口服胰岛素聚合物纳米粒：制备及其结构—性能关系
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摘要
注射胰岛素是治疗胰岛素依赖的I型糖尿病的一种传统方法，具有血糖控制不稳、每日多次注射、病人顺应性差的缺点。口服胰岛素是一种病人适用性好、服用方便的给药方式，符合内生胰岛素的分泌模式。但胰岛素口服给药时面临胃肠道酶降解和膜通透性差等多重障碍。聚合物纳米粒用于口服胰岛素给药载体时，能防止胰岛素不被酶降解，同时可以促进胰岛素吸收，有效改善其口服生物利用度。聚合物纳米粒的性能不仅由载体材料、药物的组成决定，还由颗粒的结构特性决定。研究胰岛素聚合物纳米粒的制备及其结构-性能关系，对多肽和蛋白质药物口服给药系统的设计和开发具有重要的意义。
采用改进的复乳溶剂挥发法，制备了载胰岛素的乳酸羟基乙酸共聚物/羟丙基甲基纤维素邻苯二甲酸酯（PLGA/HP55）纳米粒。通过改进复乳中油相溶剂组成以及正交实验设计，以粒径、包封率和突释程度为评价指标，优化了纳米粒的制备工艺。表征了纳米粒的形貌、粒径、胰岛素载药及体外释放，评价了胰岛素PLGA/HP55纳米粒的口服给药效果。结果表明，制得的纳米粒粒径为181nm，分散良好，为球形实体粒子；具有较好的pH敏感释放性能。糖尿病大鼠口服该纳米粒后1-8h，显示出快速和持续的降血糖效果，相对生物利用度达11.3%。
设计和制备了一种两级载体给药系统。一级载体为HP55包衣胶囊，保护纳米粒通过胃部；二级载体为乳酸羟基乙酸共聚物/尤特奇树脂RS100（PLGA/RS）纳米粒，肠溶胶囊在肠上部区域溶解后释放纳米粒，纳米粒粘附在肠上皮细胞促进胰岛素吸收。载胰岛素的PLGA/RS纳米粒采用超声乳化的复乳溶剂挥发法制备。通过对包封率和粒径的影响因素分析，确定了胰岛素PLGA/RS纳米粒的制备工艺。研究了制备参数对包封率和粒径的影响，表征了纳米粒的物理化学性质，如形貌、粒径、电位、载药能力及纳米粒在模拟肠胃介质下的稳定性。对该二级载体给药系统的体外释放性能和糖尿病大鼠口服后的体内生物活性进行了评价。PLGA/RS纳米粒粒径285nm，分散良好；具有正的zeta电位42mV；包封率和载药量分别为73.9%和6.7%；药效利用度达到9.8%。
利用聚乙二醇(PEG)分子修饰蛋白质多肽药物是延长药物在体内半衰期的一个有效途径，将修饰产物用pH敏感聚合物包载，制备成pH响应释放的聚合物纳米粒，可减少胃肠内蛋白酶对药物的降解作用，增加肠道的吸收。通过聚合物载体材料的筛选，选择分子量100000的聚乳酸（PLA）作为载体材料，复乳溶剂挥发法制备了载聚乙二醇化胰岛素的PLA/HP55纳米粒。性能表征结果表明，纳米粒粒径251nm，颗粒分散良好，包封率91%；在模拟胃酸下减少突释，模拟肠液中释放超过70%，pH敏感释放性能比较好。载聚乙二醇胰岛素的pH敏感纳米粒结合了药物半衰期长和纳米粒pH敏感释放的特性，是一种潜在的新型长效口服降血糖制剂。
最后，以pH敏感纳米粒作为研究体系，探讨聚合物纳米粒的结构-性能关系。采用二甲基亚砜（DMSO）和丙酮/水两种溶剂，通过乳液溶剂扩散法制备胰岛素PLGA/HP55聚合物纳米粒。通过组分溶解度参数、DSC和FTIR的研究显示，两种溶剂下制备的胰岛素聚合物纳米粒中，混合聚合物发生相分离，胰岛素主要分布聚合物HP55相中。纳米粒孔隙度结果表明，采用DMSO作溶剂制备的PLGA/HP55纳米粒具有较多的介孔。胰岛素可以直接从介孔中释放出来，纳米粒不具有pH敏感性。丙酮/水作溶剂制备的较少介孔的纳米粒中，胰岛素释放具有pH敏感性，纳米粒在酸性条件下胰岛素释放少，而在碱性条件下，由于pH敏感聚合物的溶解，胰岛素有效释放出来。
本文在化学产品设计的理论和方法的指导下，针对胰岛素口服给药过程中面临的障碍，提出了对聚合物纳米粒的结构进行设计与改进的方案，制备的聚合物纳米粒具有潜口服给药的潜在应用，对开发具有高生物利用度的胰岛素聚合物纳米粒具有指导作用。
Oral insulin delivery is the convenient way to diabetic patients as it is the mostphysiological and comfortable means. However, it is a tough task for orally deliveringbioactive macromolecules, due to the highly organized array of barriers existed in thegastrointestinal (GI) tract, such as rapid enzymatic degradation and the poor intestinalabsorption. The polymeric nanoparticles protect insulin against degradation and facilitate theuptake of insulin through a paracellular or a transcellular pathway. Insulin loadedpH-sensitive nanoparticles, mucoadhesiven nanoparticles and PEGylated insulin loadedpH-sensitive nanoparticles were prepared and investigated as oral delivery systems for insulindelivery. With pH-sensitive nanoparticle as a model nanoparticle, the structure-performancerelationship of nanoparticle with different preparation condition was also evaluated.
