CN102018713A - 一种药物组合物 - Google Patents
一种药物组合物 Download PDFInfo
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- CN102018713A CN102018713A CN2009101703056A CN200910170305A CN102018713A CN 102018713 A CN102018713 A CN 102018713A CN 2009101703056 A CN2009101703056 A CN 2009101703056A CN 200910170305 A CN200910170305 A CN 200910170305A CN 102018713 A CN102018713 A CN 102018713A
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- piperacillin
- tazobactam
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Abstract
本发明公开了一种药物组合物，其原料药为哌拉西林酸钠和他唑巴坦酸钠，其特征在于原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成。实验证明本发明药物组合物制备的制剂质量更加优秀。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种哌拉西林酸、他唑巴坦酸为原料的药物组合物。
背景技术
细菌的耐药性又称抗药性，一般是指细菌与药物多次接触后，对药物的敏感性下降甚至消失，致使药物对耐药菌的疗效降低或无效。时至今日，我国的耐药菌问题已变得十分突出，耐药菌引起的医院内感染人数，已占到住院感染患者总人数的30％左右，解决细菌耐药性问题已经是当务之急。青霉素和头孢菌素等β-内酰胺类抗生素是目前临床应用最多、最重要的一类抗生素，占抗生素销售总额的50％以上。青霉素和头孢菌素等β-内酰胺类抗生素的应用，为人类抵抗细菌感染作出巨大贡献，但长期使用会使细菌逐渐产生抗药性，由于细菌耐药性的增加，耐药菌引起的感染不易控制，从而导致感染死亡率增高。所有的β-内酰胺抗生素都具有一典型或不典型的β-内酰胺环，该环为抗生素的主要活性部位，此环一旦被水解破坏，抗生素就将失去抗菌活性。细菌对β-内酰胺抗生素的耐药80％左右是通过产生β-内酰胺酶水解破坏β-内酰胺环这一机制来实现。特别β-内酰胺酶，能破坏内酰胺环结构，从而降低β-内酰胺类抗生素的抗菌效果。β-内酰胺酶来源于细菌细胞壁合成酶，是由于细菌合成PBPS的过程中基因变异而造成的。β-内酰胺类药物在这类酶的作用下，使β-内酰胺环水解开环，而β-内酰胺环是与PBPS结合的活性功能部位，因此β-内酰胺环的破坏使其失去了干扰细菌细胞壁合成的功能。阻止β-内酰胺酶的水解作用有两条途径可以选择：一是提高β-内酰胺类抗生素对β-内酰胺酶的稳定性，使其不被破坏，比如伊米培能等碳青霉烯类抗生素，对β-内酰胺酶高度稳定，不易被一般β-内酰胺酶水解，只有非常少见的金属酶才能水解破坏碳青霉烯类抗生素。第二条途径是将一种β一内酰胺酶类抗生素与β-内酰胺酶抑制剂组成复合制剂，用酶抑制剂来对抗和抑制β-内酰胺酶，保护β-内酰胺类抗生素不受破坏，继续发挥抗菌作用。相比较而言，β-内酰胺类抗生素与β-内酰胺酶抑制剂组成的合剂，在临床上应用更为普遍。随着β-内酰胺酶抑制剂的开发，它与β-内酰胺类抗生素配伍使用，临床上取得了良好的效果，产生了巨大的效益。
