CN1091634A - 含有一种β-羟基-β-甲基戊二酸单酰辅酶还原酶抑制剂的稳定的药物组合物 - Google Patents
含有一种β-羟基-β-甲基戊二酸单酰辅酶还原酶抑制剂的稳定的药物组合物 Download PDFInfo
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Abstract
公开了一个含β-羟基-β-甲基戊二酸单酰辅酶
A还原酶抑制剂化合物(如fluvastatin钠)的药物剂
型,该剂型因其碱性稳定性介质能使组合物的水溶液
或分散体的pH值保持在至少pH8,从而对与pH相
关的降解作用是稳定的。
Description
本发明涉及一种含对pH敏感的药物成分的药物组合物,该组合物具有增强的贮存稳定性。
某些β-羟基-β-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶化合物,即胆固醇生物合成抑制剂,可用于治疗高脂蛋白血症和动脉粥样硬化,它们为下式所代表的化合物:
其中
R为一有机基,
X为-CH=CH-,优选是(E)-CH=CH-,和
M为一生理学上可采用的阳离子,例如碱金属阳离子或铵,优选钠或钾,特别优选钠。
它们在pH低于8时特别容易降解。这类化合物的一个实例是具有下列化学名称的化合物:
R·,S·-(E)-(±)-7-[3-(4-氟苯基)-1-(1-甲基-乙基)-1H-吲哚]-2-基]-3,5-二羟基-6-庚烯酸,钠盐[见欧洲专利申请EP-A-114027],其在美国药品名称选定委员会(USAN)的名称是fluvastatin钠。
例如,我们发现fluvastatin水溶液在不同pH值下的降解动力学如下所示:
37℃时fluvastatin的留存率(%)
pH 1小时后 24小时后
7.8 98.3 98.0
6.0 99.6 97.1
4.0 86.7 25.2
1.0 10.9 0
我们认为,fluvastatin和相关的HMG-CoA还原酶化合物的上述不稳定性是由于庚烯酸链上的β,δ-羟基非常不稳定,而且存在着双键,所以,在中性至酸性pH值下,这类化合物很容易发生消除反应,异构化反应或氧化反应而形成共轭的不饱和芳族化合物,以及苏式异构体,相应的内酯及其它降解产物。
为获得适于市场销售的含有这种化合物的剂型,必须充分保护这种化合物使免受与pH相关的去稳定作用的影响。
另外,此类化合物对热和光的敏感性以及吸湿性对其药物学剂型的生产和储存也提出了特殊的要求。
出人意料,我们已能制备具有长时间储存稳定性的这类组合物,例如在+25℃和+30℃,在2年或更长的时间后,至少95%初始量的药物仍具有活性。
将本发明的组合物经口服给药,可使药物迅即被肠道基本完全吸收。
进一步的好处是,通过水的或其它借助溶剂的方法(如湿法成粒作用)可以很容易地制备本发明的稳定性组合物。
一方面,本发明提供了一种含有由下式代表的HMG-CoA化合物的药学组合物。
其中
R为一有机基,
X为-CH=CH-,和
M为一生理学上可采用的阳离子,并且,可将至少pH8的碱度介质赋予该组合物的水溶液分散体系。
这类组合物包括药物和一个“碱性介质”,这个碱性介质能够通过将至少pH8的酸碱度环境赋予该组合物的水溶液或分散体系而使该组合物得以稳定。在组合物中,式Ⅰ所代表的化合物与碱性介质最好是紧密地联系在一起以使该药物获得最令人满意的稳定性。
发现所生成的组合物能够延长式Ⅰ化合物的储存期,即使在潮湿的条件下或该组合物含有另外的潜在的活性赋型剂(如乳糖)时也如此。本发明的组合物中药物成分的稳定性,在25℃18个月以后(甚至更长的时间)至少为95%,典型地是在98%-99%之间。
此处所用的术语“碱性介质”或“碱”意指一个或多个具有下述作用的药物学上可采用的物质,即它(们)能使本发明组合物的水溶液或分散体系的pH至少达到8,优选至少为pH9,直至约pH10。更具体的是,当组合物吸收水或向组合物中加入少量水时,这种碱介质会在组合物颗粒周围形成一个至少为pH8的微环境。此外,这种碱性介质对式Ⅰ化合物应该是不活泼的。测定pH的方法是取含有,例如,20mg fluvastatin的单位剂量或等量的属于式Ⅰ所代表的同类其它化合物的组合物,并将其分散或溶解于10-100ml水中。
包括这种碱介质的药学上可采用的碱性物质可以是水溶性的,微溶于水的,到基本上不溶于水的物质。
