CN1346281B - 用于制备有计划地实施受控卵巢刺激的药物的用途 - Google Patents
用于制备有计划地实施受控卵巢刺激的药物的用途 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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Abstract
在通过有计划地实施受控卵巢刺激(COS)和辅助生殖操作过程(ART)而进行不育症的治疗管理方法中，改进之处包括：a)在具有多个卵泡和卵母细胞成长的受控卵巢刺激(COS)和辅助生殖技术(ART)中利用LHRH拮抗剂来抑制过早排卵，b)通过只服用孕激素或者是复合口服避孕药制剂，可以有计划地开始受控卵巢刺激(COS)，c)对卵巢的卵泡的生长给予外原刺激，d)利用HCG、天然的LHRH、LHRH拮抗剂或重组体LH诱导排卵，e)应用辅助生殖技术，特别是IVF、ICSI、GIFT、ZIFT或通过精子注射进行子宫内授精。
Description
发明领域
妇女只有在有限的时间内才能生育。每十对夫妇中就有一对夫妇不能要孩子。要孩子的愿望实现不了的原因与母亲的因素(例如输卵管阻塞或缺失、多囊卵巢疾病)，或者与父亲的因素(例如精子游动不充分)有关。
为了解决这个难题，利用促性腺激素例如HMG(人绝经期促性腺激素)、FSH(促卵泡激素)或者通过利用抗雌激素克罗米酚和促性腺激素可使不能生育的夫妇中的母体产生卵巢刺激。这种治疗方法通过利用高度专业的实验室技术可刺激一个包括6-12个卵泡和卵母细胞的群体生长，以确保有足够的卵母细胞授精。在该治疗过程中，通过服用LHRH类似物(或者是LHRH拮抗剂，或者是LHRH兴奋剂)，可避免由LH和黄体酮激增而显示的过早排卵现象。
背景资料和已有技术
按照已知的治疗方案，在月经周期的第2天给服HMG。通过服用单或多剂量的0,25mg-5mgLHRH拮抗剂西曲瑞利克斯(Cetrorelix)，可在第5天避免LH激增，一直到用HCG诱导的排卵日为止(包括排卵日)(Hum.Reprod.1994May；9(5)：788-91，Hum.Reprod.1995 Jun；10(6)：1382-6，Fertil.Steril.1997；67：917-22，Hum.Reprod.1998 Sep；13(9)2411-4)。
在PCT申请WO98/58657中，在该方法中服用0,125-1mg的LHRH拮抗剂加尼瑞利克斯(ganirelix)，以便防止经受合并有外原FSH的受控的卵巢过度刺激的妇女过早产生LH激增。
EP161063还教导，在治疗妇女不育症以便抑制雌激素变异的过程中使用释放激素拮抗剂的促性腺激素，以便制备包括从HMG和FSH中选择的促性腺激素的药物组合物，在该治疗方法中，有效量的拮抗剂组合物与促性腺激素组合物一同服用。
通常为了控制诱发排卵和最终使卵泡成熟，要给服HCG(人绒毛膜促性腺激素)。此后36小时，通过经阴道的或腹腔镜卵泡穿刺术，可采集卵母细胞(OPU)。
为了使多个卵母细胞能够被父体的精子授精，可以于OPU那一天在高度专业的实验室中应用辅助生殖技术(ART)，例如IVF(体外授精法)、ICSI(胞质内精子注射法)、GIFT(配子输卵管内转移法)或ZIFT(合子输卵管内转移法)。
通常，在体外授精之后的2-4天，通过将几个胚胎放入子宫腔内以便实现妊娠可完成胚胎转移法。
由于许多卵泡的成长都伴随着受控卵巢刺激疗法(COS)，因此卵巢被扩大并且许多卵母细胞被采集。于是，卵母细胞的采集操作得在手术示范室中进行，并且需要应用全身或局部麻醉术。
此后可在高度专业的实验室中由可胜任的技术人员来完成辅助生殖技术。
优选的是，这些操作过程得包括在从星期一至星期五的常规手术示范计划中。在周末或假期完成卵母细胞的采集和胚胎的转移可避免在多数诊所中由于上班时缺乏足够的可胜任的技术人员而导致的麻烦。而且，一些医院每个月只有几天可承担这些操作，以便由高度专业的服务队伍来完成卵母细胞的采集和授精操作，从而增加所得到的卵母细胞的数目以及授精速率和高质量的胚胎数目。因此，需要有计划地(programmed)实施卵巢刺激方案。