According to the principle of multiple emulsions solvent evaporation method, theinsulin-loaded poly (lactic-co-glycolic acid)/hydroxypropyl methylcellulose phthalate(PLGA/HP55) nanoparticles were prepared. The physicochemical characteristics, in vitrorelease of insulin and in vivo efficacy in diabetic rats of the nanoparticles were evaluated. Thenanoparticles showed the size of181nm, encapsulation efficiency of94%and goodpH-sensitive release property. When administered orally to diabetic rats, the nanoparticles candecrease rapidly the blood glucose level with a maximal effect between1and8h. Therelative bioavailability compared with subcutaneous injection (5IU/kg) in diabetic rats was11.3%.
By filling of the mucoadhesive nanoparticles into the enteric capsule, we design andprepared a two-stage carrier delivery system. The stage-1carrier is the hard gelatin capsulescoated with pH sensitive enteric polymer, hydroxypropyl methylcellulose phthalate (HP55),which used to protect the nanoparticles through the stomach. The stage-2carrier is theinsulin-loaded cationic nanoparticles composed of the poly (lactic-co-glycolic acid)(PLGA)and Eurdragit RS (RS).The cationic nanoparticles aim to open the tight junction andenhance the absorption of released insulin. The nanoparticles were prepared with the multipleemulsions solvent evaporation method via ultrasonic emulsification. The optimizednanoparticles have a mean size of285nm, a positive zeta potential of42mV. The encapsulation efficiency was up to73.9%. In vitro results revealed that the initial burst releaseof insulin from nanoparticles was markedly reduced at pH1.2, which mimics the stomachenvironment. In vivo effects of the capsule containing insulin PLGA/RS nanoparticles werealso investigated in diabetic rat models. The oral delivered capsules induced a prolongedreduction in blood glucose levels. The pharmacological availability was found to beapproximately9.2%.
PEGylation is an effective method to prolong the circulation half-life of insulin in vivo,recogition by the immune system and degradation by proteolytic enzymes. We designed andevaluated the feasibility combining insulin PEGylated insulin (PEG-ins) with pH-sensitivenanoparticles for oral insulin delivery. As we introduced the PLA (Mw=100000) as the carriermaterials, the pH-sensitive release of PEG-ins from the nanoparticles was improved. Morethan70%of insulin could be released from the PLA/HP55nanoparticles with the91%ofencapsulation efficiency. All the results of in vitro indicated that the integration of PLA/HP55nanoparticles with PEG-ins may be a promising approach for oral delivery of insulin withhighly potential bioavailability.