能赋予必要的碱性水溶性碱性物质包括某些药物学上可采用的无机碳酸盐,例如碳酸钠或碳酸钾,碳酸氢钠或碳酸氢钾;磷酸盐,例如无水二价磷酸钠盐、钾盐或钙盐,或磷酸三钠;以及碱金属的氢氧化物,例如氢氧化钠,氢氧化钾或氢氧化锂;和前述各种物质的混合物。
按照本发明,稳定的组合物的例子包括:0.5-60wt.%(重量),优选的是0.5-40wt.%的药物(例如fluvastatin);和0.1-35wt.%(优选的是1-15wt.%)的可溶性碳酸盐,例如碳酸氢钠,碳酸钠及其混合物。
在构成这种组合物的稳定的碱性介质中可能有用的不溶于水或微溶于水的碱性物质包括那些通常用于抗酸配方中的化合物(例如氧化镁,氢氧化镁或碳酸镁;碳酸氢镁;氢氧化铝,氢氧化钙,碳酸铝或碳酸钙;复合的铝镁化合物,如氢氧化镁铝);以及药物学上可采用的磷酸盐,如三价磷酸钙;及其混合物。
上述碱性物质中,“药物学上可采用的碳酸盐”-指药物学上可采用的无机碳酸盐和碳酸氢盐,如碳酸钠,碳酸氢钠,碳酸钙,以及它们的混合物-在构成碱性介质中特别有效。
具有特别引人注目的贮存稳定性的组合物,其碱性介质包括一种水溶性的碱性赋型剂和一种不溶于水或微溶于水的碱性赋型剂。
例如,用一种水溶性的碳酸盐和一种不溶于水的碳酸盐,尤其是碳酸氢钠(或碳酸钠)与碳酸钙合并组成的碱性介质,将大大提高组合物的稳定性并使之具有其它的优点。
当储存过程中组合物的颗粒上吸附有湿气时,碳酸氢钠有利于中和组合物中的酸性基团。碳酸钙在储存组合物中起缓冲作用,在而对药物的释放、吸收无明显影响。进一步发现,碳酸盐足以稳定药物以致可用常规的以水为基质的制备方法(如加水研磨法或湿碾法)制备本发明的稳定的组合物。
碳酸钙可以是沉淀的或研磨的材料,但最好是沉淀的材料。
组合物中碱性介质的量将足以使组合物的水溶液或其分散系的酸碱度至少为pH8,最好至少为pH9,甚或高达pH10。一般地,本发明的组合物由约0.1-60wt.%(典型的是0.5-40wt.%)的药物成分和约0.1-60wt.%(优选20-35wt.%)的碱性介质所组成。
所用的特别稳定赋型剂的量一定程度上取决于所要用的制造方法。例如,对压片的组合物,碳酸钙的量就不能超过可方便地被压制成片所需的量,而且一般地是与更容易被压片的碱性物质,如碳酸氢钠合用。另一方面,胶囊剂型可用较不易被压制的赋型剂,其前提是整个组合物保持充分的自由移动和可塑性。
固体剂型的组合物,其碱性介质中水溶性和非水溶性碳酸盐的比例可以是,例如,1∶40到2∶1。
本发明的组合物的一个典型的片剂中,碳酸钙与碳酸氢钠之重量比可为2∶1到1∶2。在胶囊剂中,上述赋型剂的重量比可为25∶1到35∶1。
除了药物成分和碱性介质外,组合物中通常还要用填充剂以赋予其可加工性。适于作填充剂的物质是本领域技术人员所周知的(见Remington′s Pharmaceutical Sciences,18th Ed.(1990),MackPublishing Co.,Easton,PA,pp.1635-1636),包括乳糖和其它碳水化合物,予胶化淀粉,如1500R淀粉(Colorcon公司),玉米淀粉,磷酸二钙,纤维素,微晶纤维素,糖,氯化钠,及其混合物。其中优选乳糖,微晶纤维素,予胶化淀粉及它们的混合物。
由于微晶纤维素具有优良的分解和压缩性,它本身(AvicelR,FMC公司),以及由微晶纤维素和一种或多种另外的填料(如予胶化淀粉)构成的混合物特别有用。
按组合物的全量计算,全部填充剂在组合物中约占1-65wt.%。
为便于加工和/或提高产品剂型的特性,组合物中还可以掺入其它成分包括众所周知的压片用粘合剂(如明胶,糖,天然和合成的粘合剂如羧甲基纤维素,甲基纤维素,聚乙烯吡咯烷酮,羟基丙甲基纤维素,微晶纤维素,以及它们的混合物);崩解剂(如交联羧甲基纤维素,交联羧甲纤维素,交联聚维酮,淀粉甘醇酸钠),润滑剂(如硬脂酸镁,氢化植物油,巴西棕榈蜡等等),流动剂(如二氧化硅),抗粘附剂或滑动剂(如滑石)以及甜味剂,着色剂(如:三氧化二铁,铝色淀),调味剂,抗氧化剂,等等。参照标准的方法并结合制备片剂、胶囊和其它剂型的实际经验,本专业一般的技术人员都能很容易地确定选用哪一种或哪几种特定的成分及其用量。一般地,压片用粘合剂的有效用量约为1-10wt.%,最好为1-5wt.%;抗粘附剂或滑动剂的有效量约为1-10wt.%;崩解剂约为1-5wt.%;润滑剂约为0.1-2wt.%,皆根据组合物的总量计算。
