CN1980676A - 周期性黄体酮方案及试剂盒 - Google Patents
周期性黄体酮方案及试剂盒 Download PDFInfo
- Publication number
- CN1980676A CN1980676A CNA2005800227796A CN200580022779A CN1980676A CN 1980676 A CN1980676 A CN 1980676A CN A2005800227796 A CNA2005800227796 A CN A2005800227796A CN 200580022779 A CN200580022779 A CN 200580022779A CN 1980676 A CN1980676 A CN 1980676A
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- CN
- China
- Prior art keywords
- daily dose
- progesterone
- pharmaceutically acceptable
- day
- activating agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- PYVFWTPEBMRKSR-UHFFFAOYSA-N tanaproget Chemical compound CN1C(C#N)=CC=C1C1=CC=C(NC(=S)OC2(C)C)C2=C1 PYVFWTPEBMRKSR-UHFFFAOYSA-N 0.000 claims abstract description 23
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Abstract
提供了避孕方法,所述方法包括在不存在雌激素或其他类固醇化合物时送递连续21至27天的黄体酮,例如tanaproget,继之为无有效量活性剂的1至7天。也描述了便于送递该方案的可药用试剂盒。
Description
发明背景
1960年引入黄体酮/雌激素组合口服避孕药(OC)丸剂之后,很快就引入了几种仅有黄体酮的丸剂(POP)。POP中黄体酮的剂量低于组合OC中的,以使由完全卵巢抑制引起的闭经的发生最小化。因此,排卵在大约一半的POP使用者中受到抑制。(标准POP主要依赖于子宫颈粘液增稠以为排卵者提供避孕保护)。部分因为较低的黄体酮剂量、不存在外源性雌激素并且不存在规则的撤退性出血,POP使用者比组合OC使用者具有更高的不定期穿破性出血和长斑(spotting)率。主要因为出血问题,与大约30%使用组合OC的相比,仅约1~2%的避孕妇女使用POP。
所需要的是避免穿破性出血和长斑问题的含黄体酮的避孕药。
发明概述
本发明提供了避孕方案,其包括连续21至27天送递有效量的黄体酮、继之为不送递所述黄体酮的连续1至7天。在一个实施方案中,黄体酮是5-(4,4-二甲基-2-硫代-1,4-二氢-2H-苯并[d][1,3]嗪-6-基)-1-甲基-1H-吡咯-2-腈,也称为tanaproget。
本发明另外提供用于送递该方案的药用试剂盒。
从下面的发明详述,本发明的其它方面将是显而易见的。
发明详述
一方面,本发明提供了育龄雌性避孕方法。在所述方法中,将黄体酮或黄体酮组合作为唯一的活性(即抗避孕的(anti-contraceptive))剂送递一段连续的天数以防止受孕。
另一方面,本发明提供了黄体酮或黄体酮组合在制备可用于育龄雌性避孕的药物中的用途。在一个实施方案中,该药物包含一个阶段,其中,连续施用21至27个日剂量单位,每个日剂量单位含有包含黄体酮的活性剂。在另一个实施方案中,药物也包含第二阶段施用1至7个日剂量单位的可药用安慰剂。在其他实施方案中,黄体酮用于制备可用于在此所述任何避孕方法中的药物。
不期望受理论束缚,相信本发明将通过两条途径降低传统的仅含黄体酮的避孕药的出血问题。首先,由于各循环中整合了无有效量黄体酮的1至7天,所以约每28天将出现规则的撤退性出血。第二,增加黄体酮剂量高于标准的仅含黄体酮的避孕药,产生几乎完全的排卵抑制,而且,本发明的组合物不像传统的仅含黄体酮的方案那样依赖于子宫颈粘液增稠以保持避孕效力。
