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WO2007009769A1 - Contraception orale a l'aide de trimegestone - Google Patents

Contraception orale a l'aide de trimegestone Download PDF

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Publication number
WO2007009769A1
WO2007009769A1 PCT/EP2006/007103 EP2006007103W WO2007009769A1 WO 2007009769 A1 WO2007009769 A1 WO 2007009769A1 EP 2006007103 W EP2006007103 W EP 2006007103W WO 2007009769 A1 WO2007009769 A1 WO 2007009769A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethinyloestradiol
trimegestone
days
combination
administered
Prior art date
Application number
PCT/EP2006/007103
Other languages
English (en)
Inventor
Oliver Gloger
Heinrich Kugelmann
Maria Popova
Original Assignee
Grünenthal GmbH
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
Priority claimed from DE102005034498A external-priority patent/DE102005034498A1/de
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Priority to MX2008000844A priority Critical patent/MX2008000844A/es
Priority to CA002615427A priority patent/CA2615427A1/fr
Priority to AU2006271920A priority patent/AU2006271920A1/en
Priority to BRPI0614672-4A priority patent/BRPI0614672A2/pt
Priority to EP06762699A priority patent/EP1909799A1/fr
Priority to JP2008521881A priority patent/JP2009501747A/ja
Priority to NZ565829A priority patent/NZ565829A/en
Publication of WO2007009769A1 publication Critical patent/WO2007009769A1/fr
Priority to IL188751A priority patent/IL188751A0/en
Priority to NO20080824A priority patent/NO20080824L/no

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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
    • 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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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 relates to a method for contraception by the administration of trimegestone.
  • the invention further relates to pharmaceutical compositions and dosage forms which contain trimegestone.
  • Trimegestone (17 ⁇ -[(S)-2-hydroxypropanoyl]-17 ⁇ -methyl-estra-4,9-dien-3-one) is a known prior art gestagen. It may be considered as a very potent progestin with regard to strong endometrial transformation effect and moderate ovulation suppression. The pharmacodynamic profile is very close to progesterone, the natural progestin. Reference may for example be made in this connection to EP-A 007 823. Combinations of trimegestone with oestrogens for contraception are described, for example, in WO 98/04246, WO 98/04265, WO 98/04268 and WO 98/04269. WO 01/37841 discloses the administration of trimegestone in combination with oestradiol for treating the symptoms of the menopause and for preventing post-menopausal osteoporosis.
  • oral contraceptive preparations comprise a gestagen in combination with an oestrogen as the hormonal active ingredients, with administration conventionally proceeding for 21-25 days in each 28-day menstrual cycle. Thereafter, either a placebo or nothing at all is administered for 3-7 days, so initiating withdrawal bleeding.
  • a contraceptive preparation should, on the one hand, provide good cycle control and, on the other hand, exhibit no or only slight side-effects.
  • Cycle control is primarily effected by the oestrogen.
  • the cycle controlling effect of the oestrogen in turn may be influenced by the gestagen and hence, the nature and the dose of the gestagen are also important factors to be taken into account.
  • Good cycle control is in particular also distinguished by the occurrence of the desired (withdrawal) bleeding, which may inter alia be characterised by
  • gestagen/ oestrogen combination is administered either at a constant dose (monophasic) or in a bi- or multiphasic regimen.
  • WO 98/04269 discloses a monophasic regimen and WO 98/04265, WO 98/04268 and WO 98/04246 disclose multiphasic regimens, with inter alia 40-500 ⁇ g of trimegestone being administered daily in combination with an oestrogen. While according to A.E. Schindler et al., Maturitas, 2003, 46, S1 , 7-16 the ovulation inhibition dose of trimegestone is 0.5 mg per day p.o., according to WO 98/04269, WO 98/04265, WO 98/04268 and WO 98/04246 the administered daily dose of trimegestone is preferably in the range from 40 to 250 ⁇ g. However, it is at least doubtful whether a daily dose of e.g. 40 ⁇ g trimegestone is sufficient in order to provide and to maintain a reliable contraceptive effect.
  • Entirely regular administration is, however, difficult to guarantee for practical reasons. It is known, for example, that a not inconsiderable proportion of women occasionally forget to take the dose intended for a particular day and only catch up on the following day. It may also happen, that the intended dose is administered in the morning on one day and not until the evening on the following day. Similar problems may also arise if the woman vomits after having taken the contraceptive, but before the dose has been completely resorbed.
  • the consequent fluctuations in plasma concentration may, as a result of the low dose of the administered active ingredients, possibly fall to values below the minimum threshold concentration which would be necessary to ensure reliable contraception. In such cases, the effectiveness of the contraception cannot always be guaranteed with a minimised active ingredient dose.
  • the fluctuations in plasma concentration may furthermore also result in premature onset of (withdrawal) bleeding (intermenstrual bleeding, for example as spotting or breakthrough bleeding).
  • trimegestone may in some women result in a plasma concentration which is above the necessary minimum concentration, but in other women, due to faster metabolisation, a higher dose would be necessary in order to ensure effective contraception.
  • the object of the invention is to provide a contraceptive method which exhibits advantages over prior art methods. Apart from ensuring effective contraception, the method should ensure good cycle control and exhibit no or at most only slight side- effects, for example no depressive mood effect and no disadvantageous effects on carbohydrate metabolism and lipid or lipoprotein levels. These properties should be relatively insensitive to irregularities in administration of the active ingredients and to intehndividual variations. This object is achieved by the subject matter of the claims.
  • trimegestone when trimegestone is administered in combination with an oestrogen for oral contraception, the ratio of gestagen to oestrogen may be varied within relatively broad limits thereby providing a reliable contraceptive effect without consequently giving rise to increased side-effects, such as for example depressive mood effect and disadvantageous effects on carbohydrate metabolism and lipid or lipoprotein levels. It has thus surprisingly been found that the dose of trimegestone may be increased within certain limits without simultaneously also having to increase the dose of the oestrogen in order to maintain the gestagen- oestrogen balance. In this way, side-effects which would otherwise accompany an elevated dose of the oestrogen are prevented.