At last, with pH-sensitive nanopartice as a model nanoparticle, thestructure-performance relationship of nanoparticle with different preparation condition wasalso evaluated. The PLGA/HP55nanoparticles were prepared via the emulsions solventdiffusion method with two different solvents, namely, DMSO and acetone/water. Themicrostructures of the nanoparticles were studied by the solubility parameters theory, DSC,FTIR, and the nitrogen adsorption technique. Phase-separated PLGA domains were observedfrom the nanoparticles prepared with both types of solvents. Mesopores were observed fromthe nanoparticles prepared with DMSO as the solvent and almost didn’t exist withacetone/water. The formation of mesopores accelerated the release of insulin, leading to noobvious pH-sensitivity of the nanoparticles prepared with DMSO. However, for thenanoparticles prepared with acetone/water, the release of insulin was pH-dependent.
采用改进的复乳溶剂挥发法，制备了载胰岛素的乳酸羟基乙酸共聚物/羟丙基甲基纤维素邻苯二甲酸酯（PLGA/HP55）纳米粒。通过改进复乳中油相溶剂组成以及正交实验设计，以粒径、包封率和突释程度为评价指标，优化了纳米粒的制备工艺。表征了纳米粒的形貌、粒径、胰岛素载药及体外释放，评价了胰岛素PLGA/HP55纳米粒的口服给药效果。结果表明，制得的纳米粒粒径为181nm，分散良好，为球形实体粒子；具有较好的pH敏感释放性能。糖尿病大鼠口服该纳米粒后1-8h，显示出快速和持续的降血糖效果，相对生物利用度达11.3%。
设计和制备了一种两级载体给药系统。一级载体为HP55包衣胶囊，保护纳米粒通过胃部；二级载体为乳酸羟基乙酸共聚物/尤特奇树脂RS100（PLGA/RS）纳米粒，肠溶胶囊在肠上部区域溶解后释放纳米粒，纳米粒粘附在肠上皮细胞促进胰岛素吸收。载胰岛素的PLGA/RS纳米粒采用超声乳化的复乳溶剂挥发法制备。通过对包封率和粒径的影响因素分析，确定了胰岛素PLGA/RS纳米粒的制备工艺。研究了制备参数对包封率和粒径的影响，表征了纳米粒的物理化学性质，如形貌、粒径、电位、载药能力及纳米粒在模拟肠胃介质下的稳定性。对该二级载体给药系统的体外释放性能和糖尿病大鼠口服后的体内生物活性进行了评价。PLGA/RS纳米粒粒径285nm，分散良好；具有正的zeta电位42mV；包封率和载药量分别为73.9%和6.7%；药效利用度达到9.8%。
利用聚乙二醇(PEG)分子修饰蛋白质多肽药物是延长药物在体内半衰期的一个有效途径，将修饰产物用pH敏感聚合物包载，制备成pH响应释放的聚合物纳米粒，可减少胃肠内蛋白酶对药物的降解作用，增加肠道的吸收。通过聚合物载体材料的筛选，选择分子量100000的聚乳酸（PLA）作为载体材料，复乳溶剂挥发法制备了载聚乙二醇化胰岛素的PLA/HP55纳米粒。性能表征结果表明，纳米粒粒径251nm，颗粒分散良好，包封率91%；在模拟胃酸下减少突释，模拟肠液中释放超过70%，pH敏感释放性能比较好。载聚乙二醇胰岛素的pH敏感纳米粒结合了药物半衰期长和纳米粒pH敏感释放的特性，是一种潜在的新型长效口服降血糖制剂。
最后，以pH敏感纳米粒作为研究体系，探讨聚合物纳米粒的结构-性能关系。采用二甲基亚砜（DMSO）和丙酮/水两种溶剂，通过乳液溶剂扩散法制备胰岛素PLGA/HP55聚合物纳米粒。通过组分溶解度参数、DSC和FTIR的研究显示，两种溶剂下制备的胰岛素聚合物纳米粒中，混合聚合物发生相分离，胰岛素主要分布聚合物HP55相中。纳米粒孔隙度结果表明，采用DMSO作溶剂制备的PLGA/HP55纳米粒具有较多的介孔。胰岛素可以直接从介孔中释放出来，纳米粒不具有pH敏感性。丙酮/水作溶剂制备的较少介孔的纳米粒中，胰岛素释放具有pH敏感性，纳米粒在酸性条件下胰岛素释放少，而在碱性条件下，由于pH敏感聚合物的溶解，胰岛素有效释放出来。
本文在化学产品设计的理论和方法的指导下，针对胰岛素口服给药过程中面临的障碍，提出了对聚合物纳米粒的结构进行设计与改进的方案，制备的聚合物纳米粒具有潜口服给药的潜在应用，对开发具有高生物利用度的胰岛素聚合物纳米粒具有指导作用。
Oral insulin delivery is the convenient way to diabetic patients as it is the mostphysiological and comfortable means. However, it is a tough task for orally deliveringbioactive macromolecules, due to the highly organized array of barriers existed in thegastrointestinal (GI) tract, such as rapid enzymatic degradation and the poor intestinalabsorption. The polymeric nanoparticles protect insulin against degradation and facilitate theuptake of insulin through a paracellular or a transcellular pathway. Insulin loadedpH-sensitive nanoparticles, mucoadhesiven nanoparticles and PEGylated insulin loadedpH-sensitive nanoparticles were prepared and investigated as oral delivery systems for insulindelivery. With pH-sensitive nanoparticle as a model nanoparticle, the structure-performancerelationship of nanoparticle with different preparation condition was also evaluated.
