CN110711196B - 阿司匹林和对乙酰氨基酚的分子复合物,其制备,活性及应用 - Google Patents
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Abstract
本发明公开了一种摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物,公开了它的制备方法,公开了它的镇痛作用,公开了它的抗炎作用,因而本发明公开了它在制备镇痛药物和抗炎药物中的应用。
Description
技术领域
本发明涉及一种摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物,涉及它的制备方法,涉及它的镇痛作用,涉及它的抗炎作用,因而本发明涉及它在制备镇痛药物和抗炎药物中的应用。本发明属于生物医学领域。
背景技术
阿司匹林是老镇痛药,缺点是可引发胃肠道出血及耐药。非那西丁是老镇痛药,缺点是可损伤肾。咖啡因可增强镇痛药的镇痛作用,缺点是可引发中枢神经系统疾病。为增强老镇痛药的镇痛作用,出现了复方阿司匹林片或复方乙酰水杨酸片。复方乙酰水杨酸片中每片含220mg阿司匹林,150mg非那西丁及35mg咖啡因。非那西丁代谢为对乙酰氨基酚之后才发挥镇痛作用。咖啡因可引发中枢神经系统疾病。在研究复方乙酰水杨酸片的过程中发明人发现,片中的咖啡因并不必需。在研究复方乙酰水杨酸片的过程中发明人还发现,阿司匹林与对乙酰氨基酚可形成摩尔比为1比1的分子复合物。在研究复方乙酰水杨酸片的过程中发明人进一步发现,摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物的镇痛作用和抗炎作用均比复方乙酰水杨酸片强。根据这些发现,发明人提出了本发明。
发明内容
本发明的第一个内容是提供一种摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物。
本发明的第二个内容是提供制备摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物的方法。
本发明的第三个内容是提供摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物的ESI(-)-FT-MS及qCID谱。
本发明的第四个内容是提供摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物的NOESY谱。
本发明的第五个内容是评价摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物的镇痛活性。
本发明的第六个内容是评价摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物的抗炎活性。
附图说明
图1.阿司匹林与对乙酰氨基酚的分子复合物的ESI(-)-FT-MS及qCID谱。
图2.阿司匹林与对乙酰氨基酚的分子复合物的NOESY谱。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1制备阿司匹林和对乙酰氨基酚的分子复合物
将230mg阿司匹林与193mg对乙酰氨基酚溶于20mL浓度为30%-50%的乙醇水溶液使形成澄清的溶液。将得到的澄清溶液冷冻干燥,得到423mg冻干粉。这样制备的冻干粉就是本发明的摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物(后面简称复合物)。
实施例2测定复合物的ESI(-)-FT-MS谱和qCID谱
为确认实施例1制备的冻干粉是摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物,本发明首先测定了冻干粉的ESI(-)-FT-MS谱。图1表明,冻干粉的ESI(-)-FT-MS谱给出质量数为330.09771的分子离子峰,该质量数等于1分子阿司匹林的质量数与1分子对乙酰氨基酚的质量数的和减H。图1还表明,冻干粉的qCID谱中的质量数为330.09771的分子离子在ESI(-)-FT-MS条件下裂解为质量数为179.003450的阿司匹林负离子和质量数为137.0242的负离子。质量数为137.0242的负离子来自对乙酰氨基酚失甲基。可见,在实施例1制备的冻干粉是摩尔比为1比1的阿司匹林和对乙酰氨基酚的分子复合物。
实施例3测定复合物的NOESY谱
为揭示实施例1制备的冻干粉的1分子阿司匹林与1分子对乙酰氨基酚如何生成分子复合物,本发明进一步测定了冻干粉的NOESY谱。图2表明,在测定条件下复合物给出四个相关峰。相关峰A来自阿司匹林的CO2H质子与对乙酰氨基酚的苯环2-位质子的相互作用,相关峰B来自阿司匹林的CO2H质子与对乙酰氨基酚的酚羟基质子的相互作用,相关峰C来自阿司匹林的乙酰基的甲基质子与对乙酰氨基酚的酚羟基质子的相互作用,相关峰D来自阿司匹林的乙酰基的甲基质子与对乙酰氨基酚的乙酰基的甲基质子的相互作用。出现这四种相互作用的前提是所述质子间的距离小于也就是说,当1分子阿司匹林与1分子对乙酰氨基酚相互靠近生成分子复合物时必须保证所述质子间的距离小于/>
实施例4评价复合物的镇痛作用
为确认复合物在镇痛治疗中的优越性,本发明用小鼠光辐射热甩尾实验比较了复合物与西复方乙酰水杨酸片的镇痛活性。雄性ICR小鼠(体重20-22g)在温度为22±2℃的洁净环境中静息一天,之后随机分为CMC-Na组,复方乙酰水杨酸片(后面简称复方片)组及复合物组,每组10只小鼠。
复方片每片含220mg阿司匹林,150mg非那西丁及35mg咖啡因,按人用剂量换算为小鼠剂量并分为0.3片/kg(简称低剂量),0.45片/kg(简称中剂量)和0.9片/kg(简称高剂量)三个剂量组。复合物按230mg阿司匹林比193mg对乙酰氨基酚分为与0.3片/kg相当的剂量(简称低剂量,以阿司匹林为标准换算为0.29μmol/kg),与0.45片/kg相当的剂量(简称中剂量,以阿司匹林为标准换算为0.44μmol/kg)和与0.9片/kg相当的剂量(简称高剂量,以阿司匹林为标准换算为0.87μmol/kg)的三个剂量组。按照所述剂量,小鼠或口服CMCNa溶液,或口服复方片,或口服复合物。
将小鼠固定在鼠盒中,每盒一只。尾巴从小孔中穿出,暴露在盒外。静息7分钟待小鼠安静后测定基础痛阈。测定时用固定焦距的照射灯照射小鼠尾巴的1/3处,小鼠为躲避照射导致的灼痛而甩尾。从接受照射到甩尾所需要的时间定义为痛阈。7分钟后再重复测定。共重复测定4次,取平均值。基础痛阈是小鼠口服CMCNa或复方片或复合物前的痛阈,即口服药物0分钟时的痛阈。之后,小鼠口服CMCNa或复方片或复合物,并每30分钟测定一次痛阈,持续测定180分钟。表1说明,低剂量和高剂量复合物在给药60分钟和90分钟显示确切的镇痛作用,中剂量复合物在给药180分钟显示确切的镇痛作用。而复方片在三种剂量下都没有观察到确切的镇痛作用。本实施例的结果揭示,作为口服镇痛剂复合物明显优于复方片。也就是说,本发明有突出的技术效果。
表1 小鼠1次口服复合物0-180分钟的甩尾时间(均值±SD秒)
a)与CMC-Na比p<0.05;b)与CMC-Na比p<0.01,与复方片比p<0.05;c)与CMC-Na及复方片比p<0.05;n=10;t检验.
实施例5评价复合物的抗炎作用
因为二甲苯引起的小鼠耳肿胀被公认为急性炎症模型,所以本发明在二甲苯引起的小鼠耳肿胀模型上测定阿司匹林-对乙酰氨基酚分子复合物的治疗作用。本发明选西安利君制药的复方乙酰水杨酸片为阳性对照药。ICR雄性小鼠(体重42±3g)在温度为22℃的环境静息2天,自由饮水和进食。之后随机分为CMC-Na组,西安利君制药厂的复方乙酰水杨酸片(后面简称复方片)组及阿司匹林与对乙酰氨基酚分子复合物(后面简称复合物)组,每组10只小鼠。
复方片每片含220mg阿司匹林,150mg非那西丁及35mg咖啡因,按人用剂量换算为小鼠剂量并分为0.3片/kg(简称低剂量),0.45片/kg(简称中剂量)和0.9片/kg(简称高剂量)三个剂量组。复合物按230mg阿司匹林比193mg对乙酰氨基酚分为与0.3片/kg相当的剂量(简称低剂量,以阿司匹林为标准换算为0.29μmol/kg),与0.45片/kg相当的剂量(简称中剂量,以阿司匹林为标准换算为0.44μmol/kg)和与0.9片/kg相当的剂量(简称高剂量,以阿司匹林为标准换算为0.87μmol/kg)的三个剂量组。按照所述剂量,小鼠或口服CMCNa溶液,或口服复方片,或口服复合物。给药30min后,往小鼠的左耳廓均匀涂抹30μL二甲苯,2h后小鼠接受乙醚麻醉,断颈处死,剪下左右两耳,用7mm的打孔器在两耳的相同位置取圆形耳片,称重,求出两耳肿胀差值作为肿胀度。即肿胀度=左耳圆片重量–右耳圆片重量。
表2说明,三个剂量的复合物都有确切的强度相同的抗炎作用,复方片只在高剂量显示强抗炎作用而中剂量只显示中度抗炎作用。表2还表明,三个剂量的复合物的抗炎作用与高剂量复方片的抗炎作用均无显著性差异。此外,相当于0.3片/kg剂量的复合物的低剂量已是平台剂量,复合物的最低有效剂量应远低于这个剂量。本发明有突出的技术效果。
表2 复合物的抗炎活性
a)与CMC-Na比P<0.01;b)与CMC-Na比P<0.05;c)与CMC-Na比P>0.05;
d)与0.9片/kg复方片比P>0.05;n=10
综合表1和表2的数据,可以得出五点明确的结论。第一点结论是,复合物在三种剂量下都显示镇痛及抗炎两种活性。第二点结论是,复方片在三种剂量下均无镇痛活性。第三点结论是,复方片在中剂量和高剂量时显示抗炎活性。第四点结论是,复合物的剂量为复方片的高剂量的1/3时可显示镇痛及抗炎两种活性。第五点结论是,复合物的剂量降至复方片的高剂量的1/3时镇痛及抗炎两种活性仍然优秀,从而为降低用药剂量提供了实验依据。可见,本案有突出的技术效果。
Claims (9)
1.一种阿司匹林和对乙酰氨基酚的分子复合物,其特征在于:所述分子复合物由阿司匹林和对乙酰氨基酚复合而成,所述的分子复合物的制备方法包括:在30%-50%的乙醇水溶液中阿司匹林和对乙酰氨基酚按照摩尔比为1比1形成透明的溶液,之后经冷冻干燥形成冻干粉。
2.权利要求1所述的阿司匹林和对乙酰氨基酚的分子复合物,其特征在于,所述的分子复合物在ESI(-)-FT-MS测定中的质量数为330.09771,该质量数等于1分子阿司匹林的分子量与1分子对乙酰氨基酚的分子量之和减1个质子,在分子复合物中阿司匹林和对乙酰氨基酚的摩尔比为1比1。
3.权利要求2所述的阿司匹林和对乙酰氨基酚分子复合物,其特征在于,所述分子复合物在ESI(+)-FT-MS条件下的qCID谱的质量数为330.09771的分子离子可裂解为质量数为179.003450的阿司匹林负离子和质量数为150.05574的对乙酰氨基酚负离子,形成分子复合物是阿司匹林和对乙酰氨基酚存在的形态。
4.权利要求2所述的阿司匹林和对乙酰氨基酚的分子复合物,其特征在于,在800兆核磁共振的NOESY谱中阿司匹林的CO2H质子与对乙酰氨基酚的苯环2-位质子存在相互作用,阿司匹林的CO2H质子与对乙酰氨基酚的酚羟基质子存在相互作用,阿司匹林的乙酰基的甲基质子与对乙酰氨基酚的酚羟基质子存在相互作用,阿司匹林的乙酰基的甲基质子与对乙酰氨基酚的乙酰基的甲基质子存在相互作用,在阿司匹林和对乙酰氨基酚形成的摩尔比为1比1的分子复合物中这些质子间的距离都小于
5.一种制备权利要求1-4任何一项所述的阿司匹林和对乙酰氨基酚的分子复合物的制备方法,其特征在于,在45%-50%的乙醇溶液中阿司匹林和对乙酰氨基酚按照摩尔比为1比1形成透明的溶液,之后经冷冻干燥形成冻干粉。
6.权利要求1-4任何一项所述的阿司匹林和对乙酰氨基酚的分子复合物在制备镇痛药物中的应用。
7.权利要求1-4任何一项所述的阿司匹林和对乙酰氨基酚的分子复合物与各种药物制剂可接受的赋型剂的组合物在制备镇痛药物中的应用。
8.权利要求1-4任何一项所述的阿司匹林和对乙酰氨基酚的分子复合物在制备抗炎药物中的应用。
9.权利要求1-4任何一项所述的阿司匹林和对乙酰氨基酚的分子复合物与各种药物制剂可接受的赋型剂的组合物在制备抗炎药物中的应用。
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