CN105473183A - 作为提高骨矿物质密度的药剂的反式克罗米芬和它的类似物 - Google Patents
作为提高骨矿物质密度的药剂的反式克罗米芬和它的类似物 Download PDFInfo
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- CN105473183A CN105473183A CN201480032162.1A CN201480032162A CN105473183A CN 105473183 A CN105473183 A CN 105473183A CN 201480032162 A CN201480032162 A CN 201480032162A CN 105473183 A CN105473183 A CN 105473183A
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Abstract
本发明涉及施用包含反式克罗米芬或其类似物或盐的组合物以抑制受试者的骨再吸收和骨转换。本发明还涉及用于提高受试者的骨矿物质密度以及预防或治疗受试者的骨相关病症的方法,所述方法包括向所述受试者施用有效量的反式克罗米芬或其类似物或盐。
Description
相关申请的交叉引用
本申请要求2013年6月5日提交的美国临时申请号61/831,542的权益,该美国临时申请的内容以引用的方式并入本文。
技术领域
本发明涉及用于抑制骨再吸收和骨转换的组合物和方法。确切地说,本发明涉及选择性雌激素受体调节剂反式克罗米芬(trans-clomiphene)或其类似物或盐用于在这一患者组中提高骨矿物质密度和治疗或预防骨质疏松症和/或骨质减少的用途。
背景技术
骨矿物质流失可以由多种病因引起,包括慢性病况,如库兴氏综合征(Cushing'ssyndrome)、高胱氨酸尿症、高钙尿症、以及高泌乳素血症。或者,骨矿物质流失还与女性和男性这两者的正常衰老过程和伴随的性腺功能丧失相关。骨质疏松症的特征在于骨矿物质密度的显著降低、骨组织的结构退化以及对骨折的易感性增强。在这种病况之前一般是骨质减少,所述骨质减少是由世界卫生组织(WorldHealthOrganization)定义为骨矿物质密度比平均30岁白种人女性的骨矿物质密度低至少一倍标准差的病况。在男性和女性这两者中,这些病症的频率随年龄而增加,对骨折,特别是髋部骨折的易感性也是如此。
在男性中,雄激素缺乏症与包括低骨质量在内的多种症状有关。实际上,在这一患者组中骨质减少、骨质疏松症的发病率是相对高的而有相应高的骨折率。睾酮在骨矿物质密度(BMD)中起主要作用;然而,睾酮替代对BMD的作用仍存在争议,多项研究表明睾酮替代对骨的作用与安慰剂没有显著差别(SnyderPJ等,JClinEndocrinolMetab.1999;84:1966-1972)。其它研究已经报道在睾酮替代疗法期间BMD略微增加,这被认为是由睾酮转化成雌二醇所引起的。
在药物研发过程中,本申请的发明人观测到使用分离的反式克罗米芬治疗男性伴随有CTX(I型胶原C末端交联端肽)的显著减少,所述CTX是公认的骨再吸收生物标志物,与BMD呈负相关,这大概是因为骨转换减少使得骨矿化的机会相应地提高(Meunier和Boivin,Bone21:373-377(1997))。因此,反式克罗米芬和它的三苯基亚烷基类似物提供了一类安全的并且有效的用于预防和治疗骨质疏松症和/或骨质减少的化合物。
发明内容
在多个实施方案中,本发明涉及用于抑制骨再吸收的方法,所述方法包括向受试者施用有效量的组合物,所述组合物包含反式克罗米芬、其类似物或其药学上可接受的盐,所述组合物优选地基本上不含顺式克罗米芬,所述量有效降低骨再吸收标志物的水平,所述标志物诸如I型胶原C末端交联端肽(CTX)。优选地,与在不存在治疗的情况下的血清水平相比(例如与基线水平相比),反式克罗米芬或其类似物或盐的量有效地使CTX的血清水平降低至少5%,更优选地至少10%,最优选地至少15%。所述受试者可以是人类男性或女性。在一个实施方案中,所述受试者是具有低的或低而正常的睾酮(例如低于约400ng/dl)的人类男性。在另一个实施方案中,所述受试者是继发性的性腺功能减退的人类男性。根据本发明使用的优选的反式克罗米芬类似物是(E)-4-OH-克罗米芬(图4)、(E)-4-OH-脱乙基克罗米芬(图5)以及(E)-4,4'-二-OH-克罗米芬(图6)。
在相关实施方案中,本发明涉及用于抑制骨转换的方法,所述方法包括向受试者施用有效量的组合物,所述组合物包含反式克罗米芬、其类似物或其药学上可接受的盐,所述组合物优选地基本上不含顺式克罗米芬,所述量(i)有效降低诸如CTX的骨再吸收标志物的水平;以及(ii)有效降低骨形成标志物的水平,如1型前胶原N末端延长肽(P1NP)。优选地,与在不存在治疗的情况下的血清水平相比,反式克罗米芬或其类似物或盐的量有效地使CTX的血清水平降低至少5%,更优选地至少10%,最优选地至少15%并且有效地使P1NP的血清水平降低至少15%,优选地至少20%,最优选地至少25%。所述受试者可以是人类男性或女性。在一个实施方案中,所述受试者是具有低的或低而正常的睾酮(例如低于约400ng/dl)的人类男性。在另一个实施方案中,所述受试者是继发性的性腺功能减退的人类男性。
本发明还涉及一种用于提高或维持受试者的骨矿物质密度的方法,所述方法包括向所述受试者施用有效量的组合物,所述组合物包含反式克罗米芬、其类似物或其药学上可接受的盐,所述组合物优选地基本上不含顺式克罗米芬,其中维持或提高了骨矿物质密度。优选地,与基线(即治疗前)水平相比,反式克罗米芬或其类似物或盐的量有效地将全髋BMD提高了至少1.2%。所述受试者可以是被诊断患有骨质减少或骨质疏松症或有患骨质减少或骨质疏松症风险的人类男性或女性。在一个优选的实施方案中,向患有骨质减少或骨质疏松症或有患骨质减少或骨质疏松症风险的人类男性施用组合物,所述组合物包含反式克罗米芬或其类似物或药学上可接受的盐,其中所述组合物基本上不含顺式克罗米芬,借此提高了所述男性的骨矿物质密度。在一个特别优选的实施方案中,所述人类男性还具有低的或低而正常的睾酮水平。在另一个优选的实施方案中,向具有正常睾酮水平(例如高于300ng/dl)的人类男性施用组合物,所述组合物包含反式克罗米芬或其类似物或药学上可接受的盐,其中所述组合物基本上不含顺式克罗米芬,借此维持了所述男性的骨矿物质密度。
本发明还提供了一种治疗受试者的骨相关病症的方法,所述方法包括向需要这种治疗的受试者施用组合物,所述组合物包含有效量的反式克罗米芬、其类似物或其药学上可接受的盐,所述量有效提高所述受试者的骨矿物质密度,所述组合物优选地基本上不含顺式克罗米芬。优选地,所述量有效地将髋部(全髋和/或股骨颈)处的BMD提高了至少1%。在一些实施方案中,有需要的受试者是具有骨质减少或骨质疏松症特征性BMD的人类并且以有效地将所述受试者的BMD提高到正常范围内的量和治疗时间段施用反式克罗米芬或其类似物或盐。
在其它相关实施方案中,本发明涉及用于预防和/或治疗有需要的受试者的骨质减少或骨质疏松症的方法,所述方法包括向所述受试者施用有效量的组合物,所述组合物包含反式克罗米芬、其类似物或其药学上可接受的盐,所述组合物优选地基本上不含顺式克罗米芬。所述受试者可以是被诊断患有骨质减少或骨质疏松症或有患骨质减少或骨质疏松症风险的人类男性或女性。在一个优选的实施方案中,向患有骨质减少或骨质疏松症或有患骨质减少或骨质疏松症风险的人类男性施用组合物,所述组合物包含反式克罗米芬或其类似物或药学上可接受的盐,其中所述组合物基本上不含顺式克罗米芬。在一个特别优选的实施方案中,所述人类男性具有低的或低而正常的睾酮水平(例如约400ng/dl或更低)。优选地,与基线(即治疗前)水平相比,反式克罗米芬或其类似物或盐的量有效地使CTX的血清水平降低了至少5%,优选地至少10%,更优选地至少15%和/或将全髋BMD提高了至少1.2%。
