CA2301162A1 - Oral contraceptive preparation having a first phase comprising progestin/estrogen and a second phase comprising progestin - Google Patents
Oral contraceptive preparation having a first phase comprising progestin/estrogen and a second phase comprising progestin Download PDFInfo
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- CA2301162A1 CA2301162A1 CA002301162A CA2301162A CA2301162A1 CA 2301162 A1 CA2301162 A1 CA 2301162A1 CA 002301162 A CA002301162 A CA 002301162A CA 2301162 A CA2301162 A CA 2301162A CA 2301162 A1 CA2301162 A1 CA 2301162A1
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- levonorgestrel
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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
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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
- 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
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- 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
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Abstract
This invention provides a method of contraception which comprises administering to a female of child bearing age for 28 days per menstrual cycle a combination of a progestin at a daily dosage equivalent to 30-150 µg levornorgestrel and an estrogen at a daily dosage equivalent to 10-20 µg ethinyl estradiol for 23-25 days beginning on day 1 of the menstrual cycle, followed by administering a progestin at a daily dosage equivalent to 10-100 µg levornorgestrel for 3-5 days.
Description
ORAL CONTRACEPTIVE PREPARATION HAVING A FIRST PHASE COI~RISING
PROGESTllV/ESTROGEN AND A
SECOND PHASE COMPRISING PROGESTIN
BACKGROUND OF THE INVENTION
The vast majority of oral contraceptives consist of a combination of a progestin and estrogen that are administered concurrently 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. In addition, it appears that the progestin component is primarily responsible for contraceptive e~cacy 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.
Since the introduction of oral contraceptives (OCs) over a quarter-century ago, research has been directed toward developing preparations that minimize the potential for side effects while maintaining efficacy and normal menstrual patterns. The first-generation OCs contained more progestin and estrogen than was necessary to prevent conception. Adverse hemostatic and metabolic changes, clinical problems, and side effects were associated with these high-dose preparations. In 1978, the World Health Organization (WHO) recommended that the focus of OC research should be the development of products containing the lowest possible dose levels of estrogen and progestin.
The first reductions in steroid content in a combination pill were focused on estrogen because it, rather than progestin, was thought to be related to the most serious side effects. Reduction in progestin content followed, as evidence mounted that lowering progestin intake might lower the risk of cardiovascular complications such as stroke and ischemic heart disease. [Kay CR, Am J Obstet Gynecol 142:762 (1982)].
However, this evidence was not as clear as that implicating estrogen in thromboembolic disorders. [Inman WHW, Br Med J 2:203 ( 1970); Stolley PD, Am J Epidemiol 102:197 (1975)]. The need for a balance between estrogens and progestins to nunimize adverse effects on carbohydrate metabolism and on lipid and lipoprotein levels was also recognized. [Bradley DD, N Engl J Med 299:17 (1978); Wynn V, Lancet 1:1045 ( 1979)]. Researchers then found that the synergistic action between progestin and estrogen in a balanced ratio successfully inhibited ovulation at low levels of both components.
Research into low-dose progestins was advanced significantly by the development of norgestrel (Ng) and levonorgestrel (LNg). LevonorgestreI 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 (EE) is the estrogen most frequently used in combination OCs.
In attempts to fulfill the WHO objective, 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 ilg to 50 ug. Subsequently, a significant reduction in fatal myocardial infarctions was reported for women using OCs with 30 llg of EE rather than 50 Irg of EE.
[Meade TW, Br Med J 280:1157 (1980)].
In keeping with the goal of reducing the total steroidal dosage, while maintaining contraceptive efficacy, good cycle control, and minimizing side effects, numerous regimens have been developed in which the 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. In these regimens, 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.
In these regimens, 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(3-estradiol, and mestranol are typically the estrogenic components.
Several examples of attempts at reducing the total steroidal dosage by using bridged or 24-day regimens are provided below.
De Jager (European Patent Application 368,373 A) discloses 22-30 day bridged regimens consisting of the administration of 20-22 (preferrably 21 ) days of a progestin/estrogen combination followed by 2-10 (preferrably 7) days of a progestin.
Specifically disclosed regimens include (a) a combination of 150 p.g DSG and 2.0 mg 17(3-estradiol for 21 days, followed by 30 pg desogestrel for 7 days; (b) a combination of 150 pg DSG and 30 pg EE for 21 days, followed by 30 p.g desogestrel for 7 days;
(c) a combination of 50 pg DSG and 3 mg 17(3-estradiol for 7 days, followed by a combination of 150 pg DSG and 2 mg 17(3-estradiol for 14 days, followed by 30 ~,g DSG for 7 days; (d) a combination of 50 pg DSG and 35 pg EE for 7 days, followed by a combination of 150 ~.g DSG and 30 ~.g EE for 14 days, followed by 30 ~g DSG
for 7 days; (e) a combination of 50 ~g DSG and 3 mg 17j3-estradiol for 7 days, followed by a combination of 100 ~.g DSG and 2 mg 17(3-estradiol for 7 days, followed by a combination of 150 ~.g DSG and 1.5 mg 17[3-estradiol for 7 days, followed by 30 ~.g DSG for 7 days; (fj a combination of 50 p.g DSG and 3 mg 17~i-estradiol for 7 days, followed by a combination of 100 ~.g DSG and 2 mg 17~i-estradiol for 7 days, followed by a combination of 150 pg DSG and 1.5 mg 17~i-estradiol for 8 days, followed by 30 pg DSG for 6 days; (g) a combination of 50 pg LNG and 2 mg 17~i-estradiol for 11 days, followed by a combination of 150 pg LNG and 2 mg 17(3-estradiol for 11 days, followed by 125 ~.g LNg for 2 days; and (h) a combination of 50 pg LNG and 2 mg 17(3-estradiol for 6 days, followed by a combination of 75 ~.g LNG
and 2.5 mg 17~i-estradiol for 5 days, followed by a combination of 125 ug LNG
and 2 mg 17~i-estradiol for 10 days, followed by 70 ~.g LNg for 2 days, followed by SO ~g LNg for 2 days.
