CN112206258A - 一种药物组合物的制备方法及其制备的药物组合物和应用 - Google Patents
一种药物组合物的制备方法及其制备的药物组合物和应用 Download PDFInfo
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- CN112206258A CN112206258A CN201910616288.8A CN201910616288A CN112206258A CN 112206258 A CN112206258 A CN 112206258A CN 201910616288 A CN201910616288 A CN 201910616288A CN 112206258 A CN112206258 A CN 112206258A
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Abstract
本发明提供了一种药物组合物的制备方法,该制备方法通过在溶剂中使用两性离子型表面活性剂,提取金银花、葛根、黄芩、黄连、白芍和炙甘草原料。本发明还提供了该方法制备的药物组合物。本发明的制备方法避免了多种原料同提时自沉淀的问题,制备的药物组合物中各活性成分含量显著提高,能有效治疗仔猪临床腹泻。
Description
技术领域
本发明属于兽药领域,具体涉及一种治疗仔猪临床腹泻的药物组合物的制备方法、制备的药物组合物及其应用。
背景技术
CN104825615A中,在黄连解毒汤浸膏浓缩时加入适量的β-环糊精,解决了黄连解毒汤浸膏浓缩时产生沉淀的问题。CN104825615A仅解决了中药组合物在浓缩步骤时产生沉淀的问题,忽略了在中药组合物加热提取时便已产生沉淀,从而导致提取率降低。
CN108619298A中,黄芩提取物使用50%乙醇、β-环状糊精的制备方法,黄连提取物使用乙醇、水、PEG-2000的制备方法,二者组合后解决了黄芩的有效成分黄芩苷与黄连的有效成分黄连素两者联用的水溶液会产生絮状沉淀的问题。CN108619298A中,黄芩提取物与黄连提取物均为单独制备,且各提取物提取时均采用酸碱调节pH值,操作繁琐,能耗高,且生产效率较低,多次调节酸碱导致产品收率也较低。
因此,现有技术需要提供一种多种中药原料同提时避免自沉淀的提取方法。
发明内容
为克服现有技术中的不足之处,解决黄连与黄芩、黄连与甘草等水共煎产生自沉淀的问题,本发明提供了一种能够提高原料利用率和药效的药物组合物及其制备方法。
本发明的第一方面在于提供一种药物组合物的制备方法,其中,所述制备方法包括:步骤(1)将两性离子型表面活性剂,加入使其能刚好溶解的水量,搅拌,得到溶液A;步骤(2)金银花、葛根、黄芩、黄连、白芍和炙甘草,加入溶剂及所述步骤(1)的所述溶液A进行提取,过滤,得到药物提取液;步骤(3)将所述步骤(2)的所述药物提取液,减压浓缩,得到药物组合物;以及步骤(4)将所述步骤(3)的药物组合物制备成剂型。
本发明通过在提取液中添加两性离子型表面活性剂,解决了不同原料共煎产生自沉淀的问题,保证了制备的药物中活性成分具有高含量。
两性离子型表面活性剂系指分子中同时具有正、负电荷基团的表面活性剂,其在酸性及碱性条件下均具有优良的稳定性及优良的表面性能,尤其甜菜碱型两性离子型表面活性剂在酸性、中性或碱性水溶液中均易溶,适用于任何pH环境,且安全无毒。作为本发明的一种实施方式,本发明的制备方法中,所述步骤(1)中的两性离子型表面活性剂选自十二烷基乙氧基磺基甜菜碱、十二烷基羟丙基磺基甜菜碱、十二烷基二甲基甜菜碱、十四烷酰胺丙基羟丙基磺基甜菜碱、癸烷基二甲基羟丙基磺基甜菜碱、或十二烷基氨基丙酸;所述的两性离子型表面活性剂的用量为中药材量的0.1%~5%。
