CA2057747C - Contraceptive regimen - Google Patents
Contraceptive regimen Download PDFInfo
- Publication number
- CA2057747C CA2057747C CA002057747A CA2057747A CA2057747C CA 2057747 C CA2057747 C CA 2057747C CA 002057747 A CA002057747 A CA 002057747A CA 2057747 A CA2057747 A CA 2057747A CA 2057747 C CA2057747 C CA 2057747C
- Authority
- CA
- Canada
- Prior art keywords
- progestogen
- dosage
- dosage units
- estrogen
- equivalent
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- 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
-
- 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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
Abstract
A contraceptive method and regimen utilizing an initially greater amount of progestogen, which gradually tapers over the period in which the contraceptive is administered. The regimen includes a multiphasic combi-nation and contraceptive kit containing at least 21 daily sequential dosage units divided into 3 phases.
The first phase contains 6-8 dosage units, each contain-ing a progestogen at a dosage equivalent in pro-gestogenic activity to 75-150 µg desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20-25 µg ethinyl estradiol. The second phase con-tains 6-8 dosage units, each containing less progestogen than in the previous dosage units, but still having pro-gestogen equivalent to 75-125 µg desogestrel and an estrogen equivalent to 20 µg ethinyl estradiol. The third phase contains 6-8 dosage units, each containing less progestogen than in the previous dosage units, but still containing a progestogen equivalent to 75-100 µg desogestrel and an estrogen equivalent to 20 µg ethinyl estradiol. The kit may also include another phase of 4 to 7 dosage units having no contraceptive steroid.
The first phase contains 6-8 dosage units, each contain-ing a progestogen at a dosage equivalent in pro-gestogenic activity to 75-150 µg desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20-25 µg ethinyl estradiol. The second phase con-tains 6-8 dosage units, each containing less progestogen than in the previous dosage units, but still having pro-gestogen equivalent to 75-125 µg desogestrel and an estrogen equivalent to 20 µg ethinyl estradiol. The third phase contains 6-8 dosage units, each containing less progestogen than in the previous dosage units, but still containing a progestogen equivalent to 75-100 µg desogestrel and an estrogen equivalent to 20 µg ethinyl estradiol. The kit may also include another phase of 4 to 7 dosage units having no contraceptive steroid.
Description
C~NTFLACEPTIV~ R~GIld ~'echnical Field. The invention relates generally to contraceptive preparations, and more specifically to an oral contraceptive regimen.
Backaraund Art. Known oral contraceptive regimens typically involve administering tablets containing a combination of estrogen and progestogen to an adult female over her menstrual cycle, usually followed by a eepill_free~e or blank pill period. The amount of pro-gestogen in the tablets of these regimens typically increases during the administration of the regimen.
Alternatively, the amount of progestogen may remain fixed, or reaches a peak and then declines.
For example in French Patent Application No.
Backaraund Art. Known oral contraceptive regimens typically involve administering tablets containing a combination of estrogen and progestogen to an adult female over her menstrual cycle, usually followed by a eepill_free~e or blank pill period. The amount of pro-gestogen in the tablets of these regimens typically increases during the administration of the regimen.
Alternatively, the amount of progestogen may remain fixed, or reaches a peak and then declines.
For example in French Patent Application No.
2,223,018 to Drtho Pharmaceutical, a progestogen is administered from at least the fifth day to the twenty-fifth day of the menstrual cycle, the dosage of the pro-gestogen being greater during the last seven days of administration than it is during the first seven days.
Another example of era oral contraceptive regimen which increases the amount of progestaagen throughout the woman's menstrual cycle is described in European Patent Appllcat~On No. 36,229 t0 Akzo, nv.
In Belgian Patent ado. 892,801 to Syntex (USA) Inc., a method of treating menopause is described also involv ing an increase in the amount of progestogen administered during the regimen's cycle.
German Patent Application Ido. 3,229,612 to Syntex (USA) Inc. describes a contraceptive regimen wherein the amount of progestogen administered peaks at mid-cycle, but then decreases.
U. S. Patent No. x,292,315 to Vorys describes another contraceptive regimen having a mid-menstrual cycle peak of progestogen and then subsequently declines. In this regimen, during the first 7 days, no exogenous steroids are administered. During days 8 to 2 ~ e.~
14, the tablets administered may contain only a pro-ges~togen (e. g. 0.35 milligrams (''mg'°) of norethindrone).
During days 15 to 18, tablets containing both an estro-gen and the progestogen (e. g. 0.35 mg of norethindrone) are administered. During days 19 to 25, tablets con-taining both an estrogen and a progestogen (e.g. 1.0 mg of norethindrone acetate, which is approximately twice as potent as norethindrone) are administered. Finally during days 26 to 28, tablets are administered in which the amount of estrogen and progestogen are at half the daily dosage of the preceding 7 tablets (e.g. 0.35 mg norethindxone).
Canadian Patent Application PIo. 2,000,438 to Akzo, nv describes a multiphasic oral contraceptive prepara tion containing a progestogen and an estrogen in a first phase, and a progestogen only in the second phase. The amount of progestogen in the second phase is less than that in the last dosage unit of the first phase. The first phase may be split-up into three sub-phases, eacka successive sub-phase having more progestogen than 'the one earlier.
Disclosure of the Invention It is found that by initially starting with a high amount of progestogen - after the usual 7 day pill-free or blank period - than gradually tapering the progestogen dosage over the contraceptive regimen, an effective oral contraceptive regimen results having a relatively lower amount of contraceptive steroids.
The invention thus includes a multiphasic combina-tion and contraceptive kit containing from 21 to 24 daily sequential dosage units. The 21 dosage units are divided into three phases. The first phase contains 6 to 8 first dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 75 to 150 micrograms (°'~g°') desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20-25 ~,g ethinyl estradiol. The second phase contains 6 to 8, preferably 7, each containing less progestogen than in the first dosage units, but still having progestogen in a dosage equivalent in progestogenic activity to 75 to 125 ~,g desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 ~.g ethinyl est:radiol. The third phase contains 6 to 8 third dosage units, each containing less progestogen than in the earlier dosage units, but still containing a progestogen at a dosage equivalent in progestogenic activity 75 to 100 ug desogestrel and an estrogen at a dosage equivalent in estro<~enic activity to ~.g ethinyl estradiol.
