CN101578093A - 骨合成代谢蛋白质的药物递送方法 - Google Patents
骨合成代谢蛋白质的药物递送方法 Download PDFInfo
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Abstract
本发明提供了储存稳定的含有甲状旁腺激素相关蛋白(PTHrP)类似物的组合物,和使用本文所述的PTHrP类似物和PTHrP组合物治疗骨质疏松、增加骨量或提高骨质量的方法。该组合物是储存稳定的,以无菌形式存在,一般可以在室温下储存至少几周,以允许向人患者方便地肠胃外给药。
Description
相关申请
本申请要求于2006年10月3日提交的美国临时申请第60/848,960号的优先权。本文引入上述申请的完整记载作为参考。
发明背景
甲状旁腺激素相关蛋白(“PTHrP”)是一种具有139-173个氨基酸的蛋白质。已知PTHrP和某些类似物可用于在治疗骨质疏松和相关障碍中增加骨量和提高骨质量(bone quality)。但是,这些蛋白质作为药物的商业用途需要开发在储存稳定性和易于制备方面可接受的制剂。
此外,目前可用的骨质疏松药物由于不希望的副作用,如高钙血症和骨再吸收的刺激增加,在合适的剂量范围上具有限制。这些不希望的副作用和导致的剂量限制减弱了能够由这些药物实现的有益效果。因此,需要可以以一定剂量施用的化合物,所述剂量可增加有益效果而不增加不希望的副作用。
发明概述
本发明提供了含有甲状旁腺激素相关蛋白(PTHrP)类似物的储存稳定的组合物,和使用这些类似物和含有本文所述的类似物的组合物治疗骨质疏松、增加骨量或提高骨质量的方法。所述组合物是储存稳定的,以无菌形式存在,一般可以在室温下储存至少几周,以允许向人患者方便地肠胃外给药。
在一种实施方式中,本发明提供了适于向患者(例如,人)施用的储存稳定的组合物。该组合物包含PTHrP类似物和维持组合物的pH在2-7之间的有效量的缓冲液。在一种具体的实施方式中,PTHrP是[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ IDNO.:2)。
在另一种实施方式中,本发明提供了含有适于向受试者施用的储存稳定的组合物的密封容器。该组合物包含PTHrP或其类似物和维持组合物的pH在2-7之间的有效量的缓冲液。在一种具体的实施方式中,PTHrP类似物是[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
在另一种实施方式中,本发明提供了包括一个或一个以上的一次性容器的药物递送装置,所述容器包含PTHrP或其类似物和维持组合物的pH在2-7之间的有效量的缓冲液。在一种具体的实施方式中,PTHrP类似物是[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
在另一种实施方式中,本发明提供了包括一个或多个可多次使用的容器的药物递送装置,所述容器包含储存稳定的组合物,该组合物含有PTHrP或其类似物和维持组合物的pH在2-7之间的有效量的缓冲液。在一种具体的实施方式中,PTHrP类似物是[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
在另一种实施方式中,本发明提供了治疗需要治疗的受试者的骨质疏松的方法,包括以40-160μg的量向受试者施用每日单一皮下剂量的[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ IDNO.:2),持续足以治疗受试者的时间,一般为大约3-36个月。在一些实施方式中,治疗周期为大约3-18个月。
在另一种实施方式中,本发明提供了为需要的受试者增加骨量或提高骨质量的方法,包括以40-160μg的量向受试者施用每日单一皮下剂量的[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQID NO.:2),持续足以治疗受试者的时间,一般为3-36个月。在一些实施方式中,治疗周期为大约3-18个月。
本发明的PTHrP和类似物的组合物在激素组成和活性方面显示储存稳定性。此外,这些组合物一般可以以高于目前可用的骨质疏松药物的剂量施用,减少或消除不希望的副作用,如高钙血症或骨再吸收的刺激。这具有由于剂量增加而使有益的生理效应增加的优势,并可导致治疗时间缩短。
