CN103096878B - 包含苯并咪唑衍生物的固体药物组合物 - Google Patents
包含苯并咪唑衍生物的固体药物组合物 Download PDFInfo
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- CN103096878B CN103096878B CN201280002761.XA CN201280002761A CN103096878B CN 103096878 B CN103096878 B CN 103096878B CN 201280002761 A CN201280002761 A CN 201280002761A CN 103096878 B CN103096878 B CN 103096878B
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- azilsartan
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Abstract
一种调节药物溶出度和/或提高稳定性的包含苯并咪唑衍生物的固体药物组合物及其制备方法,以及该组合物用于制备治疗循环***疾病药物中的用途。
Description
技术领域
本发明涉及提高药物溶出度和/或稳定性的固体药物组合物及其制备方法,以及用于制备抗高血压药物中的用途。
背景技术
循环***疾病,又称心血管疾病,是指心脏、血管和调节血液循环的神经机构的疾病。以心脏病、高血压最多见。循环***疾病是常见病,尤其在内科疾病中所占比重甚大。心脏病常迁延不愈,影响生活和劳动,病死率亦高,随着传染病的控制,心血管疾病在人口死亡原因中所占地位更为突出。循环***疾病可分为先天性和后天性两大类。先天性心血管病为心脏大血管在胎儿期中发育异常所致。后天性心血管病,如冠状动脉硬化性心脏病、风湿性心脏病、高血压和高血压性心脏病。
血管紧张素II通过细胞膜上的血管紧张素II受体引起血管收缩并升高血压。由此,血管紧张素II受体拮抗剂可以是治疗循环***疾病比如高血压等的有效药物。肾素-血管紧张素***与醛固酮***一起在内稳态中参与控制全身血压、体液量、电解质平衡等。基于具有有效血管收缩作用的血管紧张素II通过位于细胞膜上的血管紧张素II受体升高血压的事实,现己揭示出肾素-血管紧张素和高血压之间的关系,由此,血管紧张素II的拮杭剂己被用于治疗血管紧张素诱发的高血压。迄今为止,临床业已通过口服给药施用具有血管紧张素II拮杭活性的药物,作为强烈表达血管紧张素II拮抗活性的优选化学结构,己知在联苯基侧链上具有酸基比如四唑基、羧基等的结构,临床上使用了具有这样结构特征的药物如氯沙坦、坎地沙坦西酯、奥美沙坦medoxomil等(Ruth R.Wexler等,Journal of MedicinalChemistry,vol.39,p.625(1996),JP-A-4-364171、JP-A-5-78328等)。JP-A-5-271228描述了其中在联苯基侧链上的酸基为5-氧代-4,5-二氢-1,2,4-嗯二吐-3-基的化合物,口服给药后其显示了长期且强烈的血管紧张素II拮抗活性和降压活性。此外,W003/047573描述了JP-A-5-271228中所述的苯并咪吐衍生物除了血管紧张素II受体拮抗活性外还具有胰岛素敏化活性。
阿齐沙坦(英文名称Azilsartan)是一种正处于研发中的治疗高血压症的血管紧张素II受体拮抗剂药物,通过选择性阻断血管紧张素II与血管平滑肌AT1受体的结合而阻断血管紧张素II的收缩血管作用,多用于治疗高血压症,也是目前唯一处于末期临床的血管紧张素II受体拮抗剂(沙坦类)药物。
药物产品需要具有有效性、安全性和稳定性。药物产品的有效性、安全性和稳定性,不仅和药效成分本身的有效性和安全性密切相关,而且受来自制备药剂性质的影响,比如药效成分在制剂中的稳定性、药物从制剂中的溶出特性等的影响都是非常重要的。例如,即使制剂在刚制备后满足一定水平的质量,如果在制剂中的药效成分随时间分解,那么根据药物产品的有效性和安全性该制剂是有问题的。对于药物从制剂中的溶出特性,当药物从制剂中溶出太慢时,该药物在血液中可能不能达到有效浓度且可能不能实现所期望的效果。当药物溶出太快时,可能导致体内血药浓度迅速增加,副作用的风险也可能增加。