The kit may also include a fourth phase of 4 to 7 fourth dosage units having no contraceptive steroids.
The progestogen is preferably selected from the 15 group consisting of 3-ketodesogestrel, desogestrel, levo-norgestrel, gestodene and mixtures thereof.
The estrogen is preferably selected from the group consisting of 17~i-estradiol, ethinyl estradiol, mestranol, 17-cx-ethinyl estradiol 3-methyether and mixtures thereof.
20 According to another aspect of the present invention there is provided a multiphasic combination and contraceptive kit comprising a package containing 24 daily sequential dosage units of: a first phase of 8 first dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 150 ~,g desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 25 ~g ethinyl estradiol; a second phase of 8 second dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 125 ~.g desog~estrel and an estrogen at a dosage equivalent in estrogenic activity to 20 ~.g ethinyl estradiol; and a third phase of 8 third dosage 3a units, each containing a progestogen at a dosage equivalent in progestogenic activity to 100 ~g desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 ~g ethinyl estradiol.
According to yet another aspect of the present invention there is provided a multiphasic combination and contraceptive kit containing sequential phases of dosage units having progestogen and estrogen characterized in that the amount of progestogen contained in the dosage units of each phase of the kit decreases incrementally along with the phase.
According to still yet another aspect of the present invention there is provided a process of manufacturing the combination and contraceptive kit of the invention, comprising: mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into first dosage units;
mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into second dosage units; mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into third dosage units; and optionally including fourth dosage units having no contraceptive steroids.
The invention also includes a pharmaceutical product (i.e. the birth control pack containing the dosage unit regimen), and a process of manufacturing this pharmaceutical product.
Best Mode of the Invention Preferred progestogens for use with the invention include 3-ketodesogestrel ("etonogestrel"), desogestrel, 3b levonorgestrel, norgestrel, gestodene, and other compounds with similar progestogenic activity. Especially preferred are 3-ketodesogestrel and desogestrel. As an approximation, levo-norgestrel, desogestrel, and 3-ketodesogestrel are relatively equipotent, when administered orally, in progestogenic activity. Gestodene is approximately 1.5 times as potent as these compounds orally. Norgestrel is about one-half as potent as levo-norgestrel.
Each phase preferably contains seven dosage units.
In the first dosage units, 125 ~g of desogestrel or 3-ketodesogestrel are preferably used. In the second dosage units, 100 ~g of desogestrel or 3-keto-desogestrel are preferably used. In the third dosage units, 75 ~g of desogestrel or 3-ketodesogestrel are preferably used.
~!~~~~~~"l Examples of preferred estrogens include 17B-estra-diol and ethinyl estradiol. Mestranol and 17-a-ethinyl estradiol 3-methylether are also useful estrogens. As an approximation and when administered orally, ~, mg of 1713-estradiol is equivalent in estrogenic activity to 0.015 mg of ethinyl estradiol and 0.030 mg of mestranol.
The estrogen and progestogen ("cowtraceptive steroids"), or either of them are incorporated into dosage units for oral administration. The term "dosage unit" generally refers to physically discrete units suitable as unitary dosages for humans or animals, each containing a predetermined quantity of active material {e.g. estrogen or progestogen) calculated to produce the desired effect.
Conventional techniques may be used to make dosage units according to the invention. Conventional methods and compositions for making such dosage units are well-known to those skilled in the art. For example, methods and compositions for making tablets and pills, conta:in-ing active ingredients, are described in the standard reference, Chase et al . , Remington~,'s ~h~rm~-,ceutical sci-~~C~S, {16th ed., Mack Publishing Co., Easton. PA, U.S.A., 1980) ("Reming~on's"), at pages 1553 through 1584. Methods of making powders, and their composition are described at pages 1535 through 1552 of the refer-ence. Methods of coating pharmaceutical dosage forms are described at pages 1585 to 1593 of Remgnc~ton's.
For making dosage units, e.g. tablets, the use of conventional additives, e.g. fillers, colorants, poly meric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used in the one or more of the compositions.
Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like used in suitable amounts.
Lactose is a preferred carrier. Mixtures of carriers can also be used.
A process of manufacturing the pharmaceutical prod-uct according to the invention preferably involves incorporating the desired dosages of contraceptive steroid (i.e. progestogen and estrogen) into a tablet by 5 known techniques. Tablets containing different amounts and types of contraceptive steroids may be of different colors, and kept in different portions of, for example, a blister pack. The package containing the dosage units will preferably contain 21 or 28 dosage units arranged l0 sequentially therein. Preferably there will be 28 dosage units, of which seven will be blanks.
A method of contraception using the invention com-prises administering, either enterally or parenterally, to a female of child-bearing age:
a) no contraceptive steroids for the first 4 to 7 days;
b) a progestogen at a daily dosage equivalent in progesto-genic activity to 75 to 150 ~,g desogestrel administered orally, and an estrogen at a daily dosage equivalent in estrogenic activity to 20-25 ~,g ethinyl estradiol 2o administered orally for the next 6 to 8 days:
c) a progestogen at a daily dosage equivalent in progesto-genic activity to 75 to 125 ~g desogestrel administered orally, but in an amount less than that administered during the prior 6 to 8 days, and an estrogen at a daily dosage equivalent in estrogenic activity to 20 wg ethinyl estradiol administered orally for the next 6 to 8 days: and d) a progestogen at a daily dosage equivalent in progesto genic activity 75 to 100 ~g desogestrel administered orally, but in an amount less than that administered during the prior 6 to 8 days, and an estrogen at a daily dosage equivalent in estrogenic activity to 20 ~.g ethinyl estradiol administered orally for the last 6 to 8 days.