此处所用的术语“黄体酮”指任何促孕活性化合物,即,任何结合并活化黄体酮受体的化合物。代表性黄体酮包括黄体酮合成衍生物,例如17-羟基黄体酮酯、19-降-17-羟基黄体酮酯、17α-乙炔基睾酮及其衍生物、17α-乙炔基-19-降-睾酮及其衍生物、炔诺酮、醋酸炔诺酮、双醋炔诺醇、去氢孕酮、醋酸安宫黄体酮、异炔诺酮、烯丙雌烯醇、炔雌烯醇、fuingestanol acetate、美罗孕酮、诺孕烯酮、dimethiderome、炔孕酮、环丙孕酮、左旋炔诺孕酮、炔诺孕酮、d-17α-乙酰氧基-13β-乙基-17α-a-乙炔基-甾(gon)-4-烯(en)-3-酮肟、环丙孕酮、孕二烯酮、去氧孕酮、酮去氧孕烯(etonorgestrel)、炔诺肟酯和炔雌醇(norelgestromin)。用于口服避孕药的其他具有促孕活性的化合物包括氯地孕酮、双烯孕腈和曲螺酮(drospirenone)。
在一个满意的实施方案中,黄体酮是5-(4,4-二甲基-2-硫代-1,4-二氢-2H-苯并[d][1,3]嗪-6-基)-1-甲基-1H-吡咯-2-腈,也称为tanaproget和NSP-989。所述化合物可以具有式:
并包括其可药用的盐、酯或其他前药形式。在美国专利号6,436,929、美国专利申请号11/113,794(于2005年4月25日提交)和美国临时专利申请号60/675,550(于2005年4月28日提交);60/675,551(于2005年4月28日提交);60/675,559(于2005年4月28日提交);60/675,737(于2005年4月28日提交);和60/675,738(于2005年4月28日提交)中描述了该化合物及制备该化合物的方法。
另外,美国专利号6,436,929;6,355,648;6,521,657;6,407,101;6,562,857和6,358,947、美国专利公开号2003-0158182-A1和美国临时专利申请号60/601,254(于2004年8月13日提交)中描述的其他黄体酮可用于本发明的方法和试剂盒。可以用从可药用或生理学可接受的酸或碱衍生的盐的形式使用可用于本发明的黄体酮化合物。这些盐包括但不限于下列例如盐酸、硫酸、硝酸、磷酸的无机酸、以及视情况而定例如乙酸、草酸、琥珀酸和马来酸的有机酸的盐。其他盐包括酯、氨基甲酸酯和其他常规“前药”形式的碱金属或碱土金属(例如钠、钾、钙或镁)的盐,以所述形式施用时,所述盐体内转化为活性部分。
以对应于月经周期长度的时间段(即,在23至35天范围内,平均为28天)实施本发明的方法。因此,本发明的方法包括在连续18至28天的时间段向育龄雌性送递含有由黄体酮组成的有效量活性剂的日剂量单位、继之为向受试者送递无有效量的活性剂的连续1至7天。
术语“有效量”的黄体酮是提供避孕的剂量。不受理论束缚,主要通过防止排卵而实现避孕。术语“无有效量”的黄体酮用于指送递有效量的黄体酮后的1至7天。在此时间段期间,优选不向动物送递黄体酮量。然而,可能的情况是,在此时间段期间,持续释放制剂或其他送递方法可以是“渗漏的”并继续送递对避孕无效的少量黄体酮。短语“无有效量”包括不送递黄体酮。
根据本发明,雌性优选为人。然而,如此处所用的,雌性可以包括非人类哺乳动物,例如家畜或牲畜、马、猪、家畜等。
一方面,本发明的方法包括连续28天中至少连续21天送递含有活性剂的日剂量单位。在该实施方案中,该方案由在连续21至27天的时间段向育龄雌性施用黄体酮、继之为向受试者送递无有效量的或不送递活性剂的连续1至7天组成。任选地,向受试者送递无有效量活性剂的1至7天时间段可以包括送递第二阶段的可药用安慰剂的1至7天的日剂量单位。另外,在所述“安慰剂阶段”期间,不施用安慰剂。
在一个实施方案中,本发明的方法包括将黄体酮作为唯一的活性剂送递连续21天,继之为送递无有效量的活性剂的7天。任选地,在这7天期间,可以送递第二阶段的口服和可药用安慰剂的7个日剂量单位。