这类组合物可按已知方法配制,得到标准的口服化合物的单元剂型,如5mg,10mg,20mg,40mg,等等。剂型可以是胶囊,片剂,丸剂等等。
可任意地给口服的片剂、丸剂或胶囊包上肠衣涂层材料以保护药物,防止其在到达小肠吸收点之前被胃酸过早地降解。这类材料是众所周知的,包括羟基丙甲基纤维素邻苯二甲酸酯,乙酸纤维素邻苯二甲酸酯,聚乙酸乙烯邻苯二甲酸酯,甲基纤维素邻苯二甲酸酯,共聚异丁烯酸/异丁烯酸甲基酯(如EudragitR,Rohm药厂)。优选采用这类肠衣涂层使胶囊、药丸或片芯的重量增加5-12%,优选8-12%。
给本发明的片剂组合物包上糖衣,可以防潮和防止轻微的脱色,并遮蔽药物的苦味。无论该肠衣物含有遮光剂和着色剂,或者是在片芯上包一层常用的不透明的膜,但是,都优选在先包好肠衣物质后再实施。
适于用作本发明组合物的糖衣层中的成膜剂包括,例如,聚乙二醇,聚乙烯吡咯烷酮,聚乙烯醇,亲水性多聚物如羟丙基纤维素,羟甲基纤维素及羟丙基甲基纤维素等等,其中首选羟丙基甲基纤维素(如Opadry YellowT,Colorcon公司)。适用的,用有机溶剂作载体的憎水成膜剂包括:乙基纤维素,乙酸纤维素,聚乙烯醇-马来酐共聚物等等。
包衣一般宜使药丸或片芯或药片的重量增加约1-10wt.%,优先2-6wt.%。
其它常规用作肠衣或包膜的成分包括增塑剂,如聚乙二醇(如聚乙二醇6000),柠酸三乙酯,邻苯二甲酸二乙基酯,丙二醇,丙三醇,丁基邻苯二甲酸酯(常规量),以及上面提到的遮光剂如二氧化钛,着色剂如三氧化二铁,铝色淀等等。
可用常规方法包衣,即使用水和/或常规有机溶剂(如甲醇,乙醇,异丙醇),酮(丙酮,乙基甲基酮),氯化烃(二氯甲烷,二氯乙烷)等在合适的涂层盘或流化床装置中进行包衣。
本发明的组合物包括下列各项(按组合物的总重量计百分比):
0.1-60wt.%(典型的为0.5-40wt.%)化合物(如fluvastatin),0.1-60wt.%碱性介质(如碳酸盐),及1-65wt.%填充剂(如微晶纤维素)。
这类组合物的一个实例包括(按组合物的总重量计百分比):
0.5-60wt.% HMG-CoA还原酶化合物(如fluvastatin),10-55wt.%碱性介质(如碳酸盐)和10-65wt.%填充剂(如微晶纤维素)。
本发明的组合物的另一个实例包括(按组合物的总重量计百分比):
0.5-60wt.%药物化合物(如fluvastatin),5-40wt.%碳酸钙,0.5-20wt.%碳酸氢钠,10-65wt.%填充剂(如微晶纤维素)。
本发明的胶囊组合物的实例包括(按组合物的总重量计百分比):
0.5-60wt.%(典型地为0.5-40wt.%)药物化合物(如fluvastatin),25-40wt.%碳酸钙,0.5-10wt.%碳酸氢钠,20-35wt.%微晶纤维素,以及15-30wt.%任意的另外的填充剂(如予胶化淀粉)。
本发明的片剂组合物的实例包括(按组合物的总重量计百分比):
0.5-60wt.%药物化合物(如fluvastatin),5-20wt.%碳酸钙,5-20wt.%碳酸氢钠,50-65wt.%微晶纤维素。
本发明的稳定组合物可以用本专业一般人员周知的各种方法和生产程序来制备。
在制备这种组合物时,重要的是要使药物成分与碱性介质紧密地结合在一起。将这些成分干调以形成一种十分均匀的混合物(最好在加填充剂和其余的赋型剂之前),然后再压紧,可以达到所要求的那种紧密结合。
但是,为获得非常稳定的组合物,需优选使用一种水基或以其它溶剂为基质的制备方法,由此在有很少量的,例如,水存在的情况下将药物成分和碱性介质搅合在一起以形成药物与碱性物质紧密结合在一起的混合物的颗粒。考虑到HMG-CoA还原酶抑制剂如fluvastatin的吸湿性和对潮湿的敏感性,没有想到用这种方法处理时碱性介质公使药物成分如此稳定以致能够抵御降解。
在这一方法的一个实施方案中,将药物和碱性介质加水研磨,然后将所形成的颗粒干燥。将此干燥的颗粒与原先留作此颗粒外表层的填充剂和其余的赋型剂掺和在一起,即生成适于做胶囊剂、片剂等等的组合物。
在以溶剂为基质的方法的实施方案中,该方法有助于随后在流化床中进行干燥,用已知的技术使药物成分和碱性介质湿成粒,即在潮湿状态下与一定量的填充料掺加在一起。如此形成的颗粒干燥后与所有予先留出来的填充剂和其它的,例如,粘合剂、润滑剂结合在一起之后,即可压片,制胶囊或者制成其它形状的剂型。
