WO2000009136A1 - Kit contraceptif base uniquement sur le progestogene et permettant un controle efficace du cycle - Google Patents

Kit contraceptif base uniquement sur le progestogene et permettant un controle efficace du cycle Download PDF

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Publication number
WO2000009136A1
WO2000009136A1 PCT/EP1999/005610 EP9905610W WO0009136A1 WO 2000009136 A1 WO2000009136 A1 WO 2000009136A1 EP 9905610 W EP9905610 W EP 9905610W WO 0009136 A1 WO0009136 A1 WO 0009136A1
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WO
WIPO (PCT)
Prior art keywords
progestogen
phase
daily
amount
desogestrel
Prior art date
Application number
PCT/EP1999/005610
Other languages
English (en)
Inventor
Petrus Gustaaf Wilhelmus Stokman
Gerardus Herman Vitus Korver
Original Assignee
Akzo Nobel N.V.
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 Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to AU56193/99A priority Critical patent/AU5619399A/en
Publication of WO2000009136A1 publication Critical patent/WO2000009136A1/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
    • 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

Definitions

  • the invention pertains to a contraceptive kit (drug delivery system) comprising means for the daily administration of a progestogen as the single active substance, i.e. a contraceptive regimen of the progestogen-only type, wherein the mechanism of action is based on the ovulation-inhibiting effect of the progestogen.
  • a contraceptive kit drug delivery system
  • means for the daily administration of a progestogen as the single active substance i.e. a contraceptive regimen of the progestogen-only type, wherein the mechanism of action is based on the ovulation-inhibiting effect of the progestogen.
  • Contraceptive regimens of the progestogen-only type (“progestogen-only pill' or "POP") are known.
  • POP's are available, e.g. with levonorgestrel 30 ⁇ g per day, such as Microval ® and others.
  • the second, and more modern development is that wherein the mechanism of action is based on the ovulation-inhibiting effect of the progestogen.
  • Such a POP has been disclosed in, e.g.
  • EP 491 443 which teaches that by using more selective progestagens like desogestrel or etonoogestrel as the progestogen at certain specified dosages administered over an entire menstrual cycle, consistent ovulation inhibition is achieved, without increasing the number and type of side-effects.
  • This POP works well, and is marketed under the tradename Cerazette®.
  • the present invention pertains to this latter type of POP.
  • POPs have the advantage of avoiding the administration of estrogens (unlike combined OCs), and provide a higher contraceptive security compared to traditional POPs, but have a relatively high incidence of bleeding at irregular intervals (menstrual spotting or break through bleeding). With such POPs it is also quite common that amenorrhoea occurs, especially after a longer period of use. For many women, the occurrence of bleeding during tablet intake as well as the occurrence of amenorrhoea are disconcerting since they are interpreted as signs that the contraceptive working is absent, and is thus not generally desired.
  • a contraceptive regimen in which on the fifth day of the menstrual cycle a woman receives 0.4 mg of norethindrone, and this is given daily for seven days. The dosage is increased to 0.8 mg norethindrone for the next seven days, and to 1.5 mg norethindrone for yet another seven days. Thereafter seven days without the administration of an active agent follows, and then the 0.4 mg norethindrone phase recommences.
  • This contraceptive regimen has not become commercially available, and if it is effective at all, its mechanism of action cannot be based on inhibition of ovulation, since the dose of progestogen in the first phase of progestogen administration is below the minimum ovulation-inhibiting dose of norethindrone.
  • a contraceptive regimen has been disclosed in which during the first twelve to sixteen days of the menstrual cycle a placebo is administered, the next four days a daily dose of 2-20 mg of a progestogen such as norethindrone. This high dosage serves to inhibit the function of the corpus luteum. The remainder of the cycle a dosage of 10-40% of the previous progestogen dosage is administered. In an example, the respective dosages are 5 mg and 1 mg, which makes the progestogen-burden unacceptably high.
  • a regimen has now been found by which a continuous POP of the type described in EP 491 443, i.e. a regimen in which a progestogen is the single active, ovulation-inhibiting substance, can be made to give a good cycle control. This is achieved as a result of administering the progestogen in two phases, wherein the dose of progestogen in the second phase has sharply increased vis-a-vis that in the first phase.
  • the invention is a contraceptive kit as mentioned hereinbefore, wherein the means for the daily administration of progestogen are divided into the following two sets, each set providing for either of two subsequent phases:
  • I. means for the daily administration during 10 to 20 days of a progestogen in an amount as low as possible to inhibit ovulation;
  • phase II means for the daily administration during at least 7 days of a progestogen in an amount which is at least twice that in phase I, provided that it is not lower than the dose required to cause transformation of the endometrium.
  • the invention is a drug delivery system for contraceptive use containing sequential daily (oral) dosage units in two sets, the first set comprising 10-20 units complying with the above Phase I, the second set comprising at least 7 units complying with the above Phase II.