A preferred method of contraception using the invention comprises orally administering to a female:
a) for the first 7 days, no dosage units at all;
b) for the next 7 days, first dosage units containing a progestogen at a daily dosage equivalent in progesto-genie activity to 75 to 150 ~g desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20-25 ~g ethinyl estradiol;
c) for the next 7 days, second dosage units containing less progestogen than in the first dosage units, but still having a progestogen at a daily dosage equivalent in progestogenic activity to 75 to 125 ~.g desogestrel and an estrogen at a daily dosage equivalent in estro-genic activity to 20 ~Sg ethinyl estradiol; and d) for the last 7 days, third dosage units containing less progestogen than in the second dosage units, but still containing a progestogen at a daily dosage equivalent in progestogenic activity 75 to 100 ~g desogestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 20 ~.g ethinyl estradiol.
After the completion of one cycle of the regimen, the regimen may be repeated for as long as contraception is desired. These methods might also include adminis-tering blank dosage units during the first seven days.
One or more dosage units may contain an iron salt (e. g.
75 mg of ferrous fumarate) if desired.
This regimen is effective and can be used with a relatively low amount of contraceptive steroids.
The invention is further explained lay the following illustrative EXAMPLES.
EXAMPLE I
Compositions of tablets:
A. In the first phase: (7 tablets) Compound Amount t mcr /tabl et 1 ethinyl estradiol 0.020 desogestrel 0.125 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 ~!~~~~''~~~1 B. In the second phase: (7 tablets) Compound Amoun t' mcs /t b~;L
ethinyl estradiol 0.020 desogestrel 0.100 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 C. In the third phase: (7 tablets) Compound Amoun t ~,mg%table~t) ethinyl estradiol 0,020 desogestrel 0.075 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 c'i1-a-tocopherol 0 . 080 lactose qsad 65.000 D. In the fourth phase: (7 tablets) Compound Amount (mq,/tablet) potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-~-tocopherol 0.080 lactose qsad 65.000 EXAMPLE II
Compositions of tablets:
A. In the first phase: (7 tablets) Compound Amount ~m~/tablet), ethinyl estradiol 0.020 3-ketodesogestrel 0 .125 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65,000 E. In the second phase: (7 tablets) Compound Amount md~bletl ethinyl estradiol 0.020 3-ketodesogestrel 0.100 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 C. Tn the 'third phase: (7 tablets) Compound Amount mq~tablet) ethinyl estradiol 0.020 3°ketodesogestrel 0.075 potato starch 6.500 povidone , 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 D. In the fourth phase: Same as EXAMPLE I.I~.
EXAINiPLE III
Compositions of tablets:
A. In the first phase: tablets) (7 Coulpound Amou nt l mg,Ltablet micronized(17B)estradial 2.000 desogestrel 0.125 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 In 'the second phases (7 tablets) Compound Amount-(mg~tablet) micronized estradiol 2.000 desogestrel 0.100 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 C. In the third phase: (7 tablets) Commound Amount fmc~ltablet) micronzzed estradzol 2.000 desogestrel 0.075 potato starch 6.500 povidone 1.950 stearzc acid 0.650 colloidal silicone dioxide 0.650 dl-~-tocopherol 0.080 lactose qsad 65.000 In the fourth phase: Same as EXAMPLE I.i7.
EXAMPLE IV
Compositions of tablets:
A. In the first phase: (8 tablets) Cargpound Amount ~(~m~/tablet'1 ethinyl estradiol 0.025 desogestrel 0.150 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 cll-a-tocopherol 0.080 lactose qsad 65.000 B. In the second phase: (8 tablets) Coa~ound Amount fmc~~tablet~
ethinyl estradiol 0.020 desogestrel 0.125 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-cx-tocopherol 0.080 lactose qsad 65.000 C. Tn the third phase: (8 tablets) Co~g~ound Amou nt (mq,Ltablet~
ethznyl estradiol 0.020 desogestrel 0.100 potato starch 6.500 povidone 1.950 stearzc acid 0.650 colloidal si1zcone dioxide 0.650 dl-c~-tocopherol 0 . 080 lactose qsad 65.000 ~~d~~'~~~~'~
D. In the fourth phase: Same as EXAMPLE I.D.
Reference herein to specific embodiments or exam-ples should not be interpreted as limitations to the scope of the invention, which is defined b~ the appended claims.
Another example of era oral contraceptive regimen which increases the amount of progestaagen throughout the woman's menstrual cycle is described in European Patent Appllcat~On No. 36,229 t0 Akzo, nv.
In Belgian Patent ado. 892,801 to Syntex (USA) Inc., a method of treating menopause is described also involv ing an increase in the amount of progestogen administered during the regimen's cycle.
German Patent Application Ido. 3,229,612 to Syntex (USA) Inc. describes a contraceptive regimen wherein the amount of progestogen administered peaks at mid-cycle, but then decreases.
U. S. Patent No. x,292,315 to Vorys describes another contraceptive regimen having a mid-menstrual cycle peak of progestogen and then subsequently declines. In this regimen, during the first 7 days, no exogenous steroids are administered. During days 8 to 2 ~ e.~
14, the tablets administered may contain only a pro-ges~togen (e. g. 0.35 milligrams (''mg'°) of norethindrone).
During days 15 to 18, tablets containing both an estro-gen and the progestogen (e. g. 0.35 mg of norethindrone) are administered. During days 19 to 25, tablets con-taining both an estrogen and a progestogen (e.g. 1.0 mg of norethindrone acetate, which is approximately twice as potent as norethindrone) are administered. Finally during days 26 to 28, tablets are administered in which the amount of estrogen and progestogen are at half the daily dosage of the preceding 7 tablets (e.g. 0.35 mg norethindxone).
Canadian Patent Application PIo. 2,000,438 to Akzo, nv describes a multiphasic oral contraceptive prepara tion containing a progestogen and an estrogen in a first phase, and a progestogen only in the second phase. The amount of progestogen in the second phase is less than that in the last dosage unit of the first phase. The first phase may be split-up into three sub-phases, eacka successive sub-phase having more progestogen than 'the one earlier.
Disclosure of the Invention It is found that by initially starting with a high amount of progestogen - after the usual 7 day pill-free or blank period - than gradually tapering the progestogen dosage over the contraceptive regimen, an effective oral contraceptive regimen results having a relatively lower amount of contraceptive steroids.
