CN1304322A - 利用氧化镁稳定的含ace抑制剂的组合物 - Google Patents
利用氧化镁稳定的含ace抑制剂的组合物 Download PDFInfo
- Publication number
- CN1304322A CN1304322A CN99807026A CN99807026A CN1304322A CN 1304322 A CN1304322 A CN 1304322A CN 99807026 A CN99807026 A CN 99807026A CN 99807026 A CN99807026 A CN 99807026A CN 1304322 A CN1304322 A CN 1304322A
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- China
- Prior art keywords
- compositions
- magnesium oxide
- hydrolysis
- ace inhibitor
- cyclisation
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 88
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- 239000005541 ACE inhibitor Substances 0.000 title claims abstract description 48
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 title claims abstract description 48
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 title claims abstract 11
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Abstract
本发明涉及通过氧化镁的存在稳定的含ACE抑制剂组合物。在制备稳定化试剂基本由氧化镁组成的药物组合物中防止所述ACE抑制剂喹那普利形成某些降解形式。氧化镁的存在也使其自身更适于含ACE抑制剂组合物制备中的加工条件,尤其是湿法制粒的加工条件。
Description
本发明涉及通过氧化镁的存在稳定的含ACE抑制剂的组合物。优选在基本由氧化镁组成作为稳定剂的药物组合物中防止ACE抑制剂,喹那普利在制备时一些降解形式。氧化镁的存在也使其自身在含ACE抑制剂组合物的制备过程中,尤其是湿法制粒的加工中更适合于加工条件。
一些用作抗高血压药的ACE(血管紧张素转化酶)抑制剂对于一些类型的降解作用很敏感。特别是,喹那普利和结构上相关药物的降解可以通过(1)经内部亲核性进攻环化形成取代二酮哌嗪类混合物,(2)侧链酯基水解,和(3)氧化生成常具有不利颜色的产物。
美国专利号4743450公开了可以利用一些添加剂作为稳定剂来制备含有上述类型ACE抑制剂的稳定组合物。该专利具体公开了应用周期表第Ⅰ和Ⅱ主族的金属的无机酸盐作为对一些种类降解作用敏感的含ACE抑制剂制剂的稳定剂。其中教导说碳酸镁是一种优选稳定剂。
一种ACE抑制剂,盐酸喹那普利是以商品名ACCUPRIL_市售且在其制剂中应用了碱性碳酸镁。碱性碳酸钠含有约40%至42%的氧化镁。
尽管碱式碳酸镁是喹那普利的有效稳定剂,但它在药物制剂中的应用存在一些缺陷。碱式碳酸镁是一种白色松散粉末,因其低下的压缩性、模压性和流动性而难以制成片剂。当采用湿法制粒制备组合物时,通过应用碱式碳酸镁制备含ACE抑制剂组合物所面临的困难更加突出。
为了压片通过湿法制粒的颗粒制备法是最久远且至今仍被广泛采用的方法。在干式压缩法成为可应用的加工方法之前,湿法制粒对于所有实际目标来说是唯一有效的方法。但是这种方法很繁琐,包括大量原料处理以及若干加工步骤,所以,其成本高。通常,该工艺涉及的无非是将制粒液以一定量和方式与混合粉状片剂组分(至少包括一些片剂助剂)掺混以将它们转化为均匀、湿润、粘附、非糊状的块状物,随后形成大小相当均匀的湿颗粒。此后,干燥湿颗粒且反复过筛以破碎附聚物,并且最后与其他压片助剂混合,由此获得易于压片的颗粒。