他唑巴坦(Tazobactam)的作用机理与舒巴坦相近，都属于不可逆性β-内酰胺酶抑制剂。对A类丝氨酸酶如TEM-1、TEM-2、TEM-3、PCI及D类丝氨酸酶如DXA-5和PSE-2有较好的抑制作用。研究显示，对于多β-内酰胺或β内酰胺酶抑制剂，A类酶产生OHIO-1及其突变类型，TEM-30，TME-31的大肠杆菌对复方制剂很敏感，其敏感性较克拉维酸及舒巴坦高10～25倍。此外，研究表明，对以质粒介导和染色体介导的β-内酰胺类药物酶均有灭活作用。本品单独应用时抗菌活性很弱，而与哌拉西林组成的复方制剂比哌拉西林具有更广的抗菌谱和更强的抗菌活性。据文献报道，与头孢噻肟、头孢他啶、环丙沙星、亚胺培南及替门汀相比，本品与哌拉西林的复方制剂对肺炎球菌、金葡球菌、流感嗜血杆菌、卡他莫拉菌、肠球菌、脆弱类杆菌具有更强的杀菌能力，对于大部分肠杆菌科细菌、绿脓假单孢菌也有一定活性；对厌氧菌有较强的活性可使对哌拉西林耐药的多数菌株MIC降低75％。此外，本品对潜伏染色体编码诱导头孢菌素酶的菌种与各种β-内酰胺类抗生素间没有拮抗作用，而克拉维酸却有这种作用。总之，通过本品广泛而强大的抑酶作用，达到扩展和增强哌拉西林抗菌谱和抗菌活性的目的。哌拉西林是一种广谱半合成青霉素，对于许多革兰氏阳性和革兰氏阴性的需氧菌及厌氧菌具有抗菌活性，它是通过抑制细菌的隔膜和细胞壁行使其杀菌作用的。他唑巴坦钠与哌拉西林钠的复方制剂已上市多年，具有抗菌谱广、抗菌活性强、组织穿透力强、分布广泛及不良反应少等优点，其对腹腔、呼吸道、尿路及皮肤软组织等的感染有很强的疗效。最近对于其在儿科、烧伤、血液病等领域的应用研究也很活跃。在哌拉西林/他唑巴坦配方中由于他唑巴坦的存在，增强并扩展了哌拉西林的抗菌谱，使之对许多原先对哌拉西林以及其它β-内酰胺抗生素耐药的产β-内酰胺酶细菌有效。这样，哌拉西林/他唑巴坦复合制剂就具备了广谱抗生素以及β-内酰胺酶抑制剂的双重特征。两者联合应用，通过他唑巴坦钠对β-内酰胺酶的抑制作用，使哌拉西林的抗菌活性及抗菌谱明显提高，临床常见产酶菌，如大肠杆菌、克雷伯杆菌、肠杆菌、绿脓杆菌等敏感性明显提高。
虽然哌拉西林/他唑巴坦已经上市多年，但其稳定的药物组合物一直是医药工作者研发的重点。申请号为200680040942.6的中国专利公开哌拉西林/他唑巴坦组合物制备方法，该文献公开了以哌拉西林酸/他唑巴坦酸与碳酸氢钠或碳酸钠反应，充氮气或抽真空排除二氧化碳的方法制备稳定的组合物，该方法虽然技术可行，但需要控制二氧化碳在水中的量，以保证制剂中不溶性微粒的量，而该方法的反应原料的限制，二氧化碳在水中始终会有残留，因此，制剂的稳定性和不溶性微粒始终是无法解决的，因此，研究开发新的哌拉西林/他唑巴坦药物组合物，以保证制剂的质量，保证患者的用药安全势在必行。
发明内容
基于上述原因，我们科研人员经过多次实验，确定了新的哌拉西林/他唑巴坦药物组合物，该组合物中不含有二氧化碳，采用离子交换树脂的方法将哌拉西林酸、他唑巴坦酸中的H+与Na+交换，得到哌拉西林酸钠和他唑巴坦酸钠药物组合物，该组合物中无二氧化碳的残留，制备成制剂后，不溶性微粒降低，有关物质含量更低，制剂具有更好的稳定性，使产品的质量更加优秀。
本发明通过下述技术方案实现的。
一种药物组合物，原料药为哌拉西林酸钠和他唑巴坦酸钠，其特征在于原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成。
其中哌拉西林酸钠与他唑巴坦酸钠的重量比为8∶1。
其中哌拉西林酸钠与他唑巴坦酸钠的重量比为4∶1。
其中哌拉西林酸钠与他唑巴坦酸钠的重量比为2∶1。
其中离子交换树脂为钠型离子交换树脂。
所述的哌拉西林酸钠和他唑巴坦酸钠制备方法包括但不限于：取离子交换树脂加水，与派拉西林酸、他唑巴坦酸共同或单独混合，搅拌，过滤，滤液干燥即得。
所述的哌拉西林酸钠和他唑巴坦酸钠的制备方法包括但不限于：取钠型离子交换树脂加水，与派拉西林酸、他唑巴坦酸共同或单独混合，搅拌，过滤，滤液干燥即得。
