靶向载药材料及微球的制备
摘要
药物释放系统（Drug Delivery Systems, DDS）已成为药学领域的重要发展方向，随之而来对药物载体及材料的研究也就愈加显得格外重要。因为只有选用适宜的药物载体或材料及适当的药物与载体的配比，方可获得释药速率令人满意的给药系统。因此，开发新型药物载体及相关材料对于研发新型医药产品有着重要的意义。
本文首先制备了醛端基聚乙二醇，随后采用还原法将醛基还原为胺基，且采用叶酸对壳聚糖进行修饰，制备了靶向载药材料壳聚糖－叶酸。而后采用反相乳化交联法、制备了壳聚糖微球、壳聚糖－叶酸微球和PEG化壳聚糖微球、PEG化壳聚糖－叶酸微球。具体内容主要包括以下几个方面：
1. 本文首先对PEG进行了化学改性，通过氧化反应将其一端的羟基转变为醛基，而后在碱性条件下利用还原法将醛基转化为胺基，探讨了反应条件对上述反应的影响，并利用红外光谱等测试手段对其进行初步表征。
2. 通过化学反应得到了具有靶向性分子叶酸修饰的壳聚糖大分子，初步探讨了反应条件对叶酸修饰程度的影响。并采用红外光谱对其进行初步表征。
3. 根据壳聚糖大分子的特点，采用戊二醛为交联剂、苯甲酸乙酯为有机分散介质制备了交联壳聚糖微球，探讨了反应条件对粒径的影响，并用红外光谱、扫描电镜、光学显微镜等对微球结构和形貌进行了表征。实验结果表明：采用本实验方法可得到单分散性好的壳聚糖微球。
4. 随后在以戊二醛为交联剂、苯甲酸乙酯为有机分散介质的条件下制备了载有化学键合叶酸分子的壳聚糖微球，并采用红外、扫描电镜、光学显微镜等对其结构和形貌进行表征。实验结果表明：壳聚糖经一定程度叶酸修饰后仍然可以交联，经反相乳化交联可得到单分散性较好的叶酸化壳聚糖微球。
5. 在上述研究基础上，制备了PEG化壳聚糖微球和PEG化壳聚糖－叶酸微球，并用红外、扫描电镜等对其形貌和结构进行表征。实验结果表明：采用反相乳化交联法可制备出一定粒径分散度的PEG化壳聚糖微球和PEG化壳聚糖－叶酸微球。
Targeted Drug Delivery Systems (TDDS) have been an important developing drug field, so it is necessary to develop the research of drug carrier and material. Only the proper proportion of drug carrier or material to drug is the base of satisfied Targeted Drug Delivery Systems. Therefore it is important for the development of new drugs to keen on the research of new drug vector and material revolved.
In this paper, PEGCH2COH was prepared and then was deoxidize to PEGCH2CH2NH2. In addition, folate was used to modify chitosan so chitosan-folate was obtained as an targeted delivery material. And then inverse crosslinking-emulsion was used and the chitosan microspheres, PEGlated chitosan microspheres, chitosn-folate microspheres and PEGlated chitosn-folate microspheres were obtained. The major contents include:
1. First, in this paper, PEG was modified to converse one hydroxy end group into a aldehyde group and then using reducer to revert it into amidocyanogen group under the condition of alkalescence. The reactive conditions were also discussed and PEG-COH was charactered by FT-IR.
2. Chitosan molecules were modified by introducing folate molecules through chemical reaction, and the reactive conditions that affects the reaction between chitosan and folate were studied. Chitosan-folate was charactered by FT-IR.
3. Since chitosan is a macromolecule, and has a lot of amido groups on the melecules. The chitosan microspheres were prepared using glutaraldehyde as a crosslinking agent and acetylamino benzoate as organic diffusion media respectively. The reactive conditions were also explored and the best condition was found according to the experiments. Then structure and appearance of the microspheres were charactered by IR, SEM and microscope. The results showed that the good size-distributed microspheres could be obtained under the experimental conditions.
4. Chitosan－folate(CSF) was made into microspheres by inverse emulsion using glutaraldehyde as a crosslinking agent and acetylamino benzoate as organic diffusion media respectively. Then the microspheres were charactered by IR, SEM and microscope. The results showed that the chitosan modified by folate microspheres can also be obtained
5. The PEGlated chitosan and PEGlated chitosan-folate microspheres were prepared and charactered by IR, SEM and microscope. The results show that the PEGlated chitosan and PEGlated chitosan-folate microspheres can be prepared by inverse crosslinking -emulsion.
