CN1240375C - 具有均匀药物分布和效力的低剂量药物组合物的制备方法 - Google Patents
具有均匀药物分布和效力的低剂量药物组合物的制备方法 Download PDFInfo
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- CN1240375C CN1240375C CNB028092554A CN02809255A CN1240375C CN 1240375 C CN1240375 C CN 1240375C CN B028092554 A CNB028092554 A CN B028092554A CN 02809255 A CN02809255 A CN 02809255A CN 1240375 C CN1240375 C CN 1240375C
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- phenyl
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Abstract
本发明描述了具有均匀药物分布和效力的药物组合物的制备方法,该方法使用了二氧化硅以便在制备过程中减少活性组分的损耗。该方法特别用于制备低剂量片剂组合物。
Description
发明领域
本发明涉及具有均匀药物分布和效力的药物组合物的制备方法、涉及由此生产的组合物和药剂,本发明特别涉及用于制备低剂量片剂组合物的方法和组合物,所述的低剂量片剂组合物中含有二氧化硅以便减少制备过程中活性组分的损耗。
背景技术
US 5,552,412中描述了一类用于治疗或预防乳腺癌、骨质疏松、肥胖、心血管疾病、高胆固醇血症、子宫内膜异位症和前列腺疾病的有效和具有口服活性的选择性雌激素受体调节剂(SERMS)(例如四氢化萘-2-醇衍生物)。这些特定的SERMS因其在目前商购SERMS(例如雷洛昔芬)中改善的口服生物利用度而受到关注。US 5,552,412中所述的SERMS极为有效,由此使获得低剂量剂型。然而,低剂量范围的组合物制剂对维持药物产品生产过程中的持续效力和均匀性提出了挑战。特别关注活性组分因粘附或吸附在掺合步骤中活性SERM接触的金属表面(例如接触金属掺合机刀片和容器表面)上所造成的损耗。尽管可以有效实现手工擦刷步骤来回收粘附在小尺寸设备中的金属表面的活性组分,但是手工擦刷步骤在规模生产环境中既无效、也不理想。液体加工可以将药物产品生产过程中药物损耗问题减少到最低限度;然而,对氧化敏感的化合物(例如四氢化萘-2-醇衍生物)在不使活性组分发生降解情况下使得难以进行液体加工。因此,对将活性组分粘附在生产药剂、特别是那些具有低剂量含量药剂过程中活性组分粘附在金属表面上的情况减少到最低限度的改善的制剂和方法存在需求。
概要
本发明提供了具有均匀药物分布和效力的药物组合物的制备方法。该方法包括(下列顺序)下列步骤:(1)在高剪切成粒机中将二氧化硅和至少一种药物上可接受的赋形剂、载体或稀释剂掺合适当的时间(约5分钟)以产生掺合的混合物;(2)向成粒机中加入活性组分且再掺合一定时间期限(约10-15分钟)而形成活性掺合物;(3)将该活性掺合物从成粒机中转入掺合机中;(4)任选向所述的活性掺合物中加入一种或多种其它药物上可接受的赋形剂、载体或稀释剂;和(5)掺合适当时间期限(约5分钟)以形成具有均匀活性组分分布和均匀效力的药物组合物。然后将所得掺合的组合物进一步加工成所需单位剂型。在优选的剂型中,活性组分的含量为约0.01-10.0mg/单位剂量(优选约0.05-约5.0mg/单位剂量,更优选约0.05-约4.0mg/单位剂量,甚至更优选约0.1-约3.5mg/单位剂量,且最优选约0.1-2.5mg/单位剂量),而二氧化硅的含有量约占单位剂型重量的约0.1-2%(更优选占单位剂型重量的约0.15-约1.0%且最优选占单位剂型重量的约0.25-约0.75%)。
在本发明的另一个实施方案中,提供了使用上述方法制备的药物组合物。特别提供了低剂量药物组合物,该药物组合物包括活性组分(优选拉索昔芬)、二氧化硅和至少一种药物上可接受的赋形剂、载体或稀释剂,其中所述的活性组分的含量低于4.0%w/w活性组分(更优选≥约0.01%w/w活性组分和<4%w/w活性组分,甚至更优选≥约0.01%w/w活性组分和≤约3.5%w/w活性组分,最优选≥约0.1%w/w活性组分和≤约2.5%w/w活性组分)且二氧化硅的含量为约0.1-约2重量%。
在本发明的另一个实施方案中,提供了通过上述制成单位剂型、特别是低剂量剂型的方法制备的药剂。
定义
本文所用的术语″均匀分布″指的是满足10个独立的掺合物样品的FDA标准(工业ANDA指南(Guidance for Industry ANDA′s):掺合物均匀分析(Blend Uniformity Analysis),1999年8月公布)的掺合的混合物,所述样品达到90-110%理论强度的效力且就所有掺合样品而言RSD均<5%。