  • the invention is a method of contraception, comprising continuously (for at least one cyclus) administering a progestogen to a female of child- bearing age, notably a human female, wherein the administration is conducted so as to comply with the above two phases.
  • This contraceptive regimen has the advantage of providing contraceptive efficacy combined with good cycle control.
  • the bleeding pattern mimics that of the natural menstrual cycle. Without theory being intended as binding, this can be explained as follows.
  • progestogen in Phase I which by itself inhibits ovulation and is thus contraceptively effective, follicles of sufficient size still grow, and endogenous estradiol (E2) production still occurs.
  • E2 production leads to proliferation of the endometrium.
  • the proliferated endometrium is capable of its normal transformation.
  • shedding of the transformed endometrium occurs, i.e. as if with regular menses.
  • ovulation again being inhibited by the administration of progestogen and endogenous E2 being produced as before.
  • the beneficial effect of this contraceptive regimen is bleeding at regular menstrual intervals, associated with an improved overall cyclus control, with minimised spotting.
  • progestogens commonly used for contraception can be employed in the present invention.
  • the progestogens in both phases may be different compounds, but preferably are identical.
  • the doses needed in the Phases I and II, within the bounds and limits given above, cannot be seen completely independent of each other. They should be chosen such that, apart from ovulation-inhibition, three events occur: priming of the endometrium in phase I, transformation of the endometrium in Phase II, and shedding of the endometrium as a result of the transition from Phase II in one cycle to Phase I in the next cycle.
  • Phase I It is crucial for the contraceptive regimen provided for by the present invention, that two events occur in Phase I. The first is that ovulation inhibition is guaranteed. This requires that the amount of progestogen in Phase I is at least the minimum ovulation-inhibiting dose. The second is that the endometrium is primed sufficiently for subsequent transformation to occur. Since the administration of progestogen leads to a reduction of the endogenous estradiol-production, and priming of the endometrium requires the endogenous estradiol- production to be near the natural level, it follows that the dose in Phase I should be as low as possible, but still ovulation-inhibiting. These doses are known to the person skilled in the art, see also the table below. It will be understood that a deviation of this requirement can be allowed only if the endogenous estradiol-production remains sufficient to generate an endometrium capable of transformation.
  • the amount of progestogen administered should be at least sufficient to cause transformation of the endometrium.
  • the required amounts are known to the person skilled in the art, and can be determined as follows.
  • the daily dosage needed is at least this total amount divided by the number of days. Typical figures per cycle are given in the table below, with the minimum daily dosages in case of a second phase of 14 days added.
  • the dose of progestogen should be higher than the critical amount, in order to maintain endometrium stability for the duration of Phase II and subsequently achieve the progestogen-withdrawal that is needed for shedding.
  • the dose in Phase II for some progestogens this requirement is automatically satisfied by administering the dose needed to cause transformation, since this dose is substantially higher than that needed to inhibit ovulation.
  • the dose needed for transformation is not significantly higher than the ovulation-inhibiting dose.
  • the dose in Phase II should be at least twice that in Phase II, and preferably 2.5-5 times.
  • the preferred progestogens are norethisterone, norgestimate, levonorgestrel, desogestrel, etonogestrel, gestodene, and (17 ⁇ )-17-hydroxy-l l-methylene-19-norpregna-4,15-diene-20- yn-3-one (hereinafter referred to as Org 30659).
  • Org 30659 the required doses are listed in the table below. Ref: Runnebaum et al., AmJ.Obstet.Gynecol.. October 1987, Vol.157, Number 4, Part 2, pages 1059-1063.
  • Org 30659 40 0.4-2.5 mg 30-180 ⁇ g 80 ⁇ g
  • the minimum amount needed for the transformation of a fully estradiol-primed endometrium is lower than the minimum amount for ovulation inhibition.
  • the amount given for Phase II is an absolute minimum, giving good cycle control in only a limited number of women.
  • the difference between Phase I and II is higher, i.e. 60-120 ⁇ g for desogestrel, gestodene, and Org 30659.
  • the upper limit of the dose in Phase II is determined by the maximum pharmacologically acceptable amount of a given progestogen.
  • the daily dosage units contain a progestogen selected from the group consisting of desogestrel, Org 30659, levonorgestrel, and gestodene, in an amount equivalent in ovulation-inhibiting activity with 50-75 ⁇ g desogestrel in Phase I and an amount of 120 to 300 ⁇ g per day in Phase II.
  • a progestogen selected from the group consisting of desogestrel, Org 30659, levonorgestrel, and gestodene
  • the number of daily dosage means in phase I is 14.
  • the number of daily dosage means in phase II preferably is of from 7 to 28, and most preferably also 14, in order to have a cycle of 28 days.
