用功能聚合物微球构建pH敏感及pH敏感—时滞双重型结肠定位释药体系的研究
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摘要
随着人们生活水平的提高，结肠癌和结肠炎的发病率也在不断升高。传统口服制药和注射制药到达结肠部位浓度低，药物生物利用度低，毒副作用大。为了提高结肠局部疾病的治疗效果，近年来人们大力发展研制口服结肠定位释药系统（OCDDS），该释药系统可避免药物在胃与小肠前端释放，而是将其定位于结、直肠部位释放，可大大提高病变部位的药物浓度，减少药剂用量，降低全身副作用，从而提高药物的有效性和安全性。利用药用高分子材料及药物的物理化学特性，通过分子设计的构思，构建与研发高效的OCDDS新剂型，是目前医药学领域中的重大研究课题。
本研究以具有生物相容性的交联聚乙烯醇（CPVA）微球为基质，通过接枝聚合与分子表面印迹技术，构建pH敏感型和pH敏感-时滞双重型结肠定位释药系统，对于促进OCDDS的发展具有积极的促进作用，在药物的缓、控释研究领域，具有重大的科学价值。
首先，采用铈盐-羟基氧化还原引发体系，在生物相容性微球CPVA表面引发接枝对苯乙烯磺酸钠（SSS），制得功能接枝微球CPVA-g-PSSS，并采用红外光谱、扫描电镜、Zeta电位测定对接枝微球进行了表征。实验结果表明，铈盐-羟基氧化还原引发体系可有效地引发SSS在CPVA微球表面的接枝聚合,在适宜的反应条件下,可制得PSSS接枝度为16.1g/100g的接枝微球CPVA-g-PSSS。在较大pH范围内，接枝微球CPVA-g-PSSS的Zeta电位为绝对值较高的负值，即微球表面携带有大量的负电荷。
接着，考察研究了CPVA-g-PSSS对抗结肠癌药物5-氟尿嘧啶（5-FU）的吸附性能、吸附机理及体外释药特性。在酸性条件下，5-FU高度质子化，凭借静电相互作用，接枝微球CPVA-g-PSSS对5-FU表现出很强的吸附性能，吸附容量达到105mg/g，显示出良好的载药性能。随着介质pH增大，5-FU质子化减弱，静电相互作用减弱，接枝微球CPVA-g-PSSS对5-FU的吸附量减少；另外，CPVA-g-PSSS对5-FU的吸附容量随着温度的降低而增大，显示出物理吸附的特点；随离子强度的增大吸附容量下降。体外释药实验显示，载5-FU接枝微球CPVA-g-PSSS在模拟胃液(pH=1.0)中基本不释药，在模拟小肠液(pH=6.8)中有部分释药，而在模拟结肠液(pH=7.4)中有突释现象发生，表明载药微球释药具有明显的pH敏感性，是一种pH敏感型结肠定位释药系统。
在上述研究的基础上，采用铈盐-羟基氧化还原引发体系，以生物相容性微球CPVA为基质，5-氟尿嘧啶为模板分子，SSS为功能单体，N,N′-亚甲基双丙烯酰胺（MBA）为交联剂，在水溶液中实施了5-FU分子的表面印迹，制备了5-FU分子表面印迹聚合微球MIP-PSSS/CPVA。采用红外光谱(FTIR)和扫描电子显微镜(SEM)法,对印迹微球进行了表征，重点考察研究了MIP-PSSS/CPVA对5-FU的识别选择性、结合性能及体外释药行为。实验结果表明，基于本体系特殊的羟基-铈盐表面引发体系,可有效地实现5-FU分子的表面印迹,在微球CPVA表面形成分布有大量5-FU分子印迹空穴的聚合物层。MIP-PSSS/CPVA微球对5-FU具有优良的选择识别性和特异的结合亲和性，在酸性条件下，凭借静电相互作用，可实现对5-FU有效载药，结合量达到110mg/g，而印迹微球对5-FU结构类似物替加氟（TE）和尿甘（UR），结合量却很低。与上述的接枝载药微球CPVA-g-PSSS相比，印迹载药微球MIP-PSSS/CPVA不但具有pH敏感性，还具有明显的时滞性，印迹空穴对5-FU的束缚和静电相互作用的协同限制了药物的释放速度，因此导致载药印迹微球MIP-PSSS/CPVA在模拟胃液中不释药，小肠部位只有小量释药，结肠部位突释，达到了高效的结肠定位释药作用。因此，载药印迹微球MIP-PSSS/CPVA是一种新型高效的pH敏感-时滞双重型结肠定位释药系统。
对于功能接枝微球CPVA-g-PSSS，本研究还深入考察了它对抗结肠炎药物甲硝唑的吸附性能、吸附机理及体外释药特点。实验结果表明，凭借强的静电相互作用，在酸性条件下，CPVA-g-PSSS对MTZ具有高的吸附容量，达到112mg/g，也显示出良好的载药性能。随着pH值得升高，MTZ质子化减弱，静电相互作用减弱，吸附容量降低。随着介质温度的升高和盐度的增大，吸附容量降低。体外释药实验表明，载MTZ的接枝微球CPVA-g-PSSS随着释放介质pH的升高，MTZ与PSSS之间的静电相互作用减弱，累积释放率增大，显示出释药的pH敏感性，是一种pH敏感型结肠定位释药系统。