应注意在湿法制粒中,片剂组分除了活性物质以外一般还包括其他可药用惰性原料、确定的制片助剂并且可能还包括膨胀剂。一些上述制片助剂可以在制粒液混合在其中之前就含在混合的粉状组分中,并且还可以将制片助剂涂布在颗粒的表面,和在颗粒形成之后且在颗粒通过压片机之前进行涂布。
当将化合物如碱式碳酸镁与ACE抑制剂如盐酸喹那普利混合时,湿法制粒普遍存在繁琐和成本高的特征。制造商在加工碱式碳酸镁时业已尝试了若干种限速步骤:因碱式碳酸镁混合物的密度低而限制了批次规模;制粒时间达15分钟或更长时间;当采用不同批量的碱式碳酸镁时制粒时间在15至37分钟内的可变性;需要大量的水分来获得制粒终点,并且以23-29%的起始干燥损失计可能需要较长的干燥时间(干燥损失或“LOD”是一种水分测定试验,它利用加热来测量产品中存在多少水分或溶剂);和有限的流动性。
对于制造商来说碱式碳酸镁也因其来源成为问题。
可以理解,如果要改善含ACE抑制剂制剂的湿法制粒加工条件但不损失混合物如碱式碳酸镁的稳定作用,应对现有技术进行改进。
现已发现,含上述种类的ACE抑制剂的稳定组合物可以利用氧化镁作为主要环化稳定剂来制备。在一个实施方案中,通过将ACE抑制剂-盐酸喹那普利与基本由氧化镁组成的稳定剂相混合来制备药物组合物。氧化镁的应用不但最大程度地减小了ACE抑制剂的环化降解反应,而且改进了通过湿法制粒工业成为药物组合物的ACE抑制剂制剂。在一个优选实施方案中,ACE抑制剂不但与基本由氧化镁组成的稳定剂混合,而且与可降低ACE抑制剂水解的试剂混合,从而制备药物组合物,所述降低ACE抑制剂水解的试剂例如是糖、利尿剂、磷酸二钙或对ACE抑制剂具有降低水解作用的已知常用填充剂。在一个更优选的实施方案中,通过将5.8%(重量)氧化镁和5.8%(重量)盐酸喹那普利以及88.3%(重量)的乳糖混合来制备药物组合物,制得的组合物在60℃下可以耐受氧化、水解和环化降解达10天。
在另一实施方案中,公开了一种利用氧化镁制备稳定的含ACE抑制剂组合物的方法。该方法包括将ACE抑制剂与适量的基本由氧化镁组成的稳定剂和一种或多种用于减小水解作用的水解弱化剂(如糖类)相接触的步骤。在一个优选实施方案中,该方法包括将盐酸喹那普利与适量的基本由氧化镁组成的稳定剂和一种或多种糖接触形成混合物的步骤;并且对该混合物进行湿法制粒加工。
本发明的组合物具有若干优越于不含稳定化添加剂的组合物的优点。主要是,确实能够保护含在其中的活性组分或药物不发生环化和水解。此外,降低或完全消除了有时此类ACE抑制剂在配制时和放置了很长时间后出现的变色问题。因此,可以制得稳定的压片喹那普利制剂,该制剂的氧化变色小至无法检测到。
除了具有较高的保藏稳定性,本发明的制剂更加适合于药物组合。
本发明制剂的其他优越性还在于事实上碱式碳酸镁的存在及其所固有的全部缺陷都是不必要的。利用氧化镁作为主要稳定剂来制备含ACE抑制剂和氧化镁的组合物的方法改进了湿法制粒工艺的加工。对降低成本和繁琐性的改进包括但不限于:增大批量,这归因于氧化镁制剂的高密度;制粒时间为4.5至5分钟或更短时间;当使用不同批次的氧化镁时减小制粒时间的可变性(在0.5至1分钟内);减少获得制粒终点的水分量,并且基于5%至8%的起始干燥损失(LOD),缩短了干燥时间,同时改善了流动性。
本发明的上述和其他优越性根据本发明的下列描述将更加显而易见。
本发明涉及:Ⅰ.一种药物组合物,其含有:
(a)有效量的药物成分,该成分包括易于环化、水解和/或变色的ACE抑制剂,和
(b)有效量的氧化镁和适合延缓环化、水解和/或变色的水解弱化剂,其中所述氧化镁是组合物的主要环化稳定剂成分。Ⅱ.一种用于稳定ACE抑制剂药物的方法,该方法包括将药物与下列物质接触的步骤:
(a)有效量的氧化镁和适合延缓环化、水解和/或变色的水解弱化剂,其中所述氧化镁是组合物的主要环化稳定剂成分。Ⅲ.一种制备药物剂型的方法,其中包括将该制剂中含有适量以下物质的步骤:
(a)有效量的药物成分,和
(b)有效量的氧化镁和适合延缓环化、水解和/或变色的水解弱化剂,其中所述氧化镁是组合物的主要环化稳定剂成分。
本发明制备和应用的组合物和制备方法还适宜含有一种或多种对稳定化添加剂的功能无干扰的物质。通常,润滑剂(如硬脂酸镁、氢化植物油和滑石)、粘合剂(如明胶)和/或崩解剂(如聚乙烯吡啶咯烷酮)是适用的。
药物成分
