氨基化明胶的性能及在鼻粘膜给药的应用研究
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摘要
本研究以明胶为原料，在水溶性碳二亚胺存在的条件下与乙二胺反应，首次设计并制备了一种新型带正电荷的生物可降解性聚合物—氨基化明胶。氨基化明胶的数均分子量为97.5kDa，每mg氨基化明胶含伯氨基1.655mol，比明胶具有较好的水溶性和较低的胶凝温度。热分析实验结果表明，氨基化明胶比明胶具有较低的玻璃化温度、较好的分子链柔顺性和链段运动性。
以粘液中发挥粘附作用的主要成分粘蛋白为粘液模型，分别以蒸馏水、人工胃液及人工肠液为介质模型，综合运用比浊法、粘度法、粘附力测定法及表面自由能分析法等方法，分别从胶体学、流变学、力学及热力学的角度，系统地考察氨基化修饰对明胶生物粘附性能的影响。胶体学和流变学的研究结果表明，氨基化明胶与粘蛋白在均相体系中的相互作用比明胶与粘蛋白间的相互作用显著增强，静电引力是相互作用力的主要成分。粘附力测定结果表明，氨基化明胶比明胶具有优越的生物粘附性能，氨基化明胶的快速水化及良好的分子链柔顺性是这一性能的主要原因，热力学研究结果表明，氨基化明胶与粘蛋白在界面处相互作用的自由能显著降低，其降低程度显著大于明胶与粘蛋白相互作用时自由能的降低程度，氨基化明胶溶液能够润湿和铺展于粘蛋白溶液的表面；自由能的色散分量和Lewis酸碱作用分量对这一过程均有重要贡献，但氨基化明胶与明胶之间的差异主要是由界面张力的Lewis酸碱作用分量决定的。各种实验方法得出的结果具有较好的一致性，均表明氨基化明胶与粘蛋白间的相互作用比明胶强，氨基化修饰显著改善了明胶的生物粘附性能。氨基化明胶的生物粘附性能是其正电荷性质、较好的分子链柔性及有利的表面能性质等因素共同决定的。
为进一步考察氨基化明胶的生物粘附性，并为制剂学研究奠定基础，本研究在无外加乳化剂的条件下，将氨基化明胶的水溶液分散在橄榄油中，经乳化、胶凝、脱水及交联等过程，制备了一种新型带正电荷的凝胶微球—氨基化明胶微球。微球平均粒径为40～50μm，大小分布均匀。干燥微球可吸收相当于自身重量约20倍的水形成水凝胶。氨基化明胶微球比明胶微球具有较高的氨基含量，在蒸馏水及磷酸盐缓冲液中均荷正电，在蒸馏水中的Zata电位为41.5mV。随着制备微球时交联剂戊二醛浓度的增大或交联反应时间的延长，微球的氨基含量降低。但无论交联反应的条件如何，本方法制备的氨基化明胶微球比明胶微球具有较高的伯氨基含量。氨基化明胶微球在胰蛋白酶存在的条件下可迅速降解(＜1h)，在胃蛋白酶及酸碱介质环境中降解较为缓慢(＞20h)，在磷酸盐
沈阳药科大学博士学位论文 摘要
一
缓冲液中具有较好的稳定性。
综合运用多种体内外实验方法研究了氨基化明胶微球的粘膜粘附性能。采
用比色法考察了氨基化明胶微球与两种市售粘蛋白在不同介质环境中的相互作
用，虽然这种相互作用随介质的种类、pH及离子强度的不同而不同，但是，在
相同的试验条件下，吸附到氨基化明胶微球的两种粘蛋白量比吸附到两种明胶
微球（IEP＝5刀和 9．0）的粘蛋白量多。这表明，氨基化明胶微球与粘蛋白之间
的相互作用比明胶微球强。氨基化明胶微球较高的正电荷密度是它与粘蛋白间
较强相互作用的主要原因。
结合荧光标记法及体外酶降解技术，利用离体大鼠胃灌流冲洗模型和大鼠
体内实验研究了氨基化明胶微球的生物粘附性能。结果表明，在相同的实验条
件下，滞留在离体大鼠胃中的氨基化明胶微球的数量比明胶微球多，而灌流冲
洗液的种类（人工胃液或PH 7人磷酸盐缓冲液）对微球的胃滞留性无显著影响，
这表明微球与胃粘液之间的静电相互作用不是这一模型中微球胃滞留性的决定
性因素。但是，实验中发现滞留在离体大鼠胃中的氨基化明胶微球的量随制备
微球时交联剂戊二醛浓度的增大而减少，这表明氨基化明胶微球的胃粘膜粘附
性可能受微球表面氨基含量或交联度的影响。大鼠体内实验结果表明，氨基化
明胶微球比明胶微球具有较好的粘膜粘附性能。
采用Y闪烁照相技术研究了99”m标记氨基化明胶微球在健康志愿者鼻粘膜
的粘附性能。结果表明，氨基化明胶微球比明胶微球具有优越的生物粘附性能。
明胶微球和氨基化明胶徽球在健康志愿者鼻腔内的清除半衰期分别为45和
87min。氨基化明胶微球较高的氨基含量、氨基化明胶改进的分子链柔顺性和
链段运动性、氨基化明胶微球在粘膜表面的吸水溶胀等性质在其生物粘附性方
面共同发挥着作用。
鉴于多种阳离子聚合物可以促进水溶性大分子物质从鼻粘膜的吸收，本研
究考察了新型带正电荷的聚合物一氨基化明胶用作胰岛素鼻粘膜吸收促进剂的
可行性。以健康大鼠为模型动物，考察了氨基化明胶对葡聚糖和胰岛素鼻粘膜
吸收的促进作用。结果表明，02％（WN）氨基化明胶可以显著促进分于量为
女4kDa的异硫氰酸荧光素－葡聚糖从大鼠鼻粘膜的吸收，生物利用度为23．8％。
鼻腔给予含 0二％（w／v）氨基化明胶的胰岛素磷酸盐缓冲液10 IU帅）后，血糖
水平与给予胰岛素的磷酸盐缓冲液相比显著降低。这一降糖作用与相同浓度的
A new cationic polymer, aminated gelatin, was synthesized by modification of gelatin with 1,2-ethylenediamine in the presence of a kind of water-soluble carbodiimide. Aminated gelatin presents a higher amino group content, a higher level of solubility, a lower gelling temperature and a higher molecular flexibility and chain mobility.
The mucoadhesive properties of aminated gelatin were evaluated systemically by using two kinds of commercial mucin (type I -S and type III) as mucus models and using water, simulated gastric fluid and simulated intestinal fluid as medium models respectively. Colloidal and rheological studies showed that aminated gelatin demonstrates a stronger interaction with mucin in all of the experimental conditions tested in comparison with that of native gelatin, and the electrostatic interaction is the main force involved in these interactions. Mechanical studies