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WO1994002103A2 - Agent anti-ovulatoire de contraception hormonale - Google Patents

Agent anti-ovulatoire de contraception hormonale Download PDF

Info

Publication number
WO1994002103A2
WO1994002103A2 PCT/DE1993/000656 DE9300656W WO9402103A2 WO 1994002103 A2 WO1994002103 A2 WO 1994002103A2 DE 9300656 W DE9300656 W DE 9300656W WO 9402103 A2 WO9402103 A2 WO 9402103A2
Authority
WO
WIPO (PCT)
Prior art keywords
estrogen
component
daily units
progestogen
composition according
Prior art date
Application number
PCT/DE1993/000656
Other languages
German (de)
English (en)
Other versions
WO1994002103A3 (fr
Inventor
Marika Ehrlich
Herbert Kuhl
Original Assignee
Marika Ehrlich
Herbert Kuhl
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Marika Ehrlich, Herbert Kuhl filed Critical Marika Ehrlich
Priority to JP6504082A priority Critical patent/JPH07509454A/ja
Priority to EP93915661A priority patent/EP0651644A1/fr
Priority to AU45583/93A priority patent/AU4558393A/en
Publication of WO1994002103A2 publication Critical patent/WO1994002103A2/fr
Publication of WO1994002103A3 publication Critical patent/WO1994002103A3/fr

Links

Classifications

    • 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
    • A61K31/565—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
    • A61K31/567—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 substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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