所述的两性离子型表面活性剂的用量可选自:中药材量的0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1%、1.5%、2.0%、3%、4%、5%。
作为本发明的一种实施方式,本发明的制备方法中,所述步骤(2)中金银花、葛根、黄芩、黄连、白芍、炙甘草质量比为1~20:1~20:1~5:1~5:1~5:1~5;所述的溶剂为水、或乙醇;所述乙醇浓度为40%~95%。
所述步骤(2)中金银花、葛根、黄芩、黄连、白芍、炙甘草质量比为1~20:1~20:1~5:1~5:1~5:1~5。
上述金银花质量比数值1~20包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20。
上述葛根质量比数值1~20包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20。
上述黄芩质量比数值1~5包括1、2、3、4、5。
上述黄连质量比数值1~5包括1、2、3、4、5。
上述白芍质量比数值1~5包括1、2、3、4、5。
上述炙甘草质量比数值1~5包括1、2、3、4、5。
乙醇浓度可选自40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、95%。
作为本发明的一种实施方式,本发明的制备方法中,所述步骤(2)中金银花、葛根、黄芩、黄连、白芍、炙甘草质量比为10:10:3:3:2:2。
作为本发明的一种实施方式,本发明的制备方法中,所述步骤(2)中的提取次数为1次或1次以上;当所述步骤(2)中的提取次数为1次以上时,每次提取时所述溶液A按提取次数均等分配,每次提取中以相等量加入。
作为本发明的一种实施方式,本发明的制备方法中,所述步骤(4)中所述剂型为粉剂、颗粒剂、片剂、或口服溶液。
本发明还提供了所述的制备方法制备的药物组合物。
本发明的药物组合物其中活性成分含量高,在临床上能以高有效率治疗仔猪临床腹泻。
本发明还提供了所述的药物组合物在制备仔猪临床腹泻的药物中的应用。
本发明的药物组合物能以高的有效率治疗仔猪临床腹泻,有效率达92.9%,可应用于临床治疗。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述更为清楚。但这些实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
本发明实施例中所用到的化学试剂均为分析纯,购自国药集团。本发明所述的实验方法,若无特殊说明,均为常规方法;所述的生物材料,若无特殊说明,均可从商业途径获得。
实施例1本发明制备方法制备药物组合物(可溶性粉剂)
(1)取十二烷基乙氧基磺基甜菜碱5g,加入少许水,搅拌使溶解,得溶液A;
(2)取全方药材540g(金银花180g、葛根210g、黄芩45g、黄连45g、白芍30g和炙甘草30g),第一次加入7.7kg60%乙醇及1/3溶液A,煎煮1h;第二次和第三次均加入6.6kg60%乙醇及1/3溶液A,煎煮1h,合并滤液;
(3)将滤液减压浓缩至相对密度1.05-1.10(60℃-70℃),放冷,离心,得药物组合物;
(4)将上述药物组合物继续减压浓缩至干,粉碎,即得。
实施例2本发明制备方法制备药物组合物(颗粒剂)
(1)取十二烷基羟丙基磺基甜菜碱30g,加入少许水,搅拌使溶解,得溶液A;
(2)取全方药材600g(金银花100g、葛根100g、黄芩100g、黄连100g、白芍100g和炙甘草100g),第一次加入8.4kg水及1/3溶液A,水煎煮1h;第二次和第三次均加入7.2kg水及1/3溶液A,水煎煮1h,合并滤液;
(3)将滤液减压浓缩至相对密度1.05-1.10(60℃-70℃),放冷,离心,得药物组合物;
