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CN1188189C - 基质层含有17-脱乙酰基诺孕酯的经皮贴片及基质的用途 - Google Patents

基质层含有17-脱乙酰基诺孕酯的经皮贴片及基质的用途 Download PDF

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CN1188189C
CN1188189C CNB96195390XA CN96195390A CN1188189C CN 1188189 C CN1188189 C CN 1188189C CN B96195390X A CNB96195390X A CN B96195390XA CN 96195390 A CN96195390 A CN 96195390A CN 1188189 C CN1188189 C CN 1188189C
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J·乔纳
J·奥德特
N·辛格
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Abstract

本发明涉及用于预防妇女排卵以及用于雌激素替代疗法的经皮贴片,所述贴片由背衬和基质层组成,所述基质层包括单独的或与雌激素结合的17-脱乙酰基诺孕酯和含硅氧烷和聚丁烯中至少一种的压敏粘合剂以及皮肤渗透促进剂的混合物。本发明还涉及上述基质用于制备预防妇女排卵和/或激素替代疗法的药物的用途。

Description

基质层含有17-脱乙酰基诺孕酯的经皮贴片及基质的用途
本发明涉及药物的经皮释放,更具体地说,它涉及把17-脱乙酰基诺孕酯单独或与雌激素,特别是炔雌醇结合经皮给药的贴片和方法。
诺孕酯(Ngm)和炔雌醇(EE)的组合物口服给妇女用作避孕药。Bringer J., Am.J.Obstet.Gynecol.(1992) 166:1969-77.McGuire,J.C.等,Am.J.Obstet.Gynecol.(1990) 163:2127-2131中暗示口服的Ngm代谢为17-脱乙酰基诺孕酯(17-d-Ngm)、3-酮诺孕酯和左炔诺孕酮(Lng),并且这些代谢产物对口服药物的药理反应起着主要作用。
Chien等的美国专利4,906,169描述了把雌激素类和孕激素类共同释放给妇女避孕的经皮贴片。其中提到EE作为可以从该贴片给药的雌激素而且提到Ngm和Lng作为可以给药的孕激素。
申请人没有看到描述有把17-d-Ngm单独或与任何雌激素通过经皮或其他给药途径给药的任何现有技术。
本发明提供了通过给妇女使用有效量的17-脱乙酰基诺孕酯来预防排卵或提供激素替代疗法的组合物和方法。一方面是把17-脱乙酰基诺孕酯与抑制排卵量的雌激素联合用药给妇女。该组合物优选经皮给药。
所以,本发明的一方面是预防妇女排卵的经皮贴片,它包括:背衬层;和,位于该背衬下面的基质层,该基质层包括17-d-Ngm和压敏粘合剂的混合物该贴片适合于对妇女皮肤的扩散传递并将抑制排卵量的17-d-Ngm用药到该皮肤上。
本发明的另一方面是把17-d-Ngm与雌激素给药于妇女的经皮贴片,它包括:背衬;和位于该背衬下面的基质层,该基质层包括17-d-Ngm、雌激素和压敏粘合剂的混合物,该贴片适合于对妇女皮肤的扩散传递,及把抑制排卵量的17-d-Ngm和雌激素通过皮肤给药于妇女。这些贴片也能用来提供激素替代疗法。
本发明提供了预防妇女排卵的组合物和方法,它包括给予抑制排卵量的17-脱乙酰基诺孕酯。有效量大约为150到350μg/天并优选175到300μg/天的17-脱乙酰基诺孕酯。一方面是把17-脱乙酰基诺孕酯与抑制排卵量的雌激素如炔雌醇联合用药。有效量大约为150到350μg/天并优选175到300μg/天的17-脱乙酰基诺孕酯和10到35μg/天的炔雌醇。
本发明的经皮贴片提供给妇女避孕。它们也适合于激素替代疗法。
该贴片为的是在较长的时期,一般1-7天并优选7天把17-d-Ngm,任选雌激素连续释放到皮肤上。