术语″均匀的效力″指的是将药物物质活性在整个生产过程中维持在大于或等于约90%的水平的掺合的混合物。
术语″药物上可接受的″指的是物质或组合物必须在化学和/或毒理学上与制剂中含有的其它组分和/或与用该制剂治疗的哺乳动物相容。
术语″活性组分″指的是有治疗活性的化合物及其任意前体药物和所述化合物和前体药物的药物上可接受的盐、水合物和溶剂合物。
术语″适当时间期限″或″适宜时间期限″指的是获得所需作用或结果所必需的时间期限。例如,可以将混合物掺合至使效力分布达到指定应用或应用掺合的混合物的可接受的定性范围。
本文所用的术语″单位剂量″指的是含有为产生所需治疗作用计算的活性组分预定量的物理形态上离散的单位。单位剂量可以是片剂、胶囊剂、小药囊等本文称作″单位剂型″的形式。
详细说明
本发明提供了用于维持含有高效活性组分的药物组合物生产过程中的均匀性和效力的方法。该方法包括使药物组合物或药剂生产过程中粘附在设备金属表面上的活性组分损耗减少到最低限度的措施。特别关注的活性组分是下列通式(I)的SERM化合物、其前体药物或所述化合物或所述前体药物的药物上可接受的盐、水合物或溶剂合物:
其中E和B独立地选自CH和N;R1是氢、羟基、氟或氯;且G是:
优选的化合物包括:顺式-6-(4-氟-苯基)-5-[4-(2-哌啶-1-基-乙氧基)-苯基]-5,6,7,8-四氢-萘-2-醇;(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-5,6,7,8-四氢-萘-2-醇;顺式-6-苯基-5-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-5,6,7,8-四氢萘-2-醇;顺式-1-[6′-吡咯烷乙氧基-3′-吡啶基]-2-苯基-6-羟基-1,2,3,4-四氢萘-1-(4′-吡咯烷乙氧基苯基)-2-(4″-氟苯基)-6-羟基-1,2,3,4-四氢异喹啉;顺式-6-(4-羟基苯基)-5-[4-(2-哌啶-1-基-乙氧基)-苯基]-5,6,7,8-四氢萘-2-醇;和1-(4′-吡咯烷乙氧基苯基)-2-苯基-6-羟基-1,2,3,4-四氢异喹啉;更优选的化合物是顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇;其前体药物,或所述化合物或所述前体药物的药物上可接受的盐、水合物或溶剂合物。
通式(I)的化合物是极为有效的化合物,由此需要在生产过程中进行特定控制以减少操作者的接触。此外,通式(I)的化合物可能对氧化敏感,这种氧化可以限制或妨碍药物产品生产过程中含有过氧化物污染物的液体和材料(例如聚乙二醇)的应用。用于生产片剂的常规方法一般在压制成片剂前使用湿法或干法成粒步骤。
可以将用于干法成粒的混合方法类型分成广泛的两类型:(i)批量型;和(ii)连续型。制药工业中最普遍使用的类型是批量型,该方法可一次混合部分批量或总批量的制剂。在批量型混合器中,通过旋转混合器外壳或整体使颗粒运动。就不同类型批量型混合器的略图和描述而言,参见Pharmaceutical Dosage Forms,第2卷,Lieberman,H.A.,L.Lachman;和J.B.Schwartz(编辑),Marcel Dekker,Inc.,New York,pp 40-57(1990)。
在掺合/研磨/掺合干法成粒过程中,一般使用下列步骤:
(1)使活性组分通过适宜大小的筛且然后在掺合机(例如双壳掺合机)中掺合适当时间期限以产生掺合的混合物;
(2)通过适当大小的筛过滤赋形剂掺合物并将部分过滤的赋形剂掺合物加入到含有活性组分的掺合机中;
(3)将该混合物掺合适当时间期限;
(4)通过适当大小的筛过滤活性掺合物;
(5)给掺合机添加一半剩余过滤的赋形剂掺合物,随后添加来自步骤(4)的过滤的活性掺合物;
(6)将该混合物掺合适当时间期限;
(7)向活性组分混合物中加入剩余过滤的赋形剂掺合物并掺合适当时间期限;
(8)过滤来自通过研磨机的步骤(7)的掺合的混合物;
(9)将来自步骤(8)的活性组分混合物在掺合机中掺合适当时间期限;和
(10)加入任意其它的赋形剂、载体或稀释剂并掺合至获得可接受的物质分布为止。
常规的掺合/研磨/掺合干法存在几个缺陷。例如,劳动密集,粉尘操作增加了操作者接触活性组分的机会且与金属表面接触增加了效力损耗的风险。此外,因混合物具有宽颗粒大小分布且颗粒密度差异大而观察到了分离的问题。转鼓型掺合机一般并不适合于细颗粒系统,这是因为没有足够的减少颗粒团聚的剪切力,且如果粉末自由流动,那么可能因添加低剂量活性组分而需要连续稀释。
当将上述干成粒法用于掺合含有通式(I)化合物的制剂时,通过成粒的颗粒观察到了不均匀分布的效力。尽管操作者接触活性组分的可能性在常规湿法成粒观察中得到降低,但是在增加化合物氧化可能性的工艺过程中活性组分接触液体和溶解的氧。降低通式(I)化合物在湿法成粒中的化学不稳定性的尝试并未成功。然而,申请人发现应用适合用于干法的高剪切湿法掺合设备致力于操作者接触药物并因常规干法和湿法成粒过程中观察到的氧化活性组分降解减少的问题。