Definitions

  • the invention relates to an ovulation-inhibiting agent for hormonal contraception according to the preamble of patent claim 1.
  • Combination preparations and sequence preparations are known on the one hand as hormonal ovulation inhibitors to be taken orally in daily units.
  • the desired cycle duration is 28 days
  • B. can be natural estrogen or synthetic ethinyl estradiol and after taking the aforementioned 21 daily units there is a seven-day break in which there is a withdrawal bleeding simulating the natural menstrual period.
  • substitution preparations were hormones administered during the entire cycle, for example in the sequence 10 days of estrogen preparation, 11 days of combination of estrogen and progestogen preparation, 7 days of estrogen preparation in particularly low doses, but these substitution preparations are not suitable for inhibiting ovulation .
  • the sequence preparations used in substitution therapy are particularly unsuitable for contraception because the natural estradiol in the given dose does not prevent ovulation and the phase in which progestin is administered is too short with only eleven days is.
  • the sequential arrangement described above ensures a relatively good cycle control in the substitution preparations.
  • the three most important aspects to be considered in hormonal contraception are contraceptive safety, good cycle control and a minimum of side effects.
  • the contraceptive safety is based primarily on the effects of the progestogen component; it is used in a known preparation in a dose which is approximately twice as high as the dose necessary for inhibiting ovulation.
  • progestogen is available in sufficient oral dosage in modern oral contraceptives to ensure reliable contraception.
  • the synthetic estrogen ethinyl estradiol normally used further enhances the ovulation-inhibiting effect of the gestagen.
  • estradiol is not very suitable for use in combination products.
  • the progestogen component ensures reliable contraceptive protection; but progestogen by stimulation local enzymes causes an increased inactivation of the estradiol in the endometrium and the estrogen effect on the endometrium is greatly reduced, there is a frequent bleeding with the adverse effects already described.
  • ethinyl estradiol is metabolized much more slowly in the endometrium and accordingly has a sufficient effect on the endometrium.
  • an ovulation-inhibiting agent of the generic type is known from US Pat. No. 4,921,843, in which between the ingestion of the last of the hormone daily units, such as dragées, tablets or the like, the second hormone component is a break in intake of at least one day, preferably of two days, which can be bridged by a placebo, for example, before a new daily hormone unit, namely the first of the first hormone components of the next cycle, is taken.
  • a new daily hormone unit namely the first of the first hormone components of the next cycle
  • DE-OS 26 45 307 Even with a means known from DE-OS 26 45 307 for treating climacteric failure symptoms, there is a pause in taking or at least the simulation of a Intake pause due to the temporary use of a particularly weak type of estrogen which, unlike the generic agent, does not cause a sufficient disturbance in follicular maturation, is considered necessary. Overall, the hormone doses used, in particular also the duration of the gestagen phase, are not sufficient for the contraceptive agent described in the above-mentioned publication.
  • DE-OS 24 31 704 also describes a means for alleviating climacteric complaints, in which fluctuating estrogen concentrations are provided. The progestogen only starts after the middle of the cycle, so that no contraceptive effect can be achieved. In addition, a hormone-free intake break is mandatory.
  • EP-OS 0 368 373 describes an ovulation-inhibiting agent in which a constant progestogen level is provided over the entire cycle duration and the estrogen phases are cyclically superimposed on it.
  • the disadvantage here is that there is an increased risk of intermenstrual bleeding and the continuous progestogen intake has a good contraceptive effect, but * also has a permanent vasoconstricting effect, so that especially in women with a tendency to circulatory disorders, for example with increasing age, health disadvantages cannot be excluded.
  • the invention is based on the object of further developing the ovulation-inhibiting agent of the generic type in such a way that, with a high level of contraceptive safety, better cycle control is achieved with the further avoidance of intermenstrual bleeding and side effects are avoided.
  • Preferred embodiments of the invention are the subject of claims 2 to 24.
  • the invention is based on the surprising finding that it is possible to improve the contraceptive safety and the cycle control in that, on the one hand, hormonal control is caused by an early disruption of follicular maturation within the hormone-neutral pause that was previously usual, namely by the estrogen component to be taken of follicular events over the entire cycle. Due to the fact that in the pure estrogen phase, similar to the naturally occurring conditions, an adequate build-up of mucous membrane first occurs, bleeding occurs on the other hand even with a lower dosage of the hormone components in the actual ovulation inhibition phase. in which a combination of estrogen and progestin is administered is much less common.
  • the pure estrogen phase is at least five days and can be extended to up to ten days if natural estrogen is used and up to 14 days if synthetic estrogen is used, depending on the desired cycle duration, which generally follows a longer combination phase.
  • the pure estrogen phase at the beginning of the inventive treatment enables a sufficient proliferatior. of the endometrium.
  • Reliable contraceptive protection is achieved in particular if, as is preferably proposed according to the invention, the progestogen is administered in the subsequent combination phase in the individual daily units in a double ovulation dose. After taking the last progestogen-containing tablet, the next the estrogen phase for withdrawal bleeding, while at the same time the re-proliferation of the endometrium is started by taking the estrogen.
  • the embodiment of the invention in which only natural estrogen is used is of particular advantage, since particularly low side effects are to be expected with sufficient contraceptive safety and cycle control.
  • the ovulation-inhibiting agent according to the invention is used in such a way that, for hormonal contraception within the desired cycle, a certain number of daily hormone units, such as doses, tablets or the like, of the first hormone component, which act essentially as a hormone-active substance, are consecutively contains only one estrogen preparation, and then the second hormone component, which in combination contains an estrogen and a gestagen preparation at least in doses sufficient to inhibit ovulation, are administered orally, the day after the administration of the last of the daily units of second hormone component of the cycle in question, the first of the day units of the first hormone component of the next cycle is administered, so that one hormone daily unit is taken every day with the exclusion of pauses in taking.
  • a certain number of daily hormone units such as doses, tablets or the like
  • the first hormone component which act essentially as a hormone-active substance
  • the second hormone component which in combination contains an estrogen and a gestagen preparation at least in doses sufficient to inhibit ovulation
  • the bleeding that occurs when using the ovulation-inhibiting agent according to the invention is associated with less blood loss and is less painful, due to the continuous administration of estrogen, than with the ovulation-inhibiting agent according to the prior art, from which the invention proceeds as a genus.
  • Contraceptive security is also significantly higher because there are no tablet-free days, not even one on which which could otherwise be breached by natural hormone processes, the contraceptive security. Because of the constant estrogen supply, there is also a continuously positive vasodilating effect, which means that circulatory disorders can be counteracted.
  • a further advantage of the ovulation-inhibiting agent according to the invention is that, when used, the so-called prenstrual syndrome is suppressed, which can occur in a disadvantageous manner when the estrogen is discontinued for even one or a few days, as in the natural course of the cycle.
  • the uniform estrogen level that is achieved when using the ovulation-inhibiting agent according to the invention also avoids the drop and increase in coagulation parameters during the hormone-free days or after restarting the intake in the next cycle. the coagulation system in an unstable equilibrium would otherwise be disturbed. Therefore, the ovulation-inhibiting agent according to the invention is particularly suitable for women over the age of forty, for whom it is known that the risk of circulatory disorders increases with age.
  • the agent according to the invention in contrast to such cases, it is practice in which a woman occasionally takes known ovulation-inhibiting agents in immediate succession without interruption of intake for two or more menstrual cycles.
  • B. in athletes mostly ⁇ ten ⁇ lies in the fact that the occurrence of menstrual bleeding at a certain point in time is characteristic, that bleeding occurs in each case while taking the estrogen component, that is, even if agents with several sequences of alternating estrogen and estrogen Progestagen components are taken approximately every four weeks. This is a special feature of the invention.
  • agent according to the invention for contraception is also within the scope of the inventive concept, in contrast to agents of the type discussed at the outset, which are used to reduce climacteric complaints, etc.
  • a sequence preparation was used for the ovulation-inhibiting treatment, which contained 7 daily units each with 2 mg estradiol and 21 daily units each with 4 mg oestradiol and 1 mg norethisterone acetate.
  • the agent was administered over a year and, with very good contraceptive safety, showed practically no side effects, with intermenstrual bleeding occurring significantly less frequently than with conventional low-dose preparations.
  • an ovulation-inhibiting agent in the form of a sequence preparation was used, which comprises 7 daily units with 4 mg ostradiol valerate each and 21 daily units with 4 mg ostradiol valerate each and 2 mg chlormadinone acetate.
  • the mode of action corresponded to that of Example 1.
  • An ovulation-inhibiting agent was used, which consists of 10 daily units, each with 20 ⁇ g of ethinyl estradiol and