The invention thus includes a multiphasic combina-tion and contraceptive kit containing from 21 to 24 daily sequential dosage units. The 21 dosage units are divided into three phases. The first phase contains 6 to 8 first dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 75 to 150 micrograms (°'~g°') desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20-25 ~,g ethinyl estradiol. The second phase contains 6 to 8, preferably 7, each containing less progestogen than in the first dosage units, but still having progestogen in a dosage equivalent in progestogenic activity to 75 to 125 ~,g desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 ~.g ethinyl est:radiol. The third phase contains 6 to 8 third dosage units, each containing less progestogen than in the earlier dosage units, but still containing a progestogen at a dosage equivalent in progestogenic activity 75 to 100 ug desogestrel and an estrogen at a dosage equivalent in estro<~enic activity to ~.g ethinyl estradiol.
The kit may also include a fourth phase of 4 to 7 fourth dosage units having no contraceptive steroids.
The progestogen is preferably selected from the 15 group consisting of 3-ketodesogestrel, desogestrel, levo-norgestrel, gestodene and mixtures thereof.
The estrogen is preferably selected from the group consisting of 17~i-estradiol, ethinyl estradiol, mestranol, 17-cx-ethinyl estradiol 3-methyether and mixtures thereof.
20 According to another aspect of the present invention there is provided a multiphasic combination and contraceptive kit comprising a package containing 24 daily sequential dosage units of: a first phase of 8 first dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 150 ~,g desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 25 ~g ethinyl estradiol; a second phase of 8 second dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 125 ~.g desog~estrel and an estrogen at a dosage equivalent in estrogenic activity to 20 ~.g ethinyl estradiol; and a third phase of 8 third dosage 3a units, each containing a progestogen at a dosage equivalent in progestogenic activity to 100 ~g desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 ~g ethinyl estradiol.
According to yet another aspect of the present invention there is provided a multiphasic combination and contraceptive kit containing sequential phases of dosage units having progestogen and estrogen characterized in that the amount of progestogen contained in the dosage units of each phase of the kit decreases incrementally along with the phase.
According to still yet another aspect of the present invention there is provided a process of manufacturing the combination and contraceptive kit of the invention, comprising: mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into first dosage units;
mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into second dosage units; mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into third dosage units; and optionally including fourth dosage units having no contraceptive steroids.
The invention also includes a pharmaceutical product (i.e. the birth control pack containing the dosage unit regimen), and a process of manufacturing this pharmaceutical product.
Best Mode of the Invention Preferred progestogens for use with the invention include 3-ketodesogestrel ("etonogestrel"), desogestrel, 3b levonorgestrel, norgestrel, gestodene, and other compounds with similar progestogenic activity. Especially preferred are 3-ketodesogestrel and desogestrel. As an approximation, levo-norgestrel, desogestrel, and 3-ketodesogestrel are relatively equipotent, when administered orally, in progestogenic activity. Gestodene is approximately 1.5 times as potent as these compounds orally. Norgestrel is about one-half as potent as levo-norgestrel.
Each phase preferably contains seven dosage units.
In the first dosage units, 125 ~g of desogestrel or 3-ketodesogestrel are preferably used. In the second dosage units, 100 ~g of desogestrel or 3-keto-desogestrel are preferably used. In the third dosage units, 75 ~g of desogestrel or 3-ketodesogestrel are preferably used.
~!~~~~~~"l Examples of preferred estrogens include 17B-estra-diol and ethinyl estradiol. Mestranol and 17-a-ethinyl estradiol 3-methylether are also useful estrogens. As an approximation and when administered orally, ~, mg of 1713-estradiol is equivalent in estrogenic activity to 0.015 mg of ethinyl estradiol and 0.030 mg of mestranol.
The estrogen and progestogen ("cowtraceptive steroids"), or either of them are incorporated into dosage units for oral administration. The term "dosage unit" generally refers to physically discrete units suitable as unitary dosages for humans or animals, each containing a predetermined quantity of active material {e.g. estrogen or progestogen) calculated to produce the desired effect.
Conventional techniques may be used to make dosage units according to the invention. Conventional methods and compositions for making such dosage units are well-known to those skilled in the art. For example, methods and compositions for making tablets and pills, conta:in-ing active ingredients, are described in the standard reference, Chase et al . , Remington~,'s ~h~rm~-,ceutical sci-~~C~S, {16th ed., Mack Publishing Co., Easton. PA, U.S.A., 1980) ("Reming~on's"), at pages 1553 through 1584. Methods of making powders, and their composition are described at pages 1535 through 1552 of the refer-ence. Methods of coating pharmaceutical dosage forms are described at pages 1585 to 1593 of Remgnc~ton's.
For making dosage units, e.g. tablets, the use of conventional additives, e.g. fillers, colorants, poly meric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used in the one or more of the compositions.
Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like used in suitable amounts.
Lactose is a preferred carrier. Mixtures of carriers can also be used.
A process of manufacturing the pharmaceutical prod-uct according to the invention preferably involves incorporating the desired dosages of contraceptive steroid (i.e. progestogen and estrogen) into a tablet by 5 known techniques. Tablets containing different amounts and types of contraceptive steroids may be of different colors, and kept in different portions of, for example, a blister pack. The package containing the dosage units will preferably contain 21 or 28 dosage units arranged l0 sequentially therein. Preferably there will be 28 dosage units, of which seven will be blanks.
A method of contraception using the invention com-prises administering, either enterally or parenterally, to a female of child-bearing age:
a) no contraceptive steroids for the first 4 to 7 days;
b) a progestogen at a daily dosage equivalent in progesto-genic activity to 75 to 150 ~,g desogestrel administered orally, and an estrogen at a daily dosage equivalent in estrogenic activity to 20-25 ~,g ethinyl estradiol 2o administered orally for the next 6 to 8 days:
c) a progestogen at a daily dosage equivalent in progesto-genic activity to 75 to 125 ~g desogestrel administered orally, but in an amount less than that administered during the prior 6 to 8 days, and an estrogen at a daily dosage equivalent in estrogenic activity to 20 wg ethinyl estradiol administered orally for the next 6 to 8 days: and d) a progestogen at a daily dosage equivalent in progesto genic activity 75 to 100 ~g desogestrel administered orally, but in an amount less than that administered during the prior 6 to 8 days, and an estrogen at a daily dosage equivalent in estrogenic activity to 20 ~.g ethinyl estradiol administered orally for the last 6 to 8 days.
