WO1997041870A1 - Contraceptif oral - Google Patents

Contraceptif oral Download PDF

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Publication number
WO1997041870A1
WO1997041870A1 PCT/US1997/007084 US9707084W WO9741870A1 WO 1997041870 A1 WO1997041870 A1 WO 1997041870A1 US 9707084 W US9707084 W US 9707084W WO 9741870 A1 WO9741870 A1 WO 9741870A1
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WIPO (PCT)
Prior art keywords
administered
phase
daily dosage
combination
phase combination
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PCT/US1997/007084
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English (en)
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Michael Jay Gast
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American Home Products Corporation
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Priority to AU29268/97A priority Critical patent/AU2926897A/en
Publication of WO1997041870A1 publication Critical patent/WO1997041870A1/fr

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    • 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
    • A61K31/565—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

  • oral contraceptives consist of a combination of a progestin and estrogen that are administered concurrendy for 21 days followed either by a 7 day pill free interval or by the administration of a placebo for 7 days in each 28 day cycle.
  • the most important aspects of a successful oral contraceptive product are effective contraception, good cycle control (absence of spotting and breakthrough bleeding and occurrence of withdrawal bleeding), and minimal side effects.
  • Combination oral contraceptives have traditionally acted by suppression of gonadotropins.
  • the progestin component is primarily responsible for contraceptive efficacy through inhibition of ovulation, and other peripheral effects which include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).
  • the estrogenic component intensifies the anovulatory effect of the progestin, and is also important for maintaining cycle control.
  • Levonorgestrel is the biologically active moiety of racemic norgestrel. It is strongly progestational, has no inherent estrogenic activity, is antiestrogenic, and possesses good biologic activity. The contraceptive effects of levonorgestrel are manifested throughout the hypothalamic- pituitary-gonadal-target organ axis.
  • Ethinyl estradiol is the estrogen most frequently used in combination OCs.
  • the dosage of EE in marketed OC formulations has been steadily reduced from that found in earlier OCs.
  • Thromboembolic mortality decreased when the amount of synthetic estrogen in OC formulations was reduced from 100 ⁇ g to 50 ⁇ g.
  • a significant reduction in fatal myocardial infarctions was reported for women using OCs with 30 ⁇ g of EE rather than 50 ⁇ g of EE. [Meade TW, Br Med J 280: 1157 (1980)].
  • progestin/estrogen combination is administered either as a fixed dosage combination (monophasic) or as biphasic or triphasic regimens in which the dosage of the combination is varied either once or twice throughout the menstrual cycle.
  • the progestin/estrogen combination is typically administered for 21 days followed by either a 7-day pill free period or the administration of a non-contraceptive placebo (or iron supplement) for 7 days.
  • 3-ketodesogestrel (3-KDSG), desogestrel (DSG), levonorgestrel (LNg), gestodene (GTD), norgestrel (NG), and norethindrone (NE) are typically used as the progestin while ethinyl estradiol (EE); 17 ⁇ -estradiol, and mestranol are typically the estrogenic components.
  • Spona (PCT Publication WO 95/17194) discloses contraceptive regimens which consist of the administration of a combinaton of a progestin (50 - 75 ⁇ g GTD, 75 - 125 ⁇ g LNg, 60 - 150 ⁇ g DSG, 60 - 150 ⁇ g 3-KDSG, 100 - 300 ⁇ g DRSP, 100 - 200 ⁇ g cyproterone acetate, 200 - 300 ⁇ g norgestimate, or >350 - 750 ⁇ g norethisterone) and an estrogen (15 - 20 ⁇ g EE or 2 - 6 mg 17 ⁇ -estradiol) for 23-24 days per cycle.
  • a progestin 50 - 75 ⁇ g GTD, 75 - 125 ⁇ g LNg, 60 - 150 ⁇ g DSG, 60 - 150 ⁇ g 3-KDSG, 100 - 300 ⁇ g DRSP, 100 - 200 ⁇ g cyproterone acetate