附图简述
图1是显示SEQ ID NO.2在没有任何化学稳定剂的情况下在5℃和25℃下在24个月里的稳定性的图。
图2是显示冻干的SEQ ID NO.2在5℃、25℃和40℃下在24个月里的稳定性的图。
发明详述
天然的hPTHrP(1-34)的序列如下:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile GlnAsp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile Ala Glu Ile His ThrAla(SEQ ID NO:1)。
在一种具体的实施方式中,PTHrP类似物是[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
在6,921,750、5,955,574、6,544,949、5,723,577和5,696,095中描述了其它PTHrP类似物,本文引入其完整内容作为参考。
本文所用的“缓冲液”是任何药学上可接受的、能够维持本发明的组合物在需要的pH范围之内的酸或盐的组合。公开的组合物中的缓冲液维持pH在大约2-大约7、大约3-大约6、大约4-大约6、大约4.5-大约5.6的范围或大约5.1。合适的缓冲液包括能够维持上述pH范围的任何药学上可接受的缓冲液,例如,乙酸盐、酒石酸盐、磷酸盐或柠檬酸盐缓冲液。在一种实施方式中,缓冲液是乙酸盐或酒石酸盐缓冲液。在另一种实施方式中,缓冲液是乙酸盐缓冲液。在一种实施方式中,缓冲液是乙酸和乙酸钠。
在公开的组合物中,缓冲液的浓度一般在以下范围内:大约0.1mM-大约1000mM、大约0.2mM-大约200mM、大约0.5mM-大约50mM、大约1mM-大约10mM或大约6mM。
如本文所用,抗微生物剂是适于向受试者施用的药学上可接受的防腐剂,其抑制、防止或延迟本发明的组合物中的微生物(包括,如细菌、病毒和真菌)的生长。用于本发明的组合物和方法的合适的抗微生物剂包括,但不限于:甲酚、苯甲醇、苯酚、苯扎氯铵(benzalkonium chloride)、苄索氯铵(benzethonium chloride)、氯代丁醇、苯乙醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、硫柳汞(thiomersal)和硝酸苯汞和乙酸苯汞。在一种实施方式中,抗微生物剂是间甲酚、氯甲酚或苯酚。在另一种实施方式中,抗微生物剂是氯甲酚或苯酚。在另一种实施方式中,抗微生物剂是苯酚。
如本文所用,抗微生物剂的有效量是有效地抑制、防止或延迟本发明的组合物中的微生物(包括,如细菌、病毒和真菌)生长的剂量。在本发明的组合物中,抗微生物剂的量一般在以下范围内:大约0.1-大约20mg/ml、大约0.2-大约30mg/ml、大约0.2-大约10mg/ml、大约0.25-大约5mg/ml、大约0.5-大约50mg/ml、大约1-大约10mg/ml、大约3mg/ml或大约5mg/ml。
本发明的组合物典型地是可直接施用的、无菌的、储存稳定的且药学上可接受的水溶液,而无需在施用之前重配。本发明的组合物适于向受试者施用,这意味着它们是药学上可接受的、无毒的且不含任何会不利地影响肽的生物学效应或激素效应的组分。例如,本发明的组合物不含任何细胞。
如本文所用,如果在下列之一的条件下,PTHrP的量、纯度保持为原来的量的大约95%以上,则本发明的组合物是储存稳定的:(1)在5℃下储存2年以上;或(2)在25℃下储存30天以上。
所述组合物一般储存于通常适于长期储存的密封容器、小瓶或药筒(cartridge)中。“适于长期储存”意思是当在25℃下保持至少3个月时,小瓶、容器或药筒不允许本发明的组合物的组分离开或如微生物的外来组分进入。
本发明的组合物优选地通过注射、一般通过皮下注射来施用。
本发明的组合物可以在单剂量或多剂量的密封容器、小瓶或药筒中储存。密封容器、小瓶或药筒一般适合单剂量或多剂量注射笔或给药装置中使用,该装置通常允许患者自己施用肽。密封容器可以包含一个或多个剂量的本发明的肽,其中每个剂量包含有效量的本文所述的肽。