(4)将上述药物组合物减压浓缩至1.15-1.25(60℃-70℃),加入适量蔗糖,制粒,干燥,整粒,制成1000g,即得。
实施例3本发明制备方法制备药物组合物(片剂)
(1)取十二烷基乙氧基磺基甜菜碱10g,加入少许水,搅拌使溶解,得溶液A;
(2)取全方药材400g(金银花100g、葛根100g、黄芩50g、黄连50g、白芍50g和炙甘草50g),第一次加入5.6kg水及1/3溶液A,水煎煮1h;第二次和第三次均加入4.8kg水及1/3溶液A,水煎煮1h,合并滤液;
(3)将滤液减压浓缩至相对密度1.05-1.10(60℃-70℃),放冷,离心,得药物组合物;
(4)将上述药物组合物减压浓缩至1.15-1.25(60℃-70℃),加入适量蔗糖,制粒,加入淀粉、羧甲基淀粉钠、硬脂酸镁,压片,即得。
实施例4本发明制备方法制备药物组合物(口服液体制剂)
(1)取十二烷基二甲基甜菜碱15g,加入少许水,搅拌使溶解,得溶液A;
(2)取全方药材450g(金银花150g、葛根150g、黄芩45g、黄连45g、白芍30g和炙甘草30g),第一次加入6.3kg水及1/3溶液A,水煎煮1h;第二次和第三次均加入4.5kg水及1/3溶液A,水煎煮1h,合并滤液;
(3)将滤液减压浓缩至相对密度1.05-1.10(60℃-70℃),冷藏,离心,加热煮沸30min,冷藏,离心,得药物组合物;
(4)将上述药物组合物加入3g苯甲酸钠、5g吐温-80,加水至1000ml,搅匀,滤过,灌装,灭菌,即得。
对比试验例5
本实施例中除在试剂中不添加两性离子型表面活性剂外,其他提取步骤采用本领域常规提取方法:
(1)取金银花150g、葛根150g、黄芩45g、黄连45g、白芍30g和炙甘草30g,第一次加入6.3kg水,水煎煮1h;第二次和第三次均加入4.5kg水,水煎煮1h,合并滤液;
(2)将滤液减压浓缩至相对密度1.05-1.10(60℃-70℃),冷藏,离心,加热煮沸30min,冷藏,离心,得药物组合物;
(3)将上述药物组合物加入3g苯甲酸钠、5g吐温-80,加水至1000ml,搅匀,滤过,灌装,灭菌,即得。
实施例6实施例4和对比试验例5中制备的药物组合物活性成分的检测、比较
分别对实施例4和对比试验例5制得产品进行含量测定,采用高效液相色谱法,以十八烷基硅烷键合硅胶为填充剂,绿原酸的检测以乙腈为流动相A,0.4%磷酸水溶液为流动相B,按表1的规定进行梯度洗脱,检测波长为327nm,柱温25℃,理论板数按绿原酸峰计算应不低于1000。
葛根素的检测以甲醇-0.4%磷酸水溶液(24:76)为流动相,检测波长为250nm,理论板数按葛根素峰计算应不低于4000。
黄芩苷的检测以甲醇-0.15%三氟乙酸溶液(44:56)为流动相;检测波长为277nm;理论板数按黄芩苷峰计算应不低于2500。
盐酸小檗碱的检测以乙腈-0.05mol/L磷酸二氢钾溶液(50:50)(每100ml中加十二烷基硫酸钠0.4g,再以磷酸调节pH值为4.0)为流动相;检测波长为345nm;理论板数按盐酸小檗碱峰计算应不低于5000。
甘草酸的检测以甲醇-水-36%冰醋酸(72:28:1)为流动相;检测波长为254nm;理论板数按甘草酸铵计算应不低于3000。
表1绿原酸的检测条件
时间(分钟) | 流动相A(%) | 流动相B(%) |
0~12 | 11 | 89 |
12~13 | 40 | 60 |
13~18 | 40 | 60 |
18~19 | 11 | 89 |
19~25 | 11 | 89 |
检测结果见表2。
表2各有效成分含量测定结果
由表2可以看出,相对对比试验例5,本发明的制备方法在药物提取时加入两性离子型表面活性剂后,产品中各有效成分的含量明显升高,说明本发明制备方法能最大限度地保留处方中的有效成分,从而提高原料利用率。
实施例7本发明实施例4制备的口服液制剂治疗仔猪临床腹泻试验
7.1临床试验
试验动物
10—15日龄三元杂交仔猪,选自河南偃师某养殖场。临床表现为精神不佳,食欲减退,粪便黄色糊状或稀粥样,或挟有黏液,鼻盘微干等。
动物分组
对81例自然患腹泻的仔猪随机分成三个治疗组,第1组服用实施例4制得的本发明药物,1ml/次,2次/d,连用5d;第2组服用对比试验例5制得的药物,1ml/次,2次/d,连用5d;第3组不给药,其它饲养管理及消毒措施等均相同。
疗效判断标准
治疗期间,每天给药前仔细观察各组病猪的精神状态、食欲、大便状况、肛门周围的干湿度、肛门括约肌的松紧度及鼻盘干燥程度。
显效:治疗24-48h粪便呈条状,且颜色、气味正常,仔猪精神、吃料正常,鼻盘湿润,症状完全消失。
有效:治疗48-72h粪便性状转好、水分明显减少,临床症状缓解或基本消失。
无效:治疗72h后,粪便次数与性状无好转,甚至病情加重。
7.2治疗结果见表3:
表3本发明制备方法制备的药物与对比试验例药物对仔猪腹泻的治疗效果
注:**表示与实施例4药物组比,差异极显著(p<0.01),*表示与实施例4药物组比,差异显著(0.01<p<0.05)。
结果表明,本发明药物治疗仔猪腹泻,实施例4药物的有效率为92.9%,和空白对照组(40.0%)相比差异极显著,说明本发明药物对仔猪流行性腹泻具有较好的疗效;和对比试验例5的药物(75.0%)相比差异显著,上述治疗效果表明采用本发明制备方法制备的药物具有更好的临床治疗效果。
以上所述仅是本发明的优选实施例而已,并非对本发明做任何形式上的限制,虽然本发明已以优选实施例揭露如上,然而并非用以限定本发明,任何熟悉本专业的技术人员,在不脱离本发明技术方案的范围内,当可利用上述揭示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明技术方案的范围内。
Claims (8)
1.一种药物组合物的制备方法,其中,所述制备方法包括:
步骤(1)将两性离子型表面活性剂,加入使其能刚好溶解的水量,搅拌,得到溶液A;
步骤(2)金银花、葛根、黄芩、黄连、白芍和炙甘草,加入溶剂及所述步骤(1)的所述溶液A进行提取,过滤,得到药物提取液;
步骤(3)将所述步骤(2)的所述药物提取液,减压浓缩,得到药物组合物;以及
步骤(4)将所述步骤(3)的药物组合物制备成剂型。
2.根据权利要求1所述的制备方法,其中,所述步骤(1)中的两性离子型表面活性剂选自十二烷基乙氧基磺基甜菜碱、十二烷基羟丙基磺基甜菜碱、十二烷基二甲基甜菜碱、十四烷酰胺丙基羟丙基磺基甜菜碱、癸烷基二甲基羟丙基磺基甜菜碱、或十二烷基氨基丙酸;所述的两性离子型表面活性剂的用量为中药材量的0.1%~5%。
3.根据权利要求1所述的制备方法,其中,所述步骤(2)中金银花、葛根、黄芩、黄连、白芍、炙甘草质量比为1~20:1~20:1~5:1~5:1~5:1~5;所述的溶剂为水、或乙醇;所述乙醇浓度为40%~95%。
4.根据权利要求1所述的制备方法,其中,所述步骤(2)中金银花、葛根、黄芩、黄连、白芍、炙甘草质量比为10:10:3:3:2:2。
5.根据权利要求1所述的制备方法,其中,所述步骤(2)中的提取次数为1次或1次以上;当所述步骤(2)中的提取次数为1次以上时,每次提取时所述溶液A按提取次数均等分配,每次提取中以相等量加入。
6.根据权利要求1所述的制备方法,其中,所述步骤(4)中所述剂型为粉剂、颗粒剂、片剂、或口服溶液。
7.根据权利要求1~6所述的制备方法制备的药物组合物。
8.权利要求7所述的药物组合物在制备仔猪临床腹泻的药物中的应用。
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