  • the Bergink discloses a 24 day triphasic combination regimen in which the first 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 75-100 ⁇ g DSG and an estrogen at a daily dosage equivalent to 25 ⁇ g EE, the second 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 100-125 ⁇ g DSG and an estrogen at a daily dosage equivalent to 20 ⁇ g EE, and the third 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 125-150 ⁇ g DSG and an estrogen at a daily dosage equivalent to 20 ⁇ g EE. It is preferred that the three phases be 8 days each. Following the 24 day contraceptive steroid administration, a placebo ' may be administered for 4 days, the 4 day interval may be pill free, or a progestin at a dosage equivalent to 25-35 ⁇ g DSG may be administered.
  • Lachnit-Fixson U.S. Patent 3,957,982 discloses triphasic 21-day progestin/estrogen regimens in which a combination of 40-90 ⁇ g LNg and 20-50 ⁇ g EE is administered for 4-6 days in the first phase, 50-125 ⁇ g LNg and 30-50 ⁇ g EE is administered for 4-6 days in the second phase, and 100-250 ⁇ g LNg and 25-50 ⁇ g EE is administered for 9-11 days in the third phase. It is preferred that the first, second, and third phases are 6, 5, and 10 days, respectively. Bennick (U.S.
  • Patent 5,418,2278 discloses triphasic regimens which consist of the administration of a combination progestin/estrogen in a 6-8 day phase, a second 6-8 day phase, and a third 6-8 day phase, with it being preferred that the three contraceptive steroid phases be 7 days each.
  • the first contraceptive steroid phase consists of a progestin at a daily dosage equivalent to 75 - 150 ⁇ g DSG and an estrogen at a daily dosage equivalent to 20 - 25 ⁇ g EE;
  • the second contraceptive steroid phase consists of a progestin at a daily dosage equivalent to 75 - 125 ⁇ g DSG and an estrogen at a daily dosage equivalent to 20 ⁇ g EE;
  • the third contraceptive steroid phase consists of a progestin at a daily dosage equivalent to 75 - 100 ⁇ g DSG and an estrogen at a daily dosage equivalent to 20 ⁇ g EE.
  • Placebo is administered for 7 days following the 21 -day contraceptive steroid period.
  • Bennick discloses that the progestin may be 3-KDSG, DSG, LNg, or GTD.
  • Boissonneault U.S. Patent 4,962,098 discloses triphasic progestin/estrogen combinations in which the amount of the estrogenic component is increased stepwise over the three phases. Contraceptive steroid combinations are taken for 4-7 days during the first phase (5 days being preferred); for 5-8 days during the second phase (7 days preferred); and for 7-12 days during the third phase (9 days being preferred). Following the administration of 21 -days of the contraceptive steroid combination, placebo is taken for 7 days. For all three phases, 0.5-1.5 mg of norethindrone acetate is used in the progestin, with 1 mg being preferred. 10-30 ⁇ g EE is used in the first phase, 20-40 ⁇ g in the second, and 30-50 ⁇ g in the third phase.
  • Pasquale U.S. Patent 4,628,051 discloses triphasic progestin/estrogen combination regimens in which contraceptive steroid is administered for 21 days. Contraceptive steroid combinations are taken for 5-8 days during the first phase (7 days being preferred); for 7-11 days during the second phase (7 days preferred); and for 3-7 days during the third phase (7 days being preferred). In all three phases, an estrogen at a daily dosage equivalent to 20-50 ⁇ g EE is administered in combination with a progestin having a daily dosage equivalent to 65-750 ⁇ g NE in the first phase, 0.25- 1.0 mg NE in the second phase, and 0.35-2.0 mg NE in the third phase.
  • a specific triphasic regimen discloses the administration of 35 ⁇ g EE in each of the three 7-day phases in combination with 0.5 mg, 0.75 mg, and 1.0 mg in the first, second, and third phases, respectively.
  • a second specific triphasic regimen discloses the administration of 35 ⁇ g EE in each of the three 7-day phases in combination with 50 ⁇ g, 75 ⁇ g, and 100 ⁇ g in the first, second, and third phases, respectively.
  • a third specific triphasic regimen discloses the administration of 35 ⁇ g EE in each of the three 7-day phases in combination with 25 ⁇ g, 35 ⁇ g, and 50 ⁇ g in the first, second, and third phases, respectively.