  • the invention relates to a method for contraception comprising preferably oral administration of
  • trimegestone optionally in combination with at least one oestrogen, preferably ethinyloestradiol, or optionally in combination with two oestrogens, preferably ethinylestradiol and oestradiol, and/or optionally in combination with at least one further gestagen, and/or optionally in combination with at least one further physiologically active substance,
  • the daily dose of trimegestone is more than 500 ⁇ g.
  • the daily dose of trimegestone is in the range from more than 500 ⁇ g to less than 2,000 ⁇ g, or it is more than 2,000 ⁇ g.
  • the daily dose of trimegestone is in the range from more than 500 ⁇ g to less than 2,000 ⁇ g, or it is more than 2,000 ⁇ g.
  • trimegestone is administered in combination with at least one oestrogen at least on one, preferably on all of the at least 21 , preferably 24 successive days.
  • the oestrogen is preferably selected from the group consisting of chlorotrianisene, dienestrol, diethylstilbestrol, oestradiol (17 ⁇ -oestradiol), oestriol, oestrone, ethinyloestradiol, hexoestrol, mestranol, methallenoestril, methyloestrenol, promestriene and conjugated oestrogens or the pharmaceutically acceptable esters thereof.
  • Ethinyloestradiol or a combination of ethinyloestradiol and oestradiol (17 ⁇ -oestradiol) are particularly preferred.
  • Preferred pharmaceutically acceptable esters of the above listed oestrogens are acetates, propionates and valerates (for example oestradiol valerate).
  • the daily dose of the oestrogen preferably corresponds to an equivalent dose of 5.0 to 55 ⁇ g, more preferably of 10 to 50 ⁇ g, still more preferably of 15 to 48 ⁇ g, most preferably of 20 to 45 ⁇ g and in particular of 22 to 40 ⁇ g of ethinyloestradiol. 20 ⁇ g or 30 ⁇ g are particularly preferred. If two or more oestrogens are used, the daily overall dose thereof preferably corresponds to the above-stated equivalent doses, the equivalent dose preferably being related to the ovulation inhibition effect of the oestrogen.
  • trimegestone in a daily dose of 1,000 to 3,000 ⁇ g is administered in combination with ethinyloestradiol in a daily dose of 20 ⁇ 5 ⁇ g or 30 ⁇ 5 ⁇ g, on 24 or 25 successive days of a 28-day menstrual cycle.
  • ethinyloestradiol is adminstered in a daily dose of 30 ⁇ 5 ⁇ g, preferably 30 ⁇ 2.5 ⁇ g, in combination with trimegestone, the daily dose of trimegestone being > 500 ⁇ g, ⁇ 625 ⁇ g, ⁇ 750 ⁇ g, 875 ⁇ g, > 1,000 ⁇ g, ⁇ 1,125 ⁇ g, ⁇ 1,250 ⁇ g, > 1,375 ⁇ g, > 1,500 ⁇ g, > 1,625 ⁇ g, ⁇ 1,750 ⁇ g, > 1,875 ⁇ g, > 2,000 ⁇ g, ⁇ 2,125 ⁇ g, > 2,250 ⁇ g, ⁇ 2,375 ⁇ g, ⁇ 2,500 ⁇ g, 2,625 ⁇ g, > 2,750 ⁇ g, > 2,875 ⁇ g, > 3,000 ⁇ g, > 3,125 ⁇ g, > 3,250 ⁇ g, ⁇ 3,375 ⁇ g, > 3,500 ⁇ g, > 3,625 ⁇
  • the weight ratio of ethinyloestradiol to trimegestone is below 1 :45.
  • the daily dose of trimegestone corresponds to an equivalent dose of norethisterone actetate in a weight ratio of ethinyloestradiol to norethisterone acetate of below 1 :45, the equivalent dose preferably being related to the ovulation inhibition efficacy of norethisterone acetate and trimegestone, respectively.
  • ethinyloestradiol is administered in a daily dose of 1.0 to 55 ⁇ g, preferably 20 ⁇ 5 or 30 ⁇ 5 ⁇ g, and/or oestradiol (17 ⁇ -oestradiol) is administered in a daily dose of 1 ,000 to 10,000 ⁇ g, preferably 1 ,000 to 5,000 ⁇ g.
  • trimegestone is administered either not together with oestradiol (17 ⁇ -oestradiol) or together with a combination of oestradiol (17 ⁇ -oestradiol) and ethinyloestradiol.
  • oestradiol (17 ⁇ -oestradiol) is thus preferably only administered when ethinyloestradiol is also administered.
  • trimegestone is administered in a daily dose of 1 ,000 to 3,000 ⁇ g in combination with ethinyloestradiol in a daily dose of 10 to 20 ⁇ g and oestradiol in a daily dose of 1 ,000 to 5,000 ⁇ g, on 24 or 25 successive days of a 28-day menstrual cycle.
  • trimegestone is administered in combination with at least one further physiologically active substance at least on one, preferably on all of the at least 21 , preferably 24 successive days.
  • said further physiologically active substance is selected from the group consisting of folic acid, folinic acid, vitamin C, vitamin B preparations, iron(ll) preparations, iron(lll) preparations, calcium preparations and magnesium preparations.
  • vitamin B preparations examples include vitamin Bi preparations, such as thiamine hydrochloride and thiamine nitrate; vitamin B 2 preparations, such as riboflavin and riboflavin-5'-phosphate; nicotinamid preparations; vitamin B 6 preparations, such as pyridoxine hydrochloride; panthotenic acid preparations, such as dexpanthenol; and vitamin Bi 2 preparations, such as cyanocobalamin and hydroxocobalamin acetate.
  • vitamin Bi preparations such as thiamine hydrochloride and thiamine nitrate
  • vitamin B 2 preparations such as riboflavin and riboflavin-5'-phosphate
  • nicotinamid preparations examples include vitamin B 6 preparations, such as pyridoxine hydrochloride; panthotenic acid preparations, such as dexpanthenol; and vitamin Bi 2 preparations, such as cyanocobalamin and hydroxocobalamin acetate.