According to the principle of multiple emulsions solvent evaporation method, theinsulin-loaded poly (lactic-co-glycolic acid)/hydroxypropyl methylcellulose phthalate(PLGA/HP55) nanoparticles were prepared. The physicochemical characteristics, in vitrorelease of insulin and in vivo efficacy in diabetic rats of the nanoparticles were evaluated. Thenanoparticles showed the size of181nm, encapsulation efficiency of94%and goodpH-sensitive release property. When administered orally to diabetic rats, the nanoparticles candecrease rapidly the blood glucose level with a maximal effect between1and8h. Therelative bioavailability compared with subcutaneous injection (5IU/kg) in diabetic rats was11.3%.
By filling of the mucoadhesive nanoparticles into the enteric capsule, we design andprepared a two-stage carrier delivery system. The stage-1carrier is the hard gelatin capsulescoated with pH sensitive enteric polymer, hydroxypropyl methylcellulose phthalate (HP55),which used to protect the nanoparticles through the stomach. The stage-2carrier is theinsulin-loaded cationic nanoparticles composed of the poly (lactic-co-glycolic acid)(PLGA)and Eurdragit RS (RS).The cationic nanoparticles aim to open the tight junction andenhance the absorption of released insulin. The nanoparticles were prepared with the multipleemulsions solvent evaporation method via ultrasonic emulsification. The optimizednanoparticles have a mean size of285nm, a positive zeta potential of42mV. The encapsulation efficiency was up to73.9%. In vitro results revealed that the initial burst releaseof insulin from nanoparticles was markedly reduced at pH1.2, which mimics the stomachenvironment. In vivo effects of the capsule containing insulin PLGA/RS nanoparticles werealso investigated in diabetic rat models. The oral delivered capsules induced a prolongedreduction in blood glucose levels. The pharmacological availability was found to beapproximately9.2%.
PEGylation is an effective method to prolong the circulation half-life of insulin in vivo,recogition by the immune system and degradation by proteolytic enzymes. We designed andevaluated the feasibility combining insulin PEGylated insulin (PEG-ins) with pH-sensitivenanoparticles for oral insulin delivery. As we introduced the PLA (Mw=100000) as the carriermaterials, the pH-sensitive release of PEG-ins from the nanoparticles was improved. Morethan70%of insulin could be released from the PLA/HP55nanoparticles with the91%ofencapsulation efficiency. All the results of in vitro indicated that the integration of PLA/HP55nanoparticles with PEG-ins may be a promising approach for oral delivery of insulin withhighly potential bioavailability.
At last, with pH-sensitive nanopartice as a model nanoparticle, thestructure-performance relationship of nanoparticle with different preparation condition wasalso evaluated. The PLGA/HP55nanoparticles were prepared via the emulsions solventdiffusion method with two different solvents, namely, DMSO and acetone/water. Themicrostructures of the nanoparticles were studied by the solubility parameters theory, DSC,FTIR, and the nitrogen adsorption technique. Phase-separated PLGA domains were observedfrom the nanoparticles prepared with both types of solvents. Mesopores were observed fromthe nanoparticles prepared with DMSO as the solvent and almost didn’t exist withacetone/water. The formation of mesopores accelerated the release of insulin, leading to noobvious pH-sensitivity of the nanoparticles prepared with DMSO. However, for thenanoparticles prepared with acetone/water, the release of insulin was pH-dependent.
引文
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