高速成粒机是带有大混合刮料机刀片的固定壳混合器,其中所述的大混合刮料机刀片在混合器容器中混合所述组分、消除死角并将混合器中的内含物传送至最终混合所述组分的高速切碎机刀片。该设备速度极快且提供了最终的固体/固体混合。在竖型混合器(例如商购自LODIGEIndustries,Paderborn,Germany;NIRO Inc.,Columbia,MD;和DIOSNADierks&SoehneGmbH,Osnabrueck,Germany的设备)中,旋转混合叶轮以离心方式高速混合颗粒,使物质产生高度流化的涡旋。以极高速度旋转的切碎机粉碎上升循环的物质并将产物转成垂直流动。关于更为详细的描述,参见Record,P.C.,Manuf.Chem.Aerosol.News,50,65(1979)。其它合适的高速成粒机包括SpectrumTM和Pharma MatrixTM(均商购自Niro Pharma Systems,Columbia,MD)。
本发明提供了包括下列步骤的干法:
(1)在高剪切成粒机中将二氧化硅和至少一种药物上可接受的赋形剂、载体或稀释剂掺合适当的时间;
(2)向成粒机中加入活性组分且再掺合一定时间期限而形成活性掺合物;
(3)将该活性掺合物从成粒机中转入掺合机中;
(4)任选向所述的混合物中加入一种或多种其它药物上可接受的赋形剂、载体或稀释剂;和
(5)掺合适当时间期限以便在组合物中形成具有均匀活性组分具有分布的药物组合物。
将最终的药物组合物加工成单位剂型(例如片剂、胶囊剂或小药囊)且然后包装用于分发。该加工步骤随特定的单位剂型而改变。例如,一般在压力下将片剂压制成所需形状且胶囊剂或小药囊使用简单的填充操作。本领域技术人员充分熟知用于生产不同单位剂型的方法。
活性掺合物一般包括一种或多种药物上可接受的赋形剂、载体或稀释剂。所用的具体载体、稀释剂或赋形剂取决于活性组分所应用的方式和目的。一般来说,片剂包括诸如稀释剂、粘合剂、润滑剂、崩解剂及其混合物这样的物质。合适的稀释剂包括各种类型的淀粉、乳糖、甘露糖醇、高岭土、磷酸钙或硫酸钙、无机盐(例如氯化钠)、糖粉和粉状纤维素衍生物。为了确保掺合物中内含物的均匀性,优选使用小于或等于约30微米体积平均直径的药物物质颗粒。优选的稀释剂是微晶纤维素(例如商购自FMCPharmaceutical,Philadelphia,PA的AvicelPH102或PH101)和乳糖。微晶纤维素的平均颗粒大小一般在约90μm-约200μm的范围。合适的乳糖等级包括无水乳糖(平均约152μm)、乳糖一水合物和喷雾干燥的乳糖(例如Fast FloTM乳糖,约87um的平均值,商购自Foremost Corp.,Baraboo,WI)。
如果需要,可以加入粘合剂。合适的粘合剂包括诸如纤维素(例如纤维素、甲基纤维素、乙基纤维素和羟甲基纤维素)、聚丙基吡咯烷酮、聚乙烯吡咯烷酮、明胶、阿拉伯树胶、聚乙二醇、淀粉、糖(例如乳糖、蔗糖、果糖和葡萄糖)、天然和合成树胶(例如阿拉伯胶、藻酸盐和阿拉伯树胶)和蜡这样的物质。
一般在片剂中使用润滑剂以防止片剂和冲头在冲模中粘着。合适的润滑剂包括滑润固体,诸如滑石、硬脂酸镁和硬脂酸钙、硬脂酸、无水轻质硅酸和氢化植物油。优选的润滑剂是硬脂酸镁。
还可以将崩解剂加入到组合物中以使剂型破碎并释放所述化合物。合适的崩解剂包括淀粉(例如玉米淀粉或马铃薯淀粉和羟丙基淀粉),粘土、纤维素(例如纤维素、木纤维素、甲基纤维素或乙基纤维素、低取代的羟丙基纤维素和羧甲基纤维素)、琼脂、藻胶(例如藻酸)、粉状天然海绵状物、阳离子交换树脂、柑橘属的果肉、膨润土、碳酸氢钠、磷酸钙、柠檬酸钙、十二烷基硫酸钠和树胶(例如瓜耳胶)。
其它有用的添加剂包括诸如延缓溶解剂(例如石蜡)、再吸收加速剂(例如季铵化合物)、表面活性剂(例如鲸蜡醇、硬脂酸甘油酯和十二烷基硫酸钠)、吸附载体(例如高岭土和膨润土)、防腐剂、增甜剂、着色剂、调味剂(例如柠檬酸、薄荷醇、甘氨酸或桔粉)、稳定剂(例如柠檬酸或柠檬酸钠)、粘合剂(例如羟丙基甲基纤维素)及其混合物这样的物质。
在将成分加入高剪切成粒机进行开始的掺合步骤的顺序上存在很大程度的灵活性。优选首先不将药物物质加入到高剪切筒体中。一般在高剪切成粒机中的掺合时间为约10分钟-约15分钟。尽管可以使用15分钟以上的掺合时间,但是应谨慎考虑以不使掺合物分层。成粒机叶轮的速度一般以约55%-约65%的单位能力运转且切碎机优选以最慢的速度设置运转。叶轮速度过快可以导致掺合物流化并使掺合效力损耗。
在高剪切掺合步骤后,在双壳″V″型或料箱掺合机中掺合活性掺合物。一般的掺合时间为约5分钟,不过,已经成功地将小批量掺合了高达约15分钟。然后向活性掺合物中加入润滑剂并在双壳″V″型或料箱掺合机中掺合约5分钟。