本发明还提供了一种用于监测受试者对反式克罗米芬的生理反应的方法,所述方法包括施用组合物,所述组合物包含反式克罗米芬或其类似物或盐;以及检测一种或多种骨再吸收标志物的水平,其中与治疗前水平或正常水平相比,所述患者群体的骨再吸收标志物的水平降低至少约5%、约10%、约15%或约20%或更多则表明所述治疗是有效的。所述方法可以二者择其一地或另外地包括检测一种或多种骨形成标志物的水平,其中与治疗前水平或正常水平相比,所述患者群体的骨形成标志物的水平降低至少约10%、约15%、约20%、约25%或约30%或更多则表明所述治疗是有效的。优选地,在开始治疗之前对一种或多种骨再吸收生物标志物和/或一种或多种骨形成生物标志物进行基线测量。在相关实施方案中,所述方法还包括调整反式克罗米芬或其类似物的剂量(例如如果骨再吸收的变化低于所需的变化,那么调整到更高的剂量以及如果骨再吸收的变化高于所需的变化,那么调整到更低的剂量)。
本发明还提供了一种联合疗法,其中将包含有效量的反式克罗米芬或其类似物或药学上可接受的盐的组合物与一种或多种另外的药剂相继、分别或同时共同施用。在一些实施方案中,将反式克罗米芬或其类似物或盐与被设计成进一步降低骨再吸收标志物的水平或提高骨形成标志物的水平的一种或多种药剂共同施用。在一个方面,向受试者施用反式克罗米芬或其类似物或盐以及抗再吸收药物。抗再吸收药物包括但不限于口服双膦酸盐,如阿仑膦酸盐(alendronate)(福善美(Fosamax))、利塞膦酸盐(risedronate)(安妥良(Actonel))以及伊班膦酸盐(ibandronate)(骨维壮(Boniva));以及可注射双膦酸盐,如唑来膦酸(zoledronicacid)(密固达(Reclast))。在其它方面,向受试者施用反式克罗米芬或其类似物或盐以及合成代谢药物。合成代谢药物包括但不限于通过注射施用的甲状旁腺激素(PTH),包括重组形式的PTH,如特立帕肽(teriparatide),所述特立帕肽包含人类甲状旁腺激素序列的氨基酸1-34(完整分子含有84个氨基酸)。
反式克罗米芬或其类似物或盐的优选剂量包括25mg至100mg、25mg至50mg、12.5mg至100mg、12.5mg至50mg、12.5mg至25mg、5mg至20mg、以及5mg至15mg的反式克罗米芬或其类似物或盐。优选地,每天或每隔一天施用反式克罗米芬一次,但是还可以定期,如每周一次、每两周一次或甚至每月一次施用。优选地,在定期施用反式克罗米芬之前,每天施用一次,持续足以实现治疗性睾酮水平的一段时间。
根据本文所述的方法,将反式克罗米芬或其类似物或盐施用足以实现所需结果的一段时间。在一个方面,将反式克罗米芬或其类似物或盐施用至少3个月、至少6个月、至少12个月或甚至至少2年、3年、4年或5年的治疗时间段。在本文所述的方法中的任一种中,与治疗前水平或正常水平相比,所述患者组的一种或多种骨再吸收标志物(例如CTX)的水平降低了约5%、10%、15%、20%、25%或更多,持续至少2周、至少3周、至少1个月、至少6周、至少3个月、至少6个月、至少一年或更长时间。在本文所述的方法中的任一种中,与治疗前水平或正常水平相比,所述患者组的一种或多种骨形成标志物(如P1NP)的水平降低了约10%、15%、20%、25%、30%或更多,持续至少2周、至少3周、至少1个月、至少6周、至少3个月、至少6个月、至少一年或更长时间。举例来说,与治疗前水平或正常水平相比,所述患者群体的骨再吸收标志物或骨形成标志物的水平到开始治疗后的3个月时降低了例如至少5%、至少10%、至少15%或至少20%。
附图说明
图1图示了AndroxalTM(反式克罗米芬)和对血清P1NP-1水平的作用。
图2图示了AndroxalTM(反式克罗米芬)和对血清CTX水平的作用。
图3图示了在使用AndroxalTM(反式克罗米芬)治疗6个月后全髋骨矿物质密度(BMD)的变化。
图4示出了(E)-4-OH-克罗米芬的化学结构。
图5示出了(E)-4-OH-DE-克罗米芬的化学结构。
图6示出了(E)-4,4'-二-OH-克罗米芬的化学结构。
具体实施方式
本发明至少部分地基于以下惊人的发现,即反式克罗米芬显著地降低骨再吸收的血清生物标志物,如CTX,并且降低骨形成的血清生物标志物,如P1NP。骨转换减少被证实与骨矿物质密度(BMD)增加相对应。克罗米芬被认为通过特异性刺激促性腺激素LH和FSH的分泌而在下丘脑-垂体轴水平上发挥它的作用。在男性中,促性腺激素增加与睾酮水平升高有关。继而是雌激素水平的相应升高,这是因为一定量的睾酮被芳构化。雌激素对骨矿物质密度(BMD)的作用是公认的;雄激素对BMD的作用仍存在争议。惊人的是,反式克罗米芬似乎经由与睾酮不同的机制抑制骨转换,这是因为施用外源性睾酮对骨形成标志物的水平没有影响,而在使用反式克罗米芬治疗后观测到同一种标志物的显著减少。反式克罗米芬抑制骨再吸收和骨转换的活性与BMD的增加有关并且因此使得本发明的组合物可用于治疗多种骨相关病症。
在多个实施方案中,本发明提供了用于抑制受试者的骨再吸收的方法,所述方法是通过施用有效量的组合物来实现的,所述量有效降低一种或多种骨再吸收生物标志物,如CTX的血清水平,所述组合物包含一定量的反式克罗米芬或其三苯基亚烷基类似物或盐。优选地,所述组合物基本上不含顺式异构体并且包含选自(E)-4-OH-克罗米芬(图4)和(E)-4-OH-脱乙基-克罗米芬(图5)的反式克罗米芬或代谢物。所述受试者可以是人类男性或女性。
可以测量指示骨再吸收的生物标志物水平以衡量受试者对反式克罗米芬或其类似物或盐的生理反应。这些标志物包括但不限于1型胶原C末端端肽(CTX)、1型胶原N末端端肽(NTX)、脱氧吡啶啉(DPD)、吡啶啉、尿羟脯氨酸、半乳糖基羟赖氨酸、以及抗酒石酸酸性磷酸酶。优选地,测量CTX的血清水平。反式克罗米芬(或其类似物或盐)的量优选地有效地使一种或多种骨再吸收标志物(如CTX)的水平与在施用反式克罗米芬(或其类似物或盐)之前骨再吸收标志物的水平相比降低至少约5%、约10%、约15%、约20%或更多。
在其它实施方案中,本发明提供了用于抑制受试者的骨转换的方法,所述方法是通过施用有效量的组合物来实现的,所述量(i)有效降低一种或多种骨再吸收生物标志物,如CTX的血清水平;以及(ii)有效降低一种或多种骨形成生物标志物,如1型前胶原N末端延长肽(P1NP)的血清水平,所述组合物包含一定量的反式克罗米芬或其类似物或盐。优选地,所述组合物包含反式克罗米芬并且基本上不含顺式异构体。P1NP是由成骨细胞产生的并且度量了骨形成,其中更低的P1NP水平表明更低的骨转换。骨转换减少似乎允许整个身体内骨矿化的机会增加(Meunier和Boivin,Bone21:373-377(1997))以及骨折的风险减小。
可以测量指示骨形成的生物标志物水平以衡量受试者对反式克罗米芬或其类似物或盐的反应。这些标志物包括但不限于P1NP、骨特异性碱性磷酸酶(BSAP)以及骨钙素(OstCa)。优选地,测量P1NP的血清水平。反式克罗米芬(或其类似物或盐)的量优选地有效地使一种或多种骨形成标志物(如P1NP)的水平与在施用反式克罗米芬(或其类似物或盐)之前骨形成标志物的水平相比降低至少约10%、约15%、约20%、约25%、约30%或更多。