  • iron(ll) preparations are iron(ll) sulfate, iron(ll) carbonate, iron(ll) chloride, iron(ll) tartrate, iron(ll) gluconate, iron(ll) aspartate, iron(ll) glycine sulfate, iron(ll) fumarate, iron(ll) ascorbate, iron(ll) iodate, iron(ll) succinate and ammonium iron(ll) sulfate.
  • iron(lll) preparations are iron(lll) sodium citrate, iron(lll) oxide/sucrose complex, sodium feredetate, iron(lll) hydroxide, dextriferron, iron(lll) citrate, chondroitin sulfate/iron(lll) complex, iron(lll) acetyltransferrin, iron(lll) protein succinylate and potassium/iron(lll) phosphate/citrate complex.
  • Examples of calcium preparations are calcium carbonate, calcium citrate, calcium hydrogenphosphate, calcium phosphate, calcium aspartinate, calcium bisaspartate, calcium hydrogenaspartate, calcium gluconate, calcium lactate, calcium lactogluconate, calcium glucoheptonate, calcium acetate, calcium saccharate, calcium orotate and calcium lactobionate.
  • magnesium preparations are magnesium hydrogenaspartate, magnesium L-aspartate hydrochloride, magnesium oxide, magnesium hydrogenphosphate, magnesium citrate, magnesium hydrogencitrate, magnesium sulfate, magnesium L-hydrogenglutamate, magnesium D-gluconate, magnesium orotate, mgnesium adipate and magnesium nicotinate.
  • Preferred regimens are listed in the following table, the daily dose of trimegestone being A1 , A2 or A3 and the daily dose of the at least one oestrogen, preferably ethinyloestradiol, being B:
  • the equivalent dose to ethinyloestradiol may be effected by an equivalent quantity of each suitable oestrogen, the quantity here being selected such that the oestrogenic activity corresponds to that which would be brought about by the administration of ethinyloestradiol in the stated quantity, ethinyloestradiol itself being the preferred oestrogen.
  • Two or more different oestrogens, for example ethinyloestradiol in combination with oestradiol may also be used in a quantity which corresponds overall to the stated equivalent dose, preferably being related to the ovulation inhibition effect. Suitable methods for determining the equivalent dose are known to the person skilled in the art. Trimegestone is preferably used in combination with ethinyloestradiol or in combination with ethinyloestradiol and oestradiol (17 ⁇ - oestradiol).
  • the daily dose of trimegestone and of the oestrogen is in each case constant on all days within a phase and different on two successive days of different phases.
  • Particularly preferred regimens 1', 2i ⁇ 2 2 ⁇ 3i ⁇ 3 2 ', 3 3 1 , 4-T and 4 2 ' may be found in the following table, according to which ethinyloestradiol is administered on 21-24 successive days in a daily dose of 20 ⁇ 5 ⁇ g in combination with trimegestone in daily doses A1 , A2 and A3, respectively, as defined in tables a, b, c and d supra:
  • trimegestone is not administered on all the days of the preferably 28-day menstrual cycle. Instead, it is preferred that, on the days which follow the at least 21 , preferably 24 successive days,
  • the menstrual cycle preferably lasts 28 days.
  • the menstrual cycle it is, however, also possible for the menstrual cycle to be longer than 28 days.
  • trimegestone is preferably administered on more than 28 successive days.
  • (uninterrupted) administration of trimegestone proceeds on at least 42 or 56, more preferably at least 63, still more preferably at least 84, most preferably at least 105, 112 or 120 and in particular at least 126, 140, 150, 183, 184, 189 or 365 successive days, such that it is not intended to initiate withdrawal bleeding within this period.
  • (uninterrupted) administration of trimegestone proceeds on more than 183 but less than 365 days.
  • the continuous period for which trimegestone may be administered daily may also be still longer. In principle, it is accordingly possible to administer trimegestone on all successive days over one or more years, without any withdrawal bleeding occurring.
  • trimegestone is preferably administered in a daily dose of 1 ,000 to 3,000 ⁇ g in combination with ethinyloestradiol in a daily dose of 20 ⁇ 5 ⁇ g or 30 ⁇ 5 ⁇ g on every day of said more than 28 days, e.g. more than 183 days, without interruption.
  • trimegestone is preferably administered in a daily dose of 1 ,000 to 3,000 ⁇ g in combination with ethinyloestradiol in a daily dose of 10 to 20 ⁇ g and oestradiol in a daily dose of 1 ,000 to 5,000 ⁇ g on every day of said more than 28 days, e.g. more than 183 days, without interruption.
  • the days which follow the more than 28 days preferably on the consecutive 3, 4, 5, 6 or 7 days which follow the more than 28 days,
  • trimegestone is administered in a daily dose of 1 ,000 to 3,000 ⁇ g in combination with ethinyloestradiol in a daily dose of 20 ⁇ 5 ⁇ g or 30 ⁇ 5 ⁇ g on every day of said more than 28 days, e.g. at least 84 consecutive days, without interruption, and the 7 consecutive days following said more than 28 days, ethinyloestradiol is administered in a daily dose of 5 to 10 ⁇ g in the absence of trimegestone.
  • trimegestone is administered in combination with at least one further gestagen at least on one of the at least 21 , preferably 24 successive days.
  • the further gestagen is here preferably selected from the group consisting of allyloestrenol, chlormadinone, danazol, demegestone, desogestrel, dienogest, drospirenone, dydrogesterone, ethisterone, etynodiol, gestodene, gestonorone, hydroxyprogesterone, levonorgestrel, lynoestrenol, medroxyprogesterone, medrogestone, megestrol, methyloestrenol, methylnortestosterone, nomegestrol, norethisterone, norethynodrel, norgestrel, norgestimate, progesterone, promegestone and tibolone, or the pharmaceutically acceptable
  • Preferred pharmaceutically acceptable esters of the above listed gestagens are acetates (for example chlormadinone acetate, nomegestrol acetate, medroxyprogesterone acetate, megestrol acetate, norethisterone acetate), caproates (for example hydroxyprogesterone caproate) and enantates (for example norethisterone enantate).
