TWI328453B - Use of estradiol valerate in combination with dienogest in order to obtain a multi-stage combined preparation with a total of 28 daily doses for the treatment of dysfunctional uterine bleeding in conjunction with oral contraception - Google Patents
Use of estradiol valerate in combination with dienogest in order to obtain a multi-stage combined preparation with a total of 28 daily doses for the treatment of dysfunctional uterine bleeding in conjunction with oral contraception Download PDFInfo
- Publication number
- TWI328453B TWI328453B TW095137564A TW95137564A TWI328453B TW I328453 B TWI328453 B TW I328453B TW 095137564 A TW095137564 A TW 095137564A TW 95137564 A TW95137564 A TW 95137564A TW I328453 B TWI328453 B TW I328453B
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- stage
- combination
- estradiol valerate
- dienogest
- uterine bleeding
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
九、發明說明： 【發明所屬之技術領域】 本發明係關於戊酸***與丨7α-氛基甲基-17β_羥基雌_ 4’9-二烯-3-酮（地諾孕素）併用以獲得具有總計28個每曰劑 量之多階段組合系統之用途，該多階段組合系統係用於與 口服/Q療異常子宮出血並口服避孕，且包含：第一階段， 其具有2個3毫克戊酸***之每曰劑量；第二階段，其具 有兩組不同之每曰劑量組成’其中第一組包含5個2毫克戊 酸***與2毫克地諾孕素之組合之每日劑量，且第二組 包含17個2毫克戊酸***與3毫克地諾孕素之組合之每曰 劑置，第二階段’其具有2個1毫克戊酸***之每曰劑 量；及另一階段，其具有2個醫藥學上可接受之安慰劑之 每曰劑量。 該多階段藥物組合及醫藥學上可接受之安慰劑之每曰劑 量的總數符合28天。 【先前技術】 異常子宮出血（DUB)係一種常見的婦科臨床問題，其佔 婦科門診之比例可高達33%[參看j.T· Awwad，T L ^讣及工
Schiff: Abnormal uterine bleeding in the perimenopause, Int. 丄 Fer"/·, 38 (1993)第 261-269頁]。 異常子宮出血之症狀如下： -月經週期持續超過7天， -月經週期之間隔為21天或少於21天，及 -排出80毫升或更多之異常劇烈經期出血。 僅可在排除諸如肌瘤、息肉及癌症之器官性原因之後， 114629.doc -6- 1328453 才可破珍為異常子宮出血。 DUB可發生於***期及非***期女性。其基本上係肇因 於雌荷爾蒙刺激之子宮内膜增殖與助孕素促進之子宮内膜 轉換之間的不平衡。若異常子宮出血之症狀係歸因於*** 停止延長’則問題通常在於子宮内膜產生過量之雌荷爾蒙 性增殖。此不僅可導致異常出血，且亦導致子宮内膜增生 症[參看 Speroff等人，Clinical Gynecologic Endocrinology and Infertility，第 6版，Lippincott Williams & Wilkins, 1999]。 子宮内膜增生症係子宮内膜癌之風險因素。 在先前之實驗中，使用3x5毫克每曰劑量之炔諾酮 (norethisterone)或3x10毫克每曰劑量之醋酸曱羥孕酮作為 單一高劑量助孕素來治療異常子宮出血，其中6名非*** 期女性週期之第12天至第25天服用各藥物共14天，10名排 卵期女性自週期之第5天至第25天服用各藥物共20天[參看 I.S. Fraser: dwji. iV.Z. ·/. G少《aeco/.，30，第 4期 (1990)，第353-356頁]。兩組之出血持續時間均減少，但 其中之患者並未經可靠避孕。 一評論文章指出女性對不規則且劇烈之經期出血耐受性 低（參看 M. Hickey，J. Higham及 I.S· Fraser: versus oestrogens and progestogens for irregular uterine bleeding associated with anovulation (Cochrane Review) > 於 The Cochrane Library，第 3 期，2004 中，John Wiley & Sons Ltd.，Chichester, England)。其作者們已描述使用助 114629.doc 132S453 、進子呂内膜之轉換且因此產生較穩定之月經週期之 原理S%，其、结論為該等治療之功效並未在隨機研究中 得到證實。 根據R. Steiner，可用大劑量之助孕素、雌荷爾蒙或兩者 之組合來治療異常子宮出血[參看R. Steiner: 心cA. Λ/ed. 似，91，第 46期（2〇〇〇),第 頁]。該作者推薦以每日6、5、4、3、3333之遞減 劑量口服0.01毫克块雕醇及2毫克醋酸快諾嗣歷時8天。 除此荷爾蒙療法以外，Steiner主張用4χ2錠劑每日劑量之 凝血酸來治療急性出血。 A. Davis已藉由三階段投與炔雌醇（ΕΕ)及諾孕酯 (NGM) ’並繼而投與無荷爾蒙之安慰劑經三個天之週 期來，口療異常子宮出血[參看A. Davis，gjj；wecc>/， 96，第6期（2000)，第913_92〇頁;^該療法係使炔雌醇劑量 保持恆定為0.035毫克歷時21天，而將諾孕酯劑量在21天 内逐漸增加（從第一個7天之〇18〇毫克增至下一個七天之 0.215毫克’且隨後增為最後七天之0.250毫克），且此後接 者進行七天無荷爾蒙之安慰劑過程。