当该贴片用于避孕时,一般在月经循环的第5天放在皮肤上,按需要可到完全消耗的第21天替换。例如,对7天的贴片来说,在21天期间将需要3片贴片来释放药物。如果需要的话,在连续的月经循环第5天后可用一种安慰剂的贴片。对每次月经循环重复这种方法。
17-d-Ngm和雌激素都能抑制排卵,虽然通过不同途径。17-d-Ngm抑制黄体化激素(LH),而雌激素的主要作用是抑制刺激卵泡激素(FSH)的分泌。所以,按照本发明当把17-d-Ngm与雌激素联合给药时,通过抑制排卵刺激物和/或通过抑制卵泡的生长来预防排卵。相对于母体化合物(Ngm)或其代谢物来说,人们认为17-d-Ngm给药的优点在于17-d-Ngm对雄激素活性方面只有很小或没有抑制。
17-d-Ngm抑制排卵的有效剂量一般是在约150到350μg/天,优选175到300μg/天和更优选175到250μg/天的范围。本发明的贴片一般有10到50cm2的基底表面区(即与皮肤扩散接触的区域)。雌激素抑制排卵的有效剂量一般取决于联合用药的特定雌激素。例如,当雌激素是炔雌醇时,剂量一般至少是10μg/天,优选10到35μg/天和更优选大约20μg/天。该贴片将含有足够量的17-d-Ngm和,当存在时,雌激素来给消耗的贴片提供这种每日剂量。一般这种剂量大约为20μg/天到200μg/天,优选30到150μg/天的炔雌醇。
本发明的贴片是基质或单片型层状结构。这类经皮贴片在本领域是熟知的。它们包括与压敏粘合剂和背衬混合的药物基质层。该基质作为药物库并通过它把该贴片固定在皮肤上。使用前,该贴片也包括防水的衬里层。
背衬是不渗透药物和基质中的其他组分的并限定了该贴片的上表面。它可以是由聚合物的单层或膜组成,或是一个或多个聚合物层和金属薄层的层制品。适用于制作背衬薄膜的聚合物的例子有聚氯乙烯、聚偏二氯乙烯、聚烯烃类如乙烯-乙酸乙烯酯共聚物、聚乙烯和聚丙烯、聚氨酯以及聚酯类如聚对苯二甲酸乙二醇酯。
基质中的压敏粘合剂一般是聚丙烯酸酯、聚硅氧烷或聚异丁烯(PIB)溶液。这类压敏粘合剂在经皮领域中是熟知的。例如,参见《压敏粘合技术手册》第二版(1989)Van Nostrand,Reinhold。液状压敏聚丙烯酸酯粘合剂是通过在有机溶液中共聚一种或多种丙烯酸酯单体(把“丙烯酸酯”规定为包括丙烯酸酯和甲基丙烯酸酯两种)、一种或多种改性单体和一种或多种含有功能基团的单体得到的。用于制备这些聚合物的丙烯酸酯单体一般是4-17个碳原子的烷基丙烯酸酯,优选丙烯酸2-乙基己基酯、丙烯酸丁酯和甲基丙烯酸异辛酯。改良单体一般包括能改变聚合物的Tg的单体。用于本发明目的的这类单体是乙酸乙烯酯、丙烯酸乙酯和甲基丙烯酸乙酯及甲基丙烯酸甲酯,含有功能性基团的单体提供了可以交联的部位。这些单体的功能基团优选为羧基、羟基或其混合物。提供这类基团的单体有丙烯酸、甲基丙烯酸和含有羟基的单体如丙烯酸羟基乙酯。最好用交联剂交联该聚丙烯酸酯粘合剂来改善它们的物理性能(如蠕变和剪切阻力)。由于交联程度越高将会有害地影响该共聚物的粘合性能,所以交联密度应当较低。在美国专利5,393,529中公开了交联剂的例子。溶液型聚丙烯酸酯压敏粘合剂可从3M得到市售的商标为如GELVATM和DURO-TAKTM的产品。
聚异丁烯粘合剂是高分子量(HMW)PIB和低分子量(LMW)PIB的混合物。在现有技术中如PCT/US91/02516中描述了这类混合物。HMW PIB的分子量通常在大约700,000到2,000,000Da的范围,而LMW PIB的分子量一般在大约35,000到60,000Da范围内。本文所指的分子量是重均分子量。在该粘合剂中HMW PIB与DMW PIB的重量比一般为1∶1到1∶10。PIB粘合剂一般也包括一种增粘剂如聚丁烯油和高Tg,低分子量的脂,族树脂如从Exxon Chemical得到的ESCOREZTM树脂。聚异丁烯聚合物可从Exxon Chemical得到市售的商标为VISTANEX的产品。
在形成基质中所用的聚硅氧烷粘合剂一般是高分子量的聚二甲基硅氧烷或聚二甲基二苯基硅氧烷。美国专利5,232,702、4,906,169和4,951,622中描述了在经皮贴片中可用的聚硅氧烷粘合剂的配方。
