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WO1996029078A1 - AGENT INHIBITEUR D'OVULATION POUR CONTRACEPTION HORMONALE CONTENANT 50 A 70 νg DE LEVONORGESTREL ET PLUS DE 30 A 40 νg D'ETHINYLESTRADIOL - Google Patents

AGENT INHIBITEUR D'OVULATION POUR CONTRACEPTION HORMONALE CONTENANT 50 A 70 νg DE LEVONORGESTREL ET PLUS DE 30 A 40 νg D'ETHINYLESTRADIOL Download PDF

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Publication number
WO1996029078A1
WO1996029078A1 PCT/EP1995/001097 EP9501097W WO9629078A1 WO 1996029078 A1 WO1996029078 A1 WO 1996029078A1 EP 9501097 W EP9501097 W EP 9501097W WO 9629078 A1 WO9629078 A1 WO 9629078A1
Authority
WO
WIPO (PCT)
Prior art keywords
levonorgestrel
ovulation
daily
inhibiting agent
ethinyl estradiol
Prior art date
Application number
PCT/EP1995/001097
Other languages
German (de)
English (en)
Inventor
Wilhelm Kuhnz
Michael HÜMPEL
Lothar Lange
Marianne Mahler
Barbara SCHÜTT
Original Assignee
Schering Aktiengesellschaft
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 Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU22142/95A priority Critical patent/AU2214295A/en
Priority to PCT/EP1995/001097 priority patent/WO1996029078A1/fr
Publication of WO1996029078A1 publication Critical patent/WO1996029078A1/fr

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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