为延长组合物的货架寿命,重要的是要使经研磨或湿成粒或其它水基方法制备的颗粒完全彻底地干燥,即烘干失重(L.O.D.)不超过3%,最好不高于2%。
以常规托盘干燥法或用流化床进行干燥,优选后者。典型的干燥操作是在输入温度约50℃,相对湿度低于50%的条件下进行的。
制备组合物时,在将药物物质和剂型的其余成分研磨或湿成粒之前,最好先使它们(润滑剂除外)过30-40目的筛子,一般是先使药物成分过筛,然后再与其它筛过的赋型剂掺合。另外,将干燥的颗粒或小细粒过18-20目的筛子使能与备料充分掺合。
压片的组合物在掺入润滑剂进行压制之前,典型地要过一次较密的(例如24目)筛子;这一步过筛程序一般需要有另外一步干燥程序,使得通过研磨或成粒作用获得的颗粒或小细粒干燥失重(L.O.D.)达到6-8%,然后过12-14目的筛子,再使之干燥失重达2-3%。
作为上述研磨或湿成粒法的一种替换的制备方法,可使药物成分和起稳定作用的碱性介质共同冻干,即从水溶液冷冻干燥,最好将这一操作作为药物加工的直接步骤。
正如美国专利4,739,073号(此处将其作为参考并入本发明)举例说明的,fluvastatin钠以及本发明中其它HMG-CoA还原酶抑制剂的钠盐或其它药物学上可采用的盐,典型地是通过用,例如,氢氧化钠在乙醇溶液中水解相应的酯类化合物而制备的。然后将乙醇或其它有机相蒸发,在余下的含有药物成分的相内加水形成水溶液,(一般先用有机溶剂提取),冷冻干燥回收HMG-CoA还原酶的抑制剂。
发现可将水溶性的稳定的碱性物质如碳酸钠、碳酸氢钠或其它碱性介质直接加到上述含fluvastain或其它HMG-CoA还原酶抑制剂的水相中,将此水相冷冻干燥,可得到包括与所加的碱性物质共同冻干的药化合物的颗粒。
从而可使药物和稳定剂十分紧密地相接触,达到这样一种程度,即可制得药物与碳酸钠的重量比为,例如,约为10∶1到100∶1,的本发明的稳定组合物。例如,发现仅含有0.1%(重量比)碳酸钠的本发明的共同冻干的组合物即可提供高度稳定的药物组合物。
冻干是用常规的方法和设备进行的。首先将溶液的温度由室温降到冰点以下,典型地是降到约-45℃,然后抽成高度真空,例如达到3mm汞柱甚或更低,其后再将温度升高到室温或高于室温,使含水溶剂蒸发。回收的颗粒中基本上不含溶剂,最理想的情况是非常均匀的药物和稳定剂的混合物。
所获得的颗粒可与其它赋型剂(如填充剂,粘合剂,润滑剂等等)相结合。
通过上述任何一种方法所获得的本发明的组合物,可用本技术领域周知的技术和方法,如压片,封胶,制丸,模塑等等制成一种剂型。
如前文所述,在组合物剂型外可挂一层肠衣和/或糖衣,会有特别的好处。
以水基包衣配方给以微晶纤维素为基质的片剂挂肠衣或糖衣的理想流化床温度为30-50℃,输入温度50-80℃,相对湿度低于50%。
为获得最理想的稳定性,很重要的一点是使挂有肠衣和/或糖衣的剂型干燥,使湿度不大于4%,最好不高于3%。
所制成的片剂或胶囊在贮存时需加以保护以免受温度和光线所产生的氧化作用及湿气的影响。
用本发明的组合物制成的胶囊和片剂具有引人注目的贮存稳定性。
这些剂型适于各种应用。本发明的糖及药片或胶囊的崩解时间约为10-30分钟,肠衣片或胶囊的崩解时间一般约为30分钟到6小时。
除了含有fluvastatin钠的组合物外,本发明意在复盖含有本文式Ⅰ所代表的其它HMG-CoA还原酶抑制剂的组合物。所说的化合物公开于例如下列普通的转让专利,公开的专利申请和出版物中(均作为参考并入本发明):
美国专利4,739,073和EP-A-114,027(R=吲哚基及其衍生物);EP-A-367,895(R=嘧啶基及基衍生物);美国专利5,001,255(R=茚基及其衍生物);4,613,610(R=吡唑基及其衍生物);4,851,427(R=吡咯基及其衍生物);4,755,606和4,808,607(R=咪唑基及其衍生物);4,751,235(R=中氮茚基及其衍生物);4,939,159(R=吖吲哚基及其衍生物);4,822,799(R=吡唑并吡啶基及其衍生物);4,804,679(R=萘基及其衍生物);4,876,280(R=环己基及其衍生物);4,829,081(R=噻吩基及其衍生物);4,927,851(R=呋喃基及其衍生物);4,588,715(R-苯甲硅烷基及其衍生物);以及F.G.Kathawala,Medicinal Research Reviews,Vol.11(2),p,121-146(1991).