对于提高药效成分在制剂中的稳定性的方法,加入pH调节剂是己知的,专利文献CN101677961A中仅公开了采用富马酸与氢氧化钠,或富马酸单钠作为稳定剂的方法,同时使用活性成分为阿齐沙坦酯钾盐。同时,该专利文献声称改善了药物的溶出度,但是其给出的具体实施方式均为高pH(pH6.8)条件下的溶出度实验,未能证明其在人体环境中的溶出优势。测定该专利申请所提供的药物组合物在低pH条件下的溶出度,可知其改善效果十分有限。
CN101528262A公开了包含药物有效成分、低熔点油脂状物质和低粘度粘合剂的固体药物组合物,以及改善药物有效成分由固体组合物中溶出的方法。其中,包含低熔点油脂状物质的固体剂型的药物溶出性质得到改善,但是其给出的具体实施方式均为高pH(pH6.8)条件下的溶出度实验,未能证明其在人体环境中的溶出优势。测定该专利申请所提供的药物组合物在低pH条件下的溶出度,可知其改善效果十分有限。
发明内容
本发明的目的在于提供一种固体药物组合物,其包含式(I)表示的化合物,其特征在于能够调节药物的溶出度和/或稳定性,
其中,
R1为单环含氮杂环基,该杂环基具有能被脱质子化的氢原子,R2为羧基,且R3为低级烷基,优选式(I)化合物为阿齐沙坦;
所述溶出度调节量为5%~100%,优选10%~90%。所述调节量为增加量或降低量,所述溶出度为pH1~10溶出介质中的溶出度,优选pH为4~8。
其中包含至少一种非活性成分来调节溶出度,所述的非活性成分选自乙基纤维素、醋酸纤维素、羟丙基甲基纤维素邻苯二甲酸酯、纤维素乙酸酯邻苯二甲酸酯、羧甲基乙基纤维素、甲基丙烯酸-丙烯酸乙酯共聚物、丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸三甲基铵乙基酯氯化物共聚物、甲基丙烯酸甲酯-丙烯酸乙酯共聚物、甲基丙烯酸-丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基纤维素乙酸酯琥珀酸酯和/或聚乙烯基乙酸酯邻苯二甲酸酯,所述非活性成分可存在于药物组合物的表面或分散在药物组合物内部。
发明人惊喜地发现,加入助溶剂可很好地提高阿齐沙坦的溶出。所述助溶剂选自碳酸钠、碳酸氢钠、磷酸氢钙、碳酸镁、氢氧化镁等,优选碳酸钠、碳酸氢钠。
在本发明优选的实施方案中,所述助溶剂加入量为固体药物组合物总重量的0.01%-20%,优选0.01%-10%。
一些稳定剂的加入,可提高固体药物组合物的稳定性,如马来酸与氢氧化钠、富马酸与氢氧化钠、柠檬酸与氢氧化钠、酒石酸与氢氧化钠、马来酸单钠、富马酸单钠、酒石酸钠、柠檬酸单钠、没食子酸丙酯、乙二胺四乙酸、乙二胺四乙酸二钠、丁基羟基茴香醚、亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠和/或抗坏血酸,优选马来酸与氢氧化钠、富马酸与氢氧化钠、柠檬酸与氢氧化钠、马来酸单钠、富马酸单钠和/或柠檬酸单钠。
在本发明优选的实施方案中,所述稳定剂加入量为固体药物组合物总重量的0.01%-20%,优选0.01%-10%。
本发明另一方面提供了一种含有阿齐沙坦的固体药物组合物,其中阿齐沙坦的粒径d(0.5)在1-50μm之间,d(0.9)小于或等于150μm;优选d(0.5)在1-20μm之间,d(0.9)小于或等于80μm;更优选d(0.5)在1-10μm之间,d(0.9)小于或等于40μm;最优选d(0.5)在1-5μm之间,d(0.9)小于或等于15μm。
阿齐沙坦在高pH(如pH6.8)下的溶出良好,但在低pH(如pH4.5)下溶出效果较差,然而阿齐沙坦在人体中最主要的吸收部位为空肠和十二指肠,pH值为4-7左右。发明人惊喜地发现,将阿齐沙坦处理成上述的粒径范围,可有效地改善其在低pH下的溶出。
在本发明优选的实施方案中,所述固体药物组合物还含有聚乙二醇,优选PEG4000或PEG6000,更优选PEG6000。当阿齐沙坦的粒径变小后,所述固体药物组合物有不稳定的倾向,发明人发现聚乙二醇类的加入,有效地改变了这一状况,起到了使组合物稳定的效果。所述聚乙二醇的含量没有特别限制,在本发明进一步优选的实施方案中,其占组合物总重量的0.01%-20%,优选0.01%-10%。
在本发明另一个优选的实施方案中,所述固体药物组合物还含有柠檬酸、柠檬酸钠,或它们的混合物。发明人注意到,柠檬酸、柠檬酸钠,或它们的混合物可大幅提高阿齐沙坦的生物利用度。所述柠檬酸、柠檬酸钠,或它们的混合物含量没有特别限制,在本发明进一步优选的实施方案中,其为组合物总重量的0.01%-20%,优先0.01%-10%。