本发明的组合物含有至少一种ACE抑制剂和任选的一种或多种其他药物或有益物质。可用于本发明的ACE抑制剂是任何种类的具有抗高血压性质的熟知化合物。
一组优选的化合物包括通式Ⅰ定义的化合物:其中A不存在,或是稠和5-、6-或7-元脂环族环或稠和苯环,其未经取代或被1或2个具有1-4个碳原子的烷氧基取代;n是0或1,和R是氢或具有1-5个碳原子的烷基。优选A不存在,是稠和5-或6-元脂环族环或稠和苯环,其未经取代或被2个甲氧基取代;n是0或1,R是氢或乙基。
特别有价值的是依那普利、喹那普利或吲哚普利,其相应的游离酸或其可药用酸加成盐或碱性盐。此类化合物公开在美国专利号4344949、4374829和4425355中,这些公开专利在此引入作为参考。
药物在最终组合物中的总含量应是约1%至约70%,优选约1%至约25%,和更优选约5%至约8%。
此处所有的百分比均为基于组合物总重量的重量百分比,除非另有说明。
本发明药物制剂的日剂量取决于剂型的性质、药物特性以及任何药物联合中的相互作用的类型和程度。所以,患者个体的治疗需求以及主治医师的预期目标决定了所用剂量的水平。但通常,制造商对于药物和药物联合的说明是实用的给药指南。由“医生参考手册”(thePhysicians’Desk Reference)和其他适宜的出版物可以确定适当的剂量水平。
然而,对于喹那普利和依那普利的典型剂量水平是每剂量约1mg至约80mg。
适用于本发明组合物中的除ACE抑制剂以外的药物种类可以在很大范围内变化,并且一般是任意的稳定药物联合。可例举的种类和具体实例包括:
(a)利尿剂,例如双氢克尿噻;
(b)镇咳药,例如右美沙芬、氢溴酸美沙芬、那可汀、枸橼酸喷托维林和盐酸氯丙胺丙醇;
(c)抗组胺药,例如马来酸氯苯那敏、酒石酸苯茚胺、马来酸吡拉明、琥珀酸苯吡甲醇胺和柠檬酸苄苯醇胺;
(d)减充血剂,例如盐酸苯福林、盐酸苯丙醇胺、盐酸伪麻黄碱和麻黄碱,
(e)多种生物碱,磷酸可待因、硫酸可待因和吗啡。
(f)矿物质补剂,例如氯化钾等。
在此适用的药物和/或其他有益物质可以选自多种不同的物质及其可药用形式,例如它们的酸加成盐。有机盐和无机盐都可以用来提供药物来维持其药效。酸加成盐的实例包括但不限于盐酸盐、氢溴酸盐、正磷酸盐、苯甲酸盐、马来酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、水杨酸盐、硫酸盐、乙酸盐等。也可以采用混合物。
适合与ACE抑制剂联合使用的一组优选药物包括:β阻断剂、利尿剂、钙阻断剂等。
稳定剂
通过应用适量,即有效量的氧化镁和降低ACE抑制剂水解的试剂如糖类可以克服由某些上述药物表现出的环化和水解不稳定性。虽然本发明中可以存在另外的稳定剂,其对ACE抑制剂制剂的环化稳定作用与氧化镁的稳定化作用相比很小。当与制剂中存在的氧化镁的稳定化作用相比时,即使少量的可能因氧化镁暴露于水和空气下产生的碳酸镁将会降低对ACE抑制剂制剂的稳定化作用。
氧化镁或煅烧氧化镁可以购自例如以色列的Dead SeeaPericlase公司、德国的Lohmann公司或Morton跨国公司。自然界中该化合物是以方镁石矿存在。得自菱镁矿的氧化镁市售制剂公开在美国专利号3320029。
氧化镁在出售时分为多种市售级别,它们全部属于本发明的范围内。两种优选的氧化镁形式是称作“轻质”的极松散形式和称作“重质”的致密形式。
在本发明的一个优选实施方案中,稳定的ACE抑制剂组合物基本由作为环化稳定剂的氧化镁组成。氧化镁的用量是该组合物总量的约1%至90%,优选约1%至约50%,首选约1%至约10%。通常,可以应用任何能够有效延迟或防止ACE抑制剂成分环化降解的量。
水解弱化剂
本发明的水解弱化剂是起着保护ACE抑制剂不发生水解性降解的作用。适用于本发明药物产品和方法中的水解弱化剂是那些与氧化镁相容的物质,由此它们不妨碍氧化镁在该组合物中的功能。一般地,它们是不含有明显干扰含金属成分或药物成分功能的物质的那些。本发明的有效水解弱化剂是糖类,例如甘露糖醇、乳糖和其他糖,利尿剂、磷酸二钙、双氢克尿噻,和对ACE抑制剂的水解具有削弱作用的已知填充剂。首选糖类且可采用混合物。
通常,水解弱化剂的含量是该组合物总量的约10%至约95%,优选约50%至约95%,和首选约70%至约90%。
剂型