单剂量注射笔或给药装置一般为一次性的装置,其使用包含单剂量的有效量的本文所述组合物中的PTHrP的密封容器。多剂量注射笔或给药装置一般包含多于一个剂量的有效量的本文所述组合物中的PTHrP。一般可以调节多剂量笔以施用所需体积的本文所述的储存稳定的组合物。在一些实施方式中,多剂量注射笔防止了在多次使用一个针头时可能发生的微生物污染物进入容器或药筒。
如本文所用,注射笔也可以包括两个容器,其中一个包含如下文所述的冻干粉末形式的本文所述的PTHrP,第二容器包含用于重配冻干粉末的液体。在施用之前,混合两个容器中的内容物。
如上文所述,本发明的组合物可以通过注射施用。用于注射的本发明组合物的合适的体积包括大约0.5-大约1ml、大约0.1-大约1ml、大约0.02-大约0.04ml、大约0.1-大约5.0μl或大约0.1-大约1.0μl。
在本发明的组合物中,肽的浓度是大约20mg/ml-大约20,000mg/ml、大约100mg/ml-大约10,000mg/ml、大约300mg/ml-大约300mg/ml、大约500mg/ml-大约2000mg/ml和大约2mg/ml。
也可以使用本领域内已知的冻干技术冷冻干燥本发明的组合物,并以可以在施用之前重配的粉末的形式储存。如本文所用的术语“冻干”是冷冻干燥或脱水技术,其包括从本发明的组合物中除去溶剂,优选与水混溶的溶剂,更优选水,当组合物处于冻结状态时一般通过高真空升华进行。冻干一般在冻干设备(冻干机)中进行,冻干设备包含带有可变温度控制的干燥室、收集水的冷凝器和降低干燥室中的压力的真空系统。
如本文所用的术语“冻干组合物”意思是在上文所述的冻干步骤之后产生或保持的固体残余物或粉末。本发明的冻干组合物一般还包含药学上可接受的赋形剂。如本文所用的术语“药学上可接受的赋形剂”指在冻干之前加到溶液中以提高冻干块的如颜色、质地、强度和体积等特征的物质。药学上可接受的赋形剂可以是,例如,缓冲液和pH调节剂、结晶增量赋形剂、稳定剂和张力提高剂。
在一些优选的实施方式中,药学上可接受的赋形剂是结晶增量赋形剂。如本文所用的术语“结晶增量赋形剂”或“结晶增量剂”是指为冻干块提供体积和结构的赋形剂。这些结晶增量剂是惰性的,不与肽反应。而且,结晶增量剂能够在冻干条件下结晶。
合适的结晶增量剂的例子包括亲水赋形剂,如水溶性聚合物;糖,如甘露醇、山梨醇、木糖醇、葡糖醇、卫矛醇(ducitol)、肌醇、阿拉伯糖醇(arabinitol)、阿糖醇(arabitol)、半乳糖醇、艾杜糖醇、蒜糖醇、麦芽糖醇、果糖、山梨糖、葡萄糖、木糖、海藻糖、阿洛糖、右旋糖、阿卓糖、乳糖、葡萄糖、果糖、古洛糖、艾杜糖、半乳糖、塔罗糖、核糖、阿拉伯糖、木糖、来苏糖、蔗糖、麦芽糖、乳糖、乳果糖、岩藻糖、鼠李糖、松三糖、麦芽三糖、棉子糖、阿卓糖醇(altritol)、它们的旋光形式(D-或L-型)以及相应的外消旋物;无机盐、矿物和矿物有机盐,例如钙盐,如乳酸盐、葡萄糖酸盐、甘油磷酸盐(glycerylphosphate)、柠檬酸盐、磷酸一碱盐和二碱盐、琥珀酸盐、硫酸盐和酒石酸盐,以及铝和镁的同样的盐;碳水化合物,如常用的单糖和二糖以及相应的多元醇;蛋白质,如白蛋白;氨基酸,如甘氨酸;可乳化的脂肪和聚乙烯吡咯烷酮。优选的结晶增量剂选自甘氨酸、甘露醇、葡聚糖、右旋糖、乳糖、蔗糖、聚乙烯吡咯烷酮、海藻糖、葡萄糖及其组合。特别优选的结晶增量剂包括葡聚糖。
如本文所用,稳定剂是维持肽的化学、生物学或激素稳定性的组分/化合物。稳定剂的例子包括多元醇,包括糖类,优选单糖或双糖,例如,葡萄糖、海藻糖、棉子糖或蔗糖;糖醇,如甘露醇、山梨醇或肌醇;多元醇,如甘油或丙二醇或其混合物;和白蛋白。
本文所述的组合物可以用于刺激受试者的骨生长。因此,它们可用于治疗与骨生长缺陷相关的疾病或障碍,如骨质疏松和骨折。在一种实施方式中,本发明涉及治疗受试者的骨质疏松的方法,包括向受试者施用有效量的本文所述的组合物。
如本文所用,“治疗”可以包括预防性和治疗性的处理。例如,治疗性的处理可以包括延迟、抑制或防止骨质疏松的发展,减少或消除与骨质疏松相关的症状。预防性的处理可以包括防止、抑制或延迟骨质疏松的发生。
如本文所用,有效量指足以引起预期应答的剂量。在本发明中,预期的生物应答是骨损失速度的降低和/或受试者的骨量的增加和骨质量的提高。