Endrikat (PCT Publication WO 97/23228) discloses bridged regimens consisting of the squential administration of an ovulation inhibiting dose of a progestin for at least 28 days and a natural estrogen during the last 5-10 days of the at least 28 day sequential administration. A preferred contraceptive kit consists of 28 daily dosage units with a first phase having 18-23 daily dosage units of a progestin and a second phase having 5-10 daily dosage units of a prigestin in combination with a natural estrogen. Specific disclosed regimens include: (a) administration of 100 ug LNg for 28 days, with 2.5 mg 17~-estradiol concomitantly adminsistered for the last 10 days of the 28-day administration; (b) administration of 100 llg LNg for 28 days, with 2.5 mg 17(i-estradiol concomitantly adminsistered for the last 8 days of the 28-day administration; (c) administration of 100 p.g LNg for 56 days, with 2.5 mg estradiol concomitantly adminsistered for the last 10 days of the 56-day administration;
(d) administration of 100 ~,g LNg for 84 days, with 2.5 mg 17~i-estradiol concomitantly adminsistered for the last 10 days of the 84-day administration; and equivalent regimens using 75 ~.g GTD as the progestin.
Erlich (German Patent DE 4,104,385 C1 and U.S. Patent 5,280,023) 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 p.g EE followed by 18 days of the combination of 150 p,g LNg and 20 p.g EE. Regimen (c) in Erlich provides a total steroidal load of 2.7 mg of LNg and 560 pg EE per 28 day cycle.
Lachnit (PCT Publication WO 95/26730) discloses bridged regimens consisting of the administration of a combination of a progestin/estrogen combination (50 - 125 p.g LNg and 10 - 40 p,g EE) for the first 23-24 days of the menstrual cycle followed by the administration of an estrogen (2 - 40 pg EE) for 4-10 days for a total administration of at least 28 days per cycle. The use of 100 - 300 p,g drospirenone and 10 - 40 p.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 p,g LNg and 20 p,g EE are administered in the first phase, a combination of 75 ~tg LNg and 25 pg EE are administered in the second phase, a combination of 100 p.g LNg and 20 ~tg EE are administered in the third phase, and 10 pg EE is administered in the estrogen phase. Other progestins disclosed include GTD, DSG, 3-KDSG, DRSP, cyproterone acetate, norgestimate, and norethisterone.
Moore (DE 4313926 A1) discloses bridged triphasic regimens consisting of the administration of a combination of 10 - 50 p,g LNg and 5 - 20 ~tg EE from days 1-7 of the menstrual cycle; of 50 - 75 pg LNg and 5 - 20 p.g EE from days 8-14 of the menstrual cycle; of 75 - 125 p,g LNg and 5 - 20 pg EE from days 15-21 Qf the menstrual cycle; and 5 - 20 pg EE from days 22-28 of the menstrual cycle.
Spona (U.S. Patent 5,583,129 and PCT Publication W0 95/17194) discloses contraceptive regimens which consist of the administration of a combinaton of a progestin (50 - 75 ~g GTD, 75 - 125 p.g LNg, 60 - 150 ~tg DSG, 60 - 150 pg 3-KDSG, 100 - 300 p,g DRSP, 100 - 200 ~tg cyproterone acetate, 200 - 300 ~,g norgestimate, or >350 - 750 ~.g norethisterone) and an estrogen ( 15 - 20 p,g EE or 2 - 6 mg I7~3-estradiol) for 23-24 days per cycle.
Upton (EP Patent Specification 253,b07 B 1 ) 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 p,g LNg, 10 - 70 p,g GTD, 25 - 100 ~.g DSG, 25 - 100 ~g KDSG, and 85 - 350 p.g NE used in combination with an estrogen selected from 2000 p.g 17~i-estradiol, 8 - 30 pg EE, and 15 - 60 pg mestranol. Based on relative potencies, Upton teaches that a dose of 75 p,g LNg is equivalent to 35 p.g of GTD, 75 p,g of 3-KDSG or DSG, and 250 p,g NE and that a dose of 1000 p,g of 17(3-estradiol is equivalent to a dose of 15 p,g EE and 30 p,g mestranol. Upton also teaches that NG
may be substituted for LNg, but at twice the dose.
Bergink (U.S. Patent 5,262,408) 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 100 p.g DSG and an estrogen at a daily dosage equivalent to 25 p.g EE, the second 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 125 p,g DSG and an estrogen at a daily dosage equivalent to p,g EE, and the third 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to SO p,g DSG and an estrogen at a daily dosage equivalent to 20 p.g EE. It is preferred that the three phases be 8 days each. Following the 24 day 20 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 p.g DSG
may be administered.
DESCRIPTION OF THE INVENTION
This invention provides a progestin bridged 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 per 28-day cycle. To achieve the substantial reduction in the total contraceptive steroid administered per cycle while maintaining good cycle control, the low dose progestin/estrogen combination is administered for 23-25-days per cycle followed by the administration of a progestin for the remaining 3-5 days of the cycle. Administration of the contraceptive progestin/estrogen combination is begun on the first day of menses (day 1 ), and continued for 23-25 consecutive days.
Following the 23-25-day administration period, a progestin is administered for 3-5 days to assist in maintaining good cycle control. The total administration during each cycle is 28 days.
PROGESTllV/ESTROGEN AND A
SECOND PHASE COMPRISING PROGESTIN
BACKGROUND OF THE INVENTION
The vast majority of oral contraceptives consist of a combination of a progestin and estrogen that are administered concurrently 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. In addition, it appears that the progestin component is primarily responsible for contraceptive e~cacy 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.
Since the introduction of oral contraceptives (OCs) over a quarter-century ago, research has been directed toward developing preparations that minimize the potential for side effects while maintaining efficacy and normal menstrual patterns. The first-generation OCs contained more progestin and estrogen than was necessary to prevent conception. Adverse hemostatic and metabolic changes, clinical problems, and side effects were associated with these high-dose preparations. In 1978, the World Health Organization (WHO) recommended that the focus of OC research should be the development of products containing the lowest possible dose levels of estrogen and progestin.
The first reductions in steroid content in a combination pill were focused on estrogen because it, rather than progestin, was thought to be related to the most serious side effects. Reduction in progestin content followed, as evidence mounted that lowering progestin intake might lower the risk of cardiovascular complications such as stroke and ischemic heart disease. [Kay CR, Am J Obstet Gynecol 142:762 (1982)].
However, this evidence was not as clear as that implicating estrogen in thromboembolic disorders. [Inman WHW, Br Med J 2:203 ( 1970); Stolley PD, Am J Epidemiol 102:197 (1975)]. The need for a balance between estrogens and progestins to nunimize adverse effects on carbohydrate metabolism and on lipid and lipoprotein levels was also recognized. [Bradley DD, N Engl J Med 299:17 (1978); Wynn V, Lancet 1:1045 ( 1979)]. Researchers then found that the synergistic action between progestin and estrogen in a balanced ratio successfully inhibited ovulation at low levels of both components.
Research into low-dose progestins was advanced significantly by the development of norgestrel (Ng) and levonorgestrel (LNg). LevonorgestreI 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 (EE) is the estrogen most frequently used in combination OCs.
In attempts to fulfill the WHO objective, 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 ilg to 50 ug. Subsequently, a significant reduction in fatal myocardial infarctions was reported for women using OCs with 30 llg of EE rather than 50 Irg of EE.
[Meade TW, Br Med J 280:1157 (1980)].
In keeping with the goal of reducing the total steroidal dosage, while maintaining contraceptive efficacy, good cycle control, and minimizing side effects, numerous regimens have been developed in which the 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. In these regimens, 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.
In these regimens, 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(3-estradiol, and mestranol are typically the estrogenic components.
Several examples of attempts at reducing the total steroidal dosage by using bridged or 24-day regimens are provided below.
De Jager (European Patent Application 368,373 A) discloses 22-30 day bridged regimens consisting of the administration of 20-22 (preferrably 21 ) days of a progestin/estrogen combination followed by 2-10 (preferrably 7) days of a progestin.
Specifically disclosed regimens include (a) a combination of 150 p.g DSG and 2.0 mg 17(3-estradiol for 21 days, followed by 30 pg desogestrel for 7 days; (b) a combination of 150 pg DSG and 30 pg EE for 21 days, followed by 30 p.g desogestrel for 7 days;
(c) a combination of 50 pg DSG and 3 mg 17(3-estradiol for 7 days, followed by a combination of 150 pg DSG and 2 mg 17(3-estradiol for 14 days, followed by 30 ~,g DSG for 7 days; (d) a combination of 50 pg DSG and 35 pg EE for 7 days, followed by a combination of 150 ~.g DSG and 30 ~.g EE for 14 days, followed by 30 ~g DSG
for 7 days; (e) a combination of 50 ~g DSG and 3 mg 17j3-estradiol for 7 days, followed by a combination of 100 ~.g DSG and 2 mg 17(3-estradiol for 7 days, followed by a combination of 150 ~.g DSG and 1.5 mg 17[3-estradiol for 7 days, followed by 30 ~.g DSG for 7 days; (fj a combination of 50 p.g DSG and 3 mg 17~i-estradiol for 7 days, followed by a combination of 100 ~.g DSG and 2 mg 17~i-estradiol for 7 days, followed by a combination of 150 pg DSG and 1.5 mg 17~i-estradiol for 8 days, followed by 30 pg DSG for 6 days; (g) a combination of 50 pg LNG and 2 mg 17~i-estradiol for 11 days, followed by a combination of 150 pg LNG and 2 mg 17(3-estradiol for 11 days, followed by 125 ~.g LNg for 2 days; and (h) a combination of 50 pg LNG and 2 mg 17(3-estradiol for 6 days, followed by a combination of 75 ~.g LNG
and 2.5 mg 17~i-estradiol for 5 days, followed by a combination of 125 ug LNG
and 2 mg 17~i-estradiol for 10 days, followed by 70 ~.g LNg for 2 days, followed by SO ~g LNg for 2 days.
Endrikat (PCT Publication WO 97/23228) discloses bridged regimens consisting of the squential administration of an ovulation inhibiting dose of a progestin for at least 28 days and a natural estrogen during the last 5-10 days of the at least 28 day sequential administration. A preferred contraceptive kit consists of 28 daily dosage units with a first phase having 18-23 daily dosage units of a progestin and a second phase having 5-10 daily dosage units of a prigestin in combination with a natural estrogen. Specific disclosed regimens include: (a) administration of 100 ug LNg for 28 days, with 2.5 mg 17~-estradiol concomitantly adminsistered for the last 10 days of the 28-day administration; (b) administration of 100 llg LNg for 28 days, with 2.5 mg 17(i-estradiol concomitantly adminsistered for the last 8 days of the 28-day administration; (c) administration of 100 p.g LNg for 56 days, with 2.5 mg estradiol concomitantly adminsistered for the last 10 days of the 56-day administration;
(d) administration of 100 ~,g LNg for 84 days, with 2.5 mg 17~i-estradiol concomitantly adminsistered for the last 10 days of the 84-day administration; and equivalent regimens using 75 ~.g GTD as the progestin.
Erlich (German Patent DE 4,104,385 C1 and U.S. Patent 5,280,023) 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 p.g EE followed by 18 days of the combination of 150 p,g LNg and 20 p.g EE. Regimen (c) in Erlich provides a total steroidal load of 2.7 mg of LNg and 560 pg EE per 28 day cycle.
Lachnit (PCT Publication WO 95/26730) discloses bridged regimens consisting of the administration of a combination of a progestin/estrogen combination (50 - 125 p.g LNg and 10 - 40 p,g EE) for the first 23-24 days of the menstrual cycle followed by the administration of an estrogen (2 - 40 pg EE) for 4-10 days for a total administration of at least 28 days per cycle. The use of 100 - 300 p,g drospirenone and 10 - 40 p.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 p,g LNg and 20 p,g EE are administered in the first phase, a combination of 75 ~tg LNg and 25 pg EE are administered in the second phase, a combination of 100 p.g LNg and 20 ~tg EE are administered in the third phase, and 10 pg EE is administered in the estrogen phase. Other progestins disclosed include GTD, DSG, 3-KDSG, DRSP, cyproterone acetate, norgestimate, and norethisterone.
Moore (DE 4313926 A1) discloses bridged triphasic regimens consisting of the administration of a combination of 10 - 50 p,g LNg and 5 - 20 ~tg EE from days 1-7 of the menstrual cycle; of 50 - 75 pg LNg and 5 - 20 p.g EE from days 8-14 of the menstrual cycle; of 75 - 125 p,g LNg and 5 - 20 pg EE from days 15-21 Qf the menstrual cycle; and 5 - 20 pg EE from days 22-28 of the menstrual cycle.
Spona (U.S. Patent 5,583,129 and PCT Publication W0 95/17194) discloses contraceptive regimens which consist of the administration of a combinaton of a progestin (50 - 75 ~g GTD, 75 - 125 p.g LNg, 60 - 150 ~tg DSG, 60 - 150 pg 3-KDSG, 100 - 300 p,g DRSP, 100 - 200 ~tg cyproterone acetate, 200 - 300 ~,g norgestimate, or >350 - 750 ~.g norethisterone) and an estrogen ( 15 - 20 p,g EE or 2 - 6 mg I7~3-estradiol) for 23-24 days per cycle.
Upton (EP Patent Specification 253,b07 B 1 ) 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 p,g LNg, 10 - 70 p,g GTD, 25 - 100 ~.g DSG, 25 - 100 ~g KDSG, and 85 - 350 p.g NE used in combination with an estrogen selected from 2000 p.g 17~i-estradiol, 8 - 30 pg EE, and 15 - 60 pg mestranol. Based on relative potencies, Upton teaches that a dose of 75 p,g LNg is equivalent to 35 p.g of GTD, 75 p,g of 3-KDSG or DSG, and 250 p,g NE and that a dose of 1000 p,g of 17(3-estradiol is equivalent to a dose of 15 p,g EE and 30 p,g mestranol. Upton also teaches that NG
may be substituted for LNg, but at twice the dose.
Bergink (U.S. Patent 5,262,408) 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 100 p.g DSG and an estrogen at a daily dosage equivalent to 25 p.g EE, the second 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 125 p,g DSG and an estrogen at a daily dosage equivalent to p,g EE, and the third 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to SO p,g DSG and an estrogen at a daily dosage equivalent to 20 p.g EE. It is preferred that the three phases be 8 days each. Following the 24 day 20 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 p.g DSG
may be administered.
DESCRIPTION OF THE INVENTION
This invention provides a progestin bridged 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 per 28-day cycle. To achieve the substantial reduction in the total contraceptive steroid administered per cycle while maintaining good cycle control, the low dose progestin/estrogen combination is administered for 23-25-days per cycle followed by the administration of a progestin for the remaining 3-5 days of the cycle. Administration of the contraceptive progestin/estrogen combination is begun on the first day of menses (day 1 ), and continued for 23-25 consecutive days.
Following the 23-25-day administration period, a progestin is administered for 3-5 days to assist in maintaining good cycle control. The total administration during each cycle is 28 days.
More particularly, this invention provides a method of contraception which comprises administering to a female of child bearing age a combination of a progestin at a daily dosage equivalent in progestational activity to 40-150 p.g levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 10-20 p,g ethinyl estradiol for 23-25 days beginning on day 1 of the menstrual cycle. Following the 23-25-day period, a progestin at a daily dosage equivalent to 10-100 p,g levonorgestrel is administered for 3-5 days. The total administration during each cycle is 28 days.
Preferred progestins include, but are not limited to levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone. It is more preferred that the progestin is levonorgestrel. When levonorgestrel is used as the progestin during the first 23-25 days of the cycle, it is preferred that the daily dosage of levonorgestrel is 30-150 p,g, with 50-100 ~g being more preferred, and 90 ~g being most preferred. When levonorgestrel is used as the progestin during the last 3-5 days of the cycle, it is preferred that the daily dosage be 10-100 pg, with 20-50 ~g levonorgestrel being more preferred, and 37.5 ug most preferred. Preferred dosages of the preferred progestins are provided in the table below.
PREFERRED DAILY DOSAGE
RANGES
Pr i First 23-25 CycleLast 3-5 ~rcle Davs Dad Levonorgestrel 30-150 pg I O-100 p.g Norgestrel 60-300 pg 20-200 pg Desogestrel 45-225 ~.g 15- I 50 ~.g 3-Ketodesogestrel 45-225 ~.g 15-150 ~,g Norethindrone 200 pg - 1 mg 65-650 ~.g Norethisterone Acetate 200 ~,g - 1 mg 65-650 pg Gestodene 20-115 ~.g 7.5-75 p.g Norgestimate 75-375 ~.g 25-250 pg Osaterone 250 p.g - 2.5 100 ~.g - 1.5 mg mg Trimegestone 75-375 ~,g 25-250 p.g Dienogest 500 pg - 3.75 100 ~g - 2.5 mg mg Drospirenone 500 p.g - 3.75 100 p.g - 2.5 mg mg Cyproterone Acetate 450 p.g - 2.5 150 ~.g - 1.5 mg mg _7_ Preferred estrogens include, but are not limited to ethinyl estradiol; 17~i-estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol; with ethinyl estradiol being more preferred. When ethinyl estradiol is used as the estrogen the preferred daily dosage is 10-20 ~tg, with 15 ~tg being more preferred.
When 17(3-estradiol is used as the estrogen, it is preferred that the daily dosage of 17[3-estradiol is 1-3 p,g. Preferred salts of estrone include, but are not limited to the sodium and piperate salt. When 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 p,g ethinyl estradiol.
It is preferred that the progestin/estrogen combination be administered for 24 days beginning on day 1 of the menstrual cycle, and following this 24-day period, it is preferred that the progestin be administered for 4 days.
The following daily dosages of a combination of levonorgestrel and ethinyl estradiol are preferred for contraception when administered for 23-25 consecutive days beginning on the first day of menses, followed by the administration of levonorgestrel for 3-5 days. The total administration during each cycle is 28 days.
PREFERRED DAILY DOSAGES
First 23-25 Cycle Days Last 3-5 C, cl~~
Regimen Levonorge_strelEthinvl EstradiolLevonor eg strel A 100 p,g 15 ~g 20-50 pg B 90 pg 15 ~.g 20-50 p,g C 75 pg 15 p.g 20-50 p,g D 60 ~,g 15 pg 20-50 p,g E 50 p.g 15 p.g 20-50 p,g F 40 p,g 15 p,g 20-50 p,g G 100 p.g 10 p,g 10-40 ~,g H 90 p,g 10 p,g 10-40 ~,g I 75 p,g 10 ~,g 10-40 p,g J 60 p,g 10 p.g 10-40 p.g K 50 ~,g 10 ~,g 10-40 pg L 40 ~g 10 ~.g 10-40 ~.g The following daily dosages of a combination of levonorgestrel and ethinyl estradiol are more preferred for contraception when administered for 24 consecutive days beginning on the first day of menses, followed by the administration of _g_ levonorgestrel for 4 days. The total administration during each cycle is 28 days. Of the regimens listed below, Regimens M-O are more preferred, with Regimen N being most preferred.
S MORE PREFERRED DAILY DOSAGES
First 24 Cy cle Davs Last 4 C~ cl~
a Days Regimen LevonorgestrelEthinX,l EstradiolLevonorgestrel M 75 p,g 15 p.g 37.5 p.g N 90 p,g 15 p.g 37.5 p,g O 100 p,g 15 pg 37.5 pg P 50 p,g 10 pg 25 pg Q 60 p.g 15 p,g 37.5 ~,g R 75 pg 10 p.g 25 p.g S 40 p.g 15 p,g 37.5 pg For administration during the first 23-25 days of the menstrual cycle, it is preferred that 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.
Levonorgestrel, 75 p,g Ethinyl estradiol, 15 ~.g Microcrystaline Cellulose Lactose, NF, Spray Dried Polacrillin Potassium, NF
Magnesium Stearate Opadry Pink Polyethylene Glycol, 1500, Flakes Water, Purified, USP
Wax E (Pharma) For administration during the last 3-5 days of the menstrual cycle, it is preferred that the progestin be administered in unit dosage form i.e., tablet or pill, with each unit providing the entire daily dosage. Such dosage units can be prepared by conventional methodology that is well known to one skilled in the art. In each dosage unit, the estrogen is combined with excipients, vehicles, phanmaceutically acceptable carriers, and colorants. For example, the following illustrates an acceptable estrogen composition of this invention.
Levonorgestrel, 37.5 p.g Microcrystaline Cellulose Lactose, NF, Spray Dried Polacrillin Potassium, NF
Magnesium Stearate GP~Y Pink Polyethylene Glycol, 1500, Flakes Water, Purified, USP
Wax E (Pharma) This invention also provides a contraceptive kit adapted for daily oral administration which comprises a total of 28 separate dosage units. In this kit, 23-25 dosage units each consisting of a combination of progestin at a daily dosage equivalent in progestational activity to 30-150 pg levonorgestrel and an estrogen at a daily dosage equivalent to 10-20 p,g ethinyl estradiol. The remaining 3-5 dosage units contain an progestin at a daily dosage equivalent to 10-100 ~,g levonorgestrel. 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.
Preferred progestins include, but are not limited to levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone. It is more preferred that the progestin is levonorgestrel. When levonorgestrel is used as the progestin during the first 23-25 days of the cycle, it is preferred that the daily dosage of levonorgestrel is 30-150 p,g, with 50-100 ~g being more preferred, and 90 ~g being most preferred. When levonorgestrel is used as the progestin during the last 3-5 days of the cycle, it is preferred that the daily dosage be 10-100 pg, with 20-50 ~g levonorgestrel being more preferred, and 37.5 ug most preferred. Preferred dosages of the preferred progestins are provided in the table below.
PREFERRED DAILY DOSAGE
RANGES
Pr i First 23-25 CycleLast 3-5 ~rcle Davs Dad Levonorgestrel 30-150 pg I O-100 p.g Norgestrel 60-300 pg 20-200 pg Desogestrel 45-225 ~.g 15- I 50 ~.g 3-Ketodesogestrel 45-225 ~.g 15-150 ~,g Norethindrone 200 pg - 1 mg 65-650 ~.g Norethisterone Acetate 200 ~,g - 1 mg 65-650 pg Gestodene 20-115 ~.g 7.5-75 p.g Norgestimate 75-375 ~.g 25-250 pg Osaterone 250 p.g - 2.5 100 ~.g - 1.5 mg mg Trimegestone 75-375 ~,g 25-250 p.g Dienogest 500 pg - 3.75 100 ~g - 2.5 mg mg Drospirenone 500 p.g - 3.75 100 p.g - 2.5 mg mg Cyproterone Acetate 450 p.g - 2.5 150 ~.g - 1.5 mg mg _7_ Preferred estrogens include, but are not limited to ethinyl estradiol; 17~i-estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol; with ethinyl estradiol being more preferred. When ethinyl estradiol is used as the estrogen the preferred daily dosage is 10-20 ~tg, with 15 ~tg being more preferred.
When 17(3-estradiol is used as the estrogen, it is preferred that the daily dosage of 17[3-estradiol is 1-3 p,g. Preferred salts of estrone include, but are not limited to the sodium and piperate salt. When 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 p,g ethinyl estradiol.
It is preferred that the progestin/estrogen combination be administered for 24 days beginning on day 1 of the menstrual cycle, and following this 24-day period, it is preferred that the progestin be administered for 4 days.
The following daily dosages of a combination of levonorgestrel and ethinyl estradiol are preferred for contraception when administered for 23-25 consecutive days beginning on the first day of menses, followed by the administration of levonorgestrel for 3-5 days. The total administration during each cycle is 28 days.
PREFERRED DAILY DOSAGES
First 23-25 Cycle Days Last 3-5 C, cl~~
Regimen Levonorge_strelEthinvl EstradiolLevonor eg strel A 100 p,g 15 ~g 20-50 pg B 90 pg 15 ~.g 20-50 p,g C 75 pg 15 p.g 20-50 p,g D 60 ~,g 15 pg 20-50 p,g E 50 p.g 15 p.g 20-50 p,g F 40 p,g 15 p,g 20-50 p,g G 100 p.g 10 p,g 10-40 ~,g H 90 p,g 10 p,g 10-40 ~,g I 75 p,g 10 ~,g 10-40 p,g J 60 p,g 10 p.g 10-40 p.g K 50 ~,g 10 ~,g 10-40 pg L 40 ~g 10 ~.g 10-40 ~.g The following daily dosages of a combination of levonorgestrel and ethinyl estradiol are more preferred for contraception when administered for 24 consecutive days beginning on the first day of menses, followed by the administration of _g_ levonorgestrel for 4 days. The total administration during each cycle is 28 days. Of the regimens listed below, Regimens M-O are more preferred, with Regimen N being most preferred.
S MORE PREFERRED DAILY DOSAGES
First 24 Cy cle Davs Last 4 C~ cl~
a Days Regimen LevonorgestrelEthinX,l EstradiolLevonorgestrel M 75 p,g 15 p.g 37.5 p.g N 90 p,g 15 p.g 37.5 p,g O 100 p,g 15 pg 37.5 pg P 50 p,g 10 pg 25 pg Q 60 p.g 15 p,g 37.5 ~,g R 75 pg 10 p.g 25 p.g S 40 p.g 15 p,g 37.5 pg For administration during the first 23-25 days of the menstrual cycle, it is preferred that 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.
Levonorgestrel, 75 p,g Ethinyl estradiol, 15 ~.g Microcrystaline Cellulose Lactose, NF, Spray Dried Polacrillin Potassium, NF
Magnesium Stearate Opadry Pink Polyethylene Glycol, 1500, Flakes Water, Purified, USP
Wax E (Pharma) For administration during the last 3-5 days of the menstrual cycle, it is preferred that the progestin be administered in unit dosage form i.e., tablet or pill, with each unit providing the entire daily dosage. Such dosage units can be prepared by conventional methodology that is well known to one skilled in the art. In each dosage unit, the estrogen is combined with excipients, vehicles, phanmaceutically acceptable carriers, and colorants. For example, the following illustrates an acceptable estrogen composition of this invention.
Levonorgestrel, 37.5 p.g Microcrystaline Cellulose Lactose, NF, Spray Dried Polacrillin Potassium, NF
Magnesium Stearate GP~Y Pink Polyethylene Glycol, 1500, Flakes Water, Purified, USP
Wax E (Pharma) This invention also provides a contraceptive kit adapted for daily oral administration which comprises a total of 28 separate dosage units. In this kit, 23-25 dosage units each consisting of a combination of progestin at a daily dosage equivalent in progestational activity to 30-150 pg levonorgestrel and an estrogen at a daily dosage equivalent to 10-20 p,g ethinyl estradiol. The remaining 3-5 dosage units contain an progestin at a daily dosage equivalent to 10-100 ~,g levonorgestrel. 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.
Claims (21)
1. A method of contraception which comprises administering to a female of child bearing age a combination of a progestin at a daily dosage equivalent to 30-150 µg levonorgestrel and an estrogen at a daily dosage equivalent to 10-20 µg ethinyl estradiol for 23-25 days per menstrual cycle beginning on day 1 of the menstrual cycle; wherein the same dosage of the progestin and estrogen combination is administered in each of the 23-25 days, followed by the administration of a progestin at a daily dosage equivalent to 10-100 µg levonorgestrel for 3-5 days; wherein the same dosage of the progestin is administered in each of the 3-5 days; such that the number of days of administration of the progestin and estrogen combination plus the number of days of administration of progestin is equal to 28 per menstrual cycle.
2. The method according to claim 1, wherein the combination of progestin and estrogen is administered for 24 days per menstrual cycle beginning on day of the menstrual cycle, followed by the administration of progestin for 4 days per menstrual cycle.
3. The method according to claim 1 or 2, wherein the progestin is selected from the group consisting of levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone.
4. The method according to claim 1, 2 or 3, wherein the estrogen is selected from the group consisting of ethinyl estradiol; 17.beta.-estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol.
5. The method according to any one of claims 1 to 4, wherein the progestin is levonorgestrel.
6. The method according to any one of claims 1 to 5, wherein the estrogen is ethinyl estradiol.
7. The method according to any one of claims 1 to 6, wherein levonorgestrel and ethinyl estradiol are administered for 24 days per menstrual cycle beginning on day 1 of the menstrual cycle, followed by the administration of levonorgestrel for 4 days per menstrual cycle.
8. The method according to claim 7, wherein the daily dosage of levonorgestrel administered during the first 24 days of the menstrual cycle is 50-100 µg and 20-50 µg during the last 4 days of the menstrual cycle.
9. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 90 µg; the daily dosage of ethinyl estradiol in the combination that is administered for days is 15 µg; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 µg.
10. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 75 µg; the daily dosage of ethinyl estradiol in the combination that is administered for days is 15 µg; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 µg.
11. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 100 µg; the daily dosage of ethinyl estradiol in the combination that is administered for days is 15 µg; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 µg.
12. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 50 µg; the daily dosage of ethinyl estradiol in the combination that is administered for days is 10 µg; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 25 µg.
13. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 60 ~.g;
the daily dosage of ethinyl estradiol in the combination that is administered for days is 15 ~.g; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 ~,g.
the daily dosage of ethinyl estradiol in the combination that is administered for days is 15 ~.g; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 ~,g.
14. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 75 ~.g;
the daily dosage of ethinyl estradiol in the combination that is administered for days is 10 ~,g; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 25 fig.
the daily dosage of ethinyl estradiol in the combination that is administered for days is 10 ~,g; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 25 fig.
15. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 40 µg; the daily dosage of ethinyl estradiol in the combination that is administered for days is 15 µg;and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 µg.
16. A contraceptive kit adapted for daily oral administration which comprises 28 separate dosage units, 23-25 of said dosage units each containing a combination of progestin at a daily dosage equivalent to 30-150 µg levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 10-20 µg ethinyl estradiol, wherein each of the 23-25 dosage units contains the same dosage of progestin and estrogen; and 3-5 of said dosage units containing an progestin at a daily dosage equivalent to 10-100 µg levonorgestrel, wherein each of the 3-5 dosage units contains the same dosage of progestin.
17. The contraceptive kit according to claim 16, wherein 24 of the 28 dosage units contain the progestin and estrogen combination, and 4 of the dosage units are estrogen free.
