CA2171460C - Preparation for substitution therapy, containing at least one progestogen and at least one extrogen - Google Patents
Preparation for substitution therapy, containing at least one progestogen and at least one extrogen Download PDFInfo
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- CA2171460C CA2171460C CA002171460A CA2171460A CA2171460C CA 2171460 C CA2171460 C CA 2171460C CA 002171460 A CA002171460 A CA 002171460A CA 2171460 A CA2171460 A CA 2171460A CA 2171460 C CA2171460 C CA 2171460C
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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
- A61K31/57—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
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to a preparation for substitution therapy and oral contraception comprising at least one progestogen and at least one estrogen in which the estrogen dose varies with a periodicity such that blood loss is substantially avoided, wherein the periodicity is preferably less than 10 days, more preferably less than 7 days, such as preparations containing the progestogen and/or estrogen in an oral, transdermal, parenteral and/or implantable application form.
Description
PREPARATION FOR SUBSTITUTION THERAPY, CONTAINING AT LEAST ONE PROGESTOGEN
AND AT LEAST ONE ESTROGEN.
The present invention relates to a preparation for substitution therapy and for oral contraception. More particularly the present invention on the one hand relates to relieving the effects which occur because the ovaries decrease or stop production of female hormones, for instance during the menopause. The substitution therapy is mainly intended to induce amenorrhoea with negligible blood loss.
During and after the menopause these effects comprise hot flushes and nocturnal sweating, atrophy of the vagina which can result in sexual difficulties, bone decalcification, increase in heart and blood vessel disorders and psychic symptoms with a causal connection that is usually difficult to demonstrate.
Up to the present different types of substitution therapy have been applied comprising a hormone treatment with one or more oestrogens and one or more progestogens.
According to a first therapy, low doses of oestrogens and progestogens are administered, but such a treatment is ineffective in respect of the decalcification and heart and blood vessel disorders.
In another therapy the natural cycle of oestrogen and progestogen is followed as closely as possible. This treatment inevitably results in menstruation and has the advantage of a reduced risk of cancer of the uterus.
According to yet another therapy only oestrogens are administered in a dose which lies below the threshold for menstrual bleeding. This treatment has the drawback however of an increased risk of cancer of the uterus.
According to a most recently known therapy oestrogens and progestogens are administered continuousl_ such that the endometrium does not proliferate. This therapy has the drawback however of an unacceptably high incidence of slight, irregular blood loss.
CONFIRMATION COPY
WO 95/07081 ~~1 ~~ 460 PCT/EP94/02997 = 2 0 The present invention has for its object to provide a = substitution therapy wherein the above described drawbacks occur to a much lesser extent, with the objective of inducing amenorrhoea with negligible blood loss over a long period (many months to years).
On the other hand, the present invention relates to = preparations designed for oral contraception with substantially continuous application.
In continuous application of oral contraceptive frequently intermediate bleedings occur. The preparations according to the present invention are designed to induce menstrual bleeding with a regular menstrual bleeding, with an extended cycle or eventually a constant amenorrhoea, but characterized by an optimal (cycle) control and/or by a substantially reduced ocurrence of intermediate bleeding.
EP-A-559 240 discloses preparations for substitution therapy and oral contraception in which the estrogen dose is constant and the progestagen dose is periodically alternated.
However, the improvement in inhibiting endometrium bleeding is minor. Above that, since the use of higher progestagen doses provided better results than lower doses it appears illogical to use periodically varying estrogen doses.
The present invention is based on the finding that suprisingly when using periodically varying estrogen doses the occurence of blood loss and intermediate bleeding is substantially avoided. The estrogen dose is herein oscillated such that estrogen-dominant and progestogen-dominant periods occur alternatingly with a sufficiently short periodicity.
This short periodicity in the estrogen dose is necessary to avoid blood loss.