上述药物组合物制备的制剂。
其中制剂为水针剂、输液剂、粉针剂或冻干粉针剂。
所述制剂的制备方法为：取离子交换树脂加水，与派拉西林酸、他唑巴坦酸共同或单独混合，搅拌，过滤，滤液按照药剂学常规要求制备成水针剂、输液剂、粉针剂或冻干粉针剂。
一、有关物质的检测
1、含量测定方法
照高效液相色谱法(中国药典2005年版二部附录)测定。
色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂；以甲醇-水-10％四丁基氢氧化铵溶液(450∶535∶15)(用磷酸调节pH值至3.5)为流动相；检测波长为230nm。理论板数按哌拉西林峰计不低于2000；哌拉西林峰、他唑巴坦峰与相邻杂质峰的分离度应符合要求。
测定法取制剂，精密称定，加溶剂[甲醇-水-10％四丁基氢氧化铵溶液(450∶535∶15)(用磷酸调节pH值至5.8)]超声溶解并稀释成每1ml中约含哌拉西林和他唑巴坦分别为0.4mg和0.1mg的溶液，作为供试品溶液；另取哌拉西林对照品和他唑巴坦对照品各适量，同法测定，按外标法以峰面积计算供试品中C23H27N5O7S和C10H12N4O5S的含量。
2、有关物质测定
取含量测定项下的细粉适量，加溶剂[甲醇-水-10％四丁基氢氧化铵溶液(450∶535∶15)(用磷酸调节pH值至5.8)]超声溶解并稀释制成每1ml约含哌拉西林1.6mg和他唑巴坦0.4mg的溶液，作为供试品溶液；精密量取供试品溶液3.0ml，置100ml量瓶中，加溶剂[甲醇-水-10％四丁基氢氧化铵溶液(450∶535∶15)(用磷酸调节pH值至5.8)]稀释至刻度，摇匀，作为对照溶液。照含量测定项下的方法，精密量取对照溶液20μl，注入液相色谱仪，调节检测灵敏度，使主峰高约为记录仪满量程的10％～20％，再精密量取上述两种溶液各20μl，分别注入液相色谱仪，记录色谱图至供试品溶液主峰保留时间的2倍。
3、结果比较
组别1：上市哌拉西林/他唑巴坦制剂。
组别2：申请号为200680040942.6的中国专利的哌拉西林/他唑巴坦制剂。
组别3：本发明哌拉西林/他唑巴坦制剂
表1不同制剂的有关物质的比较
二、稳定性研究
按照《中国药典》2005年版二部制剂的稳定性考察方法，对不同制剂进行加速稳定性考察，实验结果见表2-4：
组别1：上市哌拉西林/他唑巴坦制剂。
组别2：申请号为200680040942.6的中国专利的哌拉西林/他唑巴坦制剂。
组别3：本发明哌拉西林/他唑巴坦制剂
表2高温实验结果(60℃)
表3样品敞口高湿试验结果(RH75％)
表4强光试验结果(4500Lx)
三、不溶性微粒检查
组别1：上市哌拉西林/他唑巴坦制剂。
组别2：申请号为200680040942.6的中国专利的哌拉西林/他唑巴坦制剂。
组别3：本发明哌拉西林/他唑巴坦制剂
实验方法：按照中国药典(2005年版)二部附录不溶性微粒检查法中显微计数法进行检查，检查结果见表5：
表5不溶性微粒检查
四、制备实施例
实施例1
一种药物组合物，原料药为哌拉西林酸钠和他唑巴坦酸钠，原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成。
实施例2
一种药物组合物，原料药为哌拉西林酸钠和他唑巴坦酸钠，哌拉西林酸钠与他唑巴坦酸钠的重量比为8∶1，原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成。
实施例3
一种药物组合物，原料药为哌拉西林酸钠和他唑巴坦酸钠，哌拉西林酸钠与他唑巴坦酸钠的重量比为4∶1，原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成。
实施例4