在上述研究的基础上，以生物相容性微球CPVA为基质，采用铈盐-羟基氧化还原引发体系，甲硝唑为模板分子，SSS为功能单体，N,N′-亚甲基双丙烯酰胺（MBA）为交联剂，在水溶液中实施了MTZ的分子表面印迹，制备了MTZ分子表面印迹聚合微球MIP-PSSS/CPVA；重点考察研究了MIP-PSSS/CPVA对MTZ的识别选择性、结合性能及体外释药行为。实验结果表明，MIP-PSSS/CPVA对MTZ具有高的识别选择性和亲和性，而对结构类似物替硝唑（TNZ）和奥硝唑（ONZ）基本不识别、不结合。体外释药实验显示，MTZ印迹载药微球MIP-PSSS/CPVA与接枝载药微球CPVA-g-PSSS相比，印迹载药微球MIP-PSSS/CPVA不但具有pH敏感性，还具有明显的时滞性，印迹空穴对5-FU的束缚和静电相互作用协同限制了MTZ的释放速度，因此导致载药印迹微球MIP-PSSS/CPVA在模拟胃液中不释药，小肠部位只有小量释药，结肠部位突释，达到了高效的结肠定位释药作用。因此，载药印迹微球MIP-PSSS/CPVA是一种新型高效的pH敏感-时滞双重型结肠定位释药系统。
The incidence of colon cancer and colitis are rising as people living standard rise. Thetraditional oral preparation or injection to colon concentration is low, bioavailability of drugis small, and side effects are big. In order to improve treatment effect of the local colondisease, researchers develop the oral colon specific drug delivery system (OCDDS) in recentyears. The drug delivery system can avoid drug release in the stomach and small intestine, butrelease locating in colon and rectum. The targeted delivery to colon via oral route is intendedto improve the efficacy and safety of the drug therapy by exerting high drug concentrationstopically at the disease site, enhance the bioavailability of drugs, and reduce side-effects.According to the molecule design, building and developing high efficient OCDDS is animportant research subject in the field of medicine based on physical and chemical propertiesof pharmaceutical polymers and drugs.
The pH sensitive and pH-delayed double sensitive colon specific drug release systemswere constructed by surface grafted polymerization and the molecular surface imprintingtechnology based on biocompatible crosslinked poly (vinyl alcohol)(CPVA) microspheres asthe matrix. The drug delivery systems can promote the development of OCDDS, and theyhave important scientific significance in sustained and controlled drug release research area.