式Ⅰ的化合物还包括下列专利公开的那些化合物:EP-A-304,063(R=喹啉基及其衍生物):EP-A-330,057和美国专利5,026,708及4,868,185(R=嘧啶基及其衍生物);EP-A-324,347(R=哒嗪基及其衍生物);EP-A-300,278(R=吡咯基或其衍生物)和美国专利5,013,749(R=咪唑基及其衍生物)。
适于用作组合物中性成分的化合物包括如下的化合物,其中R选自吲哚基、嘧啶基、茚基、吡唑基、吡咯基、咪唑基、中氮茚基、吡咯并吡啶、吡唑并吡啶、喹啉基、苯甲硅烷苯基、萘基、环己基、苯噻吩基、苯呋喃基和哒嗪基及其衍生物。优选的式Ⅰ化合物的R选自吲哚基、嘧啶基和茚基及其衍生物,X为(E)-CH=CH-。
上述出版物中公开的适用作本发明的组合物中药物活性成分的HMG-CoA还原酶化合物的具体例子包括下面的钠盐和其它药学上可采用的盐:
3R,5S-(E)-7-[4-(4-氟苯基)-6-(1-甲乙基)-2-二甲氨基嘧啶-5-基]-3,5-二羟基-6-庚烯酸,钠盐;
赤式-(±)-(E)-7-[3-(4-氟苯基)-螺(环戊烷-1,1′-1H-茚]-2′-基]-3,5-二羟基-6-庚烯酸,钠盐;
3R,5S-(E)-7-[3-(4-氟苯基)-1-(1-甲乙基)-中氮茚-2-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[3-(4-氟苯基)-1-(1-甲乙基)-1H-吡咯并[2,3-b]吡啶-2-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4-(4-氟苯基)-2-(1-甲乙基)-喹啉-3-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[1-(4-氟苯基)-3-(1-甲乙基)-4-氧代-1,4-二氢-喹啉-2-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4-(4-氟苯基)-6-(1-甲乙基)-3-甲基-1H-吡唑并[3,4-b]吡啶-5-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[3-(1-甲乙基)-5,6-二苯基-哒嗪-4′-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4-(4-氟苯基)-6-(1-甲乙基)-2-苯基-嘧啶-5-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4-(4-氟苯基)-1-(1-甲乙基)-3-苯基-2-氧代-2,3-二氢咪唑-5-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4-(4-氟苯基)-2-(1-甲乙基)-1-氧代-1,2-二氢喹啉-3-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-7-[4-(4-氟苯基)-2-(1-甲乙基)-喹啉-3-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-7-[1-(4-氟苯基)-3-(1-甲乙基)-吡咯并[2,1-a]异喹啉-2-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-7-[4-环丙基-6-(4-氟苯基)-2-(4-甲氧苯基)-嘧啶-5-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4-(4-氟苯基)-2,6-二甲基嘧啶-5-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4-(4-氟苯基)-6-甲基-2-苯基-嘧啶-5-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4-(3,5-二甲基苯基)-6-甲基-2-苯基-嘧啶-5-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-7-[3,4-双(4-氟苯基)-6-(1-甲乙基)-哒嗪-5-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-7-[1-(4-氟苯基)-3-(1-甲乙基)-5-苯基-1H-吡咯-2-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-9,9-双(4-氟苯基)-3,5-二羟-8-(1-甲基)-1H-四唑-5-基)-6,8-壬二烯酸,钠盐;
赤式-(±)-(E)-3,5-二羟-9,9-二苯基-6,8-壬二烯酸,钠盐;
赤式-(±)-(E)-7-[4-(4-氟苯基)-1,2-双(1-甲乙基)-3-苯基-吡咯-2-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4,5-双(4-氟苯基)-2-(1-甲乙基)-1H-咪唑-1-基]-3,5-二羟-6-庚烯酸,钠盐;
3R,5S-(E)-7-[4-(4-氟苯基)-2,6-双(1-甲乙基)-5-甲氧基甲基-吡啶-3-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-[4-(4-氟苯基)-2-(1-甲乙基)-6-苯基-吡啶-3-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-[2-(4-氟苯基)-4,4,6,6-四甲基-环己烯-1-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-7-[4-(4-氟苯基)-2-环丙基-喹啉-3-基]-3,5-二羟-6-庚烯酸,钠盐;
赤式-(±)-(E)-7-[4-(4-氟苯基)-2-(1-甲乙基)-喹啉-3-基]-3,5-二羟-6-庚烯酸,钠盐;
式Ⅰ的化合物为HMG-CoA还原酶的抑制剂,即胆固醇生物合成的抑制剂,因此,正如前述专利、公开申请和出版物(这些均已作为参考并入本发明)所公开的,它们可用于治疗高血脂症和动脉粥样硬化。
下述实施例试图说明以其各种实施方案本发明,但无论如何都不是限定性的。
实施例1
按下列处方配制20mg含量的3号fluvastatin口服胶囊:
表 1
成分 量(mg)
fluvastatin 21.06
碳酸钙,USP262.84
碳酸氢钠,USP 2.00
微晶纤维素,NFb23.35
予胶化淀粉,NFc20.95
纯化水,USP q.s.*