用于本发明的组合物和方法的合适的剂量包括每天一次、每隔一天一次、每周两次、每周一次、每两周一次、每月一次施用大约40-大约160μg、大约80-大约120μg、大约80-大约100μg;或大约40-大约50μg、大约50-大约60μg、大约60-大约70μg、大约70-大约80μg、大约80-大约90μg、大约90-大约100μg、大约100-大约110μg、大约110-大约120μg、大约120-大约130μg、大约130-大约140μg、大约140-大约150μg、大约150-大约160μg;或大约40-大约45μg、大约45-大约50μg、大约50-大约55μg、大约55-大约60μg、大约60-大约65μg、大约65-大约70μg、大约70-大约75μg、大约75-大约80μg、大约80-大约85μg、大约85-大约90μg、大约90-大约95μg、大约95-大约100μg、大约100-大约105μg、大约105-大约110μg、大约110-大约115μg、大约115-大约120μg、大约120-大约125μg、大约125-大约130μg、大约130-大约135μg、大约135-大约140μg、大约140-大约145μg、大约145-大约150μg、大约150-大约155μg、大约155-大约160μg。剂量可以搏动注射(pulsatile injection),例如每月一次,导致本文所述的组合物的单一剂量的脉冲式释放。
当每天一次、每周一次等施用上述的剂量时,剂量一般为相等的量。
本文所用的受试者为动物,例如,哺乳动物,如人。
药学上可接受的盐是适于向受试者(如人)施用的盐。本发明的肽可以具有一个或多个足够酸性的质子,其能够与合适的有机或无机碱反应,以形成碱加成盐。碱加成盐包括那些源自诸如铵或碱金属或碱土金属的氢氧化物、碳酸盐、碳酸氢盐等无机碱的盐,和源自诸如醇盐(或酚盐)、烷基酰胺、烷基和芳基胺等有机碱的盐。因而,用于制备本发明的盐的这样的碱包括氢氧化钠、氢氧化钾、氢氧化铵、碳酸钾等。具有足够碱性的基团(如胺)的本发明的肽能够与有机酸或无机酸反应以形成酸加成盐。通常用来由带有碱性基团的化合物形成酸加成盐的酸是诸如盐酸、氢溴酸、氢碘酸、硫酸、磷酸等无机酸,和诸如对甲苯磺酸、甲磺酸、草酸、对溴苯基磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸等有机酸。这样的盐的例子包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、丁二酸盐、辛二酸盐、癸二酸盐、延胡索酸盐、顺丁烯二酸盐、丁炔-1,4-二酸盐、己炔-1,4-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、甘醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等。
本发明的组合物在以上列出的剂量下,一般不显示任何副作用或显示降低的副作用,如高钙血症,且一般不会增加骨再吸收刺激。这种副作用的减少允许施用比可商购的骨质疏松药物更高的剂量。
可以通过本文所述的注射施用本发明的组合物。
本发明的组合物可以单独施用,或与另外的治疗剂,如抗再吸收治疗剂,如二膦酸盐化合物(bisphonsphonates)和降钙素联合施用。
实施例
实施例1证明了在没有稳定剂而具有低浓度(1mM)乙酸盐的条件下,[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ IDNO.:2)的稳定性。
表1
qs=足量至
每0.1ml的制剂递送100mcg的(SEQ ID NO.:2)。(SEQ ID NO.:2)溶解于含有稀乙酸盐缓冲液的注射用水中,产生pH 5.1。
如图1所示,结果证实在5℃下在24个月里具有极好的化学稳定性。该溶液不含稳定剂或防腐剂,只含有6mM的乙酸盐缓冲液。
总之,对于(SEQ ID NO.:2),获得溶液中的良好的稳定性不需要稳定剂。
实施例2:在冻干形式的(SEQ ID NO.:2)中使用柠檬酸缓冲液
表2
**在经冷冻干燥步骤除去后达到pH 5-5.5。
表2中的溶液用0.9%的NaCl重配,以产生:
一小瓶2ml(=50μg/ml),提供10-80μg/天的剂量(注射200μl-1.6ml),或
一小瓶5ml(=20μg/ml溶液),提供5-40μg/天的剂量(注射250μl-2ml)。
用柠檬酸调节pH,用右旋糖提供在冻干过程中帮助冻干块形成的增量剂。