  • Lachnit-Fixson (U.S. Patent 4,621 ,079) discloses triphasic 21-day progestin/estrogen combination regimens in which a combination of 40-70 ⁇ g GTD and 20-35 ⁇ g EE is administered for 4-6 days in the first phase; 50- 100 ⁇ g GTD and 30-50 ⁇ g EE is administered for 4-6 days in the second phase; and 80-120 ⁇ g GTD and 20-50 ⁇ g EE is administered for 9-11 days in the third phase. Placebo is administered for 7 days following the 21 -day contraceptive steroid regimen.
  • Pasquale U.S. Patent 4,530,839 discloses triphasic 21 -day progestin/estrogen combination regimens in which a dose of 20-50 ⁇ g EE is administered in all three phases in combination with a contraceptively effective daily dose of progestin in the first phase, 1.5-2 times that dose of progestin in the second phase, and 2-2.5 times the first phase dose of progestin in the third phase.
  • Each of the three phases is 7 days long.
  • a specific regimen discloses 20-50 ⁇ g EE in combination with 500 ⁇ g LNg, 750 ⁇ g LNg, and 1 mg LNg during each of the three 7-day phases, respectively.
  • Edgren U.S.
  • Patent 4,390,531 discloses triphasic 21-day progestin/estrogen combination regimens in which a dose of 20-40 ⁇ g EE (or another estrogen in an equivalent dosage) is administered in all three phases in combination with 0.3-0.8 mg NE (or another progestin in an equivalent dosage) for 5-8 days in the first phase, twice the dose of NE for 7-11 days in the second phase, and the dose of NE being the same as in the first phase for 3-7 days in the third phase. It is preferred that each of the three phases is 7 days. Placebo is administered for 6-8 days following administration of the contraceptive steroid combination.
  • a specific regimen discloses a first phase of 7 days of 0.5 mg NE in combination with 35 ⁇ g EE, a second 7 day phase of 1.0 mg NE in combination with 35 ⁇ g EE, and a third 7 day phase of 0.5 mg NE in combination with 35 ⁇ g EE.
  • Upton Upton (EP Patent Specification 253,607 Bl) teaches the use of low dose progestin/estrogen combinations for combined hormone replacement therapy and contraception in climacteric women.
  • Climacteric women are defined in Upton as pre- menopausal women around 40 years of age whose hormone levels are waning. The climacteric woman still ovulates (albeit may have irregular ovulation), but she still experiences many of the symptoms of the hypoestrogenic menopausal woman, such as insomnia, hot flushes, and irritability.
  • Upton teaches the administration of a 23-26 day monophasic regimen of progestin/estrogen followed by a pill free or placebo interval of 2-5 days; with 24 days of progestin/estrogen administration followed by a 4-day pill free or placebo administration being preferred.
  • Upton teaches the use of a progestin selected from 25 - 100 ⁇ g LNg, 10 - 70 ⁇ g GTD, 25 - 100 ⁇ g DSG, 25 - 100 ⁇ g 3- KDSG, and 85 - 350 ⁇ g NE used in combination with an estrogen selected from 500 - 2000 ⁇ g 17 ⁇ -estradiol, 8 - 30 ⁇ g EE, and 15 - 60 ⁇ g mestranol.
  • Upton Based on relative potencies, Upton teaches that a dose of 75 ⁇ g LNg is equivalent to 35 ⁇ g of GTD, 75 ⁇ g of 3-KDSG or DSG, and 250 ⁇ g NE and that a dose of 1000 ⁇ g of 17 ⁇ -estradiol is equivalent to a dose of 15 ⁇ g EE and 30 ⁇ g mestranol. Upton also teaches that NG may be substituted for LNg, but at twice the dose.
  • Sartoretto (Clinica e Terapeutica 3: 399 (1974)) discloses a monophasic contraceptive regimen consisting of the administration of a combination 100 ⁇ g LNg and 20 ⁇ g EE for 21 days.
  • Erlich discloses sequential contraceptive regimens consisting of the administration of an estrogen which effects a disturbance of follicle stimulation, followed by the administration of a combination of a progestin/estrogen in a dose at least adequate to inhibit ovulation.
  • the regimen is administered for a total of 28 days per cycle. It is preferred that the estrogen is administered for 5-14 days per cycle and the progestin/estrogen combination is administered for 23-14 days per cycle, so that the total administration is for 28 days per cycle.
