聚氧乙烯—聚乳酸温敏型药物传递体系的制备与性能研究
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摘要
药用辅料对于改良药物制剂的释药性能，提高生物利用度及降低药物毒副作用等都有非常显著的作用，因此近年来新型药用辅料的开发受到药剂工作者的高度重视。含药原位凝胶传递系统可以起到缓释、控释药物的作用，并具有定位给药的优点，逐渐成为一种具有广阔发展前景的剂型。本课题即着眼于新型三嵌段共聚物聚氧乙烯．聚乳酸．聚氧乙烯(PEO-PLA-PEO)的合成及温敏型原位注射凝胶含药体系的开发与研究。
本文的主要研究内容和结论如下：
1．以乳酸单体和单甲氧基聚氧乙烯为原料，采用直接聚合法合成了二嵌段共聚物PEO-PLA。以红外光谱(IR)、氢谱(1~H-NMR)和凝胶渗透色谱(GPC)表征了产物的分子结构，并测定分子量。研究发现，反应预处理、反应压力、反应温度、反应时间、催化剂种类与用量等因素都会影响产物的分子量。如：产物分子量随反应压力减小而增大，分别随反应时间、反应温度和催化剂用量的增加而先增大后减小。结果表明，合成分子量在26000-30000左右的二嵌段共聚物的最优合成工艺为：反应时间7小时，反应温度160℃，催化剂用量0．8％。
2．以二异氰酸酯(HMDI)链接PEO-PLA分子中端羟基，合成PEO-PLA-PEO；并制备了PEO-PLA-PEO水溶液，研究溶液浓度和温度对PEO-PLA-PEO水溶液相变特性的影响。以氢谱(1~H-NMR)和凝胶渗透色谱(GPC)表征了产物的分子结构，并测定分子量；以DPH染料溶解法、动态光散射法(DLS)、胶束粒径测定和差热扫描(DCS)等方法对PEO-PLA-PEO三嵌段共聚物水溶液进行表征。结果表明，三嵌段聚合物水溶液可以在35℃-50℃之间实现溶胶一凝胶的可逆转化；其中，在48℃发生了相变，38℃再次出现相变。而且，胶束问相互作用力是水溶液发生相变的重要原因之一。
3．以羧甲基壳聚糖(Carboxymethyl Chitosan, CMCTS)为原料，氯化钙和香草醛为双重交联剂制备载药CMCTS微囊。以扫描电镜(SEM)观察微囊的外部与内部形貌特征，并按照药典的规定研究了微囊的药物释放特性。钙离子与羧甲基产生静电力，螯合交联；香草醛中醛基与羧甲基壳聚糖分子中氨基生成-C=N-(希弗碱)，且其酚羟基与羧甲基壳聚糖分子中羧基、羟基和氨基形成氢键。以Ca(Ⅱ)-香草醛复合交联羧甲基壳聚糖制备的微囊，对人体无毒，使用安全，而且制备工艺简便，因此该微囊可能是一类很有前途的新型药物载体。
4．将羧甲基壳聚糖微囊加入到聚氧乙烯-聚乳酸-聚氧乙烯三嵌段共聚物的温敏凝胶体系中，考察该复合体系的力学性能和药物释放特性。随着温度的变化，复合凝胶体系的力学性能不断发生变化。在溶胶态，体系无力学强度，体系转变为“软凝胶”态后(45℃左右)，体系开始具有很小的力学强度，而在38℃-39℃左右，体系转化为凝胶态，力学强度到达最大。相比于单纯的羧甲基微囊和凝胶基质，复合凝胶体系具有良好的药物缓释性能，药物释放时间延长到30h-40h。结果表明，该体系可以有效实现“原位注射”和“缓慢释药”的目的，有望开发应用于治疗关节腔与软组织等特定部位疾病的药物载体。
Pharmaceutical excipient is an important part of pharmaceutical preparations because it plays as key role in improving the performance of drug release profile, bioavailability and reducing the side effect. More and more scientists pay attention to development of new pharmaceutical excipient in recent years. The system of drug-loaded hydrogel in situ is used widely in the drug delivery system. Because it can retard the release of drug, especially the system can release the drug in a same site. This paper focus on the preparation of thermo-sensitive injective gel system in situ by new-style polyethylene oxide-polylactic acid-polyethylene oxide (PEO-PLA-PEO) triblock copolymer and its potential application.
The main contents and conclusions in this paper are as follows:
1. To synthesis polylactic acid- polyethylene oxide (PLA-PEO) diblock copolymer from lactic acid and monomethyl polyethylene glycol (mPEO) with direct polymerization method. The IR, ~1H-NMR and the GPC has attributed to examine the molecular structure and the molecular weight of product. The research discovered that the factors such as pretreatment, reaction pressure, reaction temperature, reaction time, catalyst sort and amount can influence the molecular weight of product. under the condition of reaction time is 7 hours, reaction temperature is 160℃, the amount of catalyst is 0.8 wt%. The molecular weight and structure of product are characterized by FTIR, ~1H-NMR and GPC. It is found that the molecular weight of PLA block which is prepared as the craft mentioned before is among 16000-20000.
