CN114848832A - 一种调控l细胞分泌glp-1的结肠靶向控释递送系统和应用 - Google Patents
一种调控l细胞分泌glp-1的结肠靶向控释递送系统和应用 Download PDFInfo
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Abstract
本发明公开了一种调控L细胞分泌GLP‑1的结肠靶向控释递送系统和应用，所述递送系统由辛烯基琥珀酸酯淀粉和磷脂制备的复合物与游离磷脂自组装而成，其粒径为230.8nm‑256.8nm，电位为‑9mV～10.9mV，抗消化淀粉含量为46.80％‑52.45％，活性蛋白在结肠的累计释放量为58.75％‑76.27％。该发明方法在OSA淀粉磷脂复合物中引入游离磷脂分子，通过调节游离磷脂分子在淀粉疏水空腔内外的分布提高递送系统对食品功能因子的装载效率，改善递送系统结肠靶向控释特性，有效调控L细胞分泌GLP‑1，可在制备预防糖尿病食品功能因子中应用或者在预防和治疗糖尿病药物中应用。
Description
技术领域
本发明涉及一种淀粉基载体材料，特别涉及一种调控L细胞分泌GLP-1的结肠靶向控释递送系统及其制备方法。
背景技术
糖尿病会引起高血糖、高血脂和乳酸性中毒等人体糖代谢和脂代谢紊乱并发症，已成为严重危害人体健康的世界性公共卫生问题，而糖尿病患者中有90％以上的患者为Ⅱ型糖尿病。膳食干预是针对Ⅱ型糖尿病预防和治疗最有效的方法(专利：一种供糖尿病患者食用含短肽的特殊膳食用食品配方，ZL200810006609.4)。GLP-1是由肠道L细胞分泌的一种胃肠道激素，能够缓解胃肠蠕动、刺激胰岛素分泌及降低人体食欲。通过诱导L细胞分泌GLP-1可调控人体胰岛素分泌及血糖平衡，从而实现对Ⅱ型糖尿病预防和治疗。
L细胞是一种主要分布在结肠部位的内分泌细胞。功能性多糖、β乳球蛋白、不饱和脂肪酸和酚类化合物等食品功能因子均能刺激L细胞分泌GLP-1。但是食品功能因子在到达L细胞所在结肠部位前，面临上消化道胃酸、胃蛋白酶、胰蛋白酶、胰脂肪酶、胰淀粉酶、胆盐以及消化道粘膜吸收等多重生理屏障，使食品功能因子在上消化道转运过程中被降解和吸收，最终无法到达L细胞表面或到达L细胞表面后丧失刺激L细胞的能力。因此需要构建结肠靶向控释系统将食品功能因子稳态化递送至结肠，并利用其调控L细胞分泌GLP-1，以实现预防和治疗糖尿病等血糖失稳病症的目标。
消化道细胞表面覆盖有带负电荷、孔径为200-300nm的黏液层。因此，调控L细胞分泌GLP-1的控释系统首先需要具备：(1)良好的抗消化性能；(2)表面带负电荷，使其不被肠粘膜吸引或穿过肠粘膜被细胞吸收，粒径大于200nm；(3)具有结肠靶向智能响应性，使控释系统特定基团裸露或较好释放能与L细胞相互作用的功能因子。目前，构建装载活性物质调控L细胞分泌GLP-1的控释系统鲜见报道。Xu等人发现谷氨酰胺在体外实验中可以有效触发GLP-1分泌，但被包埋后，对GLP-1的分泌和葡萄糖耐量没有显著影响。Shrestha等人采用高压均质制备了包埋艾塞那肽或利拉鲁肽的Precirol ATO固体脂质纳米颗粒。体外实验表明脂质载体可以有效诱导GLP-1分泌，但是肠内施用的脂质载体被粘附在黏液层上，没有产生任何降糖效果。因此用于调控L细胞分泌GLP-1控释系统的设计与构建仍面临较大的挑战。需要更多的研究来找到最佳的封装条件保证食品功能因子缓慢释放和GLP-1持续分泌。
磷脂不仅具有良好的油水界面稳定性，还可以与L细胞相互作用并诱导其分泌GLP-1，因此常常被用作脂质体、胶束、磷脂/功能因子复合物和磷脂螺旋等药物或功能因子结肠靶向递送载体。虽然磷脂载体直接与L细胞培养时，可以有效诱导GLP-1分泌。但是口服之后容易被胃肠道降解，降糖效果不明显，而且当脂质载体中表面活性剂的含量大于2mg/ml时，会产生毒性导致细胞活力降低。Ana Beloqui等人利用表面活性剂协同乳液相温度转变技术构建得到荷载艾塞那肽等的固体脂质纳米颗粒，可有效释放药物刺激L细胞分泌GLP-1。但是离体研究显示脂质纳米颗粒容易被束缚在黏液层，到达L细胞表面的效率较低，而且糖尿病类药物存在潜在副作用。目前，如何制备安全且能将功能因子靶向递送至结肠刺激L细胞分泌GLP-1的磷脂递送系统仍面临很多问题。
发明内容
为了解决现有递送系统易降解和到达L细胞效率较低的不足之处，本发明的首要目的是提供一种调控L细胞分泌GLP-1的结肠靶向控释递送系统及其制备方法；利用辛烯基琥珀酸酯淀粉(OSA淀粉)与磷脂形成复合物，并与游离磷脂分子共同构建递送系统装载食品功能因子。通过调节复合物与游离磷脂的比例，获得不同消化特性、界面性质及控释特性的递送系统，并且通过控释系统释放功能因子及磷脂触发L细胞分泌GLP-1。该递送系统具有良好的抗消化、结肠靶向控释性能和调控L细胞分泌GLP-1的能力；生物相容性好；完全无毒。