在本发明另一个优选的实施方案中,所述固体药物组合物还含有促渗剂,所述促渗剂选自十二烷基硫酸钠(简称SDS)、十二烷基肌氨酸钠、泊洛沙姆、吐温、司盘、聚氧乙烯氢化蓖麻油、蓖麻油聚烃氧酯;泊洛沙姆可以是泊洛沙姆188、泊洛沙姆407;吐温可以是吐温20、吐温60、吐温80。促渗剂的加入,使得阿齐沙坦在体内的吸收得到改善,也提高了其生物利用度。促渗剂的含量没有特别限制,在本发明进一步优选的实施方案中,其为组合物总重量的0.01%-20%,更优选0.01%-10%。
本发明的另一个优选方案是式(I)化合物被包藏于环糊精及其衍生物的空穴结构内形成包合物,其中所述环糊精及其衍生物选自α-环糊精、β-环糊精、γ-环糊精、磺丁基醚-β-环糊精、2,6二甲基β-环糊精、2,6三甲基β-环糊精、单糖基β-环糊精、双糖基β-环糊精、麦芽三糖基β-环糊精、二单糖基β-环糊精、二双糖基β-环糊精、2,3,6-三甲氧基β-环糊精、2-氧-(2-羟丙基)-β-环糊精和/或羟丙基-β-环糊精,优选为β-环糊精和/或羟丙基-β-环糊精。进一步,式(I)表示的化合物与环糊精重量比为1:20~1:2;优选为1:10~1:4;更优选为1:8~1:4。
本发明的另一目的在于一种制备所述的药物组合物的方法,其特征在于将式(I)表示的化合物分散和/或包埋于组合物中各组份内,形成固体组合物的方法。
本发明的另一目的在于提供所述的药物组合物在制备治疗循环***疾病的药物中的用途,所述疾病优选高血压。
附图说明
图1:原料粒径对制剂溶出行为的影响
图2:包合物对制剂溶出行为的影响
图3:助溶剂对制剂溶出行为的影响
图4:实施例3和对比例2溶出行为的对比
图5:原料粒径对制剂溶出行为的影响2
具体实施方式
实施例1
将采用气流粉碎处理(d(0.5)=2.61μm,d(0.9)=5.24μm)的阿齐沙坦(64g),与甘露醇(200g)、微晶纤维素(30g)、交联羧甲基纤维素钠(16g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3.3g,混合均匀。所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每159.6mg)
实施例2
将阿齐沙坦(64g),与β-环糊精(384g)混合均匀,加入768g水,研磨6h至半固体状,40℃减压干燥得固体。以适量水、甲醇洗涤所得固体,减压干燥得到包合物。取包合物适量(含阿齐沙坦32g),与甘露醇(100g)、微晶纤维素(15g)、交联羧甲基纤维素钠(8g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3.3g,混合均匀。所得混合物通过10.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每345.5mg)
实施例3
将阿齐沙坦(64g),与甘露醇(90g)、微晶纤维素(90g)、交联羧甲基纤维素钠(15g)、碳酸钠(40g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3g,混合均匀。所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每156mg)
实施例4
将阿齐沙坦(64g),与甘露醇(90g)、微晶纤维素(90g)、交联羧甲基纤维素钠(15g)、碳酸钠(40g)混合均匀,添加硬脂酸镁3g,混合均匀。所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每151mg)
实施例5
将阿齐沙坦(64g),与甘露醇(90g)、微晶纤维素(90g)、交联羧甲基纤维素钠(15g)、十二烷基硫酸钠(40g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3g,混合均匀。所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每155mg)
实施例6
将阿齐沙坦(64g),与甘露醇(90g)、微晶纤维素(90g)、交联羧甲基纤维素钠(15g)混合均匀,采用5%羟丙基纤维素水溶液(含2.5%柠檬酸,0.83%氢氧化钠)为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3g,混合均匀。所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每158.5mg)