在基质中可与17-d-Ngm结合的雌激素包括17-J-雌二醇及其酯如戊酸雌二醇酯、环戊丙酸雌二醇酯、乙酸雌二醇、苯甲酸雌二醇酯和庚酸雌二醇酯(EE)。对用于结合17-d-Ngm来说,庚酸雌二醇酯(EE)是优选的雌激素。EE/17-d-Ngm结合物可以有益地影响代谢参数从而提高血浆高密度脂蛋白和降低血浆中低密度脂蛋白/高密度脂蛋白比。
除了压敏粘合剂、17-d-Ngm和任选的雌激素外,该基质一般包括足量的渗透促进剂来增加17-d-Ngm和雌激素穿过皮肤的渗透性并提供上述范围内的助熔剂。可包括在基质中的皮肤渗透促进剂的例子在美国专利5,059,426、4,973,468、4,906,463和4,906,169中进行了描述,并且包括但不限定为C12到C18脂族醇的乳酸酯、乳酸十二烷基酯、油酸或PGML。包括在基质中的渗透促进剂的量一般取决于所用的特殊促进剂。在多数情况中,该促进剂占该基质重量的1到20%的范围。
根据所用的特殊粘合剂,该基质可以包括其它添加剂。例如可以包括抑制药物结晶的物质如聚乙烯吡咯烷酮(PVP)、改善磨损周期的亲水剂或改善该基质的物理(如冷流动)或粘合剂(如粘着性、粘结强度)特性的添加剂。
对激素替代疗法来说,也可以使用上述贴片。当用于提供激素替代疗法时,构建基质以提供用于该目的的有效量的17-d-Ngm和雌激素。一般,提供大约150到350μg/天,优选大约175到300μg/天的17-d-Ngm及共同给药的大约5到45μg/天优选大约10到35μg/天的炔雌醇来构建基质及其贴片。在另一个实施方案中,该贴片将提供约200到350μg/天,优选大约175到300μg/天的17-d-Ngm及共同给药的大约20到175μg/天和优选大约30到150μg/天的17-β-雌二醇。对治疗来说,贴片可用7天然后用新贴片(7天)替换。
用经皮贴片领域中已知的步骤可以制备本发明的贴片。该步骤一般包括配制基质(即混合粘合剂、药物、渗透促进剂和添加剂,如果必要的话),把基质充填到背衬或释放垫层上,从该基质中除去溶剂并应用背衬/释放垫层。正如本领域普通技术人员所显而易见的,能够把其中分散有有效量药物的基质组合物搀入各种经皮结构中,所以申请人没有限定在下列举例的实施方案。
下列实施例进一步详细说明本发明。这些实施例不是以任何方式限定本发明。除非另有说明,所述的百分比按重量计。
实施例
实施例1
Duro-Tak 87-2287是从National Starch and Chemical Co.得到的聚丙烯酸酯粘合剂的溶液。它的单体组分为:  乙酸乙烯酯、丙烯酸2-乙基己基酯、丙烯酸羟乙基酯和甲基丙烯酸缩水甘油酯。它不包括交联剂。它以50%固体的乙酸乙酯溶液得到。
配制Duro-Tak 87-2287、0.26%乙酰丙酮酸铝交联剂、6%的17-d-Ngm、1%EE和各种渗透促进剂的混合物。在3M 1022背衬上固化这些混合物并铸成100微米厚(湿的)层,干燥。按照U.S.5,252,334第7栏中所描述的,在所得到的组件上进行皮肤通量试验。用HPLC测定17-d-Ngm和EE。将记有Diedoarray检测器的Perkin ElmerHPLC系统分别设定在245nm和215nm来测定17-d-Ngm和EE。流动相是55%的水、45%的乙腈,流速为1.0ml/分钟。对17-d-Ngm和EE来说,保留时间为4.5和3.0分钟。下表1显示了配方和流量试验的结果。
                    表1
                         流量(ug/cm 2 /hr)
配方            17-d-Ngm        EE
2%TG+4%OL      0.30±0.04       0.061±0.007
2%TG+10%ML     0.39±0.03       0.076±0.005
2%TG+4%PGML    0.29±0.06       0.0571±0.009
3%TG            0.24±0.06       0.043±0.011
4%TG+15%ML     0.38±0.001      0.072±0.002
TG=硫代甘油    OL=油酸
ML=月桂酸甲酯  PGML=单月桂酸丙二醇酯
实施例2