Definitions

  • the present invention relates to an ovulation-inhibiting agent for hormonal contraception, which contains levonorgestrel as a gestagen component.
  • Combination preparations for oral contraception which contain a progestogen as an ovulation-inhibiting active ingredient and, as a further active component which serves to control the cycle, contain an estrogen - generally the synthetic estrogen ethinyl estradiol - have been known since the early 1960s.
  • Anovlar® was one of the first oral contraceptives.
  • Most known oral contraceptives consist of 21 drug-containing (estrogen / progestogen) dosage units and 7 drug-free coated tablets (blind pills; placebos) or information is provided on the package containing the drug-containing dosage units (this is generally a blister pack) to indicate that the daily administration of the 21 active ingredient-containing dosage units should be followed by 7 pill-free days.
  • the daily dose to be administered per dosage unit is either the same in each case (so-called single-stage preparations) or the daily dose of the active ingredients in the individual dosage units is different in individual sections over the administration cycle (multi-stage preparations). This is intended to achieve a better adaptation to the endogenous hormone levels, which also vary during a normal cycle.
  • Mcrogynon As a representative of a levonorgestrel-containing single-stage preparation, "Microgynon” may be mentioned, for example, the cycle pack of which is composed of 21 active ingredient-containing tablets, each containing 150 ⁇ g levonorgestrel and 30 g of ethinyl estradiol and 7 active ingredient-free tablets.
  • a combination preparation for substitution therapy and contraception for women before menopause emerges from EP-A-0 253 607, whose daily dosage forms can contain, for example, ethinyl estradiol in an amount of 8 to 30 ⁇ g as estrogen and levonorgestrel in an amount of 25 to 100 ⁇ g as gestagen.
  • Dosage forms containing the active ingredient are administered over 23 to 26 days of the 28-day cycle.
  • a composition selected in this way is intended to compensate for hormonal irregularities in the transition phase of the premenopause and to help alleviate the symptoms caused by the hormonal change in the female organism in this phase. At the same time, such a composition guarantees women the necessary contraceptive protection at this age.
  • Neogynon® contains 250 ⁇ g levonorgestrel and 50 ⁇ g ethinylestradiol.
  • the next single-stage preparation, Microgyno ⁇ ® contains 150 ⁇ g levonorgestrel and 30 ⁇ g ethinyl estradiol.
  • Preparations with 100 ⁇ g levonorgestrel or even lower levonorgestrel doses in combination with ethinyl estradiol are not known.
  • the daily estrogen dose must not fall below a certain limit dose range in order to ensure satisfactory cycle control can (The Gynecologist; 34, 7: 793 (1993)). In addition, if the daily estrogen dosage was too low, further positive estrogen effects such as, for example, osteoporosis prophylaxis and the balanced interplay of estrogen / progestin were lost.
  • the object of the present invention is now to provide an ovulation-inhibiting agent for hormonal contraception containing estrogen and gestagen in its daily dosage units, which has the lowest possible daily dose of gestagen ⁇ with a reduced daily total hormone load.
  • This object is made up in a packaging unit by providing the ovulation-inhibiting agent according to the invention for hormonal contraception
  • the daily gestagen dosage in the agent according to the invention is extremely low with a levonorgestrel amount of 50 to 70 ⁇ g.
  • Commercially available single-stage combination products containing levonorgestrel contain at least a daily dose of 125 ⁇ g levonorgestrel in combination with 30 ⁇ g ethinyl estradiol.
  • the daily levonorgestrel dose contained in the agent according to the invention reduces the amount of progestogen administered per cycle to approx. 50% of the lowest-dose levonorgestrel-containing single-stage combination preparation, which is achieved by only increasing the dose of ethinyl estradiol by 10-20%.
  • the ethinylestradiol dose increase does not exceed the ethinylestradiol dose range of so-called micropills.
  • micropills Combination preparations with an ethinyl estradiol content of less than 50 ⁇ g per daily dosage unit are called micropills.
  • the total amount of estrogen and gestagen administered per cycle is lower with the agent according to the invention than with other monophasic combination preparations. This results in an overall significantly reduced hormone load on the user.
  • the SHBG is a specific binding protein for levonorgestrel (Victor A., Weiner E., Johannson EDB: Sex hormone binding globulin: The carrier protein for d-norgestrel. J Clin Endocrinol Metab 1976; 43: 244-247) and leads in the course the 1st treatment cycle and all further treatment cycles to redistribute the gestagen from the tissue to the serum.
  • higher and more stable drug concentrations are achieved in the target tissues (pituitary, hypothalamus, ovary, uterus) than without stimulation of SHBG synthesis, since the binding constant of the levonorgestrel to the progesterone receptor is at least one order of magnitude higher than for binding to the SHBG.
  • the physiological mechanisms can drastically reduce the dose of progestogen per day and cycle without impairing the contraceptive effect.
  • Levo ⁇ orgestrel is made available by the agent according to the invention more specifically and to a greater extent than for other single-stage combination preparations with levonorgestrel and ethinyl estradiol for the pharmacological effect.
  • this relates to an ovulation-inhibiting agent of the type specified, comprising
  • the ovulation inhibiting agent of the present invention contains 50 to 60 ⁇ g levonorgestrel and more than 30 to 35 ⁇ g ethinyl estradiol in each daily dosage unit.
  • each daily dosage unit contains 55 ⁇ g levonorgestrel and 35 ⁇ g ethinyl estradiol.
  • the present invention relates to the combined use of 50 to 70 ⁇ g levonorgestrel and 30 to 40 ⁇ g ethinyl estradiol for the preparation of daily dosage units, which are packaged in an ovulation-inhibiting agent for hormonal contraception in a packaging unit
  • the joint formulation of ethinylestradiol and levonorgestrel for the ovulation-inhibiting agent according to the invention and for the common use for the production of daily dosage units for the ovulation-inhibiting agent is carried out in a completely analogous manner to that for conventional oral contraceptives based on the active ingredients ethinylestradiol and levonorgestrel with a dosage of 21 days ingesting active ingredient-containing dosage units Microgynon® - is known.
  • a pack containing the ovulation-inhibiting agent according to the invention is also constructed analogously to packs for already known oral contraceptives on the market, with instead of the usual 21 dosage units containing the active ingredients, there are now also 22 or 23 such dosage units and 6 or 5 blind pills can or other suitable indications that 6 or 5 days have to be bridged until the dosage units containing the active substance are continued.
  • the contraceptive safety of the preparation could be assessed as complete.
  • the extent and frequency of the intermediate bleeding occurred was demonstrated by the very good cycle control when taking the preparation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un agent inhibiteur d'ovulation pour contraception hormonale conditionné dans une unité d'emballage et comprenant: (a) 21 à 23 unités de dosage quotidiennes pour administration par voie orale de façon séquentielle, contenant 50 à 70 νg de levonorgestrel et plus de 30 à 40 νg d'éthinylestradiol, ainsi que (b) entre 7 et 5 pilules sans principe actif ou d'autres systèmes d'indication permettant d'indiquer que l'administration quotidienne de 21 à 23 unités de dosage doit être suivie par la prise de pilules sans principe actif pendant une période comprise entre 7 et 5 jours ou par aucune prise de pilule pendant cette dernière période. Cet agent se caractérise par un dosage quotidien extrêmement faible du gestagène, levonorgestrel, tout en ayant de faibles doses d'÷strogène, éthinylestradiol.
PCT/EP1995/001097 1995-03-22 1995-03-22 AGENT INHIBITEUR D'OVULATION POUR CONTRACEPTION HORMONALE CONTENANT 50 A 70 νg DE LEVONORGESTREL ET PLUS DE 30 A 40 νg D'ETHINYLESTRADIOL WO1996029078A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU22142/95A AU2214295A (en) 1995-03-22 1995-03-22 Ovulation-inhibiting agent for hormonal contraception containing between 50 and 70 mug levonurgestrel and more than 30 to 40 mug ethinyloestradiol
PCT/EP1995/001097 WO1996029078A1 (fr) 1995-03-22 1995-03-22 AGENT INHIBITEUR D'OVULATION POUR CONTRACEPTION HORMONALE CONTENANT 50 A 70 νg DE LEVONORGESTREL ET PLUS DE 30 A 40 νg D'ETHINYLESTRADIOL