Purely by administering a dose of progestogen or estrogen substantially constant in time and an estrogen or progestogen varying in time between at least two dose levels, it was possible to induce the desired amenorrhoea while no blood loss occurred over a longer period.
The invention therefore relates to a preparation for substitution therapy and for oral contraception comprising at least one progestogen and at least one estrogen in which the estrogen dose varies with a periodicity such that blood loss is substantially avoided.
According to one aspect of the present invention, there is provided preparation for substitution therapy and for oral contraception comprising at least one progestogen and at least one estrogen in which the dose of the at least one progestogen is substantially constant and the dose of the at least one estrogen varies with a periodicity such that estrogen-dominant and progestogen dominant periods alternate and blood loss is substantially avoided.
3a It is noted that the preparation is formulated such that a substantially constant blood concentration is obtained for progestogen or estrogen, while the estrogen concentration in the blood varies between two blood concentrations. The periodicity must be sufficiently short and is generally less than 10 days. The periodicity is usually less than 7 days. The periodicity generally lies between 2-9 days, preferably between 2-6 days. It will however be apparent that the periodicity is dependent on the estrogens and progestogens used and the applied doses. Both the periodicity and concentrations of estrogen and progestogen are easy to determine by routine experimentation.
According to an embodiment of the invention the preparation contains a constant progestogen dose, while the estrogen dose oscillates between two levels. This preparation is recommended because there is a greater certainty of avoiding blood loss over a longer period.
According to another embodiment the preparation contains oscillating doses of progestogen and estrogen, in varying ratios however such that blood loss is avoided and amenorrhoea is induced.
Use can be made in general of all known progestogens, such as progesterone 300-900 mg/day norethisterone acetate 2-5 mg/day medroxyprogesterone acetate 1-5 mg/day d-norgestrel 30-150 pgr/day desogestrel 30-150 pgr/day norgestimate 30-150 pgr/day cyproterone acetate 0.2-2 mg/day, gestodene 10-150 pg/day 3-ketodesogestrel 10-150 pg/day drospirenon 0.2-3.0 mg/day or combinations thereof. It is noted that the preparation can contain one or more progestogens and estrogens.
It will be apparent that the quantity of progestogen and estrogen depends on the person (constitution and age), = WO 95/07081 Z 1i 7~~~ O PCT/EP94/02997 4 ~
= the progestogen(s) and estrogen(s), anti-progestogen and anti-estrogen for use and the form of administering same.
The progestogen and estrogen can each be present in an = oral, transdermal, parenteral or implantable application form for substitution therapy. Th& preparation can for instance comprise an application form which contains the progestogen and estrogen, and a second like application form which contains the progestogen and an increased dose of estrogen.
The progestogen and estrogen can of course be present in like but separate forms of application or in mutually differing forms of application. The progestogen can for instance be an implantable application form while the oestrogen is administered orally, transdermally or parenterally in a dose which takes account of the required time period according to the invention.
The oral application form to be used comprises tablets, capsules, syrup, solutions. The transdermal forms of application comprise gels, plasters. Strips can for instance be used wherein tablets with progestogen and oestrogen in the desired ratio and periodicity are arranged in time sequence.
The parenteral application form comprises injection fluid and the like. The implantable application form comprises for example a known implantable sustained release preparation.
The preparations for oral contraceptive comprise estrogens and progestogens in common form.
Preparations according to the invention were administered over a period of 3-12 months to 40 women in the menopause. By making use of the combination preparations according to the invention a constant amenorrhoea could be obtained in the case of more than 90% of the women, wherein the clinical tolerance was perceived as optimal, wherein the woman did not discern any subjective difference between a fixed or changing oestrogen dose with a periodicity of about one week.
Using the preparations according to the invention as oral contraceptive intermediate bleeding will be substantially reduced.