本发明的组合物可以对患者单独给药,或作为组合物的部分给药,所述组合物含有其他成分如赋形剂、稀释剂和载体,这些都是所属技术领域所熟知的。所述组合物对人体或动物可以通过口服、直肠、非肠道(静脉内、肌肉内或皮下)、脑池内、阴道内、腹膜内、膀胱内、局部(粉剂、软膏或滴剂)给药,或作为经颊或经鼻喷雾剂。
本发明制备的药物制剂的最终形式可以千变万化。优选口服给药形式,即片剂、囊形片和胶囊。可以制备固体、半固体和液体制剂。但是,更优选固体。可用于本发明组合物的任选赋形剂也必须是与氧化镁相容的物质,由此不妨碍氧化镁在组合物中的功能。
适合非肠道注射的组合物可以包括生理可接受灭菌含水或非水溶液、分散体、混悬液或乳液,以及在灭菌可注射溶液或分散体中再溶的灭菌粉末。适用的含水和非水载体、稀释剂、溶剂或赋形剂的实例包括:水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、Cremophor EL(已知蓖麻油和环氧乙烷的衍生物;购自Sigma化学公司,St.Louis,MO)和它们的适当混合物、植物油(例如橄榄油),和可注射有机酯类混合物如油酸乙酯。通过例如应用包衣如卵磷脂,在分散体的情况中通过维持所需粒度,和通过应用表面活性剂,可以维持适当的流动性。
这些组合物也可以含有助剂,例如防腐剂、湿润剂、乳化剂和分散剂。利用多种杀细菌剂和抗真菌剂可以确保防止微生物的作用,例如对羟基苯甲酸酯类化合物、三氯叔丁醇、苯酚、山梨酸等。也适宜含有等渗剂,例如糖类、氯化钠等。通过应用吸收延缓试剂,如单硬脂酸铝和明胶,可以导致可注射药剂延迟吸收。
口服给药的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种惰性常规赋形剂(或载体)如柠檬酸钠或磷酸二钙混合或(a)填充剂或填料,如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;(b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如甘油;(d)崩解剂,例如琼脂、土豆或木薯淀粉、藻酸、某些复合硅酸盐、改性淀粉、聚乙烯吡咯烷酮(交联或非交联),和改性纤维素衍生物;(e)溶液阻滞剂,例如石蜡;(f)吸收促进剂,例如季铵类化合物;(g)湿润剂,例如鲸蜡醇和甘油一硬脂酸酯;(h)吸附剂,例如高龄土和膨润土;润滑剂,例如滑石、氢化植物油、硬脂酸锌、硬脂酸钙、硬脂酸镁、固态聚乙二醇、十二烷基硫酸钠;(j)颜料,和(k)着色剂或其混合物混合。在胶囊、片剂和丸剂的情况中,所述剂型中还可以含有缓冲剂。
应用了上述赋形剂如乳糖或奶糖以及高分子聚乙二醇等的类似固体组合物也可以在软和硬填充明胶胶囊中用作填充剂。
固体剂型如片剂、糖锭剂、胶囊、丸剂和颗粒剂可以用包衣和外壳制备,例如肠溶包衣和其他该技术领域所熟知的。它们可以含有遮光剂,还可以是在肠道一定部位中以延迟方式释放一种或多种活性物质的组合物。可采用的包埋式组合物的实例是聚合物和蜡。如果适合,活性化合物也可以与一种或多种上述赋形剂形成微包囊形式。
口服给药的液体剂型包括可药用乳液、溶液、混悬液、糖浆剂和酏剂。除了活性化合物以外,液体剂型含有所属技术领域所常用的惰性稀释剂,例如水或其他溶剂,增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇1,3-丁二醇、二甲基甲酰胺、油类(具体如棉籽油、花生油、棉胚油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、Cremophor EL(一种蓖麻油和环氧乙烷的衍生物;购自Sigma化学公司,St.Louis,MO)、聚乙二醇类和脱水山梨糖醇的脂肪酸酯或这些物质的混合物,等等。
除了上述惰性稀释剂以外,所述组合物也可以含有辅剂,例如湿润剂、乳化剂和助悬剂、甜味剂、矫味剂和香味剂。混悬液除了活性化合物以外可以含有助悬剂,例如乙氧基化异硬脂醇,聚氧化乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏铝酸(aluminummetahydroxide)、膨润土、琼脂和黄蓍胶,或这些物质的混合物,等等。
用于直肠给药的组合物优选是栓剂,所述栓剂可以通过将本发明的化合物与适当的无刺激赋形剂或载体如可可脂、聚乙二醇或栓剂用蜡混合来制备,所述栓剂用蜡是常温下为固态但体温下为液态的蜡,由此在直肠或阴道腔内融化并且释放活性成分。