  • acetates for example chlormadinone acetate, nomegestrol acetate, medroxyprogesterone acetate, megestrol acetate, norethisterone acetate
  • caproates for example hydroxyprogesterone caproate
  • enantates for example norethisterone enantate
  • the daily dose of the further gestagen preferably corresponds to an equivalent dose of 100 to 5,000 ⁇ g, more preferably of 250 to 4,000 ⁇ g, still more preferably of 500 to 3,500 ⁇ g, most preferably of 750 to 3,000 ⁇ g and in particular of 1 ,000 to 2,500 ⁇ g of chlormadinone acetate, the equivalent dose preferably being related to the ovulation inhibition effect of chlormadinone acetate or the endometrial effect of chlormadinone acetate.
  • the method according to the invention is carried out for at least one menstrual cycle.
  • the method according to the invention is preferably carried out for two or more, in particular for at least 3, 4, 5 or 6 successive menstrual cycles.
  • the present invention also relates to a, preferably solid, pharmaceutical composition
  • a, preferably solid, pharmaceutical composition comprising trimegestone in a quantity of more than 500 ⁇ g, preferably at least 600 ⁇ g, still more preferably at least 700 ⁇ g, yet more preferably at least 1 ,000 ⁇ g, most preferably at least 1 ,200 ⁇ g and in particular 1 ,000 to 3,000 ⁇ g, in combination with ethinyloestradiol, preferably in a quantity of 20 ⁇ 5 ⁇ g or 30 ⁇ 5 ⁇ g.
  • the present invention also relates to a, preferably solid, pharmaceutical composition
  • a, preferably solid, pharmaceutical composition comprising trimegestone in a quantity
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising trimegestone in a quantity of more than 500 ⁇ g, preferably of at least 750 ⁇ g, still more preferably of at least 1 ,000 ⁇ g, most preferably of at least 2,000 ⁇ g and in particular of at least 3,000 ⁇ g, in combination with ethinyloestradiol in a quantity of preferably at least 5 ⁇ g, more preferably 20 ⁇ 5 ⁇ g or 30 ⁇ 5 ⁇ g.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising trimegestone in a quantity of more than 500 ⁇ g, preferably of at least 750 ⁇ g, still more preferably of at least 1 ,000 ⁇ g, most preferably of at least 2,000 ⁇ g and in particular of at least 3,000 ⁇ g, in combination with ethinyloestradiol in a quantity of preferably at least 5 ⁇ g, more preferably 20 ⁇ 5 ⁇ g or 30 ⁇ 5 ⁇ g, and oestradiol in a quantity of preferably 1 ,000 to 10,000 ⁇ g, more preferably 1 ,000 to 5,000 ⁇ g.
  • the pharmaceutical composition according to the invention is preferably formulated for oral administration. It preferably assumes the form of (film coated) tablets, sugar coated tablets or multiparticulate form, preferably the form of microtablets, microcapsules, micropellets, accretion pellets, granules, extrudates, spheroids, beads or pellets, which may optionally be packaged in capsules or press-moulded to form (film coated) tablets. Dry-compacted formulations are also possible.
  • the present invention also relates to a dosage form comprising the pharmaceutical composition as described above, preferably for once daily, preferably oral administration.
  • the dosage form according to the invention comprises trimegestone in a quantity of more than 500 ⁇ g; preferably of at least 510 ⁇ g; more preferably of at least 525 ⁇ g, at least 1 ,000 ⁇ g, at least 1 ,500 ⁇ g or at least 2,000 ⁇ g; still more preferably of 550 to 950 ⁇ g; most preferably of 575 to 925 ⁇ g and in particular of 600 to 900 ⁇ g, wherein the dosage form is preferably selected from the group consisting of film coated tablets, sugar coated tablets and capsules.
  • the dosage form it comprises trimegestone in a quantity of ⁇ 1 ,000 ⁇ g and less than 2,000 ⁇ g or of ⁇ 2,000 ⁇ g.
  • the dosage form according to the invention may assume multiparticulate form, preferably the form of microtablets, microcapsules, micropellets, accretion pellets, granules, extrudates, spheroids, beads or pellets, optionally packaged in capsules or press-moulded to form (film coated) tablets. Dry-compacted formulations are also possible.
  • the dosage form according to the invention is selected from the group consisting of film coated tablets, sugar coated tablets and capsules and comprises the pharmaceutical composition according to the invention.
  • the pharmaceutical composition or dosage form according to the invention preferably additionally contains at least one oestrogen, preferably ethinyloestradiol.
  • the at least one oestrogen is here preferably selected from the group consisting of chlorotrianisene, dienestrol, diethylstilbestrol, oestradiol (17 ⁇ -oestradiol), oestriol, oestrone, ethinyloestradiol, hexoestrol, mestranol, methallenoestril, methyloestrenol, promestriene and conjugated oestrogens or the pharmaceutically acceptable esters thereof.
  • Preferred pharmaceutically acceptable esters are valerates (for example oestradiol valerate).
  • the quantity of the oestrogen preferably corresponds to an equivalent dose of 5.0 to 55 ⁇ g, more preferably of 10 to 50 ⁇ g, still more preferably of 15 to 48 ⁇ g, most preferably of 20 to 45 ⁇ g and in particular of 22 to 40 ⁇ g of ethinyloestradiol, ethinyoestradiol itself being the preferred oestrogen. If two or more oestrogens are used, the overall quantity thereof preferably corresponds to the above-stated equivalent doses, which are preferably related to the ovulation inhibition effect.
  • composition or dosage form contains
  • the pharmaceutical composition or dosage form according to the invention additionally contains at least one further gestagen apart from trimegestone.