在另一个实施方案中,本发明的方法包括将黄体酮作为唯一的活性剂送递连续23天,继之为送递无有效量的活性剂的5天。任选地,在这5天期间,可以送递第二阶段的口服和可药用安慰剂的5个日剂量单位。
在另一个实施方案中,本发明的方法包括将黄体酮作为唯一的活性剂送递连续25天,继之为送递无有效量的活性剂的3天。任选地,在这3天期间,可以送递第二阶段的口服和可药用安慰剂的3个日剂量单位。
在另一个实施方案中,本发明的方法包括将黄体酮作为唯一的活性剂送递连续27天,继之为送递无有效量的活性剂的1天。任选地,可以送递第二阶段的口服和可药用安慰剂的1个日剂量单位。
本发明包括含有一种或多种黄体酮化合物的药物组合物作用唯一的活性成分在制剂和方案中的用途。将黄体酮化合物与可药用载体或赋形剂配制。
适当地,为了通过任何合适的送递装置、以任何合适的途径送递而配制用于本发明的黄体酮,所述途径包括例如经皮、粘膜(鼻内、口腔、阴道)、经口、肠胃外等,所述送递装置其中包括例如经皮贴剂(transdermal patches)、局部乳膏或凝胶、阴道环。在另一个实施方案中,通过任何合适的途径将黄体酮以持续释放制剂施用。这类持续释放制剂为本领域技术人员所公知。
当化合物用于上述用途时,可以将其与一种或多种可药用载体或赋形剂(例如溶剂、稀释剂等)组合。当为经口送递配制时,黄体酮化合物可以是片剂、胶囊、囊片、geltab、可分散粉末、颗粒或含有例如约0.05至5%悬浮剂的悬浮液、含有例如约10至50%的糖的糖浆、以及含有例如约20至50%乙醇的酏剂等形式。当为肠胃外送递配制时,可以以无菌注射液或悬浮液的形式送递黄体酮化合物,所述悬浮液在等渗介质中含有约0.05至5%的悬浮剂。这类药物制剂可以含有例如约25%至约90%的活性成分与载体的组合,更通常为以重量计约5%至约60%。
采用的活性成分有效量可以依赖于采用的具体化合物、施用模式和所需的卵巢抑制程度而变化。然而,总体而言,当本发明的化合物在约0.03至0.6mg、或约0.1至约0.5mg的日剂量优选每日给予或以持续释放形式施用时,获得了满意的结果。可以调节该剂量方案以提供最佳治疗反应。例如,可以每日施用分开的几剂,或按照治疗情况的紧急性所示成比例地降低剂量。
可以经口施用这些活性化合物(一种或多种黄体酮)。固体载体包括淀粉、乳糖、磷酸二钙、微晶纤维素、蔗糖和高岭土,而液体载体包括无菌水、非离子表面活性剂、乙醇(例如甘油、丙二醇和液体聚乙二醇)、其合适的混合物、以及植物或食用油例如玉米、花生和芝麻油,只要适合于活性成分的性质和所需的具体施用形式。通常在药物组合物制备中采用的佐剂可以有利地包括例如调味剂、着色剂、防腐剂和抗氧化物(例如维生素E、抗坏血酸、BHT和BHA)。
从便于制备和施用的视点看,优选的药物组合物是固体组合物,特别是片剂和填紧的胶囊或液体填充的胶囊。优选经口施用该化合物。
也可以通过阴道环施用这些活性化合物。适宜地将阴道环的使用定时于28天周期。在一个实施方案中,将环插入阴道,并将其在适当的位置保持3周。在第四周期间,去除阴道环并出现月经。接下来一周插入新环,佩带另一个3周直至下一个时间段。在另一个实施方案中,每周插入阴道环,并连续三周更换。然后,在无环的一周之后,插入新环以开始新的方案。在另一个实施方案中,将阴道环插入更长或更短的时间段。
对于用于阴道环,以类似于先前所述的通过阴道环送递的避孕化合物描述的方式配制黄体酮化合物。见,例如美国专利号5,972,372;6,126,958和6,125,850。
任选地,可以为在持续释放制剂中肠胃外送递、以及通过注射(例如每月或每季度)施用而配制黄体酮组合物。
在本发明的另一方面,通过合适的途径为以乳膏或凝胶送递而配制黄体酮化合物。适宜地,这类途径的载体为本领域技术人员所公知。
在本发明另一方面,通过经皮贴剂送递黄体酮化合物。适宜地,将贴剂的使用定时于28天周期。在一个实施方案中,通过合适的粘合剂将贴剂应用于皮肤上,贴剂在此位置保留1周并在共三周的时间段内每周更换。在第四周期间,不应用贴剂,并出现月经。下一周应用新佩带的贴剂,以开始新的方案。在另一个实施方案中,贴剂将在合适的位置保留更长或更短时间段。