用于本发明化合物局部给药的剂型包括软膏、粉剂、喷雾剂和吸入剂。在灭菌条件下将活性成分与生理可接受载体和如果需要的任意防腐剂、缓冲剂或抛射剂混合。眼用制剂,本发明的范围内包括眼用软膏、粉剂和溶液。
上述含ACE抑制剂的组合物应以按照《医生参考手册》(PDR)(第47版,1993)教导的治疗量来应用,该手册在此引入作为参考,或以所属领域普通技术人员所熟知的治疗有效量来应用。
所述组合物可以以推荐的最大临床剂量或较低的剂量给药。在本发明组合物中活性化合物的剂量水平可以根据给药途径、疾病的严重程度和患者的反应而改变以获得理想的治疗反应。所属领域技术人员熟知测定特定患者最佳剂量的方法。
制备方法
本发明涉及稳定ACE抑制剂药物的方法,该方法包括将有效量的药物与有效量的氧化镁和适合延缓环化、水解和/或变色的水解弱化剂相接触的步骤,其中氧化镁是该组合物的主要环化稳定成分。尽管可以采用任何所属领域技术人员所了解的使药物和氧化镁接触的适当工艺,但优选湿法制粒。氧化镁的存在本身能够改进含ACE抑制剂组合物的湿法制粒加工,其优点将在实施例6中作详细讨论,在该实施例中对比的现有碱式碳酸钙制剂和本发明的氧化镁制剂。这些优点概括如下:
(1)氧化镁制剂紧密且利用普通设备可以提供批量;
(2)减少制粒时间,制粒时间为约4.5至约5分钟或更短;
(3)减小制粒时间的可变性,当使用不同批次的氧化镁时这种可变性在约0.5至约1分钟内;
(4)减少获得制粒终点所需的水量并且有效地缩短干燥时间,所需水分的量是约50%或更少且干燥时间是约7分钟;
(5)起始LOD是5至8%内;
(6)改善流动性或安息试验(repose test)的角度,其中氧化镁制剂的流动性或安息角是32°。
在一个优选的实施方案中,本发明涉及一种用于制备稳定药物组合物的方法,该组合物含有有效量ACE抑制剂、水解弱化剂和基本由有效量氧化镁组成的环化稳定剂,其中该方法包括:
(1)将适量的ACE抑制剂、水解弱化剂和氧化镁混合;
(2)加制粒液至混合以形成湿块;
(3)干燥颗粒;和
(4)将颗粒与无药物活性的赋形剂混合。
所述方法还包括在加入非药物活性赋形剂之前筛分干燥颗粒的任选步骤。随后可以对由此形成的粒状药物进行进一步的常规处理以成为不同的固体剂型。此后利用常规工艺将固体剂型加工为最终的剂型。
所用赋形剂的百分比不是关键因素。通常,其用量应与上述药物和稳定剂成分的量相一致(崩解剂占组合物总量的约1%至约15%;润滑剂占组合物总量的约0.1%至约5%;和粘合剂占组合物总量的约1%至约10%),即构成组合物的余量。
所述药物制剂可适于瞬时、缓慢或持久的给药性能,或它们的任意组合。所以,可以考虑可在30分钟内提供一个初始输入剂量且随后在4-12小时内持续释放剩余药物的制剂。优选持续释放和瞬时释放型制剂。可以在不背离本发明范围的条件下进行合理的改变,例如所属领域技术人员想到的那些变化。
以下实施例用于举例说明本发明的特定实施方案,但不以任何方式限定说明书和权利要求书的范围。
实施例1
通过湿法制粒方法加工下列原料以制备20mg的片剂。
盐酸喹那普利 | 21.7mg |
氧化镁 | 21.7mg |
乳糖 | 254.3mg |
明胶 | 6.4mg |
聚乙烯吡啶咯烷酮 | 12.8mg |
硬脂酸镁 | 3.2mg |
实施例2
通过湿法制粒加工下列原料,以制备未加入稳定剂的5mg片剂。
盐酸喹那普利 | 5.425g |
无水乳糖 | 119.575g |
微晶纤维素 | 14.775g |
EDTA二钠盐 | 0.225g |
Sterotex(完全氢化植物油)HM | 1.500g |
Syloid 244硅胶 | 3.000g |
硬脂酸 | 4.500g |
抗坏血酸USP | 1.000g |
纯水,USP | 2.250g |
实施例3
通过湿法制粒加工下列原料,以制备未加入本发明所述稳定剂的20mg片剂。
盐酸喹那普利 | 21.7mg |
碱式碳酸镁 | 125.0mg |
乳糖 | 33.3mg |
明胶 | 10.0mg |
聚乙烯吡啶咯烷酮 | 8.0mg |
硬脂酸镁 | 2.0mg |
实施例4
在60℃下试验10天实施例1至3中制备的片剂的稳定性。数据显示,在与不含有稳定剂(实施例2)或含有碱式碳酸镁(实施例3)的类似制剂对比时,应用的氧化镁可以有效地稳定含ACE抑制剂的组合物,如盐酸喹那普利组合物。数据不但表明氧化镁可以稳定含ACE抑制剂的组合物以及碱式碳酸镁,而且氧化镁制剂需要比碱式碳酸镁制剂(约5%)更少的明胶(约2%)来获得可接受的压缩性。
