CN1288007A - 6-羟基-3-(4-[2-(哌啶-1-基)乙氧基]苯氧基)-2-(4-甲氧基苯基)苯并[b]噻吩盐酸盐的新晶形 - Google Patents
6-羟基-3-(4-[2-(哌啶-1-基)乙氧基]苯氧基)-2-(4-甲氧基苯基)苯并[b]噻吩盐酸盐的新晶形 Download PDFInfo
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- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Abstract
本发明涉及6-羟基-3-(4-[2-(哌啶-1-基)乙氧基]苯氧基)-2-(4-甲氧基苯基)苯并[b]噻吩盐酸盐的新结晶水合物,和它们的应用,包括抑制与雌激素缺乏有关的病症,包括心血管病、高血脂和骨质疏松;和抑制其它病症,例如子宫内膜异位、子宫纤维变性、雌激素依赖性癌(包括乳腺癌和子宫癌)、前列腺癌、良性前列腺增生、包括阿尔茨海默氏症在内的CNS障碍,预防乳腺癌,和上调ChAT。
Description
US 5510357首先对6-羟基-3-(4-[2-(哌啶-1-基)乙氧基]苯氧基)-2-(4-甲氧基苯基)苯并[b]噻吩盐酸盐(arzoxifene)作了一般性描述,US 5723474(下面简称为’474)和欧洲专利申请0729956具体公开了该化合物。Arzoxifene是非甾体类混合雌激素拮抗剂/激动剂,可特别用于降低血清胆固醇,抑制血脂过高、骨质疏松、包括乳腺癌和子宫癌在内的雌激素依赖性癌、子宫内膜异位、包括阿尔茨海默氏病在内的CNS障碍、主动脉平滑肌细胞增殖、和再狭窄。
具体来说,arzoxifene可用于(并在临床上评价过)治疗受体阳性转移性乳腺癌;用于在适当系统或局部治疗后对受体阳性患者进行辅助治疗;减小侵袭性和非侵袭性乳腺癌的复发;并减小侵袭性乳腺癌与原位管癌(DCIS)的发病率。Arzoxifene还可用于与放疗、芳香酶抑制剂、LHRH类似物、和乙酰胆碱酯酶(AChE)抑制剂进行联合治疗。
按照’474公开的方法分离的大批量arzoxifene的X-射线粉末衍射(XRD)、热解重量分析(TGA)、质子核磁共振(1H NMR)和费歇尔(KF)分析表明,所得产物是水合物、结晶性不佳、并在其晶格中含有可变量的有机挥发物(乙酸乙酯)。
对于配制制剂过程来说,结晶性不佳的arzoxifene不如高结晶性的arzoxifene可取。此外,配制含有大量有机溶剂(例如乙酸乙酯)的药物通常是不可取的,这是因为有机溶剂对用药者有潜在毒性,并且这些溶剂会使药物的效能改变。
虽然通过’474公开的方法制得的arzoxifene可用作药物,但是仍非常需要找到其晶格内不含有有机溶剂、可以以工业规模重复以及高效率地制得结晶性更好的arzoxifene。
本发明涉及6-羟基-3-(4-[2-(哌啶-1-基)乙氧基]苯氧基)-2-(4-甲氧基苯基)苯并[b]噻吩盐酸盐的非化学计量水合形成的新晶形(F-Ⅰ),其中当用铜辐射源进行X-射线衍射时,所述晶形具有下述峰值的X-射线衍射图案:7.9±0.2、10.7±0.2、14.9±0.2、15.9±0.2、18.3±0.2、和20.6±0.2°(2θ范围内)。
本发明还涉及含有下述组分的药物制剂:F-Ⅰ;一种或多种可药用载体、稀释剂、或赋形剂;和任选含有的雌激素、任选含有的孕激素、任选含有的芳香酶抑制剂、任选含有的LHRH类似物、以及任选含有的乙酰胆碱酯酶(AChE)抑制剂。
此外,本发明还涉及用F-Ⅰ抑制如下所述病症的方法:子宫纤维变性、子宫内膜异位、主动脉平滑肌细胞增殖、再狭窄、乳腺癌、子宫癌、前列腺癌、良性前列腺增生、骨损失、骨质疏松、心血管疾病、高血脂、CNS障碍、和阿尔茨海默氏病,以及F-Ⅰ在制备用于抑制所述疾病的药物中的应用。
本发明还涉及用F-Ⅰ上调胆碱乙酰转移酶(ChAT)的方法,和F-Ⅰ在制备用于上调胆碱乙酰转移酶的药物中的应用。
附图1是S-Ⅱ的代表性差示扫描量热法(DSC)/TGA图示。
附图2是F-Ⅰ的代表性DSC/TGA图示。
附图3是F-Ⅲ的代表性DSC/TGA图示。
附图4表示F-Ⅰ和F-Ⅲ的吸湿等温线。
附图5表示随着干燥时间和温度的变化,S-Ⅱ的去溶剂化的变化。
将通过’474公开的方法(实施例41,从乙醇和乙酸乙酯的混合物中结晶,过滤,把滤饼在室温真空干燥至恒定重量)制得的大批量arzoxifene通过XRD进行特征确定,结果发现其结晶性不佳。1H NMR证实该大批量arzoxifene中含有6%乙酸乙酯。
然后将’474中公开的结晶方法改进,即将乙醇加到arzoxifene粗产物于回流乙酸乙酯中的悬浮液内。冷却并真空过滤,由该改进方法制得的固体是高结晶性的arzoxifene乙酸乙酯/水混合溶剂化物(下文称为S-Ⅱ),之后发现其可作为制备F-Ⅰ的原料。
F-Ⅰ是通过将S-Ⅱ在高温下真空干燥/退火来把乙酸乙酯从S-Ⅱ的晶格中除去而制得。为了制备F-Ⅰ,将S-Ⅱ退火的时间和温度可逐批不同,但是通常是在大约100℃退火5天。为了通过该方法将S-Ⅱ转化成F-Ⅰ,需要采取高温,这是因为若将S-Ⅱ在水中于室温浆化、或者将S-Ⅱ样本在98%RH贮存3周后,不能引起任何向F-Ⅰ的转化。此外,在对流烘箱中于高温下干燥S-Ⅱ也不能将S-Ⅱ去溶剂化,这意味着为了将乙酸乙酯从S-Ⅱ的晶格中除去,真空也是必需的。
优选在室温通过从四氢呋喃中结晶arzoxifene(或其任何多晶型物/溶剂化物)来方便地制备和分离F-Ⅰ。结晶可优选这样进行:首先将arzoxifene溶于含水四氢呋喃(含有1-10%、优选2.5-7.5%、最优选4.5-5.5%体积的水),然后通过常压蒸馏除去所述水。该结晶法在下面例2详述。当通过此改进结晶法制备F-Ⅰ时,相关物质(TRS)总含量预期可降至0.5%以下。
用于上述结晶法的适当arzoxifene原料包括(但不限于)S-Ⅱ、F-Ⅲ、按照’474公开的方法制得的arzoxifene、或它们的任意混合物。用何种形式的arzoxifene作为原料并不重要,因为按照本发明方法,从四氢呋喃中结晶都会生成F-Ⅰ晶体。当以工业规模合成F-Ⅰ时,加入F-Ⅰ晶种是有利的。
F-Ⅲ,arzoxifene的另一种非化学计量水合物,可通过在室温下从异丙醇(IPA)和水的混合物中结晶arzoxifene(或其任何多晶型物/溶剂化物)而容易地制备和分离。水与IPA的比例(体积比)通常约为1∶1-9∶1。该比例更优选为2.5∶1-5.6∶1,该比例最优选为3∶1-5.6∶1。IPA与水之比对于F-Ⅲ的结晶并不重要,但是会影响产率。当以工业规模合成F-Ⅲ时,加入F-Ⅲ晶种是有利的。用于上述结晶方法的适当arzoxifene原料包括(但不限于)S-Ⅱ、F-Ⅰ、按照’474公开的方法制得的arzoxifene、或它们的任意混合物。