上述工艺产生了有效混合并使活性组分的分布更为均匀而不会使活性组分发生明显的降解;然而,因化合物与设备金属表面(例如刀片和容器表面)粘附或吸附而导致的活性组分损耗尤其对低剂量制剂(例如低于4mg/剂量单位)而言提出了另外的挑战。添加诸如滑石这样的助流剂不会解决该难题。尽管向制剂中添加滑石减少了掺合工艺中活性组分的损耗(掺合的组合物中的效力由77.2%增加到91.0%),但是滑石不会完全防止与金属表面的粘附。当在掺合滑石制剂后手工实施擦刷步骤时,观察到效力增加到96.8%,这表明约有5%-约6%的活性组分仍然粘附在金属表面上。诸如通式(I)化合物这样极为有效的活性组分有5-6%损耗是显著的。然而,当向制剂中加入二氧化硅(例如得自W.R.Grace,Columbia,MD的SyloidTM244FP)时,观察到不添加手工擦刷步骤而使掺合组合物的效力从77.2%增加到了96.3%。
尽管向药物制剂中添加二氧化硅用于改善粉末掺合物的流动性并将片重的变化减小到最低限度,但是混入SiO2(如上述所观察到的)出人意料和令人意外地减少了因活性组分与加工设备金属表面吸附或粘附所导致的损耗。各种二氧化硅商购自许多商品供应商且对本领域技术人员而言是众所周知的。特别有用的二氧化硅是胶态二氧化硅,它是通过对诸如四氯化硅这样的硅化合物进行汽相水解制备的亚微热解法二氧化硅。胶态二氧化硅是商购自包括Cabot Corporation,Boston,MA(Cab-O-SilTM)、Degussa,Inc.,Düsseldorf,Germany(AerosilTM)、E.I.DuPont&Co.,Wilmington,DE和W.R.Grace&Co.,Columbia,MD(SyloidTM)在内的许多来源的非晶形粉末。胶态二氧化硅也称作胶体硅石、热解法二氧化硅、无水轻质硅酸、硅酐和烟化二氧化硅(silicon dioxide fumed)等。通过不同的生产工艺生产不同商品等级的胶态二氧化硅。这些改变不会影响二氧化硅含量、比重、折射率、颜色或晶形。然而,已知这些修改改变了胶态二氧化硅产品的颗粒大小、表面积和堆积密度。二氧化硅的平均颗粒大小一般小于或等于约15μm/堆积密度(小于或等于约21.0Ibs./ft3(336kg/m3))。优选二氧化硅是干粉形式且不是液体混悬液。
二氧化硅的含有量一般占剂型重量的约0.1-约2%、优选含量占剂型重量的约0.15-约1.0%(重量)且最优选含量占剂型重量的约0.25-约0.75%。
通式(I)化合物的制备方法描述在美国专利US 5,552,412中,将该文献引入本文作为参考,且外消旋混合物的拆分描述在WO97/16434中。可以使用活性组分本身或其药物上可接受的盐、溶剂合物和/或水合物的形式。术语″药物上可接受的盐″指的是来源于无机酸和有机酸的无毒性酸加成的盐。合适的盐衍生物包括卤化物、硫氰酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、芳基磺酸盐、烷基硫酸盐、膦酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、链烷酸盐、环烷基链烷酸盐、芳基链烷酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、乳酸盐、马来酸盐、烟酸盐、草酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、新戊酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、三氟乙酸盐等。通式(I)化合物的优选盐是酒石酸盐(特别是D-酒石酸盐)或柠檬酸盐。优选的化合物是拉索昔芬(顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇)。该活性组分在药物组合物中的一般含量小于或等于约10%w/w。就低剂量剂型应用而言,该活性组分在药物组合物中的一般含量低于4.0%w/w活性组分、更优选≥约0.01%w/w活性组分和<4%w/w活性组分,甚至更优选≥约0.01%w/w活性组分和≤约3.5%w/w活性组分,最优选≥约0.1%w/w活性组分和≤约2.5%w/w活性组分。
可以将药物组合物用于生产含有约0.05mg-约10.0活性组分/单位剂量、优选约0.1mg-约5.0mg活性组分/单位剂量的单位剂型。片剂大小(即单位剂型)一般为约100mg-600mg。本文所用的″低剂量剂型″指的是含有低于约5.0mg活性组分的单位剂量。一般的低剂量剂型含有约0.01-约5.0mg、优选约0.05mg-约4.0mg、更优选约0.1mg-约3.5mg、最优选约0.1mg-2.5mg活性组分。
例如,0.25mg、0.1mg和0.05mg片的片剂一般由含有约0.14%w/w活性组分的掺合物组成且片的大小可以改变以获得合适的剂量;而0.5mg片剂一般含有约0.68%w/w活性组分的掺合物。活性组分在最终药物组合物中的浓度一般通过增加或减少加入到该制剂中的稀释剂(例如乳糖)的量来调整。