Firstly, the graft-polymerization of sodium4-styrene sulfonate (SSS) was performed onthe surfaces of CPVA microspheres by using cerium salt-hydroxyl group redox initiationsystem, and the grafted microspheres CPVA-g-PSSS was obtained. The chemical structureand physicochemistry characters of CPVA-g-PSSS microspheres were adequatelycharacterized with infrared spectrum (FTIR), scanning electron microscope (SEM) anddetermining zeta potential. The experimental results show that cerium salt-hydroxyl groupredox initiation system can effectively initiate the polymerization of SSS on CPVA microspheres, and under the suitable conditions, PSSS grafting degree can get up to16.1g/100g. Zeta potential shows the grafted CPVA-g-PSSS have low negative value in a wide pHrange, namely there are higher density of negative charge on the surface of theCPVA-g-PSSS.
Then, the adsorption property of the grafted microspheres CPVA-g-PSSS for5-fluorouracil (5-FU), namely drug loading ability, was mainly investigated and theadsorption mechanism was explored. The in vitro release behavior of the drug-loadedmicrospheres was also examined. In the acidic medium, the amino groups in5-FU moleculewill be highly protonated, and a strong electrostatic interaction between CPVA-g-PSSS and5-FU molecule will be produced, resulting in high absorption capacity, reaching105mg/g,and displaying the high efficiency of drug loading. When pH value is increased, theprotonation degree of the amino groups in5-FU molecule decrease, and the electrostaticinteraction reduce, leading to low absorption capacity of grafted microspheres CPVA-g-PSSStowards5-FU. The adsorption capacity increases with temperature decreasing, showing thecharacteristic of physical absorption, and capacity reduce with the salinity rising. The in vitrorelease drug shows in the medium of pH=1, the drug does not be released, and in the mediumof pH=6.8, the part of drug is released, while in the medium of pH=7.4, the sudden deliveryphenomenon will be produced. The in vitro release behavior of the drug loading microspheresis highly pH-dependent and is a pH-sensitive drug delivery system.
Surface imprinting of5-FU was performed on CPVA microspheres with sodium4-styrene sulfonate (SSS) as functional monomer,5-FU as template and withN,N’-Methylene bisacrylamide (MBA) as crosslinker in aqueous solution by using ceriumsalt-hydroxyl group redox initiation system, and5-FU-imprinted microspheresMIP-PSSS/CPVA, on which there exists a layer of molecular imprinting cavies, wereobtained. The chemical structure and morphology of MIP-PSSS/CPVA microspheres werecharacterized with infrared spectrum (FTIR) and scanning electron microscope (SEM). Thebinding and recognizing property of the imprinted microspheres MIP-PSSS/CPVA for5-fluorouracil (5-FU), namely drug loading ability, was mainly investigated and the binding mechanism was explored. The in vitro release behavior of the drug-loaded microspheres wasalso examined. The experimental results show that based on the special cerium salt-hydroxylgroup redox initiation system in this investigation, the5-FU surface imprinting can beeffectively realized, and a polymer layer, in which a lot of5-FU-imprinted cavies aredistributed, can be formed on the surfaces of CPVA microspheres. In the acidic medium, theimprinted microspheres MIP-PSSS/CPVA exhibit very strong binding ability for5-FU bydriving of electrostatic interaction, displaying the high efficiency of drug loading, andbinding capacity reaching110mg/g. However, for relative to5-FU, MIP-PSSS/CPVAmicrospheres have low binding capacity towards tegafur (TE) and Uridine (UR). Compare tothe above5-FU-loaded CPVA-g-PSSS, in vitro release of the drug loaded MIP-PSSS/CPVAmicrospheres is not only pH-sensitive, but also time-delayed. The synergistic effect of strongelectrostatic interaction and the spatial resistance of drug molecule diffused from imprintedcavies delay effectively the drug release process and resulting in the slower release rate from5-FU-loaded MIP-PSSS/CPVA microspheres. The drug does not be released in the simulatedstomach fluid (pH=1), in the simulated intestine fluid (pH=6.8), the drug release is small, andin the simulated colon fluid (pH=7.4), the sudden delivery phenomenon will be produced,displaying an excellent colon-specific drug delivery behavior. Therefore, drug-loadedMIP-PSSS/CPVA microspheres are a new-style and high-efficient pH-delayed doublesensitive colon specific drug release systems.
