CN1036835C - 多阶段结合的避孕药包的制备方法 - Google Patents

多阶段结合的避孕药包的制备方法 Download PDF

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CN1036835C
CN1036835C CN91111089A CN91111089A CN1036835C CN 1036835 C CN1036835 C CN 1036835C CN 91111089 A CN91111089 A CN 91111089A CN 91111089 A CN91111089 A CN 91111089A CN 1036835 C CN1036835 C CN 1036835C
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恩基尔泊特·W·贝尔金科
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Abstract

这里披露了多阶段结合的避孕药包的制备方法，该药包包括24个连续的日剂量单位，并分为三个阶段及无药丸的第四阶段，第四阶段也可是含相当于25-35μg去氧孕烯的孕激素的四个剂量单位，有关该制备方法的详细说明见本说明书。

Description

多阶段结合的避孕药包的制备方法
本发明涉及多阶段结合的避孕药包的制备方法。
由于用药丸控制生育方案已有记载，因此人们已设想在该方案中用更低的总甾体剂量，同时在所提供的避孕中保持该方案的安全性。
例如，Ortho Pharm Corp的美国专利4,628,051披露了一三阶段口服避孕药，其要被服用21天，其含雌激素和孕激素，其具有低的每月总甾体剂量，并且各阶段的雌激素量相同，在第一阶段中，每天服用含0.02-0.05mg乙炔雌二醇(“EE”)和0.065-0.7 5mg炔诺酮(“NE”)的5-8片片剂；在第二阶段中，服用含相同剂量EE和0.2 5-1mgNE的7-11片片剂；在第三阶段中，服用含相同剂量EE和0.3 5-2mgNE的3-7片片剂。而对一适当的避孕规范讲，如有7天没服药丸，则可导致卵泡的发展并因此而怀孕。另外，优选所述规范的使用者所服用的EE量为0.735mg，这对一些人来讲是一太大的剂量。类似的避孕规范也可见Ortho Pharm Corp的美国专利4,616,006，4,544,554和4,53 0,839。
Hesslinger的德国专利申请3,341,638披露了另一种三阶段避孕方案，其中避孕药丸要服21天。该规范的第一阶段含6粒药丸，每粒含30μgEE和0.75mg3-脱氧炔诺酮；第二阶段含5粒药丸，每粒含40μgEE和1.0mg3-脱氧炔诺酮；第三阶段含11粒药丸，每粒含30μgEE和1.5mg3-脱氧炔诺酮。这导致每个循环中总雌激素剂量为710μgEE。
另一个三阶段避孕方案中降低雌激素水平的设想见ScheringAG的比利时专利823,689中。在该避孕方案中共服用21粒药丸，第一阶段服4-6粒药丸，每粒含第一剂量雌激素(例如，30μgEE)和第一剂量孕激素(例如50μgD-18-甲炔诺酮)；第二阶段含4-6粒药丸，每粒含1-2倍于第一阶段的雌激素剂量和1-0.5倍于第一阶段的孕激素剂量；第三阶段含9-11粒药丸，每粒含相同或少于第一阶段的雌激素量和最多三倍于第一阶段的孕激素量。非常相似方案还可见于Schering AG的DE3,347,125中。
Sehering AG的另一专利申请(DT2，645，307)披露了28天，分三阶段治疗更年期疾病的治疗方法。在女性中建立的28-32天为一循环的甾体方案披露于Upjohn的美国专利3,639,600中，其中在治疗周期中服用了2.550mgEE。
CF & Co.AG的DT2，431，704披露了三阶段避孕药，其中在第一阶段，服用低剂量的雌激素(例如0.030mgEE)和孕激素(例如1.00mg炔诺酮乙酸酯)6-8天；在第二阶段，服用稍微增加剂量(＜2倍)的雌激素和稍微增加的孕激素(＜1.5倍)6-8天；在第三阶段，服用的雌激素不高于第二阶段的，增加孕激素剂量(＜第一阶段的3倍)，服用6-8天。但不管如何变化，在该具体方案中，仍服用了630μgEE。
Warner Lambert Co.的南非专利8509-892-A披露了3或4阶段口服避孕药方案，其具有相对高量的炔诺酮乙酸酯(即0.5-1.5mg)和相对低量的EE(10-50μg)或其它雌激素物质。四阶段方案要需23-34天，这包括无活性阶段。
