CA1090256A - Medicament pack and agent for the treatment of climacteric deficiency symptoms - Google Patents
Medicament pack and agent for the treatment of climacteric deficiency symptomsInfo
- Publication number
- CA1090256A CA1090256A CA288,196A CA288196A CA1090256A CA 1090256 A CA1090256 A CA 1090256A CA 288196 A CA288196 A CA 288196A CA 1090256 A CA1090256 A CA 1090256A
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- oestrogen
- pack
- daily
- dosage
- daily dosages
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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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A medicament pack and agent for the treatment of climacteric deficiency symptoms. The pack comprises a pharmaceutical treatment pack for the treatment of climacteric deficiency symptoms, which comprises in or on a support member, unit dosage forms of an E2 oestrogen, an E3 oestrogen and a gestagen, which provided (I) (a) a first set of 10 - 12 daily dosages of an E2 oestrogen and (b) a first set of 10 - 12 daily of an E3 oestrogen, the ratio of the daily average dosage of E2 oestrogen to the average daily dosage of E3 oestrogen being from 2:1 to 1:8, (II)(a) a second set of 9 - 11 daily dosages of E2 oestrogen, to complete 20 - 22 daily dosages, and (b) a second set of 9 - 11 daily dosages of E3 oestrogen, to complete 20 - 22 daily dosages, the ratio of the average daily dosage of E2 oestrogen to the average daily dosage of E3 oestrogen being from 2:1 to 1:8, and (c) a set of 9 - 11 daily dosages of a gestagen, and if desired, (III) a third set of 6 - 8 daily dosages of E3 oestrogen or of hormone-free preparations, to complete 28 daily dosages, or of objects indicating 6 - 8 days of no hormone treatment, the sets being located in a particular order, together with indications and/or instructions to indicate and facilitate a treatment consisting of the administration to a human female on each of 10 - 12 successive days of one of the daily dosages Ia and one of the daily dosages Ib, on each of the immediately following 9 - 11 successive days, to complete 20 - 22 days, one of daily dosages IIa, one of the daily dosages IIb and one of the daily dosages IIc, and on each of the immediately following 6 - 8 successive days, to complete 28 days, one of the E3 oestrogen or hormone-free daily dosages III or no administration of hormone.
A medicament pack and agent for the treatment of climacteric deficiency symptoms. The pack comprises a pharmaceutical treatment pack for the treatment of climacteric deficiency symptoms, which comprises in or on a support member, unit dosage forms of an E2 oestrogen, an E3 oestrogen and a gestagen, which provided (I) (a) a first set of 10 - 12 daily dosages of an E2 oestrogen and (b) a first set of 10 - 12 daily of an E3 oestrogen, the ratio of the daily average dosage of E2 oestrogen to the average daily dosage of E3 oestrogen being from 2:1 to 1:8, (II)(a) a second set of 9 - 11 daily dosages of E2 oestrogen, to complete 20 - 22 daily dosages, and (b) a second set of 9 - 11 daily dosages of E3 oestrogen, to complete 20 - 22 daily dosages, the ratio of the average daily dosage of E2 oestrogen to the average daily dosage of E3 oestrogen being from 2:1 to 1:8, and (c) a set of 9 - 11 daily dosages of a gestagen, and if desired, (III) a third set of 6 - 8 daily dosages of E3 oestrogen or of hormone-free preparations, to complete 28 daily dosages, or of objects indicating 6 - 8 days of no hormone treatment, the sets being located in a particular order, together with indications and/or instructions to indicate and facilitate a treatment consisting of the administration to a human female on each of 10 - 12 successive days of one of the daily dosages Ia and one of the daily dosages Ib, on each of the immediately following 9 - 11 successive days, to complete 20 - 22 days, one of daily dosages IIa, one of the daily dosages IIb and one of the daily dosages IIc, and on each of the immediately following 6 - 8 successive days, to complete 28 days, one of the E3 oestrogen or hormone-free daily dosages III or no administration of hormone.
Description
1~ 56 This invention relates to the treatment of climacteric deficiency symptoms.
It is already known to treat climacteric complaints with various types of oestrogens. Thus, for example, the daily administration of oestradiol valerate for 21 days followed by a 7-day hormone-free phase eliminates the typical climacteric com-plaints such as hot flushes, outbreaks of sweating, insomnia, cardiovascular disturbances and dizziness.
Oestradiol valerate can also overcome pyschological changes that are ~anifeste~ by mental unbalance. However, a dis-advantage of oestradiol valerate is -that, during treatment, relatively severe proliferation of the endometrium results, which in turn leads to undesired uterine bleeding. The result of the strong action on the upper genital tract is that oestra-; diol valerate has a liminted indication.
In addition, the treatment of climacteric disorderswith oestriol is known. Oestriol has a favourable effect on the lower genital tract (Cervix uteri, vagina and vulva) but it has the disadvantage that the typical hormone deficiency symptoms and psychologlcal changes are not overcome satisfactorily.
The ef~ects on the deficiency symptoms can be increased and the effect on the uterus can be largely eliminated by a suit-able combination of natural oestrogens. Since a considerable synergistic action in the desired direction, and simultaneously, an antagonistic effect in an undesired direction occur, the fact that the oestrogens can be used in a relatively low dosage is a further advantage.
Suitable natural oestrogens having a strong effect on the deficiency symptoms and the upper genital tract are oestra-diol and its derivatives. These are known as E2 oestrogens. Theterm `'derivatives" indicates compounds that are formed by the esterification or etherification of oestradiol. Esters of
It is already known to treat climacteric complaints with various types of oestrogens. Thus, for example, the daily administration of oestradiol valerate for 21 days followed by a 7-day hormone-free phase eliminates the typical climacteric com-plaints such as hot flushes, outbreaks of sweating, insomnia, cardiovascular disturbances and dizziness.
Oestradiol valerate can also overcome pyschological changes that are ~anifeste~ by mental unbalance. However, a dis-advantage of oestradiol valerate is -that, during treatment, relatively severe proliferation of the endometrium results, which in turn leads to undesired uterine bleeding. The result of the strong action on the upper genital tract is that oestra-; diol valerate has a liminted indication.
In addition, the treatment of climacteric disorderswith oestriol is known. Oestriol has a favourable effect on the lower genital tract (Cervix uteri, vagina and vulva) but it has the disadvantage that the typical hormone deficiency symptoms and psychologlcal changes are not overcome satisfactorily.
The ef~ects on the deficiency symptoms can be increased and the effect on the uterus can be largely eliminated by a suit-able combination of natural oestrogens. Since a considerable synergistic action in the desired direction, and simultaneously, an antagonistic effect in an undesired direction occur, the fact that the oestrogens can be used in a relatively low dosage is a further advantage.
Suitable natural oestrogens having a strong effect on the deficiency symptoms and the upper genital tract are oestra-diol and its derivatives. These are known as E2 oestrogens. Theterm `'derivatives" indicates compounds that are formed by the esterification or etherification of oestradiol. Esters of
- 2 - `~
5:~2~
oestradiol, for example oestradiol valerate, are preferred.