发明目的
本发明特别涉及有计划地实施卵巢刺激过程的方法的改进，即，在受控卵巢刺激中服用LHRH拮抗剂，其中有计划地开始月经周期和卵巢的刺激。
发明概述
在为了避免过早排卵而用LHRH拮抗剂进行受控卵巢刺激的过程中，在月经周期的循环第1-3天开始注射促性腺激素，并持续到给服HCG的那一天为止，此时已经长成足够大的卵泡。
在有过早排卵危险的那一天给服LHRH拮抗剂。在这些治疗周期内卵巢刺激的期限通常为10天。
为了在星期一至星期五完成卵母细胞的采集和授精操作，可以有计划地开始月经周期和COS。
为了有计划地开始月经周期和受控卵巢刺激操作过程，在卵泡阶段、优选的是在月经周期开始的第1或2天或者在前一月经周期的晚黄体阶段，给服口服避孕药或只含孕激素的药剂。
以前为了此目的还成功地使用了LHRH拮抗剂Cetrorelix，即在黄体阶段给服1mg的剂量并且黄体消退2-4天后月经开始。
口服避孕药或孕激素服用的期限最少为10天，最多为25天。优选的是在星期一至星期四服用最后一片，以便在星期五至星期一月经开始出血并开始卵巢刺激疗法。此后，在星期一至星期四安排并从事卵母细胞的采集和其它ART操作过程。在受控的卵巢刺激过程中，所应用的用于阻止过早排卵的LHRH拮抗剂例如可以是cetrorelix、特威瑞利克斯(teverelix)、ganirelix、安替德(antide)或阿巴瑞利克斯(abarelix)。
在本发明范围内的另一方面是，通过口服孕激素制剂、乙炔基雌二醇和孕激素、含有避孕药制剂的复合一、二、三相避孕药制剂、美雌醇和孕激素以及通过皮下注射LHRH拮抗剂，可以有计划地实施COS和ART过程。
LHRH拮抗剂可以是cetrorelix、teverelix、ganirelix、antide或abarelix，并且应该在黄体阶段以0,5mg-10mg的剂量服用。通过服用尿液提取的或重组体FSH或HMG、使用或不用重组体LH，但利用抗雌激素(例如克罗米酚)，还联合使用抗雌激素(例如克罗米酚与促性腺激素)，可实施卵巢刺激。
本发明还涉及一种通过有计划地实施受控卵巢刺激(COS)和辅助生殖操作过程(ART)而进行不育症的治疗的药剂盒，包括：a)在受控卵巢刺激(COS)和辅助生殖技术(ART)中来抑制过早排卵的LHRH拮抗剂，b)用于有计划地开始受控卵巢刺激(COS)的单独的孕激素或者是复合口服避孕药制剂，c)对卵巢的卵泡的生长给予外原刺激的制剂，d)由于诱导排卵的HCG、天然的LHRH、LHRH拮抗剂或重组体LH，e)用于进行辅助生殖技术，特别是IVF、ICSI、GIFT、ZIFT或通过精子注射进行子宫内授精的该药剂盒的使用说明书。
本发明还提供了下列成分a、b、c和d按顺序相结合用于制备通过有计划地实施受控卵巢刺激和辅助生殖操作过程而进行不育症的治疗的药物产品的用途：
a)在受控卵巢刺激和辅助生殖技术中来抑制过早排卵的LHRH拮抗剂，
b)用于有计划地开始受控卵巢刺激的单独的孕激素或者是复合口服避孕药制剂，
c)对卵巢的卵泡的生长给予外源刺激的制剂，
d)用于诱导排卵的入绒毛膜促性腺激素。
在优选的实施方案中，服用单独的孕激素或者是复合口服避孕药制剂的时间范围是最少10天，最多25天。优选在卵泡阶段给服口服避孕药或只含孕激含孕激素的药剂从而有计划地开始月经周期和受控卵巢刺激操作过程。
在优选的实施方案中，在星期一至星期四服用最后一次只含孕激素的药剂或复合口服避孕药制剂，以便在星期五至星期一月经开始出血并开始卵巢刺激疗法，并且其后，在星期一至星期四安排并从事卵母细胞的采集和进一步的辅助生殖技术操作过程。
在优选的实施方案中，所述LHRH拮抗剂是西曲瑞利克斯、特威瑞利克斯、加尼瑞利克斯、安替德或阿巴瑞利克斯。
实施例
材料及方法