一种药物组合物，原料药为哌拉西林酸钠和他唑巴坦酸钠，哌拉西林酸钠与他唑巴坦酸钠的重量比为2∶1，原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成。
实施例5
一种药物组合物，原料药为哌拉西林酸钠和他唑巴坦酸钠，原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成，所述离子交换树脂为钠型。
实施例6
一种药物组合物，原料药为哌拉西林酸钠和他唑巴坦酸钠，哌拉西林酸钠与他唑巴坦酸钠的重量比为8∶1，原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成，所述离子交换树脂为钠型。
实施例7
一种药物组合物，原料药为哌拉西林酸钠和他唑巴坦酸钠，哌拉西林酸钠与他唑巴坦酸钠的重量比为4∶1，原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成，所述离子交换树脂为钠型。
实施例8
一种药物组合物，原料药为哌拉西林酸钠和他唑巴坦酸钠，哌拉西林酸钠与他唑巴坦酸钠的重量比为2∶1，原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成，所述离子交换树脂为钠型。
所述的派拉西林酸钠和他唑巴坦钠包括但不限于下述方法
实施例9
取离子交换树脂加水，与派拉西林酸、他唑巴坦酸共同或单独混合，搅拌，过滤，干燥，得到派拉西林酸钠和他唑巴坦钠。
上述实施例1-8的药物组合制备成药物制剂，所述的药物制剂包括但不限于水针剂、输液剂、粉针剂和冻干粉针剂。所述制备方法包括但不限于下述：
实施例10
取离子交换树脂加水，与派拉西林酸、他唑巴坦酸共同或单独混合，搅拌，过滤，滤液按照药剂学常规要求制备成水针剂、输液剂、粉针剂或冻干粉针剂。
注：本发明所要求保护的具体技术方案，不限于上述实施例所表达的技术方案的具体组合。
本领域的技术人员可以对本申请发明描述的优选方案进行各种变化和更改，这种变化和更改可以在不背离本发明实质和范围且不减小其优点的情况下进行；因此，本发明申请权利要求覆盖上述这种变化和更改，包括但不限于等同方式。
Claims (8)
1.一种药物组合物，其原料药为哌拉西林酸钠和他唑巴坦酸钠，其特征在于原料药哌拉西林酸钠是由哌拉西林酸通过离子交换树脂制备而成，原料药他唑巴坦酸钠是由他唑巴坦酸通过离子交换树脂制备而成。
2.根据权利要求1所述的药物组合物，其中哌拉西林酸钠与他唑巴坦酸钠的重量比为8∶1。
3.根据权利要求1所述的药物组合物，其中哌拉西林酸钠与他唑巴坦酸钠的重量比为4∶1。
4.根据权利要求1所述的药物组合物，其中哌拉西林酸钠与他唑巴坦酸钠的重量比为2∶1。
5.根据权利要求1所述的一种药物组合物，其中离子交换树脂为钠型离子交换树脂。
6.根据权利要求1-5所述的一种药物组合物制备的制剂。
7.根据权利要求6所述的制剂，其中制剂为水针剂、输液剂、粉针剂或冻干粉针剂。
8.根据权利要求7所述制剂的制备方法为：取离子交换树脂加水，与派拉西林酸、他唑巴坦酸共同或单独混合，搅拌，过滤，滤液按照药剂学常规要求制备成水针剂、输液剂、粉针剂或冻干粉针剂。
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| CN1732930A (zh) * | 2005-08-26 | 2006-02-15 | 华北制药集团有限责任公司 | 注射用哌拉西林钠他唑巴坦钠复方制剂 |
| CN101265263B (zh) * | 2008-05-12 | 2010-06-02 | 海南百那医药发展有限公司 | 哌拉西林钠他唑巴坦钠复方注射剂的生产方法 |
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