硅氧烷4202是从Dow Corning得到的一种聚二甲基硅氧烷粘合剂。把它与17-d-Ngm、EE、7%PVP(从BASF得到的K30,溶于正丙醇中)和各种促进剂混合。在3M 1022聚酯背衬上将这些混合物制成100微米的厚层(湿的)并干燥。如实施例1所述的所得到的组件上进行皮肤流量试验。下表2报道了该配方的详细情况和流量试验的结果。
                   表2
             配方                          流量(μg/m2/小时)
%17-d-Ngm  %EE   促进剂                17-d-Ngm   EE
4            0.5     5%ML+1%TG            0.65±0.09  0.069±0.007
6            0.5     5%ML+1%TG            0.60±0.04  0.043±0.004
6            0.5     14%PGML               0.48±0.04  0.070±0.01
6            0.5     14%(TC;PGML;80∶20) 0.58±0.05  0.062±0.01
*4           0.5     4%TG+5%ML            0.64±0.01  0.078±0.01
4            0.5     2%ML                  0.51±0.08  0.074±0.008
2            0.5     2%TG+2%ML            0.71±0.09  0.18±0.02
*包括14%PVP而不是7%PVP。
TC=透皮醇(Transcutanol)
实施例3
在硅氧烷粘合剂-17-d-Ngm/EE贴片上用两种类型的PVP进行对比研究:一种是从BASF得到的可溶性低分子量的PVP定义为PVP-K30和一种是从BASF得到的不溶性交联微化的PVP定义为PVP-CLM。
把PVP-K30溶于无水乙醇中。制备17-d-Ngm、EE和PVP-K30的混合物,然后再加入硅氧烷4202和月桂酸甲酯。把该混合物搅拌过夜。把混合物涂覆在3M1022衬垫上厚度为15mil(湿的)并在700℃干燥40分钟。
可得到PVP-CLM的微粉化的固体。把硅氧烷4202和PVP-CLM混合在一起,然后加入月桂酸甲酯、EE、17-d-Ngm和乙醇。搅拌混合物过夜并如上所述在3M1022衬垫上涂覆和干燥。
如实施例1所述在上述组件上进行皮肤通量试验。下列表3报道了这些配方的内容和皮肤通量试验的结果。
                       表3
                                 通量(μg/cm2/hr)
配方                           17-d-Ngm       EE
0.1%EE,1%17-d-Ngm,5%ML,   0.49±0.02      0.05±0.002
7%PVP-CLM,86.9%硅氧烷
0.1%E E,1%17-d-Ngm,5%ML,  0.37±0.07      0.04±0.008
7%PVP-K30,86.9%硅氧烷
实施例4
把VISTANEX  L100、Vistanex LM-MSLC和聚丁烯(IndopolH1900)溶于己烷中来制备PIB溶液。制备PVP-CLM、17-d-Ngm、EE和各种促进剂的乙醇/乙酸乙酯悬浮液。把PIB溶液加入药物悬浮液中并把所得到的混合物完全混合。在释放衬垫上涂覆10mil厚(湿的)的混合物并在70℃干燥40分钟。把Saranex 2015背材用薄板覆盖在组件上。如实施例1所述在上述组件上进行皮肤通量试验。下列表3报道了这些集合的内容和皮肤通量试验的结果。
                                            表4
                                                                      通量(μg/cm2/hr)
PIB *   %EE  %17-d-Ngm  %PVP-CLM      %促进剂%              17-d-Ngm    EE