本发明也包括为用于在此所述方案设计的药物制剂的试剂盒或包装。合适地,试剂盒含有在此所述的一种或多种黄体酮化合物。在一个实施方案中,黄体酮选自17-羟基黄体酮酯、19-降-17-羟基黄体酮酯、17α-乙炔基睾酮及其衍生物、17α-乙炔基-19-降-睾酮及其衍生物、炔诺酮、醋酸炔诺酮、双醋炔诺醇、去氢孕酮、醋酸安宫黄体酮、异炔诺酮、烯丙雌烯醇、炔雌烯醇、fuingestanol acetate、美罗孕酮、诺孕烯酮、dimethiderome、炔孕酮、环丙孕酮、左旋炔诺孕酮、炔诺孕酮、d-17α-乙酰氧基-13β-乙基-17α-a-乙炔基-甾-4-烯-3-酮肟、环丙孕酮、孕二烯酮、去氧孕酮、酮去氧孕烯、炔诺肟酯、炔雌醇、氯地孕酮、双烯孕腈和曲螺酮。另外,美国专利号6,436,929、6,355,648、6,521,657、6,407,101和6,562,857中描述的其他黄体酮可用于本发明的方法和试剂盒中。
在一个满意的实施方案中,黄体酮是NSP-989(也称为tanaproget)、或其可药用盐或前药。
对于用于本发明的试剂盒有利的是,为所需送递载体和途径配制黄体酮。例如,可以为经口送递、肠胃外送递、阴道环、经皮送递或粘膜送递配制黄体酮。
在一个实施方案中,为在28天周期中每日经口施用(优选每天一次经口施用)设计本发明的试剂盒,并将其进行组织以显示在28天周期的每天将取用的单独经口制剂或经口制剂的组合。优选各试剂盒将包括在指定的各天取用的经口片剂;优选一个经口片剂将含有所示的各个组合的日剂量。例如,本发明的试剂盒可以含有21至27个有效量活性剂的日剂量单位和任选的1至7个安慰剂日剂量单位,及其他适当成分,包括例如使用说明书。
本发明的试剂盒优选是含有按照其取用顺序排列的日剂量的包装(例如泡罩包装(blister pack))。
在另一个实施方案中,为在28天周期中通过阴道环每周或每月施用设计本发明的试剂盒。合适地,该试剂盒包含每月周期所需的各个阴道环的独立包装,即一至三个,以及其他适当组分,包括例如使用说明书。
在另一个实施方案中,为在28天周期中通过经皮贴剂每周或每月施用设计本发明的试剂盒。合适地,该试剂盒包含每月周期所需的各个贴剂的独立包装,即一至三个,以及其他适当组分,包括例如使用说明书。
在另一个实施方案中,为肠胃外送递黄体酮设计本发明的试剂盒。一般为为家庭送递设计该试剂盒,并且可以包括针、注射器及其他适当的包装和使用说明书。
在另一个实施方案中,本发明的试剂盒含有黄体酮化合物的凝胶或乳膏制剂。试剂盒可以任选地包括例如管或其他容器的适当包装、敷料器和/或使用说明书。
在此所述的各方案和试剂盒中,优选该方案的各药物活性成分的日剂量在施用的各具体阶段保持固定。也应当理解,按照所述顺序施用所述日剂量单位,其中第一阶段随后按顺序为任选的第二阶段。为了便于与各方案相适应,也优选试剂盒含有对周期最后数天所述的安慰剂。另外优选各包装或试剂盒包含指示28天周期各天的可药用包装,例如标记的泡罩包装、刻度盘分配器或其他本领域已知的包装。
可以调整这些剂量方案以提供最佳避孕效果。例如,可以每日施用各组分的分开的几剂,或按照避孕效力所示成比例增加或降低剂量。在这里的描述中,日剂量单位的涵义也可以包括在预期周期中各天过程中施用的分开的单位。
下列实施例仅为说明性的,且无意对本发明进行限制。
实施例1-黄体酮化合物NSP-989的排卵抑制
与溶于2%Tween 80/0.5%甲基纤维素载体中的参照黄体酮醋酸安宫黄体酮(MPA)和曲美孕酮(trimegestone)(TMG)一起,在三个不同的黄体酮活性大鼠模型中经口评价NSP-989的活性。在本实施例的A、B和C部分中描述了这些模型。
A.NSP-989在大鼠排卵抑制模型中的作用
排卵抑制测定测量化合物在成年雌性大鼠中抑制排卵的能力。该活性是避孕功效所必需的。在本测定中,NSP-989具有0.03mg/kg的平均ED100值,而TMG和MPA二者均具有1mg/kg的ED100值(n=2-3)。