实施例7
将阿齐沙坦(64g),与甘露醇(90g)、微晶纤维素(90g)、交联羧甲基纤维素钠(15g)混合均匀,采用5%羟丙基纤维素水溶液(含2.5%马来酸,0.83%氢氧化钠)为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3g,混合均匀。所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每158.5mg)
实施例8
将阿齐沙坦(64g),与甘露醇(90g)、微晶纤维素(90g)、交联羧甲基纤维素钠(15g)混合均匀,采用5%羟丙基纤维素水溶液(含2.5%富马酸,0.83%氢氧化钠)为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3g,混合均匀。所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每158.5mg)
实施例9
将阿齐沙坦(64g),与甘露醇(90g)、微晶纤维素(90g)、交联羧甲基纤维素钠(15g)混合均匀,采用5%羟丙基纤维素水溶液(含2.5%富马酸,0.83%氢氧化钠)为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3g,混合均匀。所得混合物通过9.0mm冲头压片得到素片。将甲基丙烯酸共聚物A型和甲基丙烯酸共聚物B型溶于95%乙醇,不断搅拌至完全溶解,缓缓加入,继续搅拌至溶解,备用。取滑石粉、柠檬酸三乙酯加入至剩余乙醇水溶液,混合后用匀化10分钟,然后慢慢加入到共聚物溶液中,继续搅拌30分钟。将素片置于高效包衣锅内进行包衣,得到以下组成的包衣片。
片芯的组成(每317mg)
包衣层的组成(每332.9mg)
实施例10
将阿齐沙坦(64g),与甘露醇(90g)、微晶纤维素(90g)、交联羧甲基纤维素钠(15g)混合均匀,采用5%羟丙基纤维素水溶液(含2.5%富马酸,0.83%氢氧化钠)为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3g,混合均匀。所得混合物通过10.0mm冲头压片得到素片。将甲基丙烯酸共聚物A型和甲基丙烯酸共聚物B型溶于95%乙醇,不断搅拌至完全溶解,缓缓加入,继续搅拌至溶解,备用。取滑石粉、柠檬酸三乙酯加入至剩余乙醇水溶液,混合后用匀化10分钟,然后慢慢加入到共聚物溶液中,继续搅拌30分钟。将素片置于高效包衣锅内进行包衣,得到以下组成的包衣片。
片芯的组成(每317mg)
包衣层的组成(每320.2mg)
实施例11
将阿齐沙坦(64g),甲基丙烯酸共聚物A型(18.65g)、甲基丙烯酸共聚物B型(55.95g)、硬脂酸镁(1.4g)混合均匀,所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每140mg)
实施例12
将阿齐沙坦(64g),磷酸氢钙(67.6g)、预胶化淀粉(7g)、硬脂酸镁(1.4g)混合均匀,所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每140mg)
实施例13
将阿齐沙坦(64g),与羟丙-β-环糊精(256g)混合均匀,加入512g水,研磨6h至半固体状,40℃减压干燥得固体。以适量水、甲醇洗涤所得固体,减压干燥得到包合物。取包合物适量(含阿齐沙坦32g),与甘露醇(100g)、微晶纤维素(15g)、交联羧甲基纤维素钠(8g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3.3g,混合均匀。所得混合物通过10.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每290mg)
实施例14
将采用气流粉碎处理(d(0.5)=1.85μm,d(0.9)=4.12μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每199.5mg)
实施例15
将采用气流粉碎处理(d(0.5)=4.47μm,d(0.9)=13.28μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每199.5mg)
实施例16