Suitable natural oestrogens with a negligible effect on deficiency symptoms and a strong effect on the lower genital tract are oestriol and its derivatives. These are ]cnown as E3 oestrogens. The term "derivatives" is used here to include, in particular, ethers and esters of oestriol. Oestriol and oestriol succinate, for example, are very suitableO
Reliable action is achieved if a combination of a natural oestrogen of type 1 (an E2 oestrogen, that is oestradiol or a derivative of oestradiol) and a natural oestrogen of type 2 (an E3 oestrogen, that is oestriol or a derivative of oestriol) is administered in the ratio of approximately 2:1 to 1:8 for 21 days and then only a natural oestrogen of type 2 (E3) or no hormones for 7 days. Adjustment to the normal female cycle is achieved with dosage over a period of 28 days.
A disadvantage of pure oestrogen therapy is the danger of an unphysiological proliferation of the endometrium and mammary tissue. We have now found that the residual action of oestrogens on the uterus and mammae can be rendered harmless by the addi-tional administration of a gestagen in the second half of thecycle for ~-11 days. The addition of gestagen brings about a transformation of theendometrium and cyclic bleeding.
The present in~ention thus provides a pharmaceutical treatment agent or composition for use in the treatment of climacteric deficiency symptoms, which comprises an E2 oestrogen and an E3 oestrogen in a ratio of from 2:1 to 1:8, and a gestagen.
The agent may be made up in the form of a pharmaceuti-cal preparation, which comprises the three components in admix-ture or conjunction with a pharmaceutically suitable carrier.
The preparation is suitably in dosage unit form.
The present invention further provides a pack which comprises an E2 oestrogen, an E3 oestrogen and a gestagen made s~;
up in discreet parts to provide (i) 10-12 daily dosages of an E2 oestrogen and an E3 oestrogen in a ratio of from 2:1 to 1:8, these daily dosages being free of gestagen, (ii) 9-11 daily dosages, to make up 20-22 daily dosages, of E2 oestrogen and E3 oestrogen in a ratio of from 2:1 to 1:8, and of gestagen, and, if desired, (iii) up to 8, especially 6-8 daily dosages up to a maximum of 28 daily dosages, of an E3 oestrogen free of E~
oestrogen and free of gestagen or of placebo.
If desired, ihere maybe an exact multiple of these daily dosages in the pack.
Suitably the components (i), (ii) and (iii) are in the form of pharmaceutical preparations comprising the active ingred-ient(s) in admixture or conjunction with a pharmaceutically suit-able carrier.
The pack may be made up in three discreet parts as follows: the E2 oestrogen, the E3 oestrogen and the gestagen;
or the 10-12 daily dosages (i), the 9-11 daily dosages (ii) and if desired, the remaining daily dosayes (iii). Also, for example the E2 and E3 oestrogens could be made up in one part, the gesta-gen in another part, and-the E3 oestrogen free of E2 oestrogen and gestagen in another part.
The present invention also provides a pharmaceutical treatment pack for the treatment of climacteric deficiency symptoms, which comprises in or on a container, card or other support member, unit dosage forms of an E2 oestrogen, an E3 oestrogen and a gestagen, which provide (I) (a) a first set of 10-12 daily dosages of an E2 oestrogen and (b) a first set of 10-12 daily dosages of an E3 oestrogen, -- 4 ~
Z5~
the ratio of the average daily dosage of E2 oestroyen to the average daily dosage of E3 oestro~en being from 2:1 to 1:8, (II) (a) a second set of 9-11 daily dosages of E2 oestrogen, to complete 20-22 daily dosages, and (b) a second set of 9-11 daily dosages of E3 oestrogen, to complete 20-22 daily dosages, the ratio of the average daily dosage of E2 oestrogen to the average daily dosage of E3 oestrogen being from 2:1 to 1:8, and (c) a set of 9~11 daily dosages of a gesta~en, and if, desired, (III) a third set of 6-8 daily dosages of E3 oestrogen or of hormone-free preparations or objects indicating no hormone treatment, to complete 28 daily dosages, the sets being located in a particular order, together with indications and/or instructions to indicate and facilitate a treatment consisting of the administration to a human female on ; each of 10-12 successive days of one of the daily dosages Ia and one of the daily dosages Ib, on each of the immediately following 9-11 successive days, to complete 20-22 days, one of the daily dosages IIa, one of the daily dosages IIb and one of the daily dosages IIc, and on each of the immediately following 6-8 success;ve days to complete 28 days, one of the E3 oestrogen or placebo daily dosages III or no administration of hormone.
The total number of days in the first, second and third stages should always be 28. If desired, there may be additional sets of dosage units in the pack so that the 28-day rhythm can be repeated. The administration of E2 oestrogen and gestagen are terminated on the same day.
The third set may be free from intake, or placebos, E3 oestrogen and/or other active substances may be administered 5~
during the 6-8 day perioa.
~ en no dosage unit is to be administered, the pack may contain objects indicating no hormone treatment. Each object may take the form of a gap, space, mark(s), relief or packing on or in the card or tube or other support member. It may be, for example, a representation of a dosage unit preparation or of a receptacle therefor, for example an empty profiled receptacle.
Each object is preferably removablel destructable or otherwise alterable, so that a check on the treatment may be kept easily.
For example, it may be an empty destructable profiled receptacle.
However, in order to avoid inadvertent omission of medication, the pack may contain E3 oestrogen preparations or placebos.
Indication of the method by which treatment is to be carried out may comprise the arrangement in the pack of the sets of preparations and, if present, objects indicating no hormone treatment. The appearance of the preparations may also provide guidance for the treatment; for example, the different prepara-tions may be of different colours. Two or more preparations may be taken per day, but generally one per day is taken. Thus, each daily dosage Ia and Ib is combined in a-single unit dosage form and each daily dosage IIa, IIb and IIc is combined in a single unit dosage form. Thus the pack may contain 28 dosage units pre-ferably for oral administration in a co-ordinated, fixed sequence, the sequence corresponding to the stages of the daily administra-tion. The pack may, among other things, be in the form of a transparent pack with for example 11 dosage units for the first stage, 10 dosage units for the second stage and 7 dosage units for the third stage, from which 1 dosage unit daily may be taken for 28 days. Generally, written or printed instructions are also given.
Suitably, the dosage of the oestrogens corresponds to ~ 3~ 5~
the usual dosage known in oestrogen therapyO
Suitable E2 oestrogens are, especially oestradiol and esters of oestradiol, e.g. oestradiol valerate and oestradiol benzoate. Preferably the quantity of E2 oestrogen used is such that it produces the same oestrogenic activity as the administration of 0.5 to 4 mg of oestradiol valerate daily. The E2 daily dosages can,of course,vary from day to day within a stage and from stage to stage, although they are preferably substantially uniform.
Especially suitable E3 oestrogens are oestriol and esters of oestriol, e.g. oestriol succinate. Preferably the quantity of E3 oestrogen used is such that it produces the same oestrogenic activity as the administration of 0.5 to 8 mg of oestriol daily. The E3 daily dosages can, of course vary from day to day within a stage and from stage to stage. Preferably the E3 daily dosage in stages I and II is substantially uniform.
The daily dosage in stage III is preferably substantially uniform and may be the same as or different from the daily dosage in the other stages, for example the daily dosage in stage III may be half the daily dosage in each of the other two stages.
The ratio of E2 to E3 administered can vary from day to day and from stage to stage, although it is also preferably substantially uniform. Usually the ratio of E2 to E3 administered each day is from 2:1 to 1:8, although it can vary slightly from this provided the average daily dosage ratio is in this range.
The preferred ratio of E2 to E3 is substantially 1:2.
It should be understood that the ratios of E2 oestrogen to E3 oestrogen mentioned herein are ratios by weight.
The gestagenic constituent present in the agent of the present invention and administered in stage II may be any gestagenically-active su~stance. Preferably the quantity used is such that it produces the same gestagenic activity as the administration of 0.1~0.5 mg of D-norgestrel daily. The gestagen ~ 7 -5~i daily dosage can of course, vary from day to day although it is preferably substantially uniform. Suitable gestagenic constitu-ents are, inter alia progesterone, 17-hydroxyprogesterone esters, l9-nor-17-hydroxyprogesterone esters, 17 ~-ethynyltestosterone, 17c~ethynyl-19-nor-testosteron (norethisterone) and 17~-ethynyl-18-methyl-19-nor-testosterone (D-norgestrel) and their derivatives.
The term "derivatives" includes compounds that are formed by the introduction of double bonds, by substituents, esterification, etherification, and ketalisation.
~dditional double bonds may be, inter alia in the 1,2-6,7-, 15,16- or 16,17-positions. Substituents may be halogen atoms, especially fluorine or bromine atoms, methyl, hydroxy, methoxy and acetoxy groups in the 4,6,7,11- and/or 16-positions and also methylene groups in the 1,2-, 6,7-, 15,16- and/or 16,17-positions. The 3-keto group of the gestagen may be reduced or eliminated. The 4,5-double bond may be displaced to the 5,6- or 5,10-position.
Suitable esters are those of acids that are normally used in steroid chemistry to esteriEy steroid alcohols e.g.
alkanecarboxylic acids having especially 1 to 11 carbon atoms.
Examples of ethers are alkyl ethers and tetrahydropyranyl ethers and examples of ketals are those of ethane diol and of propane diols.
Preferred gestagens are D-norgestrel, norethisterone acetate and cyproterone acetate ~17-acetoxy-6-chloro-1~,2c~-methylene-4,6-pregnadiene-3,20-dione).
The E2 oestrogen, E3 oestrogen and the gestagen used on different days may be the same or different, usually the same.
For example, there may be administered any of the following dosage combinations A to H:
s~
Daily dosage for Daily dosage for Daily dosage for each of 10 to 12 each of the immedi- each of the immediately successive days ately following 9 following 6 to 8 (lst stage) to 11 successive successive days days (2nd stage) to (3rd stage) to complete 20-22 days complete 28 days (Agent of the invention) 1 mg oestradiol 1 mg oestradiol valerate valerate A 2 mg oestriol 2 mg oestriol 1 mg oest~iol 0.25 mg D-norgestrel 2 mg oestradiol 2 mg oestradiol valerate valerate 2 mg oestriol 2 mg oestriol 1 mg oestriol . 0.25 mg D-norgestrel
5:~2~
oestradiol, for example oestradiol valerate, are preferred.
Suitable natural oestrogens with a negligible effect on deficiency symptoms and a strong effect on the lower genital tract are oestriol and its derivatives. These are ]cnown as E3 oestrogens. The term "derivatives" is used here to include, in particular, ethers and esters of oestriol. Oestriol and oestriol succinate, for example, are very suitableO
Reliable action is achieved if a combination of a natural oestrogen of type 1 (an E2 oestrogen, that is oestradiol or a derivative of oestradiol) and a natural oestrogen of type 2 (an E3 oestrogen, that is oestriol or a derivative of oestriol) is administered in the ratio of approximately 2:1 to 1:8 for 21 days and then only a natural oestrogen of type 2 (E3) or no hormones for 7 days. Adjustment to the normal female cycle is achieved with dosage over a period of 28 days.
A disadvantage of pure oestrogen therapy is the danger of an unphysiological proliferation of the endometrium and mammary tissue. We have now found that the residual action of oestrogens on the uterus and mammae can be rendered harmless by the addi-tional administration of a gestagen in the second half of thecycle for ~-11 days. The addition of gestagen brings about a transformation of theendometrium and cyclic bleeding.
The present in~ention thus provides a pharmaceutical treatment agent or composition for use in the treatment of climacteric deficiency symptoms, which comprises an E2 oestrogen and an E3 oestrogen in a ratio of from 2:1 to 1:8, and a gestagen.
The agent may be made up in the form of a pharmaceuti-cal preparation, which comprises the three components in admix-ture or conjunction with a pharmaceutically suitable carrier.
The preparation is suitably in dosage unit form.
The present invention further provides a pack which comprises an E2 oestrogen, an E3 oestrogen and a gestagen made s~;
up in discreet parts to provide (i) 10-12 daily dosages of an E2 oestrogen and an E3 oestrogen in a ratio of from 2:1 to 1:8, these daily dosages being free of gestagen, (ii) 9-11 daily dosages, to make up 20-22 daily dosages, of E2 oestrogen and E3 oestrogen in a ratio of from 2:1 to 1:8, and of gestagen, and, if desired, (iii) up to 8, especially 6-8 daily dosages up to a maximum of 28 daily dosages, of an E3 oestrogen free of E~
oestrogen and free of gestagen or of placebo.
If desired, ihere maybe an exact multiple of these daily dosages in the pack.
Suitably the components (i), (ii) and (iii) are in the form of pharmaceutical preparations comprising the active ingred-ient(s) in admixture or conjunction with a pharmaceutically suit-able carrier.
The pack may be made up in three discreet parts as follows: the E2 oestrogen, the E3 oestrogen and the gestagen;
or the 10-12 daily dosages (i), the 9-11 daily dosages (ii) and if desired, the remaining daily dosayes (iii). Also, for example the E2 and E3 oestrogens could be made up in one part, the gesta-gen in another part, and-the E3 oestrogen free of E2 oestrogen and gestagen in another part.
The present invention also provides a pharmaceutical treatment pack for the treatment of climacteric deficiency symptoms, which comprises in or on a container, card or other support member, unit dosage forms of an E2 oestrogen, an E3 oestrogen and a gestagen, which provide (I) (a) a first set of 10-12 daily dosages of an E2 oestrogen and (b) a first set of 10-12 daily dosages of an E3 oestrogen, -- 4 ~
Z5~
the ratio of the average daily dosage of E2 oestroyen to the average daily dosage of E3 oestro~en being from 2:1 to 1:8, (II) (a) a second set of 9-11 daily dosages of E2 oestrogen, to complete 20-22 daily dosages, and (b) a second set of 9-11 daily dosages of E3 oestrogen, to complete 20-22 daily dosages, the ratio of the average daily dosage of E2 oestrogen to the average daily dosage of E3 oestrogen being from 2:1 to 1:8, and (c) a set of 9~11 daily dosages of a gesta~en, and if, desired, (III) a third set of 6-8 daily dosages of E3 oestrogen or of hormone-free preparations or objects indicating no hormone treatment, to complete 28 daily dosages, the sets being located in a particular order, together with indications and/or instructions to indicate and facilitate a treatment consisting of the administration to a human female on ; each of 10-12 successive days of one of the daily dosages Ia and one of the daily dosages Ib, on each of the immediately following 9-11 successive days, to complete 20-22 days, one of the daily dosages IIa, one of the daily dosages IIb and one of the daily dosages IIc, and on each of the immediately following 6-8 success;ve days to complete 28 days, one of the E3 oestrogen or placebo daily dosages III or no administration of hormone.
The total number of days in the first, second and third stages should always be 28. If desired, there may be additional sets of dosage units in the pack so that the 28-day rhythm can be repeated. The administration of E2 oestrogen and gestagen are terminated on the same day.
The third set may be free from intake, or placebos, E3 oestrogen and/or other active substances may be administered 5~
during the 6-8 day perioa.
~ en no dosage unit is to be administered, the pack may contain objects indicating no hormone treatment. Each object may take the form of a gap, space, mark(s), relief or packing on or in the card or tube or other support member. It may be, for example, a representation of a dosage unit preparation or of a receptacle therefor, for example an empty profiled receptacle.
Each object is preferably removablel destructable or otherwise alterable, so that a check on the treatment may be kept easily.
For example, it may be an empty destructable profiled receptacle.
However, in order to avoid inadvertent omission of medication, the pack may contain E3 oestrogen preparations or placebos.
Indication of the method by which treatment is to be carried out may comprise the arrangement in the pack of the sets of preparations and, if present, objects indicating no hormone treatment. The appearance of the preparations may also provide guidance for the treatment; for example, the different prepara-tions may be of different colours. Two or more preparations may be taken per day, but generally one per day is taken. Thus, each daily dosage Ia and Ib is combined in a-single unit dosage form and each daily dosage IIa, IIb and IIc is combined in a single unit dosage form. Thus the pack may contain 28 dosage units pre-ferably for oral administration in a co-ordinated, fixed sequence, the sequence corresponding to the stages of the daily administra-tion. The pack may, among other things, be in the form of a transparent pack with for example 11 dosage units for the first stage, 10 dosage units for the second stage and 7 dosage units for the third stage, from which 1 dosage unit daily may be taken for 28 days. Generally, written or printed instructions are also given.
Suitably, the dosage of the oestrogens corresponds to ~ 3~ 5~
the usual dosage known in oestrogen therapyO
Suitable E2 oestrogens are, especially oestradiol and esters of oestradiol, e.g. oestradiol valerate and oestradiol benzoate. Preferably the quantity of E2 oestrogen used is such that it produces the same oestrogenic activity as the administration of 0.5 to 4 mg of oestradiol valerate daily. The E2 daily dosages can,of course,vary from day to day within a stage and from stage to stage, although they are preferably substantially uniform.
Especially suitable E3 oestrogens are oestriol and esters of oestriol, e.g. oestriol succinate. Preferably the quantity of E3 oestrogen used is such that it produces the same oestrogenic activity as the administration of 0.5 to 8 mg of oestriol daily. The E3 daily dosages can, of course vary from day to day within a stage and from stage to stage. Preferably the E3 daily dosage in stages I and II is substantially uniform.
The daily dosage in stage III is preferably substantially uniform and may be the same as or different from the daily dosage in the other stages, for example the daily dosage in stage III may be half the daily dosage in each of the other two stages.
The ratio of E2 to E3 administered can vary from day to day and from stage to stage, although it is also preferably substantially uniform. Usually the ratio of E2 to E3 administered each day is from 2:1 to 1:8, although it can vary slightly from this provided the average daily dosage ratio is in this range.
The preferred ratio of E2 to E3 is substantially 1:2.
It should be understood that the ratios of E2 oestrogen to E3 oestrogen mentioned herein are ratios by weight.
The gestagenic constituent present in the agent of the present invention and administered in stage II may be any gestagenically-active su~stance. Preferably the quantity used is such that it produces the same gestagenic activity as the administration of 0.1~0.5 mg of D-norgestrel daily. The gestagen ~ 7 -5~i daily dosage can of course, vary from day to day although it is preferably substantially uniform. Suitable gestagenic constitu-ents are, inter alia progesterone, 17-hydroxyprogesterone esters, l9-nor-17-hydroxyprogesterone esters, 17 ~-ethynyltestosterone, 17c~ethynyl-19-nor-testosteron (norethisterone) and 17~-ethynyl-18-methyl-19-nor-testosterone (D-norgestrel) and their derivatives.
The term "derivatives" includes compounds that are formed by the introduction of double bonds, by substituents, esterification, etherification, and ketalisation.
~dditional double bonds may be, inter alia in the 1,2-6,7-, 15,16- or 16,17-positions. Substituents may be halogen atoms, especially fluorine or bromine atoms, methyl, hydroxy, methoxy and acetoxy groups in the 4,6,7,11- and/or 16-positions and also methylene groups in the 1,2-, 6,7-, 15,16- and/or 16,17-positions. The 3-keto group of the gestagen may be reduced or eliminated. The 4,5-double bond may be displaced to the 5,6- or 5,10-position.
Suitable esters are those of acids that are normally used in steroid chemistry to esteriEy steroid alcohols e.g.
alkanecarboxylic acids having especially 1 to 11 carbon atoms.
Examples of ethers are alkyl ethers and tetrahydropyranyl ethers and examples of ketals are those of ethane diol and of propane diols.
Preferred gestagens are D-norgestrel, norethisterone acetate and cyproterone acetate ~17-acetoxy-6-chloro-1~,2c~-methylene-4,6-pregnadiene-3,20-dione).
The E2 oestrogen, E3 oestrogen and the gestagen used on different days may be the same or different, usually the same.
For example, there may be administered any of the following dosage combinations A to H:
s~
Daily dosage for Daily dosage for Daily dosage for each of 10 to 12 each of the immedi- each of the immediately successive days ately following 9 following 6 to 8 (lst stage) to 11 successive successive days days (2nd stage) to (3rd stage) to complete 20-22 days complete 28 days (Agent of the invention) 1 mg oestradiol 1 mg oestradiol valerate valerate A 2 mg oestriol 2 mg oestriol 1 mg oest~iol 0.25 mg D-norgestrel 2 mg oestradiol 2 mg oestradiol valerate valerate 2 mg oestriol 2 mg oestriol 1 mg oestriol . 0.25 mg D-norgestrel
3 mg oestradiol 3 mg oestradiol valerate valerate C 2 mg oestriol 2 mg oestriol 1 mg oestriol 2 mg norethisterone . acetate
4 mg oestradiol 4 mg oestradiol valerate valerate D 2 mg oestriol 2 mg oestriol 2 mg oestriol . . 0~25 mg D~norgestrel 0.5 mg oestradiol 0.5 mg oestradiol valerate val.erate E 4 mg oestriol 4 mg oestriol 2 mg oestriol 1 mg cyproterone : acetate 1 mg oestradiol 1 mg oestradiol F valerate valerate 4 mg oestriol 4 mg oestriol 2 mg oestriol .. 0.25 mg D-norgestrel ; 2 mg oestradiol 2 mg oestradiol valerate valerate G 1 mg oestriol I. mg oestriol 0.5 mg oestriol 0.25 mg D-norgestrel 1 mg oestradiol 1 mg oestradiol valerate valerate H 2 mg oestriol 2 mg oestriol No hormone 0.25 mg D-norgestrel S~i The active ingredients are preferably administered together orally but they may also be administered separately or parenterally. Each daily dosage of Ia and Ib may be combined in a single dosage unit and each daily dosage of IIa, Ilb and IIc may be similarly combined.
For formulating the dosage units, the active substances may be processed with the additives, carrier substances and/or taste correctives customary in galenical pharmacy according to methods known per se to produce the normal forms of administra-tion. Tablets, dragées, capsules, pills, suspensions or solu-tions especially are suitable for the preferred oral administra-tion and, for parenteral administration oily solutions, e.g.
sesame oil or castor oil solutions which may optionally also contain a diluting agent, e.g. benzyl benzoate or benzyl alcohol are especially preferred. ~or the preferred oral administration the three-stage agents are preferably assembled in the form of a pack.
The following Examples illustrate the invention.
Ex~nple 1 Cornposition of a dragee for each stage 1st Stage 1.000 mg oestradiol valerate 2.000 mg oestriol 43.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
. ~
~0~5~
2nd Stage 1.000 mg oestradiol valerate 2. ono mg oestriol 0.250 mg D-norgestrel 43.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to àpproxi-mately 140 mg with a normal sugar mixture.
A single d~agee of this composition is administered on each of the immediately following 10 successive days.
` 3rd Stage 1.000 mg oestriol 45.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of ~0 the immediately following 7 successive days.Example 2 ~ Composition of a dragee for each stage 1st Stage 2.000 mg oestradiol valerate 2.000 mg oestriol 42.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.600 mg talcum 0.100 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
-- 11 -- , 2nd stage 2.000 mg oestradiol valerate 2.000 mg oestriol 0.250 mg D-norgestrel 42.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.600 mg talcum 0.100 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
- A single dragee of this composition is administered on each of ; the immediately following lO successive days.
3rd Stage l.000 mg oestriol 45.500 mg lactose 26.800 mg maize starch 3~000 mg polyvinyl pyrrolidone 25 3.600 mg talcum 0.100 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 3 Composition of a dragee for each stage 1st Stage 3.000 mg oestradiol valerate 2.000 mg oestriol ; 41.500 mg lactose 26.800 mg maize starch ; 3nO00 mg polyvinyl pyxrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
~q,~1,3~5~
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 3.000 mg oestradiol valerate 2.000 mg oestriol 2.000 mg norethisterone acetate 39.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 1.000 mg oestriol 45.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 4 Composition of a dragee for each stage 1st Stage 4.000 mg oestradiol valerate 2.000 mg oestriol 40.500 mg lactose 26.800 mg maize starch 3.000 mgpolyvinyl pyrrolidone 25 3.550 mg talcum 0.150 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
3;256 A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 4.000 mg oestradiol valerate 2.000 mg oestriol 0.250 mg D-norgestrel 40.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.550 mg talcum 0.150 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 2.000 mg oestriol 44.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.550 mg talcum 0.150 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 5 Composition of a dragee for each ;stage 1st Stage 0.500 mg oestradiol valerate 4.000 mg oestriol ~ 42.000 mg lactose ; 30 26.800 mg maize starch s~;
3,000 mg polyvinyl pyrrolidone 25 3 . 7 00 mg talcum 80.000 mg total weiyht which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 0.500 mg oestradiol valerate 4.000 mg oestriol 1.000 mg cyproterone acetate 41.000 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 2.000 mg oestriol 44.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 8G.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 6 .
Composition of a dragee for each stage 1st Stage 1.000 mg oestradiol valerate 4.000 mg oestriol 41.500 mg lactose 26.800 mg maize starch 3.000 m~ polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 1.000 mg oestradiol valerate 4.000 mg oestriol 0.~50 mg D-norgestrel 41.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 2.000 mg oestriol 44.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 7 ; Composition of a dragee for each stage 1st Stage 2.000 mg oestradiol valerate 1.000 mg oestriol 43.500 mg lactose 26.800 mg maize starch
For formulating the dosage units, the active substances may be processed with the additives, carrier substances and/or taste correctives customary in galenical pharmacy according to methods known per se to produce the normal forms of administra-tion. Tablets, dragées, capsules, pills, suspensions or solu-tions especially are suitable for the preferred oral administra-tion and, for parenteral administration oily solutions, e.g.
sesame oil or castor oil solutions which may optionally also contain a diluting agent, e.g. benzyl benzoate or benzyl alcohol are especially preferred. ~or the preferred oral administration the three-stage agents are preferably assembled in the form of a pack.
The following Examples illustrate the invention.
Ex~nple 1 Cornposition of a dragee for each stage 1st Stage 1.000 mg oestradiol valerate 2.000 mg oestriol 43.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
. ~
~0~5~
2nd Stage 1.000 mg oestradiol valerate 2. ono mg oestriol 0.250 mg D-norgestrel 43.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to àpproxi-mately 140 mg with a normal sugar mixture.
A single d~agee of this composition is administered on each of the immediately following 10 successive days.
` 3rd Stage 1.000 mg oestriol 45.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of ~0 the immediately following 7 successive days.Example 2 ~ Composition of a dragee for each stage 1st Stage 2.000 mg oestradiol valerate 2.000 mg oestriol 42.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.600 mg talcum 0.100 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
-- 11 -- , 2nd stage 2.000 mg oestradiol valerate 2.000 mg oestriol 0.250 mg D-norgestrel 42.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.600 mg talcum 0.100 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
- A single dragee of this composition is administered on each of ; the immediately following lO successive days.
3rd Stage l.000 mg oestriol 45.500 mg lactose 26.800 mg maize starch 3~000 mg polyvinyl pyrrolidone 25 3.600 mg talcum 0.100 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 3 Composition of a dragee for each stage 1st Stage 3.000 mg oestradiol valerate 2.000 mg oestriol ; 41.500 mg lactose 26.800 mg maize starch ; 3nO00 mg polyvinyl pyxrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
~q,~1,3~5~
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 3.000 mg oestradiol valerate 2.000 mg oestriol 2.000 mg norethisterone acetate 39.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 1.000 mg oestriol 45.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 4 Composition of a dragee for each stage 1st Stage 4.000 mg oestradiol valerate 2.000 mg oestriol 40.500 mg lactose 26.800 mg maize starch 3.000 mgpolyvinyl pyrrolidone 25 3.550 mg talcum 0.150 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
3;256 A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 4.000 mg oestradiol valerate 2.000 mg oestriol 0.250 mg D-norgestrel 40.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.550 mg talcum 0.150 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 2.000 mg oestriol 44.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.550 mg talcum 0.150 mg magnesium stearate 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 5 Composition of a dragee for each ;stage 1st Stage 0.500 mg oestradiol valerate 4.000 mg oestriol ~ 42.000 mg lactose ; 30 26.800 mg maize starch s~;
3,000 mg polyvinyl pyrrolidone 25 3 . 7 00 mg talcum 80.000 mg total weiyht which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 0.500 mg oestradiol valerate 4.000 mg oestriol 1.000 mg cyproterone acetate 41.000 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 2.000 mg oestriol 44.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 8G.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 6 .
Composition of a dragee for each stage 1st Stage 1.000 mg oestradiol valerate 4.000 mg oestriol 41.500 mg lactose 26.800 mg maize starch 3.000 m~ polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 1.000 mg oestradiol valerate 4.000 mg oestriol 0.~50 mg D-norgestrel 41.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 2.000 mg oestriol 44.500 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
Example 7 ; Composition of a dragee for each stage 1st Stage 2.000 mg oestradiol valerate 1.000 mg oestriol 43.500 mg lactose 26.800 mg maize starch
5~"
3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum ___ 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 2.000 mg oestradiol valerate 1.000 mg oestriol 0.250 mg D-norgestrel 43.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 0.500 mg oestriol 46.000 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A singlt dragee of this composition is administered on each of the immediately following 7 successive days.
Example 8 Composition of a dragee for each stage _ 1st Stage 1.000 mg oestradiol valerate 2.000 mg oestriol 43.500 mg lactose 26.800 mg maize starch 5~j 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 1.000 mg oestradiol valerate 2.000 mg oestriol 0.250 mg D-norgestrel 43.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 8~000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 46.500 mg lactose - 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
; ~ 18 -
3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum ___ 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 2.000 mg oestradiol valerate 1.000 mg oestriol 0.250 mg D-norgestrel 43.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 0.500 mg oestriol 46.000 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A singlt dragee of this composition is administered on each of the immediately following 7 successive days.
Example 8 Composition of a dragee for each stage _ 1st Stage 1.000 mg oestradiol valerate 2.000 mg oestriol 43.500 mg lactose 26.800 mg maize starch 5~j 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of 11 successive days.
2nd Stage 1.000 mg oestradiol valerate 2.000 mg oestriol 0.250 mg D-norgestrel 43.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 8~000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 10 successive days.
3rd Stage 46.500 mg lactose - 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approxi-mately 140 mg with a normal sugar mixture.
A single dragee of this composition is administered on each of the immediately following 7 successive days.
; ~ 18 -
Claims (75)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical treatment pack for the treatment of clinacteric deficiency symptoms, which comprises in or on a support member, unit dosage forms of an E2 oestrogen, an E3 oestrogen and a gestagen, which provide (I) (a) a first set of 10-12 daily dosages of an E2 oestrogen and (b) a first set of 10-12 daily dosages of an E3 oestrogen, the ratio of the average daily dosage of E2 oestrogen to the average daily dosage of E3 oestrogen being from 2:1 to 1:8, and (II) (a) a second set of 9-11 daily dosages of E2 oestrogen, to complete 20-22 daily dos-ages, and (b) a second set of 9-11 daily dosages of E3 oestrogen, to complete 20-22 daily dosages, the ratio of the average daily dosage of E2 oestrogen to the average daily dosage of E3 oestro-gen being from 2:1 to 1:8, and (c) a set of 9-11 daily dosages of a gestagen, the sets being located in a particular order, together with indications and/or instructions to indicate and facilitate a treatment consisting of the administration to a human female on each of 10-12 successive days of one of the daily dosages Ia and one of the daily dosages Ib, on each of the immediately following 9-11 successive days, to complete 20-22 days, one of the daily dosages IIa, one of the daily dosages IIb and one of the daily dosages IIc, and on each of the immediately following 6-8 succes-sive days, to complete 28 days no administration of hormone.
2. A pack as claimed in claim 1 which additionally pro-vides III a third set of 6-8 daily dosages of E3 oestrogen or of hormone-free preparations, to complete 28 daily dosages, or of objects indicating 6-8 days of no hormone treatment and in which the indications and/or instructions indicate and facilitate the treatment which includes on each of the final 6-8 successive days to complete 28 days; one of the E3 oestrogen or hormone free daily dosages III or no administration of hormone.
3. A pack as claimed in claim 1, wherein the ratio of the average daily dosage of the first set of E2 oestrogen Ia to the average daily dosage of the first set of E3 oestrogen Ib is substantially 1:2.
4. A pack as claimed in claim 3, wherein the ratio of the average daily dosage of the second set of E2 oestrogen IIa to the average daily dosage of the second set of E3 oestrogen IIb is substantially 1:2.
5. A pack as claimed in claim 1, wherein in each set, Ia, Ib, IIa, IIb and IIc the daily dosages are of substantially uniform dosage.
6. A pack as claimed in claim 4, wherein all the E2 oestrogen daily dosages Ia and IIa are of substantially uniform dosage, and all the E3 oestrogen daily dosages Ib and IIb are of substantially uniform dosage.
7. A pack as claimed in claim 5, which includes a third set of 6-8 daily dosages of E3 oestrogen III and wherein all the E2 oestrogen daily dosages Ia and IIa are of substantially uniform dosage, all the E3 oestrogen daily dosages in the first and second sets Ib and IIb are of substantially uniform dosage, and each E3 oestrogen daily dosage in the third set III is no more than half the E3 oestrogen daily dosage in the other two sets.
8. A pack as claimed in claim 1, 2 or 3 which includes a set of objects indicating no hormone treatment III, each object being removable.
9. A pack as claimed in claim 2 which includes a set of objects indicating no hormone treatment III, each object being an empty destructable profiled receptacle.
10. A pack as claimed in claim 1, 2 or 3, wherein each E2 oestrogen daily dosage contains an amount of E2 oestrogen which produces the same oestrogenic effect as the administration of 0.5 t 4 mg of oestradiol valerate daily.
11. A pack as claimed in claim 1, 2 or 3 wherein each E3 oestrogen daily dosage contains an amount of E3 oestrogen which produces the same oestrogenic effect as the administration of 0.5 to 8 mg of oestriol daily.
12. A pack as claimed in claim 1, 2 or 3 wherein each gestagen daily dosage contains an amount of gestagen which pro-duces the same gestagenic effect as the administration of 0.1 to 0.5 mg of D-norgestrel daily.
13. A pack as claimed in claim 1, 2 or 3 wherein the or one of the E2 oestrogens in the pack is oestradiol valerate.
14. A pack as claimed in claim 1, 2 or 3 wherein the same oestrogen is present in each E2 oestrogen daily dosage.
15. A pack as claimed in claim 1, 2 or 3 wherein the or one of the E3 oestrogens in the pack is oestriol.
16. A pack as claimed in claim 1, 2 or 3, wherein the same oestrogen is present in each E3 oestrogen daily dosage.
17. A pack as claimed in claim 1, 2 or 3 wherein the or one of the gestagens in the pack is D-norgestrel, norethisterone acetate or cyproterone acetate.
18. A pack as claimed in claim 1, 2 or 3, wherein the same gestagen is present in each gestagen daily dosage.
19. A pack as claimed in claim 1, wherein the unit dosage forms provide any one of the dosage combinations A to H
given in the following Table.
given in the following Table.
20. A pack as claimed in claim 1 in which each daily dosage of Ia and Ib is combined in a single unit dosage form, each daily dosage of IIa, IIb and IIc is combined in a single unit dosage form.
21. A pack as claimed in claim 2 wherein each daily dosage of Ia and Ib is combined in a single unit dosage form, each daily dosage of IIa, IIb and IIc is combined in a single unit dosage form and each daily dosage of III is in a single dosage unit.
22. A pack as claimed in claim 1 wherein each dosage unit is in a form suitable for oral administration.
23. A pack as claimed in claim 22 wherein each dosage unit is in the form of a tablet or dragee.
24. A pack as claimed in claim 1, 2 or 3 wherein each dosage unit is in a form suitable for parenteral administration.
25. A pack as claimed in claim 1, wherein the first and second sets Ia, Ib and IIa, IIb and IIc provide daily dosages for 21 days.
26. A pack as claimed in claim 25, wherein the first set Ia and Ib provides daily dosages for 11 days and the second set IIa, IIb and IIc provides daily dosages for 10 days.
27. A pharmaceutical treatment agent for use in the treatment of climacteric deficiency symptoms, which comprises an E2 oestrogen and an E3 oestrogen in a ratio of from 2:1 to 1:8 and a gestagen, the E2 and E3 oestrogen being present in a first set to provide for administration for 22 days and the gestagen being only present in a second set which comprises 9 to 11 daily doses of the E2 and E3 oestrogen.
28. An agent as claimed in claim 27 wherein the E2 oestrogen is oestradiol valerate.
29. An agent as claimed in claim 28 wherein the E3 oestrogen is oestriol.
30. An agent as claimed in claim 27, 28 or 29 where in the gestagen is D-norgestrel, norethisterone acetate or cyproter-one acetate.
31. An agent as claimed in claim 27, 28 or 29 wherein the ratio of E2 oestrogen to E3 oestrogen is substantially 1:2.
32. A pharmaceutical preparation which comprises an agent as claimed in claim 27, in admixture or conjunction with a pharmaceutically suitable carrier.
33. A pharmaceutical preparation as claimed in claim 32, which is in unit dosage form.
34. A pharmaceutical preparation as claimed in claim 33, wherein each dosage unit contains an amount of E2 oestrogen which produces the same oestrogenic effect as the administration of 0.5 to 4 mg of oestradiol valerate.
35. A pharmaceutical preparation as claimed in claim 34, wherein each dosage unit contains an amount of E3 oestrogen which produces the same oestrogenic effect as the administration of 0.5 to 8 mg of oestriol.
36. A pharmaceutical preparation as claimed in claim 33, 34, or 35 wherein each dosage unit contains an amount of gestagen which produces the same gestagenic effect as the administration of 0.1 to 0.5 mg of D-norgestrel.
37. A pharmaceutical preparation as claimed in claim 33 wherein each dosage unit contains any one of the agents indi-cated for the second stage in A to H given in the following Table.
38. A pharmaceutical preparation as claimed in claim 33, which consists of 9-11 dosage units or a multiple thereof.
39. A pharmaceutical preparation as claimed in claim 38 which consists of 10 dosage units or a multiple thereof.
40. A pharmaceutical preparation as claimed in claim 38 wherein the dosages of E2 oestrogen, E3 oestrogen and gestagen are of substantially uniform dosage in all dosage units.
41. A pharmaceutical preparation as claimed in claim 32, which is in a form suitable for oral administration.
42. A pharmaceutical preparation as claimed in claim 37 which is in the form of a tablet or dragee.
43. A pharmaceutical preparation as claimed in claim 32, 33 or 34 which is in a form suitable for parenteral adminis-tration.
44. A pack which comprises an E2 oestrogen, an E3 oestrogen and a gestagen made up in discreet parts to provide (i) 10-12 daily dosages of an E2 oestrogen and an E3 oestrogen in a ratio of from 2:1 to 1:8, these daily dosages being free of gestagen, (ii) 9-11 daily dosages, to complete 20-22 daily dosages of E2 oestrogen and E3 oestrogen in a ratio of from 2:1 to 1:8, and of gestagen, and (iii) 0 to 8 daily dosages, up to a maximum of 28 daily dosages, of an E3 oestrogen free of E2 oestrogen and free of gestagen, or of a hormone-free preparation, or a multiple of these daily dosages.
45. A pack as claimed in claim 44 in which in (iii) there are 6 to 8 daily dosages.
46. A pack as claimed in claim 44 which is made up in discreet parts as follows: (i) 10-12 daily dosages of E2 oestrogen and E3 oestrogen in a ratio of from 2:1 to 1:8, and (ii) 9-11 daily dosages, to complete 20-22 daily dosages, of E2 oestrogen and E3 oestrogen in a ratio of from 2:1 to 1:8, and of gestagen, or in each discreet part, a multiple of these daily dosages.
47. A pack as claimed in claim 46 in which there is also present (iii) 6-8 daily dosages to complete 28 daily dosages of E3 oestrogen.
48. A pack as claimed in claim 46 or 47 wherein the E2 oestrogen and E3 oestrogen in part (i) are in a ratio of sub-stantially 1:2.
49. A pack as claimed in claim 46 or 47 wherein the E2 oestrogen and E3 oestrogen in part (ii) are in a ratio of sub-stantially 1:2.
50. A pack as claimed in claim 44 which is made up in discreet parts as follows:
(i) 20-22 daily dosages of E2 oestrogen, (ii) 20-22 daily dosages of E3 oestrogen, and (iii) 9-11 daily dosages of gestagen.
or in each part, a multiple of these daily dosages.
(i) 20-22 daily dosages of E2 oestrogen, (ii) 20-22 daily dosages of E3 oestrogen, and (iii) 9-11 daily dosages of gestagen.
or in each part, a multiple of these daily dosages.
51. A pack as claimed in claim 50 in which in part (ii) or as an additional discreet part, 6-8 daily dosages, to complete 28 daily dosages, of E3 oestrogen.
52. A pack as claimed in claim 50 or 51 wherein the E2 oestrogen and E3 oestrogen in parts (i) and ( i) are in a ratio of substantially 1:2.
53. A pack as claimed in claim 44 made up in discreet parts as follows:
(i) 20-22 daily dosages of E2 oestrogen and E3 oestrogen in a ratio of from 2:1 to 1:8, (ii) 9-11 daily dosages of gestagen and if desired (iii) 6-8 daily dosages of E3 oestrogen to complete 28 daily dosages, or in each part, a multiple of these daily dosages.
(i) 20-22 daily dosages of E2 oestrogen and E3 oestrogen in a ratio of from 2:1 to 1:8, (ii) 9-11 daily dosages of gestagen and if desired (iii) 6-8 daily dosages of E3 oestrogen to complete 28 daily dosages, or in each part, a multiple of these daily dosages.
54. A pack as claimed in claim 53 wherein the E2 oestrogen and E3 oestrogen in part (i) are in a ratio of substan-tially 1:2.
55. A pack as claimed in claim 54 wherein each dis-creet part is in the form of one or more pharmaceutical prepara-tions comprising the active ingredient(s) in admixture or conjunc-tion with a pharmaceutically suitable carrier.
56. A pack as claimed in claim 55 wherein each phar-maceutical preparation is in dosage unit form.
57. A pack as claimed in claim 56 wherein in each dis-creet part each daily dosage of the active ingredient(s) is in a single dosage unit.
58. A pack as claimed in claim 57 wherein in each dis-creet part the daily dosages are of substantially uniform dosage.
59. A pack as claimed in claim 58 wherein all the E2 oestrogen daily dosages are of substantially uniform dosage and all the E3 oestrogen daily dosages are of substantially uniform dosage.
60. A pack as claimed in claim 58 which includes 6-8 daily dosages of E3 oestrogen to complete the 28 daily dosages, wherein the other E3 oestrogen daily dosages are of substantially uniform dosage, each of the 6-8 daily dosages of E3 oestrogen is no more than half this daily dosage, and wherein all the E2 oestro-gen daily dosages are of substantially uniform dosage.
61. A pack as claimed in claim 44, 45 or 46 wherein each E2 oestrogen daily dosage provided produces the same oestro-genic activity as the administration of 0.5 to 4 mg of oestradiol valerate daily.
62. A pack as claimed in claim 44, 45 or 46 wherein each E3 oestrogen daily dosage provided produces the same oestro-genic activity as the administration of 0.5 to 8 mg of oestriol daily.
63. A pack as claimed in claim 44, 45 or 46 wherein each gestagen daily dosage provided produces the same gestagenic activity as the administration of 0.1 to 0.5 mg of D-norgestrel daily.
64. A pack as claimed in claim 44, 45 or 46 wherein the or one of the E2 oestrogens in the pack is oestradiol valerate.
65. A pack as claimed in claim 44, 45 or 46 wherein the same oestrogen is present in each E2 oestrogen daily dosage.
66. A pack as claimed in claim 44, 45 or 46 wherein the or one of the E3 oestrogens in the pack is oestriol.
67. A pack as claimed in claim 44, 45 or 46 wherein the same oestrogen is present in each E3 oestrogen daily dosage.
68. A pack as claimed in claim 44, 45 or 46 wherein the or one of the gestagens in the pack is D-norgestrel, norethis-terone acetate or cyproterone acetate.
69. A pack as claimed in claim 44, 45 or 46 wherein the same gestagen is present in each gestagen daily dosage.
70. A pack as claimed in claim 44, 45 or 46 wherein the unit dosage forms provide any one of the dosage combinations A to H given in the following Table.
71. A pack as claimed in claim 44 wherein the daily dosages are in a form suitable for oral administration.
72. A pack as claimed in claim 71 wherein the daily dosages are in the form of tablets or dragees.
73. A pack as claimed in claim 44, 45 or 46 wherein the daily dosages are in a form suitable for parenteral adminis-tration.
74. A pack as claimed in claim 44 which provides a total of 21 daily dosages of E2 oestrogen and E3 oestrogen free of gestagen and of E2 oestrogen, E3 oestrogen and gestagen.
75. A pack as claimed in claim 74 which provides 11 daily dosages of E2 oestrogen and E3 oestrogen free of gestagen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762645307 DE2645307A1 (en) | 1976-10-05 | 1976-10-05 | NEW MEANS AND NEW METHODS FOR TREATING CLIMATE FAILURE |
| DEP2645307.6 | 1976-10-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1090256A true CA1090256A (en) | 1980-11-25 |
Family
ID=5989934
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA288,196A Expired CA1090256A (en) | 1976-10-05 | 1977-10-05 | Medicament pack and agent for the treatment of climacteric deficiency symptoms |
Country Status (9)
| Country | Link |
|---|---|
| AU (1) | AU512918B2 (en) |
| BE (1) | BE859410A (en) |
| CA (1) | CA1090256A (en) |
| DE (1) | DE2645307A1 (en) |
| DK (1) | DK438077A (en) |
| GB (1) | GB1578240A (en) |
| NL (1) | NL7709742A (en) |
| SE (1) | SE7711102L (en) |
| ZA (1) | ZA775980B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8153616B2 (en) | 2005-10-17 | 2012-04-10 | Bayer Pharma Aktiengesellschaft | Combination preparation for oral contraception and oral therapy of dysfunctional uterine bleeding containing estradiol valerate and dienogest and method of using same |
| US8349820B2 (en) | 2006-10-20 | 2013-01-08 | Bayer Pharma Aktiengesellschaft | Use of estradiol valerate or 17β-estradiol in combination with dienogest for oral therapy to maintain and/or increase feminine libido |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3029726A1 (en) * | 1980-08-06 | 1982-02-25 | Werner Dr.med. 4400 Münster Steinschulte | Post coital contraceptive for enteral or parenteral admin. - contg. racemic norgestrel or levonorgestrel |
| US4390531A (en) * | 1981-08-10 | 1983-06-28 | Syntex Pharmaceuticals International Ltd. | Method of contraception using peak progestogen dosage |
| US4826831A (en) * | 1983-08-05 | 1989-05-02 | Pre Jay Holdings Limited | Method of hormonal treatment for menopausal or post-menopausal disorders involving continuous administration of progestogens and estrogens |
| EP0300523B1 (en) * | 1987-07-06 | 1991-08-14 | Akzo N.V. | Pharmaceutical dosage unit for the prevention or treatment of climacteric complaints |
| NO301689B1 (en) * | 1987-09-24 | 1997-12-01 | Jencap Research Ltd | Contraceptive preparation in the form of a package |
| US5276022A (en) * | 1987-09-24 | 1994-01-04 | Jencap Research Ltd. | Hormone preparation and method |
| DE4019670A1 (en) * | 1990-06-22 | 1992-01-09 | Erhard Dr Med Roemer | Treatment of menopause to protect women from breast cancer - uses pharmaceutical contg. oestrogen and progesterone deriv. chloro:madinone ethanoate |
| DE4104385C1 (en) * | 1991-02-09 | 1992-08-13 | Marika Dr.Med. 6509 Framersheim De Ehrlich | |
| DE4308406C1 (en) * | 1993-03-12 | 1994-06-16 | Jenapharm Gmbh | Contraceptive compsn. with reduced hormone dose and reduced side-effects - contg. synergistic mixt. of biogenic, synthetic oestrogen and gestagen |
| DE4313926A1 (en) * | 1993-04-28 | 1994-11-03 | Jenapharm Gmbh | Multiphase pharmaceutical product for hormonal contraception |
| DE4429374C1 (en) * | 1994-08-12 | 1996-02-01 | Jenapharm Gmbh | Pharmaceutical preparations for contraception / hormone substitution with biogenic estrogen component |
| DE102004019743B4 (en) | 2004-04-20 | 2008-11-27 | Bayer Schering Pharma Aktiengesellschaft | Multiphase preparation for contraception based on natural estrogen |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1175468A (en) * | 1967-10-19 | 1969-12-23 | Merck Ag E | Pharmaceutical Compositions |
| US3639600A (en) * | 1969-08-28 | 1972-02-01 | Upjohn Co | Process of establishing cyclicity in a human female |
| DE2529523A1 (en) * | 1975-06-30 | 1977-01-27 | Schering Ag | NEW MEANS AND METHODS OF TREATING CLIMATE DEFAULT |
-
1976
- 1976-10-05 DE DE19762645307 patent/DE2645307A1/en active Granted
-
1977
- 1977-09-05 NL NL7709742A patent/NL7709742A/en not_active Application Discontinuation
- 1977-10-03 GB GB40925/77A patent/GB1578240A/en not_active Expired
- 1977-10-04 SE SE7711102A patent/SE7711102L/en not_active Application Discontinuation
- 1977-10-04 DK DK438077A patent/DK438077A/en not_active Application Discontinuation
- 1977-10-05 BE BE181485A patent/BE859410A/en not_active IP Right Cessation
- 1977-10-05 ZA ZA00775980A patent/ZA775980B/en unknown
- 1977-10-05 AU AU29364/77A patent/AU512918B2/en not_active Expired
- 1977-10-05 CA CA288,196A patent/CA1090256A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8153616B2 (en) | 2005-10-17 | 2012-04-10 | Bayer Pharma Aktiengesellschaft | Combination preparation for oral contraception and oral therapy of dysfunctional uterine bleeding containing estradiol valerate and dienogest and method of using same |
| US8349820B2 (en) | 2006-10-20 | 2013-01-08 | Bayer Pharma Aktiengesellschaft | Use of estradiol valerate or 17β-estradiol in combination with dienogest for oral therapy to maintain and/or increase feminine libido |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA775980B (en) | 1978-05-30 |
| GB1578240A (en) | 1980-11-05 |
| SE7711102L (en) | 1978-04-06 |
| DE2645307A1 (en) | 1978-04-06 |
| AU2936477A (en) | 1979-04-12 |
| AU512918B2 (en) | 1980-11-06 |
| DE2645307C2 (en) | 1988-10-13 |
| NL7709742A (en) | 1978-04-07 |
| DK438077A (en) | 1978-04-06 |
| BE859410A (en) | 1978-04-05 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |