2-芳基丙酸类含糖大分子药物的制备及其释药研究
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摘要
近年来,含有生物活性成分的大分子药物日益受到研究者们的关注。将小分子药物和生物活性成分(如糖,叶酸等)引入大分子前药,可以达到药物缓释的作用、提高药物的选择性和生物相容性、降低小分子药物的毒性和提高药物的靶向性等。同时高分子载体将药物输送到靶位点释放药物后,可被机体吸收或通过尿液等排出,不会在体内长时间积累。
文章以2-芳基丙酸类药物(布洛芬Ibuprofen、萘普生Naproxen、酮洛芬Ketoprofen)为药物模型,它们属于非甾体抗炎药(nonsteroidal anti-inflammatory drugs, NSAIDs),具有抗炎、止痛和解热作用,临床上用于减轻或控制由炎症引起的症状和体征,如痛经、急慢性附件炎、盆腔炎所致的腰腹部疼痛、术后疼痛、关节或软组织的疼痛。但是小分子原药对胃肠道有较强的刺激性,体液中溶解性差、半衰期短等缺点限制了它们的临床应用。为了提高药物的生物利用度,必须降低其副作用,延长药物的作用时间。
本论文用化学法和酶促法合成了三种可聚合的药物乙烯酯和不同糖的乙烯酯衍生物,通过两类聚合单体的自由基聚合反应制备了一系列含糖聚合物前药。产物经红外光谱(FT-IR)、核磁共振(1HNMR, 13CNMR)和凝胶渗透色谱(GPC)等表征手段,确认其结构和分子量。
其中,本论文研究了不同聚合条件对聚合物前药性质的影响,如聚合反应单体摩尔比(1：1,1：2,2：1,4：1,mol/mol)、引发剂AIBN含量(1%,2%,4%,w/w)等。研究结果表明,当引发剂AIBN含量为2%时,聚合物分子量较高；增加反应中AIBN含量,聚合物分子量降低,大分子中的载药量增加；随着药物乙烯酯单体在聚合反应投料中比例的增加,聚合物的分子量逐渐下降,大分子药物的载药量则逐步增加；两种聚合单体的摩尔比例为1：1时,得到的聚合物前药分子量较大。
另外,论文系统考察了聚合物前药的体外药物释放行为和释放动力学。研究结果表明将酮洛芬、布洛芬和萘普生制备成含糖大分子药物可以有效避免小分子药物的暴释现象,能够达到药物缓释的效果,提高药物的利用率。
药物释放曲线表明,含双糖残基的聚合物前药的药物释放速率较快,10d内酮洛芬的累积释放量为60%,含单糖侧链的聚合物前药释放速率较双糖的低,酮洛芬均聚物前药的药物释放速率最慢,10d药物的累积释放量仅为22%；糖侧链与高分子主链间的连接臂链长较短的聚合物前药释放速率较快,链长较长的药物释放速率则较慢；聚合物中糖残基含量越高,药物释放速率越快；聚合物载药量越高,药物释放速率越慢。
聚合物前药在不同条件下的体外药物释放曲线显示释放介质的pH和温度对药物释放的影响比较明显。释放介质的pH越大、温度越高,药物释放速率越快。以酮洛芬含糖聚合物前药为例,其在pH10.0.0.5M NaOH溶液和温度为50℃时12h的药物累积释放量分别达到42.3%,87%,15.8%,而在pH 1.2、0.5N HCl溶液和温度为25℃时12h的药物累积释放量分别为2.5%,2.5%,2.2%；离子强度对药物释放亦有微弱影响,随着溶液离子强度的增加,药物释放速率缓慢增大,聚合物在去离子水中12h的药物释放量为1.5%,而相同时间内在0.5M NaCl溶液中为5.6%。对药物释放曲线的动力学方程模拟结果显示,不同条件下的药物释放遵循不同的动力学方程模型。
实验通过静电纺丝方法,以DMF/C2H5OH (1/1, v/v)为溶剂,将酮洛芬聚合物前药与聚乙烯吡咯烷酮(PVP)制备成纳米载药纤维。由于纤维表面积的快速增大和PVP良好的水溶性等性质,使得聚合物前药载药纤维的药物释放速率大大加快,同时纳米载药纤维还保持了聚合物前药的药物缓释作用。因此制备大分子药物的纳米载药纤维具有一定的意义。
Studies on macromolecules containing saccharide as selective drug delivery system have been developed for biomedicinal application. It has been reported that these systems provide many advantages including prolonged drug release, changed biodistribution, reduced toxicity and increased patient acceptance.
Ibuprofen, naproxen and ketoprofen are used as model drug. They are a commonly 2-Arylpropionic acid used as non-steroidal anti-inflammatory drugs (NSAIDs) and widely applied to alleviate pain and inflammation associated with tissue injury. However, the drugs are poorly soluble in aqueous media and cause irritant side effects especially on the gastro-enteric mucosal membranes. Therefore, polymeric prodrugs with saccharide through chemical bond can be designed to overcome such problems and merging the relative advantages of saccharide and macromolecules into a single system. This system can be useful to both increase drug stability and avoid the rapid release.
In this paper, a facile and efficient enzymatic and polymerization process was used to prepare polymeric drug-saccharide conjugates with 2-Arylpropionic acid pendants. A series of polymeric prodrugs with different saccharide branches were synthesized and the structures and molecular weight were confirmed by FT-IR, NMR and GPC.
Firstly, the paper investigated the influence of various factors to preparation of polymeric prodrugs, such as the molar ratio of drug vinyl ester and sugar vinyl ester (1:1,1:2,2:1,4:1, mol/mol), and the mass of initiator (AIBN,1%,2%,4%, w/w). The obersevations suggested that the molecular weight was influenced by the saccharides variation. Polymeric prodrug with lactose pendant had the highest molecular weight, with Mn of 7.527×104. By increasing saccharide derivatives in raction feed, it caused a decrease in molecular weight of the polymeric prodrugs. For example, the loading capacity of ketoprofen in the polymeric prodrug was only 22.74% (w/w) when glucose vinyl ester was 67% (mol/mol) in the feed, while it reached 42.28% (w/w) when it was 20% in the feed. A reduction of molecular weight was noted by increasing the ratio of initiator. The results suggested that the molecular weight and conversion of the polymeric prodrugs were greatly influenced by the concentration of initiator and the molar ratio of monomers.
And then, factors to the in vitro drug release were systematically studied, such as the effects of different saccharides with varying carbon chain length, drug carrier, pH, temperature, ionic strength and solution variation.
The drug release profiles could be influenced by the characteristics of these polymers. Among the polymeric conjugates, drug from prodrug with disaccharide pendant was released rapidly. It implied that the type of saccharide branch influenced release capabilities of polymeric prodrugs. The structures of monosaccharides appeared having a little influence on the drug release. The release of drugs was seen to decrease along with increasing the length of spacer bond between saccharide and polymer main chain. The release rate of drug from polymeric prodrugs increased with the raising of saccharide pendants in the macromoleculars.
Drug release also could be affected by environmental conditions. It was concluded that different release profiles occurred and these fitted to various kinetic models that were dependent on variations on temperature and pH. It was released rapidly in higher pH, temperature solution. The cumulative drug released in pH 10.0,0.5M NaOH and 50℃solution after 12h reached 42.3%,87%,15.8%, respectively. While it reached 2.5%,2.5%,2.2% after 12h, respectively in pH 1.2,0.5N HC1 and 25℃solution. Ionic strength of the medium appears to have only a minor effect on drug release and higher ionic strength induced a faster drug release. Cumulative drug released was only 1.5% after 12h in distilled water; while it reached 5.6%in 0.5M NaCl.lt was apparent that the polymeric drug-saccharide conjugate had the potential to be developed as a system that enhanced drug delivery.
Then, the homopolymer and copolymer of ketoprofen were prepared to nanofibers through electrospinning. The drug release behavior revealed that both polymer drugs and electrospun fibers could prolong the drug release. While, the electrospun fibers had a different drug release mechanism, and the drug release rate was higher than that of polymer particles. The release profiles also suggested that it was possible to control the drug release rate by changing the concentration of polymer drug conjugates in the solution for electrospinning. Over all, the electrospun fibers prepared by electrospinning could increase drug release rate effectively, and also maintain the drug sustained release characteristics.
文章以2-芳基丙酸类药物(布洛芬Ibuprofen、萘普生Naproxen、酮洛芬Ketoprofen)为药物模型,它们属于非甾体抗炎药(nonsteroidal anti-inflammatory drugs, NSAIDs),具有抗炎、止痛和解热作用,临床上用于减轻或控制由炎症引起的症状和体征,如痛经、急慢性附件炎、盆腔炎所致的腰腹部疼痛、术后疼痛、关节或软组织的疼痛。但是小分子原药对胃肠道有较强的刺激性,体液中溶解性差、半衰期短等缺点限制了它们的临床应用。为了提高药物的生物利用度,必须降低其副作用,延长药物的作用时间。
本论文用化学法和酶促法合成了三种可聚合的药物乙烯酯和不同糖的乙烯酯衍生物,通过两类聚合单体的自由基聚合反应制备了一系列含糖聚合物前药。产物经红外光谱(FT-IR)、核磁共振(1HNMR, 13CNMR)和凝胶渗透色谱(GPC)等表征手段,确认其结构和分子量。
其中,本论文研究了不同聚合条件对聚合物前药性质的影响,如聚合反应单体摩尔比(1：1,1：2,2：1,4：1,mol/mol)、引发剂AIBN含量(1%,2%,4%,w/w)等。研究结果表明,当引发剂AIBN含量为2%时,聚合物分子量较高；增加反应中AIBN含量,聚合物分子量降低,大分子中的载药量增加；随着药物乙烯酯单体在聚合反应投料中比例的增加,聚合物的分子量逐渐下降,大分子药物的载药量则逐步增加；两种聚合单体的摩尔比例为1：1时,得到的聚合物前药分子量较大。
另外,论文系统考察了聚合物前药的体外药物释放行为和释放动力学。研究结果表明将酮洛芬、布洛芬和萘普生制备成含糖大分子药物可以有效避免小分子药物的暴释现象,能够达到药物缓释的效果,提高药物的利用率。
药物释放曲线表明,含双糖残基的聚合物前药的药物释放速率较快,10d内酮洛芬的累积释放量为60%,含单糖侧链的聚合物前药释放速率较双糖的低,酮洛芬均聚物前药的药物释放速率最慢,10d药物的累积释放量仅为22%；糖侧链与高分子主链间的连接臂链长较短的聚合物前药释放速率较快,链长较长的药物释放速率则较慢；聚合物中糖残基含量越高,药物释放速率越快；聚合物载药量越高,药物释放速率越慢。
聚合物前药在不同条件下的体外药物释放曲线显示释放介质的pH和温度对药物释放的影响比较明显。释放介质的pH越大、温度越高,药物释放速率越快。以酮洛芬含糖聚合物前药为例,其在pH10.0.0.5M NaOH溶液和温度为50℃时12h的药物累积释放量分别达到42.3%,87%,15.8%,而在pH 1.2、0.5N HCl溶液和温度为25℃时12h的药物累积释放量分别为2.5%,2.5%,2.2%；离子强度对药物释放亦有微弱影响,随着溶液离子强度的增加,药物释放速率缓慢增大,聚合物在去离子水中12h的药物释放量为1.5%,而相同时间内在0.5M NaCl溶液中为5.6%。对药物释放曲线的动力学方程模拟结果显示,不同条件下的药物释放遵循不同的动力学方程模型。
实验通过静电纺丝方法,以DMF/C2H5OH (1/1, v/v)为溶剂,将酮洛芬聚合物前药与聚乙烯吡咯烷酮(PVP)制备成纳米载药纤维。由于纤维表面积的快速增大和PVP良好的水溶性等性质,使得聚合物前药载药纤维的药物释放速率大大加快,同时纳米载药纤维还保持了聚合物前药的药物缓释作用。因此制备大分子药物的纳米载药纤维具有一定的意义。
Studies on macromolecules containing saccharide as selective drug delivery system have been developed for biomedicinal application. It has been reported that these systems provide many advantages including prolonged drug release, changed biodistribution, reduced toxicity and increased patient acceptance.
Ibuprofen, naproxen and ketoprofen are used as model drug. They are a commonly 2-Arylpropionic acid used as non-steroidal anti-inflammatory drugs (NSAIDs) and widely applied to alleviate pain and inflammation associated with tissue injury. However, the drugs are poorly soluble in aqueous media and cause irritant side effects especially on the gastro-enteric mucosal membranes. Therefore, polymeric prodrugs with saccharide through chemical bond can be designed to overcome such problems and merging the relative advantages of saccharide and macromolecules into a single system. This system can be useful to both increase drug stability and avoid the rapid release.
In this paper, a facile and efficient enzymatic and polymerization process was used to prepare polymeric drug-saccharide conjugates with 2-Arylpropionic acid pendants. A series of polymeric prodrugs with different saccharide branches were synthesized and the structures and molecular weight were confirmed by FT-IR, NMR and GPC.
Firstly, the paper investigated the influence of various factors to preparation of polymeric prodrugs, such as the molar ratio of drug vinyl ester and sugar vinyl ester (1:1,1:2,2:1,4:1, mol/mol), and the mass of initiator (AIBN,1%,2%,4%, w/w). The obersevations suggested that the molecular weight was influenced by the saccharides variation. Polymeric prodrug with lactose pendant had the highest molecular weight, with Mn of 7.527×104. By increasing saccharide derivatives in raction feed, it caused a decrease in molecular weight of the polymeric prodrugs. For example, the loading capacity of ketoprofen in the polymeric prodrug was only 22.74% (w/w) when glucose vinyl ester was 67% (mol/mol) in the feed, while it reached 42.28% (w/w) when it was 20% in the feed. A reduction of molecular weight was noted by increasing the ratio of initiator. The results suggested that the molecular weight and conversion of the polymeric prodrugs were greatly influenced by the concentration of initiator and the molar ratio of monomers.
And then, factors to the in vitro drug release were systematically studied, such as the effects of different saccharides with varying carbon chain length, drug carrier, pH, temperature, ionic strength and solution variation.
The drug release profiles could be influenced by the characteristics of these polymers. Among the polymeric conjugates, drug from prodrug with disaccharide pendant was released rapidly. It implied that the type of saccharide branch influenced release capabilities of polymeric prodrugs. The structures of monosaccharides appeared having a little influence on the drug release. The release of drugs was seen to decrease along with increasing the length of spacer bond between saccharide and polymer main chain. The release rate of drug from polymeric prodrugs increased with the raising of saccharide pendants in the macromoleculars.
Drug release also could be affected by environmental conditions. It was concluded that different release profiles occurred and these fitted to various kinetic models that were dependent on variations on temperature and pH. It was released rapidly in higher pH, temperature solution. The cumulative drug released in pH 10.0,0.5M NaOH and 50℃solution after 12h reached 42.3%,87%,15.8%, respectively. While it reached 2.5%,2.5%,2.2% after 12h, respectively in pH 1.2,0.5N HC1 and 25℃solution. Ionic strength of the medium appears to have only a minor effect on drug release and higher ionic strength induced a faster drug release. Cumulative drug released was only 1.5% after 12h in distilled water; while it reached 5.6%in 0.5M NaCl.lt was apparent that the polymeric drug-saccharide conjugate had the potential to be developed as a system that enhanced drug delivery.
Then, the homopolymer and copolymer of ketoprofen were prepared to nanofibers through electrospinning. The drug release behavior revealed that both polymer drugs and electrospun fibers could prolong the drug release. While, the electrospun fibers had a different drug release mechanism, and the drug release rate was higher than that of polymer particles. The release profiles also suggested that it was possible to control the drug release rate by changing the concentration of polymer drug conjugates in the solution for electrospinning. Over all, the electrospun fibers prepared by electrospinning could increase drug release rate effectively, and also maintain the drug sustained release characteristics.
引文
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