在其它方面,本发明提供了一种用于提高受试者的骨矿物质密度(BMD)的方法,所述方法包括向所述受试者施用有效提高所述受试者的BMD的量的组合物,所述组合物包含反式克罗米芬或其类似物或盐。在相关实施方案中,所述量有效降低骨再吸收标志物的水平并且任选地还降低骨形成标志物的水平。优选地,所述组合物基本上不含顺式异构体并且包含反式克罗米芬。BMD可以被测量为“全身”(头、躯干、手臂以及腿)BMD或髋部(例如全髋和/或股骨颈)、脊椎、腕部、手指、胫骨和/或脚跟处的BMD,但是优选地被测量为髋部BMD。BMD通常与30岁健康成人的峰值密度相比较,从而产生所谓的“T分数”。受试者的BMD分数还可以与年龄匹配的骨密度相比较。受试者的BMD与健康年轻成人的BMD之间的差异在常规上是用“标准差”的倍数来提及的,所述标准差通常等于骨密度降低约10%至约12%。与年轻成人参考平均值相差1倍标准差以内的BMD值(至少-1的T分数)是“正常的”。骨质减少是由低于年轻成人平均值超过1倍标准差,但是少于2倍标准差的BMD值(T分数是-1至-2.5)来指示的。低于标准超过2.5倍标准差的t分数指示骨质疏松症的诊断。(世界卫生组织骨质疏松症预防和管理科学组(WorldHealthOrganizationScientificGrouponthePreventionandManagementofOsteoporosis),WHO技术报告系列(WHOTechnicalReportSeries);921,瑞士的日内瓦(Geneva,Switzerland)(2000))。可以向受试者施用本发明的组合物以提高BMD而与受试者的T分数无关。优选地,与治疗前测量结果相比,反式克罗米芬或其类似物或盐的量有效地将髋部BMD提高至少约1%,更优选地至少约1.2%。BMD的这种增加可以对应于在同一个治疗时间段内与同一个患者群体中未经过治疗的受试者相比增加了至少约1.5%、约1.6%或约1.75%或更多。
在临床上可以使用例如双能X射线吸收测定术(DXA),例如对髋部来测定人类受试者的BMD。其它合适的技术包括但不限于超声波检查法、单能X射线吸收测定术(SXA)以及定量计算机断层摄影术(OCT)。可以测量中轴骨骼部位,如脊椎和髋部和/或可以测量外周部位,如前臂、手指、腕部或脚跟。这些技术涉及将所获得的结果与一种或多种规范数据库比较。
在其它实施方案中,本发明提供了一种用于预防或治疗受试者的骨相关病症的方法,所述方法是通过施用有效预防或治疗所述病症的量的组合物来实现的,所述组合物包含一定量的反式克罗米芬或其类似物或盐。在一个方面,向患有选自由以下各项组成的组的骨相关病症的人类受试者施用所述组合物:软骨发育不全、锁骨颅骨发育不全、软骨发育异常、纤维异常增殖症、高雪氏病(Gaucher'sDisease)、低磷血症性佝偻病、马凡氏综合征(Marfan'ssyndrome)、多发性遗传性外生骨疣、神经纤维瘤病、成骨不全症、骨硬化病、脆弱性骨硬化、硬化损伤、假关节形成、化脓性骨髓炎、牙周病、抗癫痫药物诱发的骨质流失、原发性和继发性甲状旁腺功能亢进症、家族性甲状旁腺功能亢进综合征、失重诱发的骨质流失、男性骨质疏松症、经绝后骨质流失、骨关节炎、肾性骨营养不良、骨浸润性病症、口腔骨质流失、颚骨坏死、青少年佩吉特氏病(juvenilePaget'sdisease)、肢骨纹状肥大、代谢性骨病、肥大细胞增多症、镰状细胞性贫血/疾病、器官移植相关的骨质流失、肾脏移植相关的骨质流失、全身性红斑狼疮、强直性脊柱炎、癫痫症、青少年关节炎性皮疹、地中海贫血、粘多糖贮积症、法布里病(FabryDisease)、特纳综合征(TurnerSyndrome)、唐氏综合征(DownSyndrome)、克氏综合征(KlinefelterSyndrome)、麻风病、佩氏病(Perthe'sDisease)、青少年特发性脊柱侧凸、婴儿期发病的多系统炎症性疾病、温彻斯特综合征(WinchesterSyndrome)、门克斯病(MenkesDisease)、威尔逊氏病(Wilson'sDisease)、缺血性骨病(如累-卡-佩三氏病(Legg-Calve-Perthesdisease)和局限性移行性骨质疏松症)、贫血状态、由类固醇所引起的病况、糖皮质激素诱发的骨质流失、肝素诱发的骨质流失、骨髓病症、坏血病、营养不良、钙缺乏症、骨质疏松症、骨质减少、酒精中毒、慢性肝病、经绝后状态、慢性炎症性病况、类风湿性关节炎、炎症性肠病、溃疡性结肠炎、炎症性结肠炎、克罗恩氏病(Crohn'sdisease)、月经过少、闭经、妊娠、糖尿病、甲状腺功能亢进症、甲状腺病症、甲状旁腺病症、库兴氏病、肢端肥大症、性腺功能减退、制动状态或废用、反射性交感神经营养不良综合征、局限性骨质疏松症、骨软化症、与关节置换相关的骨质流失、HIV相关的骨质流失、与生长激素丧失相关的骨质流失、与囊性纤维化相关的骨质流失、化学疗法相关的骨质流失、肿瘤诱发的骨质流失、癌症相关的骨质流失、激素消融性骨质流失、多发性骨髓瘤、药物诱发的骨质流失、神经性厌食症、疾病相关的面部骨质流失、疾病相关的颅骨骨质流失、疾病相关的颚骨骨质流失、疾病相关的头骨骨质流失、与衰老相关的骨质流失、与衰老相关的面部骨质流失、与衰老相关的颅骨骨质流失、与衰老相关的颚骨骨质流失、以及与衰老相关的头骨骨质流失。在优选的实施方案中,向人类施用所述组合物以治疗或预防骨质疏松症或骨质减少。在相关实施方案中,所述人类是具有低的或低而正常的睾酮的人类男性,如继发性的性腺功能减退的男性。在相关方面,与在不存在治疗的情况下的血清水平相比,反式克罗米芬或其类似物或盐的量有效地使骨再吸收标志物(如CTX)的水平降低至少5%,更优选地至少10%,最优选地至少15%。
应当了解的是,本发明的方法不需要治愈患有骨相关病症的受试者或完全防止骨相关病症的发病以实现治疗上有益的反应。可以预防性地使用所述方法,意图是完全或部分防止骨相关病症或其症状。还可以治疗性地使用所述方法以完全或部分缓解骨相关病症或其症状,或者完全或部分防止骨相关病症或症状的进一步进展。本发明的方法可用于随时间推移提高BMD以及维持升高的BMD并且因此特别可用于预防骨质减少的发病、预防骨质减少向骨质疏松症进展以及治疗骨质减少和骨质疏松症。
代表了克罗米芬类似物的三苯基亚烷基衍生物的家族在此被定义为包括所有未修饰的反式形式、以及反式克罗米芬的4-羟基化类似物、N-脱烷基化类似物以及4-羟基-N-脱烷基化类似物中的每一种、以及具有基本上相似的结构的所有其它分子。反式克罗米芬的类似物,如Ernst等,J.Pharmaceut.Sci.65:148(1976)中所述的那些和本文所述的代谢物也可用于实施本发明。
在一些实施方案中,需要通过本发明的方法中的任一种加以治疗的受试者是继发性的性腺功能减退的男性。在相关实施方案中,需要通过本发明的方法中的任一种加以治疗的受试者是具有以下身体质量指数的人类男性:至少20、至少21、至少22、至少23、至少24、至少25、至少26、至少27、至少28、至少29、至少30、至少31或至少32。举例来说,需要治疗的受试者可以是具有至少25的身体质量指数的人类男性。
在相关实施方案中,需要通过本发明的方法中的任一种加以治疗的受试者是患有2型糖尿病的人类男性或女性,在这种情况下,优先施用本发明的组合物作为被设计成降低骨折风险的给药方案的一部分。在一个实施方案中,所述受试者是患有2型糖尿病的人类男性并且将反式克罗米芬或其类似物或盐与二甲双胍(metformin)、苯乙双胍(phenformin)或丁福明(buformin)相继或同时向所述受试者共同施用。