~ 5 Example 1 A preparation according to the invention comprised tablets of the type A which contained 10 gamma aethinyl-estradiol, 1 mg estradiol valerianate and 0.5 mg norethisterone, and tablets of the type B which contained gamma instead of 10 gamma aethinyl-estradiol. By alternatingly administering the tablets A and B over a time period of 7 days an amenorrhoea could be induced without blood loss for a very long period of time.
10 Example 2 A preparation according to the invention contained 1 mg norethisterone or 0.5 mg cyproterone acetate and 2 mg estradiol valerianate. The preparation moreover contained tablets of the type B having 3 mg instead of 2 mg estradiol 15 valerianate. By using the preparation with alternate administering (4-5 days) of the tablets A and B or B and A an amenorrhoea could be induced without blood loss for a longer period of time.
Example 3 A preparation according to the invention comprised tablets of the type A which contained 15 gamma aethinyl-estradiol and 1 mg oestradiol valerianate and 1 mg norethisterone. The preparation moreover contained tablets of the type B having 1.5 mg instead of 1 mg norethisterone. By alternatingly administering the tablets A and B with a periodicity of 4-7 days an amenorrhoea could be induced without blood loss for a very long period of time.
Example 4 A preparation according to the invention for oral contraceptive with optimal cycle control comprises tablets of type A comprising 20 pg aethinyl-estradiol and 75 pg gestoden. The preparation contained tablets of type B
comprising 30 pg instead of 20 pg aethinyl-estradiol. Tablets A and B are used in four alternating periods of six days.
Example 5 A preparation according to the invention for oral contraceptive with optimal cycle control comprises tablets of type A comprising 15 pg aethinyl-estradiol and 75 pg gestoden, and tablets of type B comprising 25 pg instead of 15 pg aethinyl-estradiol. Tablets A and B are used in six alternating periods of four days.
In example 4 and 5 only aethinyl-estradiol is used in order to use a estrogen dose which is as low as possible.
However, higher estrogen doses may be used. Instead of using a constant progestogen dose fluctuating doses may be use fluctuating simultaneously and/or progressively in view of the varying estrogen dose.
Example 6 A preparation for oral contraceptive according to the invention comprises tablets of type A comprising 20 pg aethinyl-estradiol and 75 pg gestoden, and tablets of type B
comprising 30 pg aethinyl-estradiol and 75 pg gestoden and 50 pg onapristone. The tablets A and B are used in four alternating periods of each six days. After four periods the whole cycle is repeated without allowing a free period.
Example 7 A preparation according to the invention for hormone substitution treatment comprises tablets of type A comprising 2 pg estradiol valerianate and 50 pg gestoden. The tablets of type B comprised 3 pg estradiol valerianate and 25-100 pg onapristone. By alternatingly admininstering the tablets A
and B over a time period of seven days amennorrhoea could be induced without blood loss for a very long period of time.
It is obvious for a skilled person in the examples in association with intermittently given antiprogestogen or anti-estrogen can be alternated alone or simultaneous with estrogens and/or progestagens. For instance, the antiprogestagen is added in a constant dose to the actual and the above mentioned combinations of estrogens and ~ 7 progestagens in products for hormone replacement therapy and for contraception.
*****
a
AND AT LEAST ONE ESTROGEN.
The present invention relates to a preparation for substitution therapy and for oral contraception. More particularly the present invention on the one hand relates to relieving the effects which occur because the ovaries decrease or stop production of female hormones, for instance during the menopause. The substitution therapy is mainly intended to induce amenorrhoea with negligible blood loss.
During and after the menopause these effects comprise hot flushes and nocturnal sweating, atrophy of the vagina which can result in sexual difficulties, bone decalcification, increase in heart and blood vessel disorders and psychic symptoms with a causal connection that is usually difficult to demonstrate.
Up to the present different types of substitution therapy have been applied comprising a hormone treatment with one or more oestrogens and one or more progestogens.
According to a first therapy, low doses of oestrogens and progestogens are administered, but such a treatment is ineffective in respect of the decalcification and heart and blood vessel disorders.