本发明的另一目的在于提供一种上述具有调控L细胞分泌GLP-1的结肠靶向控释递送系统的应用。
本发明的目的通过下述技术方案来实现：
一种调控L细胞分泌GLP-1的结肠靶向控释递送系统，所述递送系统由辛烯基琥珀酸酯淀粉和磷脂制备的复合物与游离磷脂自组装而成，其粒径为230.8nm-256.8nm，电位为-9mV～10.9mV，抗消化淀粉含量为46.80％-52.45％，活性蛋白在结肠的累计释放量为58.75％-76.27％。
优选地，所述调控L细胞分泌GLP-1的结肠靶向控释递送系统的制备方法包括以下步骤：
(1)将辛烯基琥珀酸酯淀粉与磷脂混合，制备淀粉/磷脂复合物，将上述复合物加入水中，加热溶解，离心取上清液，得到淀粉/磷脂复合物溶液；经检测磷脂的含量为24.58-27.41(mg/g淀粉)；
(2)向获得的淀粉/磷脂复合物溶液，加入磷脂的乙醇溶液，在35-65℃条件下加热1.0-3.0h，调节溶液pH为2.0-4.0；之后再向上述溶液中缓慢加入带正电荷的活性蛋白水溶液，进行自组装，得到装载活性蛋白的调控L细胞分泌GLP-1的结肠靶向控释递送系统。
优选地，步骤(1)所述辛烯基琥珀酸酯淀粉的分子量为3.98×104-5.06×104g/mol，辛烯基琥珀酸酯取代度为0.0192-0.0197。
优选地，步骤(1)所述淀粉/磷脂复合物中磷脂的含量为24.58-27.41(mg/g淀粉)，所述的磷脂为大豆卵磷脂、蛋黄卵磷脂和牛奶卵磷脂中的一种或两种以上。
优选地，步骤(2)所述淀粉/磷脂复合物和游离磷脂的质量比为(3.75-30)：1；更优选地，所述淀粉/磷脂复合物和游离磷脂的质量比为(3.75-25)：1。
优选地，步骤(2)淀粉/磷脂复合物溶液的浓度为1～10mg/ml；磷脂的乙醇溶液浓度为0.2-1.6mg/ml。
优选地，步骤(1)所述加热溶解的条件为：80～100℃下加热30～60min。
优选地，步骤(2)加热温度为50-65℃，时间1-2h；自组装温度为20-35℃，时间为10±5min。
优选地，所述的带正电的活性蛋白为β-乳球蛋白或乳清蛋白；带正电荷的活性蛋白水溶液的浓度为1～5mg/ml；所述淀粉/磷脂复合物与活性蛋白的质量比为(1～5)：1，更优选地，所述淀粉/磷脂复合物与活性蛋白的质量比为2-3:1。
上述结肠靶向控释递送系统在制备预防糖尿病食品功能因子中应用或者在预防和治疗糖尿病药物中应用。
本发明与现有技术相比，具有如下优点和有益效果：
(1)本发明利用淀粉/磷脂复合物与游离磷脂协同制备了具有结肠靶向控释功能的淀粉/磷脂复合递送系统，产品具有良好的带电性能和抗消化性能，生物相容性好、安全无毒。
(2)本发明制备的递送系统可以提高带正电荷活性蛋白的装载效率和不同加工环境(稀释、盐离子及pH)、储存条件稳定性及带正电荷活性蛋白的结肠靶向控释功能(结肠靶向释放率可达76％)。
(3)通过调控磷脂在淀粉疏水空腔内外分布，获得不同消化特性、界面性质及控释特性的淀粉与磷脂复合递送系统，并且通过控释系统释放功能因子及磷脂触发L细胞分泌GLP-1。
(4)本发明结肠靶向控释递送系统，应用于食品功能因子稳态化递送诱导L细胞分泌GLP-1，进而调控人体血糖水平。
附图说明
图1为实施例1-9中装载β-乳球蛋白的淀粉磷脂复合递送系统在胃液，小肠和结肠中消化一定时间的释放性能图。
图2为实施例10-12中装载乳清蛋白的淀粉磷脂复合递送系统在胃液，小肠和结肠中消化一定时间的释放性能图。
图3为实施例1-9中装载β-乳球蛋白的淀粉磷脂复合递送系统经上消化道处理后与细胞培养不同时间对L细胞分泌GLP-1的影响效果图。
图4为实施例10-12中装载乳清蛋白的淀粉磷脂复合递送系统经上消化道处理后与细胞培养不同时间对L细胞分泌GLP-1的影响效果图。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1
(1)称取取代度为0.0192，分子量为5.06×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于80℃下加热60min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为24.58(mg/g淀粉)。