showed that aminated gelatin possesses stronger mucoadhesive strengths than the native gelatins, which is ascribed to the properties of quick hydration and the higher flexibility of aminated gelatin. The results of thermodynarnic studies indicated that the interfacial interaction between hydrated aminated gelatin and mucin is a process accompanied with a negative Gibbs free energy, and aminated gelatin solution can spread over the surface of mucin solution sp
ontaneously. The change of interaction surface energy between aminated gelatin film and mucin is also negative. Both the dispersive and polar components of the Gibbs free energy contribute to this phenomenon. However, the difference between gelatin and aminated gelatin mainly comes from polar component of surface energy.
To further investigate the bioadhesive properties and the mechanisms of bioadhesion of aminated gelatin, aminated gelatin microspheres were prepared by surfactant-free emulsification of aminated gelatin solution in olive oil, followed by cross-linking reaction with glutaraldehyde. The microspheres are in a sphere shape, with a mean diameter of about 40-50 um, and present a good biodegradability. The amino group contents of the aminated gelatin microspheres were determined using a 2,4,6-trinitrobenzenesulfonic acid method. Aminated gelatin microsphere presents a significantly higher amino group content than the two kinds of native gelatin microspheres. However, with the increase of the glutaraldehyde concentration and/or cross-linking reaction time, the amino group content of the microspheres decreased accordingly.
The mucoadhesive properties of aminated gelatin microspheres were evaluated both in vitro and in vivo in rats and healthy volunteers. The interactions of native and
aminated gelatin microspheres with two kinds of commercial mucin (type I -S and type III) were investigated in different aqueous media. As a result, a larger amount of mucin was adsorbed to aminated gelatin microspheres than to either of the native gelatin microspheres under all the conditions investigated, although the amount of mucin adsorbed to microspheres varied significantly in different media. These results indicated that there is a stronger interaction between mucin and aminated gelatin microspheres than that between mucin and native gelatin microspheres. The electrostatic attraction is the main force for these interactions.
In the in vitro model of isolated and perfused rat stomach, the amount of aminated gelatin microspheres that remained in the stomach after perfusion was significantly larger than that of the native gelatin microspheres. No significant difference in gastric retention was observed whether the test was performed in simulated gastric fluid (SGF) or in phosphate buffered saline (PBS, pH7.4), nor differences observed between the two native gelatin microspheres. These results suggested that the electrostatic interaction is not the decisive force for the mucoadhesion of the microspheres in this model.
In the in vivo mucoadhesion experiment, the amount of aminated gelatin microspheres remained in the stomach two hours after oral administration in a capsule inc
以粘液中发挥粘附作用的主要成分粘蛋白为粘液模型，分别以蒸馏水、人工胃液及人工肠液为介质模型，综合运用比浊法、粘度法、粘附力测定法及表面自由能分析法等方法，分别从胶体学、流变学、力学及热力学的角度，系统地考察氨基化修饰对明胶生物粘附性能的影响。胶体学和流变学的研究结果表明，氨基化明胶与粘蛋白在均相体系中的相互作用比明胶与粘蛋白间的相互作用显著增强，静电引力是相互作用力的主要成分。粘附力测定结果表明，氨基化明胶比明胶具有优越的生物粘附性能，氨基化明胶的快速水化及良好的分子链柔顺性是这一性能的主要原因，热力学研究结果表明，氨基化明胶与粘蛋白在界面处相互作用的自由能显著降低，其降低程度显著大于明胶与粘蛋白相互作用时自由能的降低程度，氨基化明胶溶液能够润湿和铺展于粘蛋白溶液的表面；自由能的色散分量和Lewis酸碱作用分量对这一过程均有重要贡献，但氨基化明胶与明胶之间的差异主要是由界面张力的Lewis酸碱作用分量决定的。各种实验方法得出的结果具有较好的一致性，均表明氨基化明胶与粘蛋白间的相互作用比明胶强，氨基化修饰显著改善了明胶的生物粘附性能。氨基化明胶的生物粘附性能是其正电荷性质、较好的分子链柔性及有利的表面能性质等因素共同决定的。
为进一步考察氨基化明胶的生物粘附性，并为制剂学研究奠定基础，本研究在无外加乳化剂的条件下，将氨基化明胶的水溶液分散在橄榄油中，经乳化、胶凝、脱水及交联等过程，制备了一种新型带正电荷的凝胶微球—氨基化明胶微球。微球平均粒径为40～50μm，大小分布均匀。干燥微球可吸收相当于自身重量约20倍的水形成水凝胶。氨基化明胶微球比明胶微球具有较高的氨基含量，在蒸馏水及磷酸盐缓冲液中均荷正电，在蒸馏水中的Zata电位为41.5mV。随着制备微球时交联剂戊二醛浓度的增大或交联反应时间的延长，微球的氨基含量降低。但无论交联反应的条件如何，本方法制备的氨基化明胶微球比明胶微球具有较高的伯氨基含量。氨基化明胶微球在胰蛋白酶存在的条件下可迅速降解(＜1h)，在胃蛋白酶及酸碱介质环境中降解较为缓慢(＞20h)，在磷酸盐
沈阳药科大学博士学位论文 摘要
一
缓冲液中具有较好的稳定性。
综合运用多种体内外实验方法研究了氨基化明胶微球的粘膜粘附性能。采
用比色法考察了氨基化明胶微球与两种市售粘蛋白在不同介质环境中的相互作
用，虽然这种相互作用随介质的种类、pH及离子强度的不同而不同，但是，在
相同的试验条件下，吸附到氨基化明胶微球的两种粘蛋白量比吸附到两种明胶
微球（IEP＝5刀和 9．0）的粘蛋白量多。这表明，氨基化明胶微球与粘蛋白之间
的相互作用比明胶微球强。氨基化明胶微球较高的正电荷密度是它与粘蛋白间
较强相互作用的主要原因。
结合荧光标记法及体外酶降解技术，利用离体大鼠胃灌流冲洗模型和大鼠
体内实验研究了氨基化明胶微球的生物粘附性能。结果表明，在相同的实验条
件下，滞留在离体大鼠胃中的氨基化明胶微球的数量比明胶微球多，而灌流冲
洗液的种类（人工胃液或PH 7人磷酸盐缓冲液）对微球的胃滞留性无显著影响，
这表明微球与胃粘液之间的静电相互作用不是这一模型中微球胃滞留性的决定
性因素。但是，实验中发现滞留在离体大鼠胃中的氨基化明胶微球的量随制备
微球时交联剂戊二醛浓度的增大而减少，这表明氨基化明胶微球的胃粘膜粘附
性可能受微球表面氨基含量或交联度的影响。大鼠体内实验结果表明，氨基化
明胶微球比明胶微球具有较好的粘膜粘附性能。
采用Y闪烁照相技术研究了99”m标记氨基化明胶微球在健康志愿者鼻粘膜
的粘附性能。结果表明，氨基化明胶微球比明胶微球具有优越的生物粘附性能。
明胶微球和氨基化明胶徽球在健康志愿者鼻腔内的清除半衰期分别为45和
87min。氨基化明胶微球较高的氨基含量、氨基化明胶改进的分子链柔顺性和
链段运动性、氨基化明胶微球在粘膜表面的吸水溶胀等性质在其生物粘附性方
面共同发挥着作用。
鉴于多种阳离子聚合物可以促进水溶性大分子物质从鼻粘膜的吸收，本研
究考察了新型带正电荷的聚合物一氨基化明胶用作胰岛素鼻粘膜吸收促进剂的
可行性。以健康大鼠为模型动物，考察了氨基化明胶对葡聚糖和胰岛素鼻粘膜
吸收的促进作用。结果表明，02％（WN）氨基化明胶可以显著促进分于量为
女4kDa的异硫氰酸荧光素－葡聚糖从大鼠鼻粘膜的吸收，生物利用度为23．8％。
鼻腔给予含 0二％（w／v）氨基化明胶的胰岛素磷酸盐缓冲液10 IU帅）后，血糖
水平与给予胰岛素的磷酸盐缓冲液相比显著降低。这一降糖作用与相同浓度的
A new cationic polymer, aminated gelatin, was synthesized by modification of gelatin with 1,2-ethylenediamine in the presence of a kind of water-soluble carbodiimide. Aminated gelatin presents a higher amino group content, a higher level of solubility, a lower gelling temperature and a higher molecular flexibility and chain mobility.
The mucoadhesive properties of aminated gelatin were evaluated systemically by using two kinds of commercial mucin (type I -S and type III) as mucus models and using water, simulated gastric fluid and simulated intestinal fluid as medium models respectively. Colloidal and rheological studies showed that aminated gelatin demonstrates a stronger interaction with mucin in all of the experimental conditions tested in comparison with that of native gelatin, and the electrostatic interaction is the main force involved in these interactions. Mechanical studies showed that aminated gelatin possesses stronger mucoadhesive strengths than the native gelatins, which is ascribed to the properties of quick hydration and the higher flexibility of aminated gelatin. The results of thermodynarnic studies indicated that the interfacial interaction between hydrated aminated gelatin and mucin is a process accompanied with a negative Gibbs free energy, and aminated gelatin solution can spread over the surface of mucin solution sp
ontaneously. The change of interaction surface energy between aminated gelatin film and mucin is also negative. Both the dispersive and polar components of the Gibbs free energy contribute to this phenomenon. However, the difference between gelatin and aminated gelatin mainly comes from polar component of surface energy.
To further investigate the bioadhesive properties and the mechanisms of bioadhesion of aminated gelatin, aminated gelatin microspheres were prepared by surfactant-free emulsification of aminated gelatin solution in olive oil, followed by cross-linking reaction with glutaraldehyde. The microspheres are in a sphere shape, with a mean diameter of about 40-50 um, and present a good biodegradability. The amino group contents of the aminated gelatin microspheres were determined using a 2,4,6-trinitrobenzenesulfonic acid method. Aminated gelatin microsphere presents a significantly higher amino group content than the two kinds of native gelatin microspheres. However, with the increase of the glutaraldehyde concentration and/or cross-linking reaction time, the amino group content of the microspheres decreased accordingly.
The mucoadhesive properties of aminated gelatin microspheres were evaluated both in vitro and in vivo in rats and healthy volunteers. The interactions of native and
aminated gelatin microspheres with two kinds of commercial mucin (type I -S and type III) were investigated in different aqueous media. As a result, a larger amount of mucin was adsorbed to aminated gelatin microspheres than to either of the native gelatin microspheres under all the conditions investigated, although the amount of mucin adsorbed to microspheres varied significantly in different media. These results indicated that there is a stronger interaction between mucin and aminated gelatin microspheres than that between mucin and native gelatin microspheres. The electrostatic attraction is the main force for these interactions.
In the in vitro model of isolated and perfused rat stomach, the amount of aminated gelatin microspheres that remained in the stomach after perfusion was significantly larger than that of the native gelatin microspheres. No significant difference in gastric retention was observed whether the test was performed in simulated gastric fluid (SGF) or in phosphate buffered saline (PBS, pH7.4), nor differences observed between the two native gelatin microspheres. These results suggested that the electrostatic interaction is not the decisive force for the mucoadhesion of the microspheres in this model.
In the in vivo mucoadhesion experiment, the amount of aminated gelatin microspheres remained in the stomach two hours after oral administration in a capsule inc
引文
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