GB1578240A

GB1578240A - Medicament pack and agent for the treatment of climacteric deficiency symptoms

Info

Publication number: GB1578240A
Application number: GB40925/77A
Authority: GB
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1976-10-05
Filing date: 1977-10-03
Publication date: 1980-11-05
Also published as: DE2645307A1; DK438077A; AU512918B2; SE7711102L; AU2936477A; DE2645307C2; CA1090256A; NL7709742A; ZA775980B; BE859410A

Description

(54) MEDICAMENT PACK AND AGENT FOR THE TREATMENT OF CLIMACTERIC DEFICIENCY SYMPTOMS (71) We, SCHERING AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of Berlin and Bergkamen, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- 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 complaints such as hot flushes, outbreaks of sweating, insomnia, cardiovascular disturbances and dizziness.

Oestradiol valerate can also overcome psychological changes that are manifested by mental unbalance. However, a disadvantage 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 oestradiol valerate has a limited indication.

In addition, the treatment of climacteric disorders with oestriol is known.

Oestriol has a favourable effect on the lower genital tract (Cervix uteri, vagina and yulva) but it has the disadvantage that the typical hormone deficiency symptoms and psychological changes are not overcome satisfactorily.

The effects on the deficiency symptoms can be increased and the effect on the uterus can be largely eliminated by a suitable 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 oestradiol and its derivatives. These are known as E2 oestrogens. The term "derivatives" indicates compounds that are formed by the esterification or etherification of oestradiol. Esters of 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 known as E3 oestrogens. The term "derivatives" is used here to denote eithers and esters of oestriol. Oestriol and oestriol succinate, for example, are very suitable.

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 additional administration of a gestagen in the second half of the cycle for 9-11 days. The addition of gestagen brings about a transformation of the endometrium and cyclic bleeding.

The present invention 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 pharmaceutical preparation, which comprises the three components in admixture or conjunction with a pharmaceutically suitable carrier. The preparation is suitably in dosage unit form.

The present further provides a pack which comprises an E2 oestrogen, an E3 oestrogen and a gestagen made up in discreet parts to provide (I) 1W12 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) 911 daily dosages, to make up 222 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 E2 oestrogen and free of gestagen, or of placebo.

If desired, there may be 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 ingredient(s) in admixture or conjunction with a pharmaceutically suitable carrier.

The pack may be made up in three discreet parts as follows: the E2 oestrogen, the E3 oestrogen and the gestagen; or the 1(1--12 daily dosages (I), the 911 daily dosages (II) and, it desired, the remaining daily dosages (III). Also, for example, the E2 and E3 oestrogens could be made up in one part, the gestagen 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 1W12 daily dosages of an E2 oestrogen and (b) a first set of 1-12 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, (II) (a) a second set of 9-11 daily dosages of E2 oestrogen, to complete 222 daily dosages, and (b) a second set of 911 daily dosages of E3 oestrogen, to complete 222 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 911 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 indications of lack of treatment, for this period, 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 1W12 successive days of one of the daily dosages Ia and one of the daily dosages Ib, on each of the immediately following 911 successive days, to complete 2022 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 successive days, to complete 28 days, one of the E3 oestrogen or hormone-free 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.

It should be understood that the term "hormone" used here denotes all natural and synthetic hormones. 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 during the 6-8-day period.

When no dosage unit is to be administered, the pack may be provided with special indications of this lack of treatment, for example in the form of a gap, space, mark(s), relief or packing on or in the card or tube of other support member for each day treatment is to be omitted. It may he, for example, a representation of a dosage unit preparation or of a receptacle therefor, for example an empty profiled receptacle. Each indication of 1 day's omission of treatment is preferably a removable, destructable or otherwise allerable object, 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 inadvertant 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, indications of no hormone treatment. The appearance of the preparations may also provide guidance for the treatment; for example, the different preparations 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 preferably for oral administration in a co-ordinated, fixed sequence, the sequence corresponding to the stages of the daily administration. 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 I 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 the usual dosage known in oestrogen therapy.

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 are 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 in the specification 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 substance. 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 daily dosage can, of course, vary from day to day although it is preferably substantially uniform.

Suitable gestagenic constituents are, inter alia, progesterone, 17-hydroxyprogesterone esters, 19 - nor - 17 - hydroxyprogesterone esters, l7aethynyl- testosterone, 17a - ethynyl - 19 - nor - testosterone (norethisterone) and 17a ethynyl - 18 - methyl - 19 - nor - testerone (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.

Additional double bonds may be, inter alia, in the 1,2-, 6,7-, 15,16- or 16,17positions. Substituents may be halogen atoms, especially fluorine or bromine atoms, methyl, hydroxy, methoxy and acetoxy groups in the 4,6,7,11- and/or 16positions, and also methylene groups in the 1,2-, 6,7-, 15, 16- and/or 16,17positions. The 3-keto group of the gestagen may be reduced or eliminated. The 4,5double 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 esterify steroid alcohols, e.g. alkanecarboxylic acids having especially 1 to 11 carbon atoms. Examples of ethers are alkyl ethers and tetrahydropropyranyl 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 - la,2a - methylene - 4,6 - pregnadiene 3,20 - dione).

TheE2 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:

Daily dosage for each Daily dosage for of the immediately each of the following 9 to 11 immediately Daily dosage for successive days (2nd following 6 to 8 each of 10 to 12 stage) to complete successive days successive days 20-22 days (Agent (3rd stage) to (lust stage) of the invention) complete 28 days 1 1 mg oestradiol 1 mg oestradiol valerate valerate A 2 mg oestriol 2 mg oestriol 1 mg oestriol 0.25 mg D-norgestrel 2 2 mg oestradiol 2 mg oestradiol valerate valerate B 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 valerate E 4 mg oestriol 4 mg oestriol 2 mg oestriol 1 mg cyproterone acetate 1 1 mg oestradiol 1 mg oestradiol valerate valerate F 4 mg oestriol 4 mg oestriol 2 mg oestriol 0.25 mg D-norgestrel

Daily dosage for each Daily dosage for of the immediately each of the following 9 to 11 immediately Daily dosage for successive days (2nd following 6 to 8 each of 10 to 12 stage) to complete successive days successive days 20--22 days (Agent (3rd stage) to (lust stage) of the invention) complete 28 days 2 mg oestradiol 2 mg oestradiol valerate valerate G 1 mg oestriol 1 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 i 0.25 mg D-norgestrel 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, IIb 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 administration. Tablets, drawees, capsules, pills, suspensions or solutions especially are suitable for the preferred oral administration 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. For the preferred oral administration, the three-stage agents are preferably assembled in the form of a pack.

The following Examples illustrate the invention.

EXAMPLE 1 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 3.00 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approximately 140 mg with a normal sugar mixture.

A single drawee 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 80.000 mg total weight which is made up to approximately 140 mg with a normal sugar mixture 3rd stage 1.000 mg oestriol 45.500 mg lactose 26.800 mg maize starch 3.000rung polyvinyl pylrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approximately 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 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 approximately 140mg with a normal sugar mixture.

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 approximately 140 mg with a normal sugar mixture.

A single dragee of this composition is administercd 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 3.600 mg talcum 0.100 mg magnesium stearate 80.000 mg total weight which is made up to approximately 140 mg with a normal sugar mixture.

A single drawee of this composition is administered on each of the immediately following 7 successive days.

EXAMPLE 3 Composition of a dragPefor each stage Ist Stage 3.000 mg oestradiol valerate 2.000 mg oestriol 41.500 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 approximately 140 mg with a normal sugar mixture.

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 approximately 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 approximately 140 mg with a normal sugar mixture.

A single drag e 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 mg polyvinyl pyrrolidone 25 3.550 mg talcum 0.150 mg magnesium stearate 80.000 mg total weight which is made up to approximately 140 mg with a normal sugar mixture.

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 approximately 140 mg with a normal sugar mixture.

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 approximately 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 drape for each stage 1st Stage 0.500 mg oestradiol valerate 4.000 mg oestriol 42.000 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 approximately 140 mg with a normal sugar mixture.

2nd Stage 0.500 mg oestradiol valerate 4.000 mg oestriol 1.000 mg cyproterone acetate 41.000mg lactose 26.000 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approximately 140 mg with a normal sugar mixture.

A single drage of this composition is administered on each of the immediately following 10 successive days.

3rd Stage 2.000 mg oestriol 44.500mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrrolidone 25 3.700 mg talcum 80.00 mg total weight which is made up to approximately 140 mg with a normal sugar mixture.

EXAMPLE 6 Composition of a dragee for each stage Ist Stage 1.000 mg oestradiol valerate 4.000 mg oestriol 41.500mg 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 approximately 140 mg with a normal sugar mixture.

A single dragee of this composition is administered on each of the 11 successive days.

2nd Stage 1.000 mg oestradiol valerate 4.000 mg oestriol 0.250 mg D-norgestrel 41.250 mg lactose 26.800 mg maize starch 3.000 mg polyvinyl pyrolidone 25 3.700 mg talcum 80.000 mg total weight which is made up to approximately 140 mg with a normal sugar mixture.

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 approximately 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 Ist Stage 2.000 mg oestradiol valerate 1.000 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 approximately 140 mg with a normal sugar mixture.

A single drawee of this composition is administered on each 11 successive days. 2nd Stage 2.000 mg oestradiol valerate 1.000 mg oestriol 0.250 mg D-norgestrel 43.250mg 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 approximately 140 mg with a normal sugar mixture.

A single drag e of this composition is administered on each of the immediately following 10 successive days.

3rd Stage 0.500 mg oestriol 46.000mg 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 approximately 140 mg with a normal sugar mixture.

EXAMPLE 8 Composition of a drag e 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 approximately 140 mg with a normal sugar mixture.

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 80.000 mg total weight which is made up to approximately 140 mg with a normal sugar mixture.

A single drawee 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 approximately 140 mg with a normal sugar mixture.

WHAT WE CLAIM IS: 1. A pharmaceutical treatment pack for the treatment of clamacteric deficiency symptoms, which comprises in or on a container, card or other support member, unit dosage forms of an E2 oestrogen as hereinbefore defined an E3 oestrogen as hereinbefore defined and a gestagen, which provide (I) (a) a first set of 1012 daily dosages of an E2 oestrogen and (b) a first set of 1012 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, (II) (a) a second set of 9-11 daily dosages of E2 oestrogen, to complete 2022 daily dosages, and (b) a second set of 911 daily dosages of E3 oestrogen, to complete 2022 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 indications of 6-8 days of no treatment, the sets being located in a particular order, together with indications and/or instruction to indicate and facilitate a treatment consisting of the administration to a human female on each of 1012 successive days of one of the daily dosages Ia and one of the daily dosages Ib, on each of the immediately following

Claims

**WARNING** start of CLMS field may overlap end of DESC **. 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 80.000 mg total weight which is made up to approximately 140 mg with a normal sugar mixture. A single drawee 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 approximately 140 mg with a normal sugar mixture. A single drawee of this composition is administered on each of the immediately following 7 successive days. WHAT WE CLAIM IS:

1. A pharmaceutical treatment pack for the treatment of clamacteric deficiency symptoms, which comprises in or on a container, card or other support member, unit dosage forms of an E2 oestrogen as hereinbefore defined an E3 oestrogen as hereinbefore defined and a gestagen, which provide (I) (a) a first set of 1012 daily dosages of an E2 oestrogen and (b) a first set of 1012 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, (II) (a) a second set of 9-11 daily dosages of E2 oestrogen, to complete 2022 daily dosages, and (b) a second set of 911 daily dosages of E3 oestrogen, to complete 2022 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 indications of 6-8 days of no treatment, the sets being located in a particular order, together with indications and/or instruction to indicate and facilitate a treatment consisting of the administration to a human female on each of 1012 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 2022 days, one of the daily dosages IIa, one of the daily dosages Ilb 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.

2. 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 lb is substantially 1:2.

3. A pack as claimed in claim I or claim 2, 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.

4. A pack as claimed in any one of claims 1 to 3, wherein in each set, la, lb, IIa, IIb, IIc and, if present, III, the daily dosages are of substantially uniform dosage.

5. A pack as claimed in claim 4, wherein all the E2 oestrogen daily dosages of I and II are of substantially uniform dosage, and all the E3 oestrogen daily dosages of I, II and, if present, III are of substantially uniform dosage.

6. A pack as claimed in claim 4, which includes a third set of 6-8 daily dosages of E3 oestrogen III and wherein all the E2 oestrogen daily dosages of I and II are of substantially uniform dosage, all the E3 oestrogen daily dosages in the first and second sets of I and II 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.

7. A pack as claimed in any one of claims 1 to 5, which includes a set of indications of no treatment III, each indication being a removable object.

8. A pack as claimed in any one of claims 1 to 5, which includes a set of indications of no treatment III, each indication being an empty destructable profiled receptable.

9. A pack as claimed in any one of claims 1 to 8, whcrein each E2 oestrogen daily dosage contains an amount of E2 oestrogen which produces the same oestrogenic effec. as the administration of 0.5 to 4 mg of oestradiol valerate daily.

10. A pack as claimed in any one of claims 1 to 9, 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.

Il. A pack as claimed in any one of claims 1 to 10, wherein each gestagen daily dosage contains an amount of gestagen which produces the same gestagenic effect as the administration of 0.1 to 0.5 mg of D-norgestrel daily.

12. A pack as claimed in any one of claims 1 to 11, wherein the or one of the E2 oestrogens in the pack is oestradiol valerate.

13. A pack as claimed in any one of claims 1 to 12, wherein the same oestrogen is present in each E2 oestrogen daily dosage.

14. A pack as claimed in any one of claims 1 to 13, wherein the or one of the E3 oestrogens in the pack is oestriol.

15. A pack as claimed in any one of claims 1 to 14, wherein the same oestrogen is present in each E3 oestrogen daily dosage.

16. A pack as claimed in any one of claims 1 to 15, wherein the or one of the gestagens in the pack is D-norgestrel, norethisterone acetate or cyproterone acetate.

17. A pack as claimed in any one of claims 1 to 16, wherein the same gestagen is present in each gestagen daily dosage.

18. A pack as claimed in claim 1, wherein the unit dosage forms provide any one of the dosage combinations A to H herein.

19. A pack as claimed in any one of claims 1 to 18, 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, if present, each daily dosage of III is in a single dosage unit.

20. A pack as claimed in any one of claims 1 to 19, wherein each dosage unit is in a form suitable for oral administration.

21. A pack as claimed in claim 20, wherein each dosage unit is in the form of a tablet or drag.

22. A pack as claimed in any one of claims 1 to 19, wherein each dosage unit is in a form suitable for parenteral administration.

23. A pack as claimed in any one of claims 1 to 22, wherein the first and second sets Ia, Ib and IIa, IIb and IIc provide daily dosages for 21 days.

24. A pack as claimed in claim 23, 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.

25. A pack as claimed in claim 1, wherein the unit dosage forms are substantially as indicated in any one of the Examples 1 to 8 herein.

26. 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.

27. An agent as claimed in claim 26, wherein the E2 oestrogen is oestradiol valerate.

28. An agent as claimed in claim 26 or claim 27, wherein the E3 oestrogen is oestriol.

29. An agent as claimed in any one of claims 26 to 28, wherein the gestagen is D-norgestrel, norethisterone acetate or cyproterone acetate.

30. An agent as claimed in any one of claims 26 to 29, wherein the ratio of E2 oestrogen to E3 oestrogen is substantially 1:2.

31. A pharmaceutical preparation which comprises an agent as claimed in any one of claims 26 to 30, in admixture or conjunction with a pharmaceutically suitable carrier.

32. A pharmaceutical preparation as claimed in claim 31, which is in unit dosage form.

33. A pharmaceutical preparation as claimed in claim 32, 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.

34. A pharmaceutical preparation as claimed in claim 32 or claim 33, 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.

35. A pharmaceutical preparation as claimed in any one of claims 32 to 34, 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.

36. A pharmaceutical preparation as claimed in claim 32, wherein each dosage unit contains any one of the agents indicated for the second stage in A to H herein.

37. A pharmaceutical preparation as claimed in any one of claims 32 to 36, which consists of 9-11 dosage units or a multiple thereof.

38. A pharmaceutical preparation as claimed in claim 37, which consists of 10 dosage units or a multiple thereof.

39. A pharmaceutical preparation as claimed in claim 37 or claim 38, wherein the dosages of E2 oestrogen, E3 oestrogen and gestagen are of substantially uniform dosage in all dosage units.

40. A pharmaceutical preparation as claimed in any one of claims 31 to 39.

which is in a form suitable for oral administration.

41. A pharmaceutical preparation as claimed in claim 40, which is in the form of a tablet or drag.

42. A pharmaceutical preparation as claimed in any one of claims 31 to 39, which is in a form suitable for parenteral administration.

43. A pharmaceutical preparation as claimed in claim 31, which is substantially as indicated for the second stage in any one of the Examples 1 to 8 herein.

44. A pack which comprises as E2 oestrogen, an E3 oestrogen and a gestagen made up in discreet parts to provide (I) 1012 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--1 1 daily dosages, to complete 2022 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 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, which is made up in discrete parts as follows: (I) 10-12 daily dosages of E2 oestrogen and E3 oestrogen in a ratio of from 2:1 to 1:8, (1I) 9-11 1 daily dosages, to complete 2022 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) 6-8 daily dosages, to complete 28 daily dosages, of E3 oestrogen, or, in each discrete part, a multiple of these daily dosages.

46. A pack as claimed in claim 45, wherein the E2 oestrogen and E3 oestrogen in part (I) and/or in part(II) are in a ratio of substantially 1:2.

47. A pack as claimed in claim 44, which is made up in discrete parts as follows: (a) 2022 daily dosages of E2 oestrogen, (b) 2022 daily dosages of E3 oestrogen, (c) 9-11 daily dosages of gestagen, and if desired, in part (b) or as an additional discrete part, 6-8 daily dosages, to complete 28 daily dosages, of E3 oestrogen, or, in each part, a multiple of these daily dosages.

48. A pack as claimed in claim 44, made up in discrete parts as follows: (1) 2022 daily dosages of E2 oestrogen and E3 oestrogen in a ratio of from 2:1 to (2) 9-11 daily dosages of gestagen, and, if desired, (3) 6-8 daily dosages of E3 oestrogen to complete 28 daily dosages, or in each part, a multiple of these daily dosages.

49. A pack as claimed in claim 47 or claim 48, wherein the E2 oestrogen and E3 oestrogen are in a ratio of substantially 1:2.

50. A pack as claimed in any one of claims 44 to 49, wherein each discrete part is in the form of one or more pharmaceutical preparations comprising the active ingredient(s) in admixture or conjunction with a pharmaceutically suitable carrier.

51. A pack as claimed in claim 50, wherein each pharmaceutical preparation is in dosage unit form.

52. A pack as claimed in claim 51, wherein in each discrete part each daily dosage of the active ingredient(s) is in a single dosage unit.

53. A pack as claimed in claim 51 or claim 52, wherein in each discrete part the daily dosages are of substantially uniform dosage.

54. A pack as claimed in claim 53, wherein the daily dosages are as specified in claim 5 or claim 6.

55. A pack as claimed in any one of claims 44 to 54, wherein the daily dosages are as specified in any one or more of claims 9 to 11.

56. A pack as claimed in any one of claims 44 to 55, wherein the oestrogenic content is as specified in any one or more of claims 12 to 15.

57. A pack as claimed in any one of claims 44 to 56, wherein the gestagenic content is as specified in one or both of claims 16 and 17.

58. A pack as claimed in any one of claims 44 to 54, wherein the unit dosage forms provide any one of the dosage combinations A to H herein.

59. A pack as claimed in any one of claims 44 to 58, wherein the daily dosages are as specified in any one of claims 20 to 22.

60. A pack as claimed in any one of claims 44 to 59, 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.

61. A pack as claimed in claim 60, which provides 11 daily dosages of E2 oestrogen and E3 oestrogen free of gestagen.

62. A pack as claimed in claim 44, which comprises the unit dosage forms substantially as indicated in any one of the Examples 1 to 8 herein.