在此安慰劑對照研究 中’ 450/〇女性出現過量經血（子宮出血、月經過多症及月經 次數過多症（polymenorrhoea)) ’而約55%經血減少（月經次 數過少（oligomenorrhoea))。此第二組展示與安慰劑相比之 最佳結果’其中誘發規則性出血消退。月經次數過少並非 為異常子宮出血之必要症狀，但已知其需要治療。 美國專利第6,797,282號主要揭不，歷時三個月以上之長 114629.doc 1328453 期服用口服避孕藥可用於治療月經過多症，月經過多症為 一種類型之異常子宮出血。 【發明内容】 本發明之目的在於提供—種治療異常子宮出血之方法， 其主要可減少出血量，預防異常子宮出血之復發且同時 提供可靠且耐受性良好之口服避孕藥。 本文所用術語“異常子宮出血，，表示無器官性原因之下述 病症之-：月經週期持續超過7天、子宮出血之間隔為21 天或紐於21天，或排出8〇1111或更多月經之劇烈出血。 本發明之目的因使戊酸***與17α氰基甲基部經基 雌-4,9-二婦-3,（地諾孕素）併用以提供多階段組合製劑而 達成，該多階段組合製劑係用於與口服治療異常子宮出血 並口服避孕。本文使用之戊酸***_地諾孕素組合包 含.第一階段，2個3毫克戊酸***之每曰劑量’·第二階 段，其具有兩組不同之每日劑量，其中第'组包含5個2毫 克戊酸***與2毫克地諾孕素之組合之每曰劑量，且第 二組包含17個2毫克戊酸***與3毫克地諾孕素之組合之 每曰劑量，第二階段，其具有2個丨毫克戊酸***之每曰 劑量；及另一階段，2個醫藥學上可接受之安慰劑之每曰 劑量。 該多階段藥物組合及醫藥學上可接受之安慰劑之每曰劑 量的總數符合28天。 該療法至少採用一個週期，治療長度視患者之避孕需要 而定° 114629.doc -9- 1328453 【實施方式】 本發明調配物之作用研究 對180名年齡在18-50歲之女性進行隨機雙盲安慰劑對照 臨床研究，該等女性已提供書面參與研究同意書，彼等有 現異常子宮出血之症狀，且就該等女性而言，已借助於適 當診斷方法（即***超音掃描及血液荷爾蒙含量測定）而排 除了器官性原因。在該組中，120名女性給與根據本發明 之戍酸***及地諾孕素之組合，而6〇名女性則接受安慰 劑。 該研究包含確定出血不規則性之嚴重程度之9〇天試行階 段，隨後為六個月經週期之治療，最後為後續追蹤階段。 使用在整個研究期間該等女性所收集且交至研究中心之 衛生巾及類似物，借助於鹼性血色素法定量測定出血強 度。由電子日記本中所記錄之日誌來測定出血之持續時間 及非出血間隔之長度。
114629.doc
Claims (1)
1328453 /第095137564號專利申請案 __________________t _ : 中‘文申請專利範圍替換本(99年2月）年y :.口：二本丨卜., 十、申請專利範圍·· L__ ——…· - „」i…. * 1. 一種戊酸雌一醇與17α-氰基甲基·17β-經基雌_4,9-二稀-3 •酮（地諾孕素；dienogest)併用以獲得具有總計28個每曰 劑量之多階段組合製劑之用途，其包含： 第一階段’其具有2個3毫克戊酸***之每曰劑量； 第二階段’其具有兩組不同之每日劑量， 其中第一組包含5個2毫克戊酸***與2毫克地諾孕 素之組合之每日劑量，且 _ 第二組包含17個2毫克戊酸***與3毫克地諾孕素 之組合之每日劑量； ’ • 第三階段，其具有2個1毫克戊酸***之每日劑量；及 另一階段，其具有2個醫藥學上可接受之安慰劑之每 曰劑量，係用於治療與口服避孕藥有關之異常子宮出
I14629-990212.doc
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05022324A EP1787649B1 (de) | 2005-10-13 | 2005-10-13 | Verwendung von Estradiolvalerat in Kombination mit Dienogest zur oralen Therapie der dysfunktionellen uterinen Blutung in Einheit mit einer oralen Kontrazeption |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW200731977A TW200731977A (en) | 2007-09-01 |
| TWI328453B true TWI328453B (en) | 2010-08-11 |
Family
ID=35811580
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW095137564A TWI328453B (en) | 2005-10-13 | 2006-10-12 | Use of estradiol valerate in combination with dienogest in order to obtain a multi-stage combined preparation with a total of 28 daily doses for the treatment of dysfunctional uterine bleeding in conjunction with oral contraception |
| TW096100872A TW200829255A (en) | 2005-10-13 | 2007-01-09 | Use of oestradiol in combination with dienogest for the oral treatment of dysfunctional uterine bleeding in conjunction with oral contraception |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW096100872A TW200829255A (en) | 2005-10-13 | 2007-01-09 | Use of oestradiol in combination with dienogest for the oral treatment of dysfunctional uterine bleeding in conjunction with oral contraception |