将采用气流粉碎处理(d(0.5)=8.46μm,d(0.9)=25.13μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每199.5mg)
实施例17
将采用机械粉碎处理(d(0.5)=17.94μm,d(0.9)=56.82μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每199.5mg)
实施例18
将采用机械粉碎处理(d(0.5)=46.77μm,d(0.9)=83.14μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每199.5mg)
实施例19
将采用气流粉碎处理(d(0.5)=3.26μm,d(0.9)=8.21μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液(含聚乙二醇6000)为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每205.5mg)
实施例20
将采用气流粉碎处理(d(0.5)=3.26μm,d(0.9)=8.21μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每199.5mg)
实施例21
将采用气流粉碎处理(d(0.5)=3.26μm,d(0.9)=8.21μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液(含柠檬酸/柠檬酸钠)为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每209.5mg)
实施例22
将采用气流粉碎处理(d(0.5)=3.26μm,d(0.9)=8.21μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液(含泊洛沙姆188)为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每209.5mg)
对比例1
将采用过60目筛的阿齐沙坦(64g),与甘露醇(200g)、微晶纤维素(30g)、交联羧甲基纤维素钠(16g)混合均匀,采用羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁3.3g,混合均匀。所得混合物通过7.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每159.6mg)
对比例2
参见CN101528262A的实施例1制备。
对比例3
将采用纳米化处理(d(0.5)=290nm,d(0.9)=520nm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每199.5mg)
对比例4
将采用过80目筛处理(d(0.5)=61.2μm,d(0.9)=144.8μm)的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每199.5mg)
对比例5
将采用过60目筛的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液(含聚乙二醇6000)为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每205.5mg)
对比例6
将采用过60目筛的阿齐沙坦(80g),与甘露醇(250g)、微晶纤维素(37.5g)、交联羧甲基纤维素钠(20g)混合均匀,采用5%羟丙基纤维素水溶液(为粘合剂,制粒,流化床干燥,1.0mm筛网整粒。向整粒后颗粒中添加硬脂酸镁4.0g,混合均匀。所得混合物通过8.0mm冲头压片得到具有以下组成的素片。
制剂的组成(每199.5mg)
实验例1
测定阿齐沙坦在不同介质中的近似溶解度,如下所示。
参照中国药典2010版近似溶解度测定方法:在定量的各介质中加入过量的阿齐沙坦,25℃条件下每5分钟强力振摇30秒。30分钟后,用0.45μm微孔滤膜过滤,HPLC测定续滤液中阿齐沙坦浓度。
表1阿齐沙坦在不同介质中的近似溶解度
由上述结果可知,pH4.5醋酸盐缓冲液+5%十二烷基硫酸钠可以满足37mg以下规格制剂的漏槽条件,pH6.8磷酸盐缓冲液则可满足250mg以下规格制剂的漏槽条件。