  • the kit according to the invention preferably contains 14 dosage units containing a progestogen in the dose required for Phase I and 14 dosage units containing a progestogen in the dose required for phase II.
  • the regimen provided for by the present invention is based on desogestrel or Org 30659 as the progestogen, has two phases of 14 days each, and is selected from the following group:
  • Phase II Phase II
  • the progestogen is incorporated into dosage units for oral administration.
  • dosage unit generally refers to physically discrete units suitable as unitary dosages for humans, each containing a predetermined quantity of active material calculated to produce the desired effect, for instance tablets, pills, powders, suppositories, capsules and the like.
  • the dosage units are packed so as to form a kit with such design and instructions that the daily administration of the dosage units in the right, biphasic order is safeguarded.
  • Suitable packages e.g. push-through strips with consecutive numbering of the days of the cyclus, are known in the art and do not require elucidation here.
  • the invention also pertains to the use of a first composition containing a progestogen as the sole contraceptively active ingredient at a daily dose equivalent in ovulation-inhibiting activity in the range of 40-75 ⁇ g desogestrel and a follow-up composition containing, as the sole contraceptively active ingredient, a daily dosage of the progestogen which is at least twice that of the first composition, but which dose is within the range needed to cause endometrial transformation, for the preparation of a two phase contraceptive for use in a method of contraception, which method comprises orally and daily administering to a human female of child-bearing age the first composition daily during 10 to 18 days from the onset of menses and the second composition daily for at least 7 days and preferably up to 28 days.
  • Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like used in suitable amounts. Lactose is a preferred carrier. Mixtures of carriers can also be used.
  • a process of manufacturing the kit of the invention comprises mixing predetermined quantities of progestogen with predetermined quantities of excipients and converting the mixture into dosage units containing the progestogen.
  • two different types of dosage units are made, i.e. with two different quantities of progestogen, each type having the amount of progestogen required for either phase.
  • a preferred process of manufacturing the pharmaceutical product according to the invention involves incorporating the desired dosages of contraceptive steroid, for example desogestrel, etonogestrel (which is also known as 3-ketodesogestrel), or mixtures thereof into tablets by techniques such as wet granulation tableting techniques.
  • contraceptive steroid for example desogestrel, etonogestrel (which is also known as 3-ketodesogestrel)
  • etonogestrel which is also known as 3-ketodesogestrel
  • mixtures thereof into tablets by techniques such as wet granulation tableting techniques.
  • the invention also includes a pharmaceutical product (i.e. the dosage units or the package containing the dosage units), a method of using the product, and a process of manufacturing the pharmaceutical product.
  • a pharmaceutical product i.e. the dosage units or the package containing the dosage units
  • a method of using the product i.e. the dosage units or the package containing the dosage units
  • a process of manufacturing the pharmaceutical product i.e. the process of manufacturing the pharmaceutical product.
  • the invention also includes a method of providing contraception involving administering to a woman the above-mentioned regimens.
  • redient Amount (mg/tablet) desogestrel 0.075 corn starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 ⁇ -tocopherol 0.080 lactose qsad 65.000
  • Coating laver (filmcoat-drv) ingredient Amount (mg/tablet) hydroxypropylmethylcellulose 0.75 polyethylene glycol 400 0.15 titanium dioxide 0.1125 talc 0.1875
  • Examples 1(a) and 11(a) were tested in 13 and 15 healthy female volunteers respectively, in the course of a non-public, double-blind randomised study. Upon continuous administration, ovulation was completely inhibited in all women, which fully validates that the doses are sufficient to inhibit ovulation during the proliferative phase (Phase I) of the cycle.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Reproductive Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un régime contraceptif du type uniquement basé sur le progestogène. Ce régime, très efficace en matière de contrôle du cycle et de contraception, est basé sur l'administration du progestogène en deux phases: 1) Durant 10 à 20 jours, de préférence pendant 14 jours, une quantité de progestogène au moins suffisante pour inhiber l'ovulation mais suffisamment limitée pour que la production d'oestradiol endogène ait encore lieu -) Durant au moins 7 jours, de préférence pendant 14 jours, une quantité de progestogène qui est suffisamment importante pour provoquer une transformation de l'endomètre et qui est au moins deux fois supérieure à la quantité de la phase 1. Selon l'invention, un régime type peut être appliqué au moyen d'un kit comportant deux ensembles à 14 unités posologiques chacun, le premier ensemble contenant 60 νg -'Org 30659 et le deuxième 120 νg.
PCT/EP1999/005610 1998-08-11 1999-08-04 Kit contraceptif base uniquement sur le progestogene et permettant un controle efficace du cycle WO2000009136A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56193/99A AU5619399A (en) 1998-08-11 1999-08-04 Progestogen-only contraceptive kit providing good cycle control