一般通过在旋转压力机中压制来制备片剂。不过,对用于片剂形成的具体方法无限制且是本领域技术人员众所周知的。在片剂形成后,通常给片剂包一层或多层包衣层。可以给片剂包衣以掩盖气味,起密封层的作用和/或起刻印片剂表面徽标或商标的接受者的作用。常用的包衣层是糖包衣层(例如蔗糖或山梨醇包衣层)。另一方面,可以给片剂包成膜保护剂以改变片剂的溶出特性。例如,可以给片剂包衣防止预定时间期限内溶解的成膜包衣层,由此使活性组分延缓或延长释放。合适的成膜保护剂包括纤维素(例如羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素)、聚乙烯吡咯烷酮和丙烯酸乙酯-甲基丙烯酸甲酯共聚物。包衣制剂还可以包括诸如加溶剂(例如三醋精)、防腐剂、增甜剂、调味剂、着色剂这样的添加剂和为药物提供优美外观的其它已知添加剂。还可以通过在制剂中使用大量诸如甘露糖醇这样味道良好的物质将所述的化合物配制成口嚼片。
另一方面,可以将活性药物掺合物填入胶囊。对具体的胶囊和用于填充胶囊的方法无限制且是药物生产领域的普通技术人员众所周知的。
可以按照各种方式包装药物组合物(或制剂)。一般来说,用于分发的制品包括在含有适宜形式的药物组合物的容器。合适的容器是本领域技术人员众所周知的且包括诸如瓶(塑料和玻璃)、小药囊、箔泡罩包等这样的材料。容器还可以包括防止不慎进入包装内含物的防填塞装置。此外,容器一般在其上带有说明容器内含物和任何适当警告或指示的标签。
含有本文所述的通式(I)化合物的药物组合物特别用于治疗或预防乳腺癌、骨质疏松、肥胖、心血管疾病、高胆固醇血症、子宫内膜异位症和前列腺疾病。因此,可以将含有通式(I)化合物的本文所述的药物制剂和方法用于生产上述治疗应用的药剂。可以将治疗有效量生产的药剂根据这类治疗或预防的需要对人给药。本文所用的术语″治疗有效量″指的是能够抑制或预防上述涉及的各种病理情况或其症状以及后遗症的活性组分的用量。术语″抑制″指的是阻止、治疗、减轻、改善、停止、遏制、缓解或逆转涉及所治疗相应疾病或由其导致的病理情况或症状发展或降低其严重程度。如果合适,可以照此将药物制剂用于医学治疗(急性或慢性)和/或预防(预防)性给药。剂量、给药频率和期限随诸如所治疗疾病的性质和严重程度、宿主的年龄和一般健康情况和宿主对活性组分的耐受性而改变。每日可以以单剂量给予药物组合物或药剂或在当天分多次剂量给药。该方案可以持续约2-3天或几周或几周以上。一般来说,将该组合物对人患者给药,每天1-4次,单位剂量为约0.05mg-约50mg,但上述剂量可以适当改变,这取决于患者的年龄、体重和医学情况以及给药类型。优选对人体患者的给药方案为每日给药约0.25mg/kg-约25mg/kg。
下列实施例解释通式(I)化合物的制备方法及其在本发明药物组合物和生产方法中的应用。尽管将特定的SERM化合物(拉索昔芬)用于解释本发明,但是本领域技术人员可以理解的是可以将本发明的方法用于得益于用本发明方法使药物组合物中活性组分效力和分布均匀性增加的任意化合物。这些实施例并不在任何方面用来限定本发明的范围且不应如此解释。
实施例
顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-
醇(″拉索昔芬″)的制备:
如美国专利US5,552,412所述制备拉索昔芬并再现如下。
在20℃和60psi(0.41MPa)下使1-[2-[4-(6-甲氧基-2-苯基-3,4-二氢萘-1-基)苯氧基]乙基]吡咯烷盐酸盐(盐酸萘福昔定(nafoxidenehydrochloride))(1.0g,2.16mmol)于20mL含有1.0g氢氧化钯/碳的无水乙醇中的溶液氢化19小时。过滤并蒸发而得到863mg(93%)的顺式-1-{2-[4-(6-甲氧基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基]乙基}吡咯烷。
1H-NMR(CDCl3.):δ3.50-3.80(m,3H),3.85(s,3H),4.20-4.40(m,3H),6.80-7.00(m,3H);MS 428(P+1)。
在0℃搅拌下向400mg(0.94mmol)的顺式-1-{2-[4-(6-甲氧基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基]乙基}吡咯烷于25mL二氯甲烷中的溶液中逐滴加入4.7ml(4.7mmol)1.0M三溴化硼的二氯甲烷溶液。在室温下3小时后,将该反应体系倾入100mL快速搅拌的饱和碳酸氢钠水溶液中。分离有机层、用硫酸钠干燥、过滤并浓缩至得到287mg(产率74%)的拉索昔芬、为游离碱。