实验例2
实施例1和对比例1中获得的素片的药物溶出行为评价条件如下:
溶出介质:pH4.5醋酸盐缓冲液+5%十二烷基硫酸钠,pH6.8磷酸盐缓冲液
溶出介质体积:900ml
溶出方法:参照中国药典2010版溶出度测定方法,选择溶出度测定第二法(即桨法),转速为50rpm。
采用HPLC方法测定溶出曲线见图1。
如图1所示,减小原料粒径后可显著改善阿齐沙坦在低pH条件(pH4.5)下的溶出行为。
实验例3
实施例2和对比例1中获得的素片的药物溶出行为评价条件如下:
溶出介质:pH4.5醋酸盐缓冲液+5%十二烷基硫酸钠
溶出介质体积:900ml
溶出方法:参照中国药典2010版溶出度测定方法,选择溶出度测定第二法(即桨法),转速为50rpm。
采用HPLC方法测定溶出曲线见图2。
如图2所示,采用β-环糊精为包合材料制备包合物后可显著改善阿齐沙坦在此条件下的溶出行为。
实验例4
将实施例2和对比例1中获得的素片进行防潮包装,分别置于40℃、60℃条件下,分别于7天、14天取样,通过HPLC方法测定分解产物的增加量,结果见表2。
表2包合物对制剂稳定性的影响
结果表明,采用β-环糊精为包合材料制备包合物后可改善阿齐沙坦稳定性,抑制降解。
实验例5
实施例3和对比例1中获得的素片的药物溶出行为评价条件如下:
溶出介质:pH4.5醋酸盐缓冲液,pH4.5醋酸盐缓冲液+5%十二烷基硫酸钠
溶出介质体积:900ml
溶出方法:参照中国药典2010版溶出度测定方法,选择溶出度测定第二法(即桨法),转速为50rpm。
采用HPLC方法测定溶出曲线见图3。
如图3所示,采用碳酸钠作为助溶剂可显著改善阿齐沙坦在此条件下的溶出行为。
实验例6
将实施例7和对比例1中获得的素片进行防潮包装,分别置于40℃、60℃条件下,分别于7天、14天取样,通过HPLC方法测定分解产物的增加量,结果见表3。
表3稳定剂对制剂稳定性的影响
结果表明,采用马来酸和氢氧化钠为稳定剂可显著改善阿齐沙坦稳定性。
实验例7
将实施例6、8和对比例1中获得的素片进行防潮包装,分别置于40℃、60℃条件下,分别于7天取样,通过HPLC方法测定分解产物的增加量,结果见表4。
表4稳定剂对制剂稳定性的影响
结果表明,采用富马酸或柠檬酸和氢氧化钠为稳定剂可改善阿齐沙坦稳定性。
实验例8
将实施例19、20和对比例5、6中获得的素片进行防潮包装,分别置于60℃条件下,分别于7天、14天取样,通过HPLC方法测定分解产物的增加量,结果见表5。
表5稳定剂对制剂稳定性的影响
结果表明,采用过60目筛的原料制备样品时,聚乙二醇6000可改善阿齐沙坦稳定性,但效果有限;当采用较小粒径原料药(经气流粉碎)制备样品时,聚乙二醇6000可起到意想不到的稳定剂效果。
实验例9
实施例3、对比例1、2中获得的素片的药物溶出行为评价条件如下:
溶出介质:pH4.5醋酸盐缓冲液+5%十二烷基硫酸钠,pH6.8磷酸盐缓冲液
溶出介质体积:900ml
溶出方法:参照中国药典2010版溶出度测定方法,选择溶出度测定第二法(即桨法),转速为50rpm。
采用HPLC方法测定溶出曲线见图4。
如图4所示,对比例2技术方案较对比例1在高pH(pH6.8)条件下溶出行为均相当,低pH(pH4.5)条件下的改善溶出作用有限,说明加入聚乙二醇6000做为助溶剂作用不显著。实施例3采用碳酸钠做为助溶剂较对比例2在高pH(pH6.8)条件下溶出行为相当,低pH(pH4.5)条件下更好的改善阿齐沙坦在的溶出,具有意想不到的效果。
实验例10
实施例14、15、16、17、18和对比例3、4中获得的素片的药物溶出行为评价条件如下:
溶出介质:pH4.5醋酸盐缓冲液+5%十二烷基硫酸钠
溶出介质体积:900ml
溶出方法:参照中国药典2010版溶出度测定方法,选择溶出度测定第二法(即桨法),转速为50rpm。
溶出曲线见图5。
如图5所示,实施例14、15、16、17、18和对比例4的溶出行为依次变慢,但对比例3的溶出度比实施例14低。可见随着阿齐沙坦原料粒径变小溶出速度更快,更充分。但阿齐沙坦原料药粒径减小到一定程度后(如进行纳米化处理)溶出度反而下降,这一点超出本领域持术人员的常识。因此,阿齐沙坦原料粒径应控制在一定范围内。
实验例11
实施例20和21分别进行人体药代动力学研究。空腹口服40mg后,实施例20的Cmax和AUC(0-∞)分别为4025ng/ml和26968ng/ml*h,实施例21的Cmax和AUC(0-∞)分别为4436ng/ml和36895ng/ml*h。实施例21的AUC(0-∞)是实施例20的1.37倍,可见柠檬酸/柠檬酸钠的加入提高了制剂的生物利用度。