  • the further gestagen is here preferably selected from the group consisting of allyloestrenol, chlormadinone, danazol, demegestone, desogestrel, dienogest, drospirenone, dydrogesterone, ethisterone, etynodiol, gestodene, gestonorone, hydroxyprogesterone, levonorgestrel, lynoestrenol, medroxyprogesterone, medrogestone, megestrol, methyloestrenol, methylnortestosterone, nomegestrol, norethisterone, norethynodrel, norgestrel, norgestimate, progesterone, promegestone and tibolone, or the pharmaceutically acceptable esters thereof.
  • Preferred pharmaceutically acceptable esters are acetates (for example chlormadinone acetate, medroxyprogesterone acetate, megestrol acetate, norethisterone acetate), caproates (for example hydroxyprogesterone caproate) and enantates (for example norethisterone enantate).
  • acetates for example chlormadinone acetate, medroxyprogesterone acetate, megestrol acetate, norethisterone acetate
  • caproates for example hydroxyprogesterone caproate
  • enantates for example norethisterone enantate
  • the quantity of the further gestagen preferably corresponds to an equivalent dose of 100 to 5,000 ⁇ g, more preferably of 250 to 4,000 ⁇ g, still more preferably of 500 to 3,500 ⁇ g, most preferably of 750 to 3,000 ⁇ g and in particular of 1 ,000 to 2,500 ⁇ g of chlormadinone acetate, the equivalent dose preferably being related to the ovulation inhibition effect of chlormadinone acetate or the endometrial effect, i.e. endometrial transformation effect, of chlormadinone acetate.
  • the pharmaceutical composition or dosage form according to the invention contains further active ingredients, in particular at least one oestrogen (such as ethinyloestradiol) and/or a further gestagen, these are preferably present as a mixture within the same administration unit.
  • Such dosage forms may be produced with the assistance of conventional methods and auxiliary substances. Suitable auxiliary substances are known to the person skilled in the art. In this connection, reference may be made, for example, to HP. Fiedler, Lexikon der Hilfsstoffe f ⁇ r Pharmazie, Kosmetik und angrenzende füre, Editio Cantor Aulendorff, 2002; and R.C. Rowe et al., Handbook of Pharmaceutical Excipients, APhA Publications, 4 th edition, 2003 in their entirety.
  • auxiliary substances are salt formers, buffers, emulsifiers, solubilising agents (solubilisers), wetting agents, antifoaming agents, gel formers, thickeners, film formers, surfactants, binders, slip agents, lubricants, embedding agents, mould release agents, flow-control agents, disintegration accelerators (disintegrants), chelating agents, sorbents, fillers, pharmaceutical solvents, antioxidants (for example ⁇ -tocopherol), preservatives, plasticizers, flavour and odour correctives and colorants.
  • solubilising agents solubilisers
  • wetting agents wetting agents
  • antifoaming agents gel formers
  • thickeners thickeners
  • film formers film formers
  • surfactants binders
  • slip agents lubricants
  • embedding agents mould release agents
  • flow-control agents disintegration accelerators (disintegrants)
  • chelating agents sorbents
  • fillers pharmaceutical solvents
  • extenders are lactose, mannitol, calcium diphosphate, starch, microcrystalline cellulose, calcium carbonate (E170) and magnesium carbonate.
  • disintegration accelerators examples include starch, for example maize starch, potato starch, crosslinked polyvinylpyrrolidone and low substituted sodium carboxymethylcellulose.
  • binders are starch (e.g. potato starch, maize starch), gelatin, polyvinylpyrrolidone, cellulose ethers, sugars, for example sucrose and glucose syrup.
  • slip agents examples include talcum, sodium stearyl fumarate, fatty acid esters and macrogol.
  • lubricants are stearic acid, magnesium stearate, calcium stearate and zinc stearate.
  • An example of a flow-control agent is colloidal silicon dioxide.
  • Examples of pharmaceutical solvents are propylene glycol and glycerol.
  • a surfactant is polyoxyethylene/sorbitan fatty acid ester (for example Polysorbate 80).
  • colorants are indigo carmine (E132), titanium dioxide (E171 ) and quinoline yellow (E104).
  • film formers are shellac, methylcellulose, hypromellose (hydroxypropyl- methylcellulose, HPMC), hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, polyacrylates and polymethacrylates.
  • Plasticizers, such as propylene glycol and/or polyethylene glycol may additionally be contained in the film coating composition.
  • embedding agents are carnauba wax, montan glycol wax, stearic/ palmitic acid, glycerol trioleate and cetylstearyl alcohol.
  • chelating agents are citric acid, phenylalanine, sodium calcium edetate and disodium edetate (EDTA-Na 2 ).
  • iron(ll) preparations such as for example iron(ll) sulfate, iron(ll) carbonate, iron(ll) chloride, iron(ll) tartrate, iron(ll) gluconate, iron(ll) aspartate, iron(ll) glycine sulfate, iron(ll) fumarate, iron(ll) ascorbate, iron(ll) iodate, iron(ll) succinate and ammonium iron(ll) sulfate
  • iron(lll) preparations such as for example iron(lll) sodium citrate, iron(lll) oxide/sucrose complex, sodium feredetate, iron(lll) hydroxide, dextriferron, iron(lll) citrate, chondroitin sulfate/iron(lll) complex, iron(lll) acetyltransferrin, iron(lll) protein succinylate and potassium/iron(lll) phosphate/citrate complex.
  • iron(ll) preparations such as for example
  • a preparation containing iron is administered in combination with folic acid, folinic acid and/or a salt thereof.
  • the following iron preparations are particularly suitable for this embodiment: iron/amino acid complex, iron(ll) fumarate, iron(ll) sulfate, dextriferron, ammonium iron(ll) sulfate, iron(ll) glycine sulfate and iron(ll) gluconate.
  • the folic acid and the folinic acid, respectively, is here preferably present in free form or as its calcium salt.