所述溶液在玻璃瓶中冻干,并在不同温度下储存最多24个月。对在不同时间从储存中取出的样品进行[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)的含量、纯度和物理测试。作为剩余百分比的肽浓度的结果如图2所示。图2的数据显示在2-8℃下在24个月里具有极好的稳定性。
实施例3:筛选[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)制剂,以比较不同的防腐剂
下面的表3显示对羟基苯甲酸甲酯和苯甲醇不是适合[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)的防腐剂,因为可见沉淀和/或防腐剂活性失活。
表3
制备含有2mg/ml的[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)、6mM的乙酸盐缓冲液和注射用水的溶液,其中以推荐的具有有效抗微生物活性的浓度添加各种不同的防腐剂。溶液的制备是在室温下,在注射用水中溶解各种成分,搅拌<30分钟以确保完全溶解。通过0.2微米过滤器过滤溶液,并装到玻璃瓶中,盖上橡胶塞,在适当的位置卷边,以确保完全封闭。
由于在制成溶液后立即出现沉淀和失活,含有对羟基苯甲酸甲酯的溶液不能接受。然后将溶液在25℃下储存多达3个月,在5℃下储存多达4.5个月,如实施例5所述重复防腐剂效力测试。
实施例4:各种浓度的[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)组合物的抗微生物防腐剂效力的评估(稳定性研究)
表4
P87228 | P87229 | P87230 | P87231 | |
(SEQ ID NO.:2) | 2mg/mL | 2mg/mL | 2mg/mL | 2mg/mL |
抗微生物剂 | 苯酚5mg/mL | 氯甲酚3mg/mL | 氯甲酚2mg/mL | 苯甲醇10mg/mL |
乙酸盐缓冲液 | pH 5.1 | pH 5.1 | pH 5.1 | pH 5.1 |
根据《欧洲药典》(European Pharmacopoeia)第5.1.3章″Efficacite de la conservation anti-microbienne″(抗微生物防腐剂效力测试)测试所述溶液,以证明防腐剂的效力。
表5:制备之后的防腐剂效力测试
cfu数=菌落形成单位数
表5续:25℃储存3个月之后的防腐剂效力测试结果
表5续:5℃储存4.5个月之后的防腐剂效力测试结果
表5显示对于细菌和酵母/霉菌,苯酚、氯甲酚和苯甲醇都在制备之后立即产生合格的结果。在储存3个月和4.5个月之后,苯酚和氯甲酚对于细菌和酵母/霉菌的防腐剂效力得到保持。但是,苯甲醇对于细菌的效力是不合格的,因为数据显示杀死金黄色葡萄球菌的速度不足(表5)。
实施例5:不同制剂的化学稳定性
表6详述了实施例4所述的制剂的化学稳定性。
表6:[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQID NO.:2)的稳定性结果
从表6中可以看出,选择的防腐剂对[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)溶液稳定性没有明显影响。
表7详述了同样的制剂的每种防腐剂的含量。
表7:防腐剂稳定性结果
从表7可以看出,氯甲酚是具有较低稳定性的防腐剂,在5℃和25℃储存下,防腐剂含量有较大的损失。
尽管已经用实施例、实施方式具体展示并描述了本发明,但本领域的技术人员应当理解,可以在不背离所附权利要求书涵盖的本发明范围的情况下,在形式和细节上进行各种改变。
Claims (49)
1.一种适于向受试者施用的储存稳定的组合物,其包含:
a)具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQID NO.:2)序列的PTHrP类似物;和
b)维持pH在2-7之间的有效量的缓冲液。
2.如权利要求1所述的储存稳定的组合物,其中,所述缓冲液选自乙酸盐、酒石酸盐、磷酸盐和柠檬酸盐缓冲液。
3.如权利要求2所述的储存稳定的组合物,其中,所述缓冲液是乙酸盐缓冲液。
4.如权利要求3所述的储存稳定的组合物,其中,所述缓冲液是乙酸和乙酸钠。
5.如权利要求1所述的储存稳定的组合物,其中,所述pH维持在3-7之间。