喹那普利(%)初始/10天 | 降解产物(%) | ||
二酮基哌嗪 | 水解产物 | ||
实施例1实施例2a,b实施例3 | 98.7/98.968.197.7/96.1 | --32.4-- | --<1-- |
a原形喹那普利的百分含量
b试验是在60℃下进行1个月
实施例5
制备含氧化镁的喹那普利制剂和含碱式碳酸镁的喹那普利用于在湿法制粒加工中对比。通过将以下组分混合来制备制剂(1.5kg MgO和1.5kg MgCO3):
结果·氧化镁制剂比碱式碳酸镁制剂致密。2.5kg的氧化镁制剂能够在10LGral中制粒,相比之下在10L Gral中碱式碳酸镁制剂只能制粒1.5kg。对于喹那普利/氧化镁来说在加入明胶溶液之前混合物的堆密度是0.70g/mL,而对于喹那普利/碱式碳酸镁来说是0.27g/mL。·氧化镁制剂比碱式碳酸镁制剂(15-37分钟)缩短的制粒时间(4.5至5分钟)。·减小了制粒时间的可变性;采用不同批次碱式碳酸镁的时间变化约为15-17分钟,而采用不同批次氧化镁的时间变化为0.5至1分钟。·减少了获得制粒终点所用的水量;氧化镁制剂比碱式碳酸镁制剂少用50%的水。·对于氧化镁制剂来说初始LOD为5%至8%,相比之下碱式碳酸镁制剂为23%至29%。·氧化镁制剂比碱式碳酸镁制剂(15-18分钟)干燥得更快(7分钟)。·在氧化镁制剂中与碱式碳酸镁制剂不同的是避免采用第二步湿法碾磨,这归因于其中观察不到湿润导致的结块。·流动性或安息试验的角度表明,氧化镁制剂具有比碱式碳酸镁制剂(安息角35°)更好的安息角(安息角32°)。·在以四种强度(5、10、20和40mg)传递或制造盐酸喹那普利时仅需要一种含氧化镁制剂,相比之下,以5/10mg和20/40mg的强度传递盐酸喹那普利时需要两种制剂。
盐酸喹那普利 | 162.5g | 101.7g |
氧化镁 | -- | 101.7g |
碱式碳酸镁 | 937.5g | -- |
乳糖 | 250.0g | 1191.6g |
明胶 | 75.0g | 30.0g |
聚乙烯吡啶咯烷酮 | 60.0g | 60.0g |
硬脂酸镁 | 15.0g | 15.0g |
Claims (17)
1.一种药物组合物,其中含有:
(a)药物成分,其中含有适量的易于环化、水解和/或变色的ACE抑制剂,
(b)适量的延缓环化和变色的稳定剂,所述稳定剂基本由氧化镁组成,和
(c)适量的可抑制水解的水解弱化剂。
2.权利要求1的组合物,其中(a)是喹那普利或其可药用酸加成盐。
3.权利要求1的组合物,其中(a)含有至少一种附加药物。
4.权利要求1的组合物,其中氧化镁是唯一存在于该组合物中的碱土金属盐。
5.权利要求1的组合物,其中(b)含有以该制剂总重量计约1%至约90%的氧化镁。
6.权利要求1的组合物,其中(c)含有至少一种甘露糖醇和乳糖。
7.权利要求1的组合物,其中该组合物还含有至少一种选自粘合剂、崩解剂和润滑剂的材料。
8.权利要求1的组合物,其中所述水解弱化剂是糖。
9.一种药物组合物,其中含有:(a)式Ⅰ的化合物或其可药用酸加成盐:
其中A不存在,或是稠和5-、6-或7-元脂环族环或稠和苯环,其未经取代或被1或2个具有1-4个碳原子的烷氧基取代;n是0或1,和R是氢或具有1-5个碳原子的烷基;(b)适量的延迟环化和变色的稳定剂,该稳定剂基本由氧化镁组成;和(c)适量的抑制水解的糖。
10.权利要求9的组合物,其中A不存在,或是稠和5-或6-元脂环族环或稠和苯环,其未经取代或被2个甲氧基取代;n是0或1,R是氢或乙基,或其可药用酸加成盐。
11.权利要求9的组合物,其中(a)是盐酸喹那普利。
12.含有权利要求1的组合物的片剂。
13.含有权利要求11的组合物的片剂。
14.一种用于稳定ACE抑制剂药物不发生环化的方法,该方法包括令该药物与以下物质接触的步骤:
(a)适量的延迟环化的氧化镁,其中氧化镁是主要的稳定剂,和
(b)一种或多种糖。
15.权利要求14所述的方法,其中所述药物选自喹那普利、依那普利和吲哚普利,或它们的可药用酸加成盐。
16.权利要求14的方法,其中该方法还包括以下步骤:
将适量的ACE抑制剂、水解弱化剂和氧化镁混合在一起;