  • Specific regimens include (a) 4 mg estradiol for 7 days followed by 21 days of the combination of 1 mg norethisterone acetate and 4 mg estradiol; (b) 2 mg estradiol valerate for 7 days followed by 21 days of the combination of 2 mg chlormadinone acetate and 4 mg estradiol valerate; and (c) 20 ⁇ g EE followed by 18 days of the combination of 150 ⁇ g LNg and 20 ⁇ g EE.
  • Regimen (c) in Erlich provides a total steroidal load of 2.7 mg of LNg and 560 ⁇ g EE per 28 day cycle. Pasquale (U.S.
  • Patent 4,921,843 discloses combination progestin/estrogen contraceptive regimens which contain 0.5 to 1 mg of progestin and an estrogen having a dose equivalent to 10-40 ⁇ g of EE.
  • NE, LNg, D-17 ⁇ -acetoxy-13 ⁇ -ethyl-17 ⁇ -ethinyl- gon-4-en-3-one oxime, and 19-nor-17-hydroxy progesterone ester are disclosed as progestins, with NE being preferred.
  • Specifically disclosed regimens include a uniphasic regimen (2 days of placebo, 5 days of 20 ⁇ g EE, and 21 days of a combination of 500 ⁇ g NE and 35 ⁇ g EE); a uniphasic regimen (2 days of placebo, 5 days of 40 ⁇ g EE, and 21 days of a combination of 500 ⁇ g NE and 35 ⁇ g EE); and a triphasic regimen (2 days of placebo; 5 days of 20-40 ⁇ g EE; 7 days of a combination of 500 ⁇ g NE and 35 ⁇ g EE; 7 days of a combination of 750 ⁇ g NE and 35 ⁇ g EE; and 7 days of a combination of 1 mg NE and 35 ⁇ g EE).
  • Lachnit-Fixson U.S. Patent 3,969,502 discloses biphasic progestin/estrogen combination regimens in which a combination of 50-125 ⁇ g LNg and 25-35 ⁇ g EE are administered for 10-12 days in the first phase and 100-350 ⁇ g LNg and 30-50 ⁇ g EE are administered for 10-12 days in the second phase. Placebo is administered for 5-7 days following the administration of the contraceptive steroid regimen.
  • Lachnit (PCT Publication WO 95/26730) discloses bridged regimens consisting of the administration of a combination of a progestin/estrogen combination (50 - 125 ⁇ g LNg and 10 - 40 ⁇ g EE) for the first 23-24 days of the menstrual cycle followed by the administration of an estrogen (2 - 40 ⁇ g EE) for 4-10 days for a total administration of at least 28 days per cycle.
  • the use of 100 - 300 ⁇ g drospirenone and 10 - 40 ⁇ g EE as the 23-24 day progestin/estrogen combination is disclosed.
  • Lachnit also discloses a triphasic plus bridging regimen (4-9 days, 4-9 days, 9-13 days, and 28 days for the three phases and estrogen phase, respectively) in which a combination of 50 ⁇ g LNg and 20 ⁇ g EE are administered in the first phase, a combination of 75 ⁇ g LNg and 25 ⁇ g EE are administered in the second phase, a combination of 100 ⁇ g LNg and 20 ⁇ g EE are administered in the third phase, and 10 ⁇ g EE is administered in the estrogen phase.
  • Other progestins disclosed include GTD, DSG, 3-KDSG, DRSP, cyproterone acetate, norgestimate, and norethisterone.
  • Moore discloses bridged triphasic regimens consisting of the administration of a combination of 10 - 50 ⁇ g LNg and 5 - 20 ⁇ g EE from days 1-7 of the menstrual cycle; of 50 - 75 ⁇ g LNg and 5 - 20 ⁇ g EE from days 8-14 of the menstrual cycle; of 75 - 125 ⁇ g LNg and 5 - 20 ⁇ g EE from days 15-21 of the menstrual cycle; and 5 - 20 ⁇ g EE from days 22-28 of the menstrual cycle.
  • Oettel (EP 628,312 Al) discloses combination contraceptive combinations containing the combination of three components: a biogenic estrogen (estradiol, estrone, or estriol), a synthetic estrogen (EE or mestranol), and a progestin (LNg, desogestrel, progesterone, norethisterone acetate, DSGT, chlormadinone acetate, gestodene, or cyproterone acetate).
  • the combination is administered for 21 days followed by the administration of placebo (or pill free) or an estrogen on days 22-28 of the cycle.
  • Oettel (EP 696,454 A2) discloses a three phase contraceptive regimen in which the first phase consists of the administration for 3-4 days of a composition containing at least one biogenic estrogen; the second phase consists of the administration for 20-22 days of at least one biogenic estrogen and at least one progestin (progesterone, DGST, desogestrel, 3-KDSG, GTD, LNg, norgestimate, notethisterone, norethisterone acetate, dehydrogestrone, chloromadinone acetate, cyproterone acetate, medroxyprogesterone acetate, or megestrol acetate); and the third phase consists of the administration for 3-4 days of a composition containing at least biogenic one estrogen.