美国人Home Proels的欧洲专利申请253,607披露了单阶段避孕制剂，其含23-25剂量单位，每单位含0.008-0.030mgEE和0.025-0.100mg去氧孕烯，其需服用23-25天，优选24天，顺后有2-5天不服药丸。
将连续口服避孕药中的雌激素降低到最小水平的另一设想披露于Unisearch Ltd的荷兰专利申请6911920中。该专利申请记载了一含至少28粒药丸的药包，其中25-27粒是活性的。在活性药丸中，17-20粒仅含雌激素(例如乙炔雌二醇)，其余的含雌激素和孕激素.低雌激素药丸含0.050-0.080mg雌激素，而高雌激素药丸含0.07-0.08mg雌激素。合并的药丸含0.07-0.12mg雌激素和0.8-1.4mg孕激素。即使用这种最小雌激素水平的避孕药，至少也要服用1.610mg雌激素，而在优选方案中，服用的是1.90mg。
AKZO的欧洲专利申请36,229披露了一种多阶段结合型的连续口服避孕药，其由20-22片片剂组成，每片含孕激素和雌激素。该第一阶段含相对低剂量的孕激素(例如，少于50μg去氧孕烯)，以后的阶段含更多孕激素(例如，在第二和第三阶段中分别为100μg和200μg去氧孕烯)。
现需要一种有效的低剂量避孕药使用方案，其有益于多阶段服用(例如，理想的循环控制)，而在无药粒期间仍能防止卵泡的发展。
现已发现，通过适当选择，在多阶段避孕方案中可得到低水平的雌激素剂量，该避孕药服用24天，而同时缓慢增加服用的孕激素，从而得到含低剂量雌激素和孕激素的高安全性的避孕方案。
因此本发明包括多阶段结合的避孕包，其至少包括三个阶段的避孕剂量。这三个阶段是由24天连续口服的日剂量单位组成，即第一阶段具有7-9个不同第一剂量单位，第一剂量单位含孕激素和雌激素，孕激素在日剂量中的活性相当于75-100μg去氧孕烯，雌激素在日剂量中的活性相当于2 5 μg乙炔雌二醇；第二阶段有7-9个第二剂量单位，每个第二剂量单位含孕激素和雌激素，孕激素的日剂量活性相当于100-125μg去氧孕烯，雌激素的日剂量活性相当于20μg乙炔雌二醇；第三阶段有7-9个第三剂量单位，每个第三剂量单位含孕激素和雌激素，孕激素在日剂量中的活性相当于125-150μg去氧孕烯，雌激素在日剂量中的活性相当于20μg乙炔雌二醇。
该避孕包含28个目剂量单位(即包括第四阶段)，其中第四阶段的日剂量单位不含避孕甾体(例如是“空白”或安慰剂或铁剂)。或者也可利用四天“无药丸”期，或者第四阶段也可是四个日剂量单位，日剂量单位含孕激素，孕激素在日剂量中的活性相当于25-35μg去氧孕烯。
本发明也包括避孕产品(即控制生育药包，其含剂量单位的避孕方案)，和制备该产品的方法。
优选用于本发明的孕激素包括： 3-酮去氧孕烯(“etonogestrel”)，去氧孕烯，左旋18-甲基炔诺酮，18-甲基炔诺酮，孕二烯酮和具有类似孕激素活性的其它化合物。特别优选的是3-酮去氧孕烯和去氧孕烯，从大概上讲，左旋18-甲基炔诺酮，去氧孕烯和3-酮去氧孕烯在孕激素活性上基本是等效力的。孕二烯酮的效力约是这些化合物的1.5倍。18-甲基炔诺酮的效力约是左旋18-甲基炔诺酮的0.5倍。
优选的雌激素包括17β-雌二醇和乙炔雌二醇。美雌醇和17-α-乙炔雌二醇3-甲基醚也是有用的雌激素。1mg17β-雌二醇在雌激素活性上大约相当于0.015mg乙炔雌二醇和0.030mg美雌醇。
雌激素和孕激素(“避孕甾体”)，或它们二者，被加入到口服单位剂量中。术语“剂量单位”一般指适用于人体或动物的单元剂量的物理分散单位，每单位含经计算能产生所要作用的预测量活性物质(例如，雌激素或孕激素)。
制备这些剂量单位的方法和组合物对本领域技术人员讲是已知的。例如，制备含活性成份的片剂和丸剂的方法和组合物见标准参考文献，Chase等人，Remington′s  PharmaceutiealSciences，(16th ed.，Ma ck  Publishing Co.，Ea sto n.PA，U.S.A.，1980)(“Remington′s”)，1553-1584页。制备粉剂和它们的组合物的方法见该参考文献的1535-1552页。将药物剂量制剂包衣的方法见Remington′s的1585-1593页。
对于制备剂量单位，如片剂，可考虑使用常规添加剂，如填充剂，着色剂，聚合物粘合剂等。一般在一或多种组合物中可使用不影响活性成份功能的任何药用添加剂。
加到给药组合物中的适宜载体包括以适量使用的乳糖，淀粉，纤维素衍生物等。优选乳糖作为载体。也可用载体混合物。