In another therapy the natural cycle of oestrogen and progestogen is followed as closely as possible. This treatment inevitably results in menstruation and has the advantage of a reduced risk of cancer of the uterus.
According to yet another therapy only oestrogens are administered in a dose which lies below the threshold for menstrual bleeding. This treatment has the drawback however of an increased risk of cancer of the uterus.
According to a most recently known therapy oestrogens and progestogens are administered continuousl_ such that the endometrium does not proliferate. This therapy has the drawback however of an unacceptably high incidence of slight, irregular blood loss.
CONFIRMATION COPY
WO 95/07081 ~~1 ~~ 460 PCT/EP94/02997 = 2 0 The present invention has for its object to provide a = substitution therapy wherein the above described drawbacks occur to a much lesser extent, with the objective of inducing amenorrhoea with negligible blood loss over a long period (many months to years).
On the other hand, the present invention relates to = preparations designed for oral contraception with substantially continuous application.
In continuous application of oral contraceptive frequently intermediate bleedings occur. The preparations according to the present invention are designed to induce menstrual bleeding with a regular menstrual bleeding, with an extended cycle or eventually a constant amenorrhoea, but characterized by an optimal (cycle) control and/or by a substantially reduced ocurrence of intermediate bleeding.
EP-A-559 240 discloses preparations for substitution therapy and oral contraception in which the estrogen dose is constant and the progestagen dose is periodically alternated.
However, the improvement in inhibiting endometrium bleeding is minor. Above that, since the use of higher progestagen doses provided better results than lower doses it appears illogical to use periodically varying estrogen doses.
The present invention is based on the finding that suprisingly when using periodically varying estrogen doses the occurence of blood loss and intermediate bleeding is substantially avoided. The estrogen dose is herein oscillated such that estrogen-dominant and progestogen-dominant periods occur alternatingly with a sufficiently short periodicity.
This short periodicity in the estrogen dose is necessary to avoid blood loss.
Purely by administering a dose of progestogen or estrogen substantially constant in time and an estrogen or progestogen varying in time between at least two dose levels, it was possible to induce the desired amenorrhoea while no blood loss occurred over a longer period.
The invention therefore relates to a preparation for substitution therapy and for oral contraception comprising at least one progestogen and at least one estrogen in which the estrogen dose varies with a periodicity such that blood loss is substantially avoided.
According to one aspect of the present invention, there is provided preparation for substitution therapy and for oral contraception comprising at least one progestogen and at least one estrogen in which the dose of the at least one progestogen is substantially constant and the dose of the at least one estrogen varies with a periodicity such that estrogen-dominant and progestogen dominant periods alternate and blood loss is substantially avoided.
3a It is noted that the preparation is formulated such that a substantially constant blood concentration is obtained for progestogen or estrogen, while the estrogen concentration in the blood varies between two blood concentrations. The periodicity must be sufficiently short and is generally less than 10 days. The periodicity is usually less than 7 days. The periodicity generally lies between 2-9 days, preferably between 2-6 days. It will however be apparent that the periodicity is dependent on the estrogens and progestogens used and the applied doses. Both the periodicity and concentrations of estrogen and progestogen are easy to determine by routine experimentation.
According to an embodiment of the invention the preparation contains a constant progestogen dose, while the estrogen dose oscillates between two levels. This preparation is recommended because there is a greater certainty of avoiding blood loss over a longer period.
According to another embodiment the preparation contains oscillating doses of progestogen and estrogen, in varying ratios however such that blood loss is avoided and amenorrhoea is induced.
Use can be made in general of all known progestogens, such as progesterone 300-900 mg/day norethisterone acetate 2-5 mg/day medroxyprogesterone acetate 1-5 mg/day d-norgestrel 30-150 pgr/day desogestrel 30-150 pgr/day norgestimate 30-150 pgr/day cyproterone acetate 0.2-2 mg/day, gestodene 10-150 pg/day 3-ketodesogestrel 10-150 pg/day drospirenon 0.2-3.0 mg/day or combinations thereof. It is noted that the preparation can contain one or more progestogens and estrogens.