从Charles River Laboratory(Boston,MA)获得随机循环(Random cycling)成熟雌性Sprague-Dawley大鼠(约200g)。于0900h以及再次于1600h以每只大鼠皮下(sc)施用2μg LHRH(溶于含有0.1%牛血清清蛋白的磷酸缓冲盐水中)而将大鼠同步化于动情期。在施用测试化合物之前使动物休息8天。然后将动物分组,每个处理组7-9只大鼠。LHRH处理后第九天早晨,通过强饲法以测试化合物每天一次处理大鼠。该处理持续连续4天。最后一次处理后的早晨对动物实施安死术。取出输卵管,置于两个载玻片之间,并通过解剖显微镜观察以计数卵细胞。记录各处理组在输卵管中出现卵细胞的动物的数目及各动物输卵管中的卵细胞数目。
B.大鼠蜕膜化模型
确定促孕活性的第二个大鼠模型是卵巢切除的成年大鼠的子宫蜕膜化测定。由于黄体酮是将子宫基质细胞转化为分化的蜕膜细胞所绝对需要的,所以在此模型中,仅黄体酮受体激动剂化合物是有活性的。
如以前所述进行大鼠蜕膜化测定[Lundeen SG等人,“Rat uterinecomplement C3 expression as a model for progesterone receptormodulators:characterization of the new progestin trimegestone”,JSteroid Biol Mol Biol.2001;78:137-143]。
简单而言,在处理前至少10天将成熟雌性Sprague-Dawley大鼠(约220g)进行卵巢切除以降低循环性类固醇。通过强饲法(0.5ml)将NSP-989在2%Tween 80/0.5%甲基纤维素载体中每日一次经口施用七天。第三次每日处理后约24小时,通过以21-号钝针刮拭子宫系膜对向腔上皮(antimesometrial luminal epithelium),在各麻醉大鼠的一个子宫角中诱导蜕膜化。对侧角不经刮拭,并作为未刺激的对照。末次处理后24小时通过CO2窒息对动物实施安死术。取出子宫并修整脂肪,且分别将蜕膜化的(D)和对照(C)角称重。将蜕膜反应表示为D/C。
NSP-989以0.01mg/kg的ED50值(n=23)诱导子宫内膜蜕膜化,并且效力分别为MPA和TMG的约40和100倍(表1)。
表1.NSP-989在各种啮齿类动物模型中的促孕活性概括
化合物 | 大鼠排卵抑制测定(ED100,mg/kg,口服(po)) | 大鼠蜕膜测定(ED50,mg/kg,口服) | 大鼠C3测定(ED50,mg/kg,口服) | 兔Clauberg测定(AED50,mg/kg,口服) |
NSP-989MPATMG | 0.031.01.0 | 0.010.41.0 | 0.00050.030.005 | 0.0010.030.001 |
C.大鼠子宫C3模型
第三个PR激动剂活性模型是成年卵巢切除的大鼠子宫C3模型。该测定评估黄体酮在子宫上皮中阻断雌激素诱导的C3表达的能力。
从Harlan(Indianapolis,IN)获得60天龄的卵巢切除的雌性Sprague-Dawley大鼠。在处理前至少8天由供应商实施卵巢切除。将大鼠随机化并安排为6只一组。通过强饲法(口服)以0.5ml体积将动物每日一次经口处理2天。在处理第二天,也通过强饲法将动物以EE(0.08mg/kg体重(BW))经口处理。末次处理之后约24小时,通过CO2窒息对动物实施安死术。然后取出子宫,剥除残留脂肪和肠系膜,称重,并于干冰上速冻。按照厂商说明使用TrizolReagent(GibcoBRL)从子宫分离总RNA。使用以前报导的实时逆转录聚合酶链反应(RT-PCR)[Sampath D等人,“Aberrant expressionof Cyr61,a member of the CCN(CTGF/Cyr61/Cef10/NOVH)family,and dysregulation by 17b-estradiol and basic fibroblast growth factorin human uterine leiomyomas”J Clin Endocrinol Metab.2001;86:1707-1715]对互补C3表达定量。简要的说,使用无DNA试剂盒(Ambion)将RNA样品进行DNA酶I处理。使用C3特异性引物对(5’引物GGTCGGTCAAGGTCTACTCCTACTA[SEQ ID NO:1],3’引物CACAGCGGCACATTTCATTG[SEQ ID NO:2])和定制探针(6FAM-AGCATTCCATCGTCCTTCTCCGGATG-TAMRA[SEQID NO:3])对共50ng RNA一式三份地进行分析。使用由PE AppliedBiosystems提供的引物和探针将C3信使RNA(mRNA)水平对各样品反应物中含有的18S核糖体RNA进行标准化。