加入制粒液混合形成湿块;
干燥颗粒;和
将颗粒与非药物活性的赋形剂混合。
17.权利要求16的方法,其中该方法进一步包括以下步骤:
在加入非药物活性赋形剂之前将干燥颗粒过筛。
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US4344949A (en) * | 1980-10-03 | 1982-08-17 | Warner-Lambert Company | Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids |
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US4743450A (en) * | 1987-02-24 | 1988-05-10 | Warner-Lambert Company | Stabilized compositions |
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US5622985A (en) * | 1990-06-11 | 1997-04-22 | Bristol-Myers Squibb Company | Method for preventing a second heart attack employing an HMG CoA reductase inhibitor |
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IT1251153B (it) * | 1991-08-06 | 1995-05-04 | Vectorpharma Int | Composizioni farmaceutiche solide per somministrazione orale aventi proungata residenza gastrica |
JP3414539B2 (ja) * | 1994-05-11 | 2003-06-09 | 有限会社ドット | 経鼻吸収用組成物 |
IT1282650B1 (it) * | 1996-02-19 | 1998-03-31 | Jagotec Ag | Compressa farmaceutica,caratterizzata da elevato aumento di volume a contatto con liquidi biologici |
CN1144598C (zh) * | 1998-06-05 | 2004-04-07 | 沃尼尔·朗伯公司 | 利用氧化镁稳定的含ace抑制剂的组合物 |
NZ333206A (en) * | 1998-12-08 | 2000-07-28 | Bernard Charles Sherman | Solid pharmaceutical compositions comprising a stable magnesium salt of quinapril that acts as a ACE (Angiotensin Converting Enzyme) inhibitor |
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1999
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- 1999-05-10 AU AU39793/99A patent/AU755616B2/en not_active Ceased
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- 1999-05-10 AT AT99922899T patent/ATE295184T1/de not_active IP Right Cessation
- 1999-05-10 JP JP2000551814A patent/JP3727848B2/ja not_active Expired - Fee Related
- 1999-05-10 BR BR9910947-6A patent/BR9910947A/pt not_active Application Discontinuation
