disclose that the porosity of the drug‐loaded film enhances with an increase immersing time. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 71: 303–309, 1999     

Hydrogels of modified ethylenediaminetetraacetic dianhydride gelatin conjugated with poly(ethylene glycol) dialdehyde as a drug‐release matrix

Hydrogels have been recognized as versatile biomaterials in biomedical applications. This article describes the synthesis and characterization of a poly(ethylene glycol) (PEG) dialdehyde derivative, the modification of gelatin with ethylenediaminetetraacetic dianhydride (EDTAD), and the conjugation of PEG dialdehyde for enhanced hydrophilicity, biocompatibility, and flexibility. Hydrogels of gelatin conjugated with various percentages of PEG dialdehyde (10–30%), 35% EDTAD‐modified gelatin, and 12% PEG dialdehyde conjugated with 31% EDTAD‐modified gelatin with or without 1% chlorhexidine were prepared. For all the synthesized gel formulations, the swelling kinetics and drug release in pH 7.4 and pH 4.5 buffers at 37°C were studied. Gels of PEG‐conjugated gelatin, 35% EDTAD‐modified gelatin, and 12% PEG conjugated with 31% EDTAD‐modified gelatin, with or without 1% chlorhexidine, showed significantly improved swelling ratios in comparison with gelatin. The drug release was unaffected by an increase in the percentage of PEG conjugation with gelatin. Complete drug release was recorded within 48 h in the pH 4.5 buffer, whereas in the pH 7.4 buffer, the drug release was accomplished within 128 h. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 1059–1067, 2004     

Synthesis and characterization of biodegradable block copolymers of poly(propylene fumarate‐co‐sebacate)‐co‐poly(ethylene glycol) and poly(ethylene fumarate‐co‐sebacate)‐co‐poly(ethylene glycol)

The synthesis of two low molecular weight linear unsaturated oligoester precursors, poly(propylene fumarate‐co‐sebacate) (PPFS) and poly(ethylene fumarate‐co‐sebacate) (PEFS), are described. PPFS, PEFS, and poly(ethylene glycol) are then used to prepare poly(propylene fumarate‐co‐sebacate)‐co‐poly(ethylene glycol) (PPFS‐co‐PEG) and poly(ethylene fumarate‐co‐sebacate)‐co‐poly(ethylene glycol) (PEFS‐co‐PEG) block copolymers. The products thus obtained are investigated in terms of the molecular weight, composition, structure, thermal properties, and solubility behavior. A number of design parameters including the molecular weights of PPFS, PEFS, and PEG, the reaction time in the polymer synthesis, and the weight ratio of PEG to PPFS or to PEFS are varied to assess their effects on the product yield and properties. The hydrolytic degradation of PPFS‐co‐PEG and PEFS‐co‐PEG in an isotonic buffer (pH 7.4, 37°C) is investigated, and it is found that the fumarate ester bond cleaves faster than does the sebacate ester bond. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 295–300, 2004     

Preparation of a topologically linked branch polymer containing cyclodextrin

Macromolecules containing topological linkages made of α‐cyclodextrin (αCD) and poly(ethylene glycol) (PEG) were prepared by condensation of mono‐6‐O‐deoxy‐mono‐6‐amino‐α‐cyclodextrin (NH₂‐αCD) with PEG dicarboxylic acid (PEG‐diCOOH) having one carboxyl group at both chain ends. The analysis of ¹H NMR and ¹³C NMR spectra of the condensation products showed completion of the condensation reaction between NH₂ and COOH groups, and the absence of ester linkages, thus indicating that all of the PEG chains carried one αCD molecule at both chain ends through amide linkages. Gel permeation chromatography analysis of these condensation products showed that NH₂‐αCD formed inclusion complexes with PEG‐diCOOH prior to condensation, resulting in macromolecules having topological linkages. In addition, the amount of the topological linkages increased with the increase of molecular weight of PEG‐diCOOH. This result shows that the complexation equilibrium of NH₂‐αCD with PEG‐diCOOH depends on the concentration of ethylene glycol units. Copyright © 2007 Society of Chemical Industry