(2)递准确配置2mL浓度为1mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为0.2mg/ml的磷脂乙醇溶液(淀粉与磷脂复合物和游离磷脂质量比为5：1)，65℃下加热1h，在不断搅拌的条件下调节溶液pH为2.0。向上述溶液中缓慢加入2mL浓度为1.0mg/ml的β-乳球蛋白水溶液，于35℃下组装5min，得到装载β-乳球蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为231.3nm，电位为-9.0mV，抗消化淀粉含量为46.80％，β-乳球蛋白的结肠靶向累计释放量为64.76％，L细胞分泌GLP-1的含量为11.2pg/mL。
实施例2
(1)称取取代度为0.0197，分子量为4.84×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为26.24(mg/g淀粉)。
(2)准确配置2mL浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为1.6mg/ml的磷脂乙醇溶液(淀粉与磷脂复合物和游离磷脂质量比为3.75:1)，35℃下加热3h，在不断搅拌的条件下调节溶液pH为2.0。向上述溶液中缓慢加入2mL浓度为3.0mg/ml的β-乳球蛋白水溶液，于35℃下组装10min，得到装载β-乳球蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为250.8nm，电位为-10.6mV，抗消化淀粉含量为51.25％，β-乳球蛋白的结肠靶向累计释放量为74.27％，L细胞分泌GLP-1的含量为13.6pg/mL。
实施例3
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确配置2mL浓度为10mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为0.4mg/ml的磷脂乙醇溶液(淀粉磷脂复合物和游离磷脂质量比为25:1)，50℃下加热2h，在不断搅拌的条件下调节溶液pH为2.0。向上述溶液中缓慢加入2mL浓度为2.0mg/ml的β-乳球蛋白水溶液，于35℃下组装15min，得到装载β-乳球蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为256.2nm，电位为-10.8mV，抗消化淀粉含量为50.90％，β-乳球蛋白的结肠靶向累计释放量为72.25％，L细胞分泌GLP-1的含量为13.2pg/mL。
实施例4
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确配置2mL浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为1.6mg/ml的磷脂乙醇溶液(淀粉磷脂复合物和游离磷脂质量比为3.75:1)，65℃下加热2h，在不断搅拌的条件下调节溶液pH为4.0。向上述溶液中缓慢加入2mL浓度为3.0mg/ml的β-乳球蛋白水溶液，于35℃下组装10min，得到装载β-乳球蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为252.8nm，电位为-10.9mV，抗消化淀粉含量为52.45％，β-乳球蛋白的结肠靶向累计释放量为76.27％，L细胞分泌GLP-1的含量为14.9pg/mL。
实施例5
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确配置2mL浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为1.2mg/ml的磷脂乙醇溶液(淀粉磷脂复合物和游离磷脂质量比为5:1)，65℃下加热2h，在不断搅拌的条件下调节溶液pH为4.0。向上述溶液中缓慢加入2mL浓度为3.0mg/ml的β-乳球蛋白水溶液，于35℃下组装10min，得到装载β-乳球蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统,该结肠靶向递送系统粒径为248.6nm，电位为-10.0mV，抗消化淀粉含量为51.82％，β-乳球蛋白的结肠靶向累计释放量为73.25％，L细胞分泌GLP-1的含量为13.8pg/mL。
实施例6