制备混合物和避孕药包的方法包括将预测量的孕激素和预测量的雌激素混合，然后将该混合物转变为第一剂量单位(例如，用该混合物和任何所需赋形剂填充成胶囊或压成片剂)；将预测量孕激素和预测量雌激素混合，然后将该混合物转变成第二剂量单位；和将预测量孕激素和预测量雌激素混合，然后将该混合物转变成第三剂量单位。
本发明制备避孕产品的优选方法包括通过已知技术将所需剂量的避孕甾体(即孕激素和有或无雌激素)加入到片剂中。含不同量和类型的避孕甾体的片剂可带不同颜色并保存在不同大小的药包中。含剂量单位的药包优选含24-28个按顺序放在其中的剂量单位。优选含28个剂量单位。
本发明的优选避孕方法包括给绝经前妇女服用：
头7-9天，分开服用含孕激素和雌激素的第一剂量单位，孕激素日剂量为相当于100μg去氧孕烯，雌激素日剂量为相当于25μg乙炔雌二醇；
下一个7-9天，服用含孕激素和雌激素的第二剂量单位，其中孕激素日剂量为相当于125μg去氧孕烯，雌激素日剂量为相当于20μg乙炔雌二醇；
再下一个7-9天，服用含孕激素和雌激素的第三剂量单位，其中孕激素日剂量为相当于150μg去氧孕烯，雌激素日剂量为相当于20μg乙炔雌二醇；和
下一个4天并完成该避孕周期，服用不含避孕甾体的剂量单位(即无药丸期)，或含孕激素的剂量单位，其中孕激素日剂量为相当于25-35μg去氧孕烯。第一、第二和第三剂量单位总共服用24天。完成避孕周期后，只要需要避孕，就重复该避孕周期。如需要，一或多个剂量单位可含一种铁盐(如75mg富马酸亚铁)。
优选避孕方案按下面时间用28天，施用于未成年女性：
(a)服用8天含25μg乙炔雌二醇和100μg去氧孕烯或
   相当量的其它孕激素的组合物；
(b)服用8天含20μg乙炔雌二醇和125μg去氧孕烯或
   等量的其它孕激素的组合物；
(c)服8天含20μg乙炔雌二醇和150μg去氧孕烯或等
   量的其它孕激素的组合物；和
(d)服4天含25-35μg去氧孕烯或等量的其它孕激素的
   组合物。
本发明通过下面的实例进一步解释。
             实例I片剂组成A.在第一阶段中：(8片)组分                 量(mg/片)乙炔雌二醇             0.025去氧孕烯               0.100马铃薯淀粉             8.000聚乙烯吡咯烷酮         2.400硬酯酸                 0.800二氧化硅               0.800dl-α-生育酚           0.080乳糖              qsad80.000B.在第二阶段中：(8片)  组分                    量(mg/片)乙炔雌二醇                0.020去氧孕烯                  0.125马铃薯淀粉                8.000聚乙烯吡咯烷酮            2.400硬脂酸                    0.800二氧化硅                  0.800dl-α-生育酚              0.080乳糖                  qsad80.00C.在第三阶段中：(8片)组分                    量(mg/片)乙炔雌二醇                0.020去氧孕烯                  0.150马铃薯淀粉                8.000聚乙烯吡咯烷酮            2.400硬脂酸                    0.800二氧化硅                  0.800dl-α-生育酚              0.080乳糖                  qsad80.00D.在第四阶段中：(4片)组分                    量(mg/片)去氧孕烯                  0.030马铃薯淀粉                  8.000聚乙烯吡咯烷酮              2.400硬脂酸                      0.800二氧化硅                    0.800dl-α-生育酚                0.080乳糖                    qsad80.000
                          实例II
除第四阶段用无甾体的片剂代替外，其余与实例I相同。