  • folic acid, folinic acid and/or a salt thereof When folic acid, folinic acid and/or a salt thereof is administered, its daily dose is preferably within the range of from 0.1 to 7.5 mg, more preferably from 0.2 to 5.0 mg, still more preferably from 0.3 to 3.0 mg, most preferably from 0.4 to 2.5 mg and in particular from 0.5 to 2 mg.
  • particularly preferred auxiliary substances are talc, long chain fatty acids, magnesium stearate, stearic acid, calcium stearate, polyethylene glycol, palmitic acid, and hydrogenated vegetable oils, such as hydrogenated castor oil.
  • the pharmaceutical composition or dosage form according to the invention contains a buffer with a pH value in the range from 2.0 to 5.5.
  • the buffer is preferably formed by a mixture of citric acid and disodium hydrogenphosphate.
  • the pharmaceutical composition or dosage form according to the invention contains a cyclodextrin, such as ⁇ -cyclodextrin or ⁇ -cyclodextrin, preferably ⁇ -hydroxypropyl-cyclodextrin ( ⁇ -HP).
  • a cyclodextrin such as ⁇ -cyclodextrin or ⁇ -cyclodextrin, preferably ⁇ -hydroxypropyl-cyclodextrin ( ⁇ -HP).
  • the cyclodextrin forms a complex with trimegestone and/or an oestrogen, e.g. with ethinyloestradiol.
  • the pharmaceutical composition or dosage form according to the invention contains a further physiologically active substance, such as folic acid, folinic acid or a suitable derivative or salt, for example the calcium salt, vitamin C, vitamin B preparations, iron(ll) preparations, iron(lll) preparations, calcium preparations and magnesium preparations.
  • a further physiologically active substance such as folic acid, folinic acid or a suitable derivative or salt, for example the calcium salt, vitamin C, vitamin B preparations, iron(ll) preparations, iron(lll) preparations, calcium preparations and magnesium preparations.
  • the pharmaceutical composition or dosage form according to the invention contains the following auxiliary substances in the following preferred quantities (percentages are relative to the total weight of the dosage form):
  • the pharmaceutical composition or dosage form according to the invention contains the following auxiliary substances in the following preferred quantities (percentages are relative to the total weight of the dosage form):
  • composition or dosage form according to the invention may, for example, contain the following substances in the following preferred quantities:
  • Film-coated tablets may, for example, have the following composition:
  • the storage stability of the pharmaceutical composition or dosage form according to the present invention meets international standards (cf. European, Japanese and U.S. Pharmacopoeia).
  • the present invention also relates to a kit comprising at least one of the above- described dosage forms according to the invention.
  • the kit according to the invention is preferably designed for in each case once daily administration of the dosage forms contained therein.
  • the kit preferably comprises all the dosage forms containing trimegestone which are necessary for administering trimegestone for at least one menstrual cycle.
  • the kit is preferably made up such that the above-described method for contraception according to the invention may be carried out without entailing the acquisition of further dosage forms containing trimegestone which are not contained in the kit.
  • the kit preferably contains one dosage form for each day, as administration preferably proceeds once daily.
  • the kit according to the invention preferably comprises at least as many dosage forms containing trimegestone as are necessary for administering trimegestone on at least 21 , preferably 24 successive days of the 28-day menstrual cycle. If trimegestone is administered on fewer than 28 days, for the remaining days up to the end of the 28 days of the menstrual cycle, the kit according to the invention may contain either no dosage forms at all, or preparations containing iron, preparations containing folic acid, folates, folinic acid, folinates or placebos, preferably a preparation containing iron. It is necessary here for at least one of the dosage forms containing trimegestone of the kit according to the invention to be a dosage form according to the invention as described above.
  • the number of dosage forms containing trimegestone contained in the kit according to the invention is correspondingly increased, wherein preferably again at least one of the dosage forms containing trimegestone is a dosage form according to the invention as described above.
  • the kit according to the invention comprises all the dosage forms containing trimegestone which are necessary for administering trimegestone for at least two, more preferably at least three, still more preferably at least four, most preferably at least five and in particular at least six menstrual cycles.
  • the kit according to the invention is designed for mono- or multiphasic administration of trimegestone in combination with an oestrogen, preferably ethinyloestradiol.
  • the menstrual cycle is here preferably 28 days long.
  • the daily dose of trimegestone and of the oestrogen is in each case constant on all days within a phase and different on two successive days of different phases.
  • Trimegestone is preferably used in the dosage forms in combination with ethinyloestradiol or in combination with ethinyloestradiol and oestradiol (17 ⁇ - oestradiol).
  • Preferred embodiments no. 1, 2i, 22, 3i, 3 2 , 3 3 , 4i and 4 2 of the kit according to the invention comprise in total 21-25, preferably 24 dosage forms, containing trimegestone, wherein, depending on the number of phases, these contain trimegestone in doses A1 , A2, A3 and at least one oestrogen, preferably ethinyloestradiol, in dose B according to the following table:
  • a particularly preferred kit according to the invention contains all dosage forms that are necessary in order to allow for the administration of trimegestone in combination with ethinyloestradiol on 21-24 successive days of the menstrual cycle, thereby following any of regimens 1 ⁇ 2i ⁇ 2 2 ', 3i', 3 2 1 , 3 3 ⁇ 4i' and 4 2 ' as described above in connection with the method according to the invention.
  • kits according to the invention contains all dosage forms that are necessary in order to allow for the administration of trimegestone in combination with ethinyloestradiol on 21-24 successive days of the menstrual cycle, thereby following any of regimens 1", 2 ⁇ 2i ⁇ 3i", 3 2 ", 3 3 ", 4i” and 4 2 " as described above in connection with the method according to the invention.
  • kits according to the invention comprise 84 dosage forms containing 1 ,000-3,000 ⁇ g trimegestone in combination with 20 ⁇ 5 ⁇ g or 30 ⁇ 5 ⁇ g ethinyloestradiol and 7 dosage forms containing 10 ⁇ 5 ⁇ g ethinyloestradiol alone, i.e. in the absence of trimegestone.