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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)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un agent anti-ovulatoire de contraception hormonale comprend deux composants hormonaux spatialement séparés dans une unité d'emballage et destinés à être administrés successivement par voie orale. Les composants hormonaux comprennent chacun un certain nombre d'unités journalières d'hormones spatialement séparées dans l'unité d'emballage et susceptibles d'en être retirées individuellement. Un composant hormonal (composant '÷strogène') contient en tant que substance active hormonale exclusivement une composition d'÷strogène qui entrave la maturation du follicule et l'autre composant hormonal (composant '÷strogène-gestagène') contient une combinaison d'une composition d'÷strogène et d'au moins une dose suffisante d'une composition de gestagène pour inhiber l'ovulation. L'agent anti-ovulatoire se caractérise par le fait que le ou les composants ÷strogènes comprennent 5 à 14 unités journalières qui alternent avec 23 à 14 unités journalières du ou des composants ÷strogène-gestagène. Le nombre de composants ÷strogènes est égal au nombre de composants ÷strogène-gestagène. Le nombre d'unités journalières de composants ÷strogènes est inférieur au nombre d'unités journalières de composants ÷strogène-gestagène. Dans le cas où l'on utilise de l'÷stradiol d'éthinyle comme composition d'÷strogène, la dose d'÷stradiol d'éthinyle s'élève à au maximum 30νg par unité journalière.
PCT/DE1993/000656 1992-07-24 1993-07-26 Agent anti-ovulatoire de contraception hormonale WO1994002103A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP6504082A JPH07509454A (ja) 1992-07-24 1993-07-26 ホルモン避妊のための排卵抑止剤
EP93915661A EP0651644A1 (fr) 1992-07-24 1993-07-26 Agent anti-ovulatoire de contraception hormonale
AU45583/93A AU4558393A (en) 1992-07-24 1993-07-26 Ovulation inhibitor for hormonal contraception

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4224534.6 1992-07-24
DE4224534A DE4224534A1 (de) 1992-07-24 1992-07-24 Ovulationshemmendes Mittel zur hormonalen Kontrazeption

Publications (2)

Publication Number Publication Date
WO1994002103A2 true WO1994002103A2 (fr) 1994-02-03
WO1994002103A3 WO1994002103A3 (fr) 1994-05-11

Family

ID=6464040

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE1993/000656 WO1994002103A2 (fr) 1992-07-24 1993-07-26 Agent anti-ovulatoire de contraception hormonale

Country Status (6)

Country Link
EP (1) EP0651644A1 (fr)
JP (1) JPH07509454A (fr)
AU (1) AU4558393A (fr)
CA (1) CA2140011A1 (fr)
DE (1) DE4224534A1 (fr)
WO (1) WO1994002103A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0696454A3 (fr) * 1994-08-12 1996-07-17 Jenapharm Gmbh Préparation pharmaceutique pour la contraception/traitement hormonal de substitution avec des composés oestrogéniques biogéniques
US6723351B2 (en) 1997-11-10 2004-04-20 Memorial Sloan-Kettering Cancer Center Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol
US7871994B2 (en) 2001-01-11 2011-01-18 Bayer Schering Pharma Ag Hormone replacement therapy method and its administration form