备料:
微晶纤维素 33.88
予胶化淀粉 20.95
滑石,USP 9.43
硬脂酸镁,NF 1.05
a重质,沉淀的
b微晶纤维素,pH102,FMC公司
c淀粉1500,Colorcon公司
*在制备过程中除去
(a)将fluvastatin,2mg碳酸氢钠,62.84mg碳酸钙,23.35mg微晶纤维素和20.95mg予胶化淀粉混合5分钟,将混合物过40目筛,搅合3分钟。
(b)向混合物中加水,同时搅合约4分钟,形成一种湿性颗粒。
(c)用输入温度为50℃的流化床干燥器使湿性颗粒干燥到L.O.D.为1.59%。
(d)将干燥的颗粒过20目筛,然后与微晶纤维素和予胶化淀粉备料掺和约10分钟。再向此混合物中加入予先用60目筛布筛过的滑石粉和硬脂酸镁,同时搅拌约5分钟。
生成的组合物L.O.D.为2.65%。
将此组合物分解在10-100ml水,其pH值为10。
(e)将此组合物装入兰色不透明的胶囊,用盐手工抛光。
以美国药典(USP)制浆方法,这种胶囊在30分钟内溶解度达到75%。
此药物在30℃,避光防潮环境下保存18个月后,其中完好率为99%。
实施例2
以实施例1所述之相同的方法,用表1中各成分的两倍的量,制得两倍No.3胶囊大小的、含40mg组合物的胶囊。
实施例3
以实施例1所述之相同的方法,除了利用10mg另外的微晶纤维素外,制得了10mg的No.3 fluvastatin胶囊。
实施例4
制备的20mg口服fluvastatin片含下列成分:
表 2
成分 量(mg)
fluvastatin 21.06
碳酸钙,USP 25.00
碳酸氢钠,USP 25.00
微晶纤维素,NFd118.94
交联羧甲纤维素钠,NFe3.00
聚乙烯吡咯烷酮,USPf6.00
硬脂酸镁,NF 1.00
纯化水,USP q.s.*
d 微晶纤维素pH101(FMC公司)
e Ac-Di-Sol(FMC公司)
f Kollidon 30(BASF公司)
*制备过程中除去
(a)将fluvastatin、碳酸钙、碳酸氢钠、微晶纤维素、聚乙烯吡咯烷酮和交联羧甲纤维素钠分别过40目筛,然后放在一起混合3分钟,将此混过物过40目筛,再继续混合2分钟。
(b)向生成的混合物内加水,同时搅拌约5分钟以形成湿性颗粒。
(c)用输入温度为50℃的流化床干燥器使湿性颗粒干燥,直到颗粒的L.O.D.达到6-8%。将颗粒过14目筛,再干燥,直到L.O.D.不大于2.5%。再将干燥的颗粒过24目筛,并掺和搅拌3分钟。
(d)将硬脂酸镁过60目筛布,然后加到上述混合物中,同时搅拌5分钟。
生成的组合物L.O.D.不大于2%。
将组合物分散到10-100ml水中,pH为10。
(e)用8mm的冲压器将生成的淡黄色组合物冲压成200mg的片芯。
(f)用羟丙甲基纤维素糖衣配方[Opadry黄T,YS-1-6347-G,Colorcon公司(10%水悬液)],在输入温度为70-75℃的流化床给片芯挂糖衣,使药片增得5-6%。
产生的药片符合溶解规格-以美国药典制浆法可使药片在30分钟溶解75%。
将此药片在30℃、避光、防潮的环境中保存18个月,其完好率为99%。
实施例5
以实施例4所述之相同的方法制备40mg的fluvastatin片剂,片芯中各成分的量为实施例4的两倍。
实施例6
以实施例4所述之相同的方法制备10mg的fluvastatin片剂,片芯中各成分的量为实施例4的一半。
实施例7
用床温30-50℃、输入温度50-85℃、相对湿度低于50%的流化床,以含EudragitR(Rohm药厂)的肠溶衣配方或羟丙甲基纤维素的邻苯二甲酸酯给按上述任一实施例记述的方法制备的fluvastatin片芯或胶囊涂上糖衣,使其增重约5-12%。
实施例8
按上述任一实施例所述之方法制备的本发明的组合物,它包括3R,5S-(E)-7-[4-(4-氟苯基)-6-(1-甲乙基)-2-二甲氨基-嘧啶-5-基]-3,5-二羟-6-庚烯酸钠盐为活性成分。
实施例9
按上述任一实施例所述之方法制备的本发明的组合物,它包括赤式-(±)-(E)-7-[3-(4-氟苯基)-螺[环戊烷-1,1′-1H-茚]-2′-基]-3,5-二羟-6-庚烯酸钠盐为活性成分。
Claims (13)
2、一种药物组合物,该组合物包括如权利要求1所限定的式Ⅰ所代表的化合物,以及与其紧密混合的至少一种碳酸盐。
3、一种药物组合物,该组合物包括R·,S·-(E)-(±)-7-[3-(4-氟苯基)-1-(1-甲基-乙基)-1H-吲哚]-2-基]-3,5-二羟基-6-庚烯酸钠盐(fluvastatin钠)和一种药物学上可采用的碱性介质,该碱性介质能使该组合物的水溶液或分散体的pH值至少保持在pH8。
4、权利要求2的药物组合物,其中的碳酸盐为一种水溶性碳酸盐和一种不溶于水或微溶于水的碳酸盐的混合物。
5、权利要求3的组合物,其中的碱性介质选自碳酸钠,碳酸氢钠,碳酸钙或其混合物。
6、一种药物组合物,该组合物包括R·,S·-(E)-(±)-7-[3-(4-氟苯基)-1-(1-甲基-乙基)-1H-吲哚]-2-基]-3,5-二羟基-6-庚烯酸钠盐(fluvastatin钠),(ⅰ)碳酸钙和(ⅱ)碳酸钠或碳酸氢钠。
7、权利要求6的药物组合物,其中水溶性碳酸盐与不溶于水或微溶于水的碳酸盐的比例为1∶40至2∶1。
8、权利要求1的组合物,该组合物包括0.5-60wt.%HMG-CoA还原酶化合物,0.5-40wt.%碳酸钙,0.5-20wt.%碳酸氢钠,和10-65wt.%微晶纤维素。
9、固体单位剂型的前述任一项权利要求的组合物。
10、用于释放R·,S·-(E)-(±)-7-[3-(4-氟苯基)-1-(1-甲基-乙基)-1H-吲哚]-2-基]-3,5-二羟基-6-庚烯酸钠盐(fluvastatin钠),25-40wt.%碳酸钙,0.5-10wt.%碳酸氢钠,和20-35wt.%微晶纤维素。
11、用作释放HMG-CoA还原酶抑制剂的口服片剂药物组合物,它包括0.5-60wt.%R·,S·-(E)-(±)-7-[3-(4-氟苯基)-1-(1-甲基-乙基)-1H-吲哚]-2-基]-3,5-二羟基-6-庚烯酸钠盐(fluvastatin钠),5-20wt.%碳酸钙,5-20wt.%碳酸氢钠,和50-65wt.%微晶纤维素。
12、权利要求1的药物组合物制备方法,该方法包括使药物和碱性介质紧密接触。
13、按权利要求12的方法,包括使HMG-CoA还原酶抑制剂化合物与碱性稳定性介质共同冻干燥。
Priority Applications (32)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU9203780A HU217629B (hu) | 1991-12-12 | 1992-11-30 | Eljárás fluvasztatint tartalmazó stabilizált gyógyszerkészítmények előállítására |