  • progestin progesterone, DGST, desogestrel, 3-KDSG, GTD, LNg, norgestimate, notethisterone, norethisterone acetate, dehydroges
  • This invention provides a triphasic combination progestin/estrogen oral contraceptive regimen for females of child-bearing age that provides effective contraception, good cycle control, and minimal side effects while greatly reducing the total contraceptive steroid administered (particularly the estrogenic component) per 28- day cycle.
  • the low dose progestin/estrogen combination is administered for 23-25-days per cycle according to a triphasic regimen that is described below.
  • Administration of the contraceptive progestin/estrogen combination is begun on the first day of menses (day 1), and continued for 23-25 consecutive days.
  • a non-contraceptive placebo (devoid of progestins and estrogens) can be provided for 3-5 days, so that the total administration period per cycle is 28 days per cycle to aid in compliance with the desired contraceptive regimen.
  • the 3-5-day interval can be pill free.
  • this invention provides a method of contraception which comprises administering to a female of child bearing age a first phase of a combination of a progestin at a daily dosage equivalent in progestational activity to 40- 125 ⁇ g levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 10- 20 ⁇ g ethinyl estradiol for 3-8 days beginning on day 1 of the menstrual cycle.
  • the same daily dosage of the progestin and estrogen is administered for each of the 3-8 days.
  • a second phase of a combination of a progestin at a daily dosage equivalent in progestational activity to 40-125 ⁇ g levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 10-20 ⁇ g ethinyl estradiol is administered for 4-15 days beginning on the day immediately following the last day of administration of the first phase.
  • the same daily dosage of the progestin and estrogen is administered for each of the 4-15 days.
  • a third phase of a combination of a progestin at a daily dosage equivalent in progestational activity to 40-125 ⁇ g levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 10-20 ⁇ g ethinyl estradiol is administered for 4-15 days beginning on the day immediately following the last day of administration of the second phase.
  • the same daily dosage of the progestin and estrogen is administered for each of the 4-15 days.
  • the total administration for all three phases is 23-25 days.
  • the daily dosage of the progestin/estrogen combination administered in any phase is distinct from the dosage of the progestin/estrogen combination administered in either of the other two phases.
  • a non-contraceptive placebo which may contain an iron supplement, such as 75 mg of ferrous fumarate, may be administered for 3-5 days (through day 28 of the menstrual cycle) or the 3-5 days following administration of the contraceptive combination may be pill free.
  • total administration of the progestin/estrogen combination be 24 days.
  • Preferred phase lengths are shown in the following table, with Phase Regimens A and B being most preferred for the triphasic rising regimens that are described below, and Phase Regimens E and F are most preferred for the triphasic midpeak regimens that are described below.
  • progestins include, but are not limited to levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, and norgestimate. It is more preferred that the progestin is levonorgestrel. When levonorgestrel is used as the progestin, it is preferred that the daily dosage of levonorgestrel is 40-60 ⁇ g when levonorgestrel is administered as the progestin in the first phase, is 50-100 ⁇ g when administered as the progestin in the second phase, and is 50-100 ⁇ g when administered as the progestin in the third phase.
  • Preferred estrogens include, but are not limited to ethinyl estradiol; 17 ⁇ - estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol; with ethinyl estradiol being more preferred.
  • the daily dosage of ethinyl estradiol is 10-15 ⁇ g when ethinyl estradiol is administered as the estrogen in the first phase, is 10-20 ⁇ g when administered as the estrogen in the second phase, and is 10-20 ⁇ g when administered as the estrogen in the third phase.