1H-NMR(CDCl3):δ3.35(dd,1H),4.00(t,2H),4.21(d,1H),6.35(ABq,4H)。通过用过量4N HCl的二噁烷溶液处理该碱溶液、随后蒸发至干并用乙醚一起研制来制备相应的盐酸盐(MS:415[P+1])。
另一方面,可以使用下列方法制备拉索昔芬。
1-[2-[4-(6-甲氧基-2-苯基-3,4-二氢萘-1-基)苯氧基]乙基]吡咯烷的制备:将无水CeCl3(138g,560mmol)和THF(500mL)的混合物剧烈搅拌2小时。在独立的烧瓶中,将1-[2-(4-溴苯氧基)乙基]吡咯烷(l00g,370mmol)的THF(1000mL)溶液冷却至-78℃并在20分钟内缓慢加入n-BuU(2.6M的己烷溶液,169mL,440mmol)。在15分钟后,将该溶液通过套管加入到在-78℃下冷却的CeCl3淤浆中并将该反应体系在-78℃下搅拌2小时。在-78℃下将6-甲氧基-1-四氢萘酮(65.2g,370mmol)的THF(1000mL)溶通过套管加入到芳基铈试剂中。将该反应体系缓慢温热至室温并总计搅拌16小时。将该混合物通过CeliteTM垫过滤。在真空中浓缩滤液并加入3N HCl(500mL)和Et2O(500mL)。在搅拌15分钟后,分离各层。用Et2O(2x)进一步洗涤水层。干燥(MgSO4)干燥合并的有机层、过滤并浓缩得到6-甲氧基-1-四氢萘酮(22g)。用5N NaOH将水层碱化至pH12并加入15%(NH4)2CO3水溶液(1000mL)。用CH2Cl2(2x)提取该含水混合物。干燥(MgSO4)有机溶液、过滤并浓缩得到棕色油状物。蒸馏出杂质(110℃-140℃,0.2mmHg)而得到产物(74g,57%)。
1HNMR(250MHz,CDCl3):δ7.27(d,J=8.7Hz,2H),6.92-6.99(m,3H),6.78(d,J=2.6Hz,1H),6.65(dd,J=8.6,2.6Hz,1H),5.92(t,J=4.7Hz,1H),4.15(t Hz,2H),3.80(s,3H),2.94(t,J=6.0Hz,2H),2.81(t,J=7.6Hz,2H),2.66(m,2H),2.37(m,2H),1.84(m,4H)。
1-[2-[4-(2-溴-6-甲氧基-3,4-二氢萘-1-基)苯氧基]乙基]吡咯烷的制备:向1-[2-[4-(6-甲氧基-3,4-二氢萘-1-基)苯氧基]乙基]吡咯烷(23g,72mmol)的THF(700mL)的溶液中分部分加入溴化吡啶鎓过溴化物(21.22g,60.55mmol)。将该反应体系搅拌60小时。通过Celite(塞利特硅藻土)垫借助于THF过滤沉淀。将黄白色固体溶于CH2Cl2和MeOH并将其从Celite中过滤出来。用0.5N HCl水溶液、随后用饱和NaHCO3(水溶液)洗涤该有机溶液。干燥(MgSO4)该有机溶液、过滤并浓缩至得到棕色固体(21.5g,83%)。
1HNMR(250MHz,CDCl3):δ7.14(d,J=8.7Hz,2H),6.97(d,J=8.8Hz,2H),6.71(d,J=2.2Hz,1H),6.55(m,2H),4.17(t,J=6.0Hz,2H),3.77(s,3H),2.96m,(4H),2.66(m,4H),1.85(m,4H)。
1-[2-[4-(6-甲氧基-2-苯基-3,4-二氢萘-1-基)苯氧基]乙基]吡咯烷盐酸盐(盐酸萘福昔定)的制备:向1-[2-[4-(2-溴-6-甲氧基-3,4-二氢萘-10-基)苯氧基]乙基]吡咯烷(19g,44mmol)、苯基硼酸(7.0g,57mmol)和四(三苯膦鎓)合钯(1.75g,1.51mmol)在THF(300mL)中的混合物中加入Na2CO3(13g,123mmol)的H2O(100mL)溶液。将该反应体系在回流状态下加热18小时。分离各层并用H2O、随后用盐水洗涤有机层。干燥(MgSO4)该有机溶液、过滤并浓缩至得到17.96g的棕色固体。将残余物溶于CH2Cl2与EtOAc的1∶1混合物(250mL)并加入1NHCl的Et2O溶液(100mL)。在搅拌2小时后,使产物从溶液中结晶并通过过滤收集到11g物质。浓缩母液至其体积的一半而又得到7.3g产物。
1-[2-[4-(6-甲氧基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基]乙基]吡咯烷的制备:将1-[2-[4-(6-甲氧基-2-苯基-3,4-二氢萘-1-基)苯氧基]乙基]吡咯烷盐酸盐(盐酸萘福昔定)(75g,162mmol)溶于1000mL的EtOH和300mL的MeOH。加入干燥的Pd(OH)2/碳并使该混合物在50℃和50psi(0.34MPa)下的帕尔振荡器上氢化68小时。用Celite过滤出催化剂并在真空中除去溶剂。将所得白色固体溶于CH2Cl2并用饱和NaHCO3(水溶液)洗涤该溶液。干燥(MgSO4)该有机溶液、过滤并浓缩至得到黄白色固体(62.6g,90%)。
顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇的制备:将顺式-1-[2-[4-(6-甲氧基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基]乙基]吡咯烷(12g,28mmol)、乙酸(75mL)和48%HBr(75mL)的混合物在100℃下加热15小时。将该溶液冷却并通过过滤收集所得白色沉淀。将该氢溴酸盐(9.6g,69%)溶于CHCl3/MeOH并与饱和NaHCO3(水溶液)一起搅拌。分离各层并用CHCl3/MeOH进一步提取水层。干燥(MgSO4)合并的有机层、过滤并浓缩至得到产物、为黄白色泡沫。
1HNMR(250MHz,CDCl3):δ7.04(m,3H),6.74(m,2H),6.63(d,J=8.3Hz,2H),6.50(m,3H),6.28(d,J=8.6Hz,2H),4.14(d,J=4.9Hz,1H),3.94(t,J=5.3Hz,2H),3.24(dd,J=12.5,4.1Hz,1H),2.95(m,4H),4H),2.14(m,1H),1.88(m,4H),1.68(m,1H)。
下列实施例将常规的成粒湿法和溶液湿成粒法与本发明(干成粒法)进行了比较。
实施例1
实施例1中所用的下列物质可以从下述相应的来源获得:
AvicelTM PH101(微晶纤维素) FMC Pharmaceutical(Philadelphia,
PA)
Lactose Fast FloTM 316 Foremost Corp.(Baraboo,WI)
硬脂酸镁 Mallinckrodt(St.Louis,MO)
羟丙基纤维素 Hercules Inc.(Hopewell,VA)
交联羧甲基纤维素钠 FMC Pharmaceutical(Philadelphia,
PA)
β-环糊精磺丁基醚 使用美国专利US6,153,746中所述的
方法制备
二氧化硅 Grace Davison(Columbia,MD)
ProSolvTM 50(硅化微晶纤维素) Penwest,Patterson,NJ
拉索昔芬常规湿成粒法(对比法)
按照所列顺序将下列组分加入到高剪切掺合机中。
乳糖 5.000g
微晶纤维素 17.432g
交联羧甲基纤维素钠 1.000g
羟丙基纤维素 1.250g
二氧化硅 0.125g
拉索昔芬 0.068g
将该混合物掺合约15分钟。在掺合的同时,在8.5分钟期限内加入适量水(约占干掺合物的63%w/w)且然后再持续掺合30秒至得到所需的湿团。随后将该湿团在真空(约50毫巴(mB))中干燥至水分低于约2%。通过安装有0.04英寸(0.10cm)筛和设定在1750rpm速度的圆边叶轮的圆锥形研磨机研磨干燥的颗粒。将该混合物在Turbula混合器上的150cc玻璃瓶中掺合约10分钟。向该混合物中加入硬脂酸镁(0.125g)且然后掺合约5分钟。然后使用KilianTMT100压片机(购自Kilian&Co.,Inc.,Horsham,PA)将该活性掺合物压制成片剂。
拉索昔芬药物的溶液湿成粒法(对比法)
向安装了混合器的250mL玻璃烧杯中加入水(100mL)。在搅拌的同时,加入β-环糊精磺丁基醚(0.452g),随后加入拉索昔芬(0.113g)并搅拌至β-环糊精磺丁基醚和拉索昔芬溶解且形成溶液。然后按照所列顺序将下列组分加入到高剪切掺合机中。
乳糖 5.000g
硅化微晶纤维素 17.540g
交联羧甲基纤维素钠 1.000g
羟丙基纤维素 1.250g
将该混合物掺合约2分钟。在掺合的同时,在3分钟期限内加入拉索昔芬:水溶液。随后将湿团在50℃和强制热空气烘箱中干燥至水分低于约1%。使干燥的颗粒通过安装有0.005英寸(0.14cm)筛和设定在1750rpm速度的圆边叶轮的圆锥形研磨机。向该混合物中加入硬脂酸镁(0.125g)且然后掺合约5分钟。然后使用ManestyTM F-压片机(购自Thoms Engineering Inc.,Hoffman Estates,IL)将该活性掺合物压制成片剂。
拉索昔芬干成粒法
按照所列顺序将下列组分加入到高剪切掺合机中。
乳糖 1052.25g
微晶纤维素 375.00g
交联羧甲基纤维素钠 45.00g
二氧化硅 7.50g
拉索昔芬 5.25g
将乳糖、微晶纤维素、交联羧甲基纤维素钠和二氧化硅掺合5分钟。接下来加入拉索昔芬并掺合约15分钟。然后从该剪切掺合机中放出活性掺合物并在双壳″V″型掺合机中掺合约5分钟。向该活性掺合物中加入硬脂酸镁(7.50g)并掺合约5分钟。在Vector FreundTM滚筒式压制装置中对活性掺合物进行辊压并通过安装了0.033″(0.084cm)筛的旋转成粒机(均购自Vector Corp.,Marion,IA)研磨。将该活性颗粒在双壳″V″型掺合机中掺合约5分钟。向该颗粒中再加入部分硬脂酸镁(7.50g)并掺合约5分钟。将最终的掺合物在KilianTM T100旋转压片机上压制成片剂。
