MXPA98000026A - Combined pharmaceutical preparation, equipment and method for hormo contraception - Google Patents

Abstract

The present invention relates to a combined two-step pharmaceutical preparation for hormonal contraception containing at least 30 daily doses. The hormonal active substance in the first step is a combination of an estrogen preparation and a gestagen preparation in an individual stage form in an amount at least sufficient to inhibit ovulation. In the second stage, the hormonal active substance is a preparation only desestrogen. The first stage comprises not less than 25 and not more than 77 daily doses, the total number of daily units that is equal to the total number of days of the desired cycle, that is, at least 30 and not more than 84 days. The combined preparation can be made available, for example, a monthly package and is used to control fertility in women. It reduces to a minimum the estrogen content in each individual dose and also has a low total hormonal content for the dosage cycle, while ensuring high contraceptive reliability, low incidence of follicle development, excellent cycle control and reliable prevention of menstrual intercyclic bleeding and side effects not wanted

Description

COMBINED PHARMACEUTICAL PREPARATION. EQUIPMENT AND METHOD FOR HORMONAL CONTRACEPTION DESCRIPTION OF THE INVENTION The present invention relates to a combined two-step pharmaceutical preparation for hormonal contraception containing at least 30 doses of units per day, wherein its preparation, in its first stage, comprises as a hormonal active ingredient a combination of an estrogen preparation and, in a dose which is at least sufficient to inhibit ovulation, a gestagen preparation, in an individual stage form and, in the second stage comprises as a hormonal active ingredient a preparation only of estrogen, wherein the first step comprises a minimum of 25 and a maximum of 77 doses of discrete or continuous daily units and the second stage 5, 6 or 7 doses of discrete or continuous daily units, and where the total number of daily units is equal to the total number of days of the desired cycle of a minimum of 30 and a maximum of 84 days, and is also related to a corresponding package (contraceptive equipment) that c It has that combined preparation, and a contraceptive method that uses the previous contraceptive preparation.