1∶5∶4  0.3    4.0          20              15.山梨酸二丁酯          0.23±0.02  0.06±0.005
1∶5∶4  0.2    1.0          20              5.AMIFAT                 0.32±0.02  0.05±0.004
1∶5∶4  0.2    4.0          20              5.月桂酰N,N-二甲基酰胺  0.33±0.02  0.04±0.001
2∶4∶4  0.3    4.0          20              20.月桂酸丙酯            0.35±0.09  0.06±0.002
1∶5∶4  0.2    2.0          20              5.月桂酰二乙醇胺         0.40±0.05  0.06±0.001
1∶5∶4  0.3    4.0          20              15.棕榈酸异丙酯          0.44±0.06  0.07±0.001
1∶5∶4  0.3    4.0          20              15.油酸乙酯              0.46±0.06  0.10±0.001
1∶5∶4  0.3    4.0          20              8.PGIS                   0.48±0.04  0.10±0.001
1∶5∶4  0.2    2.0          20              3.油酸                   0.60±0.11  0.06±0.002
1∶5∶4  0.2    3.0          20              3.油酸                   0.60±0.24  0.04±0.002
1∶5∶4  0.2    2.0          20              10.PGML                  0.59±0.05  0.09±0.001
1∶5∶4  0.2    3.0          20              10.PGML                  0.67±0.07  0.07±0.001
1∶5∶4  0.3    4.0          20              8/3.PGML/油酸            0.79±0.04  0.14±0.001
1∶5∶4  0.2    2.0          20              10/0 5.PGML/油酸         0.68±0.09  0.10±0.001
*Vistanex L100∶Vistanex LM-MS-LC∶聚丁烯的重量比
AMIFAT来自甘油、油酸和2-吡咯烷酮-5-甲酸。
PGIS=异硬脂酸丙二醇酯。
*Vistanex L100∶Vistanex LM-MS-LC∶聚丁烯的重量比
AMIFAT来自甘油、油酸和2-吡咯烷酮-5-甲酸。
PGIS=异硬脂酸丙二醇酯。
实施例5
如下制备适合于激素替代疗法的组合物和基质。把2%17β-雌二醇、2%17-去乙酰基诺孕酯、20%PVP-CLM和76%PIB粘合剂(1∶5∶2.5∶1.5Vistanex L100∶Vistanex LM-MS-LC∶聚丁烯∶Zonester 85FG)溶于己烷、乙酸乙酯和乙醇的混合物中。把它涂覆到聚酯释放衬垫上并在70℃干燥45分钟。在通量试验之前使用聚酯背材。如实施例1所描述的进行通量试验。
                  表5
甾体                       通量(μg/cm2/hr)
17-d-Ngm                   0.10
17-β-雌二醇               0.20
实施例6
如下制备具有由PIB粘合剂、PVP-CLM、乳酸月桂酯或肉豆蔻酯、17-d-Ngm和EE组成的基质的经皮贴片:
