WO1994004156A1 - Contraceptifs contenant un antiprogestatif - Google Patents

Contraceptifs contenant un antiprogestatif Download PDF

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Publication number
WO1994004156A1
WO1994004156A1 PCT/EP1993/002139 EP9302139W WO9404156A1 WO 1994004156 A1 WO1994004156 A1 WO 1994004156A1 EP 9302139 W EP9302139 W EP 9302139W WO 9404156 A1 WO9404156 A1 WO 9404156A1
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WO
WIPO (PCT)
Prior art keywords
daily dosage
phase
dosage units
progestogen
contraceptive
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1993/002139
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English (en)
Inventor
Engelbert Willem Bergink
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Akzo NV
Akzo Nobel NV
Original Assignee
Akzo NV
Akzo Nobel NV
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 Akzo NV, Akzo Nobel NV filed Critical Akzo NV
Priority to AU47089/93A priority Critical patent/AU4708993A/en
Publication of WO1994004156A1 publication Critical patent/WO1994004156A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 invention relates generally to contraceptive preparations, and more specifically to a multiphasic preparation containing an antiprogestogen.
  • RU 486 (“ ifepristone") has been a rather contro ⁇ versial drug acting as an abortifacient. Twenty-five milligrams of mifepristone administered during the follicular phase of the menstrual cycle results in inhibition of estradiol synthesis. Luukkainen et al.
  • Kekkonen et al. "Interference with ovu ⁇ lation by sequential treatment with the antiprogesterone RU 486 and synthetic progestin". Fertility and Steril- ity, 53(4): 747-750 (1990).
  • Kekkonen et al. discloses a discontinuous regimen wherein 25 mg of mifepristone was administered daily on days 1 to 14 of the menstrual cycle followed by 3 mg of the progestogen norethisterone for days 15 to 24, followed by 5 placebo days. This regimen was administered over three cycles.
  • the invention thus includes a contraceptive regimen with: a first phase of 5-20, especially 10-20, and more especially 14, sequential daily dosage units each containing an anti-progestogen at a daily dosage sufficient to inhibit ovulation in the female, and a second phase of 10-25, especially 14, sequential daily dosage units containing a progestogen at a dosage equivalent to 40-120 ⁇ g desogestrel administered orally vis-a-vis ovulation inhibition.
  • the regimen is effective even during the first month of adminstration.
  • an estrogen such as 17 ⁇ -estradiol (from 0.50 to 2.5 mg daily) to allow for the possibility of making a sequential regimen.
  • the daily dosage units of the contraceptive regimen are administered to a mammalian (e.g. human) female in need of, or desiring, contraception for as long as needed or desired (e.g. 14 days of first phase tablets, followed by 14 days of second phase tablets, after which the cycle is repeated if desired, etc.), and thus the invention also includes a method of contraception.
  • These contraceptive regimens can display several advantages including a decreased risk of inducing hema- tologic disorders which are currently associated with presently available oral contraceptive regimens (e.g. DVT's); a decreased chance of breast cancer since antiprogestogens are thought to prevent breast tumor development, and with a 28 day administration (e.g. with two 14 day phases) the regimen mimics a natural menstrual cycle.
  • the invei ion also includes a contraceptive product (i.e. the birtn control pack containing the dosage unit regimen) , and a process of manufacturing this product.
  • Daily dosage units e.g. tablets and capsules
  • methods for making them are well-known, see e.g. Remington's Pharmaceutical Sciences, (18th edition 1980).
  • Known daily dosage units can be adapted to include the described ingredients.
  • Preferred antiprogestogens for use with the inven ⁇ tion include 11-aryloestrane and 11-arylpregnane deriva ⁇ tives such as those disclosed in U.S. Patent No. 4,871,724 to Groen et al., e.g.
  • Doses of antiprogestogen in each daily dosage unit are sufficient to inhibit ovulation even during the first cycle of administration.
  • doses will preferably be equivalent to less than 20 mg of (6 ⁇ , ll ⁇ ,17 ⁇ )-11-(4-dimethylaminophenyl)-6-methyl-4' ,5'-dihy ⁇ drospiro[estra-4,9-diene-17,2' (3'H)-furan]-3-one taken orally.
  • the contraceptive regimen of the invention also includes at least 10 daily dosage units containing a progestogenic component.