18. The contraceptive kit according to claim 16 or 17, wherein the progestin is selected from the group consisting of levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone, and the estrogen is selected from the group consisting of ethinyl estradiol;
17.beta.-estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol.
17.beta.-estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol.
19. The contraceptive kit according to claim 16, 17 or 18 wherein the estrogen is ethinyl estradiol and the progestin is levonorgestrel.
20. The contraceptive kit according to claim 19 wherein the dosage of levonorgestrel in each of the estrogen containing dosage units is 50-100 µg, and in the estrogen free dosage units is 20-50 µg.
21. The contraceptive kit according to claim 20 wherein the dosage of ethinyl estradiol in each progestin containing dosage unit is 15 µg and the dosage of levonorgestrel in each estrogen containing dosage unit is 90 µg and in each estrogen free dosage unit is 37.5 µg.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92853097A | 1997-09-12 | 1997-09-12 | |
| US08/928,530 | 1997-09-12 | ||
| PCT/US1998/018850 WO1999013882A1 (en) | 1997-09-12 | 1998-09-09 | Oral contraceptive preparation having a first phase comprising progestin/estrogen and a second phase comprising progestin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2301162A1 true CA2301162A1 (en) | 1999-03-25 |
Family
ID=25456367
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002301162A Abandoned CA2301162A1 (en) | 1997-09-12 | 1998-09-09 | Oral contraceptive preparation having a first phase comprising progestin/estrogen and a second phase comprising progestin |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1011681A1 (en) |
| JP (1) | JP2001516720A (en) |
| CN (1) | CN1270521A (en) |
| AU (1) | AU759925B2 (en) |
| CA (1) | CA2301162A1 (en) |
| WO (1) | WO1999013882A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8338396B2 (en) | 2001-12-05 | 2012-12-25 | Teva Women's Health, Inc. | Oral contraceptives to prevent pregnancy and diminish premenstrual symptomatology |
| US8415332B2 (en) | 2004-10-07 | 2013-04-09 | TEVA Woman's Health, Inc. | Methods of hormonal treatment utilizing ascending-dose extended cycle regimens |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001030355A1 (en) * | 1999-10-25 | 2001-05-03 | Laboratoire Theramex | Contraceptive medicine based on a progestational agent and an oestrogen and preparation method |
| FR2754179B1 (en) | 1996-10-08 | 1998-12-24 | Theramex | NOVEL HORMONONAL COMPOSITION AND ITS USE |
| WO2003041719A1 (en) * | 2001-11-15 | 2003-05-22 | Pantarhei Bioscience B.V. | Method of contraception in mammalian females and pharmaceutical kit for use in such method |
| CA2478336A1 (en) * | 2002-03-11 | 2003-09-25 | Janssen Pharmaceutica N.V. | Extended cycle estrogen and sulfatase inhibiting progestogen contraceptive regimens |
| JP2005519964A (en) * | 2002-03-11 | 2005-07-07 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Sulfatase-inhibiting progestogen-only contraceptive regimen |
| WO2003077925A1 (en) * | 2002-03-11 | 2003-09-25 | Janssen Pharmaceutica N.V. | Sulfatase inhibiting continuous progestogen contraceptive regimens |
| CN104546870B (en) * | 2015-01-27 | 2018-01-12 | 唐凡兰 | A kind of contraceptive |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0368373A1 (en) * | 1988-10-13 | 1990-05-16 | Akzo Nobel N.V. | Multi-phase contraceptive preparation |
| DE19549264A1 (en) * | 1995-12-23 | 1997-06-26 | Schering Ag | Contraception procedure and kit |
-
1998
- 1998-09-09 CN CN98809067A patent/CN1270521A/en active Pending
- 1998-09-09 EP EP98944837A patent/EP1011681A1/en not_active Withdrawn
- 1998-09-09 AU AU92286/98A patent/AU759925B2/en not_active Ceased
- 1998-09-09 WO PCT/US1998/018850 patent/WO1999013882A1/en not_active Application Discontinuation
- 1998-09-09 CA CA002301162A patent/CA2301162A1/en not_active Abandoned
- 1998-09-09 JP JP2000511503A patent/JP2001516720A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8338396B2 (en) | 2001-12-05 | 2012-12-25 | Teva Women's Health, Inc. | Oral contraceptives to prevent pregnancy and diminish premenstrual symptomatology |
| US8680084B2 (en) | 2001-12-05 | 2014-03-25 | Teva Women's Health, Inc. | Oral contraceptives to prevent pregnancy and diminish premenstrual symptomatology |
| US8415332B2 (en) | 2004-10-07 | 2013-04-09 | TEVA Woman's Health, Inc. | Methods of hormonal treatment utilizing ascending-dose extended cycle regimens |
| US8450299B2 (en) | 2004-10-07 | 2013-05-28 | Teva Womans's Health, Inc. | Methods of hormonal treatment utilizing ascending-dose extended cycle regimens |
Also Published As
| Publication number | Publication date |
|---|---|
| AU759925B2 (en) | 2003-05-01 |
| JP2001516720A (en) | 2001-10-02 |
| WO1999013882A1 (en) | 1999-03-25 |
| AU9228698A (en) | 1999-04-05 |
| CN1270521A (en) | 2000-10-18 |
| EP1011681A1 (en) | 2000-06-28 |
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