S-Ⅱ、F-Ⅰ和F-Ⅲ的特征确定和区别
使用DSC/TGA和XRD法来鉴定S-Ⅱ、F-Ⅰ和F-Ⅲ的特征。对于区别不同固体形式的物质,TGA通常非常有用,这是因为物质内发生物理变化时的温度通常是多晶型物或溶剂化物的特征。DSC是通常用于筛选化合物多晶型和溶剂化物形成的技术。XRD是探测晶体材料内长程序的技术。
按照’474公开的方法制得的arzoxifene的XRD图案具有不良信噪比和高基线,这意味着它是结晶性不佳的物质。因此,将F-Ⅰ和F-Ⅲ与通过上述改进的arzoxifene结晶法(把乙醇加到arzoxifene在回流乙酸乙酯中的悬浮液内)制得的物质(S-Ⅱ)进行比较。
S-Ⅱ、F-Ⅰ和F-Ⅲ的代表性DSC/TGA图形分别如附图1、2和3所示。S-Ⅱ的DSC图形显示,在约62℃宽的吸热线开始,这相当于乙酸乙酯和水从晶格中失去。在约152℃开始的吸热线代表熔点。大约2.5%的TGA重量损失与第一个转变同时发生,而剩余的0.5%重量损失在熔化开始时发生,这表明有些溶剂分子更紧密地保持在晶格内。
F-Ⅰ的DSC图形显示,在约75℃宽的吸热线开始,之后在约155℃开始相当于熔点的第二个吸热线。F-Ⅰ的TGA图形显示,0.3%的逐渐重量损失之后有1.5%的急剧损失,共同代表晶格的脱水。第一个DSC转变以及相应的TGA重量损失的开始有轻度错位,这是因为加热速度的差异所致。起初的重量损失代表弱固定水合水,第二个重量损失代表存在于晶格中的非常低的相对水分(低于5%-参见吸湿数据)相当于大约0.5摩尔水。
F-Ⅲ的DSC图形显示,在约30℃宽的低温吸热线开始,然后在约70℃开始第二个宽的并且相对弱的吸热线,在约146℃开始相当于熔点的最后一个转变。在TGA中,与第一个吸热线同时发生的1.5%(约0.5摩尔)的急剧重量损失相当于弱固定水分子,在60℃以上的另外约1.6%重量损失代表更紧密固定水分子的损失,即以非常低的相对湿度存在的水分子的损失。在170℃以上观察到的重量损失相当于F-Ⅲ的分解。
F-Ⅰ和F-Ⅲ的XRD图案特性是,有表示高结晶性物质的尖锐峰和平坦基线。F-Ⅰ、F-Ⅲ和S-Ⅱ代表性样本的2θ范围内角峰位置和相应的I/I0数据列在表1中。虽然许多强反射通常是以相似衍射角反射,但是每一反射都给出了不同的粉末图案,使得S-Ⅱ、F-Ⅰ和F-Ⅲ之间有清楚区别。
在晶体学领域众所周知的是,对于任何给定的多晶型物,因为某些因素,例如晶体形态,导致的优选定向,衍射峰的相对强度可能会改变。当存在优选定向时,峰强度会改变,但是多晶型物的峰位置不会改变。参见,例如美国药典#23(The United States Pharmacopeia#23),National Formulary #18,第1843-1844页,1995。因此,当用铜辐射源进行X-射线衍射时,根据峰强度和峰位置,可通过下述位置是否存在峰来确定F-Ⅰ:7.9±0.2、10.7±0.2、14.9±0.2、15.9±0.2、18.3±0.2、和20.6±0.2°(2θ范围内)。
表1
表1(续)F-Ⅰ和F-Ⅲ的其它特征确定
用F-Ⅰ和F-Ⅲ进行吸温性实验。F-Ⅰ和F-Ⅲ的吸湿等温线如附图4所示。首先将样本置于大约5%RH时,F-Ⅰ和F-Ⅲ分别立即获得了1.5%和1.7%水分的重量增加,这相当于约0.5摩尔水。这两种晶形在整个湿度范围内都表现出持续的吸湿作用,看来是由于水分子掺入到晶格内所致。
这两种晶形在吸湿方面的差异可能反映了可掺入到两种晶格内的水分的量(即可进入到能容纳水分子的晶格内的水分的量)。F-Ⅰ和F-Ⅲ的吸收-解吸等温线中没有滞后现象,这意味着晶体能在任意给定湿度下迅速形成平衡。
F-Ⅰ和F-Ⅲ的吸湿图表明,这两种晶形基本上是非化学计量水合物。在环境相对湿度(约50%RH)下,F-Ⅰ含有约1.7%水相当于0.5摩尔水,而F-Ⅲ吸收了约3.0%水相当于0.85摩尔水。大块状的F-Ⅰ和F-Ⅲ能迅速地与空气达到平衡,这样通过分析技术测得的水分含量能反映出数据收集时的相对湿度。DSC数据中发现的逐批差异可能是由于样本因在不同环境贮存条件下被水合到不同程度所致。
XRD图案是用不同相对湿度(0%、22%、50%和80%)下贮存的F-Ⅱ和F-Ⅲ样本获得的。随着相对湿度的增加,在约13.8、17.6、18.0、20.5和24.0°(2θ范围内)的初始(0%RH)F-Ⅲ峰逐渐迁移,并且较低强度峰也轻度迁移。据推测,当相对湿度增加,在F-Ⅲ的XRD衍射图案中观察到的这些变化意味着晶胞大小发生了改变,推测用以容纳弱固定水分子。峰随着湿度增加而发生的连续迁移与表明该RH范围内重量逐渐增加的吸湿数据相关性很好,这提供了形成不同水合物的证据。
对F-Ⅰ进行了类似实验,以确定改变相对湿度是否对其晶格有类似影响(0%、25%、52%、73%和95%RH)。随着相对湿度增加,观察到在约7.7、18.3、18.5、20.5和20.8°(2θ范围内)的0%RH峰发生了非常轻微的迁移。在较高相对湿度下,在约7.7、20.8、和24.1°的峰似乎稍微变宽了一些,并且分辨度变低了,这表明水被吸收到非晶形组分内(或增塑该固体),尤其在73%和95%RH下更是如此。置于不同相对湿度时,F-Ⅰ XRD图案中的峰迁移不如F-ⅢXRD图案中的峰迁移剧烈。这表明F-Ⅰ晶格没有经历过与F-Ⅲ晶格相同的扩展和/或收缩。
发现F-Ⅰ和F-Ⅲ在整个相对湿度范围内都是稳定的,尽管F-Ⅲ能吸收几乎是F-Ⅰ所吸收的2倍的水。发现这两种晶形都具有差不多的晶体大小、形态、水溶解度、和溶解速度。
进行干燥实验,以监测随着干燥时间和温度的变化,S-Ⅱ的去溶剂化情况(参见附图5)。在该去溶剂化实验期间,在不同时间点测定XDR图案。在S-Ⅱ去溶剂化实验期间测得的许多衍射峰看来是与F-Ⅰ类似的角出现的,这证实了S-Ⅱ与F-Ⅰ的晶格非常相似。经过仅仅最低限度干燥后,在约6.8、7.2和14.0°(2θ范围内)的峰消失了,这反映了晶体平面可能含有乙酸乙酯分子的部分电子密度。
将该溶剂化物质在真空高温下进行长时间退火就制得了F-Ⅰ。通过XRD测定,发现由该方法制得的F-Ⅰ具有高度结晶性。按照’474公开的方法,通过在乙醇和乙酸乙酯的溶液中结晶、然后真空干燥而制得的产物具有很差的结晶性,这是因为该方法制得的是部分去溶剂化的S-Ⅱ。