NSP-989的平均ED50值为0.0005mg/kg(n=6)。MPA和TMG在该测定中分别具有0.03和0.005mg/kg的平均ED50值。总而言之,在大鼠中,在几种无关的黄体酮活性模型中,NSP-989的效力为用于这些研究的参照黄体酮的3010至10060倍。
D.兔子宫内膜转化(Clauberg)测定
除了上述大鼠促孕模型之外,也在兔子宫内膜转化模型的经典促孕测定Clauberg模型中评估了NSP-989[McPhail MK,“The assay ofprogestin.”J Physiol.1934;83:145-1567]。简单而言,以5μg 17β-雌二醇(E2)/兔/天对未成熟雌性新西兰大白兔(约1kg体重)皮下注射连续六天。末次E2注射后的开始24个小时,经口给予单独载体或测试化合物连续五天。通过子宫重量和子宫内膜腺成树状分枝(McPhail指数)的增加确定促孕活性。
在有限的剂量反应研究中,NSP-989具有0.001mg/kg的估计ED50(AED50)。其在此测定中的效力与TMG类似,并为MPA的约30倍。
实施例2-使用黄体酮化合物的周期方案
安排三剂NSP-989在继之为7天安慰剂丸剂的21天方案中、以及比较物(comparator)(类固醇OC去氧孕酮(DSG)150μg/20μg炔雌醇的组合,进行21天,继之为2天的安慰剂丸剂,随后为5天的10μg EE,以名称Mircette在美国上市)的2期随机双盲多中心剂量范围研究。
大约20个地点参与,每地点约16名受试者。然而,注册将是竞争性的,且在任何地点可以注册额外的受试者。
研究将有2部分。研究的第一部分(1-84天)将评价NSP-989产生卵巢抑制的能力、并评价周期控制、副作用和代谢数据。第二部分(85-168天)将继续跟随受试者以收集周期控制、副作用和代谢数据。盲法方案医学监控和研究队伍将关于功效失败和安全性对该研究进行例行监控。取决于受试者筛选时间段的长度,各受试者将参与最长至9个月。观察八个周期。第一个周期将成为排卵的基线观察。六个治疗周期将尾随以一个治疗后观察周期,以评价回复排卵。受试者是在随机化时年龄大于等于18岁小于36岁的健康女性。受试者在进入预处理观察周期之前必须在三个月的时间段具有自发的规则的(24至32天)月经周期,从而排除流产后和非母乳喂养的产后受试者。流产后和非母乳喂养的产后受试者在进入预处理观察周期之前必须已完成了至少一个规则的(24至32天)自发月经周期。对所有受试者的预处理观察周期将在完成研究前筛选后发生的自发月经的第一天开始(诊视1)。
预处理观察周期是对照周期;不施用测试物(test article)。各受试者将在其月经出血第一天开始测试物(仅第一个受试者包装(subject pack))。各受试者包装将含有NSP-989或类固醇组合OC比较物。受试者将口服NSP-989,21天中每日一次(第1天至第21天),继之为7天的安慰剂丸剂(第22至28天),持续6个周期。分配给类固醇组合OC比较物(DSG 150μg)的受试者将口服测试物,21天中每日一次(第1至第21天),继之为2天的安慰剂丸剂(第22至23天),继之为5天的10μg EE(第24至28天),持续6个周期。同样也有治疗后周期,其间将不施用测试物,并将评价回复排卵。
随机指定各受试者接受下列之一:
组
处理
A 100μg NSP-989,21天,继之为7天的安慰剂丸剂
B 200μg NSP-989,21天,继之为7天的安慰剂丸剂
C 300μg NSP-989,21天,继之为7天的安慰剂丸剂