在一个优选的实施方案中,本发明的组合物包含可以在1mg至200mg或5mg至100mg范围内的剂量的反式克罗米芬或其盐,如反式克罗米芬柠檬酸盐。反式克罗米芬的剂量还可以是5mg至10mg、5mg至12.5mg、5mg至15mg、5mg至20mg、10mg至15mg、10mg至20mg、12.5mg至25mg、12.5mg至50mg、或25mg至50mg。反式克罗米芬的剂量还可以是12.5mg、25mg或50mg。
在一个实施方案中,本发明的组合物包含反式克罗米芬或其类似物的一种或多种药学上可接受的盐。根据工艺条件,所获得的盐化合物可以呈中性形式或盐形式。盐形式包括水合物和其它溶剂化物以及结晶多晶型物。可以根据本发明使用这些最终产物的游离碱和盐这两者。
可以使用诸如碱之类的碱性试剂或通过离子交换将酸加成盐转化成游离碱。所获得的游离碱还可以与有机酸或无机酸形成盐。
在制备酸加成盐时,优选地使用这样的酸,所述酸适当地形成药学上可接受的盐。这些酸的实例是盐酸、硫酸、磷酸、硝酸、脂族酸、脂环族羧酸或磺酸,如甲酸、乙酸、丙酸、丁二酸、乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、反丁烯二酸、顺丁烯二酸、羟基顺丁烯二酸、丙酮酸、天冬氨酸、谷氨酸、对羟基苯甲酸、双羟萘酸、乙磺酸、羟基乙磺酸、苯乙酸、扁桃酸、卤代苯磺酸、甲苯磺酸、半乳糖二酸、半乳糖醛酸或萘磺酸。可以根据本发明使用所有晶形多晶型物。优选的盐是柠檬酸盐。
还可以根据本发明使用碱加成盐并且所述碱加成盐可以通过以常规方式使游离酸形式与足量的所需碱接触而产生盐来制备。所述游离酸形式可以通过以常规的方式使所述盐形式与酸接触并且分离所述游离酸而再生。药学上可接受的碱加成盐是使用金属或胺,如碱金属和碱土金属或有机胺而形成的。用作阳离子的金属的实例是钠、钾、钙、镁等。合适的胺的实例是氨基酸(如赖氨酸)、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺等。
本发明的组合物可以适用于口服、肠胃外、透皮、经直肠、经粘膜、或局部施用的一种或多种剂量单位的形式被制备。肠胃外施用包括但不限于静脉内、动脉内、腹膜内、皮下、肌内、鞘内以及关节内施用。优选地,本发明的组合物以适用于口服施用的形式被制备。
术语“口服施用”或“可口服递送”在本文包括任何形式的向受试者递送治疗剂或其组合物,其中将所述药剂或组合物放在所述受试者的口中,无论所述药剂或组合物是否被吞咽。因此,“口服施用”包括颊面施用和舌下施用以及食道(例如吸入)施用。
在再另一个实施方案中,本发明的组合物被配制成直肠栓剂,所述直肠栓剂可以含有栓剂基质,包括但不限于可可油或甘油酯。
本发明的组合物还可以被配制用于吸入,它们可以呈包括但不限于溶液、混悬液或乳液的形式,所述形式可以干粉形式或以气溶胶形式,使用推进剂,如二氯氟甲烷或三氯氟甲烷来施用。
本发明的组合物还可以被配制成例如乳膏剂、软膏剂、洗剂、糊剂、凝胶剂、含药药膏、贴剂或膜以用于透皮递送。这样的组合物可以包含任何合适的赋形剂,例如渗透增强剂等。
本发明的组合物还可以被配制用于肠胃外施用,包括但不限于通过注射或连续输注来施用。用于注射的制剂可以呈于油性或水性媒介物中的混悬液、溶液或乳液的形式。这样的组合物还可以使用合适的媒介物复原的粉末形式提供,所述媒介物包括但不限于无菌无热原水、WFI等。
本发明的组合物还可以被配制成贮库制剂,所述贮库制剂可以通过植入或通过肌内注射来施用。这样的组合物可以使用合适的聚合材料或疏水性材料(被配制成例如于可接受的油中的乳液)、离子交换树脂来配制、或被配制成微溶衍生物(被配制成例如微溶盐)。
本发明的组合物还可以被配制成脂质体制剂。脂质体制剂可以包含脂质体,所述脂质体渗透所关注的细胞或角质层并且与细胞膜融合,从而使得脂质体的内含物被递送到所述细胞中。举例来说,可以使用诸如Yarosh的美国专利号5,077,211、Redziniak等的美国专利号4,621,023、或Redziniak等的美国专利号4,508,703中所述的那些脂质体的脂质体。
本发明的组合物可以呈固体剂量单位的形式,所述固体剂量单位诸如片剂(例如混悬片剂、咬食混悬片剂、快速分散片剂、咀嚼片剂、泡腾片剂、双层片剂等)、囊片、胶囊(例如软明胶胶囊或硬明胶胶囊)、粉剂(例如包装的粉剂、可分配粉剂或泡腾粉剂)、糖锭、小药囊、扁囊剂、糖衣锭、丸剂、颗粒剂、微颗粒剂、封装微颗粒剂、粉末气溶胶制剂、或合理地适用于施用的任何其它固体剂型。优选的剂型是软明胶胶囊或硬明胶胶囊。另一种优选的剂型是片剂。
片剂可以根据许多相关的公知的药学技术中的任一种来制备。在一个实施方案中,片剂或其它固体剂型可以通过如下的工艺来制备,所述工艺利用包括但不限于以下各项的方法中的一种或组合:(1)干混;(2)直接压制;(3)研磨;(4)干法或非水性造粒;(5)湿法造粒;或(6)熔合。
片剂制备的湿法造粒工艺中的单个步骤通常包括研磨和筛分成分、干粉混合、湿法块化、造粒以及最终研磨。干法造粒包括在重型旋转式压片机上将粉末混合物压制成粗制片剂或“坯料”。然后通过研磨操作,通常通过穿过摇摆式造粒机将所述坯料分解成粒状颗粒。单个步骤包括将粉末混合、压制(击压)以及研磨(坯料减小或造粒)。通常,在所述步骤中的任一个中不包括湿粘结剂或水分。
在另一个实施方案中,固体剂型可以通过将抗雌激素药与一种或多种药物赋形剂混合以形成基本上均相的预制剂共混物来制备。然后可以将预制剂共混物细分并且任选地进一步加工(例如压制、封装、包装、分散等)成任何所需的剂型。
压制片剂可以通过压实本发明的粉末或造粒组合物来制备。术语“压制片剂”一般指的是适用于口服摄取、通过单次压制或通过预压振实,继而进行最终压制来制备的无包衣素片。本发明的片剂可以被包覆或以其它方式被配混以提供赋予改进的处理或储存特征的优势的剂型。在一个实施方案中,任何这样的包衣将被选择以使得在向受试者施用后基本上不会延迟本发明的组合物的治疗作用的起效。如本文所用的术语“混悬片剂”指的是在被放置在水中后快速崩解的压制片剂。
本发明的组合物的合适的液体剂型包括溶液、水性或油性混悬液、酏剂、糖浆、乳液、液体气溶胶制剂、凝胶剂、乳膏剂、软膏剂等。这些组合物还可以被配制成在使用前用水或其它合适的媒介物复原的干燥产品。
在一个实施方案中,在被维持在室温、冷藏(例如约5℃-10℃)温度或冷冻温度的封闭容器中储存约1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、或12个月的时间段之后,液体或半固体组合物表现出其中所存在的原始抗雌激素化合物的至少约90%、至少约92.5%、至少约95%、或至少约97.5%。
如果需要的话,本发明的组合物可以包括一种或多种药学上可接受的赋形剂。术语“赋形剂”在本文意指本身并非治疗剂的任何物质,所述物质用作用于向受试者递送治疗剂的载体或媒介物或被添加到药物组合物中以改进它的处理或储存特性或容许或有助于组合物的单位剂量的形成。赋形剂以说明而非限制的方式包括稀释剂、崩解剂、粘结剂、粘合剂、湿润剂、润滑剂、助流剂、表面改性剂或表面活性剂、香料、助悬剂、乳化剂、非水性媒介物、防腐剂、抗氧化剂、粘合剂、调节pH值和渗透压的试剂(例如缓冲剂)、防腐剂、增稠剂、甜味剂、调味剂、掩味剂、着色剂或染料、渗透增强剂以及被添加以改进组合物的外观的物质。
任选地被用于本发明的组合物中的赋形剂可以是固体、半固体、液体或其组合。含有赋形剂的本发明的组合物可以通过任何已知的药学技术来制备,所述技术包括将赋形剂与药物或治疗剂混合。