A preferred method of contraception using the invention comprises orally administering to a female:
a) for the first 7 days, no dosage units at all;
b) for the next 7 days, first dosage units containing a progestogen at a daily dosage equivalent in progesto-genie activity to 75 to 150 ~g desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20-25 ~g ethinyl estradiol;
c) for the next 7 days, second dosage units containing less progestogen than in the first dosage units, but still having a progestogen at a daily dosage equivalent in progestogenic activity to 75 to 125 ~.g desogestrel and an estrogen at a daily dosage equivalent in estro-genic activity to 20 ~Sg ethinyl estradiol; and d) for the last 7 days, third dosage units containing less progestogen than in the second dosage units, but still containing a progestogen at a daily dosage equivalent in progestogenic activity 75 to 100 ~g desogestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 20 ~.g ethinyl estradiol.
After the completion of one cycle of the regimen, the regimen may be repeated for as long as contraception is desired. These methods might also include adminis-tering blank dosage units during the first seven days.
One or more dosage units may contain an iron salt (e. g.
75 mg of ferrous fumarate) if desired.
This regimen is effective and can be used with a relatively low amount of contraceptive steroids.
The invention is further explained lay the following illustrative EXAMPLES.
EXAMPLE I
Compositions of tablets:
A. In the first phase: (7 tablets) Compound Amount t mcr /tabl et 1 ethinyl estradiol 0.020 desogestrel 0.125 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 ~!~~~~''~~~1 B. In the second phase: (7 tablets) Compound Amoun t' mcs /t b~;L
ethinyl estradiol 0.020 desogestrel 0.100 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 C. In the third phase: (7 tablets) Compound Amoun t ~,mg%table~t) ethinyl estradiol 0,020 desogestrel 0.075 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 c'i1-a-tocopherol 0 . 080 lactose qsad 65.000 D. In the fourth phase: (7 tablets) Compound Amount (mq,/tablet) potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-~-tocopherol 0.080 lactose qsad 65.000 EXAMPLE II
Compositions of tablets:
A. In the first phase: (7 tablets) Compound Amount ~m~/tablet), ethinyl estradiol 0.020 3-ketodesogestrel 0 .125 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65,000 E. In the second phase: (7 tablets) Compound Amount md~bletl ethinyl estradiol 0.020 3-ketodesogestrel 0.100 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 C. Tn the 'third phase: (7 tablets) Compound Amount mq~tablet) ethinyl estradiol 0.020 3°ketodesogestrel 0.075 potato starch 6.500 povidone , 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 D. In the fourth phase: Same as EXAMPLE I.I~.
EXAINiPLE III
Compositions of tablets:
A. In the first phase: tablets) (7 Coulpound Amou nt l mg,Ltablet micronized(17B)estradial 2.000 desogestrel 0.125 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 In 'the second phases (7 tablets) Compound Amount-(mg~tablet) micronized estradiol 2.000 desogestrel 0.100 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-a-tocopherol 0.080 lactose qsad 65.000 C. In the third phase: (7 tablets) Commound Amount fmc~ltablet) micronzzed estradzol 2.000 desogestrel 0.075 potato starch 6.500 povidone 1.950 stearzc acid 0.650 colloidal silicone dioxide 0.650 dl-~-tocopherol 0.080 lactose qsad 65.000 In the fourth phase: Same as EXAMPLE I.i7.
EXAMPLE IV
Compositions of tablets:
A. In the first phase: (8 tablets) Cargpound Amount ~(~m~/tablet'1 ethinyl estradiol 0.025 desogestrel 0.150 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 cll-a-tocopherol 0.080 lactose qsad 65.000 B. In the second phase: (8 tablets) Coa~ound Amount fmc~~tablet~
ethinyl estradiol 0.020 desogestrel 0.125 potato starch 6.500 povidone 1.950 stearic acid 0.650 colloidal silicone dioxide 0.650 dl-cx-tocopherol 0.080 lactose qsad 65.000 C. Tn the third phase: (8 tablets) Co~g~ound Amou nt (mq,Ltablet~
ethznyl estradiol 0.020 desogestrel 0.100 potato starch 6.500 povidone 1.950 stearzc acid 0.650 colloidal si1zcone dioxide 0.650 dl-c~-tocopherol 0 . 080 lactose qsad 65.000 ~~d~~'~~~~'~
D. In the fourth phase: Same as EXAMPLE I.D.
Reference herein to specific embodiments or exam-ples should not be interpreted as limitations to the scope of the invention, which is defined b~ the appended claims.
Claims (10)
1. A multiphasic combination and contraceptive kit comprising a package containing 21 to 24 daily sequential dosage units of:
a first phase of 6 to 8 first dosage units, said first dosage units each containing a progestogen at a dosage equivalent in progestogenic activity to a value of from 75 to 150 micrograms desogestrel and an estrogen at a dosage equivalent in estrogenic activity to a value of from 20 to 25 micrograms ethinyl estradiol;
a second phase of 6 to 8 second dosage units, said second dosage units each containing less progestogen than in the first dosage units, but still having a progestogen at a dosage equivalent in progestogenic activity to a value of from 75 to 125 micrograms desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 micrograms ethinyl estradiol; and a third phase of 6 to 8 third dosage units, said third dosage units each containing less progestogen than in the second dosage units, but still containing a progestogen at a dosage equivalent in progestogenic activity to a value of from 75 to 100 micrograms desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 micrograms ethinyl estradiol.
a first phase of 6 to 8 first dosage units, said first dosage units each containing a progestogen at a dosage equivalent in progestogenic activity to a value of from 75 to 150 micrograms desogestrel and an estrogen at a dosage equivalent in estrogenic activity to a value of from 20 to 25 micrograms ethinyl estradiol;
a second phase of 6 to 8 second dosage units, said second dosage units each containing less progestogen than in the first dosage units, but still having a progestogen at a dosage equivalent in progestogenic activity to a value of from 75 to 125 micrograms desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 micrograms ethinyl estradiol; and a third phase of 6 to 8 third dosage units, said third dosage units each containing less progestogen than in the second dosage units, but still containing a progestogen at a dosage equivalent in progestogenic activity to a value of from 75 to 100 micrograms desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 micrograms ethinyl estradiol.