It will be apparent that the quantity of progestogen and estrogen depends on the person (constitution and age), = WO 95/07081 Z 1i 7~~~ O PCT/EP94/02997 4 ~
= the progestogen(s) and estrogen(s), anti-progestogen and anti-estrogen for use and the form of administering same.
The progestogen and estrogen can each be present in an = oral, transdermal, parenteral or implantable application form for substitution therapy. Th& preparation can for instance comprise an application form which contains the progestogen and estrogen, and a second like application form which contains the progestogen and an increased dose of estrogen.
The progestogen and estrogen can of course be present in like but separate forms of application or in mutually differing forms of application. The progestogen can for instance be an implantable application form while the oestrogen is administered orally, transdermally or parenterally in a dose which takes account of the required time period according to the invention.
The oral application form to be used comprises tablets, capsules, syrup, solutions. The transdermal forms of application comprise gels, plasters. Strips can for instance be used wherein tablets with progestogen and oestrogen in the desired ratio and periodicity are arranged in time sequence.
The parenteral application form comprises injection fluid and the like. The implantable application form comprises for example a known implantable sustained release preparation.
The preparations for oral contraceptive comprise estrogens and progestogens in common form.
Preparations according to the invention were administered over a period of 3-12 months to 40 women in the menopause. By making use of the combination preparations according to the invention a constant amenorrhoea could be obtained in the case of more than 90% of the women, wherein the clinical tolerance was perceived as optimal, wherein the woman did not discern any subjective difference between a fixed or changing oestrogen dose with a periodicity of about one week.
Using the preparations according to the invention as oral contraceptive intermediate bleeding will be substantially reduced.
~ 5 Example 1 A preparation according to the invention comprised tablets of the type A which contained 10 gamma aethinyl-estradiol, 1 mg estradiol valerianate and 0.5 mg norethisterone, and tablets of the type B which contained gamma instead of 10 gamma aethinyl-estradiol. By alternatingly administering the tablets A and B over a time period of 7 days an amenorrhoea could be induced without blood loss for a very long period of time.
10 Example 2 A preparation according to the invention contained 1 mg norethisterone or 0.5 mg cyproterone acetate and 2 mg estradiol valerianate. The preparation moreover contained tablets of the type B having 3 mg instead of 2 mg estradiol 15 valerianate. By using the preparation with alternate administering (4-5 days) of the tablets A and B or B and A an amenorrhoea could be induced without blood loss for a longer period of time.
Example 3 A preparation according to the invention comprised tablets of the type A which contained 15 gamma aethinyl-estradiol and 1 mg oestradiol valerianate and 1 mg norethisterone. The preparation moreover contained tablets of the type B having 1.5 mg instead of 1 mg norethisterone. By alternatingly administering the tablets A and B with a periodicity of 4-7 days an amenorrhoea could be induced without blood loss for a very long period of time.
Example 4 A preparation according to the invention for oral contraceptive with optimal cycle control comprises tablets of type A comprising 20 pg aethinyl-estradiol and 75 pg gestoden. The preparation contained tablets of type B
comprising 30 pg instead of 20 pg aethinyl-estradiol. Tablets A and B are used in four alternating periods of six days.
Example 5 A preparation according to the invention for oral contraceptive with optimal cycle control comprises tablets of type A comprising 15 pg aethinyl-estradiol and 75 pg gestoden, and tablets of type B comprising 25 pg instead of 15 pg aethinyl-estradiol. Tablets A and B are used in six alternating periods of four days.
In example 4 and 5 only aethinyl-estradiol is used in order to use a estrogen dose which is as low as possible.
However, higher estrogen doses may be used. Instead of using a constant progestogen dose fluctuating doses may be use fluctuating simultaneously and/or progressively in view of the varying estrogen dose.