The adsorption abilities and mechanism of the grafted microspheres CPVA-g-PSSS forMetronidazole (MTZ) were also studies. The in vitro release behavior of the MTZ-loadedmicrospheres was also examined. The experiment results show that CPVA-g-PSSSmicrospheres possess also very strong adsorption ability for MTZ by right of electrostaticinteraction, and the adsorption capacity reaches112mg/g. The protonation degree of theamino groups in MTZ molecule decreases when pH value increases, and the electrostaticinteraction weaken, resulting in low absorption capacity. The adsorption capacity decreaseswith the rise of temperature and this reveals the character of physical adsorption. And theincrease of salinity causes the decrease of the adsorption capacity. The in vitro release experiments show the release of the MTZ-loaded CPVA-g-PSSS microspheres increases withthe pH rises, and electrostatic interaction weakens, showing pH-sensitivity.
Subsequently, MTZ surface imprinting was performed on CPVA with sodium4-styrenesulfonate (SSS) as functional monomer, MTZ as template and N, N’-Methylenebisacrylamide (MBA) as crosslinking agent in aqueous solution by using ceriumsalt-hydroxyl group redox initiation system, and obtaining MTZ surface imprintedmicrospheres MIP-PSSS/CPVA. The binding property of the imprinted microspheresMIP-PSSS/CPVA for MTZ, namely drug loading ability, was mainly investigated profoundlywith static method and the binding mechanism was explored. The in vitro release behavior ofthe drug-loaded microspheres was also examined. The experimental results show that in theacidic medium, the MIP-PSSS/CPVA microspheres exhibit very strong binding ability forMTZ by driving of electrostatic interaction while the binding ability is weak for Tinidazole(TNZ) and Ornidazole (ONZ). The in vitro release of the MTZ-loaded MIP-PSSS/CPVA isnot only pH-sensitive but also time-delayed in contrast to MTZ-loaded CPVA-g-PSSS. Thesynergistic effect of strong electrostatic interaction and the spatial resistance of drug moleculediffused from imprinted cavies delay effectively the drug release process and resulting in theslower release rate from MTZ-loaded MIP-PSSS/CPVA microspheres. The release behaviorshows in simulated gastric fluid (pH=1), the drug do not be released, and in the simulatedsmall intestine fluid (pH=6.8), the drug release is smaller, whereas, in the simulated colonfluid (pH=7.4), an abrupt release will be firstly produced and then sustained and slowedrelease occur, displaying an excellent pH-delayed double sensitive colon specific drug releasesystems.
本研究以具有生物相容性的交联聚乙烯醇（CPVA）微球为基质，通过接枝聚合与分子表面印迹技术，构建pH敏感型和pH敏感-时滞双重型结肠定位释药系统，对于促进OCDDS的发展具有积极的促进作用，在药物的缓、控释研究领域，具有重大的科学价值。
首先，采用铈盐-羟基氧化还原引发体系，在生物相容性微球CPVA表面引发接枝对苯乙烯磺酸钠（SSS），制得功能接枝微球CPVA-g-PSSS，并采用红外光谱、扫描电镜、Zeta电位测定对接枝微球进行了表征。实验结果表明，铈盐-羟基氧化还原引发体系可有效地引发SSS在CPVA微球表面的接枝聚合,在适宜的反应条件下,可制得PSSS接枝度为16.1g/100g的接枝微球CPVA-g-PSSS。在较大pH范围内，接枝微球CPVA-g-PSSS的Zeta电位为绝对值较高的负值，即微球表面携带有大量的负电荷。