  • Trimegestone optionally in combination with an oestrogen and/or a further gestagen, may also be taken optionally for a period of more than 28 days for therapeutic reasons, such as for example for the treatment and/or prevention of at least one of the complaints or conditions selected from the group consisting of bleeding disorders; dysmenorrhoea; conditions dependent on the menstrual cycle, such as endometriosis, polycystic ovarian syndrome (PCOS), uterus myomatosus, functional cysts, premenstrual syndrome and headaches/migraine; conditions influenced by the menstrual cycle, such as epilepsy, multiple sclerosis, diabetes mellitus, depression, schizophrenia, asthma and Parkinson's disease; and androgen-induced disorders, such as seborrhoea, acne, androgenetic alopecia and hirsutism.
  • the complaints or conditions selected from the group consisting of bleeding disorders; dysmenorrhoea; conditions dependent on the menstrual cycle, such as endometrio
  • the present invention accordingly also relates to the use of trimegestone, optionally in combination with an oestrogen (such as ethinyloestradiol) and/or a further gestagen, for the production of a medicine (e.g.
  • an oral contraceptive preferably with a dose of trimegestone of more than 500 ⁇ g and preferably less than 2,000 ⁇ g, for the treatment and/or prevention of at least one of the complaints or conditions selected from the group consisting of bleeding disorders; dysmenorrhoea; conditions dependent on the menstrual cycle, such as endometriosis, polycystic ovarian syndrome (PCOS), uterus myomatosus, functional cysts, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD) and headaches/migraine; and androgen-induced disorders, such as seborrhoea, acne, androgenetic alopecia and hirsutism.
  • the dosage forms according to the invention may be prepared by conventional processes. The following examples are not to be considered as limiting the scope of the invention:
  • Ethinyloestradiol (EE) and povidone K30 are dissolved in 600 ml of ethanol. Trimegestone (particle size 90% ⁇ 50 ⁇ m), lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution. The moist composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular product is disagglomerated through a 0.6 mm screen, mixed with magnesium stearate and colloidal silicon dioxide and pressed on a tablet press with 5 mm punches into tablets with a weight of 50 mg.
  • composition a The tablets of composition a) are coated with a hypromellose-based coating (e.g. Opadry YS-1-2184 made by Colorcon), coating composition 2 mg per tablet, and packaged into a packaging comprising 24 hormone-containing daily units and 4 hormone-free daily units with the same composition but without hormones.
  • a hypromellose-based coating e.g. Opadry YS-1-2184 made by Colorcon
  • composition b The tablets of composition b) are coated with a hypromellose-based coating (e.g. Opadry YS-1-2184 made by Colorcon) of the following composition (coating composition 2 mg per tablet).
  • a hypromellose-based coating e.g. Opadry YS-1-2184 made by Colorcon
  • Ethinyloestradiol (EE) and povidone K30 are dissolved in 950 ml of ethanol. Trimegestone (particle size 90% ⁇ 50 ⁇ m), lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution. The moist composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular product is disagglomerated through a 0.6 mm screen, mixed with magnesium stearate and pressed on a tablet press with 6 mm punches into tablets with a weight of 80 mg.
  • Trimegestone particle size 90% ⁇ 50 ⁇ m
  • lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution.
  • the moist composition is forced through a
  • composition a The tablets of composition a) are coated with a hypromellose-based coating (e.g. Opadry YS-1-2184 made by Colorcon), coating composition 2 mg per tablet, and packaged into a packaging comprising 24 hormone-containing daily units and 4 hormone-free daily units.
  • a hypromellose-based coating e.g. Opadry YS-1-2184 made by Colorcon
  • composition b The tablets of composition b) are coated with a hypromellose-based coating (e.g. Opadry YS-1-2184 made by Colorcon) of the following composition (coating composition 1 mg per tablet).
  • a hypromellose-based coating e.g. Opadry YS-1-2184 made by Colorcon
  • Ethinyloestradiol (EE) and povidone K30 are dissolved in 600 ml of ethanol. Trimegestone (particle size 90% ⁇ 50 ⁇ m), lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution. The moist composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular product is disagglomerated through a 0.6 mm screen, mixed with magnesium stearate and colloidal silicon dioxide and pressed on a tablet press with 5 mm punches into tablets with a weight of 50 mg.
  • hormone-free, folic acid-containing tablets with a weight of 50 mg are produced, wherein the sodium salt of the folic acid is dissolved in 600 ml of aqueous ethanol.
  • Some tablets are produced as disclosed under a)
  • the tablets under a) and b) are coated with a hypromellose-based coating (e.g. Opadry YS-1-2184 made by Colorcon), coating composition 2 mg per tablet.
  • a hypromellose-based coating e.g. Opadry YS-1-2184 made by Colorcon
  • 12 hormone-containing daily units produced according to a) and 12 hormone-containing daily units produced according to b) and 4 hormone-free daily units are packed in a package marked for a daily administration.
  • Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) and sodium folate are dissolved in 600 ml of ethanol.
  • Trimegestone (particle size 90% ⁇ 50 ⁇ m), lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution.
  • the moist composition is forced through a 3 mm screen and dried in a vacuum drying cabinet.
  • the dried granular product is disagglomerated through a 0.6 mm screen, mixed with magnesium stearate and colloidal silicon dioxide and pressed on a tablet press with 5 mm punches into tablets with a weight of 50 mg.
  • hormon-free, folic acid containing tablet having a weight of 50 mg are prepared by dissolving sodium folate in 600 ml aqueous ethanol.
  • the tablets a) and b), respectively, are coated with a coating based on hypromellose (e.g. Opadry YS-1-2184, Colorcon); coating composition 2 mg per tablet.
  • hypromellose e.g. Opadry YS-1-2184, Colorcon
  • hormone-containing daily units produced according to a) and 7 hormone-free daily units produced according to b) are packed in a package marked for a daily administration.
  • Example 6 120 tablets according to Example 1 a) are packed in a blister and marketed for daily administration on 120 successive days.