Example 6 A preparation for oral contraceptive according to the invention comprises tablets of type A comprising 20 pg aethinyl-estradiol and 75 pg gestoden, and tablets of type B
comprising 30 pg aethinyl-estradiol and 75 pg gestoden and 50 pg onapristone. The tablets A and B are used in four alternating periods of each six days. After four periods the whole cycle is repeated without allowing a free period.
Example 7 A preparation according to the invention for hormone substitution treatment comprises tablets of type A comprising 2 pg estradiol valerianate and 50 pg gestoden. The tablets of type B comprised 3 pg estradiol valerianate and 25-100 pg onapristone. By alternatingly admininstering the tablets A
and B over a time period of seven days amennorrhoea could be induced without blood loss for a very long period of time.
It is obvious for a skilled person in the examples in association with intermittently given antiprogestogen or anti-estrogen can be alternated alone or simultaneous with estrogens and/or progestagens. For instance, the antiprogestagen is added in a constant dose to the actual and the above mentioned combinations of estrogens and ~ 7 progestagens in products for hormone replacement therapy and for contraception.
*****
a
Claims (10)
1. Preparation for substitution therapy and for oral contraception comprising at least one progestogen and at least one estrogen in which the dose of the at least one progestogen is substantially constant and the dose of the at least one estrogen varies with a periodicity such that estrogen-dominant and progestogen dominant periods alternate and blood loss is substantially avoided.
2. Preparation as claimed in claim 1, wherein the periodicity is less than 10 days.
3. Preparation as claimed in claim 1, wherein the periodicity is less than 7 days.
4. Preparation as claimed in claim 1, wherein the periodicity amounts to 2 to 9 days.
5. Preparation as claimed in claim 1, wherein the periodicity amounts to 2 to 6 days.
6. Preparation as claimed in any one of claims 1 to 5, wherein the at least one progestogen comprises progesterone 300-900 mg/day norethisterone acetate 0,2-5 mg/day medroxyprogesterone acetate 1-5 mg/day d-norgestrel 30-150 µgr/day desogestrel 30-150 µgr/day norgestimate 30-150 µgr/day cyproterone acetate 0,2-2 mg/day gestodene 10-150 µg/day 3-ketodesogestrel 10-150 µg/day drospirenon 0,2-3,0 mg/day or combinations thereof.
7. Preparation as claimed in any one of claims 1 to 6, wherein the at least one estrogen comprises aethinylestradiol 5-15 gamma/day oestradiol valerianate 1-4 mg/day oestradiol 1-2 mg/day conjugated estrogen 0,3-1,25 mg/day oestriol 1-4 mg/day or combinations thereof.
8. Preparation as claimed in any one of claims 1 to 7, comprising anti-progestogen.
9. Preparation as claimed in any one of claims 1 to 8, comprising anti-estrogen.
10. Preparation as claimed in any one of claims 1 to 9, wherein one or both of the at least one progestogen and the at least one estrogen are independently in an oral, transdermal, parenteral or implantable application form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL9301562 | 1993-09-09 | ||
| NL9301562A NL9301562A (en) | 1993-09-09 | 1993-09-09 | Substitution therapy preparation. |
| PCT/EP1994/002997 WO1995007081A1 (en) | 1993-09-09 | 1994-09-08 | Preparation for substitution therapy, containing at least one progestogen and at least one extrogen |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2171460A1 CA2171460A1 (en) | 1995-03-16 |
| CA2171460C true CA2171460C (en) | 2007-05-22 |
Family
ID=38152429
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002171460A Expired - Fee Related CA2171460C (en) | 1993-09-09 | 1994-09-08 | Preparation for substitution therapy, containing at least one progestogen and at least one extrogen |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2171460C (en) |
-
1994
- 1994-09-08 CA CA002171460A patent/CA2171460C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2171460A1 (en) | 1995-03-16 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20130910 |