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4344405C2 (de) * 1993-12-24 1995-12-07 Marika Dr Med Ehrlich Ovulationshemmendes Mittel und Verfahren zur hormonalen Kontrazeption
DE19504227C2 (de) * 1995-02-09 1999-04-29 Klaus Dr Med Umbreit Ovulationshemmendes Mittel zur hormonalen Kontrazeption
DE19525017A1 (de) * 1995-06-28 1997-01-02 Schering Ag Pharmazeutisches Kombinatonspräparat, Kit und Methode zur hormonalen Kontrazeption
DE19540253C2 (de) * 1995-10-28 1998-06-04 Jenapharm Gmbh Mehrphasenpräparat zur Kontrazeption auf der Basis natürlicher Estrogene
AU3888697A (en) * 1996-07-26 1998-02-20 American Home Products Corporation Progestin/estrogen oral contraceptive
DE60101276T2 (de) * 2001-05-23 2004-04-22 Pantarhei Bioscience B.V. Zubereitungen für die hormonale Kontrazeption
EP2305230B1 (fr) 2001-12-05 2015-11-04 Teva Women's Health, Inc. Contraceptifs oraux pour empêcher les grossesses
EP1648382A4 (fr) * 2003-07-16 2009-09-16 Duramed Pharmaceuticals Inc Procedes de traitement hormonal utilisant des posologies contraceptives avec administration continue d'oestrogenes
DE102004019743B4 (de) 2004-04-20 2008-11-27 Bayer Schering Pharma Aktiengesellschaft Mehrphasenpräparat zur Kontrazeption auf der Basis eines natürlichen Estrogens
DE102004026671A1 (de) 2004-05-28 2005-12-15 Grünenthal GmbH Darreichungsform zur hormonalen Kontrazeption
DE102004026670A1 (de) 2004-05-28 2005-12-15 Grünenthal GmbH Hormonales Kontrazeptivum enthaltend eine Kombination aus Ethinylestradiol und Chlormadinonacetat
US20070111975A1 (en) 2004-10-07 2007-05-17 Duramed Pharmaceuticals, Inc. Methods of Hormonal Treatment Utilizing Ascending-Dose Extended Cycle Regimens
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 (fr) 2006-10-20 2008-06-11 Bayer Schering Pharma Aktiengesellschaft Utilisation de valvérate d'estradiol ou de 17ß-estradiol combiné à du dienogest pour traiter par voie orale la récupération et/ou l'augmentation de la libido féminine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4104385C1 (fr) * 1991-02-09 1992-08-13 Marika Dr.Med. 6509 Framersheim De Ehrlich

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0696454A3 (fr) * 1994-08-12 1996-07-17 Jenapharm Gmbh Préparation pharmaceutique pour la contraception/traitement hormonal de substitution avec des composés oestrogéniques biogéniques
US6723351B2 (en) 1997-11-10 2004-04-20 Memorial Sloan-Kettering Cancer Center Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol
US6855339B2 (en) 1997-11-10 2005-02-15 Memorial Sloan-Kettering Cancer Center Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol
US6861076B2 (en) 1997-11-10 2005-03-01 Memorial Sloan-Kettering Cancer Center Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol
US6884439B2 (en) 1997-11-10 2005-04-26 Memorial Sloan-Kettering Cancer Center Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol
US6982096B2 (en) 1997-11-10 2006-01-03 Memorial Sloan-Kettering Cancer Center Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol
US7879364B2 (en) 1997-11-10 2011-02-01 Memorial Sloan-Kettering Cancer Center Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol
US8273379B2 (en) 1997-11-10 2012-09-25 Memorial Sloan-Kettering Cancer Center Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol
US7871994B2 (en) 2001-01-11 2011-01-18 Bayer Schering Pharma Ag Hormone replacement therapy method and its administration form

Also Published As

Publication number Publication date
WO1994002103A3 (fr) 1994-05-11
EP0651644A1 (fr) 1995-05-10
DE4224534A1 (de) 1994-01-27
JPH07509454A (ja) 1995-10-19
AU4558393A (en) 1994-02-14
CA2140011A1 (fr) 1994-01-25

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