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确配置2mL浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为0.8mg/ml的磷脂乙醇溶液(淀粉磷脂复合物和游离磷脂质量比为7.5:1)，65℃下加热2h，在不断搅拌的条件下调节溶液pH为4.0。向上述溶液中缓慢加入2mL浓度为3.0mg/ml的β-乳球蛋白水溶液，于35℃下组装10min，得到装载β-乳球蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为249.4nm，电位为-10.3mV，抗消化淀粉含量为51.40％，β-乳球蛋白的结肠靶向累计释放量为74.23％，L细胞分泌GLP-1的含量为13.5pg/mL。
实施例7
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确配置2mL浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为0.4mg/ml的磷脂乙醇溶液(淀粉磷脂复合物和游离磷脂质量比为15:1)，65℃下加热2h，在不断搅拌的条件下调节溶液pH为4.0。向上述溶液中缓慢加入2mL浓度为3.0mg/ml的β-乳球蛋白水溶液，于35℃下组装10min，得到装载β-乳球蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为249.0nm，电位为-9.5mV，抗消化淀粉含量为50.80％，β-乳球蛋白的结肠靶向累计释放量为71.23％，L细胞分泌GLP-1的含量为12.7pg/mL。
实施例8
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确配置2mL浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为0.2mg/ml的磷脂乙醇溶液(淀粉磷脂复合物和游离磷脂质量比为30:1)，65℃下加热2h，在不断搅拌的条件下调节溶液pH为4.0。向上述溶液中缓慢加入2mL浓度为3.0mg/ml的β-乳球蛋白水溶液，于35℃下组装10min，得到装载β-乳球蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为230.8nm，电位为-9.2mV，抗消化淀粉含量为47.60％，β-乳球蛋白的结肠靶向累计释放量为71.03％，L细胞分泌GLP-1的含量为12.2pg/mL。
实施例9
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确配置2mL浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，65℃下加热2h，在不断搅拌的条件下调节溶液pH为4.0。向上述溶液中缓慢加入2mL浓度为3.0mg/ml的β-乳球蛋白水溶液，于35℃下组装10min，得到装载β-乳球蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为256.8nm，电位为-9.0mV，抗消化淀粉含量为48.20％，β-乳球蛋白的结肠靶向累计释放量为58.75％，L细胞分泌GLP-1的含量为9.0pg/mL。
实施例10
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确2mL配置浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为1.6mg/ml的磷脂乙醇溶液(淀粉磷脂复合物和游离磷脂质量比为3.75:1)，65℃下加热2h，在不断搅拌的条件下调节溶液pH为4.0。向上述溶液中缓慢加入2mL浓度为5.0mg/ml的乳清蛋白水溶液，于35℃下组装5min，得到装载乳清蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为251.8nm，电位为-10.6mV，抗消化淀粉含量为51.58％，乳清蛋白的结肠靶向累计释放量为73.76％，L细胞分泌GLP-1的含量为14.2pg/mL。
实施例11
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确2mL配置浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为1.6mg/ml的磷脂乙醇溶液(淀粉磷脂复合物和游离磷脂质量比为3.75:1)，65℃下加热2h，在不断搅拌的条件下调节溶液pH为4.0。向上述溶液中缓慢加入2mL浓度为3.0mg/ml的乳清蛋白水溶液，于25℃下组装10min，得到装载乳清蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为252.7nm，电位为-10.4mV，抗消化淀粉含量为51.12％，乳清蛋白的结肠靶向累计释放量为72.76％，L细胞分泌GLP-1的含量为13.8pg/mL。