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98202699 1998-08-11
EP98202699.9 1998-08-11

Publications (1)

Publication Number Publication Date
WO2000009136A1 true WO2000009136A1 (fr) 2000-02-24

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Application Number Title Priority Date Filing Date
PCT/EP1999/005610 WO2000009136A1 (fr) 1998-08-11 1999-08-04 Kit contraceptif base uniquement sur le progestogene et permettant un controle efficace du cycle

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AU (1) AU5619399A (fr)
PE (1) PE20000887A1 (fr)
WO (1) WO2000009136A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010066883A1 (fr) * 2008-12-12 2010-06-17 Laboratoire Hra-Pharma Méthode de contraception
WO2010119029A1 (fr) * 2009-04-14 2010-10-21 Laboratoire Hra-Pharma Methode de contraception à la demande
EP2730284A1 (fr) * 2012-11-12 2014-05-14 Naari AG Composition uniquement à base de levonorgestrel pour contraception orale optimisée avec contenu de lévonorgestrel défini, posologie et préparation pharmaceutique
WO2023007312A1 (fr) * 2021-07-26 2023-02-02 Navad Life Sciences Pte Contraception orale à base de progestatif seul

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2223018A1 (fr) * 1973-03-26 1974-10-25 Ortho Pharma Corp
EP0491443A1 (fr) * 1990-12-17 1992-06-24 Akzo Nobel N.V. Progestogène comme seul contraceptif
WO1994004157A1 (fr) * 1992-08-21 1994-03-03 Schering Aktiengesellschaft Agent d'application transdermique contenant du 3-ceto-desogestrel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2223018A1 (fr) * 1973-03-26 1974-10-25 Ortho Pharma Corp
EP0491443A1 (fr) * 1990-12-17 1992-06-24 Akzo Nobel N.V. Progestogène comme seul contraceptif
WO1994004157A1 (fr) * 1992-08-21 1994-03-03 Schering Aktiengesellschaft Agent d'application transdermique contenant du 3-ceto-desogestrel

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010066883A1 (fr) * 2008-12-12 2010-06-17 Laboratoire Hra-Pharma Méthode de contraception
US9180131B2 (en) 2008-12-12 2015-11-10 Laboratoire Hra Pharma Method for contraception
JP2012523446A (ja) * 2009-04-14 2012-10-04 ラボラトワール・アシュエールア−ファルマ オンデマンド避妊方法
EP2419108A1 (fr) 2009-04-14 2012-02-22 Laboratoire HRA Pharma Methode de contraception à la demande
WO2010119029A1 (fr) * 2009-04-14 2010-10-21 Laboratoire Hra-Pharma Methode de contraception à la demande
US9283233B2 (en) 2009-04-14 2016-03-15 Laboratoire Hra-Pharma Method for on-demand contraception
JP2016188232A (ja) * 2009-04-14 2016-11-04 ラボラトワール・アシュエールア−ファルマＬａｂｏｒａｔｏｉｒｅ Ｈｒａ−Ｐｈａｒｍａ オンデマンド避妊方法
EP3106167A1 (fr) * 2009-04-14 2016-12-21 Laboratoire HRA Pharma Procédé de contraception à la demande
US9616073B2 (en) 2009-04-14 2017-04-11 Laboratoire Hra-Pharma Method for on-demand contraception
EP2730284A1 (fr) * 2012-11-12 2014-05-14 Naari AG Composition uniquement à base de levonorgestrel pour contraception orale optimisée avec contenu de lévonorgestrel défini, posologie et préparation pharmaceutique
WO2014072245A1 (fr) * 2012-11-12 2014-05-15 Naari Ag Composition de lévonorgestrel seul pour une contraception par voie orale optimisée présentant une teneur définie en lévonorgestrel, régime posologique et préparation pharmaceutique
EA029329B1 (ru) * 2012-11-12 2018-03-30 Наари Пте. Лтд. Композиция левоноргестрела для оптимальной пероральной контрацепции с определенным содержанием левоноргестрела, режим дозирования и фармацевтический препарат
WO2023007312A1 (fr) * 2021-07-26 2023-02-02 Navad Life Sciences Pte Contraception orale à base de progestatif seul
US11679114B2 (en) 2021-07-26 2023-06-20 Navad Life Sciences Pte Progestogen-only oral contraception

Also Published As

Publication number Publication date
PE20000887A1 (es) 2000-09-15
AU5619399A (en) 2000-03-06

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