Country Status (22)
| Country | Link |
|---|---|
| EP (2) | EP1787649B1 (zh) |
| JP (2) | JP5735200B2 (zh) |
| KR (2) | KR101218872B1 (zh) |
| CN (1) | CN101312733A (zh) |
| AR (1) | AR056694A1 (zh) |
| AT (2) | ATE424828T1 (zh) |
| CA (1) | CA2623024C (zh) |
| CL (1) | CL2011000283A1 (zh) |
| CY (2) | CY1110321T1 (zh) |
| DE (2) | DE502005006837D1 (zh) |
| DK (2) | DK1787649T3 (zh) |
| DO (1) | DOP2006000221A (zh) |
| ES (2) | ES2322479T3 (zh) |
| HR (1) | HRP20090256T1 (zh) |
| ME (1) | ME01056B (zh) |
| PE (2) | PE20100090A1 (zh) |
| PL (2) | PL1787649T3 (zh) |
| PT (2) | PT1787649E (zh) |
| SI (2) | SI1787649T1 (zh) |
| TW (2) | TWI328453B (zh) |
| UY (1) | UY29861A1 (zh) |
| WO (1) | WO2007042296A1 (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102004019743B4 (de) | 2004-04-20 | 2008-11-27 | Bayer Schering Pharma Aktiengesellschaft | Mehrphasenpräparat zur Kontrazeption auf der Basis eines natürlichen Estrogens |
| DK1787649T3 (da) * | 2005-10-13 | 2009-06-02 | Bayer Schering Pharma Ag | Anvendelse af estradiovalerat i kombination med dienogest til oral behandling af dysfunktionel uterin blöding i enhed med en oral kontraception |
| US8153616B2 (en) | 2005-10-17 | 2012-04-10 | Bayer Pharma Aktiengesellschaft | Combination preparation for oral contraception and oral therapy of dysfunctional uterine bleeding containing estradiol valerate and dienogest and method of using same |
| EP1930010A1 (de) | 2006-10-20 | 2008-06-11 | Bayer Schering Pharma Aktiengesellschaft | Verwendung von Estradiolvalerat oder 17ß-Estradiol in Kombination mit Dienogest zur oralen Therapie für den Erhalt und/oder die Steigerung der weiblichen Libido |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4429374C1 (de) * | 1994-08-12 | 1996-02-01 | Jenapharm Gmbh | Pharmazeutische Präparate zur Kontrazeption/Hormonsubstitution mit biogener Estrogenkomponente |
| DE19540253C2 (de) * | 1995-10-28 | 1998-06-04 | Jenapharm Gmbh | Mehrphasenpräparat zur Kontrazeption auf der Basis natürlicher Estrogene |
| JP2000515889A (ja) * | 1996-07-26 | 2000-11-28 | アメリカン・ホーム・プロダクツ・コーポレイション | プロゲスチンとエストロゲンとの混合剤からなる二相性避妊法およびキット |
| US6251956B1 (en) | 1998-08-20 | 2001-06-26 | Ortho Pharmaceutical Corporation | Combination progestin oral contraceptive regimen |
| EP1462106A1 (en) * | 2003-03-28 | 2004-09-29 | Pantarhei Bioscience B.V. | Pharmaceutical compositions and kits comprising 17-beta-estradiol and a progesteron for the treatment of gynecological disorders |
| DE102004019743B4 (de) * | 2004-04-20 | 2008-11-27 | Bayer Schering Pharma Aktiengesellschaft | Mehrphasenpräparat zur Kontrazeption auf der Basis eines natürlichen Estrogens |
