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WO2000028995A1 - Contraceptif progestatif gradue - Google Patents

Contraceptif progestatif gradue Download PDF

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Publication number
WO2000028995A1
WO2000028995A1 PCT/US1999/025705 US9925705W WO0028995A1 WO 2000028995 A1 WO2000028995 A1 WO 2000028995A1 US 9925705 W US9925705 W US 9925705W WO 0028995 A1 WO0028995 A1 WO 0028995A1
Authority
WO
WIPO (PCT)
Prior art keywords
norethindrone
composition
amount
ethinyl estradiol
days
Prior art date
Application number
PCT/US1999/025705
Other languages
English (en)
Inventor
Roger M. Boissonneault
Original Assignee
Warner Chilcott Laboratories Ireland Limited
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 Warner Chilcott Laboratories Ireland Limited filed Critical Warner Chilcott Laboratories Ireland Limited
Priority to AU15189/00A priority Critical patent/AU1518900A/en
Priority to EP99957497A priority patent/EP1148884A4/fr
Publication of WO2000028995A1 publication Critical patent/WO2000028995A1/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
    • 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

Definitions

  • the present invention generally relates to a contraceptive method and delivery system, and in particular a contraceptive method and delivery system involving novel multi-phasic norethindrone/ethinyl estradiol combinations, wherein the amount of norethindrone is increased substantially stepwise over the cycle.
  • compositions contain both estrogenic and progestogenic compounds.
  • estrogen/progestogen combinations are highly effective in controlling ovulation and conception.
  • U.S. Patent No. 4,390,531 discloses the use of norethindrone as the progestogenic component in one type of estrogen/progestogen combination. However, such combinations are generally associated with high incidence of breakthrough bleeding.
  • U.S. Patent No. 3,733,407 discloses a product which attempts to mimic the phases of the natural menstrual cycle by varying the progestational component.
  • U.S. Patent No. 4,962,098 discloses contraceptive methods and delivery systems based on novel triphasic estrogen/progestogen combinations, wherein the amount of estrogen is increased stepwise over the three phases.
  • compositions used correspond to phases comprising, in sequence, about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol in a first phase (Phase I), about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol in a second phase (Phase II), about 0.75 to 1.5 mg norethindrone and about 10 to 30 meg ethinyl estradiol in a third phase (Phase III), and a suitable quantity of placebo in an inactive phase (Phase IV).
  • phases comprising, in sequence, about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol in a first phase (Phase I), about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol in a second phase (Phase II), about 0.75 to 1.5 mg norethindron
  • the present invention in a preferred embodiment, may be characterized in that the amount of norethindrone is increased with each succeeding phase. That is, the amount of norethindrone is increased for each composition with different compositions being used in each phase.
  • cycle control is problematic mid to late cycle. By increasing the amount of norethindrone in pharmacologic doses during mid to late cycle, this problem is ameliorated.
  • the present invention in a preferred embodiment, may be administered in a variety of cycles, including 22 day to 35 day cycles, with 23 to 25 day cycles being preferred.
  • the first phase will be about four to six days
  • the second phase will be about five to seven days
  • the third phase will be about ten to fifteen days
  • the pill free interval will be about three to seven days.
  • the present invention includes a method and a kit for the use of a graduated multi phase, sequentially-administered combination of compositions.
  • the compositions employed in accordance with the present invention contain in Phase I about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol, in Phase II about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol, and in Phase III about 0.75 to 1.5 mg norethindrone and about 10 to 30 meg ethinyl estradiol.
  • the amount of norethindrone is preferably increased stepwise over the three compositions.
  • a first composition is administered for about five days and comprises about 0.4 mg norethindrone and about 20 meg ethinyl estradiol
  • a second composition is administered for about six days and comprises about 0.70 mg norethindrone and about 20 meg ethinyl estradiol
  • a third composition is administered for about thirteen days comprising 1.0 mg norethindrone and about 20 meg ethinyl estradiol.
  • the invention is directed to a method of contraception comprising the steps of sequentially administering, to a female of child bearing age: for about four to about six days, a first composition comprising about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol, for about five to seven days, a second composition comprising about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol, for about ten to fifteen days, a third composition comprising 0.75 to 1.5 mg norethindrone and about 10 to 30 meg ethinyl estradiol, wherein the amount of norethindrone is increased stepwise by the amount of 0.30 mg in each step.
  • the invention is directed to a graduated multiphase combination and contraceptive kit comprising a package comprising daily dosages of a Phase I composition comprising norethindrone and ethinyl estradiol, a Phase II composition comprising norethindrone and ethinyl estradiol, and a Phase III composition comprising norethindrone and ethinyl estradiol, wherein the amount of norethindrone is increased in a substantially stepwise fashion over the three compositions.
  • a pill free interval which comprises one or more placebos, may be used in conjunction with the other three compositions.
  • compositions may be consumed or administered in a numeric sequence with the Phase I composition being used first, the Phase II composition being used second, etc.
  • the method and kit described herein can be employed as part of a larger scheme for contraception or treatment of gynecological disorders. While the sequence in which the combinations are administered is generally important to their operation, variations in timing and dosage may be tolerated when medical considerations so dictate.
  • the present invention provides several advantages over prior art methods which employ estrogen/progestogen combinations. Principal among its advantages are ease of administration and the benefits of graduated progestin, i.e., maintaining low overall estrogen exposure while increasing progestogen mid to late cycle which results in increased stability of the developing and mature endometrium.
  • the present invention maintains a relatively low level of estrogen throughout the entire cycle. In a preferred embodiment, the estrogen level is maintained at a substantially constant dosage of about 20 meg throughout the cycle. The user is not required to be exposed to dosages as high as 35 meg at the end of the cycle, as in some prior art techniques. By thereby reducing estrogen exposure, the present invention tends to increase safety of the present invention in contrast to other prior art contraceptives.
  • the present invention requires that the progestin dose must be increased in a step-like fashion every seven days, to mimic the natural menstrual cycle. Since cycle control is problematic mid to late cycle, the present invention makes use of stepwise pharmacologic increases in norethindrone (graduated norethindrone), rather than attempting to mimic natural physiology
  • the present invention tends to reduce side effects, such as breakthrough bleeding, that occur with existing low dosage pills.
  • the active pill taking period is increased from about 21 days to between about 23 and 25 days. Extending the third phase (highest progestin dose) results in improved cycle control. Reducing the pill free interval, number of placebo pills, should also improve the overall efficacy of the regimen.
  • the present invention encompasses the use of other conventional additives, e.g., fillers, colorants, polymeric binders, and the like.
  • additives e.g., fillers, colorants, polymeric binders, and the like.
  • pharmaceutically-acceptable additives which may be used in one or more of the compositions without significantly interfering with the function of the active components.
  • suitable carriers with which the compositions can be administered include, without limitation, lactose, starch, cellulose derivatives and the like used in suitable amounts. Lactose is a preferred carrier. Mixtures of carriers may also be used.
  • norethindrone which may be used in the present invention is NoriutinTM, a product believed to be (or have been) manufactured by Parke-Davis.
  • ethinyl estradiol which may be used in the present invention is EstinylTM, a product manufactured by Schering Plough.
  • the norethindrone component may be completely or partially replaced with one or more alternative components, including, for example, norethindrone acetate, norgestrel, desogestrel or norgestimate.
  • the ethinyl estradiol component may be completely or partially replaced with one or more alternative components, including, for example mestranol.
  • meg refers to micrograms and “mg” to milligrams.
  • Phase IV is not essential to the operation of the other three phases.
  • a method or kit which does not contain the Phase IV component is operable and, in fact, may be preferred when suitable factors, e.g., economy, dictate the non-use of the Phase IV component.
  • method and kit as used herein may include any drug delivery systems via the use of which the 3- or 4-phase scheme outlined above can be effectively administered to human females. Combinations of various dosage forms may also be used.
  • a unique dosage pattern i.e., a unique sequence of administrations of a novel norethindrone/ethinyl estradiol combination has been discovered which minimizes certain side effects, notably breakthrough bleeding, commonly associated with conventional low dosage pills.