  • Preferred progestogens for use with the invention include 3-ketodesogestrel ("etono- gestrel"), desogestrel, levo-norgestrel, norgestrel, norgestimate, gestodene, and other compounds with similar progestogenic activity.
  • Desogestrel and 3-keto- desogestrel can be used in oral doses of 40 to 120 ⁇ g, especially 75 ⁇ g, per day. Equivalent doses of other progestogens can also be used.
  • Gestodene is approx ⁇ imately 1.5 times as potent as these compounds.
  • Norgestrel is about one-half as potent as levo- norgestrel. Most of these progestogens are readily commercially available.
  • 17 ⁇ -estradiol is preferred, co-administered with the anti-progestogen at a daily dose of about 1 mg. 17 ⁇ -estradiol is readily commercially available. The use of natural estrogens is preferred.
  • estrogens which can be used include ethinyl estradiol, mestranol and 17- ⁇ -ethinyl estradiol 3- methylether.
  • 1 mg of 17 ⁇ -estradiol is equivalent in estrogenic activity to 0.015 mg of ethinyl estradiol and 0.030 mg of mestranol.
  • the antiprogestogen, estrogen and progestogen are preferably incorporated into dosage units for oral administration.
  • dosage unit gener ⁇ ally refers to physically discrete units suitable as unitary dosages for humans or animals, each containing a predetermined quantity of active material (e.g. antipro ⁇ gestogen or progestogen) calculated to produce the desired effect.
  • compositions for making such dosage units are well-known to those skilled in the art. For example, methods for making capsules, tablets and pills, contain ⁇ ing active ingredients and pharmaceutical excipients, are described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed. , Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). Methods of making powders, and their composition, and methods of coating pharmaceutical dosage forms are also described in Remington's (see especially chapters 88 and 90 respectively). For ..vking dosage units, e.g. tablets, the use of conventional add : tives such as fillers, colorants, polymeric binders tand the like is contem ⁇ plated.
  • any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
  • suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. Lactose is a preferred carrier.
  • a process of manufacturing the combination and con- traceptive kit involves mixing predetermined quantities of antiprogestogen with appropriate amounts of pharma ⁇ ceutical excipients, optionally together with predeter ⁇ mined quantities of estrogen, and converting the mixture into first daily dosage units (e.g. by filling capsules or molding tablets with the mixture and any desired excipients); and mixing predetermined quantities of pro ⁇ gestogen with predetermined quantities of appropriate pharmaceutical excipients and converting that mixture into second daily dosage units.
  • a preferred process of manufacturing the contra ⁇ ceptive product according to the invention involves incorporating the desired dosages of steroid (e.g. antiprogestogen with or without estrogen) into a tablet by known techniques.
  • Tablets containing different amounts and types of steroids may be of different col ⁇ ors, and kept in different portions of, for example, a blister pack.
  • the package containing the dosage units may contain 20 to 40 dosage units arranged sequentially therein. Preferably there will be 28 dosage units consisting of two phases of 14 tablets each.
  • a method of contraception with invention involves administering to a pre-menopausal fertile female in 20 to 40 day cycles for so long as contraception is desired, the following: for a first 5 to 20 days, an antiprogestogen atnsas.daily dosage sufficient to inhibit ovulation; and for ⁇ tfee next 10 to 25 days, a progestogen at a daily dosage equivalent in progestogenic activity to 40 to 120 ⁇ g desogestrel administered orally. If contraception is still desired, the administration is continued, again starting with the first phase of tablets immediately after the first complete regimen is completed.
  • a preferred regimen involves administering to a female of child bearing age at the following times over a 28 day period:
  • Compound Amount (mg/tablet) desogestrel 0.075 potato or corn starch 8 . 000 polyvinyl pyrrolidone 2 . 400 stearic acid 0. 800 silica 0 . 800 dl- ⁇ -tocopherol 0. 080 lactose qsad 80.000
  • a first sub-phase of 10 capsules each containing: Compound Amount (m ⁇ /capsule)
  • 17,2'(3'H)-furan]-3-one 20.000 corn starch 8.000 polyvinyl pyrrolidone 2.400 stearic acid 0.800 silica 0.800 dl- ⁇ -tocopherol 0.080 lactose qsad 80.000