本发明的组合物任选地包含一种或多种药学上可接受的稀释剂作为赋形剂。合适的稀释剂以说明方式包括单独的以下各项或以下各项的组合:乳糖,包括无水乳糖和乳糖一水合物;淀粉,包括可直接压缩淀粉和水解淀粉(例如CelutabTM和EmdexTM);甘露醇;山梨糖醇;木糖醇;右旋糖(例如CereloseTM2000)和右旋糖一水合物;磷酸氢钙二水合物;基于蔗糖的稀释剂;糖粉;硫酸钙一水合物;硫酸钙二水合物;颗粒状乳酸钙三水合物;葡萄糖结合剂;肌醇;水解谷物固体;直链淀粉;纤维素,包括微晶纤维素、α-纤维素和无定形纤维素(例如RexcelTM)的食品级来源以及粉状纤维素;碳酸钙;甘氨酸;膨润土;聚乙烯吡咯烷酮;等。这些稀释剂如果存在的话占所述组合物的总重量的总共约5%至约99%、约10%至约85%、或约20%至约80%。所选择的任何一种或多种稀释剂优选地表现出合适的流动特性以及在需要片剂的情况下表现出可压缩性。
可以通过使用颗粒外微晶纤维素(即在干燥步骤后被添加到湿造粒组合物中的微晶纤维素)来改进硬度(对于片剂)和/或崩解时间。
本发明的组合物任选地包含一种或多种药学上可接受的崩解剂作为赋形剂,特别是对于片剂、胶囊或其它固体制剂来说。合适的崩解剂包括单独的以下各项或以下各项的组合:淀粉,包括羟基乙酸淀粉钠(例如PenWest公司的ExplotabTM)和预胶凝化玉米淀粉(例如NationalTM1551、NationalTM1550以及ColocornTM1500);粘土(例如VeegumTMHV);纤维素,如纯化纤维素、微晶纤维素、甲基纤维素、羧甲基纤维素以及羧甲基纤维素钠、交联羧甲基纤维素钠(例如FMC公司的Ac-Di-SolTM);藻酸盐;交联聚乙烯吡咯烷酮;以及树胶,如琼脂、瓜尔胶、黄原胶、刺槐豆胶、刺梧桐胶、果胶以及黄蓍胶。
可以在制备组合物期间在任何合适的步骤时,特别是在造粒步骤之前或在压制前在润滑步骤期间添加崩解剂。这些崩解剂如果存在的话占所述组合物的总重量的总共约0.2%至约30%、约0.2%至约10%、或约0.2%至约5%。
本发明的组合物任选地包含一种或多种药学上可接受的粘结剂或粘合剂作为赋形剂,特别是对于片剂制剂来说。这些粘结剂和粘合剂优选地赋予正被制片的粉末以足够的粘聚力以允许正常的加工操作,如筛分、润滑、压制以及包装,但仍允许在摄取后片剂崩解并且组合物被吸收。合适的粘结剂和粘合剂包括单独的以下各项或以下各项的组合:阿拉伯胶;黄蓍胶;蔗糖;明胶;葡萄糖;淀粉,诸如但不限于预胶凝化淀粉(例如NationalTM1511和NationalTM1500);纤维素,诸如但不限于甲基纤维素和羧甲基纤维素钠(例如TyloseTM);藻酸和藻酸盐;硅酸镁铝;PEG;瓜尔胶;多糖酸;膨润土;聚维酮,例如聚维酮K-15、K-30以及K-29/32;聚甲基丙烯酸酯;HPMC;羟丙基纤维素(例如KlucelTM);以及乙基纤维素(例如EthocelTM)。这些粘结剂和/或粘合剂如果存在的话占所述组合物的总重量的总共约0.5%至约25%、约0.75%至约15%、或约1%至约10%。
本发明的组合物任选地包含一种或多种药学上可接受的湿润剂作为赋形剂。可以用作本发明的组合物中的湿润剂的表面活性剂的非限制性实例包括季铵化合物,例如苯扎氯铵、苄索氯铵以及氯化十六烷基吡啶;磺基丁二酸二辛酯钠;聚氧乙烯烷基苯基醚,例如壬苯醇醚9、壬苯醇醚10以及辛苯聚醇9;泊洛沙姆(聚氧乙烯和聚氧丙烯嵌段共聚物);聚氧乙烯脂肪酸甘油酯和油,例如聚氧乙烯(8)辛酸/癸酸甘油一酯和甘油二酯(例如嘉法狮公司(Gattefossé)的LabrasolTM)、聚氧乙烯(35)蓖麻油以及聚氧乙烯(40)氢化蓖麻油;聚氧乙烯烷基醚,例如聚氧乙烯(20)鲸蜡硬脂醚;聚氧乙烯脂肪酸酯,例如聚氧乙烯(40)硬脂酸酯;聚氧乙烯脱水山梨糖醇酯,例如聚山梨醇酯20和聚山梨醇酯80(例如ICI公司的TweenTM80);丙二醇脂肪酸酯,例如丙二醇月桂酸酯(例如嘉法狮公司的LauroglycolTM);十二烷基硫酸钠;脂肪酸和其盐,例如油酸、油酸钠以及油酸三乙醇胺酯;脂肪酸甘油酯,例如单硬脂酸甘油酯;脱水山梨糖醇酯,例如脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯以及脱水山梨糖醇单硬脂酸酯;泰洛沙泊(tyloxapol);以及其混合物。这些湿润剂如果存在的话占所述组合物的总重量的总共约0.25%至约15%、约0.4%至约10%、或约0.5%至约5%。
本发明的组合物任选地包含一种或多种药学上可接受的润滑剂(包括抗粘剂和/或助流剂)作为赋形剂。合适的润滑剂包括单独的以下各项或以下各项的组合:山嵛酸甘油酯(例如CompritolTM888);硬脂酸和其盐,包括硬脂酸镁、硬脂酸钙以及硬脂酸钠;氢化植物油(例如SterotexTM);胶态二氧化硅;滑石粉;蜡;硼酸;苯甲酸钠;乙酸钠;反丁烯二酸钠;氯化钠;DL-亮氨酸;PEG(例如CarbowaxTM4000和CarbowaxTM6000);油酸钠;十二烷基硫酸钠;以及十二烷基硫酸镁。这些润滑剂如果存在的话占所述组合物的总重量的总共约0.1%至约10%、约0.2%至约8%、或约0.25%至约5%。
合适的抗粘剂包括滑石粉、玉米淀粉、DL-亮氨酸、十二烷基硫酸钠以及金属硬脂酸盐。滑石粉是所使用的抗粘剂或助流剂以例如减少粘到设备表面上的制剂以及减少共混物中的静电。一种或多种抗粘剂如果存在的话占所述组合物的总重量的约0.1%至约10%、约0.25%至约5%、或约0.5%至约2%。
可以使用助流剂来促进固体制剂的粉末流动。合适的助流剂包括胶态二氧化硅、淀粉、滑石粉、磷酸三钙、粉状纤维素以及三硅酸镁。胶态二氧化硅是特别优选的。
本发明的组合物可以包含一种或多种消泡剂。二甲基硅油是说明性消泡剂。消泡剂如果存在的话占所述组合物的总重量的约0.001%至约5%、约0.001%至约2%、或约0.001%至约1%。
用于本发明中的说明性抗氧化剂包括但不限于丁基化羟基甲苯、丁基化羟基苯甲醚、偏亚硫酸氢钾等。如果需要的话,一种或多种抗氧化剂通常以如下量存在于本发明的组合物中:约0.01重量%至约2.5重量%,例如约0.01重量%、约0.05重量%、约0.1重量%、约0.5重量%、约1重量%、约1.5重量%、约1.75重量%、约2重量%、约2.25重量%、或约2.5重量%。
在各种实施方案中,本发明的组合物可以包含防腐剂。合适的防腐剂包括但不限于苯扎氯铵、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯或对羟基苯甲酸丁酯、苯甲醇、苯乙醇、苄索氯铵、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯以及山梨酸或其组合。通常,任选的防腐剂以约0.01重量%至约0.5重量%或约0.01重量%至约2.5重量%的量存在。
在一个实施方案中,本发明的组合物任选地包含缓冲剂。缓冲剂包括减小pH值变化的试剂。用于本发明的各种实施方案中的缓冲剂的说明性类别包含第IA族金属的盐,包括例如第IA族金属的碳酸氢盐、第IA族金属的碳酸盐、碱金属或碱土金属缓冲剂、铝缓冲剂、钙缓冲剂、钠缓冲剂、或镁缓冲剂。合适的缓冲剂包括前述物质中的任一种的碳酸盐、磷酸盐、碳酸氢盐、柠檬酸盐、硼酸盐、乙酸盐、邻苯二甲酸盐、酒石酸盐、丁二酸盐,例如钠或钾的磷酸盐、柠檬酸盐、硼酸盐、乙酸盐、碳酸氢盐以及碳酸盐。
合适的缓冲剂的非限制性实例包括氢氧化铝、氢氧化镁、甘氨酸铝、乙酸钙、碳酸氢钙、硼酸钙、碳酸钙、柠檬酸钙、葡萄糖酸钙、甘油磷酸钙、氢氧化钙、乳酸钙、邻苯二甲酸钙、磷酸钙、丁二酸钙、酒石酸钙、磷酸氢二钠、磷酸氢二钾、磷酸二钾、磷酸氢二钠、丁二酸二钠、干氢氧化铝凝胶、乙酸镁、铝酸镁、硼酸镁、碳酸氢镁、碳酸镁、柠檬酸镁、葡萄糖酸镁、氢氧化镁、乳酸镁、偏硅酸铝酸镁、氧化镁、邻苯二甲酸镁、磷酸镁、硅酸镁、丁二酸镁、酒石酸镁、乙酸钾、碳酸钾、碳酸氢钾、硼酸钾、柠檬酸钾、偏磷酸钾、邻苯二甲酸钾、磷酸钾、聚磷酸钾、焦磷酸钾、丁二酸钾、酒石酸钾、乙酸钠、碳酸氢钠、硼酸钠、碳酸钠、柠檬酸钠、葡萄糖酸钠、磷酸氢二钠、氢氧化钠、乳酸钠、邻苯二甲酸钠、磷酸钠、聚磷酸钠、焦磷酸钠、倍半碳酸钠、丁二酸钠、酒石酸钠、三聚磷酸钠、合成水滑石、焦磷酸四钾、焦磷酸四钠、磷酸三钾、磷酸三钠、以及氨丁三醇。(部分地基于默克索引(TheMerckIndex),新泽西州拉威的默克公司(Merck&Co.Rahway,N.J.)(2001)中所提供的清单)。此外,在本文所述的药物组合物中可以使用上述缓冲剂中的任何两种或更多种的组合或混合物。如果需要的话,一种或多种缓冲剂以约0.01重量%至约5重量%或约0.01重量%至约3重量%的量存在于本发明的组合物中。
在各种实施方案中,本发明的组合物可以包括增加粘度的一种或多种试剂。增加粘度的说明性试剂包括但不限于甲基纤维素、羧甲基纤维素钠、乙基纤维素、角叉菜胶、卡波姆和/或其组合。通常,如果需要的话,一种或多种增粘剂以约0.1重量%至约10重量%或约0.1重量%至约5重量%的量存在于本发明的组合物中。
在各种实施方案中,本发明的组合物包含“感官剂”以改进组合物的感官特性。术语“感官剂”在本文指的是可以改进本发明的组合物的口味或气味或有助于掩蔽本发明的组合物的令人不快的口味或气味的任何赋形剂。这些试剂包括甜味剂、调味剂和/或掩味剂。合适的甜味剂和/或调味剂包括为药物组合物加甜或提供风味的任何试剂。任选的感官剂通常以约0.1mg/ml至约10mg/ml、约0.5mg/ml至5mg/ml或约1mg/ml的量存在于本发明的组合物中。
说明性甜味剂或调味剂包括但不限于阿拉伯胶糖浆、大茴香脑、大茴香油、芳香酏剂、苯甲醛、苯甲醛酏剂、环糊精、葛缕子、葛缕子油、小豆蔻油、小豆蔻籽、小豆蔻醑、小豆蔻酊、樱桃汁、樱桃糖浆、肉桂、肉桂油、肉桂水、柠檬酸、柠檬酸糖浆、丁香油、可可、可可糖浆、芫荽油、右旋糖、圣草、圣草流浸膏、芳香圣草糖浆、乙酸乙酯、乙基香兰素、小茴香油、姜、姜流浸膏、姜油树脂、右旋糖、葡萄糖、糖、麦芽糊精、甘油、甘草、甘草酏剂、甘草提取物、纯甘草提取物、甘草流浸膏、甘草糖浆、蜂蜜、等醇酏剂、熏衣草油、柠檬油、柠檬酊、甘露醇、水杨酸甲酯、肉豆蔻油、苦橙酏剂、苦橙油、橙花油、橙花水、橙油、苦橙皮、甜橙皮酊、橙醑、橙糖浆、胡椒薄荷、胡椒薄荷油、胡椒薄荷醑、胡椒薄荷水、苯乙醇、覆盆子汁、覆盆子糖浆、迷迭香油、玫瑰油、浓玫瑰水、糖精、糖精钙、糖精钠、菝葜糖浆、菝葜山梨糖醇溶液、绿薄荷、绿薄荷油、蔗糖、蔗糖素、糖浆、百里香油、吐鲁香脂、吐鲁香脂糖浆、香草、香草酊、香兰素、野樱桃糖浆或其组合。
说明性掩味剂包括但不限于环糊精、环糊精乳液、环糊精颗粒、环糊精复合物或其组合。
说明性助悬剂包括但不限于山梨糖醇糖浆、甲基纤维素、葡萄糖/糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶、以及氢化食用脂肪。
说明性乳化剂包括但不限于卵磷脂、脱水山梨糖醇单油酸酯以及阿拉伯胶。非水性媒介物包括但不限于食用油、杏仁油、分馏的椰子油、油酯、丙二醇、以及乙醇。
上述赋形剂可以具有如本领域已知的多种作用。举例来说,淀粉可以用作填充剂以及崩解剂。上述赋形剂的分类不应当以任何方式被视为具有限制性。
本发明的组合物可以任何方式被施用,所述方式包括但不限于口服、肠胃外、舌下、透皮、经直肠、经粘膜、局部、经由吸入、经由颊面施用、或其组合。肠胃外施用包括但不限于静脉内施用、动脉内施用、腹膜内施用、皮下施用、肌内施用、鞘内施用、关节内施用、脑池内施用以及心室内施用。
对于在治疗中使用来说所需的组合物的治疗有效量随需要活性的时间长度以及欲治疗的患者的年龄和病况以及其它因素而变,并且最终由主治医生决定。然而,一般来说,用于人类治疗的剂量通常在每天约0.001mg/kg至约500mg/kg的范围内,例如每天约1μg/kg至约1mg/kg或每天约1μg/kg至约100μg/kg。对于大多数的哺乳动物来说,总日剂量是约1mg至100mg,优选地约2mg至80mg。可以对给药方案进行调整以提供最佳的治疗反应。所需的剂量可以便利地以单次剂量或以适当的时间间隔施用的多次剂量,例如以每天两次、三次、四次或更多次亚剂量施用。
作为说明,可以如下量向受试者施用本发明的组合物以向受试者提供抗雌激素药:每公斤体重约1μg至约1mg,例如每公斤体重约1μg、每公斤体重约25μg、每公斤体重约50μg、每公斤体重约75μg、每公斤体重约100μg、每公斤体重约125μg、每公斤体重约150μg、每公斤体重约175μg、每公斤体重约200μg、每公斤体重约225μg、每公斤体重约250μg、每公斤体重约275μg、每公斤体重约300μg、每公斤体重约325μg、每公斤体重约350μg、每公斤体重约375μg、每公斤体重约400μg、每公斤体重约425μg、每公斤体重约450μg、每公斤体重约475μg、每公斤体重约500μg、每公斤体重约525μg、每公斤体重约550μg、每公斤体重约575μg、每公斤体重约600μg、每公斤体重约625μg、每公斤体重约650μg、每公斤体重约675μg、每公斤体重约700μg、每公斤体重约725μg、每公斤体重约750μg、每公斤体重约775μg、每公斤体重约800μg、每公斤体重约825μg、每公斤体重约850μg、每公斤体重约875μg、每公斤体重约900μg、每公斤体重约925μg、每公斤体重约950μg、每公斤体重约975μg、或每公斤体重约1mg。
在一个优选的实施方案中,根据本发明的组合物包含1mg至约200mg的剂量的反式克罗米芬(尽管对最佳剂量的确定是在本领域的普通技术人员的水平范围内)。所述组合物可以包含以下剂量的反式克罗米芬:约1mg、2mg、3mg、4mg、5mg、10mg、12mg、12.5mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg或它们之间的剂量。所述组合物优选地基本上不含顺式克罗米芬并且可以包含0%w/w的顺式克罗米芬。克罗米芬的反式异构体的类似物,如Ernst等(同上)中所述的那些也可用于实施本发明。
还可以长期施用本发明的组合物。在这方面,可以将所述组合物施用以下时间段:至少1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天、22天、23天、24天、25天、26天、27天、28天、29天、30天、31天或更多天。还可以将所述组合物施用以下的施用时间段:至少1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、12个月或更多个月。还可以将所述组合物施用以下的施用时间段:至少1年、2年、3年、4年、5年、6年、7年、8年、9年、10年或更多年。在施用时间段期间,可以每天或定期,如每隔一天等施用所述组合物一次。
还可以间歇地施用本发明的组合物。举例来说,可以将所述组合物施用1周、2周、3周、4周、5周或更多周的施用时间段,继而中止一段时间,继而施用1周、2周、3周、4周、5周或更多周的施用时间段,诸如此类。
本文所提到的所有参考文献以引用的方式整体并入本文。
以下实施例意图说明本发明并且不意图限制如所附权利要求书所阐述的本发明的范围。