实验例12
实施例20和22分别进行人体药代动力学研究。空腹口服40mg后,实施例20的Cmax和AUC(0-∞)分别为4025ng/ml和26968ng/ml*h,实施例22的Cmax和AUC(0-∞)分别为4559ng/ml和37725ng/ml*h。实施例22的AUC(0-∞)是实施例20的1.40倍,可见泊洛沙姆188的加入提高了制剂的生物利用度。
Claims (7)
1.一种固体药物组合物,其包含阿齐沙坦,其特征在于包含助溶剂,所述助溶剂为碳酸钠。
2.根据权利要求1所述的固体药物组合物,其中所述助溶剂用量为固体药物组合物总重量的0.01%-20%。
3.根据权利要求1所述的固体药物组合物,其中所述助溶剂用量为固体药物组合物总重量的0.01%-10%。
4.根据权利要求1至3任意一项所述的组合物,其特征在于还包含稳定剂,所述稳定剂选自马来酸与氢氧化钠、富马酸与氢氧化钠、柠檬酸与氢氧化钠、马来酸单钠、富马酸单钠和/或柠檬酸单钠。
5.根据权利要求4所述的组合物,其特征在于所述稳定剂用量为组合物总重量的0.01%-20%。
6.根据权利要求5所述的组合物,其特征在于所述稳定剂用量为组合物总重量的0.01%-10%。
7.权利要求1~6任意一项所述的药物组合物在制备治疗循环***疾病的药物中的用途,所述疾病为高血压。
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CN102824343A (zh) * | 2011-06-16 | 2012-12-19 | 江苏豪森药业股份有限公司 | 包含苯并咪唑衍生物的固体药物组合物 |
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2012
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- 2012-05-18 JP JP2014511719A patent/JP2014515359A/ja active Pending
- 2012-05-18 KR KR1020137032234A patent/KR20140030237A/ko not_active Application Discontinuation
- 2012-05-18 CN CN201280002761.XA patent/CN103096878B/zh not_active Expired - Fee Related
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2013
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WO2019130277A1 (en) * | 2017-12-30 | 2019-07-04 | Lupin Limited | Pharmaceutical formulations of azilsartan medoxomil |
WO2022003643A1 (en) * | 2020-07-03 | 2022-01-06 | Piramal Pharma Limited | Stable solid formulation of azilsartan kamedoxomil, or azilsartan or pharmaceutically acceptable salts thereof |
Also Published As
Publication number | Publication date |
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WO2012159552A1 (zh) | 2012-11-29 |
KR20140030237A (ko) | 2014-03-11 |
JP2014515359A (ja) | 2014-06-30 |
HK1182638A1 (zh) | 2013-12-06 |
CN103096878A (zh) | 2013-05-08 |
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