6.如权利要求5所述的储存稳定的组合物,其中,所述pH维持在4-6之间。
7.如权利要求6所述的储存稳定的组合物,其中,所述pH维持在4.5-5.5之间。
8.如权利要求1所述的储存稳定的组合物,其中,所述组合物在密封容器中。
9.如权利要求8所述的储存稳定的组合物,其中,所述组合物在20℃下稳定至少28天。
10.如权利要求1所述的储存稳定的组合物,其中,所述组合物不含有化学稳定剂。
11.如权利要求1所述的储存稳定的组合物,其中,所述组合物进一步含有有效量的抗微生物剂。
12.如权利要求11所述的储存稳定的组合物,其中,所述抗微生物剂选自甲酚、苯酚、苯扎氯铵、苄索氯铵、氯代丁醇、苯乙醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、硫柳汞、硝酸苯汞和乙酸苯汞。
13.如权利要求12所述的储存稳定的组合物,其中,所述抗微生物剂是苯酚或氯甲酚。
14.如权利要求13所述的储存稳定的组合物,其中,所述抗微生物剂是苯酚。
15.如权利要求1所述的储存稳定的组合物,其中,所述组合物包含20-20,000mg/mL的具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)序列的PTHrP类似物。
16.如权利要求15所述的储存稳定的组合物,其中,所述组合物包含100-10,000mg/mL的具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)序列的PTHrP类似物。
17.如权利要求16所述的储存稳定的组合物,其中,所述组合物包含300-3,000mg/mL的具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)序列的PTHrP类似物。
18.如权利要求17所述的储存稳定的组合物,其中,所述组合物包含500-2,000mg/mL的具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)序列的PTHrP类似物。
19.一种适于向受试者施用的储存稳定的组合物,基本由以下组分组成:
a)具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQID NO.:2)序列的PTHrP类似物;和
b)维持pH在2-7之间的有效量的缓冲液。
20.一种适于向受试者施用的储存稳定的组合物,基本由以下组分组成:
a)具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQID NO.:2)序列的PTHrP类似物;
b)维持pH在2-7之间的有效量的缓冲液;和
c)有效量的抗微生物剂。
21.一种适于向受试者施用的储存稳定的组合物,基本由以下组分组成:
a)[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ IDNO.:2);和
b)维持pH在2-7之间的有效量的缓冲液。
22.如权利要求21所述的储存稳定的组合物,其中,所述[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)以500-20,000mg/mL的浓度存在;所述缓冲液是乙酸和乙酸钠缓冲液;所述pH在4.5-5.5之间。
23.一种适于向受试者施用的储存稳定的组合物,基本由以下组分组成:
a)浓度为500-20,000mg/mL的[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2);
b)乙酸和乙酸钠缓冲液;和
c)浓度范围是1-10mg/mL的苯酚,
其中,pH在4.5-5.5之间。
24.一种含有适于向受试者施用的储存稳定的组合物的密封容器,所述组合物包含:
a)具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQID NO.:2)序列的PTHrP类似物;和
b)维持pH在2-7之间的有效量的缓冲液。
25.一种包括一个或一个以上的一次性容器的药物递送装置,所述容器包含:
a)具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQID NO.:2)序列的PTHrP类似物;和