总共30个病人，来自每个德国研究中心的15人被作为一个治疗周期的会员。在前治疗周期内，每个病人服用单相口服避孕药(OC)丸，该药丸含有30μg复合有左炔诺孕酮(levonogastrel)的雌二醇。在OC治疗之后停止出血的第一天开始服用150IU或225IU的Gonal-从实施刺激的第5天晚上/第6天早晨开始每天给服0.25mg的西曲泰德直到服用hCG之前的那一天为止。在第9/10天实施超声扫描的基础上以及计算出卵泡每天长2mm，服用hCG以便触发排卵(此时大于等于18mm的2个卵泡是可见的)。所估计的有效终点包括第9/10天≥18mm的卵泡数目、所用的瓶数和Gonal-安瓿数、和Gonal-治疗期限、服用hCG的病人数、实施卵母细胞提取的病人数、卵母细胞提取个数、预定卵母细胞提取日的可靠性以及妊娠率。可指示出安全终点和不利事件的严重性。
结果
来自17个病人的初步结果表明，在第9/10天≥18mm的卵泡平均数目是2,2。在服用的最后一天，直径≤14mm、15-17mm及≥18mm的卵泡平均数目分别是2.7，4.9及2.7。24安瓿、75IU的Gonal-的中间数目需服用10天，并且每天注射0,25mg的分别平均注射5.7天。所有服用hCG的17个妇女都接受卵子采集和胚胎转移。总之，有8,8个卵母细胞平均数目被提取并且有2个胚胎平均值被转移。
每次尝试/周期的妊娠率为41％。OPU的预定日与实际日之差平均为2天。没有OHSS情况或恶性事件发生。
结论
这是在由Ocs有计划地实施COS的周期内使用
的首要结果。总之，该刺激结果类似于非计划性周期中观察到的结果。
在OC计划性周期中似乎是有效的、耐受性好并且预定的卵母细胞提取日可靠。因此在计划性刺激周期中使用代表另一步骤，即ART中耐受性好、有效便利的操作过程。
是注册的LHRH拮抗剂cetrorelix的商品名。
此处业已描述的这些不同的实施例都是代表性的，而非限定性的，因为在不脱离本发明的精髓和范围的情况下，可对本发明进行各种变型和改进。
Claims (10)
1.下列成分a、b、c和d按顺序相结合用于制备通过有计划地实施受控卵巢刺激和辅助生殖操作过程而进行不育症的治疗的药物产品的用途：
a)在受控卵巢刺激和辅助生殖技术中来抑制过早排卵的LHRH拮抗剂，
b)用于有计划地开始受控卵巢刺激的单独的孕激素或者是复合口服避孕药制剂，
c)对卵巢的卵泡的生长给予外源刺激的制剂，
d)用于诱导排卵的人绒毛膜促性腺激素。
2.根据权利要求1所述的用途，其中服用单独的孕激素或者是复合口服避孕药制剂的时间范围是最少10天，最多25天。
3.根据权利要求1所述的用途，其特征在于在卵泡阶段给服口服避孕药或只含孕激素的药剂从而有计划地开始月经周期和受控卵巢刺激操作过程。
4.根据权利要求3所述的用途，其特征在于在月经周期开始的第1或2天或者在前一月经周期的晚黄体阶段给服口服避孕药或只含孕激素的药剂从而有计划地开始月经周期和受控卵巢刺激操作过程。
5.根据权利要求1所述的用途，其特征在于在星期一至星期四服用最后一次只含孕激素的药剂或复合口服避孕药制剂，以便在星期五至星期一月经开始出血并开始卵巢刺激疗法，并且其后，在星期一至星期四安排并从事卵母细胞的采集和进一步的辅助生殖技术操作过程。
6.按照权利要求1所述的用途，其中LHRH拮抗剂是西曲瑞利克斯。
7.按照权利要求1所述的用途，其中LHRH拮抗剂是特威瑞利克斯。
8.按照权利要求1所述的用途，其中LHRH拮抗剂是加尼瑞利克斯。
9.按照权利要求1所述的用途，其中LHRH拮抗剂是安替德。
10.按照权利要求1所述的用途，其中LHRH拮抗剂是阿巴瑞利克斯。
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| EP1719504A1 (de) * | 2005-05-02 | 2006-11-08 | Schering AG | Festes transdermales therapeutisches System mit UV-Absorber |