D 去氧孕酮150μg,21天,继之为2天安慰剂丸剂,继之为5天10μg EE
各受试者将在其月经出血第一天开始测试物(仅第一个受试者包装)。受试者将在各天大约相同的时间口服测试物,28天中每日一次。所有后来的受试者包装都将在前一个丸剂包装的第28天后开始。在治疗周期期间,受试者将不间断每日服用测试物。
预期接受本发明方案的一个或多个治疗组A、B和C将具有体验有效性避孕(experience effective contraception)、排卵停止,而且所有组将在处理各月的第四周期间具有撤退性出血。
实施例3
使用卡片纸板、纸板、箔或塑料衬背制备具有28个泡罩容器的泡罩包装,并以合适的盖封闭。安排泡罩容器以容纳21个各提供NSP-989日剂量100μg的丸剂及随后7个安慰剂丸剂日剂量(或7个空泡罩)的顺序。可以常规地将各泡罩容器编号或另外标记,例如,以含有活性成分的21个剂量单位的第一个开始,随后为7个空泡罩或不含活性剂的7个剂量单位。
在本说明书中列举的所有专利、专利公开物和其他公开物、以及序列表在此引用作为参考。尽管关于具体的实施方案对本发明进行描述,但应当理解,在不背离本发明的精神下可以进行修改。这类修改意欲在附加的权利要求的范围内。
序列表
<110>Wyeth
Grubb,Gary S.
Constantine,Ginger D.
<120>周期性黄体酮方案及试剂盒
<130>AM-101677PCT
<150>US 60/586,045
<151>2004-07-07
<160>3
<170>PatentIn version 3.3
<210>1
<211>25
<212>DNA
<213>人工序列
<220>
<223>C3特异性引物
<400>1
ggtcggtcaa ggtctactcc tacta 25
<210>2
<211>20
<212>DNA
<213>人工序列
<220>
<223>C3特异性引物
<400>2
cacagcggca catttcattg 20
<210>3
<211>26
<212>DNA
<213>人工序列
<220>
<223>定制的探针
<400>3
agcattccat cgtccttctc cggatg 26
Claims (22)
1.黄体酮在制备用于育龄雌性避孕的药物中的用途,其中所述药物在连续28天时间段中施用,所述药物包括:
(a)第一阶段,其中施用活性剂的21至27个日剂量单位,各日剂量单位含有包含黄体酮的有效量的活性剂;以及
(b)1至7天的第二阶段,其中施用无有效量的活性剂。
2.根据权利要求1的用途,其中所述黄体酮选自17-羟基黄体酮酯、19-降-17-羟基黄体酮酯、17α-乙炔基睾酮及其衍生物、17α-乙炔基-19-降-睾酮及其衍生物、炔诺酮、醋酸炔诺酮、双醋炔诺醇、去氢孕酮、醋酸安宫黄体酮、异炔诺酮、烯丙雌烯醇、炔雌烯醇、fuingestanolacetate、美罗孕酮、诺孕烯酮、dimethiderome、炔孕酮、环丙孕酮、左旋炔诺孕酮、炔诺孕酮、d-17α-乙酰氧基-13β-乙基-17α-a-乙炔基-甾-4-烯-3-酮肟、环丙孕酮、孕二烯酮、去氧孕酮、酮去氧孕烯、炔诺肟酯、炔雌醇、氯地孕酮、双烯孕腈和曲螺酮。
4.根据权利要求1至3中任一项的用途,其中在第二阶段送递1至7个日剂量单位的可药用安慰剂。
5.根据权利要求1至4中任一项的用途,其中所述药物包括:
(a)21个日剂量单位的第一阶段;以及
(b)7个日剂量单位的口服和可药用安慰剂的第二阶段。
6.根据权利要求1至4中任一项的用途,其中所述药物包括:
(a)23个日剂量单位的第一阶段;以及
(b)5个日剂量单位的口服和可药用安慰剂的第二阶段。
7.根据权利要求1至4中任一项的用途,其中所述药物包括:
(a)25个日剂量单位的第一阶段;以及
(b)3个日剂量单位的口服和可药用安慰剂的第二阶段。
8.根据权利要求1至4中任一项的用途,其中所述药物包括:
(a)27个日剂量单位的第一阶段;以及
(b)1个日剂量单位的口服和可药用安慰剂的第二阶段。
9.根据权利要求1至8中任一项的用途,其中所述黄体酮是5-(4,4-二甲基-2-硫代-1,4-二氢-2H-苯并[d][1,3]嗪-6-基)-1-甲基-1H-吡咯-2-腈(Tanaproget)。