| DK1787649T3 (da) * | 2005-10-13 | 2009-06-02 | Bayer Schering Pharma Ag | Anvendelse af estradiovalerat i kombination med dienogest til oral behandling af dysfunktionel uterin blöding i enhed med en oral kontraception |
-
2005
- 2005-10-13 DK DK05022324T patent/DK1787649T3/da active
- 2005-10-13 PL PL05022324T patent/PL1787649T3/pl unknown
- 2005-10-13 ES ES05022324T patent/ES2322479T3/es active Active
- 2005-10-13 ME MEP-2009-171A patent/ME01056B/me unknown
- 2005-10-13 PT PT05022324T patent/PT1787649E/pt unknown
- 2005-10-13 DE DE502005006837T patent/DE502005006837D1/de active Active
- 2005-10-13 AT AT05022324T patent/ATE424828T1/de active
- 2005-10-13 EP EP05022324A patent/EP1787649B1/de not_active Revoked
- 2005-10-13 SI SI200530672T patent/SI1787649T1/sl unknown
-
2006
- 2006-10-12 PE PE2009001256A patent/PE20100090A1/es not_active Application Discontinuation
- 2006-10-12 TW TW095137564A patent/TWI328453B/zh active
- 2006-10-12 DK DK06806225.6T patent/DK1933843T3/da active
- 2006-10-12 KR KR1020107014574A patent/KR101218872B1/ko active IP Right Grant
- 2006-10-12 EP EP06806225A patent/EP1933843B1/de active Active
- 2006-10-12 CA CA2623024A patent/CA2623024C/en active Active
- 2006-10-12 WO PCT/EP2006/009867 patent/WO2007042296A1/de active Application Filing
- 2006-10-12 PE PE2006001241A patent/PE20070555A1/es not_active Application Discontinuation
- 2006-10-12 DE DE502006008853T patent/DE502006008853D1/de active Active
- 2006-10-12 SI SI200630991T patent/SI1933843T1/sl unknown
- 2006-10-12 ES ES06806225T patent/ES2360302T3/es active Active
- 2006-10-12 AT AT06806225T patent/ATE497387T1/de active
- 2006-10-12 PT PT06806225T patent/PT1933843E/pt unknown
- 2006-10-12 JP JP2008534936A patent/JP5735200B2/ja active Active
- 2006-10-12 CN CNA2006800381810A patent/CN101312733A/zh active Pending
- 2006-10-12 PL PL06806225T patent/PL1933843T3/pl unknown
- 2006-10-12 KR KR1020087011203A patent/KR20080065651A/ko not_active Application Discontinuation
- 2006-10-13 UY UY29861A patent/UY29861A1/es not_active Application Discontinuation
- 2006-10-13 DO DO2006000221A patent/DOP2006000221A/es unknown
- 2006-10-13 AR ARP060104489A patent/AR056694A1/es not_active Application Discontinuation
-
2007
- 2007-01-09 TW TW096100872A patent/TW200829255A/zh unknown
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2009
- 2009-05-05 HR HR20090256T patent/HRP20090256T1/xx unknown
- 2009-06-11 CY CY20091100621T patent/CY1110321T1/el unknown
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2011
- 2011-02-10 CL CL2011000283A patent/CL2011000283A1/es unknown
- 2011-05-02 CY CY20111100422T patent/CY1111406T1/el unknown
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2012
- 2012-11-19 JP JP2012253067A patent/JP2013047269A/ja active Pending
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