实施例1
反式克罗米芬和外源性睾酮治疗对骨再吸收血清标志物的作用
在患有继发性性腺功能减退的人类男性中评估分离的反式克罗米芬异构体对骨再吸收生物标志物的血清水平的作用。
在三个月的时间段内,向具有早晨总睾酮血液水平<300ng/dl和血清LH<15IU/ml的成年男性受试者施用反式克罗米芬(12毫克/天或25毫克/天,经由口服胶囊)或局部睾酮凝胶(每天涂敷50mg)。在受试者中,通过免疫测定对基线血清(循环)雌激素(E2)、二氢睾酮(DHT)、性激素结合球蛋白(SHBG)、P1NP-1以及CTX测量结果进行定量测定。然后开始使用反式克罗米芬(12.5mg或25mg)或进行治疗。在初始剂量后3周时、初始剂量后6个月时以及停止治疗后一个月时进行随访测量。结果呈现于下表1中:
表1:治疗对血清激素和SHBG水平的作用
*相比于TxT前有差异
^相比于Testim有差异
相比于安慰剂有差异
ng/DL
pg/mL
§nmol/L
在6周和3个月的每天施用反式克罗米芬之后,观测到血清雌二醇17β(E2)显著增加。即局部外源性睾酮使血清雌激素升高到与反式克罗米芬相等的程度并且使DHT升高到比反式克罗米芬更大的程度。在停止使用反式克罗米芬治疗之后,与基线相比,血清雌激素水平仍升高。鉴于SHBG结合血清中的睾酮和雌激素这两者,在治疗期间SHBG水平的相对稳定表明游离睾酮或雌激素没有发生变化。重要的是,没有观测到反式克罗米芬升高雌二醇水平的能力与相比存在差异。
反式克罗米芬和对骨形成血清生物标志物(P1NP)和骨再吸收血清生物标志物(CTX)的水平的作用图示于图1和图2中。在接受任何一种剂量的反式克罗米芬治疗的受试者中观测到血清P1NP-1水平降低;然而,在对照组和组中没有观测到变化或观测到略微增加(图1)。治疗不能简单地通过增加睾酮来降低P1NP-1表明了与反式克罗米芬的作用相比有显著的差异。观测到P1NP-1水平的降低具有剂量依赖性,其中25mg的剂量与12.5mg的剂量相比表现出更强的降低作用。在这两种反式克罗米芬剂量下P1NP-1的更低水平完全在正常范围内(15μg/L-80μg/L)。在这两种反式克罗米芬剂量下还观测到CTX水平的降低;然而,在25mg的剂量下,降低作用要强得多。相比之下,在对照受试者中观测到CTX水平相对于基线的显著升高。治疗组表现出CTX水平的中等降低。根据意向性治疗(ITT)分析,血清生物标志物的变化是相同的,尽管ITT群体含有退出者。
在反式克罗米芬治疗的情况下所观测到的P1NP-1和CTX的降低似乎与血清睾酮、DHT或雌激素的水平无关(表1),这鉴于单独的治疗在那些激素作用方面没有显著差异,而反式克罗米芬在每天25mg剂量下表现出这些生物标志物的更强降低。惊人的是,似乎反式克罗米芬和通过不同的机制来发挥它们对骨骼的作用。
在治疗前具有25至42范围内的身体质量指数(BMI)并且没有骨病(包括骨质减少)迹象的15名性腺功能减退男性(早晨睾酮低于300ng/dL)中,通过双能X射线吸收测定术(DEXA)扫描来评估反式克罗米芬对全髋骨矿物质密度(BMD)的作用。在使用反式克罗米芬治疗前进行DEXA扫描以确定基线测量结果并且在6个月的每天施用反式克罗米芬之后进行DEXA扫描。在整个6个月的时间段期间,15名受试者中有四名接受12.5mg反式克罗米芬,每天施用一次。15名受试者中有十一名从12.5毫克/天的剂量开始,但是随后向上滴定到25毫克/天。还在25名安慰剂(对照)受试者中,在相同的时间点评估全髋BMD。将接受治疗的受试者和对照受试者这两者在6个月时间点时的BMD测量结果与基线测量结果相比较。结果呈现于图3中。在6个月的时间段期间接受反式克罗米芬治疗的受试者中观测到髋部BMD提高了约1.23%,从而确认反式克罗米芬提高BMD的能力。另一方面,对照(安慰剂)受试者在相同的时间段内表现出BMD降低0.59%。
讨论
总之,这些结果表明反式克罗米芬显著降低骨再吸收生物标志物和骨形成生物标志物的血清水平并且这种骨形成减少是通过与睾酮的机制显然不同的机制而发生的,并且这种对骨转换的抑制与骨矿物质密度升高有关,从而表明反式克罗米芬和它的类似物可用于治疗多种骨病症。
实施例2
使用反式克罗米芬或其类似物或盐抑制骨再吸收
可以在具有足以实现所需结果的持续时间的治疗时间段内,向需要或期望减少骨再吸收(例如以提高骨矿物质密度、减小骨折的可能性和/或预防或治疗一种或多种骨相关病症)的受试者施用有效量的反式克罗米芬(或其盐或类似物)。在这种情况下,将在开始治疗前评估一种或多种骨再吸收生物标志物,然后在治疗过程期间对所述生物标志物进行监测。通过非限制性实施例的方式,每天或每隔一天向有患骨相关病症风险或被诊断患有骨相关病症的受试者施用5mg至100mg的反式克罗米芬,持续至少三个月,优选地至少六个月的治疗时间段。可根据所述方法使用的优选的骨再吸收生物标志物是CTX。可根据所述方法使用的其它骨再吸收生物标志物包括但不限于1型胶原N末端端肽(NTX)、脱氧吡啶啉(DPD)、吡啶啉、尿羟脯氨酸、半乳糖基羟赖氨酸、以及抗酒石酸酸性磷酸酶,尽管应当了解的是,可以使用任何公认的骨再吸收生物标志物来评估骨再吸收。
实施例3
使用反式克罗米芬或其类似物或盐抑制骨转换
可以在具有足以实现所需结果的持续时间的治疗时间段内,向需要或期望减少骨转换(例如以提高骨矿物质密度、减小骨折的可能性和/或预防或治疗一种或多种骨相关病症)的受试者施用有效量的反式克罗米芬(或其盐或类似物)。在这种情况下,将在开始治疗前评估一种或多种骨再吸收生物标志物和一种或多种骨形成生物标志物,然后在治疗过程期间对所述生物标志物进行监测。通过非限制性实施例的方式,每天或每隔一天向有患骨相关病症风险或被诊断患有骨相关病症的受试者施用5mg至100mg的反式克罗米芬,持续至少三个月,优选地至少六个月的治疗时间段。可根据所述方法使用的优选的骨再吸收生物标志物包括但不限于CTX、NTX、DPD、吡啶啉、尿羟脯氨酸、半乳糖基羟赖氨酸、以及抗酒石酸酸性磷酸酶。可根据所述方法使用的优选的骨形成生物标志物包括但不限于P1NP、骨特异性碱性磷酸酶(BSAP)以及骨钙素(OstCa)。然而,应当了解的是,可以使用任何公认的骨再吸收生物标志物和骨形成生物标志物来评估骨转换。
Claims (28)
1.一种用于抑制有需要的人类受试者的骨再吸收的方法,所述方法包括向所述受试者施用组合物,所述组合物包含约5mg至约100mg的量的反式克罗米芬或其类似物或药学上可接受的盐,所述组合物基本上不含顺式克罗米芬,其中所述量有效降低所述受试者的一种或多种骨再吸收血清生物标志物的水平。
2.如权利要求1所述的方法,其中所述一种或多种骨再吸收血清生物标志物包括I型胶原C末端交联端肽(CTX)。
3.如权利要求1或2所述的方法,其中所述反式克罗米芬或其类似物或盐的量有效地使所述受试者的所述CTX的血清水平降低至少约5%、至少约10%、至少约15%、或至少约20%。
4.如前述权利要求中任一项所述的方法,其中所述有需要的受试者是患有骨相关病症,优选地骨质疏松症或骨质减少的人类男性。
5.一种用于抑制有需要的人类受试者的骨转换的方法,所述方法包括向所述受试者施用组合物,所述组合物包含约5mg至约100mg的量的反式克罗米芬或其类似物或药学上可接受的盐,所述组合物基本上不含顺式克罗米芬,其中所述量在所述受试者中(i)有效降低一种或多种骨再吸收血清生物标志物的水平;以及(ii)有效降低一种或多种骨形成血清生物标志物的水平。
6.如权利要求5所述的方法,其中所述一种或多种骨再吸收血清生物标志物包括CTX。