  • Example 6
  • Ethinyloestradiol (EE) and povidone K30 are dissolved in 600 ml of ethanol. Trimegestone (particle size 90% ⁇ 50 ⁇ m), lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution. The moist composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular product is disagglomerated through a 0.6 mm screen, mixed with magnesium stearate and colloidal silicon dioxide and pressed on a tablet press with 5 mm punches into tablets with a weight of 50 mg.
  • the tablets are coated with a hypromellose-based coating of the following composition (coating composition 2 mg per tablet):
  • the tablets are packed into a blister containing 189 daily units and marketed for daily administration on 189 successive days.
  • Ethinyloestradiol (EE) and povidone K30 are dissolved in 950 ml of ethanol. Trimegestone (particle size 90% ⁇ 50 ⁇ m), lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution. The moist composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular product is disagglomerated through a 0.6 mm screen, mixed with magnesium stearate and pressed on a tablet press with 6 mm punches into tablets with a weight of 80 mg.
  • Trimegestone particle size 90% ⁇ 50 ⁇ m
  • lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution.
  • the moist composition is forced through a
  • the tablets are coated with a hypromellose-based coating of the following composition (coating composition 2 mg per tablet):
  • the tablets are packed into a blister containing 365 daily units and are marketed for daily administration on 365 successive days.
  • Ethinyloestradiol (EE) and povidone K30 are dissolved in 950 ml of ethanol. Trimegestone (particle size 90% ⁇ 50 ⁇ m), lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution. The moist composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular product is disagglomerated through a 0.6 mm screen, mixed with magnesium stearate and pressed on a tablet press with 6 mm punches into tablets with a weight of 80 mg.
  • Trimegestone particle size 90% ⁇ 50 ⁇ m
  • lactose and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution.
  • the moist composition is forced through a
  • the tablets are coated with a hypromellose-based coating of the following composition (coating composition 1 mg per tablet):
  • the tablets are packed into a blister containing 150 daily units and are marketed for daily administration on 150 successive days.

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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
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Abstract

L'invention concerne une méthode de contraception comprenant l'administration de trimégestone combinée à de l'éthinyloestradiol à une femme en âge de procréer pendant au moins 21 jours successifs, en commençant le premier jour du cycle menstruel. Au moins l'un des au moins 21 jours successifs, la dose quotidienne de trimégestone est supérieure à 500 µg.
PCT/EP2006/007103 2005-07-20 2006-07-19 Contraception orale a l'aide de trimegestone WO2007009769A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
MX2008000844A MX2008000844A (es) 2005-07-20 2006-07-19 Anticoncepcion oral con trimegestona.
CA002615427A CA2615427A1 (fr) 2005-07-20 2006-07-19 Contraception orale a l'aide de trimegestone
AU2006271920A AU2006271920A1 (en) 2005-07-20 2006-07-19 Oral contraception with trimegestone
BRPI0614672-4A BRPI0614672A2 (pt) 2005-07-20 2006-07-19 contracepção oral com trimegestona
EP06762699A EP1909799A1 (fr) 2005-07-20 2006-07-19 Contraception orale a l'aide de trimegestone
JP2008521881A JP2009501747A (ja) 2005-07-20 2006-07-19 トリメゲストンによる経口避妊
NZ565829A NZ565829A (en) 2005-07-20 2006-07-19 Oral contraception with trimegestone at a dose of over 500ug per day and 5 to 55ug ethinyloestradiol
IL188751A IL188751A0 (en) 2005-07-20 2008-01-14 Oral contraception with trimegestone
NO20080824A NO20080824L (no) 2005-07-20 2008-02-15 Oral prevensjon med trimegeston

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE102005034498A DE102005034498A1 (de) 2005-07-20 2005-07-20 Orale Kontrazeption mit Trimegeston
DE102005034498.4 2005-07-20
US11/348,545 2006-02-06
US11/348,545 US20070021396A1 (en) 2005-07-20 2006-02-06 Oral contraception with trimegestone

Publications (1)

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WO2007009769A1 true WO2007009769A1 (fr) 2007-01-25

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KR (1) KR20080031435A (fr)
AR (1) AR056674A1 (fr)
AU (1) AU2006271920A1 (fr)
CA (1) CA2615427A1 (fr)
WO (1) WO2007009769A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004246A2 (fr) * 1996-07-26 1998-02-05 American Home Prod Contraceptif oral
FR2801218A1 (fr) * 1999-11-23 2001-05-25 Hoechst Marion Roussel Inc Compositions pharmaceutiques comprenant de la trimegestone, leurs procedes de preparation ainsi que le conditionnement primaire les renfermant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004246A2 (fr) * 1996-07-26 1998-02-05 American Home Prod Contraceptif oral
FR2801218A1 (fr) * 1999-11-23 2001-05-25 Hoechst Marion Roussel Inc Compositions pharmaceutiques comprenant de la trimegestone, leurs procedes de preparation ainsi que le conditionnement primaire les renfermant

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SCHINDLER ADOLF E ET AL: "Classification and pharmacology of progestins.", MATURITAS, vol. 46, no. Suppl. 1, 10 December 2003 (2003-12-10), pages S7 - S16, XP002404629, ISSN: 0378-5122 *
SHIRK REBECCA A ET AL: "Differential effects of estrogens and progestins on the anticoagulant tissue factor pathway inhibitor in the rat.", THE JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY. MAR 2005, vol. 94, no. 4, March 2005 (2005-03-01), pages 361 - 368, XP009073861, ISSN: 0960-0760 *
WINNEKER R C ET AL: "The preclinical biology of a new potent and selective progestin: trimegestone", STEROIDS, ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, US, vol. 68, no. 10-13, November 2003 (2003-11-01), pages 915 - 920, XP004479940, ISSN: 0039-128X *

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EP1909799A1 (fr) 2008-04-16
AR056674A1 (es) 2007-10-17
AU2006271920A1 (en) 2007-01-25
KR20080031435A (ko) 2008-04-08
CA2615427A1 (fr) 2007-01-25

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