HU9203780A HU9203780D0 (en) | 1991-12-12 | 1992-11-30 | Stabilized pharmaceutical products of hmg-coa reductase inhibitor and method for producing them |
DE4240430A DE4240430B4 (de) | 1991-12-12 | 1992-12-02 | Stabilisiertes pharmazeutisches Mittel, enthaltend einen HMG-CoA-Reduktase-Inhibitor Wirkstoff |
ITRM920870A IT1256698B (it) | 1991-12-12 | 1992-12-04 | Composizioni farmaceutiche stabilizzate comprendenti un composto inibitore di hmg-coa riduttasi e relativo metodo di preparazione. (caso 600-7163) |
CH3751/92A CH684309A5 (de) | 1991-12-12 | 1992-12-07 | Stabilisiertes pharmazeutisches Mittel, enthaltend einen HMG-CoA-Reduktase-Inhibitor Wirkstoff. |
EP92810962A EP0547000B1 (en) | 1991-12-12 | 1992-12-08 | Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound |
DK92810962T DK0547000T3 (da) | 1991-12-12 | 1992-12-08 | Stabiliserede farmaceutiske præparater indeholdende en HMG-CoA reduktase-inhibitorforbindelse |
ES92810962T ES2142819T3 (es) | 1991-12-12 | 1992-12-08 | Composiciones farmaceuticas estabilizadas que comprenden un compuesto inhibidor de hmg-coa reductasa. |
PT92810962T PT547000E (pt) | 1991-12-12 | 1992-12-08 | Composicoes farmaceuticas estabilizadas que contem um composto inibidor de reductase de hmg-coa |
GB9225659A GB2262229B (en) | 1991-12-12 | 1992-12-08 | Pharmaceutical compositions of pH at least 8 comprising an HMG-CoA reductase i nhibitor |
FI925615A FI114284B (fi) | 1991-12-12 | 1992-12-10 | Menetelmä farmaseuttisen koostumuksen valmistamiseksi |
NZ245421A NZ245421A (en) | 1991-12-12 | 1992-12-10 | Alkaline compositions of a salt of a 3,5-dihydroxy hept-6-enoic acid derivative |
MX9207152A MX9207152A (es) | 1991-12-12 | 1992-12-10 | Composiciones farmaceuticas estabilizadas que comprenden un compuesto inhibidor de la hmg-coa reductasa y metodo para su preparacion. |
JP4352222A JP2774037B2 (ja) | 1991-12-12 | 1992-12-10 | HMG−CoAリダクターゼ抑制活性を有する化合物を含んでなる安定化された製薬学的組成物 |
IL10404192A IL104041A (en) | 1991-12-12 | 1992-12-10 | Stabilized pharmaceutical preparations containing AOC-GMH inhibitory compound and method of preparation |
CS19923633A CZ287776B6 (cs) | 1991-12-12 | 1992-12-10 | Stabilizovaný farmaceutický prostředek |
CA002085037A CA2085037C (en) | 1991-12-12 | 1992-12-10 | Stabilized pharmaceutical compositions comprising an hmg-coa reductase inhibitor compound |
SK3633-92A SK281710B6 (sk) | 1991-12-12 | 1992-12-10 | Farmaceutická kompozícia obsahujúca inhibítor hmg-coa reduktázy |
AU30069/92A AU661075B2 (en) | 1991-12-12 | 1992-12-10 | Stabilized Pharmeceutical Compositions of HMG-CoA Reductase Inhibitors |
KR1019920023818A KR100253824B1 (ko) | 1991-12-12 | 1992-12-10 | Hmg-coa 환원효소 억제제 화합물을 포함하는 안정화된 약학 조성물 |
RO92-01545A RO111542B1 (ro) | 1991-12-12 | 1992-12-10 | Compozitie farmaceutica stabilizata |