b)维持pH在2-7之间的有效量的缓冲液。
26.一种包括一个或多个可多次使用的容器的药物递送装置,所述容器包含:
a)具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQID NO.:2)序列的PTHrP类似物;和
b)维持pH在2-7之间的有效量的缓冲液。
27.一种包括一个或多个可多次使用的容器的药物递送装置,所述容器包含:
a)具有[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQID NO.:2)序列的PTHrP类似物;和
b)维持pH在2-7之间的有效量的缓冲液;和
c)有效量的抗微生物剂。
28.一种治疗需要治疗的受试者的骨质疏松的方法,包括以大约40μg/周-大约1120μg/周的量,向受试者施用[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
29.一种治疗需要治疗的受试者的骨质疏松的方法,包括以大约280μg/周-大约1120μg/周的量,向受试者施用[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
30.如权利要求28所述的方法,其中,所述受试者是人。
31.如权利要求20所述的方法,其中,所述施用方式包括皮下注射。
32.如权利要求28所述的方法,其中,每周一次以单一剂量施用(SEQ ID NO.:2)。
33.如权利要求28所述的方法,其中,每周两次以单一剂量施用(SEQ ID NO.:2)。
34.如权利要求33所述的方法,其中,所述每个单一剂量具有相等的量。
35.如权利要求28所述的方法,其中,每天一次以单一剂量施用(SEQ ID NO.:2)。
36.如权利要求35所述的方法,其中,所述(SEQ ID NO.:2)的单一剂量是大约80μg-大约100μg。
37.如权利要求36所述的方法,其中,所述每个单一剂量具有相等的量。
38.一种治疗需要治疗的受试者的骨质疏松的方法,包括每天一次向受试者施用大约40μg-大约50μg的[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
39.如权利要求38所述的方法,其中,施用大约40μg-大约45μg。
40.如权利要求39所述的方法,其中,所述受试者是人,且其中,所述施用方式包括皮下注射。
41.一种治疗需要治疗的受试者的骨质疏松的方法,包括每天一次向受试者施用大约70μg-大约80μg的[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
42.如权利要求41所述的方法,其中,施用大约75μg-大约80μg。
43.如权利要求42所述的方法,其中,所述受试者是人,且其中,所述施用方式包括皮下注射。
44.一种为需要的受试者增加骨量的方法,包括每天一次向受试者施用大约40μg-大约50μg的[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
45.如权利要求44所述的方法,其中,施用大约40μg-大约45μg。
46.如权利要求45所述的方法,其中,所述受试者是人,且其中,所述施用方式包括皮下注射。
47.一种为需要的受试者增加骨量或提高骨质量的方法,包括每天一次向受试者施用大约70μg-大约80μg的[Glu22,25,Leu23,28,31,Aib29,Lys26,30]hPTHrP(1-34)NH2(SEQ ID NO.:2)。
48.如权利要求47所述的方法,其中,施用大约75μg-大约80μg。
49.如权利要求48所述的方法,其中,所述受试者是人,且其中,所述施用方式包括皮下注射。
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Cited By (2)
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CN108025042A (zh) * | 2015-07-06 | 2018-05-11 | 董正欣 | PTHrP类似物的新型制剂 |
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