本文首先制备了醛端基聚乙二醇，随后采用还原法将醛基还原为胺基，且采用叶酸对壳聚糖进行修饰，制备了靶向载药材料壳聚糖－叶酸。而后采用反相乳化交联法、制备了壳聚糖微球、壳聚糖－叶酸微球和PEG化壳聚糖微球、PEG化壳聚糖－叶酸微球。具体内容主要包括以下几个方面：
1. 本文首先对PEG进行了化学改性，通过氧化反应将其一端的羟基转变为醛基，而后在碱性条件下利用还原法将醛基转化为胺基，探讨了反应条件对上述反应的影响，并利用红外光谱等测试手段对其进行初步表征。
2. 通过化学反应得到了具有靶向性分子叶酸修饰的壳聚糖大分子，初步探讨了反应条件对叶酸修饰程度的影响。并采用红外光谱对其进行初步表征。
3. 根据壳聚糖大分子的特点，采用戊二醛为交联剂、苯甲酸乙酯为有机分散介质制备了交联壳聚糖微球，探讨了反应条件对粒径的影响，并用红外光谱、扫描电镜、光学显微镜等对微球结构和形貌进行了表征。实验结果表明：采用本实验方法可得到单分散性好的壳聚糖微球。
4. 随后在以戊二醛为交联剂、苯甲酸乙酯为有机分散介质的条件下制备了载有化学键合叶酸分子的壳聚糖微球，并采用红外、扫描电镜、光学显微镜等对其结构和形貌进行表征。实验结果表明：壳聚糖经一定程度叶酸修饰后仍然可以交联，经反相乳化交联可得到单分散性较好的叶酸化壳聚糖微球。
5. 在上述研究基础上，制备了PEG化壳聚糖微球和PEG化壳聚糖－叶酸微球，并用红外、扫描电镜等对其形貌和结构进行表征。实验结果表明：采用反相乳化交联法可制备出一定粒径分散度的PEG化壳聚糖微球和PEG化壳聚糖－叶酸微球。
Targeted Drug Delivery Systems (TDDS) have been an important developing drug field, so it is necessary to develop the research of drug carrier and material. Only the proper proportion of drug carrier or material to drug is the base of satisfied Targeted Drug Delivery Systems. Therefore it is important for the development of new drugs to keen on the research of new drug vector and material revolved.
In this paper, PEGCH2COH was prepared and then was deoxidize to PEGCH2CH2NH2. In addition, folate was used to modify chitosan so chitosan-folate was obtained as an targeted delivery material. And then inverse crosslinking-emulsion was used and the chitosan microspheres, PEGlated chitosan microspheres, chitosn-folate microspheres and PEGlated chitosn-folate microspheres were obtained. The major contents include:
1. First, in this paper, PEG was modified to converse one hydroxy end group into a aldehyde group and then using reducer to revert it into amidocyanogen group under the condition of alkalescence. The reactive conditions were also discussed and PEG-COH was charactered by FT-IR.
2. Chitosan molecules were modified by introducing folate molecules through chemical reaction, and the reactive conditions that affects the reaction between chitosan and folate were studied. Chitosan-folate was charactered by FT-IR.
3. Since chitosan is a macromolecule, and has a lot of amido groups on the melecules. The chitosan microspheres were prepared using glutaraldehyde as a crosslinking agent and acetylamino benzoate as organic diffusion media respectively. The reactive conditions were also explored and the best condition was found according to the experiments. Then structure and appearance of the microspheres were charactered by IR, SEM and microscope. The results showed that the good size-distributed microspheres could be obtained under the experimental conditions.
4. Chitosan－folate(CSF) was made into microspheres by inverse emulsion using glutaraldehyde as a crosslinking agent and acetylamino benzoate as organic diffusion media respectively. Then the microspheres were charactered by IR, SEM and microscope. The results showed that the chitosan modified by folate microspheres can also be obtained
5. The PEGlated chitosan and PEGlated chitosan-folate microspheres were prepared and charactered by IR, SEM and microscope. The results show that the PEGlated chitosan and PEGlated chitosan-folate microspheres can be prepared by inverse crosslinking -emulsion.
引文
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[2] Katayama K，Kato Y，Onishi H et al.，Preparation of novel double liposomes using the glass-filter method，International Journal of Pharmaceutics， 2002，248(1-2): 93 – 99.
[3] Charman S A, Charman W N, Rogge M C, et al.，Self-emulsifying drug delivery system: formulation and biopharmaceutic evaluation of an investigational lipophilic compound，Pharmacological Research, 1992,9(1):87-93.
[4] Yang Yi Yan， Shi Meng， Goh S H, et al.， POE/PLGA composite microspheres: formation and in vitro behavior of double walled microspheres， Journal of Controlled Release，2003,88（2）:201-213.
[5] El-Gibaly, Ibrahim，Development and in vitro evaluation of novel floating chitosan microcapsules for oral use: comparison with non-floating chitosan microspheres，International Journal of Pharmaceutics，2002，249（1-2）:7-12
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