Oral contraceptives in the form of combination preparations have been known since 1960 as so-called monophase preparations. A preparations consisting of 21 doses of units comprising the active ingredient and 7 tablets or pills that are free of the active ingredient. The daily unit dose is composed of an estrogen and gestagen. In monophase preparations the dose of the active ingredient to be administered daily is the same in each unit dose. If the dose that is administered daily of the active components in the dose of individual units is different in the individual sections on the administration cycle, then the preparation refers to the so-called multi-phase preparation. Tricillary can be mentioned as an especially well-known example (DE-AS 23 65 103). As a result of the development of new progestins, more active than those contained in the first oral contraceptives, a continuous reduction of the daily dose of gestagen has been possible. It has also been possible to reduce the daily dose of estrogen although, as before, the estrogen contained in the hormonal contraceptives is usually ethinylestradiol. In the development of new, improved oral contraceptives, the following three factors have been (and are) dominant: (1) contraceptive reliability (2) good cycle control, that is, a low incidence of intermediate bleeding and (3) a minimum of unwanted side effects should be insured. The contraceptive reliability is carried out in particular by the gestagenic component. The amount of daily dose of that component corresponds at least to the threshold dose considered necessary for the gestagen in question to inhibit ovulation. The ethinylestradiol usually used as the estrogen in the combined preparations should increase the effect of ovulation inhibition of the gestagen and in particular ensure the stability of the cycle. In the case of the administration of only ethinylestradiol, the daily dose that has been used for the purpose of inhibiting ovulation is 100 μg. The preparations combined with the most recent generation of gestagen are, for example, the monophase preparations Femovan (DE-PS 2 546 062) and Marvelon (DE-OS 2 361 120). Milvane® can be mentioned as an example of a multi-phase preparation in which the dose of the unit contains a gestagen of the most recent generation, namely gestodene (EP-0 148 724). In those three-phase preparations, usually 4-6 pills are administered in the first phase, each pill comprising a low dose of estrogen and a low dose of gestagen. In the second phase of 4-6 pills, each unit dose comprises an estrogen in the same dose or a dose that is slightly increased (up to a maximum of two times) and a gestagen in the same dose or in a dose that is slightly increased (up to a maximum of 1.5 times). In a third phase of 9-11 units, each pill comprises an estrogen in the same dose or a dose that is slightly reduced, at the most reduced to the initial amount, and a gestagen in a dose that is further increased, to a maximum of 3 times the initial amount. Then the 7 days off of pills continue. Recently, combined multi-phase preparations have been proposed that can provide extended administration of the doses of units containing the active ingredient, ie, up to 24 days in the 28-day cycle. In those preparations the daily dose of gestagen either increases from the first, over the second, to the third phase (EP-A 0 491 415) or decreases (EP-A 0 491 438). In order to complete the 28-day cycle, in the first case there are 4 days of abortion pills, 4 placebos or 4 doses of units containing only gestagen, and in the second case of 4 to 7 days of abortion pills or from 4 to 7 placebos. The purpose of the development of new oral contraceptives that have a reduced daily hormonal dose is to minimize the side effects described in the epidemiological studies. The most recent epidemiological data point to a trend for improved tolerability of low-dose preparations with respect to cardiovascular side effects [Thorogood M. Oral Contraceptives and Cardiovascular Disease: an Epidemiologic Overview; Pharmacoepidemiology and Drug Safety, Vol. 2: 3-16 (1993); Gerstman B. B., Piper J. M. Tomita D K , Ferguson W. J. Stadel B .V. , Lundin F. E .; Oral Contraceptive Estrogen Dose and the Risk of Deep Venous Thromboembolic Disease, Am. J. E., Vol. 133, No. 1, 32-36 (1991); Lidegaard O., Oral contraception and the risk of a cerebral thromboembolic attack: results of a case-control study; BMJ Vol. 306, 956-63 (1993); Vessey M. Mant D., Smith A., Yeates D., Oral contraceptives and venous thromboembolism: findings in a large prospective study; BMJ, Vol. 292 (1986); Mishell D. R. , Oral Contraception: Past, Present and Future Perspectives; Int. J. Fertile , 36 Suppl. , 7-18 (1991)]. A connection is accepted between the daily dose of estrogen and the frequency of cardiovascular complications. The preparation that currently has the lowest dose of estrogen is sold as Mercilon® and contains 20 μg of ethinylestradiol in combination with 150 μg of desogestrel in each unit dose per day over a period of 21 days with a period remaining 7-pill-free. days. As expected, the control of the cycle of that preparation compared to preparations that have a higher dose of estrogen is somewhat deficient. A further clinically significant problem is the observation, which has been made in various studies, of a decreased ovarian suppression of that preparation containing 20 μg of ethinylestradiol. Clearly, below that very low dose of estrogen, the maturation of follicles occurs in many women, which can be detected by ultrasound examinations and hormonal tests [Lunell N. O., Carlstrom K., Zador G., Ovulation inhibition with a combined oral contraceptive containing 20 μg ethynyloestradiol and 250 μg levonorgestrel; Acta Obstet. Gynecol. Scand. Suppl. 88: 1 7-21 (1979); Mall-Haefeli M. , Werner-Zodrow I. , Huber P. R., Klinische Erfahrungen mit Mercilon und Marvelon unter besonderer Berücksichtigung der Ovar-Funktion (Clinical experiences with Mercilon and Marvelon with special consideration given to ovary function); Geburtsh and Frauenheilk. 51, 35-38, Georg Thieme Verlag, Stuttgart-New York (1991); Strobel E., Behandlung mit oralen Kontrazeptiva (Treatment with oral contraceptives); Fortsch. Med. 1 10 Jg. No. 20 (1992); Letter to Editor, Contraception 45: 519-521 (1992); Teichmann A.T., Brill K., Can Dose Reduction of Ethynylestradiol in OCs Jeopardize Ovarian Suppression and Cycle Control? Abstract Book, Vlllth World Congress on Human Reproduction, Bali, Indonesia (1993)].

Until recently, the interruption of several days of the administration of pills containing the active ingredient was considered necessary in order to promote the presentation of bleeding and ensure adequate control of the cycle. Other preparations containing an estrogenic and gestagenic active ingredient have been described and are generally administered in constant amounts in each single unit dose over a period of 21 days, the administration of those unit doses containing an estrogenic and gestagenic active ingredient which it precedes the administration of doses of estrogen-only units (Ijzerman, US-A 3 502 772, Pasquale, US-A 4 921 843, Kuhl et al., EP-A 0 499 348). With those preparations, at the beginning of the administration, either on the first day of the cycle (Kuhl) or at the earliest on the second day of the cycle (Pasquale), the administration of the doses of units containing an ingredient is initiated active only, in a dose that is below the dose of ovulation inhibition of the estrogenic component such that, especially in the first cycle of administration, follicle development can occur. The development of the follicle is considered responsible for interfering with ovulation (Chowdry et al., "Escape" ovulation in women due to the lack of low dose combination oral contraceptive pills, Contraception, 22: 241-247, 1980; Molloy B.G. et aL, "Missed pill" conception: fact or fiction? Brit. Med. J. 290, 1474-1475, 1985). Contraceptive protection is consequently in doubt. The risk of a pregnancy is, therefore, especially high in the case of forgetfulness in the administration between preparations of 20 μg of ethinylestradiol. DE-OS 43 13 926 describes a pharmaceutical preparation for contraception having a minimum of four phases, wherein the preparation consists of a fixed or sequential combination, consisting of a minimum of three phases, of ethinylestradiol or mestranol or other synthetic estrogen , and also a gestagen, and an estrogen preparation which is administered at least in the fourth phase of the cycle and which contains ethinylestradiol or mestranol and / or other endogenous and / or synthetic estrogen. That preparation is to be administered during the woman's total cycle and is limited to a 28-day administration. Common in all preparations for hormonal contraception on the market so far is that it is fixed to the package unit for a 28-day course of administration (4-week rhythm). For a one-year prevention period, that is, 12 months, the administration of the contents of the units of 13 packages is therefore necessary.

It is already known, of course, for a long time that the onset of menstruation, when taking an oral contraceptive where there is a continuous daily administration of both doses of units containing estrogen and especially containing gestagen, can differ until the end of administration of gestagen-containing unit doses [Hamerlynck J .V. Th. H. et al .., Contraception 35.3: 199-205 (1987); Luodon N. B., I PPF Med. Bull. 13.1: 2-3 (1979); Luodon N. B. et a, Brit. Med. J. 60085: 487-490 (1977/2)]. After stopping doses of gestagen-containing units, the presentation of bleeding begins. Although the ovulation inhibiting agent according to EP-A 0 499 348 is not limited to a desired administration of a 28-day cycle, the number of daily hormone units containing both estrogen and gestagen are restricted to an upper limit of 23 units per day. The purpose of the present invention is to provide a combined preparation having as low as possible an estrogen content in each individual unit dose, but at the same time also a low total hormonal content per cycle of administration, with which, with a high degree of contraceptive reliability, an incidence as low as possible of follicle development even in the first cycle of administration, and satisfactory control of the cycle with reliable prevention of intermediate bleeding, such as interference from bleeding and spotting, are achieved and thereby avoiding the effects unwanted side This object is achieved by the provision of a combined preparation of two stages described at the beginning and also a corresponding package containing that combined preparation (contraceptive equipment) and a contraceptive method using the described contraceptive preparation. The preferred arrangements of the present invention relate to a combined pharmaceutical preparation of the type mentioned at the beginning in which - the first stage comprises 25 or 26 daily units doses, - the first stage comprises a minimum of 28 and a maximum of 84 dose of daily units, - the first stage comprises 28 doses of daily units, - the first stage includes 28 plus 7, or 28 plus a multiple of 7, daily units dose, - the second stage comprises 7 doses of daily units, - the first stage comprises 25 or 26 doses of daily units, and the second stage comprises 5 or 6 doses of daily units, such that the combined preparation has a total of 30 or 31 doses of daily units.

The present invention further relates to a contraceptive kit containing a minimum of 30 and a maximum of 84 doses of daily units, each comprising at least one hormonal active ingredient, in which the equipment has a first and a second stage , wherein, in its first step, the kit comprises as a hormonal active ingredient a combination of an estrogen preparation and, in a dose at least sufficient to inhibit ovulation, a gestagen preparation, in an individual stage form, and , in the second stage, comprises as hormonal active ingredient a preparation only of estrogen, the first stage comprising a minimum of 25 and a maximum of 77 doses of discrete or continuous daily units and the second stage comprising 5, 6 or 7 doses of continuous or discrete daily units, and the total number of daily units that are equal to the total number of days of the desired cycle of a minimum of 30 and a maximum 84 days Preferred contraceptive devices, according to the present invention, are characterized as follows: - the first stage comprises 25 or 26 doses of daily units, - the first stage comprises a minimum of 28 and a maximum of 84 doses of daily units, - the first stage comprises 28 doses of daily units, - the first stage comprises 28 plus 7, or 28 plus a multiple of 7, dose of daily units, - the second stage comprises 7 doses of daily units, - the first stage comprises 25 or 26 doses of daily units, and the second stage comprises 5 or 6 doses of daily units, in such a way that the equipment has a total of 30 or 31 doses of daily units. In a further embodiment of the contraceptive equipment, according to the invention, some of the doses of units of the first stage are arranged in periodic repeating subunits that are spatially separated from one another and / or by other marks. Preferably, the unit doses are arranged in sub-units in the most initial 26va. dose of daily units, the individual sub-units can be separated from each other by perforations or other suitable means for separation, 7 doses of units are contained in each of the separate sub-units, the first stage comprises 28 plus 7, or 28 plus 1 multiple of 7, dose of daily units, and / or the second stage comprises 7 doses of daily units.

In the case of the contraceptive method, according to the invention, which employs the combined preparation described, in the first stage, beginning with the first day of the cycle, a unit dose comprising an estrogen in combination with a gestagenic component is administered. daily over a minimum period of 25 and a maximum period of 77 days. Then follows the second stage in which over the remaining period of the cycle, with the cycle comprising a minimum of 30 and a maximum of 84 days, an estrogen is administered during days 5, 6 or 7 days. In this way, a unit dose comprising a hormonal active ingredient is administered on each day of the cycle. With the administration of the combined preparation, according to the invention, the restoration of the dominant follicle, which occurs in the spontaneous cycle during the first 6 days of the menstrual cycle, is efficiently suppressed. In this way, with the combined preparation of the present invention, follicle development can be surprising and, consequently, interference ovulations are avoided, which increases the contraceptive reliability. This is of great importance especially where there are errors in the administration, particularly in the case of hormonal contraceptives that have a low daily dose of ethinylestradiol. Since it is known that 25% of women who take the pill have errors (that omit dose of units or that extend the interval between the daily administration of two doses of unit for more than 24 hours) (Finlay I .G., Scott M.G. B.: Patterns of contraceptive pill-taking in an inner city practice. Br. Med. J. 1986, 293: 601-602), the combined preparation, according to the invention, when used as an ovulation inhibiting agent, increases contraceptive reliability. This is true in particular in the case of lower dose preparations. In particular, however, this larger number of doses of daily units comprising both estrogen and gestagen results in a prolongation of the cycle and a reduced frequency of presentation of bleeding. The subsequent stage, in which the doses of units comprising as an active hormonal ingredient only an estrogenic component is administered daily for 5, 6 or 7 days, ensures a presentation of the bleeding and causes a stimulation of the progesterone receptors in the endometrium, as a result of which a reduced ratio of intermediate bleeding is achieved compared with the conventional low dose preparations in the subsequent administration cycle. Together with the prolonged phase of administration of the unit doses containing estrogen and gestagen, for example, it is in this way possible to prolong the menstrual cycles to 30 or 31 days (monthly packaging).

According to the preferred variants, it is possible to optionally stop the presentation of bleeding until the day 77, bleeding that begins after doses of units comprising estrogen and gestagen have been stopped. A variable manipulation of the beginning of the presentation of the bleeding is possible with the contraceptive equipment according to the present invention, in which the doses of units of the first stage, in the most initial ones since the 26th. daily unit dose, are arranged in subunits that can be separated from each other by perforations or some other suitable means of separation. The contraceptive equipment, according to the invention, is constructed, for example, in the form of an ampoule in which each individual segment, each of which preferably contains 7 doses of units of the first stage, can conveniently and easily be separated by means of perforations made in the base of the ampoule plate. However, it is also possible for the subunits to be each in the form of individual separate ampoules or, for example, to stop the 28 doses of units of the first stage to be in a first ampoule and for the next units of the first ampoule. stage being in a second blister in which the sub-units may be separated from one another by perforations in the manner described.

Preferably, in all embodiments of the invention, the estrogen of the first hormone component is selected from the group of compounds 1 7β-estradiol, ethinylestradiol and 1 7β-estradiol valerate and the gestagen is selected from the group of compounds dienogest gestodene, levonogestrel , desogestrel, 3-ketodesogestrel, drospironenone, cyproterone acetate, norgestimate and norethisterone and also the estrogen of the second hormonal component is selected from the group of compounds of 1 7ß-estradiol, ethinylestradiol and 1 7β-estradiol valerate. Preferably, in the present invention, the estrogen of the first hormonal component is contained in each dose of daily unit in a dose of from 1.0 to 6.0 mg of 1 7β-estradiol, from 0.015 to 0.025 mg of ethinylestradiol, of 1.0. to 4.0 mg of 1 7β-estradiol valerate and the gestagen is contained in each dose of daily unit in a dose of 1.0 to 3.0 mg of dienogest from 0.05 to 0.075 mg of gestodene, from 0.05 to 0.125 mg of levonorgestrel, from 0.06 to 0.15 mg of desogestrel, from 0.06 to 0.15 mg of 3-ketodesogestrel, from 1.0 to 3.0 mg of drospironenone, from 1.0 to 2.0 mg of cyproterone acetate, from 0.2 mg to 0.3 mg of norgestimate of 0.35 to 0.75 mg of norethisterone. The second hormonal component comprises estrogen in each unit dose per day, preferably in an amount of from 1.0 to 6.0 mg of 1,7-estradiol, from 0.002 to 0.04 mg of ethinylestradiol, from 1.0 to 4.0 mg of valerate. of 1 7ß-estrad iol. According to an especially preferred embodiment, the second hormonal component contains as estrogen ethinylestradiol in an amount of 0.01 to 0.015 mg in each unit dose per day.

It is considered as estrogen for the first and for the second hormonal component especially ethinylestradiol or natural estradiol. Of the mentioned progestins for the second hormonal component attention is directed to gestodene; Levonorgestrel is also preferred. The 1-β-estradiol valerate, which may be contained as estrogen in both the first and the second hormonal component, is mentioned only as a possible representative of those esters of 17β-estradiol; other homologous esters of that type can also be used as the estrogen component within the scope of the present invention. The following examples serve to illustrate the present invention in more detail: Example 1 Day Composition Dfa 8 9 10 11 12 13 14 Composition C C C c C C C Day 15 16 17 18 19 20 21 Composition C C C c C C C Dfa 22 23 24 25 Composition C C C C Day 26 27 28 29 30 Composition E E E E E Example 2: Day 1 2 3 4 5 6 7 Composition C C C C C C C Day 8 9 10 11 12 13 14 Composition C C C c C C C Day 15 16 17 18 19 20 21 Composition C C C c C C C Day 22 23 24 25 26 Composition C C C C C Day 27 28 29 30 31 Composition E E E E E Example 3: Day 1 2 3 4 5 6 7 Composition c C C C C C C Day 8 9 10 11 12 13 14 Composition C C c c C C C Dfa 15 16 17 18 19 20 21 Composition C C C C C C C Dfa 2 222 23 24 25 Composition C C C C Dfa 26 27 28 29 30 31 Composition E e E E E E Example 4:: Day 1 2 3 4 5 6 7 Composition C C C C C C C Day 8 9 10 11 12 13 14 Composition C C c C C C C Day 15 16 17 18 19 20 21 Composition C C C C C C C Day 22 23 24 25 26 27 28 Composition C C C C C C C Day 29 30 31 32 33 34 35 Composition C C C C C C C Day 36 37 38 49 40 41 42 Composition C C C C C C C Dfa 43 44 45 46 47 48 4S Composition C C C C C C C Day 50 51 52 53 54 55 5 < Composition C C C C C C C Day 57 58 59 60 61 62 63 Composition E E E E E E E Example 5: Day 1 2 3 4 5 6 7 Composition c C C C C C C Day 8 9 10 11 12 13 14 Composition C C c c C C C Day 1 155 16 17 18 19 20 21 Composition C C C C C C C Day 22 23 24 25 26 27 28 Composition C C C C C C C Dfa 29 30 31 32 33 34 35 Composition C C C C C C C Day 36 37 38 49 40 41 42 Composition C C C C C C C Day 43 44 45 46 47 48 49 Composition C C C C C C C Day 50 51 52 53 54 55 56 Composition C C C C C C C Day 57 58 59 60 61 62 63 Composition C C C C C C C Dfa 64 65 66 67 68 69 70 Composition C C C C C C C Day 71 72 73 74 75 76 77 Composition C C C C C C C Day 78 79 80 81 82 83 84 Composition E E E E E E E Example ß: Day 1 2 3 4 5 6 7 Composition c C C C C C C Dfa 8 9 10 11 12 13 14 Composition C C C C C C C Dfa 15 16 17 18 19 20 21 Composition C C c c C C C Day 22 23 24 25 26 27 28 Composition C C C C C C C Day 29 30 31 32 33 34 35 Composition C C C C C C C Day 36 37 38 49 40 41 42 Composition C C C C C C C Day 43 44 45 46 47 48 49 Composition C C C C C C C Day 50 51 52 53 54 55 56 Composition EEEEEEE Day = day of the menstrual cycle, day 1 is the first day of bleeding C = combination of estrogen and gestagen (= first hormonal component) E = estrogen (= second hormonal component) P = perforation The formulation of the unit doses is carried out in a conventional manner with the use of known auxiliaries for the preparation of tablets, pills, dragees containing estrogen / gestagen and exclusively containing estrogen, etc. The combined preparation, according to the invention, serves to prevent fecundation in women by administering doses of daily units of the first hormonal component for a minimum of 25 and a maximum of 77 days, beginning on day 1 of the menstrual cycle ( first day of menstrual bleeding), followed by 5, 6 or 7 doses of daily units of the second hormonal component, which contains only one estrogen (E), for a total of a minimum of 30 and a maximum of 84 days in the cycle of administration . In the second menstrual cycle (following), the administration of the first unit dose of the first hormonal component of a new packing unit (equipment) of the combined pharmaceutical preparation, according to the invention starts on day 1 of that cycle, without any break in the administration. With that combined preparation, prolonged ovarian suppression can be achieved without frequent follicle maturation, and also excellent cycle control, with a low daily dose of estrogen, a low total amount of estrogen and a low total amount of hormone per cycle of administration. The advantages of this combined preparation, according to the invention (ovulation inhibiting agent) administered for a minimum of 30 and a maximum of 84 days per cycle compared with the preparations described up to now, especially those having a daily dose of ethinylestradiol less than 30 μg and those with a pill-free period, can be characterized as follows: 1. A significantly lower frequency of follicle development in the user. This means a lower risk of ovulation interference and consequently greater contraceptive reliability especially where there are errors in the administration. 2. Restoration of the dominant follicle is effectively suppressed by prolongation of the administration of the combination. 3. The administration of 5, 6 or 7 doses of daily units of estrogen that follow the administration of the combined dose of the first stage results in a clearly improved control of the cycle and in a lower incidence of side effects, such as pain of head within the context of premenstrual syndrome. 4. Other clinical symptoms that are attributable to strongly fluctuating endogenous levels of estrogen, such as, for example, breast tenderness, are likely to be distinctly reduced with respect to significantly strong ovarian suppression. 5. As a result of the freedom of bleeding (amenorrhea) for a longer period, there is an increased acceptance by the user; this is true especially as the number of doses of units in the first stage increases. 6. Negative effects that occur with or as a result of bleeding, such as, for example, anemia, cramps, nausea, etc. It occurs less frequently. 7. Low constant levels of estrogen and gestagen; consequently, it avoids the metabolic variations and as a result an improvement of the tolerability. 8. A possible pregnancy is recognized as a result of errors in administration due to the absence of bleeding after stopping doses of units containing estrogen and gestagen.

The formulation of an estrogen and gestagen for the preparation of a combined preparation according to the invention is carried out in a manner completely analogous to that already known for conventional oral contraceptives having a 21-day administration period of the active ingredients, such as , for example, Femovan® (ethinylestradiol / gestodene) or Microgynon® (ethinylestradiol / levonorgestrel). The formulation of doses of units containing exclusively estrogen can also be carried out in a manner completely analogous to that known for estrogen-containing agents designed for oral administration which are already available, for example ProgynonCR. The doses of the units of the first stage of the preparation, according to the invention, can also be in the form of a patch (transdermal application), an implant or another distribution of formulation and thus be administered continuously). As a way to package the combined preparation according to the invention, a blister package constructed in the form according to the invention is generally used; however, other forms of packaging known for this purpose are also possible. In order to determine the equivalently effective amounts of ethinylestradiol and 17β-estradiol on the one hand and of different progestins, such as gestodene, levonorgestrel, desogestrel and 3-ketodesogestrel, on the other hand, reference is made to the data given in EP- A-0 253-607. Additional details to determine the dose equivalents of different gestagenic active ingredients can be found, for example, in "Probleme der Dosisfindung: Sexualhormone" (Problems of dosage determination: sexual hormones); F. Neumann et al., In "Arzneimittelforschung" (Drug Research) 27, 2a, 296-318 (1977) and in "Aktuelle Entwicklungen in der Hormonal Kontrazeption" (Current developments in hormonal contraception), H. Kuhl in "Gynácologe" 25: 231 -240 (1992).

Claims (40)

1. CLAIMS 1 . A two-step combined pharmaceutical preparation for hormonal contraception containing at least 30 doses of units per day, wherein the preparation, in its first stage, comprises as a hormonal active ingredient a combination of an estrogen preparation and, in a dose that is at least sufficient to inhibit ovulation, a gestagen preparation, in an individual stage form and, in the second stage comprises as a hormonal active ingredient a single estrogen preparation, characterized in that the first stage comprises a minimum of 25 and a maximum of 77 doses of discrete or continuous daily units and the second stage comprises 5, 6 or 7 doses of discrete or continuous daily units, and where the total number of daily units is equal to the total number of days of the desired cycle of a minimum of 30 and a maximum of 84 days. 2. The combined preparation, according to claim 1, characterized in that the first stage comprises 25 or 26 doses of daily units. 3. The combined preparation, according to claim 1, characterized in that the first stage comprises a minimum of 28 and a maximum of 84 doses of daily units. 4. The combined preparation, according to claim 3, characterized in that the first stage comprises 28 doses of daily units. 5. The combined preparation, according to claim 3, characterized in that the first stage comprises 28 plus 7, or 28 plus a multiple of 7, dose of daily units. 6. The combined preparation, according to claim 1, characterized in that the second stage comprises 7 doses of daily units. 7. The combined preparation, according to claim 2, characterized in that the second stage comprises 5 or 6 doses of daily units, such that the combined preparation has a total of 30 or 31 doses of daily units. 8. The combined preparation according to any one of the preceding claims 1 to 7, characterized in that the estrogen of the first stage is selected from the group of compounds of 17β-estradiol, ethinylestradiol and 1 7β-estradiol valerate and the gestagen is selected from the group of compounds dienogest gestodene, levonogestrel, desogestrel, 3-ketodesogestrel, drospironenone, cyproterone acetate, norgestimate and norethisterone and also the estrogen of the second hormonal component is selected from the group of compounds of 1 7ß-estradiol, ethinylestradiol and 1 7β-estradiol valerate . 9. The combined preparation according to any of the preceding claims 1 to 8, characterized in that the estrogen of the first stage is contained in each dose of daily unit in a dose of from 1.0 to 6.0 mg of 1 7β-estradiol, from 0.015 to 0.025 mg of ethinylestradiol, 1.0 to 4.0 mg of 17β-estradiol valerate, and gestagen is contained in each unit dose per day at a dose of 1.0 to 3.0 mg of dienogest from 0.05 to 0.075 mg of gestodene, 0.05 to 0.125 mg of levonorgestrel, 0.06 to 0.15 mg of desogestrel, 0.06 to 0.15 mg of 3-ketodesogestrel, 1.0 to 3.0 mg of drospironenone, 1.0 to 2.0 mg of cyproterone acetate, from 0.2 mg to 0.3 mg of norgestimate from 0.35 to 0.75 mg of norethisterone. 10. The combined preparation, according to any of the preceding claims 1 to 9, characterized in that it is contained in each dose of daily unit in the second stage an amount of from 1.0 to 6.0 mg of 1 7β-estradiol, from 0.002 to 0.04. mg ethinylestradiol, from 1.0 to 4.0 mg of 17-estradiol valerate. eleven . The contraceptive equipment that contains at least 30 doses of daily units, each containing at least one hormonal active ingredient, which has a first and a second stage, in which the equipment, in its first stage, comprises as an active ingredient hormone a combination of an estrogen preparation and, in a dose that is at least sufficient to inhibit ovulation, a gestagen preparation, in an individual stage form and, in the second stage, comprises as a hormonal active ingredient a preparation only of estrogen, characterized in that the first stage it comprises a minimum of 25 and a maximum of 77 doses of discrete or continuous daily units and the second stage comprises 5, 6 or 7 doses of continuous or discrete units per day, and where the total number of daily units is equal to the total number of units. days of the desired cycle of a minimum of 30 and a maximum of 84 days. 12. The contraceptive equipment, according to claim 11, characterized in that the first stage comprises 25 or 26 doses of daily units. 13. The contraceptive equipment, according to claim 11, characterized in that the first stage comprises a minimum of 28 and a maximum of 84 doses of daily units. 14. The contraceptive equipment, according to claim 13, characterized in that the first stage comprises 28 doses of daily units. 15. The contraceptive equipment, according to claim 13, characterized in that the first stage comprises 28 plus 7, or 28 plus a multiple of 7, dose of daily units. 16. The contraceptive equipment, according to claim 11, characterized in that the second stage comprises 7 doses of daily units. The contraceptive device, according to claim 12, characterized in that the second stage comprises 5 or 6 doses of daily units, in such a way that the equipment has a total of 30 or 31 doses of daily units. 18. The contraceptive equipment according to any of the preceding claims 1 to 17, characterized in that the estrogen of the first stage is selected from the group of compounds 1 7β-estradiol, ethinylestradiol and valerate of 1 7β-estradiol and the gestagen is selected of the group of compounds dienogest gestodene, levonogestrel, desogestrel, 3-ketodesogestrel, drospironenone, cyproterone acetate, norgestimate and norethisterone and also the estrogen of the second hormonal component is selected from the group of compounds 1 7ß-estradiol, ethinylestradiol and valerate of 1 7ß- estradiol. 19. The contraceptive equipment, according to any of the preceding claims 1 to 18, characterized in that the estrogen of the first stage is contained in each dose of daily unit in a dose of from 1.0 to 6.0 mg of 1 7β-estradiol, 0.015 to 0.025 mg of ethinyl estradiol, 1.0 to 4.0 mg of 17-estradiol valerate, and gestagen is contained in each unit dose per day at a dose of 1.0 to 3.0 mg of dienogest from 0.05 to 0.075 mg of gestodene, 0.05 to 0.125 mg of levonorgestrel, 0.06 to 0.15 mg of desogestrel, 0.06 to 0.15 mg of 3-ketodesogestrel, 1.0 to 3.0 mg of drospironenone, 1.0 to 2.0 mg of cyproterone acetate , from 0.2 mg to 0.3 mg of norgestimate from 0.35 to 0.75 mg of norethisterone. 20. The contraceptive device, according to any of the preceding claims 1 to 19, characterized in that it is contained in each dose of daily unit in the second stage an amount of from 1.0 to 6.0 mg of 1 7β-estradiol, from 0.002 to 0.04 mg of ethinyl estradiol, 1.0 to 4.0 mg of 1 7-estradiol valerate. twenty-one . The contraceptive equipment that contains at least 30 doses of daily units, each containing at least one hormonal active ingredient, which has a first and a second stage, in which the equipment, in its first stage, comprises as an active ingredient A combination of an estrogen preparation and, in a dose that is at least sufficient to inhibit ovulation, a preparation of gestagen, in an individual stage form and, in its second stage, comprises as a single active ingredient a hormonal active ingredient. of estrogen, characterized in that the first stage comprises a minimum of 25 and a maximum of 77 doses of discrete or continuous daily units and the second stage comprises 5, 6 or 7 doses of continuous or discrete units per day, and wherein the total number of daily units is equal to the total number of days of the desired cycle of a minimum of 30 and a maximum of 84 days, some of the doses of units of the first stage that is they are arranged in sub-units of periodic repetition that are separated from each other spatially and by other markings. 22. The contraceptive equipment, according to claim 21, characterized in that the unit doses are arranged in sub-units in the most initial ones since 26th. daily unit dose. 23. The contraceptive equipment, according to claim 21 or 22, characterized in that individual sub-units can be separated from one another by perforations or other suitable means for separation. 24. The contraceptive equipment, according to any of claims 21, 22 and 23, characterized in that the separate subunits each contain a dose of 7 units. 25. The contraceptive equipment, according to any of the preceding claims 21 to 24, characterized in that the first stage comprises 28 plus 7, or 28 plus a multiple of 7, dose of daily units. 26. The contraceptive equipment, according to any of the preceding claims 21 to 25, characterized in that the second stage comprises 7 doses of daily units. 27. The contraceptive equipment, according to any of the preceding claims 21 to 26, characterized in that the estrogen of the first step is selected from the group of compounds of 1 7β-estradiol, ethinylestradiol and 1 7β-estradiol valerate and the gestagen is selected from the group consisting of group of compounds dienogest gestodene, levonogestrel, desogestrel, 3-ketodesogestrel, drospironenone, cyproterone acetate, norgestimate and norethisterone and also the estrogen of the second hormonal component is selected from the group of compounds 1 7β-estradiol, ethinylestradiol and 1 7β-estradiol valerate . 28. The contraceptive equipment, according to any of the preceding claims 21 to 27, characterized in that the estrogen of the first stage is contained in each dose of daily unit in a dose of from 1.0 to 6.0 mg of 1 7β-estradiol, from 0.015 to 0.025 mg of ethinylestradiol, 1.0 to 4.0 mg of 1-β-estradiol valerate, and gestagen is contained in each unit dose per day at a dose of 1.0 to 3.0 mg of dienogest from 0.05 to 0.075 mg of gestodene, 0.05 to 0.125 mg of levonorgestrel, 0.06 to 0.15 mg of desogestrel, 0.06 to 0.15 mg of 3-ketodesogestrel, 1.0 to 3.0 mg of drospironenone, 1.0 to 2.0 mg of cyproterone acetate , from 0.2 mg to 0.3 mg of norgestimate from 0.35 to 0.75 mg of norethisterone. 29. The contraceptive equipment, according to any of the preceding claims 21 to 28, characterized in that it is contained in each dose of daily unit in the second stage an amount of from 1.0 to 6.0 mg of 17β-estradiol, from 0.002 to 0.04 mg of eti nilestradiol, from 1.0 to 4.0 mg of 1-β-estradiol valerate. 30. A method for contraception in female mammals, characterized in that it comprises a sequential administration for a minimum of 30 and a maximum of 84 days of doses of daily units of a minimum of 25 and a maximum of 77 doses of discrete or continuous units per day during a first stage and 5, 6 or 7 doses of discrete or continuous units daily during a second stage, comprising as a hormonal active ingredient in the first stage a combination of an estrogen preparation and, in a dose that is at least sufficient to inhibit the ovulation, a gestagen preparation, in an individual stage form, and comprising as a hormonal active ingredient in the second stage a preparation only of estrogen. 31 The method, according to claim 30, characterized in that in the first stage, 25 or 26 doses of units per day are administered. 32. The method, in accordance with the claim 30, characterized in that a minimum of 28 and a maximum of 77 doses of daily units are administered in the first stage. 33. The method, according to claim 32, characterized in that in the first stage 28 doses of units per day are administered. 34. The method, according to claim 32, characterized in that in the first stage 28 plus 7, or 28 plus a multiple of 7, dose of daily units are administered. 35. The method according to any of the preceding claims 30 to 34, characterized in that in the second stage 7 doses of units per day are administered. 36. The method, according to claim 31, characterized in that in the second stage, 5 or 6 doses of units per day are administered. 37. The method according to any of the preceding claims 30 to 36, characterized in that the estrogen in the unit doses of the first stage is selected from the group of compounds 1 7β-estradiol, ethinylestradiol and 1 7β-estradiol valerate and the gestagen is selected from the group of compounds dienogest gestodene, levonogestrel, desogestrel, 3-ketodesogestrel, drospironenone, cyproterone acetate, norgestimate and norethisterone and also the estrogen in the doses of units of the second hormonal component is selected from the group of compounds 1 7β-estradiol, ethinylestradiol and 1 7β-estradiol valerate. 38. The method, according to any of the preceding claims 30 to 37, characterized in that the estrogen of the first step is administered in each dose of daily unit in a dose of from 1.0 to 6.0 mg of 1 7β-estradiol, of 0.015. 0.025 mg of ethinyl estradiol, 1.0 to 4.0 mg of 1 7-estradiol valerate, and gestagen is administered in each unit dose per day at a dose of 1.0 to 3.0 mg of dienogest from 0.05 to 0.075 mg. gestodene, 0.05 to 0.125 mg of levonorgestrel, 0.06 to 0.15 mg of desogestrel, 0.06 to 0.15 mg of 3-ketodesogestrel, 1.0 to 3.0 mg of drospironenone, 1.0 to 2.0 mg of cyproterone acetate, from 0.2 mg to 0.3 mg of norgestimate from 0.35 to 0.75 mg of norethisterone. 39. The method, according to any of the preceding claims 30 to 38, characterized in that it is administered in each dose of daily unit in the second stage an amount of from 1.0 to 6.0 mg of 1 7β-estradiol, from 0.002 to 0.04 mg of ethinylestradiol, from 1.0 to 4.0 mg of 17β-estradiol valerate. 40. The method, according to any of claims 30 to 39, characterized in that the female mammal is a homo sapiens.