7.如权利要求5或6所述的方法,其中所述一种或多种骨形成血清生物标志物包括1型前胶原N末端延长肽(P1NP)。
8.如权利要求5至7中任一项所述的方法,其中所述反式克罗米芬或其类似物或盐的量有效地使所述受试者的所述CTX的血清水平降低至少约5%、至少约10%、至少约15%、或至少约20%和/或有效地使所述P1NP的血清水平降低至少约10%、至少约15%、至少约20%、至少约25%或至少约30%。
9.一种用于提高有需要的人类受试者的骨矿物质密度(BMD)的方法,所述方法包括向所述受试者施用组合物,所述组合物包含约5mg至约100mg的量的反式克罗米芬或其类似物或药学上可接受的盐,所述组合物基本上不含顺式克罗米芬,其中所述量有效地将所述受试者的髋部中的BMD提高至少1%。
10.如权利要求9所述的方法,其中所述量有效地将所述受试者的髋部中的BMD提高至少1.2%。
11.如权利要求9或10所述的方法,其中所述量有效地使所述受试者的CTX的血清水平降低至少约5%、至少约10%、至少约15%、或至少约20%和/或有效地使P1NP的血清水平降低至少约10%、至少约15%、至少约20%、至少约25%或至少约30%。
12.如权利要求9至11中任一项所述的方法,其中所述有需要的受试者是患有骨相关病症,优选地骨质减少或骨质疏松症的人类男性。
13.一种用于治疗人类受试者的骨相关病症的方法,所述方法包括向所述受试者施用组合物,所述组合物包含约5mg至约100mg的量的反式克罗米芬或其类似物或药学上可接受的盐,所述组合物基本上不含顺式克罗米芬,其中所述量有效地使所述受试者的一种或多种骨再吸收血清生物标志物的水平降低至少约5%、至少约10%、至少约15%或至少约20%和/或将所述受试者的BMD提高至少约1%。
14.如权利要求13所述的方法,其中所述一种或多种骨再吸收血清生物标志物包括CTX。
15.如前述权利要求中任一项所述的方法,其中所述组合物包含5mg至20mg的反式克罗米芬。
16.如权利要求1至14中任一项所述的方法,其中所述组合物包含12.5mg至25mg的反式克罗米芬。
17.如权利要求1至14中任一项所述的方法,其中所述组合物包含12.5mg至50mg的反式克罗米芬。
18.如权利要求17所述的方法,其中所述组合物包含25mg至50mg的反式克罗米芬。
19.如前述权利要求中任一项所述的方法,其中每天施用所述组合物一次。
20.如前述权利要求中任一项所述的方法,其中将所述组合物施用至少六周、至少3个月、至少6个月或至少一年的时间段。
21.如前述权利要求中任一项所述的方法,其中所述受试者是人类男性。
22.如权利要求21所述的方法,其中所述男性具有低于约400ng/dl或低于约300ng/dl的睾酮水平。
23.如权利要求22所述的方法,其中所述男性是继发性的性腺功能减退的男性。
24.如权利要求21至23中任一项所述的方法,其中所述人类男性是至少50岁的人类男性。
25.如权利要求24所述的方法,其中所述人类男性是至少60岁的人类男性。
26.如前述权利要求中任一项所述的方法,其中所述组合物包含选自由以下各项组成的组的反式克罗米芬的类似物:(E)-4-OH-克罗米芬和(E)-4-OH-N-脱乙基克罗米芬或其药学上可接受的盐。
27.如前述权利要求中任一项所述的方法,其中所述组合物包含反式克罗米芬或其药学上可接受的盐并且包含0%w/w的顺式克罗米芬。
28.如权利要求23所述的方法,其中所述组合物包含反式克罗米芬柠檬酸盐。
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US201361831542P | 2013-06-05 | 2013-06-05 | |
US61/831542 | 2013-06-05 | ||
PCT/US2014/040704 WO2014197477A1 (en) | 2013-06-05 | 2014-06-03 | Trans-clomiphene and its analogues as agents that increase bone mineral density |
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US (1) | US9616034B2 (zh) |
EP (1) | EP3003487A4 (zh) |
JP (1) | JP6417409B2 (zh) |
KR (1) | KR20160016792A (zh) |
CN (1) | CN105473183A (zh) |
AU (1) | AU2014275101B2 (zh) |
CA (1) | CA2914503A1 (zh) |
HK (1) | HK1223318A1 (zh) |
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WO2017123577A1 (en) * | 2016-01-12 | 2017-07-20 | Repros Therapeutics Inc. | Trans-clomiphene and progesterone receptor antagonist combination therapy for treating hormone-dependent conditions |
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US4970237A (en) * | 1987-03-20 | 1990-11-13 | Yale University | Use of clomiphene to increase bone mass in premenopausal women |
JP2008543855A (ja) * | 2005-06-13 | 2008-12-04 | ライジェル ファーマシューティカルズ, インコーポレイテッド | 変形性骨疾患を処置するための方法および組成物 |
CA2865234A1 (en) | 2012-02-29 | 2013-09-06 | Repros Therapeutics Inc. | Combination therapy for treating androgen deficiency |
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HK1223318A1 (zh) | 2017-07-28 |
EP3003487A4 (en) | 2017-01-25 |
US20160128953A1 (en) | 2016-05-12 |
CA2914503A1 (en) | 2014-11-12 |
MX2015016093A (es) | 2016-03-21 |
JP2016520657A (ja) | 2016-07-14 |
KR20160016792A (ko) | 2016-02-15 |
AU2014275101B2 (en) | 2019-10-24 |
WO2014197477A1 (en) | 2014-12-11 |
US9616034B2 (en) | 2017-04-11 |
EP3003487A1 (en) | 2016-04-13 |
JP6417409B2 (ja) | 2018-11-07 |
AU2014275101A1 (en) | 2015-12-03 |
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