2. The HMDI is used as link agent reacts with end hydroxyl in the PEO-PLA to synthesis PEO-PLA-PEO. And the PEO-PLA-PEO aqueous solution is prepared to research the influences of solution concentration and the temperature changes on the PEO-PLA-PEO system's phase transform characteristic. 1H-NMR and GPC are attributed to examined the molecular structure and the molecular weight of product; the PEO-PLA-PEO aqueous solution is prepared for characterization with dye solubilization method, dynamic light scattering studying (DLS) and differential scanning calorimetry (DSC) for studying the micellization behaviors of triblock copolymer solution. It is found that the triblock copolymer solution can reversibly transformation between the state of gel and sol among the temperature of 35℃-50℃. And, the spot of phase changing appears at 48℃and the other spot appears at 38℃.Moreover, the interact force which forms the micelle in the solution is one of important reasons to cause the phase transformation.
3. Carboxymethyl Chitosan (CMCTS) is chosen as material, the calcium chloride and the vanilla are selected as dual crosslinking agents to prepared drug-loaded microcapsules. The outlook and inner structure of microcapsules are observed by SEM. As the stipulation of Chinese Pharmacopoeia, the drug release characteristic of microcapsules is studied. The electrostatic force between calcium ion and the canboxymethyl, and the Schiff base which is formed between the aldehyde of vanillin and amino of CMC are the reasons to produce microcapsules. The vanilla is the national legal edible spice and widely applies to drink, food, cosmetics and tobacco. The CMC microcapsules crossliked with Ca (II) and vanilla is easy to prepare, non-toxic and security, therefore, the microcapsules possibly is a kind of valuable new drug carrier.
4. The microcapsules of carbomethyl chitasan is prepared and mixed with the thermo-sensitive system which is prepared by polyethylene glycol-polylactic acid-polyethylene glycol. The mechanical capacity and drug release profiles of the system are characterized. It is found the mechanics capacity of compound system is changing with the change of temperature and the phase transform of itself. In sol state, the system has any mechanical capacity, but it increases in soft gel state (about 45℃), and the mechanical capacity achieves to maximum in gel state about 38℃-39℃. Compared to the microcapsules and matrix, the gel system has the outstanding drug release profiles which can prolong the drug releasing period to 30h-40h. The result indicates that this system can effectively achieve the goal of "injection in situ", then releases contained drug slowly. So it is hopeful to be applied to cure the illness of some specific spot such as joint cavity and soft tissue.
本文的主要研究内容和结论如下：
1．以乳酸单体和单甲氧基聚氧乙烯为原料，采用直接聚合法合成了二嵌段共聚物PEO-PLA。以红外光谱(IR)、氢谱(1~H-NMR)和凝胶渗透色谱(GPC)表征了产物的分子结构，并测定分子量。研究发现，反应预处理、反应压力、反应温度、反应时间、催化剂种类与用量等因素都会影响产物的分子量。如：产物分子量随反应压力减小而增大，分别随反应时间、反应温度和催化剂用量的增加而先增大后减小。结果表明，合成分子量在26000-30000左右的二嵌段共聚物的最优合成工艺为：反应时间7小时，反应温度160℃，催化剂用量0．8％。
2．以二异氰酸酯(HMDI)链接PEO-PLA分子中端羟基，合成PEO-PLA-PEO；并制备了PEO-PLA-PEO水溶液，研究溶液浓度和温度对PEO-PLA-PEO水溶液相变特性的影响。以氢谱(1~H-NMR)和凝胶渗透色谱(GPC)表征了产物的分子结构，并测定分子量；以DPH染料溶解法、动态光散射法(DLS)、胶束粒径测定和差热扫描(DCS)等方法对PEO-PLA-PEO三嵌段共聚物水溶液进行表征。结果表明，三嵌段聚合物水溶液可以在35℃-50℃之间实现溶胶一凝胶的可逆转化；其中，在48℃发生了相变，38℃再次出现相变。而且，胶束问相互作用力是水溶液发生相变的重要原因之一。
3．以羧甲基壳聚糖(Carboxymethyl Chitosan, CMCTS)为原料，氯化钙和香草醛为双重交联剂制备载药CMCTS微囊。以扫描电镜(SEM)观察微囊的外部与内部形貌特征，并按照药典的规定研究了微囊的药物释放特性。钙离子与羧甲基产生静电力，螯合交联；香草醛中醛基与羧甲基壳聚糖分子中氨基生成-C=N-(希弗碱)，且其酚羟基与羧甲基壳聚糖分子中羧基、羟基和氨基形成氢键。以Ca(Ⅱ)-香草醛复合交联羧甲基壳聚糖制备的微囊，对人体无毒，使用安全，而且制备工艺简便，因此该微囊可能是一类很有前途的新型药物载体。
4．将羧甲基壳聚糖微囊加入到聚氧乙烯-聚乳酸-聚氧乙烯三嵌段共聚物的温敏凝胶体系中，考察该复合体系的力学性能和药物释放特性。随着温度的变化，复合凝胶体系的力学性能不断发生变化。在溶胶态，体系无力学强度，体系转变为“软凝胶”态后(45℃左右)，体系开始具有很小的力学强度，而在38℃-39℃左右，体系转化为凝胶态，力学强度到达最大。相比于单纯的羧甲基微囊和凝胶基质，复合凝胶体系具有良好的药物缓释性能，药物释放时间延长到30h-40h。结果表明，该体系可以有效实现“原位注射”和“缓慢释药”的目的，有望开发应用于治疗关节腔与软组织等特定部位疾病的药物载体。