接着，考察研究了CPVA-g-PSSS对抗结肠癌药物5-氟尿嘧啶（5-FU）的吸附性能、吸附机理及体外释药特性。在酸性条件下，5-FU高度质子化，凭借静电相互作用，接枝微球CPVA-g-PSSS对5-FU表现出很强的吸附性能，吸附容量达到105mg/g，显示出良好的载药性能。随着介质pH增大，5-FU质子化减弱，静电相互作用减弱，接枝微球CPVA-g-PSSS对5-FU的吸附量减少；另外，CPVA-g-PSSS对5-FU的吸附容量随着温度的降低而增大，显示出物理吸附的特点；随离子强度的增大吸附容量下降。体外释药实验显示，载5-FU接枝微球CPVA-g-PSSS在模拟胃液(pH=1.0)中基本不释药，在模拟小肠液(pH=6.8)中有部分释药，而在模拟结肠液(pH=7.4)中有突释现象发生，表明载药微球释药具有明显的pH敏感性，是一种pH敏感型结肠定位释药系统。
在上述研究的基础上，采用铈盐-羟基氧化还原引发体系，以生物相容性微球CPVA为基质，5-氟尿嘧啶为模板分子，SSS为功能单体，N,N′-亚甲基双丙烯酰胺（MBA）为交联剂，在水溶液中实施了5-FU分子的表面印迹，制备了5-FU分子表面印迹聚合微球MIP-PSSS/CPVA。采用红外光谱(FTIR)和扫描电子显微镜(SEM)法,对印迹微球进行了表征，重点考察研究了MIP-PSSS/CPVA对5-FU的识别选择性、结合性能及体外释药行为。实验结果表明，基于本体系特殊的羟基-铈盐表面引发体系,可有效地实现5-FU分子的表面印迹,在微球CPVA表面形成分布有大量5-FU分子印迹空穴的聚合物层。MIP-PSSS/CPVA微球对5-FU具有优良的选择识别性和特异的结合亲和性，在酸性条件下，凭借静电相互作用，可实现对5-FU有效载药，结合量达到110mg/g，而印迹微球对5-FU结构类似物替加氟（TE）和尿甘（UR），结合量却很低。与上述的接枝载药微球CPVA-g-PSSS相比，印迹载药微球MIP-PSSS/CPVA不但具有pH敏感性，还具有明显的时滞性，印迹空穴对5-FU的束缚和静电相互作用的协同限制了药物的释放速度，因此导致载药印迹微球MIP-PSSS/CPVA在模拟胃液中不释药，小肠部位只有小量释药，结肠部位突释，达到了高效的结肠定位释药作用。因此，载药印迹微球MIP-PSSS/CPVA是一种新型高效的pH敏感-时滞双重型结肠定位释药系统。
对于功能接枝微球CPVA-g-PSSS，本研究还深入考察了它对抗结肠炎药物甲硝唑的吸附性能、吸附机理及体外释药特点。实验结果表明，凭借强的静电相互作用，在酸性条件下，CPVA-g-PSSS对MTZ具有高的吸附容量，达到112mg/g，也显示出良好的载药性能。随着pH值得升高，MTZ质子化减弱，静电相互作用减弱，吸附容量降低。随着介质温度的升高和盐度的增大，吸附容量降低。体外释药实验表明，载MTZ的接枝微球CPVA-g-PSSS随着释放介质pH的升高，MTZ与PSSS之间的静电相互作用减弱，累积释放率增大，显示出释药的pH敏感性，是一种pH敏感型结肠定位释药系统。
在上述研究的基础上，以生物相容性微球CPVA为基质，采用铈盐-羟基氧化还原引发体系，甲硝唑为模板分子，SSS为功能单体，N,N′-亚甲基双丙烯酰胺（MBA）为交联剂，在水溶液中实施了MTZ的分子表面印迹，制备了MTZ分子表面印迹聚合微球MIP-PSSS/CPVA；重点考察研究了MIP-PSSS/CPVA对MTZ的识别选择性、结合性能及体外释药行为。实验结果表明，MIP-PSSS/CPVA对MTZ具有高的识别选择性和亲和性，而对结构类似物替硝唑（TNZ）和奥硝唑（ONZ）基本不识别、不结合。体外释药实验显示，MTZ印迹载药微球MIP-PSSS/CPVA与接枝载药微球CPVA-g-PSSS相比，印迹载药微球MIP-PSSS/CPVA不但具有pH敏感性，还具有明显的时滞性，印迹空穴对5-FU的束缚和静电相互作用协同限制了MTZ的释放速度，因此导致载药印迹微球MIP-PSSS/CPVA在模拟胃液中不释药，小肠部位只有小量释药，结肠部位突释，达到了高效的结肠定位释药作用。因此，载药印迹微球MIP-PSSS/CPVA是一种新型高效的pH敏感-时滞双重型结肠定位释药系统。
The incidence of colon cancer and colitis are rising as people living standard rise. Thetraditional oral preparation or injection to colon concentration is low, bioavailability of drugis small, and side effects are big. In order to improve treatment effect of the local colondisease, researchers develop the oral colon specific drug delivery system (OCDDS) in recentyears. The drug delivery system can avoid drug release in the stomach and small intestine, butrelease locating in colon and rectum. The targeted delivery to colon via oral route is intendedto improve the efficacy and safety of the drug therapy by exerting high drug concentrationstopically at the disease site, enhance the bioavailability of drugs, and reduce side-effects.According to the molecule design, building and developing high efficient OCDDS is animportant research subject in the field of medicine based on physical and chemical propertiesof pharmaceutical polymers and drugs.