下表1概括了对三种不同方法使用高效液相色谱法得到的稳定性结果。
表1
拉索昔芬稳定性比较 | |||
生产方法 | 干法成粒 | 常规的湿法成粒(对比) | 药物的溶液湿法成粒(对比) |
加入的药物百分比 | 0.14 | 0.28 | 0.068 |
最初的杂质总百分比 | 0.02 | 未得到 | 0.95 |
5℃下杂质总百分比 | 12个月时为0.13 | 6周时为0.54 | 6周时为1.43 |
30℃下杂质总百分比 | 12个月时为0.13 | 6周时为1.21 | 6周时为2.03 |
40℃/75%RH下的杂质总百分比 | 6个月时为0.41 | 6周时为4.3 | 6周时为3.10 |
50℃下的杂质总百分比 | 6个月时为0.39 | 6周时为5.26 | 6周时为4.25 |
Claims (14)
1.制备具有均匀药物分布和效力的药物组合物的干方法,该方法包括下列顺序的步骤:
(1)在高剪切成粒机中将二氧化硅和至少一种药物上可接受的赋形剂、载体或稀释剂掺合适当的时间以产生掺合的混合物;
(2)向成粒机中加入活性组分且再掺合一定时间而形成活性掺合物;
(3)将该活性掺合物从成粒机中转入掺合机中;
(4)任选向所述的活性掺合物中加入一种或多种其它药物上可接受的赋形剂、载体或稀释剂;和
(5)掺合适当时间以形成具有均匀活性组分分布和均匀效力的药物组合物;
其中所述活性组分是通式(1)的化合物或所述化合物的药物上可接受的盐、水合物或溶剂合物:
其中E和B独立地选自CH和N;R1是氢、羟基、氟或氯;且G是:
2.权利要求1的方法,其中:
步骤(1)进行5分钟以产生掺合的混合物;
步骤(2)进行10-约15分钟而形成活性掺合物;和
步骤(5)进行5-15分钟以形成具有均匀活性组分分布和均匀效力的药物组合物。
3.权利要求1或权利要求2的方法,其中所述的活性成分选自下列化合物组成的组的化合物:顺式-6-(4-氟-苯基)-5-[4-(2-哌啶-1-基-乙氧基)-苯基]-5,6,7,8-四氢-萘-2-醇;(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-5,6,7,8-四氢-萘-2-醇;顺式-6-苯基-5-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-5,6,7,8-四氢萘-2-醇;顺式-1-[6′-吡咯烷基乙氧基-3′-吡啶基]-2-苯基-6-羟基-1,2,3,4-四氢萘-1-(4′-吡咯烷基乙氧基苯基)-2-(4″-氟苯基)-6-羟基-1,2,3,4-四氢异喹啉;顺式-6-(4-羟基苯基)-5-[4-(2-哌啶-1-基-乙氧基)-苯基]-5,6,7,8-四氢萘-2-醇;和1-(4′-吡咯烷基乙氧基苯基)-2-苯基-6-羟基-1,2,3,4-四氢异喹啉;或所述化合物的药物上可接受的盐、水合物或溶剂合物。
4.权利要求3的方法,其中所述的活性成分是顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇;或其药物上可接受的盐、水合物或溶剂合物。
5.权利要求3的方法,其中所述的活性成分是(-)顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇;或其药物上可接受的盐、水合物或溶剂合物。
6.权利要求3所述的方法,其中所述活性组分是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇的D-酒石酸盐。
7.上述权利要求中任意一项的方法,进一步包括将所述药物组合物加工成单位剂型的步骤。
8.权利要求7的方法,其中所述的活性组分在所述单位剂型中的含量为0.01-10.0mg。
9.权利要求8的方法,其中所述的活性组分在所述单位剂型中的含量为0.1-3.5mg。
10.权利要求7的方法,其中所述的二氧化硅的含量占所述单位剂型重量的0.1-2%。
11.权利要求10的方法,其后所述的二氧化硅的含量占所述单位剂型重量的0.15%-1.0%。
12.根据权利要求1方法制备的药物组合物,所述组合物包括活性组分、二氧化硅和至少一种药物上可接受的赋形剂、载体或稀释剂,其中所述活性组分的含有量低于4.0%w/w且所述的二氧化硅的含有量为0.1-2重量%。
13.权利要求12的药物组合物,其中所述的活性组分是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇的D-酒石酸盐。
14.权利要求13的药物组合物,其中所述(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇的D-酒石酸盐的含有量低于或等于4.0%w/w。
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