- 1999-05-10 US US09/700,883 patent/US6417196B1/en not_active Expired - Fee Related
- 1999-05-10 DE DE69925269T patent/DE69925269T2/de not_active Revoked
- 1999-05-10 TR TR2000/03600T patent/TR200003600T2/xx unknown
- 1999-05-10 IL IL13959099A patent/IL139590A0/xx not_active IP Right Cessation
- 1999-05-10 PL PL99344586A patent/PL344586A1/xx not_active Application Discontinuation
- 1999-05-10 EP EP99922899A patent/EP1083931B1/en not_active Revoked
- 1999-05-10 CA CA002330581A patent/CA2330581A1/en not_active Abandoned
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- 1999-05-10 KR KR1020007013714A patent/KR20010052557A/ko not_active Application Discontinuation
- 1999-05-10 ES ES99922899T patent/ES2242398T3/es not_active Expired - Lifetime
- 1999-05-18 TW TW088108107A patent/TW565455B/zh not_active IP Right Cessation
- 1999-06-03 HN HN1999000088A patent/HN1999000088A/es unknown
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- 1999-06-04 AR ARP990102642A patent/AR019150A1/es not_active Application Discontinuation
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- 1999-06-04 PE PE1999000475A patent/PE20000543A1/es not_active Application Discontinuation
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- 1999-06-04 UY UY25546A patent/UY25546A1/es not_active IP Right Cessation
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2000
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2002
- 2002-01-18 HK HK02100407.5A patent/HK1038879B/zh not_active IP Right Cessation
- 2002-04-22 US US10/127,181 patent/US7015232B2/en not_active Expired - Fee Related
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2005
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102512656A (zh) * | 2011-12-27 | 2012-06-27 | 天津市嵩锐医药科技有限公司 | 盐酸喹那普利药物组合物 |
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