Pharmaceutical excipient is an important part of pharmaceutical preparations because it plays as key role in improving the performance of drug release profile, bioavailability and reducing the side effect. More and more scientists pay attention to development of new pharmaceutical excipient in recent years. The system of drug-loaded hydrogel in situ is used widely in the drug delivery system. Because it can retard the release of drug, especially the system can release the drug in a same site. This paper focus on the preparation of thermo-sensitive injective gel system in situ by new-style polyethylene oxide-polylactic acid-polyethylene oxide (PEO-PLA-PEO) triblock copolymer and its potential application.
The main contents and conclusions in this paper are as follows:
1. To synthesis polylactic acid- polyethylene oxide (PLA-PEO) diblock copolymer from lactic acid and monomethyl polyethylene glycol (mPEO) with direct polymerization method. The IR, ~1H-NMR and the GPC has attributed to examine the molecular structure and the molecular weight of product. The research discovered that the factors such as pretreatment, reaction pressure, reaction temperature, reaction time, catalyst sort and amount can influence the molecular weight of product. under the condition of reaction time is 7 hours, reaction temperature is 160℃, the amount of catalyst is 0.8 wt%. The molecular weight and structure of product are characterized by FTIR, ~1H-NMR and GPC. It is found that the molecular weight of PLA block which is prepared as the craft mentioned before is among 16000-20000.
2. The HMDI is used as link agent reacts with end hydroxyl in the PEO-PLA to synthesis PEO-PLA-PEO. And the PEO-PLA-PEO aqueous solution is prepared to research the influences of solution concentration and the temperature changes on the PEO-PLA-PEO system's phase transform characteristic. 1H-NMR and GPC are attributed to examined the molecular structure and the molecular weight of product; the PEO-PLA-PEO aqueous solution is prepared for characterization with dye solubilization method, dynamic light scattering studying (DLS) and differential scanning calorimetry (DSC) for studying the micellization behaviors of triblock copolymer solution. It is found that the triblock copolymer solution can reversibly transformation between the state of gel and sol among the temperature of 35℃-50℃. And, the spot of phase changing appears at 48℃and the other spot appears at 38℃.Moreover, the interact force which forms the micelle in the solution is one of important reasons to cause the phase transformation.
3. Carboxymethyl Chitosan (CMCTS) is chosen as material, the calcium chloride and the vanilla are selected as dual crosslinking agents to prepared drug-loaded microcapsules. The outlook and inner structure of microcapsules are observed by SEM. As the stipulation of Chinese Pharmacopoeia, the drug release characteristic of microcapsules is studied. The electrostatic force between calcium ion and the canboxymethyl, and the Schiff base which is formed between the aldehyde of vanillin and amino of CMC are the reasons to produce microcapsules. The vanilla is the national legal edible spice and widely applies to drink, food, cosmetics and tobacco. The CMC microcapsules crossliked with Ca (II) and vanilla is easy to prepare, non-toxic and security, therefore, the microcapsules possibly is a kind of valuable new drug carrier.
4. The microcapsules of carbomethyl chitasan is prepared and mixed with the thermo-sensitive system which is prepared by polyethylene glycol-polylactic acid-polyethylene glycol. The mechanical capacity and drug release profiles of the system are characterized. It is found the mechanics capacity of compound system is changing with the change of temperature and the phase transform of itself. In sol state, the system has any mechanical capacity, but it increases in soft gel state (about 45℃), and the mechanical capacity achieves to maximum in gel state about 38℃-39℃. Compared to the microcapsules and matrix, the gel system has the outstanding drug release profiles which can prolong the drug releasing period to 30h-40h. The result indicates that this system can effectively achieve the goal of "injection in situ", then releases contained drug slowly. So it is hopeful to be applied to cure the illness of some specific spot such as joint cavity and soft tissue.
引文
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