与上述现有技术形式的arzoxifenen相比,F-Ⅰ和F-Ⅲ具有数个优点。与按照’474公开的方法制得的arzoxifenen相比,F-Ⅰ和F-Ⅲ在室温更稳定,因此更适于药物应用,即更适于制成药物制剂。此外,F-Ⅰ和F-Ⅲ的结晶性比’474中公开的arzoxifenen好很多。与非晶形物质相比,结晶物质通常更不易吸温和更稳定(例如更不易化学降解、能保持一致效力),因此更适于制剂加工。此外,与按照’474公开的方法制得的、其晶格中含有乙酸乙酯和水的arzoxifenen形式不同,F-Ⅰ和F-Ⅲ仅含有水。特征确定方法
DSC测定是用连接有热分析仪3100、并装配有冷冻冷却系统的TA装置2920调制DSC进行的。将样本(3-5mg)在波形铝盘中以2℃/分钟的速度从10℃加热至240℃。
TGA分析是用连接有热分析仪3100的TA装置2050热重量分析仪进行的。将样本(5-10mg)在敞开盘中以5℃/分钟的速度从25℃加热至250℃。
XRD图案是用装配有CuKα源(λ=1.54056)和Kevex固体探测器的Siemens D5000 X-射线粉末衍射仪、在50kV和40mA操作条件下测得的。将每一样本在4°-35°(2θ)扫描。在进行数据收集之前,将样本在所需温度和/或相对湿度下平衡至少30分钟。
F-Ⅰ和F-Ⅲ的吸湿性测定是用下述VTI法进行的。将每一样本在60℃真空干燥直至不能检测到任何重量损失为止,期间把样本放置室设置为0%相对湿度。吸湿等温线是在25℃,采用以下述条件平衡的VTI真空湿度环境测得的:样本量10-15mg,吸附/解吸范围0-95%相对湿度,步骤间隔5%,样本间隔10分钟。
以下述实施例进一步举例说明制备本发明水合物的方法。这些实施例不是、并且也不应当理解为以任何方式对本发明方法范围加以限制。制备制备1S-Ⅱ
将arzoxifene(通过US 5723474的实施例41中公开的方法制得的1.58g产物,该文献引入本发明作为参考)悬浮在28ml乙酸乙酯中,加热至回流。加入乙醇(18ml)以促进溶解。将该溶液回流20分钟,然后冷却至室温。通过真空过滤分离沉淀,用30ml乙酸乙酯洗涤,获得1.05g粉末状白色固体。
实施例
实施例1
由S-Ⅱ制备F-Ⅰ
将S-Ⅱ在真空烘箱中(-25Hg)于100℃干燥118小时以获得F-Ⅰ。
实施例2
由Arzoxifene制备F-Ⅰ的改进方法
将25.0g Arzoxifene、475ml四氢呋喃和25ml水置于安装有回流冷凝器和顶部搅拌器的1L三颈园底烧瓶中。然后将反应容器装配好进行简单回流。将该反应混合物加热回流并除去250ml馏出液。简单地移去加热器,把250ml新鲜的无水四氢呋喃加到该容器中。继续进行常压蒸馏,并除去250ml馏出液。简单地移去加热器,加入250ml新鲜的四氢呋喃,再除去250ml馏出液。再加入250ml四氢呋喃,将该反应混合物回流。随着这次加入四氢呋喃,形成了白色沉淀。将该搅拌的反应混合物缓慢地冷却3小时,期间又沉淀出了固体,使该浆状液冷却至室温。将该结晶浆状液过滤,并在弱N2净化下于50℃真空干燥48小时。获得了22.50g(90.0%)产物。XRD分析表明该湿滤饼与干燥固体的光谱基本上相同,并与前面制备的F-Ⅰ基本相同。DSC分析表明熔点为157℃,TGA分析表明从室温到100℃损失1.5%重量。按游离碱计算的HPLC纯度为88.1%,理论效能是92.9%。HPLC分析表明相关物质总含量为0.44%。
实施例3用[6-苄氧基-3-(4-[2-(哌啶-1-基)乙氧基]苯氧基)-2-(4-甲氧基苯基)]苯并[b]噻吩-(S-氧化物)制备F-Ⅰ
将四氢呋喃(261ml)、水(45ml)、浓硫酸(6.14g)、和[6-苄氧基-3-(4-[2-(哌啶-1-基)乙氧基]苯氧基)-2-(4-甲氧基苯基)]苯并[b]噻吩-(S-氧化物)(HPLC测得效能为99%,HPLC测得相关物质总含量为0.35%)合并,并搅拌直至均匀。加入10%Pd/C(5.6g在22ml水中的浆状液),用5ml水洗涤。将所得浆状液排气,充入60psi氢气。将反应温度调节至30℃。2小时后,加入10%Pd/C(5.6g)和水(30ml)。在30℃和60psi再继续氢化22小时。加入30ml水中的4.40g10%Pd/C,在30℃和60psi再继续氢化2.5小时。过滤除去催化剂,用50%氢氧化钠把滤液pH调节至7.24。加入溶解在水(18ml)中的氯化钠(8.66g),将该两相溶液搅拌30分钟。分离各相,用50ml四氢呋喃萃取水相。合并有机相,常压蒸馏浓缩至50ml体积。在24℃用1小时向该浓缩液中加入180ml甲醇。把所得结晶浆状液在24℃搅拌30分钟,冷却至0℃并搅拌1小时。过滤分离固体,依次用39ml水和39ml甲醇洗涤,然后在50℃真空干燥过夜。产量:15.52g(67.8%)
按照实施例2的方法将一部分上述产物(10g)以四氢呋喃和水重结晶。
实用性
本说明书所用术语“有效量”是指能有效地抑制本文所述病症、或病症为害结果的F-Ⅰ量。当F-Ⅰ与雌激素、孕激素、芳香酶抑制剂、LHRH类似物、或AChE抑制剂联合给药时,术语“有效量”也表示能实现其预定作用的这些活性剂量。
术语“抑制”包括其通常含义,即预防、阻止、遏制、减轻、改善、缓解、停止、或逆转本文所述病症的发展或严重性、或病症的后遗症。
本说明书所用术语“预防”是指使F-Ⅰ接受者减少患上或发生本文所述病症或它们的后遗症的可能性。
术语“缺乏雌激素”和“雌激素缺乏”是指,天然发生或临床诱发的雌激素减少,女性不能产生足够内源性雌激素来维持雌激素依赖性功能,例如月经、骨质内环境稳定、神经功能、心血管功能等状况。这种雌激素缺乏情境是由于下述原因(但不限于下述原因)引起的:绝经、手术或化学卵巢切除术,包括其功能同等事件,例如用芳香酶抑制剂、GnRH激动剂或拮抗剂、ICI 182780等进行药物治疗。与雌激素缺乏有关的病症包括(但不限于):骨损失、骨质疏松、心血管疾病和高血脂。
本说明书所用术语“雌激素”包括具有雌激素活性的甾体化合物,例如17β-雌二醇、雌酮、共轭雌激素(Premarin)、马雌激素17β-乙炔基雌二醇等。优选的雌激素为基础的化合物是Premarin和异炔诺酮。
本说明书所用术语“孕激素”包括具有促孕活性的化合物,例如孕酮、异炔诺酮、炔诺孕酮(nongestrel)、乙酸甲地孕酮、炔诺酮等。炔诺酮是优选的孕激素为基础的活性剂。
本说明书所用术语“芳香酶抑制剂”包括能抑制芳香酶的化合物,例如市售芳香酶抑制剂,如氨鲁米特(aminoglutemide)(CYTANDREN)、阿拉斯特唑[Anastrazole(ARIMIDEX)]、来曲唑(FEMARA)、福美司坦(LENATRON)、依西美坦(AROMASTIN)等。
本说明书所用术语“LHRH类似物”是指绝经前妇女中抑制雌激素生成的释放黄体化激素的激素类似物,例如包括性瑞林(ZOLADEX)、亮丙瑞林(LUPRON)等。
本说明书所用术语“AChE抑制剂”包括能抑制乙酰胆碱酯酶的化合物,例如水杨酸毒扁豆碱、盐酸他克林、盐酸多奈皮兹(donepezil)等。
术语“上调ChAT”是指增加ChAT的酶活性,即促进胆碱转化成乙酰胆碱。该促进包括提高ChAT与胆碱反应的效率和/或速度,和/或提高ChAT在反应位点存在的量。酶存在量的增加可能是由于基因调控、或酶形成的其它合成步骤和/或酶失活和代谢的下降。选择的实验方法
常规大鼠准备方法:从Charles River实验室(Portage,MI)获得75天龄(除非另外指出)的雌性Sprague Dawley大鼠。在CharlesRiver实验室中,将大鼠两侧卵巢切除(OVX),或进行Sham手术操作,1周后用船运送。到达后,把大鼠放置在悬挂的金属笼子中,每个笼子放3只或4只,使它们能随意摄取食物(钙含量约为0.5%)和水,放置1周。将房间温度保持在22.2±1.7℃,最小相对湿度为40%。房间光周期为12小时光照和12小时黑暗。
按一定方案给药后收集组织:经过1周的新环境适应后(因此是卵巢切除2周后),开始用F-Ⅰ每天给药。除非另外指出,否则17α-乙炔基雌二醇或F-Ⅰ均是作为在1%羧甲基纤维素中或溶解在20%环糊精中的悬浮液而口服给药的。对大鼠每天给药,给药4天。该给药方案进行完后,将大鼠称重,用氯胺酮:甲苯噻嗪(2∶1体积比)混合物麻醉,通过心脏穿刺采集血样。然后用CO2窒息把大鼠处死,通过中线切口取出子宫,测定子宫湿重。17α-乙炔基雌二醇得自SigmaChemical Co.,St.Louis,MO。心血管疾病/高血脂
将上述血样在室温凝结2小时,以3000rpm离心10分钟后获得血清。用Boehringer Mannheim Diagnostics高效胆固醇分析测定血清胆固醇。简言之,将胆固醇氧化成胆甾-4-烯-3-酮和过氧化氢。然后在过氧化酶存在下将过氧化氢与苯酚和4-氨基安替比林反应,以生成对醌亚胺染料,通过分光光度计在500nm读取对醌亚胺浓度。然后通过标准曲线计算胆固醇浓度。整个分析都是用BiomekAutomated Workstation自动进行的。子宫嗜酸性细胞过氧化物酶(EPO)分析
将上述子宫保持在4℃直至开始进行酶分析。然后将子宫在50体积50mM含有0.005%Triton X-100的Tris缓冲液(pH=8.0)中匀化。加入Tris缓冲液中的0.01%过氧化氢和10mM邻苯二胺(终浓度),在450nm监测1分钟吸收度的增加。子宫中存在嗜酸性细胞是化合物雌激素活性的指征。通过反应曲线的初始直线部分确定15秒间隔的最大速度。抑制骨损失(骨质疏松)的测试方法
进行完上述常规准备操作后,将大鼠每天都进行治疗,治疗35天(每个治疗组包含6只大鼠),在第36天用CO2窒息把大鼠处死。35天时间足以使本说明书所述方法测定的骨密度有最大减小。在处死时,取出子宫,解剖掉外部组织,在测定湿重之前将流体内容物排出,以确定与完全子宫切除有关的雌激素缺乏。由于子宫切除,子宫重量通常下降了约75%。然后将子宫置于10%中性缓冲福尔马林中,随后进行组织学分析。
切除右股骨,用X-射线进行数字化分析,在远侧干骺端通过图象分析程序(NIH图象)进行分析。也通过定量计算机断层扫描来扫描胫骨邻面。依据上述操作,将在20%羟基丙基β-环糊精中的F-Ⅰ或乙炔基雌二醇(EE2)对测试大鼠口服给药。F-Ⅰ还用于和雌激素或孕激素联合给药。MCF-7增殖分析
将MCF-7乳腺癌细胞(ATCC HTB 22)保持在补充有10%胎牛血清(FBS)(V/V)、L-谷氨酰胺(2mM)、丙酮酸钠(1mM)、HEPES{(N-[2-羟基乙基]哌嗪-N’-[2-乙磺酸]10mM)、非必需氨基酸和牛胰岛素(1ug/ml)(维持培养基)的MEM(最低必需培养基,不含酚红,Sigma,St.Louis,MO)中。在分析前10天,将MCF-7细胞转换至维持培养基中即以10%葡聚糖包覆的活性炭脱色的胎牛血清(DCC-FBS)检测培养基补充来代替10%FBS,以耗尽甾体化合物内贮存。用细胞解离培养基(补充有10mM HEPES和2mM EDTA的不含Ca++/Mg++的HBSS(不含酚红))将MCF-7细胞从维持瓶中取出。用检测培养基将细胞洗涤2次,并调节至80000个细胞/ml。将大约100ml(8000个细胞)加到平底微培养孔(Costar 3596)中,在37℃、5%CO2潮湿恒温箱中培养48小时,以使细胞转移后粘着并平衡。在检测培养基中制备系列稀释的药物,或作为稀释剂对照物的DMSO,将50ml转移到微培养基中(一式三份),然后加入分析培养基以使终体积为200ml。在5%CO2潮湿恒温箱中再培养48小时后,将微培养基与含氚胸腺嘧啶核苷(1uCi/孔)脉冲4小时。通过在-70℃冷冻24小时来终止培养,然后用Skatron半自动细胞收集器融解并收集微培养基。用WallacBetaPlaceβ计数器通过液体闪烁来给样本计数。DMBA-诱发的乳腺癌抑制
购自Harlan Industries,Indianapolis,Indiana的雌性Sprague-Dawley鼠产生依赖于雌激素的乳腺癌。使55天龄的大鼠单次口服20mg 7,12-二甲基苯并蒽(DMBA)。口服DMBA 6周后,以每周一次的间隔触诊乳腺以确定肿块外观。每当出现一个或多个肿块时,用度量卡尺测定每一肿块的最长和最短直径,记录测量值,选择该大鼠进行实验。要使治疗组和对照组中肿块大小均匀分配,这样将平均大小的肿块在测试组间均等地分布。对于每一实验,对照组和测试组包含5-9只大鼠。
将F-Ⅰ通过在2%阿拉伯胶中经由腹膜内注射或口服给药。将口服给药的化合物溶解或悬浮在0.2ml玉米油中。对每一测试动物每天进行包括阿拉伯胶和玉米油治疗在内的治疗。初始肿块测量和测试动物选择之后,通过上述方法每周测量肿块。大鼠的治疗和测定持续3-5周,在结束时测定肿块的最终面积。对于每一化合物和对照治疗组,均测定平均肿块面积的变化。子宫纤维变性测试方法
测试1:对患有子宫纤维变性的3-20个妇女给予F-Ⅰ。该化合物的给药量为0.1-1000mg/天,给药期间为3个月。在给药期间和停止给药后直至3个月观察这些妇女,以确定对子宫纤维变性的影响。
测试2:采用与测试1相同的方法,只是给药期间为6个月。
测试3:采用与测试1相同的方法,只是给药期间为1年。
测试4:采用长期雌激素刺激使性成熟雌性豚鼠诱导平滑肌瘤。给豚鼠每周注射3-5次雌二醇,注射2-4个月或者直至长出肿瘤为止。每天给予F-Ⅰ或载体来进行治疗,治疗3-16周,然后把豚鼠处死,取出子宫并分析肿瘤消退情况。
测试5:将人平滑肌瘤组织植入性成熟、去生殖腺、雌性、裸小鼠的腹膜腔和/或子宫肌层。补给外源性雌激素以诱导该移植组织生长。在某些情况下,在移植前将收集的肿瘤细胞进行体外培养。每天通过胃灌法进行F-Ⅰ或载体治疗,治疗3-16周,取出移植物,测定其生长或消退。在处死时,取出子宫以判断该器官的情况。
测试6:收集人子宫纤维瘤组织并体外保存以作为初始非转化培养物。将手术样本通过无菌网或筛,或者挑开周围组织,以制备单细胞悬浮液。将细胞保持在含有10%血清和抗生素的培养基中。测定存在和不存在雌激素情况下的生长速度。分析细胞产生补体组分C3的能力,和它们对生长因子和生长激素的反应。评定用孕激素、GnRH、F-Ⅰ、和载体治疗后体外组织的增殖反应。每周一次评定甾体激素受体的水平,以测定在体外是否保持重要的细胞特征。使用取自5-25名患者的组织。
测试7:基本上按照Fuchs-Young等人“通过选择性雌激素受体调节剂抑制雌激素刺激的子宫平滑肌瘤生长”,M01.Car.,17(3):151-159(1996)的方法(该文献引入本发明作为参考),测定F-Ⅰ抑制雌激素刺激的、衍生自平滑肌瘤的ELT细胞系增殖的能力。子宫内膜异位测试方法
测试1:使用12-30只成年CD株系雌性大鼠作为测试动物。将它们分成等数量的3组。监测所有动物的动情周期。在动情前期这天,对每一雌鼠进行手术。切除每一组雌鼠的子宫左侧角,切成小方块,将小方块在邻近肠系膜血流的不同位点宽松地缝合。此外,切除第2组雌鼠的卵巢。从手术后那天开始,给第1组和第2组雌鼠腹膜内注射水,注射14天,在相同期间内,给第3组雌鼠腹膜内以1.0mg/kg之量注射F-Ⅰ。治疗14天后,将每一雌鼠处死,取出子宫内膜外植体、肾上腺、剩余子宫、和卵巢(如果有的话),并制备以进行组织学检查。称重卵巢和肾上腺。
测试2:使用12-30只成年CD株系雌性大鼠作为测试动物。将它们分成等数量的2组。监测所有动物的动情周期。在动情前期这天,对每一雌鼠进行手术。切除每一组中雌鼠的子宫左侧角,切成小方块,将小方块在邻近肠系膜血流的不同位点宽松地缝合。手术约50天后,给第1组雌鼠腹膜内注射水,注射21天,在相同期间内,给第2组雌鼠腹膜内以1.0mg/kg之量注射F-Ⅰ。治疗21天后,将每一雌鼠处死,取出子宫内膜外植体和肾上腺并称重。测定外植体作为生长的指征。监测动情周期。
测试3:对大鼠和/或兔子使用子宫内膜组织划皮术来诱导子宫内膜异位。将生殖成熟期的雌鼠进行两侧卵巢切除术,补充外源性雌激素以提供具体且恒定的激素水平。将自体子宫内膜组织移植到5-150只大鼠的腹膜内,补充雌激素以诱导该外植入组织的生长。按日用本发明化合物通过胃灌注进行治疗,治疗3-16周,取出移植体并测定其生长或消退情况。在处死动物时,收集完整的子宫角,以评价该子宫内膜的情况。
测试4:将人子宫内膜损伤组织植入到性成熟、去生殖腺、雌性、裸小鼠的腹膜内。补充外源性雌激素以诱导该外植入组织的生长。在某些情况下,在植入前将收集的子宫内膜细胞体外培养。按日用F-Ⅰ通过胃灌注进行治疗,治疗3-16周,取出移植体并测定其生长或消退情况。处死动物时,取出子宫,以评价该完整子宫内膜的情况。
测试5:收集人子宫内膜损伤组织并体外保存,以作为初始非转化培养物。将手术样本通过无菌网或筛,或者挑除周围组织,以制备单细胞悬浮液。将细胞保持在含有10%血清和抗生素的培养基中。测定存在和不存在雌激素下的生长速度。分析细胞产生补体组分C3的能力,和它们对生长因子和生长激素的反应。评定用孕激素、GnRH、F-Ⅰ、和载体治疗后体外组织的增殖反应。每周评定甾体激素受体的水平,以测定在体外是否保持重要的细胞特征。使用取自5-25名患者的组织。包括阿尔茨海默氏病在内的CNS障碍
雌激素、例如17β-雌二醇通过结合位于一些细胞降体的胞质内的雌激素受体(ER)来调控基因转录。对于复合物的核运输,所述复合物结合上13个碱基对的回文DNA同感序列(雌激素反应单元,或ERE)并开始装配在适当靶基因的活化中达到顶峰的转录装置时,ER的配体活化是先决条件。已经确定了多种通过雌激素调控的基因,其包括细胞骨架蛋白、神经递质生物合成和代谢酶与受体、以及其它激素和神经肽。已经在许多雌激素反应性基因中确定了ERE’s,包括卵黄生成素、c-fos、催乳素、和黄体化激素。
在中枢神经系统中非常重要的是,已经在p75ngr和trkA中确定了类ERE序列,对于下述神经营养蛋白,p75ngr和trkA都起信号传导分子的作用:神经生长因子(NGF)、脑神经生长因子(BDNGF)、和神经营养蛋白-3。
据证明BDNF和NGF促进培养物中胆碱能神经元的存活。据推测,如果神经营养蛋白和雌激素之间的相互作用对于基础前脑神经元(其在阿尔茨海默氏症中退化)的发展和存活很重要,则雌激素缺乏(例如绝经后)的临床症状可以造成这些神经元损失。
在切除卵巢的大鼠(如上所述处理的)中进行下述实验,以确定F-Ⅰ和雌激素在影响不同脑区域中基因表达方面的相似性和/或不同。将6周龄的大鼠每日皮下注射雌二醇苯甲酸酯(0.03mg/kg)、F-Ⅰ或载体(对照)。治疗5周后,把大鼠处死,将它们的脑取出,通过显微解剖收集海马组织。将海马组织在液氮中迅速冷冻并贮存在-70℃。用得自适当治疗组和对照组的汇集组织制备总RNA,用3’低聚核苷酸引物(选择其用于特异性mRNA(聚-A+)种辟)进行逆转录。以下述组分构成的“鸡尾酒”进行聚合酶链反应(PCR):无规5’低聚核苷酸(长度为10个碱基对;共150)、反应缓冲剂、Taq聚合酶、和32PdTCP。
扩增40轮后,将反应产物在6%TBE-尿素凝胶上按分子大小分离,干燥并露置于X-射线薄膜上。比较治疗组之间的所得mRNA显示图案。F-Ⅰ与雌激素的联合应用
绝经期间和绝经后妇女经常要接受激素替代治疗(HRT)来对抗循环内源性雌激素下降引起的不利后果,例如治疗热潮红。然而,HRT会使患包括子宫癌和乳腺癌在内的一些癌症的危险性增加。可将F-Ⅰ与HRT联合应用以抑制这些危险。F-Ⅰ与芳香酶抑制剂的联合应用
按照定义,绝经妇女的卵巢不能行使其功能。她们仅有的雌激素来源是通过在周围组织(包括脂肪、肌肉和乳腺肿瘤本身)中发现的芳香酶把肾上腺雄激素转化成雌激素。因此,抑制芳香酶的药物(芳香酶抑制剂)能使绝经后妇女的循环雌激素耗尽。对于患有转移性乳腺癌的患者,通过抑制芳香酶来导致雌激素缺乏是重要的治疗选择。在用芳香酶抑制剂治疗期间,缺乏循环雌激素可能会导致消极的、不利的副作用,例如血清脂质水平。可采用F-Ⅰ来抑制这些不利作用。F-Ⅰ与LHRH类似物的联合应用
连续地给予LHRH(释放黄体化激素的激素)类似物能通过使垂体脱敏,而使得垂体不能刺激卵巢产生雌激素而抑制绝经前妇女的雌激素生成。临床效应是“药物卵巢切除术”,停止使用LHRH类似物后,这种效应是可逆的。在用LHRH治疗期间,缺乏循环雌激素可能会导致消极的、不利的副作用,例如血清脂质水平。可采用F-Ⅰ来抑制这些不利作用。提高乙酰胆碱水平
已知与没患阿尔茨海默氏症的人相比,阿尔茨海默氏症患者海马中的胆碱能神经元水平显著下降。在这些患者中,所述胆碱能神经元的渐进性损失看来是记忆和认识功能损失的反映。据认为这些神经元减少的一个原因是神经递质-乙酰胆碱的功能损失或下降。
神经元内乙酰胆碱的水平基本上是由其生物合成和生物降解之间的平衡决定的。胆碱乙酰转移酶(ChAT)是使其合成的主要酶,乙酰胆碱酯酶(AChE)是使其降解的主要酶。
为了确定F-Ⅰ对ChAT水平的作用,进行下述实验:进行完上述常规大鼠准备操作之后,每天给40只大鼠皮下注射或口服含10%环糊精载体的3mg/kg/天F-Ⅰ、0.03或0.3mg/kg/天雌二醇苯甲酸酯、或对照载体。将大鼠治疗3天或10天。每一给药方案包含20只大鼠。在适当时间间隔,将大鼠处死并解剖其脑。将脑的特定部分匀浆化并分析。将海马和前皮层匀浆物加工,并通过放射标记分析乙酰胆碱的生物合成来测定ChAT的活性。Schoepp等人在《神经传递杂志》(J.Neural Transmiss.),78:183-193,1989中描述了该方法,该文献引入本发明作为参考。
正如所预期的那样,与假操作对照组大鼠相比,在OVX大鼠中,ChAT水平下降了50%以上(p<0.001)。
在本发明另一实施方案中,将F-Ⅰ与AChE抑制剂联合使用。使用AChE抑制剂能通过抑制AChE来阻断乙酰胆碱降解而提高乙酰胆碱水平。良性前列腺增生(BPH)
对于雌激素作用与BPH和前列腺癌的治疗之间的联系的背景技术,参见PCT申请WO 98/07247,国际出版日期:1998年10月15日。
在下述实验中,以几例人前列腺癌细胞系评价F-Ⅰ结合雌激素受体的能力.
在包含50nM Tris.HCl pH7.4、1.5mM乙二胺四乙酸(EDTA)、0.4M KCl、10%甘油、0.5mM 2-ME、和10mM钼酸钠、以及还含有胃蛋白酶抑制剂(1mg/ml)、抑蛋白酶肽(2mg/ml)、抑肽酶(5mg/ml)和苯甲磺酰氟(PMSF,0.1mM)的TEG培养基(TEGP)中制备LNCaP、DU-45和PC-3的人前列腺癌细胞系的溶解产物。
将细胞溶解产物离心,把离心沉积物重悬在冷的TEGP中(1mlTEGP/100mg离心沉积物),并用Branson Model 450 Sonifier超声处理30秒(占空度70%,排出量1.8)。通过在40℃以10000×G的转速离心将溶解产物沉积,之后弃去上清液,立即使用或在-70℃贮存。
竞争性结合分析:结合缓冲液是其中用50mM NaCl替代0.4MKcl、并且再加入1mg/ml卵清蛋白的TEG(TEGO)。将F-Ⅰ在TEGO中稀释至20nM,用该稀释液制备3重系列稀释液。在园底聚丙烯微平板的三重微孔中进行分析。每一孔中加入35ml含氚17β-雌二醇(0.5nM,特异活性60.1Ci/mmol、DuPont-New England Nuclear,Boston,MA)和35ml冷的竞争性测试化合物(0.1nM-5mM)或TEGO,然后在4℃,振摇下培养5分钟,加入70ml MCF-7细胞系溶解产物。
将平板在4℃培养24小时,然后向每一孔中加入70ml葡聚糖包覆活性炭(DCC),之后在4℃剧烈振摇8分钟。然后将平板在4℃以1500×G的转速离心10分钟。把每一孔中的上清液收集到软聚苯乙烯微平板中,在Wallac Microbeta Model 1450计数器中进行闪烁计数。放射活性表示为计数效率(35-40%)和本底校正后的每分钟衰变次数(DPM)。附加对照组是总的计数,和总计数+DCC(定义可推断DCC计数的下限)。使用下述公式,以平均结合百分比(%结合)+/-标准偏差表示这些竞争性结合分析的结果:%结合=(DPM测试化合物-DPM总计数+DCC)/(DPM非测试化合物-DPM总计数+DCC)×100预防乳腺癌
本发明还涉及将F-Ⅰ对有患de novo乳腺癌危险的个体给药。本说明书所用术语“de novo”表示最初没有正常乳腺细胞转化或变态形成癌细胞或恶性细胞的情况。这种转化可能在该细胞或其子代细胞中经过多个阶段发展过程而发生,或者可在单一关键事件中发生。该de novo过程与已经转化或恶化的细胞从初始肿瘤位点向新位点转移、移生、或展开的过程不同。
并非特别危险会发展成乳腺癌的人,是可能发展de novo乳腺癌的人,并没有任何证据或疑点表明其患该病的危险超过正常人、且从来没有被诊断出曾患有该病。发展成乳腺癌的最大危险因素是患有该疾病的个人病史、或该疾病的早期发生,即使当时处于没有症状的缓解期也是如此。另一危险因素是该疾病的家族史。
通过给予致癌物N-亚硝基-N-甲基脲在大鼠中诱导乳腺癌是研究乳腺癌的广为接受的动物模型,并且已经发现其适于用来分析化学预防剂的作用。
在两个独立的实验中,给55天龄的雌性Sprague-Dawley大鼠静脉内(实验1)或腹膜内(实验2)给予50mg N-亚硝基-N-甲基脲/kg体重,1周后让这些大鼠随意食用混合有不同量的F-Ⅰ、(Z)-2-[4-(1,2-二苯基-1-丁烯基)苯氧基]-N,N-二甲基乙胺碱(他莫昔芬碱)、或对照物的饮食。
在实验1中,60mg/kg食物和20mg/kg食物的饮食剂量粗略地相当于3和1mg/kg(测试动物体重)的药物剂量。
在实验2中,20、6、2、和0.6mg/kg食物的饮食剂量粗略地相当于1、0.3、0.1、和0.03mg/kg(测试动物体重)的药物剂量。
每周一次观察大鼠的毒性迹象、并称重和触诊肿瘤形成。13周(实验1)或18周(实验2)后将大鼠处死,在尸体剖检时确认肿瘤并称重。
制剂
说明书中,当术语“药物的”作为形容词使用时,基本上指由哺乳动物接受无害的。“药物制剂”是指载体、稀释剂、赋形剂和活性成分必须与该制剂中的其它组分相容,并且对其接受者无害。
在给药前优选将F-I配制。制剂的选择应当由主治医师考虑涉及确定有效剂量相应的因素来决定。
该制剂中,活性成分总量占该制剂重量的0.1%-99.9%。在所述制剂中,优选包含不超过2种活性成分。也就是说,优选将F-Ⅰ与选自雌激素、孕激素、芳香酶抑制剂、LHRH类似物和AChE抑制剂的另一种活性成分一起配制。最优选的制剂是其中F-Ⅰ是唯一活性成分的制剂。
本发明药物制剂是通过本领域已知方法、用众所周知且易得的成分制得的。可将F-Ⅰ单独或者和雌激素、孕激素、芳香酶抑制剂、LHRH类似物或AChE抑制剂一起与常规赋形剂、稀释剂、或载体配制成片剂、胶囊、悬浮剂、溶液剂、注射剂、气雾剂、粉剂等。
用于非胃肠道给药的本发明药物组合物包含无菌水或非水溶液、分散体、悬浮液、或乳液,以及在使用前即刻重配成无菌溶液或悬浮液的无菌粉末。适当无菌水或非水载体、稀释剂、溶剂或赋形剂的实例包括水、生理盐水、乙醇、多元醇(例如甘油、丙二醇、聚(乙二醇)等)、和它们的适当混合物、植物油(例如橄榄油)、可注射有机酯例如油酸乙酯。通过使用卵磷脂之类的包衣材料,维持分散剂和悬浮剂适当粒径、和使用表面活性剂等来保持适当流动性。
非胃肠道给药组合物还含有助剂,例如防腐剂、湿润剂、乳化剂、和分散剂,通过加入杀菌和抗杀菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸等来防止微生物体的作用。还可以加入等渗剂,例如糖、氯化钠等。通过加入延迟吸收的物质,例如硬脂酸铝和明胶可制得缓释注射剂。
在某些情况下,为了延迟药物的作用,需要在皮下或肌内注射后减缓药物的吸收。这可通过使用低水溶性结晶材料的液体悬浮剂或通过把药物溶解或悬浮在油性载体中来实现。当皮下或肌内注射含有低水溶性药物的悬浮剂时,药物的吸收速度取决于其溶解速度。
F-Ⅰ的“贮库”注射制剂可通过将药物在生物可降解聚合物,例如聚(乳酸)、聚(乙醇酸)、乳酸和乙醇酸的共聚物、聚(原酸酯)、和聚(酸酐)等本领域已知聚合物中形成微胶囊基质来制得。根据药物与聚合物的比例和所用特定聚合物的特性,可控制药物的释放速度。
可通过例如细菌截留滤器过滤、或通过在混合前把混合物组分预灭菌而将注射剂在生产时或给药前灭菌(例如双室注射器包装实例)。
口服给药固体剂型包括胶囊、片剂、丸剂、粉剂、和粒剂。在这种固体剂型中,将F-Ⅰ与下述物质混合:至少一种惰性药物载体,例如柠檬酸钠、或磷酸氢二钙;和/或(a)填充剂或填料,例如淀粉、包括乳糖和葡萄糖在内的糖、甘露糖醇、和硅酸,(b)粘合剂,例如羧甲基纤维素和其它纤维素衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶,(c)湿润剂,例如甘油,(d)崩解剂,例如琼脂、碳酸钙、碳酸氢钠、土豆淀粉或木薯淀粉、藻酸、硅酸盐和碳酸钠,(e)增温剂,例如甘油,(f)溶液阻滞剂,例如石蜡,(g)吸收促进剂,例如季铵化合物,(h)湿润剂,例如鲸蜡醇和甘油单硬脂酸酯,(i)吸收剂,例如高龄土膨润土,和(j)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠、和它们的混合物。对于胶囊、片剂、和丸剂等剂型还可以含有缓冲剂。
相似类型的固体组合物还可包含用赋形剂,例如乳糖以及高分子量聚乙二醇等填充于软或硬明胶胶囊中。
固体剂型例如片剂、糖锭剂、胶囊、丸剂和粒剂还可制成具有包衣或外壳,例如肠溶包衣或制药领域其它众所周知的包衣剂型。包衣可含有不透明剂、或在尤其是部分消化道内释放活性组分的物质,例如用于在胃中释放活性组分的酸溶性包衣、或用于在肠道内释放活性组分的碱溶性包衣。
还可以将活性组分微囊包封在缓释包衣中,其中微胶囊构成胶囊制剂药丸的一部分。
F-Ⅰ的口服液体剂型包括溶液剂、乳剂、悬浮剂、糖浆剂和酏剂。除了活性组分以外,液体制剂还可包含本领域常用惰性稀释剂,例如水或其它药用溶剂,稳定剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其是棉籽油、坚果油、玉米油、胚芽油、橄榄油、蓖麻油、和芝麻油)、甘油、四氢糠醇、聚乙二醇、山梨醇脂肪酸酯、和它们的混合物。
除了惰性稀释剂以外,液体口服制剂还可包含助剂,例如润湿剂、乳化剂和悬浮剂、以及甜味剂、矫味剂、和香料。
除了活性组分以外,液体悬浮制剂还可包含悬浮剂,例如乙氧基化异硬脂醇、聚氧化乙烯山梨醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂、和西黄蓍胶、以及它们的混合物。
直肠或阴道内给药用组合物是这样制得的:将F-Ⅰ与适当非刺激赋形剂,例如椰子油、聚乙二醇、或在室温是固体、但在体温下是液体,并因此在直肠或阴道腔内能熔化释放活性组分的各种栓剂蜡混合。将化合物溶解在熔化的蜡中,塑成所需形状、使其变硬以形成最终的栓剂。
F-Ⅰ还可以以脂质体形式给药。正如本领域已知的那样,脂质体通常是用磷脂或其它脂类制得的。脂质体制剂是通过将分散在水介质中的液晶进行单层或多层水合而形成的。可使用所有能形成脂质体的无毒、可药用、以及可代谢脂类物质。除了F-Ⅰ以外,本发明脂质体剂型组合物还可含有稳定剂、赋形剂、防腐剂等。优选的脂类物质是磷脂和磷脂酰胆碱(卵磷脂),天然的和合成的均可。
形成脂质体的方法在本领域内是已知的,例如在Prescott,Ed.,《细胞生物方法》(Methods in Cell Biology),第XIV卷,AcademicPress,New York,N.Y.(1976),p.33中描述的方法。
下述制剂实施例仅是举例说明,而不是限制本发明的范围。
制剂1:明胶胶囊
可按照合理的变更改变上述制剂。
将F-Ⅰ、淀粉、和纤维素过NO.45目U.S.筛并充分混合。把所得粉末与聚乙烯吡咯烷酮溶液混合,然后过NO.14目U.S.筛。将由此制得的颗粒在50-60℃干燥,并过NO.18目U.S.筛.把羧甲基纤维素钠、硬脂酸镁、和滑石先过NO.60目U.S.筛,然后加到上述颗粒中,混合后,用制片机压制成片。
按如下所述制备每5ml分别含有0.1-1000mg F-Ⅰ的各种悬浮液:制剂5:悬浮液
将药物过N0.45目U.S.筛,并与羧甲基纤维素钠和糖浆混合形成光滑糊状物。将苯甲酸溶液、矫味剂、和着色剂与水稀释,并在搅拌下加入。然后加入足量水以制得所需体积。
制备含有下述组分的气雾剂溶液:制剂6:气雾剂
将F-Ⅰ与乙醇混合,把混合物加到一部分推进剂22中,冷却至30℃,转移到填充装置中。然后把所需量装到不锈钢容器中,并用剩余推进剂稀释,然后把阀门部件安装在该容器上.
按如下所述制备栓剂:
将F-Ⅰ过NO.60目U.S.筛,悬浮在饱和脂肪酸甘油酯中,然后用最小所需热量熔化。之后将混合物倒入2g标准容量的栓剂模中,冷却。
按如下所述制备静脉内给药制剂:制剂8:静脉内给药溶液
剂量
本发明F-Ⅰ的具体给药剂量取决于每一种病例的具体情况。这些条件包括给药途径、受治疗者的先前病史、欲治疗的病症或症状、欲治疗的病症/症状的严重程度、和受治疗者的年龄和性别。
F-Ⅰ的最小有效日剂量通常是大约1、5、10、15、或20mg。有效剂量通常是大约800、100、60、50、或40mg。最通常的剂量为15mg-60mg。可依据医学领域受治疗者“剂量逐步确定”法的标准实施手段确定准确剂量;也就是说,先给予低剂量的本发明化合物,然后逐渐提高剂量直至观察到理想治疗效果。
对于上述联合治疗,虽然需要逐步确定受治疗者的给药剂量,但是除F-Ⅰ外的其它活性组分的剂量通常如下:乙炔基雌激素(0.01-0.03mg/天)、美雌醇(0.05-0.15mg/天)、共轭雌激素(例如Premarin,Wyeth-Ayerst;0.3-2.5mg/天)、甲羟孕酮(2.5-1.0mg/天)、异炔诺酮(1.0-10.0mg/天)、炔诺酮(0.5-2.0mg/天)、氨鲁米特(250-1250mg/天,优选250mg/天、分4次给药)、anastrazole(1-5mg/天,优选每天一次1mg)、来曲唑(2.5-10mg/天,优选2.5mg/天、每天给药1次)、福美司坦(250-1250mg/周,优选250mg/周、每周2次给药)、依西美坦(25-100mg/天,优选25mg/天、每天给药1次)、性瑞林(3-15mg/3个月,优选3.6-7.2mg/3个月、每3个月给药1次)、和亮丙瑞林(3-15mg/月,优选3.75-7.5mg/月、每月给药1次)。
给药途径
F-Ⅰ可通过多种给药途径给药,包括口服给药、直肠给药、透皮给药、皮下给药、静脉内给药、肌内给药、和鼻内给药。各雌激素和孕激素给药方法与本领域已知给药方法一致。F-Ⅰ单独或与雌激素、孕激素、或AChE抑制剂一起通常是以适宜制剂给药。
可通过口服、直肠、阴道内、非胃肠道、局部、经颊、舌下、或经鼻给药途径将本发明药物组合物施于人或其它哺乳动物(例如狗、猫、马、猪等).在本说明书中,术语“非胃肠道给药”是指包括静脉内、肌内、腹膜内、胸骨内、皮下、或关节内注射或输注在内的给药方式。
给药方式/时间
对于本发明的主要给药方法,可将F-Ⅰ连续给药,每天给药1-3次,或者按需要时常给药,把有效量的F-Ⅰ输送给受治疗者。当治疗子宫内膜异位时,周期治疗可能特别适用,当经受到疾病的疼痛攻击时,可采用迅速治疗方式。对于再狭窄,在医疗处置,例如血管成形术之后,治疗可限制在短期间隔(1-6个月)。
Claims (16)
1.6-羟基-3-(4-[2-(哌啶-1-基)乙氧基]苯氧基)-2-(4-甲氧基苯基)苯并[b]噻吩盐酸盐水合物晶体(F-Ⅰ),当用铜辐射源进行X-射线衍射时,所述晶形具有包含下述峰值的X-射线衍射图案:7.9±0.2、10.7±0.2、14.9±0.2、15.9±0.2、18.3±0.2、和20.6±0.2°(2θ范围内)。
2.含有下述组分的药物制剂:权利要求1的晶体化合物;一种或多种可药用载体、稀释剂、或赋形剂;和任选含有的雌激素、任选含有的孕激素、任选含有的芳香酶抑制剂、任选含有的LHRH类似物、以及任选含有的乙酰胆碱酯酶(AChE)抑制剂。
3.权利要求2的制剂,其中含有权利要求1的晶体化合物;一种或多种可药用载体、稀释剂、或赋形剂;和雌激素。
4.权利要求3的制剂,其中所述雌激素是共轭雌激素(Premarin)。
5.权利要求2的制剂,其中含有权利要求1的晶体化合物;一种或多种可药用载体、稀释剂、或赋形剂;和孕激素。
6.权利要求5的制剂,其中所述孕激素选自异炔诺酮和炔诺酮。
7.权利要求2的制剂,其中含有权利要求1的晶体化合物;一种或多种可药用载体、稀释剂、或赋形剂;和AChE抑制剂。
8.权利要求7的制剂,其中所述AChE抑制剂选自水杨酸毒扁豆碱、盐酸他克林、和盐酸多奈皮兹(donepezil)。
9.权利要求2的制剂,其中含有权利要求1的晶体化合物;一种或多种可药用载体、稀释剂、或赋形剂;雌激素;和孕激素。
10.用于抑制选自下述疾病的病理学症状的权利要求1的化合物:子宫纤维变性、子宫内膜异位、主动脉平滑肌细胞增殖、再狭窄、乳腺癌、子宫癌、前列腺癌、良性前列腺增生、骨损失、骨质疏松、心血管疾病、高血脂、CNS障碍、和阿尔茨海默氏症。
11.用于抑制乳腺癌的权利要求10的化合物。
12.权利要求11的化合物,其中所述抑制方式是预防。
13.用于抑制卵巢癌的权利要求10的化合物。
14.用于抑制子宫内膜癌的权利要求10的化合物。
15.用于在哺乳动物中上调胆碱乙酰转移酶(ChAT)的权利要求1的化合物。
16.制备权利要求1的化合物的方法,包括从四氢呋喃中结晶6-羟基-3-(4-[2-(哌啶-1-基)乙氧基]苯氧基)-2-(4-甲氧基苯基)苯并[b]噻吩盐酸盐。
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EP1757291A3 (en) * | 2000-05-08 | 2009-07-15 | Eli Lilly & Company | Stabilized formulations of 6-hydroxy-3-(4-[2-(piperidin-1-YL)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene and salts thereof |
US7122203B2 (en) | 2000-05-08 | 2006-10-17 | Eli Lilly And Company | Stabilized formulations of 6-hydroxy-3-(-4-[2-(piperidin-1-yl) ethoxy]phenoxy)-2-(4-methoxyphenyl) benzo[b]thiophene and salts thereof |
DZ3376A1 (fr) * | 2000-05-08 | 2001-11-15 | Lilly Co Eli | Formulations stabilisees de 6-hydroxy-3-(4-[2-(piperidin-1-yl) ethoxy]phenoxy)-2-(4-methoxyphenyl) benzo[b]thiophene et sels de ces composes |
EP1157996A1 (de) * | 2000-05-23 | 2001-11-28 | JENAPHARM GmbH | Neue Festkörperformen des Mesoprogestins 11Beta-[4E-(Hydroxyiminomethyl)-phenyl]-17Alpha-methoxymethyl-17Beta-methoxy-estra-4,9-dien-3-on |
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2000
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- 2000-07-17 AU AU63356/00A patent/AU6335600A/en not_active Abandoned
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Publication number | Priority date | Publication date | Assignee | Title |
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CN100430058C (zh) * | 2002-07-12 | 2008-11-05 | 伊莱利利公司 | 结晶的2,5-二酮-3-(1-甲基-1h-吲哚-3-基)-4-[1-(吡啶-2-甲基)哌啶-4-基]-1h-吲哚-3-基]-1h-吡咯单盐酸盐 |
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