10.适于每日经口施用的可药用试剂盒,其包括:
(a)活性剂的21至27个日剂量单位,各日剂量单位含有包含黄体酮的有效量的活性剂;以及
(b)所述日剂量单位的一个或多个包装。
11.根据权利要求10的可药用试剂盒,其中所述黄体酮选自17-羟基黄体酮酯、19-降-17-羟基黄体酮酯、17α-乙炔基睾酮及其衍生物、17α-乙炔基-19-降-睾酮及其衍生物、炔诺酮、醋酸炔诺酮、双醋炔诺醇、去氢孕酮、醋酸安宫黄体酮、异炔诺酮、烯丙雌烯醇、炔雌烯醇、fuingestanol acetate、美罗孕酮、诺孕烯酮、dimethiderome、炔孕酮、环丙孕酮、左旋炔诺孕酮、炔诺孕酮、d-17α-乙酰氧基-13β-乙基-17α-a-乙炔基-甾-4-烯-3-酮肟、环丙孕酮、孕二烯酮、去氧孕酮、酮去氧孕烯、炔诺肟酯、炔雌醇、氯地孕酮、双烯孕腈和曲螺酮。
13.根据权利要求10至12中任一项的可药用试剂盒,另外包括1至7个日剂量单位的可药用安慰剂。
14.根据权利要求10至13中任一项的适于每日经口施用的可药用试剂盒,其包括:
(a)活性剂的21个日剂量单位;以及
(b)口服和可药用安慰剂的7个日剂量单位。
15.根据权利要求10至13中任一项的适于每日经口施用的可药用试剂盒,其包括:
(a)活性剂的23个日剂量单位;以及
(b)口服和可药用安慰剂的5个日剂量单位。
16.根据权利要求10至13中任一项的适于每日经口施用的可药用试剂盒,其包括:
(a)活性剂的25个日剂量单位;以及
(b)口服和可药用安慰剂的3个日剂量单位。
17.根据权利要求10至13中任一项的适于每日经口施用的可药用试剂盒,其包括:
(a)活性剂的27个日剂量单位;以及
(b)口服和可药用安慰剂的1个日剂量单位。
18.根据权利要求10至17中任一项的可药用试剂盒,其中所述日剂量单位为片剂形式。
19.根据权利要求10至17中任一项的可药用试剂盒,其中所述日剂量单位为局部乳膏或凝胶形式。
20.根据权利要求10至17中任一项的可药用试剂盒,其中所述日剂量单位通过持续释放送递系统送递,所述持续释放送递系统选自经皮、跨粘膜或经阴道的药物送递系统。
21.根据权利要求10至20中任一项的试剂盒,其中所述黄体酮是5-(4,4-二甲基-2-硫代-1,4-二氢-2H-苯并[d][1,3]嗪-6-基)-1-甲基-1H-吡咯-2-腈。
22.育龄雌性避孕方法,其包括在连续18至28天的时间段向育龄雌性送递含有有效量活性剂的日剂量单位、继之为对受试者送递无有效量活性剂的连续1至7天,所述活性剂由黄体酮组成。
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CA2571377A1 (en) | 2006-02-09 |
AR049707A1 (es) | 2006-08-30 |
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AU2005269938A1 (en) | 2006-02-09 |
BRPI0512991A (pt) | 2008-04-22 |
JP2013040181A (ja) | 2013-02-28 |
US20060009428A1 (en) | 2006-01-12 |
CN104208067A (zh) | 2014-12-17 |
SV2006002165A (es) | 2006-05-09 |
JP5288796B2 (ja) | 2013-09-11 |
PE20060378A1 (es) | 2006-06-02 |
JP2008505909A (ja) | 2008-02-28 |
MXPA06014579A (es) | 2007-03-01 |
WO2006014476A1 (en) | 2006-02-09 |
US20140094458A1 (en) | 2014-04-03 |
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