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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

On décrit des traitements avec des contraceptifs oraux comprenant une phase d'administration d'un antiprogestatif combinée à une phase d'aministration d'un progestatif. Un traitement contraceptif comprend: une première phase de 5-20 et tout particulièrement de 14 doses unitaires journalières successives d'un antiprogestatif en une quantité suffisante pour inhiber l'ovulation chez la femme traitée, et une seconde phase de 10-25 et tout particulièrement de 14 doses unitaires, journalières d'un progestatif équivalent à 40-120 νg de désogestrel, l'administration se faisant par voie orale. Pendant la première phase, on utilise de préférence un oestrogène tel que le 17β-oestradiol (de 0,50 à 2,5 mg par jour) pour réaliser le traitement séquentiel. L'invention concerne également un produit contraceptif (c'est-à-dire un conditionnement contenant les doses unitaires du traitement) et un procédé pour fabriquer ce produit.
PCT/EP1993/002139 1992-08-14 1993-08-10 Contraceptifs contenant un antiprogestatif Ceased WO1994004156A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47089/93A AU4708993A (en) 1992-08-14 1993-08-10 Antiprogestogen containing contraceptives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP92202504 1992-08-14
EP92202504.4 1992-08-14

Publications (1)

Publication Number Publication Date
WO1994004156A1 true WO1994004156A1 (fr) 1994-03-03

Family

ID=8210854

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1993/002139 Ceased WO1994004156A1 (fr) 1992-08-14 1993-08-10 Contraceptifs contenant un antiprogestatif

Country Status (4)

Country Link
AU (1) AU4708993A (fr)
MX (1) MX9304931A (fr)
WO (1) WO1994004156A1 (fr)
ZA (1) ZA935617B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0646008A4 (fr) * 1992-05-06 1995-10-11 Hampton Roads Medical College Procede pour reduire au minimum les hemorragies uterines secondaires liees a la prise de progesterone.
WO1996019227A1 (fr) * 1994-12-19 1996-06-27 Ortho Pharmaceutical Corporation Dosage posologique cyclophasique d'hormones contenant une antiprogestine et une progestine
WO1997049407A1 (fr) * 1996-06-25 1997-12-31 Akzo Nobel N.V. Schemas posologiques de progestogene et anti-progestogene
WO1999025360A3 (fr) * 1997-11-14 1999-07-29 Akzo Nobel Nv Regime progestatif-antiprogestatif
WO1999061406A3 (fr) * 1998-05-22 2000-01-27 Abbott Lab Medicament anti-angiogenique pour le traitement du cancer, de l'arthrite et de la retinopathie
WO2000066129A3 (fr) * 1999-04-29 2001-04-19 Akzo Nobel Nv Utilisation d'antiprogestagenes en therapie combinee
US6506390B2 (en) 1996-06-25 2003-01-14 Akzo Nobel Progestogen-anti-progestogen regimens
US6632961B1 (en) 1998-05-22 2003-10-14 Abbott Laboratories Antiangiogenic drug to treat cancer, arthritis and retinopathy

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Anti-Progestins - A New Approach to Contraception", TRENDS IN MEDICINAL CHEMISTRY; 9TH INT.SYMP., BERLIN, WEST GERMANY, SEPT. 14-18, 1986. IX+634P., vol. 0, no. 0, 1987, pages 565 - 580 *
CONTRACEPT.FERTIL. SEX, vol. 10, no. 6, 1982, pages 389 - 393 *
FERTILITY AND STERILITY, vol. 49, no. 6, June 1988 (1988-06-01), pages 961 - 963 *
FERTILITY AND STERILITY, vol. 53, no. 4, April 1990 (1990-04-01), pages 747 - 750 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0646008A4 (fr) * 1992-05-06 1995-10-11 Hampton Roads Medical College Procede pour reduire au minimum les hemorragies uterines secondaires liees a la prise de progesterone.
WO1996019227A1 (fr) * 1994-12-19 1996-06-27 Ortho Pharmaceutical Corporation Dosage posologique cyclophasique d'hormones contenant une antiprogestine et une progestine
AU725670B2 (en) * 1996-06-25 2000-10-19 Akzo Nobel N.V. Progestogen-anti-progestogen regimens
WO1997049407A1 (fr) * 1996-06-25 1997-12-31 Akzo Nobel N.V. Schemas posologiques de progestogene et anti-progestogene
US6506390B2 (en) 1996-06-25 2003-01-14 Akzo Nobel Progestogen-anti-progestogen regimens
US6642219B1 (en) 1997-11-14 2003-11-04 Akzo Nobel N.V. Progestogen-antiprogestogen regimens
WO1999025360A3 (fr) * 1997-11-14 1999-07-29 Akzo Nobel Nv Regime progestatif-antiprogestatif
RU2215540C2 (ru) * 1997-11-14 2003-11-10 Акцо Нобель Н.В. Схемы приема гестаген-антигестагена
WO1999061406A3 (fr) * 1998-05-22 2000-01-27 Abbott Lab Medicament anti-angiogenique pour le traitement du cancer, de l'arthrite et de la retinopathie
US6632961B1 (en) 1998-05-22 2003-10-14 Abbott Laboratories Antiangiogenic drug to treat cancer, arthritis and retinopathy
US6849757B2 (en) 1998-05-22 2005-02-01 Abbott Laboratories Antiangiogenic drug to treat cancer, arthritis and retinopathy
WO2000066129A3 (fr) * 1999-04-29 2001-04-19 Akzo Nobel Nv Utilisation d'antiprogestagenes en therapie combinee
RU2234321C2 (ru) * 1999-04-29 2004-08-20 Акцо Нобель Н.В. Применение антипрогестагенов в комбинированной терапии

Also Published As

Publication number Publication date
AU4708993A (en) 1994-03-15
ZA935617B (en) 1994-03-07
MX9304931A (es) 1994-08-31

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