The pH sensitive and pH-delayed double sensitive colon specific drug release systemswere constructed by surface grafted polymerization and the molecular surface imprintingtechnology based on biocompatible crosslinked poly (vinyl alcohol)(CPVA) microspheres asthe matrix. The drug delivery systems can promote the development of OCDDS, and theyhave important scientific significance in sustained and controlled drug release research area.
Firstly, the graft-polymerization of sodium4-styrene sulfonate (SSS) was performed onthe surfaces of CPVA microspheres by using cerium salt-hydroxyl group redox initiationsystem, and the grafted microspheres CPVA-g-PSSS was obtained. The chemical structureand physicochemistry characters of CPVA-g-PSSS microspheres were adequatelycharacterized with infrared spectrum (FTIR), scanning electron microscope (SEM) anddetermining zeta potential. The experimental results show that cerium salt-hydroxyl groupredox initiation system can effectively initiate the polymerization of SSS on CPVA microspheres, and under the suitable conditions, PSSS grafting degree can get up to16.1g/100g. Zeta potential shows the grafted CPVA-g-PSSS have low negative value in a wide pHrange, namely there are higher density of negative charge on the surface of theCPVA-g-PSSS.
Then, the adsorption property of the grafted microspheres CPVA-g-PSSS for5-fluorouracil (5-FU), namely drug loading ability, was mainly investigated and theadsorption mechanism was explored. The in vitro release behavior of the drug-loadedmicrospheres was also examined. In the acidic medium, the amino groups in5-FU moleculewill be highly protonated, and a strong electrostatic interaction between CPVA-g-PSSS and5-FU molecule will be produced, resulting in high absorption capacity, reaching105mg/g,and displaying the high efficiency of drug loading. When pH value is increased, theprotonation degree of the amino groups in5-FU molecule decrease, and the electrostaticinteraction reduce, leading to low absorption capacity of grafted microspheres CPVA-g-PSSStowards5-FU. The adsorption capacity increases with temperature decreasing, showing thecharacteristic of physical absorption, and capacity reduce with the salinity rising. The in vitrorelease drug shows in the medium of pH=1, the drug does not be released, and in the mediumof pH=6.8, the part of drug is released, while in the medium of pH=7.4, the sudden deliveryphenomenon will be produced. The in vitro release behavior of the drug loading microspheresis highly pH-dependent and is a pH-sensitive drug delivery system.