| US8962013B2 (en) * | 2005-05-02 | 2015-02-24 | Bayer Intellectual Property Gmbh | Multi-layered transdermal system with triazine UV absorber |
| CA2615795C (en) * | 2005-07-22 | 2013-05-28 | Takeda Pharmaceutical Company Limited | Premature ovulation preventive agent |
| ES2607150T3 (es) * | 2012-11-09 | 2017-03-29 | Iasomai Ab | N-acetil-L-cisteína para su uso en la fertilización in vitro |
| EP3194581A4 (en) | 2014-09-15 | 2018-04-25 | Children's Medical Center Corporation | Methods and compositions to increase somatic cell nuclear transfer (scnt) efficiency by removing histone h3-lysine trimethylation |
| DK3662925T3 (da) | 2015-04-17 | 2021-06-28 | Ferring Bv | Sammensætning, der omfatter fsh, til behandling af infertilitet |
| IL311335A (en) | 2016-09-30 | 2024-05-01 | Sumitomo Pharma Switzerland Gmbh | Methods for treating female infertility |
| RU2665967C1 (ru) * | 2017-06-14 | 2018-09-05 | Федеральное государственное бюджетное учреждение "Уральский научно-исследовательский институт охраны материнства и младенчества" Министерства здравоохранения Российской Федерации (ФГБУ "НИИ ОММ" Минздрава России) | Способ стимуляции роста фолликулов в программах экстракорпорального оплодотворения у пациенток с бесплодием различного генеза и "бедным ответом на стимуляцию" |
| CN107982520A (zh) * | 2017-12-25 | 2018-05-04 | 上海交通大学医学院附属第九人民医院 | 外源性MPA与hMG在制备动物模型药物中的应用 |
| CN110570952B (zh) * | 2018-06-05 | 2022-04-12 | 北京大学第三医院 | 预测拮抗剂方案下受试者卵巢低反应概率的系统及指导促性腺激素起始用药剂量选择的系统 |
| CN110491505B (zh) * | 2019-08-22 | 2021-06-01 | 北京大学第三医院（北京大学第三临床医学院） | 预测受试者卵巢刺激过程中获得的卵母细胞数量的系统 |
| CN113456801A (zh) * | 2021-08-05 | 2021-10-01 | 浙江大学医学院附属第四医院 | 人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用 |
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