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1995/001097 WO1996029078A1 (fr) 1995-03-22 1995-03-22 AGENT INHIBITEUR D'OVULATION POUR CONTRACEPTION HORMONALE CONTENANT 50 A 70 νg DE LEVONORGESTREL ET PLUS DE 30 A 40 νg D'ETHINYLESTRADIOL

Publications (1)

Publication Number Publication Date
WO1996029078A1 true WO1996029078A1 (fr) 1996-09-26

Family

ID=8165981

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/001097 WO1996029078A1 (fr) 1995-03-22 1995-03-22 AGENT INHIBITEUR D'OVULATION POUR CONTRACEPTION HORMONALE CONTENANT 50 A 70 νg DE LEVONORGESTREL ET PLUS DE 30 A 40 νg D'ETHINYLESTRADIOL

Country Status (2)

Country Link
AU (1) AU2214295A (fr)
WO (1) WO1996029078A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4313926A1 (de) * 1993-04-28 1994-11-03 Jenapharm Gmbh Pharmazeutisches Mehrphasenpräparat zur hormonalen Kontrazeption
DE4406915A1 (de) * 1994-02-28 1995-08-31 Schering Ag Ovulationshemmendes Mittel zur hormonalen Kontrazeption

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4313926A1 (de) * 1993-04-28 1994-11-03 Jenapharm Gmbh Pharmazeutisches Mehrphasenpräparat zur hormonalen Kontrazeption
DE4406915A1 (de) * 1994-02-28 1995-08-31 Schering Ag Ovulationshemmendes Mittel zur hormonalen Kontrazeption

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BUNDESVERBAND DER PHARM. INDUSTRIE E.V.: "ROTE LISTE 1995", 1995, EDITIO CANTOR, AULENDORF/WÜRTT., XP002011051 *
K. FOTHERBY ET AL.: "Interactions of contraceptive steroids with binding proteins and the clinical implications", ANN. NY ACAD. SCI., vol. 538, 1988, pages 313 - 320, XP002011048 *
K. FOTHERBY: "Levonorgestrel. Clinical Pharmacokinetics", CLIN. PHARMACOKINET., vol. 28, no. 3, March 1995 (1995-03-01), pages 203 - 215, XP002011050 *
W. KUHNZ ET AL.: "Pharmocokinetics of levonorgestrel and ethinylestradiol in 9 women who received a low-dose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation", CONTRACEPTION, vol. 46, no. 5, 1992, pages 455 - 69, XP002011049 *

Also Published As

Publication number Publication date
AU2214295A (en) 1996-10-08

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