                          实例III片剂的组成：A.在第一阶段中：(8片)组分                     量(mg/片)乙炔雌二醇                 0.0253-酮去氧孕烯               0.100马铃薯淀粉                 8.000聚乙烯吡咯烷酮             2.400硬脂酸                     0.800二氧化硅                   0.800dl-α-生育酚               0.080乳糖                   qsad80.00B.在第二阶段中：(8片)组分                 量(mg/片)乙炔雌二醇             0.0203-酮去氧孕烯           0.125马铃薯淀粉             8.000聚乙烯吡咯烷酮         2.400硬脂酸                 0.800二氧化硅               0.800dl-α-生育酚           0.080乳糖               qsad80.00C.在第三阶段中：(8片)组分                 量(mg/片)乙炔雌二醇             0.0203-酮去氧孕烯           0.150马铃薯淀粉             8.000聚乙烯吡咯烷酮         2.400硬脂酸                 0.800二氧化硅               0.800dl-α-生育酚           0.080乳糖               qsad80.00D.在第四阶段中：(4片)组分                 量(mg/片)3-酮去氧孕烯            0.030马铃薯淀粉                8.000聚乙烯吡咯烷酮            2.400硬脂酸                    0.800二氧化硅                  0.800dl-α-生育酚              0.080乳糖                  qsad80.00
                          实例IV
除用不含甾体的片剂取代第四阶段外，其余与实例III相同。
                          实例V片剂组成：A.在第-阶段中：(8片)组分                    量(mg/片)微粒化雌二醇              3.0003-酮去氧孕烯              0.1000马铃薯淀粉                8.000聚乙烯吡咯烷酮            2.4000硬脂酸                    0.800二氧化硅                  0.800dl-α-生育酚              0.080乳糖                 qsad80.000B.在第二阶段中：(8片)组分                  量(mg/片)微粒化雌二醇            2.0003-酮去氧孕烯            0.125马铃薯淀粉              8.000聚乙烯吡咯烷酮          2.400硬脂酸                  0.800二氧化硅                0.800dl-α-生育酚            0.080乳糖                qsad80.000C.在第三阶段中：(8片)组分                  量(mg/片)微粒化雌二醇            2.0003-酮去氧孕烯            0.150马铃薯淀粉              8.000聚乙烯吡咯烷酮          2.400硬脂酸                  0.800二氧化硅                0.800dl-α-生育酚            0.080乳糖                qsad80.00D.在第四阶段中：(4片)组分                 量(mg/片)3-酮去氧孕烯           0.030马铃薯淀粉             8.000聚乙烯吡咯烷酮         2.400硬脂酸                 0.800二氧化硅               0.800dl-α-生育酚           0.080乳糖               qsad80.00
                          实例VI