实施例12
(1)称取取代度为0.0196，分子量为3.98×104g/mol的辛烯基琥珀酸酯淀粉，采用水/DMSO反溶剂法(水/DMSO比例为1/1.5)制备淀粉/磷脂复合物(Lalush,I.,Bar,H.,Zakaria,I.,Eichler,S.,and Shimoni,E.(2005).Utilization of amylose-lipidcomplexes as molecularnanocapsules for conjugated linoleicacid.Biomacromolecules,6,121-130)，将其加入水中，于100℃下加热30min，离心取上清液，得到淀粉/磷脂复合物的溶液，经检测复合物中磷脂含量为27.41(mg/g淀粉)。
(2)准确2mL配置浓度为6mg/ml步骤(1)中获得的淀粉/磷脂复合物溶液，加入2mL浓度为1.6mg/ml的磷脂乙醇溶液(淀粉磷脂复合物和游离磷脂质量比为3.75:1)，65℃下加热2h，在不断搅拌的条件下调节溶液pH为4.0。向上述溶液中缓慢加入2mL浓度为3.0mg/ml的乳清蛋白水溶液，于20℃下组装15min，得到装载乳清蛋白的具有调控L细胞分泌GLP-1的结肠靶向控释递送系统，该结肠靶向递送系统粒径为254.3nm，电位为-9.8mV，抗消化淀粉含量为51.09％，乳清蛋白的结肠靶向累计释放量为70.96％，L细胞分泌GLP-1的含量为12.6pg/mL。
Claims (10)
1.一种调控L细胞分泌GLP-1的结肠靶向控释递送系统，其特征在于，所述递送系统由辛烯基琥珀酸酯淀粉和磷脂制备的复合物与游离磷脂自组装而成，其粒径为230.8nm-256.8nm，电位为-9mV～10.9mV，抗消化淀粉含量为46.80％-52.45％，活性蛋白在结肠的累计释放量为58.75％-76.27％。
2.根据权利要求1所述的结肠靶向控释递送系统，其特征在于，制备方法包括以下步骤：
(1)将辛烯基琥珀酸酯淀粉与磷脂混合，制备淀粉/磷脂复合物，将上述复合物加入水中，加热溶解，离心取上清液，得到淀粉/磷脂复合物溶液；
(2)向获得的淀粉/磷脂复合物溶液，加入磷脂的乙醇溶液，在35-65℃条件下加热1.0-3.0h，调节溶液pH为2.0-4.0；之后再向上述溶液中缓慢加入带正电荷的活性蛋白水溶液，进行自组装，得到装载活性蛋白的调控L细胞分泌GLP-1的结肠靶向控释递送系统。
3.根据权利要求2所述的结肠靶向控释递送系统，其特征在于，步骤(1)所述辛烯基琥珀酸酯淀粉的分子量为3.98×104-5.06×104g/mol，辛烯基琥珀酸酯取代度为0.0192-0.0197。
4.根据权利要求3所述的结肠靶向控释递送系统，其特征在于，步骤(1)所述淀粉/磷脂复合物中磷脂的含量为24.58-27.41(mg/g淀粉)，所述的磷脂为大豆卵磷脂、蛋黄卵磷脂和牛奶卵磷脂中的一种或两种以上。
5.根据权利要求4所述的结肠靶向控释递送系统，其特征在于，步骤(2)所述淀粉/磷脂复合物和游离磷脂的质量比为(3-30)：1。
6.根据权利要求1～5任意一项所述的结肠靶向控释递送系统，其特征在于，步骤(2)淀粉/磷脂复合物溶液的浓度为1～10mg/ml；磷脂的乙醇溶液浓度为0.2-1.6mg/ml；所述淀粉/磷脂复合物和游离磷脂的质量比为(3.75-25)：1。
7.根据权利要求1～5任意一项所述的结肠靶向控释递送系统，其特征在于，步骤(1)所述加热溶解的条件为：80～100℃下加热30～60min。
8.根据权利要求1～5任意一项所述的结肠靶向控释递送系统，其特征在于，步骤(2)加热温度为50-65℃，时间1-2h；自组装温度为20-35℃，时间为10±5min。
9.根据权利要求8所述的结肠靶向控释递送系统，其特征在于，所述的带正电的活性蛋白为β-乳球蛋白或乳清蛋白；带正电荷的活性蛋白水溶液的浓度为1～5mg/ml；所述淀粉/磷脂复合物与活性蛋白的质量比为(1～5)：1。
10.根据权利要求1-9所述的结肠靶向控释递送系统在制备预防糖尿病食品功能因子中应用或者在预防和治疗糖尿病药物中应用。
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