  • Preferred salts of estrone include, but are not limited to the sodium and piperate salt.
  • conjugated estrogens USP are used as the estrogen, it is preferred that the daily dosage is 0.3-5 mg, with a daily dose of 1.25 mg conjugated estrogens, USP being equivalent to a daily dose of 15 ⁇ g ethinyl estradiol.
  • the dosage of progestin is higher in the second phase than in the first phase and is higher in the third phase than in the second phase.
  • the third phase will generally have the longest duration.
  • the estrogen dosage in the second phase is greater than the first phase
  • the estrogen dosage in third phase is greater than the second phase; can rise from the first phase to the second phase, and then remain the same for the third phase; or can remain the same for all three phases.
  • the daily dosage of levonorgestrel is 40-60 ⁇ g when administered as the progestin in the first phase; is 50-75 ⁇ g when administered as the progestin in the second phase; and is 65- 100 ⁇ g when administered as the progestin in the third phase.
  • levonorgestrel is abbreviated as LNg and ethinyl estradiol is abbreviated as EE.
  • PREFERRED DAILY DOSAGES in ⁇ g
  • the dosage of progestin is typically highest in the second phase.
  • the dosage of progestin in the third phase is generally higher in the first phase.
  • the second phase will generally have the longest duration.
  • the estrogen can rise so that the dosage in the second phase is greater than the first phase, and the dosage in third phase is greater than the second phase; can rise from the first phase to the second phase, and then remain the same for the third phase; can remain the same for all three phases; or can be "mid-peak" so that the dose in the second phase is highest, with the dose in the third phase generally being higher than the first phase.
  • levonorgestrel When levonorgestrel is used as the progestin in a triphasic mid-peak regimen, it is preferred that the daily dosage of levonorgestrel is 40-60 ⁇ g when administered as the progestin in the first phase; is 65-100 ⁇ g when administered as the progestin in the second phase; and is 50-75 ⁇ g when administered as the progestin in the third phase.
  • levonorgestrel is abbreviated as LNg and ethinyl estradiol is abbreviated as EE.
  • PREFERRED DALLY DOSAGES in ⁇ g
  • the combination progestin/estrogen contraceptive be administered in unit dosage form i.e., tablet or pill, with each unit providing the entire daily dosage. It is preferred that the progestin and estrogen are admixed together in the same dosage unit. Such dosage units can be prepared by conventional methodology that is well known to one skilled in the art. In each dosage unit, the contraceptively active progestin and estrogen are combined with excipients, vehicles, pharmaceutically acceptable carriers, and colorants. For example, the following illustrates an acceptable composition of a contraceptive progestin/estrogen combination of this invention.
  • This invention also provides a contraceptive kit adapted for daily oral administration which comprises, 3-8 first phase dosage units each containing fixed dosage of a combination of progestin at a daily dosage equivalent in progestational activity to 40-125 ⁇ g levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 10-20 ⁇ g ethinyl estradiol; 4-15 second phase dosage units each containing fixed dosage of a combination of progestin at a daily dosage equivalent in progestational activity to 40- 125 ⁇ g levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 10-20 ⁇ g ethinyl estradiol, and 4-15 third phase dosage units each containing fixed dosage of a combination of progestin at a daily dosage equivalent in progestational activity to 40-125 ⁇ g levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to
  • the contraceptive kit contains 28 daily dosage units with 4 being a non- contraceptive placebo, that may contain an iron supplement, such as 75 mg ferrous fumarate.
  • the daily dosage arrangements are preferably arranged in a blister pack or in a dial pack type tablet dispenser. Specific referred progestins and estrogens and the specifically preferred dosages of each combination dosage unit are described above.