2. The multiphasic combination and contraceptive kit of claim 1 wherein the kit further comprises a fourth phase of 4 to 7 fourth dosage units containing no contraceptive steroids.
3. The multiphasic combination and contraceptive kit 11a of claim 1 or claim 2 wherein said progestogen is selected from the group consisting of 3-ketodesogestrel, desogestrel, levo-norgestrel, gestodene, and mixtures thereof.
4. The multiphasic combination and contraceptive kit of claim 3 wherein the progestogen in all phases containing a progestogen is desogestrel or 3-ketodesogestrel.
5. The multiphasic combination and contraceptive kit of claim 1, claim 2, claim 3, or claim 4 wherein said estrogen is selected from the group consisting of 17.beta.-estradiol, ethinyl estradiol, mestranol, 17-.alpha.-ethinyl estradiol 3-methylether, and mixtures thereof.
6. The multiphasic combination and contraceptive kit of claim 5 wherein the estrogen is 17.beta.-estradiol or ethinyl estradiol.
7. A multiphasic combination and contraceptive kit comprising a package containing 24 daily sequential dosage units of:
a first phase of 8 first dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 150 µg desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 25 µg ethinyl estradiol;
a second phase of 8 second dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 125 µg desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 µg ethinyl estradiol; and a third phase of 8 third dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 100 µg desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 µg ethinyl estradiol.
a first phase of 8 first dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 150 µg desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 25 µg ethinyl estradiol;
a second phase of 8 second dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 125 µg desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 µg ethinyl estradiol; and a third phase of 8 third dosage units, each containing a progestogen at a dosage equivalent in progestogenic activity to 100 µg desogestrel and an estrogen at a dosage equivalent in estrogenic activity to 20 µg ethinyl estradiol.
8. A multiphasic combination and contraceptive kit containing sequential phases of dosage units having progestogen and estrogen characterized in that the amount of progestogen contained in the dosage units of each phase of the kit decreases incrementally along with the phase.
9. A process of manufacturing the combination and contraceptive kit of any one of claims 1 to 8, comprising:
mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into first dosage units;
mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into second dosage units;
mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into third dosage units; and optionally including fourth dosage units having no contraceptive steroids.
mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into first dosage units;
mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into second dosage units;
mixing predetermined quantities of progestogen with predetermined quantities of estrogen and converting the resulting mixture into third dosage units; and optionally including fourth dosage units having no contraceptive steroids.
10. A method of contraception comprising:
cyclically administering to a female of child-bearing age, for so long as contraception is desired:
a) no contraceptive steroids for the first 4 to 7 days;
b) a progestogen at a daily dosage equivalent in progestogenic activity to a value of from 77 to 150 µg desogestrel administered orally, and an estrogen at a daily dosage equivalent in estrogenic activity to a value of from 20-25 µg ethinyl estradiol administered orally for the next 6 to 8 days;
c) a progestogen at a daily dosage equivalent in progestogenic activity to a value of from 76 to 125 µg desogestrel administered orally, but in an amount less than that administered during the prior 6 to 8 days, and an estrogen at a daily dosage equivalent in estrogenic activity to 20 µg ethinyl estradiol administered orally for the next 6 to 8 days; and d) a progestogen at a daily dosage equivalent in progestogenic activity to a value of from 75 to 100 µg desogestrel administered orally, but in an amount less than that amdinistered during the prior 6 to 8 days, and an estrogen at a daily dosage equivalent in estrogenic activity to a value of from 20 µg ethinyl estradiol administered orally for the last 6 to 8 days.
cyclically administering to a female of child-bearing age, for so long as contraception is desired:
a) no contraceptive steroids for the first 4 to 7 days;
b) a progestogen at a daily dosage equivalent in progestogenic activity to a value of from 77 to 150 µg desogestrel administered orally, and an estrogen at a daily dosage equivalent in estrogenic activity to a value of from 20-25 µg ethinyl estradiol administered orally for the next 6 to 8 days;
c) a progestogen at a daily dosage equivalent in progestogenic activity to a value of from 76 to 125 µg desogestrel administered orally, but in an amount less than that administered during the prior 6 to 8 days, and an estrogen at a daily dosage equivalent in estrogenic activity to 20 µg ethinyl estradiol administered orally for the next 6 to 8 days; and d) a progestogen at a daily dosage equivalent in progestogenic activity to a value of from 75 to 100 µg desogestrel administered orally, but in an amount less than that amdinistered during the prior 6 to 8 days, and an estrogen at a daily dosage equivalent in estrogenic activity to a value of from 20 µg ethinyl estradiol administered orally for the last 6 to 8 days.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP90203372 | 1990-12-17 | ||