把17-d-Ngm和EE溶于乙酸乙酯并向该溶液中加入PVP-CL和乳酸月桂酯或乳酸肉豆蔻酯(从新泽西Belleville的ISP VanDYK得到)。在剧烈混合下把PIB粘合剂(1∶5∶4Vistanex L100∶Vistanex LM-MS-LC∶Indopol H 1900)的己烷溶液加入甾体溶液中。把10%PVP-CLM重量的的N-丙醇缓慢加入最终组合物中。把该混合物涂覆在释放衬垫上并在70℃干燥40分钟。干燥的基质重量为7.5mg/cm2。把基质释放衬垫组件用薄板覆盖在聚酯(Scotchpak 1012)背衬上。把其它组件用薄板覆盖在非纺织的聚酯层(Remay 2250)。把释放层从背衬组件上取下并把它涂到非纺织层组件而得到5层由背衬/粘合剂基质/非纺织/粘合剂基质/释放衬垫组成的层。
如实施例1中所述在这些贴片上进行皮肤流通量试验。下表5报道了这些贴片的内容和通量试验的结果。
                            表6
基质配方        皮肤渗透性   17-d-Ngm通量    EE通量
                             (μg/cm2/小时) (μg/cm2/小时)
72.85%PIB      低            0.23           0.02
20%PVP-CLM     中等          0.45           0.05
0.15%EE        高            0.82           0.08
5%乳酸月桂酯
70.8%PIB       低            0.20           0.03
20%PVP-CLM     中等          0.55           0.08
0.2%EE
2%17-d-Ngm
7%乳酸月桂酯
72.8%PIB       -             0.64           0.09
20%PVP-CLM
0.2%EE
2%17-d-Ngm
5%乳酸肉豆蔻酯
对实施本发明来说,经皮贴片领域普通技术人员对上述模式进行的显而易见的改良也包括在下列权利要求的范围中。

Claims (26)

1.预防妇女排卵的经皮贴片,它包括:
(a)背衬;和
(b)位于该背衬下面的基质层,该基质层包括抑制排卵量的17-脱乙酰基诺孕酯和含硅氧烷和聚异丁烯中至少一种的压敏粘合剂以及皮肤渗透促进剂的混合物。
2.根据权利要求1的贴片,其中所述量是175到300μg/天。
3.根据权利要求1的贴片,其中压敏粘合剂是聚异丁烯。
4.根据权利要求1的贴片,其中皮肤渗透促进剂选自C12到C18脂族醇的乳酸酯、油酸或单月桂酸丙二醇酯。
5.根据权利要求4的贴片,其中皮肤渗透促进剂是乳酸十二烷基酯。
6.预防妇女排卵或为妇女提供激素替代疗法的经皮贴片,它包括:
(a)背衬;和
(b)位于该背衬下面的基质层,该基质层包括抑制排卵量的17-脱乙酰基诺孕酯、雌激素和含硅氧烷和聚异丁烯中至少一种的压敏粘合剂以及皮肤渗透促进剂的混合物。
7.根据权利要求6的贴片,其中压敏粘合剂是聚异丁烯。
8.根据权利要求6的贴片,其中雌激素是雌二醇。
9.根据权利要求8的贴片,其中雌二醇是炔雌醇或17-β-雌二醇。
10.根据权利要求9的贴片,其中雌二醇是炔雌醇。
11.根据权利要求10的贴片,其中所述量是175到300μg/天的17-脱乙酰基诺孕酯和10到35μg/天的炔雌醇。
12.根据权利要求9的贴片,其中雌二醇是17-β-雌二醇。
13.根据权利要求12的贴片,其中所述量是175到300μg/天的17-脱乙酰基诺孕酯和30到150μg/天的17-β-雌二醇。
14.根据权利要求6的贴片,其中皮肤渗透促进剂选自C12到C18脂族醇的乳酸酯、油酸或单月桂酸丙二醇酯。
15.根据权利要求14的贴片,其中皮肤渗透促进剂是乳酸十二烷基酯。
16.包括抑制排卵量的17-脱乙酰基诺孕酯和含硅氧烷和聚异丁烯中至少一种压敏粘合剂以及皮肤渗透促进剂的混合物的基质用于制备预防妇女排卵的经皮贴剂的用途。
17.根据权利要求16的用途,其中所述量是175到300μg/天。
18.包括抑制排卵量的17-脱乙酰基诺孕酯、雌激素和含硅氧烷和聚异丁烯中至少一种压敏粘合剂以及皮肤渗透促进剂的混合物的基质用于制备预防妇女排卵的经皮贴剂的用途。
19.根据权利要求18的用途,其中雌激素是炔雌醇。
20.根据权利要求19用途,其中的量是175到300μg/天的17-脱乙酰基诺孕酯和10到35μg/天的炔雌醇。
21.包括治疗量的17-脱乙酰基诺孕酯和含硅氧烷和聚异丁烯中至少一种压敏粘合剂以及皮肤渗透促进剂的混合物的基质用于制备妇女激素替代疗法所用药物的用途。
22.根据权利要求21的用途,其中17-脱乙酰基诺孕酯的量是175到300μg/天。
23.包括治疗量的17-脱乙酰基诺孕酯、雌激素和含硅氧烷和聚异丁烯中至少一种压敏粘合剂以及皮肤渗透促进剂的混合物的基质用于制备妇女激素替代疗法所用药物的用途。
24.根据权利要求23的用途,其中雌激素是炔雌醇。
25.根据权利要求24的用途,其中17-脱乙酰基诺孕酯的量是175到300μg/天而炔雌醇的量是10到35μg/天。
26.预防妇女排卵的经皮贴片,其包括:
a)背衬层;和
b)位于背衬层下的基质层,基质层包括排卵抑制量的17-脱乙酰基诺孕酯、聚异丁烯压敏粘合剂、聚乙烯吡咯烷酮以及皮肤渗透促进剂的混合物。
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NO975586D0 (no) 1997-12-03
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WO1996040355A1 (en) 1996-12-19
HUP9802326A2 (hu) 1999-02-01
MX9709666A (es) 1998-10-31
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US5876746A (en) 1999-03-02
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CA2222133A1 (en) 1996-12-19
UA48973C2 (uk) 2002-09-16
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AU703593B2 (en) 1999-03-25
DK0836506T4 (da) 2012-01-30
RU2177311C2 (ru) 2001-12-27
CA2222133C (en) 2002-12-24
PL323729A1 (en) 1998-04-14
HUP9802326A3 (en) 1999-07-28
DE69625483T2 (de) 2003-10-30
EP0836506B1 (en) 2002-12-18
AU6259796A (en) 1996-12-30
IL122432A0 (en) 1998-06-15
EP0836506A4 (en) 1999-05-26
EP0836506B2 (en) 2011-12-21
CN1190351A (zh) 1998-08-12
DK0836506T3 (da) 2003-04-07
KR100301226B1 (ko) 2002-07-06
US5972377A (en) 1999-10-26
ES2190472T3 (es) 2003-08-01
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HU228434B1 (en) 2013-03-28
US6071531A (en) 2000-06-06
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EP0836506A1 (en) 1998-04-22
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ATE229828T1 (de) 2003-01-15
DE69625483T3 (de) 2012-05-10

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