除用不含避孕甾体的片剂代替第四阶段外，其余与实例V相同。
                          实例VII片剂组成：A.在第-阶段中：(8片)组分                  量(mg/片)乙炔雌二醇            0.025去氧孕烯              0.075马铃薯淀粉            8.000聚乙烯吡咯烷酮        2.400硬脂酸                0.800二氧化硅              0.800dl-α-生育酚               0.080乳糖                   qsad80.00B.在第二阶段中：(8片)组分                     量(mg/片)乙炔雌二醇                 0.020去氧孕烯                   0.125马铃薯淀粉                 8.000聚乙烯吡咯烷酮             2.400硬脂酸                     0.800二氧化硅                   0.800dl-α-生育酚               0.080乳糖                   qsad80.00C.在第三阶段中：(8片)组分                     量(mg/片)乙炔雌二醇                 0.020去氧孕烯                   0.150马铃薯淀粉                 8.000聚乙烯吡咯烷酮             2.400硬脂酸                     0.800二氧化硅                   0.800dl-α-生育酚               0.080乳糖                   qsad80.00D.在第四阶段中：(4片)组分                   量(mg/片)马铃薯淀粉               8.000聚乙烯吡咯烷酮           2.400硬脂酸                   0.800二氧化硅                 0.800dl-α-生育酚             0.080乳糖                 qsad80.00

Claims (8)

1.多阶段结合的避孕药包的制备方法，该药包包括三个阶段，所述三个阶段是由24个连续日剂量单位组成，其中：
第一阶段包括7-9个分开的第一剂量单位，该第一剂量单位含孕激素和雌激素，孕激素活性剂量相当于75-100μg去氧孕烯，雌激素活性剂量相当于25μg乙炔雌二醇；第二阶段包括7-9个第二剂量单位，每个第二剂量单位含孕激素和雌激素，孕激素活性剂量相当于100-125μg去氧孕烯，雌激素活性剂量相当于20μg乙炔雌二醇；和
第三阶段包括7-9个第三剂量单位，每个第三剂量单位含孕激素和雌激素，孕激素活性剂量相当于125-150μg去氧孕烯，雌激素活性剂量相当于20μg乙炔雌二醇，该方法包括：
将所述剂量孕激素与所述剂量雌激素混合，然后将该混合物转化为第一剂量单位，
将所述剂量孕激素与所述剂量雌激素混合，然后将该混合物转化为第二剂量单位，
将所述剂量孕激素与所述剂量雌激素混合，然后将该混合物转化为第三剂量单位。
2.权利要求1的方法，其还含第四阶段，第四阶段包括不合避孕甾体的4个剂量单位。
3.权利要求1的方法，其还包括第四阶段，该第四阶段包括4个剂量单位，每个剂量单位含孕激素，孕激素活性剂量相当于25-35μg去氧孕烯。
4.权利要求1，2或3的方法，其中所述孕激素选自去氧孕烯，3-酮去氧孕烯，左旋18-甲基炔诺酮，孕二烯酮和它们的混合物。
5.权利要求4的方法，其中所述孕激素是去氧孕烯或3-酮去氧孕烯。
6.权利要求5的方法，其中所述孕激素在第一剂量单位中是以100μg存在的，在第二剂量单位中以125μg存在，第三剂量单位中以150μg存在。
7.权利要求1，2或3的方法，其中所述雌激素选自17β-雌二醇，乙炔雌二醇，美雌醇，17α-乙炔雌二醇3-甲基醚，和它们的混合物。
8.权利要求7的方法，其中所述雌激素为17β-雌二醇或乙炔雌二醇。
CN91111089A 1990-12-13 1991-12-12 多阶段结合的避孕药包的制备方法 Expired - Fee Related CN1036835C (zh)

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