Surface imprinting of5-FU was performed on CPVA microspheres with sodium4-styrene sulfonate (SSS) as functional monomer,5-FU as template and withN,N’-Methylene bisacrylamide (MBA) as crosslinker in aqueous solution by using ceriumsalt-hydroxyl group redox initiation system, and5-FU-imprinted microspheresMIP-PSSS/CPVA, on which there exists a layer of molecular imprinting cavies, wereobtained. The chemical structure and morphology of MIP-PSSS/CPVA microspheres werecharacterized with infrared spectrum (FTIR) and scanning electron microscope (SEM). Thebinding and recognizing property of the imprinted microspheres MIP-PSSS/CPVA for5-fluorouracil (5-FU), namely drug loading ability, was mainly investigated and the binding mechanism was explored. The in vitro release behavior of the drug-loaded microspheres wasalso examined. The experimental results show that based on the special cerium salt-hydroxylgroup redox initiation system in this investigation, the5-FU surface imprinting can beeffectively realized, and a polymer layer, in which a lot of5-FU-imprinted cavies aredistributed, can be formed on the surfaces of CPVA microspheres. In the acidic medium, theimprinted microspheres MIP-PSSS/CPVA exhibit very strong binding ability for5-FU bydriving of electrostatic interaction, displaying the high efficiency of drug loading, andbinding capacity reaching110mg/g. However, for relative to5-FU, MIP-PSSS/CPVAmicrospheres have low binding capacity towards tegafur (TE) and Uridine (UR). Compare tothe above5-FU-loaded CPVA-g-PSSS, in vitro release of the drug loaded MIP-PSSS/CPVAmicrospheres is not only pH-sensitive, but also time-delayed. The synergistic effect of strongelectrostatic interaction and the spatial resistance of drug molecule diffused from imprintedcavies delay effectively the drug release process and resulting in the slower release rate from5-FU-loaded MIP-PSSS/CPVA microspheres. The drug does not be released in the simulatedstomach fluid (pH=1), in the simulated intestine fluid (pH=6.8), the drug release is small, andin the simulated colon fluid (pH=7.4), the sudden delivery phenomenon will be produced,displaying an excellent colon-specific drug delivery behavior. Therefore, drug-loadedMIP-PSSS/CPVA microspheres are a new-style and high-efficient pH-delayed doublesensitive colon specific drug release systems.
The adsorption abilities and mechanism of the grafted microspheres CPVA-g-PSSS forMetronidazole (MTZ) were also studies. The in vitro release behavior of the MTZ-loadedmicrospheres was also examined. The experiment results show that CPVA-g-PSSSmicrospheres possess also very strong adsorption ability for MTZ by right of electrostaticinteraction, and the adsorption capacity reaches112mg/g. The protonation degree of theamino groups in MTZ molecule decreases when pH value increases, and the electrostaticinteraction weaken, resulting in low absorption capacity. The adsorption capacity decreaseswith the rise of temperature and this reveals the character of physical adsorption. And theincrease of salinity causes the decrease of the adsorption capacity. The in vitro release experiments show the release of the MTZ-loaded CPVA-g-PSSS microspheres increases withthe pH rises, and electrostatic interaction weakens, showing pH-sensitivity.
Subsequently, MTZ surface imprinting was performed on CPVA with sodium4-styrenesulfonate (SSS) as functional monomer, MTZ as template and N, N’-Methylenebisacrylamide (MBA) as crosslinking agent in aqueous solution by using ceriumsalt-hydroxyl group redox initiation system, and obtaining MTZ surface imprintedmicrospheres MIP-PSSS/CPVA. The binding property of the imprinted microspheresMIP-PSSS/CPVA for MTZ, namely drug loading ability, was mainly investigated profoundlywith static method and the binding mechanism was explored. The in vitro release behavior ofthe drug-loaded microspheres was also examined. The experimental results show that in theacidic medium, the MIP-PSSS/CPVA microspheres exhibit very strong binding ability forMTZ by driving of electrostatic interaction while the binding ability is weak for Tinidazole(TNZ) and Ornidazole (ONZ). The in vitro release of the MTZ-loaded MIP-PSSS/CPVA isnot only pH-sensitive but also time-delayed in contrast to MTZ-loaded CPVA-g-PSSS. Thesynergistic effect of strong electrostatic interaction and the spatial resistance of drug moleculediffused from imprinted cavies delay effectively the drug release process and resulting in theslower release rate from MTZ-loaded MIP-PSSS/CPVA microspheres. The release behaviorshows in simulated gastric fluid (pH=1), the drug do not be released, and in the simulatedsmall intestine fluid (pH=6.8), the drug release is smaller, whereas, in the simulated colonfluid (pH=7.4), an abrupt release will be firstly produced and then sustained and slowedrelease occur, displaying an excellent pH-delayed double sensitive colon specific drug releasesystems.
引文
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