| EP90203372.9 | 1990-12-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2057747A1 CA2057747A1 (en) | 1992-06-18 |
| CA2057747C true CA2057747C (en) | 2003-07-29 |
Family
ID=8205204
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002057747A Expired - Fee Related CA2057747C (en) | 1990-12-17 | 1991-12-16 | Contraceptive regimen |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5418228A (en) |
| EP (1) | EP0491438B1 (en) |
| JP (1) | JPH04290830A (en) |
| KR (1) | KR100186780B1 (en) |
| CN (1) | CN1036833C (en) |
| AT (1) | ATE136219T1 (en) |
| AU (1) | AU645637B2 (en) |
| CA (1) | CA2057747C (en) |
| DE (1) | DE69118494T2 (en) |
| DK (1) | DK0491438T3 (en) |
| ES (1) | ES2087965T3 (en) |
| FI (1) | FI98985C (en) |
| GR (1) | GR3020181T3 (en) |
| IE (1) | IE62665B1 (en) |
| NO (1) | NO179311C (en) |
| NZ (1) | NZ240970A (en) |
| PT (1) | PT99819B (en) |
| ZA (1) | ZA919770B (en) |
Families Citing this family (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4227989A1 (en) * | 1992-08-21 | 1994-06-09 | Schering Ag | Agent for transdermal application containing 3-keto-desogestrel |
| US6407082B1 (en) * | 1996-09-13 | 2002-06-18 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of a vitamin D compound |
| DE4344462C2 (en) | 1993-12-22 | 1996-02-01 | Schering Ag | Composition for contraception |
| DK0782449T3 (en) * | 1994-09-22 | 2003-08-04 | Akzo Nobel Nv | Process for preparing dosage units by wet granulation |
| CA2159419C (en) * | 1994-10-17 | 2006-07-04 | Pieter De Haan | Solid pharmaceutical composition comprising an excipient capable of binding water |
| DE19540253C2 (en) * | 1995-10-28 | 1998-06-04 | Jenapharm Gmbh | Multi-phase preparation for contraception based on natural estrogens |
| AU2926897A (en) * | 1996-05-08 | 1997-11-26 | American Home Products Corporation | Oral contraceptive |
| US5747480A (en) * | 1996-05-08 | 1998-05-05 | American Home Products Corporation | Oral contraceptive |
| US5858405A (en) * | 1996-07-26 | 1999-01-12 | American Home Products Corporation | Oral contraceptive |
| US5888543A (en) * | 1996-07-26 | 1999-03-30 | American Home Products Corporation | Oral contraceptives |
| AU713016B2 (en) * | 1996-07-26 | 1999-11-18 | Wyeth | Oral contraceptive |
| US6479475B1 (en) | 1996-07-26 | 2002-11-12 | Wyeth | Oral contraceptive |
| US6451778B1 (en) | 1996-07-26 | 2002-09-17 | Wyeth | Oral contraceptive |
| WO1998004267A1 (en) * | 1996-07-26 | 1998-02-05 | American Home Products Corporation | Progestin/estrogen oral contraceptive |
| US6028064A (en) | 1996-09-13 | 2000-02-22 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of progestin products |
| US6034074A (en) | 1996-09-13 | 2000-03-07 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of a Vitamin D compound |
| US6765002B2 (en) | 2000-03-21 | 2004-07-20 | Gustavo Rodriguez | Prevention of ovarian cancer by administration of products that induce transforming growth factor-β and/or apoptosis in the ovarian epithelium |
| US6511970B1 (en) * | 1996-09-13 | 2003-01-28 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of products that induce transforming growth factor-beta and/or apoptosis in the ovarian epithelium |
| FR2754179B1 (en) | 1996-10-08 | 1998-12-24 | Theramex | NOVEL HORMONONAL COMPOSITION AND ITS USE |
| WO2001030355A1 (en) | 1999-10-25 | 2001-05-03 | Laboratoire Theramex | Contraceptive medicine based on a progestational agent and an oestrogen and preparation method |
| DE19739916C2 (en) * | 1997-09-11 | 2001-09-13 | Hesch Rolf Dieter | Use of a combination of a progestogen and an estrogen for the continuous inhibition of ovulation and possibly simultaneous treatment and / or prophylaxis of tumors of the mammary glands |
| US6028057A (en) * | 1998-02-19 | 2000-02-22 | Thorn Bioscience, Llc | Regulation of estrus and ovulation in gilts |
| US6214815B1 (en) | 1998-12-23 | 2001-04-10 | Ortho-Mcneil Pharmaceuticals, Inc. | Triphasic oral contraceptive |
| US7989436B2 (en) | 2003-07-23 | 2011-08-02 | Duramed Pharmaceuticals, Inc. | Estrogenic compounds and pharmaceutical formulations comprising the same |
| US7459445B2 (en) * | 2000-03-10 | 2008-12-02 | Duramed Pharmaceuticals, Inc. | Estrogenic compounds and topical pharmaceutical formulations of the same |
| US6855703B1 (en) | 2000-03-10 | 2005-02-15 | Endeavor Pharmaceuticals | Pharmaceutical compositions of conjugated estrogens and methods of analyzing mixtures containing estrogenic compounds |
| US6660726B2 (en) | 2000-03-10 | 2003-12-09 | Endeavor Pharmaceuticals | Estrogenic compounds, pharmaceutical compositions thereof, and methods of using same |
| US20040176336A1 (en) * | 2000-03-21 | 2004-09-09 | Rodriguez Gustavo C. | Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium |
| US20050113351A1 (en) * | 2000-03-21 | 2005-05-26 | Rodriguez Gustavo C. | Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium |
| US20010044431A1 (en) * | 2000-03-21 | 2001-11-22 | Rodriguez Gustavo C. | Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium |
| US7297688B2 (en) | 2000-06-08 | 2007-11-20 | Wyeth | Starter kit for low dose oral contraceptives |
| JP2004140323A (en) * | 2002-08-20 | 2004-05-13 | Sharp Corp | Semiconductor laser and its manufacturing method |
| US6992075B2 (en) * | 2003-04-04 | 2006-01-31 | Barr Laboratories, Inc. | C(14) estrogenic compounds |