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Abstract

Cette invention se rapporte à un procédé de contraception qui consiste à administrer à une femme en âge de procréer, pendant 23 à 25 jours consécutifs, (1) une combinaison de première phase constituée d'une dose quotidienne de progestérone équivalant, s'agissant de l'activité progestative, à 40-125 νg de levonorgestrel et d'une dose quotidienne d'oestrogène équivalant, s'agissant de l'activité oestrogénique, à 10-20 νg d'éthinyloestradiol, pendant 3 à 8 jours, à partir du premier jour du cycle menstruel, la même dose de la combinaison de progestérone et d'oestrogène étant administrée chaque jour de cette première phase, (2) une combinaison de deuxième phase constituée d'une dose quotidienne de progestérone équivalant, s'agissant de l'activité progestative, à 40-125 νg de levonorgestrel et d'une dose quotidienne d'oestrogène équivalant, s'agissant de l'activité oestrogénique, à 10-20 νg d'éthinyloestradiol, pendant 4 à 15 jours, à compter du premier jour suivant immédiatement le dernier jour d'administration de la combinaison de première phase, la même dose de la combinaison de progestérone et d'oestrogène étant administrée chaque jour de cette deuxième phase, (3) une combinaison de troisième phase constituée d'une dose quotidienne de progestérone équivalant, s'agissant de l'activité progestative, à 40-125 νg de levonorgestrel et d'une dose quotidienne d'oestrogène équivalant, s'agissant de l'activité oestrogénique, à 10-20 νg d'éthinyloestradiol, pendant 4 à 15 jours, à compter du premier jour suivant immédiatement le dernier jour d'administration de la combinaison de deuxième phase, la même dose de la combinaison de progestérone et d'oestrogène étant administrée chaque jour de cette troisième phase, à condition que la dose quotidienne de la combinaison administrée au cours de la première phase ne soit pas identique à la dose quotidienne de la combinaison administrée au cours de la deuxième phase et que la dose quotidienne de la combinaison administrée au cours de la deuxième phase ne soit pas identique à la dose quotidienne de la combinaison administrée au cours de la troisième phase.
PCT/US1997/007084 1996-05-08 1997-04-28 Contraceptif oral WO1997041870A1 (fr)

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US64708796A 1996-05-08 1996-05-08
US08/647,087 1996-05-08

Publications (1)

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WO1997041870A1 true WO1997041870A1 (fr) 1997-11-13

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/007084 WO1997041870A1 (fr) 1996-05-08 1997-04-28 Contraceptif oral

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AU (1) AU2926897A (fr)
WO (1) WO1997041870A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001093848A2 (fr) * 2000-06-08 2001-12-13 Wyeth Kit de depart pour contraceptifs oraux a faible dose
US7749987B2 (en) 1996-10-08 2010-07-06 Laboratorie Theramek Contraception method

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0036229A1 (fr) * 1980-03-18 1981-09-23 Akzo N.V. Préparation pour contraception orale du type combinaison multi-phase et séquentiel et méthode de contraception orale
EP0491438A1 (fr) * 1990-12-17 1992-06-24 Akzo Nobel N.V. Régime contraceptif

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0036229A1 (fr) * 1980-03-18 1981-09-23 Akzo N.V. Préparation pour contraception orale du type combinaison multi-phase et séquentiel et méthode de contraception orale
EP0491438A1 (fr) * 1990-12-17 1992-06-24 Akzo Nobel N.V. Régime contraceptif

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7749987B2 (en) 1996-10-08 2010-07-06 Laboratorie Theramek Contraception method
WO2001093848A2 (fr) * 2000-06-08 2001-12-13 Wyeth Kit de depart pour contraceptifs oraux a faible dose
WO2001093848A3 (fr) * 2000-06-08 2003-01-09 Wyeth Corp Kit de depart pour contraceptifs oraux a faible dose
CN1313095C (zh) * 2000-06-08 2007-05-02 惠氏公司 低剂量口服避孕药启动试剂盒
US7297688B2 (en) 2000-06-08 2007-11-20 Wyeth Starter kit for low dose oral contraceptives

Also Published As

Publication number Publication date
AU2926897A (en) 1997-11-26

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