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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

L'invention concerne des méthodes contraceptives et des systèmes d'administration de contraceptif présentant peu d'effets secondaires indésirables pendant l'administration et basés sur de nouvelles combinaisons multiphases de noréthindrone/éthinyloestradiol dans lesquelles la dose de noréthindrone est augmentée sensiblement progressivement pendant les phases.
PCT/US1999/025705 1998-11-12 1999-11-03 Contraceptif progestatif gradue WO2000028995A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU15189/00A AU1518900A (en) 1998-11-12 1999-11-03 Graduated progestin contraceptive
EP99957497A EP1148884A4 (fr) 1998-11-12 1999-11-03 Contraceptif progestatif gradue

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19014698A 1998-11-12 1998-11-12
US09/190,146 1998-11-12

Publications (1)

Publication Number Publication Date
WO2000028995A1 true WO2000028995A1 (fr) 2000-05-25

Family

ID=22700189

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/025705 WO2000028995A1 (fr) 1998-11-12 1999-11-03 Contraceptif progestatif gradue

Country Status (3)

Country Link
EP (1) EP1148884A4 (fr)
AU (1) AU1518900A (fr)
WO (1) WO2000028995A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4390531A (en) * 1981-08-10 1983-06-28 Syntex Pharmaceuticals International Ltd. Method of contraception using peak progestogen dosage
US4530839A (en) * 1983-09-26 1985-07-23 Ortho Pharmaceutical Corporation Triphasic oral contraceptive
US4921843A (en) * 1988-10-20 1990-05-01 Pasquale Samuel A Contraception system and method
US5276022A (en) * 1987-09-24 1994-01-04 Jencap Research Ltd. Hormone preparation and method
US5340584A (en) * 1991-04-12 1994-08-23 University Of Southern California Methods and formulations for use in inhibiting conception and in treating benign gynecological disorders
US5898032A (en) * 1997-06-23 1999-04-27 Medical College Of Hampton Roads Ultra low dose oral contraceptives with less menstrual bleeding and sustained efficacy

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4390531A (en) * 1981-08-10 1983-06-28 Syntex Pharmaceuticals International Ltd. Method of contraception using peak progestogen dosage
US4530839A (en) * 1983-09-26 1985-07-23 Ortho Pharmaceutical Corporation Triphasic oral contraceptive
US5276022A (en) * 1987-09-24 1994-01-04 Jencap Research Ltd. Hormone preparation and method
US5382573A (en) * 1987-09-24 1995-01-17 Jencap Research Ltd. Hormone preparation and method
US4921843A (en) * 1988-10-20 1990-05-01 Pasquale Samuel A Contraception system and method
US5340584A (en) * 1991-04-12 1994-08-23 University Of Southern California Methods and formulations for use in inhibiting conception and in treating benign gynecological disorders
US5898032A (en) * 1997-06-23 1999-04-27 Medical College Of Hampton Roads Ultra low dose oral contraceptives with less menstrual bleeding and sustained efficacy

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1148884A4 *

Also Published As

Publication number Publication date
AU1518900A (en) 2000-06-05
EP1148884A1 (fr) 2001-10-31
EP1148884A4 (fr) 2003-06-11

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