NO924768A NO302099B1 (no) | 1991-12-12 | 1992-12-10 | Farmasöytisk preparat |
AT0244992A AT401870B (de) | 1991-12-12 | 1992-12-11 | Stabilisiertes pharmazeutisches mittel, enthaltend einen hmg-coa-reduktase-inhibitor wirkstoff |
ZA929642A ZA929642B (en) | 1991-12-12 | 1992-12-11 | Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound. |
LU88201A LU88201A1 (fr) | 1991-12-12 | 1992-12-11 | Compositions pharmaceutiques stabilisées comprenant un composé inhibituer de la HMG-CoA réductase et procédé pour leur préparation |
RU92004564A RU2121835C1 (ru) | 1991-12-12 | 1992-12-11 | Фармацевтическая композиция |
FR9215142A FR2684876B1 (fr) | 1991-12-12 | 1992-12-14 | Compositions pharmaceutiques stabilisees comprenant un compose inhibiteur de la hmg-coa reductase et procede pour leur preparation. |
US07/995,252 US5356896A (en) | 1991-12-12 | 1992-12-22 | Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound |
CN93100650A CN1041794C (zh) | 1991-12-12 | 1993-01-30 | 含有一种β-羟基-β-甲基戊二酸单酰辅酶A还原酶抑制剂的稳定的药物组合物 |
HK25597A HK25597A (en) | 1991-12-12 | 1997-03-06 | Pharmaceutical compositions of pH at least 8 comprising an HMG-CoA reductase inhibitor |
CY199497A CY1994A (en) | 1991-12-12 | 1997-09-05 | Pharmaceutical compositions of pH at least 8 comprising an HMG-CoA reductase inhibitor |
GR20000400625T GR3032929T3 (en) | 1991-12-12 | 2000-03-10 | Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US80566791A | 1991-12-12 | 1991-12-12 | |
CN93100650A CN1041794C (zh) | 1991-12-12 | 1993-01-30 | 含有一种β-羟基-β-甲基戊二酸单酰辅酶A还原酶抑制剂的稳定的药物组合物 |
Publications (2)
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CN1091634A true CN1091634A (zh) | 1994-09-07 |
CN1041794C CN1041794C (zh) | 1999-01-27 |
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CN93100650A Expired - Lifetime CN1041794C (zh) | 1991-12-12 | 1993-01-30 | 含有一种β-羟基-β-甲基戊二酸单酰辅酶A还原酶抑制剂的稳定的药物组合物 |
Country Status (31)
Country | Link |
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US (1) | US5356896A (zh) |
EP (1) | EP0547000B1 (zh) |
JP (1) | JP2774037B2 (zh) |
KR (1) | KR100253824B1 (zh) |
CN (1) | CN1041794C (zh) |
AT (1) | AT401870B (zh) |
AU (1) | AU661075B2 (zh) |
CA (1) | CA2085037C (zh) |
CH (1) | CH684309A5 (zh) |
CY (1) | CY1994A (zh) |
CZ (1) | CZ287776B6 (zh) |
DE (1) | DE4240430B4 (zh) |
DK (1) | DK0547000T3 (zh) |
ES (1) | ES2142819T3 (zh) |
FI (1) | FI114284B (zh) |
FR (1) | FR2684876B1 (zh) |
GB (1) | GB2262229B (zh) |
GR (1) | GR3032929T3 (zh) |
HK (1) | HK25597A (zh) |
HU (2) | HU9203780D0 (zh) |
IL (1) | IL104041A (zh) |
IT (1) | IT1256698B (zh) |
LU (1) | LU88201A1 (zh) |
MX (1) | MX9207152A (zh) |
NO (1) | NO302099B1 (zh) |
NZ (1) | NZ245421A (zh) |
PT (1) | PT547000E (zh) |
RO (1) | RO111542B1 (zh) |
RU (1) | RU2121835C1 (zh) |
SK (1) | SK281710B6 (zh) |
ZA (1) | ZA929642B (zh) |
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