| US20040259851A1 (en) * | 2003-04-11 | 2004-12-23 | Leonard Thomas W. | Methods of administering estrogens and progestins |
| EA018356B1 (en) * | 2003-06-13 | 2013-07-30 | Джон Клод Савуар | Microspheres of estradiol and cholesterol |
| RU2006114791A (en) * | 2003-10-01 | 2007-11-27 | Янссен Фармацевтика Н.В. (Be) | EXTENDED MODES OF THREE-PHASE CONTRACEPTIVES |
| CA2540838C (en) | 2003-10-03 | 2014-12-16 | Thorn Bioscience, Llc | Process for the synchronization of ovulation for timed breeding without heat detection |
| EP1853272A1 (en) * | 2005-02-03 | 2007-11-14 | Duramed Pharmaceuticals, Inc. | Compositions of unconjugated estrogens and methods for their use |
| US20070197435A1 (en) * | 2006-02-17 | 2007-08-23 | Webel Stephen K | Process for the synchronization of ovulation for timed breeding without heat detection |
| ES2795455T3 (en) | 2008-10-08 | 2020-11-23 | Agile Therapeutics Inc | Transdermal delivery |
| US9192614B2 (en) | 2008-10-08 | 2015-11-24 | Agile Therapeutics, Inc. | Contraceptive transdermal delivery of hormones |
| EP2343963B1 (en) | 2008-10-08 | 2019-04-10 | Agile Therapeutics, Inc. | Transdermal delivery |
| WO2010111488A1 (en) | 2009-03-27 | 2010-09-30 | Agile Therapeutics, Inc. | Transdermal delivery |
| WO2010124220A1 (en) | 2009-04-23 | 2010-10-28 | Pennatek, Llc | Method and composition for synchronizing time of insemination |
| CN113398243A (en) | 2012-11-28 | 2021-09-17 | 联合动物健康第二有限责任公司 | Method for synchronizing insemination times of gilts |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL8001593A (en) * | 1980-03-18 | 1981-10-16 | Akzo Nv | MULTI-PHASIC COMBINATION PREPARATION FOR ORAL ANTI-CONCEPTION. |
| US4530839A (en) * | 1983-09-26 | 1985-07-23 | Ortho Pharmaceutical Corporation | Triphasic oral contraceptive |
| US4962098A (en) * | 1987-06-15 | 1990-10-09 | Warner-Lambert Company | Graduated estrogen contraceptive |
| DK174724B1 (en) * | 1986-07-15 | 2003-10-06 | Wyeth Corp | Use of a composition comprising an estrogen and a progestogen for the preparation of a dosage form to provide hormone replacement therapy and contraception for women during the premenopause and pack to provide the composition |
-
1991
- 1991-12-09 IE IE427291A patent/IE62665B1/en not_active IP Right Cessation
- 1991-12-11 ZA ZA919770A patent/ZA919770B/en unknown
- 1991-12-12 AT AT91203282T patent/ATE136219T1/en not_active IP Right Cessation
- 1991-12-12 DK DK91203282.8T patent/DK0491438T3/en active
- 1991-12-12 DE DE69118494T patent/DE69118494T2/en not_active Expired - Fee Related
- 1991-12-12 EP EP91203282A patent/EP0491438B1/en not_active Expired - Lifetime
- 1991-12-12 ES ES91203282T patent/ES2087965T3/en not_active Expired - Lifetime
- 1991-12-13 NZ NZ240970A patent/NZ240970A/en not_active IP Right Cessation
- 1991-12-13 AU AU89679/91A patent/AU645637B2/en not_active Ceased
- 1991-12-16 PT PT99819A patent/PT99819B/en not_active IP Right Cessation
- 1991-12-16 FI FI915914A patent/FI98985C/en not_active IP Right Cessation
- 1991-12-16 KR KR1019910023067A patent/KR100186780B1/en not_active IP Right Cessation
- 1991-12-16 NO NO914969A patent/NO179311C/en unknown
- 1991-12-16 CA CA002057747A patent/CA2057747C/en not_active Expired - Fee Related
- 1991-12-17 JP JP3333718A patent/JPH04290830A/en active Pending
- 1991-12-17 CN CN91107996A patent/CN1036833C/en not_active Expired - Fee Related
-
1994
- 1994-01-14 US US08/182,304 patent/US5418228A/en not_active Expired - Lifetime
-
1996
- 1996-06-07 GR GR960401543T patent/GR3020181T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE914272A1 (en) | 1992-06-17 |
| FI98985C (en) | 1997-09-25 |
| EP0491438A1 (en) | 1992-06-24 |
| FI915914A0 (en) | 1991-12-16 |
| NZ240970A (en) | 1994-05-26 |
| AU645637B2 (en) | 1994-01-20 |
| CA2057747A1 (en) | 1992-06-18 |
| ZA919770B (en) | 1992-09-30 |
| PT99819B (en) | 2001-05-31 |
| US5418228A (en) | 1995-05-23 |
| EP0491438B1 (en) | 1996-04-03 |
| GR3020181T3 (en) | 1996-09-30 |
| KR100186780B1 (en) | 1999-05-01 |
| CN1062464A (en) | 1992-07-08 |
| ATE136219T1 (en) | 1996-04-15 |
| FI915914A (en) | 1992-06-18 |
| JPH04290830A (en) | 1992-10-15 |
| DK0491438T3 (en) | 1996-07-08 |
| NO179311C (en) | 1996-09-18 |
| NO179311B (en) | 1996-06-10 |
| IE62665B1 (en) | 1995-02-22 |
| NO914969L (en) | 1992-06-18 |
| ES2087965T3 (en) | 1996-08-01 |
| AU8967991A (en) | 1992-06-18 |
| PT99819A (en) | 1992-12-31 |
| DE69118494D1 (en) | 1996-05-09 |
| DE69118494T2 (en) | 1996-08-22 |
| KR920011515A (en) | 1992-07-24 |
| CN1036833C (en) | 1997-12-31 |
| NO914969D0 (en) | 1991-12-16 |
| FI98985B (en) | 1997-06-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2057747C (en) | Contraceptive regimen | |
| US5262408A (en) | Low estrogen oral contraceptives | |
| RU2189819C2 (en) | Schemes for progestogen - antiprogestogen intake | |
| US5461041A (en) | Progestogen-only contraceptive | |
| US6506390B2 (en) | Progestogen-anti-progestogen regimens | |
| EP1747001A2 (en) | Management of breakthrough bleeding in extended hormonal contraceptive regimens | |
| EP1735056B1 (en) | Extended cycle multiphasic oral contraceptive method | |
| WO1994004156A1 (en) | Antiprogestogen containing contraceptives | |
| WO1999051214A2 (en) | Progestogen-only contraceptive kit | |
| WO2000009136A1 (en) | Progestogen-only contraceptive kit providing good cycle control | |
| AU2011226911B2 (en) | Management of breakthrough bleeding in extended hormonal contraceptive regimens | |
| Vikhliaeva | Current trends in the development of hormonal contraception |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |