MXPA06006031A - Extended use combination comprising estrogens and progestins - Google Patents

Abstract

A pharmaceutical preparation to obtain a continuous hormonal treatment over a desired period of time longer than 21-28 days comprising a first composition containing at least one estrogen and/or at least one progestin in a predetermined amount to be administered in the first 21-28 days and a second composition which contains at least one estrogen and/or at least one progestin in a predetermined amount higher than the amount of the first composition and comprises a mono or multiphase sequence of pharmaceutical dosages.

Description

EXTENDED USE OF COMBINATION THAT COMPRISES ESTROGENS AND PROGESTINES FIELD OF THE INVENTION The present invention relates to the extended use of a pharmaceutical preparation comprising estrogens and progestins, wherein the progressive increase in the dosage of estrogens and / or progestins after a typical period of 28 days allows to obtain a stimulation. continuous endometrium. This leads to the desired endo-metrial stability and an extended bleeding-free regimen. More particularly, the present invention relates to a pharmaceutical preparation that allows a continuous hormonal treatment to be obtained during a desired period of time longer than 21-28 days, comprising a first composition containing at least one estrogen and / or less a progestin in a predetermined amount, which is administered in the first 21-28 days, and a second composition containing at least one estrogen and / or at least one progestin, in a predetermined amount greater than the amount of the first composition, and comprising a mono or multiphase sequence of pharmaceutical dosages. Furthermore, the present invention relates to a method for inhibiting ovulation in a mammal, in particular a human being, comprising administering to said mammal a first composition containing a determined amount of an estrogen, alone or in combination with a progestin, for 21-28 days, followed by an additional administration of a second composition containing an estrogen and a progestin, to obtain a continuous hormonal treatment for a period of time longer than 21-28 days. The second composition contains an amount of estrogen and progestin that is greater than the amount of the first composition. The second composition further comprises mono or multiphase sequences of pharmaceutical dosages. The use of a pharmaceutical preparation for the manufacture of an agent to inhibit ovulation in a mammal, in particular a human being, which induces a long-term amenorrhea and which reduces the symptoms related to the lack of hormones, is also a object of the present invention.

The present invention is further related to a pharmaceutical assembly that can be used in a pharmaceutical treatment with an extended regimen.

BACKGROUND OF THE INVENTION Contraceptive pharmaceutical preparations containing a large amount of hormonal components were developed for use in different administration schemes.

A classification divides the common contraceptive preparations in the market into two general groups. The first covers contraceptives containing a constant amount of estrogen and progestin, which are prepared, for example, in the form of 21 tablets with the combination of active agents and 7 tablets without active agents. The amount of active agent is the same in each tablet. They are known as monophasic preparations. The undesired effects associated with this type of pills depend to some extent on the balance between estrogen and progestin. The second group of contraceptives comprises preparations in which the levels of estrogen or progestin vary with time. According to the amount of hormone levels, biphasic or polyphasic preparations are obtained. A typical pattern for this group of contraceptives comprises an administration of estrogen and progestin, where a relatively dominant amount of an estrogenic formulation is administered at the beginning of the treatment cycle, with increasing progestogenic activity toward the end. This pattern of administration seems to be able to achieve greater endometrial stability, which limits hemorrhages or marks due to a poor endometrial epithelization. Contraceptive reliability is provided primarily by the progestin component administered during treatment. So, at least the minimum dosage of progestin must be administered to effectively inhibit ovulation, with each daily dosage. On the other hand, estrogen increases the effects of inhibition of progestin ovulation and ensures the stability of the cycle. The typical regimen for hormonal contraceptive treatments is similar to the natural course of the cycle, with a free interval of administration of approximately 7 days, where the hemorrhage due to lack of administration resembles natural menstruation. Therefore, as previously mentioned, hormone administration intervals of 21 days to 7 days are alternated during which hormones are not administered. Since the psychological and physical capacities of women during the premenstrual phase are subject to limitations, a delay in menstruation may now be necessary under certain circumstances. Typical cases are, for example, sports competitions, private medical examinations or certain travel situations. The delay in menstruation can easily be achieved in women treated with hormonal preparation, such as those mentioned previously, as described in the literature ("Kontrazeption mit Hormonen: ein Leitfaden filr die Praxis", Hans-dieter Taubert and Herbert Kuhl, 2nd edition 1996, Georg Thieme Verlag, pp. 199-201). With a monophasic preparation, for example, it is possible to obtain this delay simply by beginning the 22nd day of treatment with a new set of contraceptive pills, and maintaining the treatment for the desired period of time, up to 2-3 days, before of causing hemorrhage due to lack of administration. Only the dose of the last phase should be applied to delay menstruation when polyphasic hormonal preparations are used. In general, with the methods mentioned previously, a delay in bleeding can be obtained due to a lack of administration of at least 7 days. The hormonal treatment can be directed not only to the prevention of pregnancy, but also can prevent all the related symptoms related to the lack of hormones, such as, for example, premenstrual symptoms, dysmenorrhea, endometriosis, menstrual migraine and the acne . In these cases, a longer inhibition of ovulation, obtained through hormonal contraception, will overcome the problems related to hormonal changes, which will be well accepted and will be particularly effective for a period of three months (84 days). . Said treatment longer than 21-28 days is also known as an extended use regimen.

WO03 / 049744 describes oral female contraceptives that prevent pregnancy and serve to treat premenstrual syndrome (PMS), including premenstrual dysphoric disorder (PMDD). Said document further describes a method for preventing pregnancy and. treat PMS, including PMDD, which allows avoiding the complete lack of estrogen at the end of the treatment period, or between periods of treatment, which includes the administration of oral contraceptives in an extended regime without interruptions. According to the previous document, premenstrual symptoms are rare when menstruation is not frequent, for this reason, users of oral contraceptives will have lower rates of premenstrual symptoms when exposed to high and stable doses of endogenous progesterone, with a protective effect against PMDD. WO03 / 049744 further describes a method for preventing pregnancy, which comprises administering one or two oral contraceptive combination regimens. Hormone treatment is applied for 110 consecutive days. The main disadvantages of the method described in WO03 / 049744 are related to the variation of hormonal levels during extended treatment. The increase and decrease of the estrogen and progestin dosages determine the instability of the endometrium, with an increase in side effects, such as unexpected hemorrhages. An altered conventional oral contraceptive regimen of 21 days / 7 days is also known in the art, comprising the use of a monophasic pill with between 30 and 35 μg of ethinyl estradiol and different types of progestins, to delay menstruation and reduce the symptoms of the lack of hormones (PJ Sula et al., Am J Obstet Gynecol, 2002; 186: 1142-1149). In this case, one of the main side effects is also related to a high incidence of unexpected hemorrhages, which is a common cause of regime abortion. WO99 / 09993 describes an oral contraceptive regimen comprising the consecutive administration of two or more progestational agents having different effects on the human endometrium, in combination with an estrogen. Particularly described is the widespread use of an oral contraceptive regimen comprising the consecutive administration of two or more progestational agents, in combination with an estrogen. Again, the extended regimen is based on the modulation of the progestational agent with a wavy pattern, while the dose of estrogen remains constant. Extended use regimens are clearly desirable to inhibit ovulation and offer freedom from the symptoms of menstrual and premenstrual failure for extended periods of time. These regimens of extended use also have a favorable therapeutic use on the symptoms of premenstrual type, dysmenorrhea and menstrual migraine. The continued use of an oral contraceptive can also have a favorable effect on acne, since acne typically occurs again during the period when no pills are administered. Said method should not present the incidence of abnormalities, such as unexpected marks or hemorrhages, particularly during the prolonged period without desired hemorrhages, at the same time that it should have a favorable effect on the endomentrial morphology.

SUMMARY OF THE INVENTION Pharmaceutical preparation for a continuous hormonal treatment for a period of time longer than 21-28 days, comprising two compositions of estrogen and / or progestin.

DETAILED DESCRIPTION OF THE INVENTION The present invention aims to eliminate the disadvantages related to the technical background, and particularly aims to provide a pharmaceutical preparation that allows to obtain a continuous hormonal treatment, during a desired period of time longer than 21- 28 days, comprising a first co-position containing at least one estrogen and / or at least one progestin in a predetermined amount., which is administered in the first 21-28 days, and a second composition comprising at least one estrogen and / or at least one progestin, in a predetermined amount greater than the amount of the first composition, and which also comprises a mono sequence or multiphase pharmaceutical dosages. The use of a pharmaceutical preparation for the manufacture of an agent to inhibit ovulation in a mammal, in particular a human being, and to diminish the symptoms related to the lack of hormonal administration, is also an objective of the present invention. Another object of the present invention is to provide a method for inhibiting ovulation in a mammal, in particular a human being, comprising administering to said mammal a first composition containing at least one estrogen and / or at least one progestin in one. predetermined amount, by 21-28 days, which further comprises the administration of a second composition containing at least one estrogen and at least one progestin in a predetermined amount, which is effected to obtain a continuous hormonal treatment for a desired period of time more Prolonged that 21-28 days. The second composition contains at least one estrogen and / or at least one progestin in a predetermined amount, which is greater than the amount of the first composition, and comprises a mono or multiphase sequence of pharmaceutical dosages. Said method can also be used advantageously in the syndrome related to the lack of hormones, in order to reduce the premenstrual symptoms, dysmenorrhea, endometriosis and menstrual migraine. The continued use of an oral contraceptive according to the above method also has a favorable effect on acne, since acne typically appears again during the period when no pills are administered. The present invention further relates to a pharmaceutical set for an extended treatment regimen longer than 21-28 days, comprising a first composition containing at least one estrogen and / or at least one progestin in a predetermined amount, which is administered in the first 21-28 days, and a second composition containing at least one estrogen and / or at least one progestin, in a predetermined amount greater than the amount of the first composition, which must be administered after the treatment and which comprises a mono or multiphase sequence of pharmaceutical dosages. The concept of a prolonged hormonal treatment to inhibit ovulation, for example, for a period of three months, with a stepwise increase in hormone dosage, originates from the observation that, during pregnancy, Abnormal hemorrhages are observed very infrequently. In addition, during pregnancy, the hormone levels of estrogen and progestin increase gradually over time. According to the present invention, a progressive increase in the dosage of estrogen and / or progestin allows stepwise stimulation of the endometrium, which leads to the desired stability of the endometrium and to an extended regimen without hemorrhages. The pharmaceutical preparation that allows obtaining a continuous hormonal treatment, for a desired period of time longer than 21-28 days, comprises, according to the present invention, a first composition containing at least one estrogen and / or at least one progestin in a predetermined amount, which is administered in the first 21-28 days. After said first composition, a second composition comprising at least one estrogen and / or at least one progestin follows, in a predetermined amount greater than the amount of the first composition, and which also comprises a mono or multiphase sequence of dosages. Pharmaceutical In greater detail, in the second composition of the pharmaceutical preparation, only the amount of estrogen or only the amount of progestin, or the amount of estrogen and progestin, are greater than the respective amount contained in the first composition. The estrogen used in the first and / or the second composition can be at least one synthetic estrogen, at least one biogenic estrogen or mixtures thereof. According to the invention, said synthetic estrogen may be selected from the group consisting of: ethinylestradiol, mestranol, kinestranol, precursors capable of releasing said estrogen when used in the present pharmaceutical preparation, and mixtures thereof. More preferably, the synthetic estrogen is ethinylestradiol or a precursor capable of releasing ethinylestradiol. The daily hormonal units to be used during the extended treatment preferably contain synthetic estrogen in an amount equivalent to 0.005-0.050 mg of ethinyl estradiol, more preferably an amount equivalent to 0.005-0.030 mg of ethinyl estradiol. The biogenic estrogen is preferably selected from the group consisting of: estradiol, estrone, estrane, es-triol, estetrol, conjugated equine estrogens, precursors capable of releasing said estrogen when used in the present pharmaceutical preparation, and mixtures thereof. More preferably, the biogenic estrogen is estradiol or a precursor capable of releasing estradiol, where the term estradiol encompasses 17beta-estradiol. More preferably, the biogenic sterogen is estradiol or a precursor thereof.

The daily hormonal units to be used during the extended treatment preferably contain biogenic estrogen in an amount equivalent to 0.1-5 mg of estradiol, more preferably in an amount equivalent to 0.1-3.0 mg of estradiol. The progestin contained in the pharmaceutical preparation according to the invention is preferably selected from the group consisting of levonorgestrel, norgestimate, norethisterone, dihydrogesterone, drospirenone, 3-beta-hydro-xidesogestrel, 3-keto desogestrel (= etonogestrel), 17-deacetyl norgestimate, 19-norprogesterone, acetoxipregne-nolone, allystrenol, anagestone, chlormadinone acetate, cyproterone acetate, demegestone, desogestrel, dienogest, dihydrogesterone, dimetisterone, ethisterone, ethinodiol diacetate, flurogestone acetate, gastrinon, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, linestrenol (= linoestrenol), medrogestone, me-droxiprogesterone acetate, egestrol, melengestrol, nomegestrol, no-retindrona (= norethisterone), norethynodrel, norgestrel (includes d-norgestrel and di norgestrel), norgestrienone, nor-metisterone, progesterone , quingestanol, (17-alpha) -17-hi-droxy-ll-methylene-19-norpregna-4,15-dien-20-in-3-one, tibolo-na, alg estone, acetophenide, nestorone, promegestone, esters of 17-hydroxyprogesterone, 19-nor-17-hydroxyprogesterone, 17-alpha-ethynyl-testosterone, 17-alpha-ethynyl-19-nor-testosterone, oxime of d-17beta- acetoxy-13-beta-ethyl-17-alpha-ethynyl-gon-4-en-3-one, hydroxytriendione ((21S) -21-hydroxy-21-methyl-14, 17-ethan-19-nor-pregna- 4,, 15-trien-3, 20-dione), 5-. { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-trifluoromethyl-propionylamino) -phthalide and precursors of these compounds. Specific examples of progestin precursors that may be employed in accordance with the present invention comprise: anagestone acetate, gestodene acetate, hydroxymethylprogesterone acetate, hydroxyprogesterone acetate, hydroxyprogesterone hexanoate, hydroxyprogesterone caproate, hydroxyprogesterone enanthate, megestrol, melengestrol acetate, nomegestrol acetate, norethindrone acetate, noretserone acetate, norethisterone acetate, norethisterone enanthate, quingestanol acetate, (17-alpha) -17-hydroxy-ll-methylene-19-norpregna-4, 15-dien-20-in-3-one, tibolone, algestone acetophenide, nestorone, promegestone, esters of 17-hydroxyprogesterone, esters of 19-nor-17-hydroxyprogesterone, 17-alpha-ethynyl-testosterone. Preferably, the progestin is selected from the group consisting of levonorgestrel, dienogest, gestodene, dros-pirenone and precursors thereof. The daily hormonal units to be used during the extended treatment preferably contain at least one progestin in an amount of 0.03-0.25 mg of levonorgestrel, and / or 0.5-5 mg of dienogest, and / or 0.03-0.15 mg of gestodene, and / or 0.5-5 mg of drospirenone, or equivalent dosages of other progestins. The best results are obtained with the pharmaceutical preparation according to the invention when the estrogen is ethinylestradiol and / or estradiol, or a precursor thereof, and when the progestin is selected from the group consisting of levonorgestrel, dienogest, gestodene, drospirenone, and its predecessors. Accordingly, in a preferred embodiment, the pharmaceutical preparation that allows a continuous hormonal treatment to be obtained during a desired period of time, longer than 21-28 days, comprises, according to the pre-senté invention, a first composition containing ethinylestradiol and / or estradiol, or precursors thereof, in an amount effective for therapeutic use, which allows to inhibit ovulation, and / or a progestin preferably selected from the group consisting of levonorgestrel, dieno-gest, gestodene, drospirenone and its precursors , in an effective amount for the predetermined therapeutic use, which is administered in the first 21-28 days. To said first composition follows a second composition comprising at least one estrogen and / or at least one progestin, wherein both are selected from the groups of estrogens and progestins mentioned previously, in an amount effective for the predetermined therapeutic use, greater than the amount of the first composition. According to a particularly favorable embodiment of the present invention, the second composition comprises a mono or multiphase sequence of pharmaceutical dosages, so that the hormonal concentration of estrogen and progestin can be gradually increased over time. The hormonal dosages of estrogen and progestin described previously refer particularly to oral formulations. The formulation of an estrogen and a progestin for the preparation of a combined preparation according to the invention is carried out in a manner analogously to that already known for conventional oral contraceptives having a period of administration of active ingredients of the invention. days, such as, for example, Femovan®, Meliane® and Mirelle® (ethinylestra-diol / gestodene), or Miranova® and Microgynon® (ethinylestra-diol / levonorgestrel), or Yasmin® and Yaz® (ethinylestradiol / drospirenone) ) or Valette® (ethinylestradiol / dienogest). The formulation of doses exclusively containing progestin can also be carried out in a manner completely analogous to that known for progestin-containing agents, designed for the orally available forms of administration, for example Microlut® with 0.03 mg of LN. The unit doses of the first composition of the pharmaceutical preparation according to the invention can also take the form of a plaster (transdermal application), an implant, a vaginal ring or other depot formulation, and, therefore, can be administered in a keep going. The hormonal units according to the invention can also be administered parenterally, for example, in a daily amount of 0.01-0.10 mg of estradiol, or of other equivalent biogenic estrogens, sublingually, transdermally, intravaginally. , intranasal or buccal. The daily hormonal units can be administered appropriately orally, transdermally or intravaginally. For such administration, which allows to avoid the effect of a first passage, lower hormonal doses are administered, eg, lower doses of biogenic estrogens, equivalent to 0.005-0.030 mg of ethinyl estradiol can be used. A particularly favorable form of an embodiment of this invention relates to a preparation for transdermal administration, for example, in the form of a plaster, comprising said first or second composition with an appropriate formulation, for example, dissolved in a convenient percentage in a non-fluid gel, acceptable for physiological use, which is dispersed in a cross-linked silicone elastomer. In order to determine effective effective amounts of ethinylestradiol and estradiol on the one hand, and of different progestins, such as levonorgestrel, dienogest, ges-todene and drospirenone, on the other, reference may be made to the data provided in EP-A-0 253 607. Additional details can be found to determine equivalent dosages of various progestogenic active ingredients, for example, in "Probleme der Dosisfindung: Sexualhormone" (Problem of dosing determination: sex hormones); F. Neumann et al. in "Arzneimittelforschung" (Investigations of drugs) 27, 2a, 296-318 (1977) and in "Aktue-lle Entwicklungen in der Hormonalen IContrazeption" (Current developments of hormonal contraception), H. Kuhl in "Gynakologe" 25: 231- 240 (1992). According to the present invention, the pharmaceutical preparation can comprise pharmaceutical dosages that are administered for a total time of 56, 84, 112 or 140, 168 days. The preferred administration regimen can encompass a total time of between 84 and 112 days. Between the administration of two consecutive pharmaceutical preparations, there may be a period free of hormonal administrations of 1-7 days. Said period is in accordance with a particular form of an embodiment of the invention of 4-7 days.

The present invention further relates to a method for inhibiting ovulation in a mammal, in particular a human being, comprising administering to said mammal said first composition, which contains at least one estrogen and / or at least one progestin in a predetermined amount. , for 21-28 days, and additionally administering said second composition, which contains at least one estrogen and at least one progestin, in a predetermined amount, to obtain a continuous hormonal treatment for a desired period of time longer than 21-28 days . Said second composition previously described contains at least one estrogen and / or at least one progestin, in a predetermined amount which is greater than the amount of the first composition, and comprises a mono or multi-phasic sequence of pharmaceutical dosages. The method according to this invention can also be advantageously used to reduce the symptoms related to the lack of hormones, such as premenstrual symptoms, dysmenorrhea, endometriosis and migra-. menstrual The continued use of an oral contraceptive can also have a favorable effect on acne, since acne typically occurs again during the period when no s are administered. The method according to the present invention, which comprises a stepwise increase of the hormonal administration, presents an optimal combination of contraceptive reliability, cycle control and minimal side effects for the full extended regimen. According to a particular form of an embodiment of the method according to this invention, the user of this particular extended regimen begins with the administration of the lowest dose on the first day of menstruation. Said lower dose corresponds to said first composition. The individual takes this first dose uninterruptedly until he experiences signs of marks (eg brown vaginal discharge), usually for at least 28 days. At this time, the first marks of marks appeared, the user resorts to the administration of the form with the second highest dosage, corresponding to said second composition, or, according to a particular embodiment of this invention, to a of the multiple phase sequences of said second composition. The user follows this step increment schedule until spots appear during the administration of the tablets with the highest doses. At that time, the administration period ends and a period of 7 days begins without any administration, which allows the hemorrhage to occur due to lack of administration. After this one-week period, the processing period begins again.

A pharmaceutical set for an extended treatment regimen longer than 21-28 days is also part of the present invention, and comprises: a first composition containing at least one estrogen and / or at least one progestin in a predetermined amount, which administered in the first 21-28 days - a second composition containing at least one estrogen and / or at least one progestin, in a predetermined amount greater than the amount of the first composition, which is administered after treatment and which comprises a mono or multiphase sequence of pharmaceutical dosages. A particularly favorable form of an embodiment of the invention comprises, as a form of packaging the pharmaceutical preparation, an ampoule; although other forms of packaging known for this purpose are also possible.

DESCRIPTION OF SOME FORMS OF EMBODIMENTS Other features and advantages of the invention will be apparent from the following description of some favorable forms of embodiments, provided only as non-restrictive examples: Example 1 The following clinical study is performed to examine the efficacy of the regimens of increasing doses suggested for the extended use of hormonal contraceptives. The study is designed to evaluate the hypothesis that a regimen with phases with increasing dosages, for example, of estrogen and progestin, results in bleeding-free intervals of 84 days, while maintaining the contraceptive protection. In the present study, two regimens with different phases are considered with a conventional 21-day regimen, based on the number of days of hemorrhage during an observation period of 84 days. The number and type of adverse events are compared, and the number of pregnancies is also recorded. An open-label, three-arm, multi-center, randomized study is designed with young fertile women 18-35 years of age with regular menstrual cycles. Exclusion criteria included the contraindications of hormonal contraceptives. Test treatments (EE = ethinylestradiol, DRSP = drospirenone) Preparation A 0.015 mg of EE plus 2.0 mg of DRSP for 28 days 0.020 mg of EE plus 2.5 mg of DRSP for 28 days 0.030 mg of EE plus 3.0 DRSP mg for 28 days Preparation B 0.020 mg of EE plus 2.0 mg of DRSP for 28 days 0.020 mg of EE plus 2.5 mg of DRSP for 28 days 0.020 mg of EE plus 3.0 mg of DRSP for 28 days Preparation C 0.020 mg of EE plus 3.0 mg of DRSP per 21 (reference) days, plus 7 days of placebo 0.020 mg of EE plus 3.0 mg of DRSP for 21 days, plus 7 days of placebo 0.020 mg of EE plus 3.0 mg of DRSP for 21 days, plus 7 days of placebo. The primary efficacy variable is the number of days of hemorrhage (light and intense bleeding) during the entire observation period of 84 days. The variable of secondary efficacy is the number of adverse events and pregnancies. The number of subjects is determined in biometric form, with approximately 200 subjects per test group. EXAMPLE 2 Another clinical study is carried out according to the pro-tocol of example 1, but with the following test treatment (EE = ethinylestradiol, GSD = gestodene): Preparation A 0.015 mg EE plus 0.060 mg GSD per 28 days 0.020 mg of EE plus 0.075 mg of GSD for 14 days 0.030 mg of EE plus 0.075 mg of GSD for 14 days 0.030 mg of EE plus 0.100 mg of GSD for 14 days Preparation B 0.030 mg of EE plus 0.060 mg of GSD for 28 days 0.030 mg of EE plus 0.075 mg of GSD for 28 days 0.030 mg of EE plus 0.100 mg of GSD for 28 days Preparation C 0.015 mg of EE plus 0.060 mg of GSD per 24 (ref.) Days, plus 4 days of placebo 0.015 mg of EE plus 0.060 mg of GSD for 24 days, plus 4 days of placebo 0.015 mg of EE plus 0.060 mg of GSD for 24 days, plus 4 days of placebo. Example 3 Another clinical study is performed according to the protocol of example 1, but with the following test treatment (EE = ethinylestradiol, LNG = levonorgestrel): Preparation A 0.020 mg of EE plus 0.080 mg of LNG for 28 days 0.030 mg of EE plus 0.100 mg of LNG for 28 days 0.030 mg of EE plus 0.125 mg of LNG for 28 days 0.030 mg of EE plus 0.150 mg of LNG for 28 days Preparation B 0.030 mg of EE plus 0.080 mg of LNG for 28 days 0.030 mg of EE plus 0.100 mg of LNG for 28 days 0.030 mg of EE plus 0.125 mg of LNG for 28 days 0.030 mg of EE plus 0.150 mg of LNG for 28 days Preparation C 0.020 mg of EE plus 0.100 mg of LNG for 21 (ref.) Days, plus 7 days of placebo 0.020 mg of EE plus 0.100 mg of LNG for 21 days, plus 7 days of placebo 0.020 mg of EE plus 0.100 mg of LNG for 21 days-, plus 7 days of placebo 0.020 mg of EE plus 0.100 mg of LNG for 21 days, plus 7 days of placebo. Example 4 Another clinical study is carried out according to the protocol of example 1, but with the following test treatment (EE = ethinylestradiol, DNG = dienogest): Preparation A 0.010 mg of EE plus 1.50 mg of DNG for 28 days 0.015 mg of EE plus 2.00 mg of DNG for 28 days 0.020 mg of EE plus 2.50 mg of DNG for 28 days 0.030 mg of EE plus 2.50 mg of DNG for 28 days Preparation B 0.010 mg of EE plus 2.00 mg of DNG for 28 days 0.015 mg of EE plus 2.00 mg of DNG for 28 days 0.020 mg of EE plus 2.00 mg of DNG for 28 days 0.030 mg of EE plus 2 , 00 mg of DNG for 28 days Preparation C 0.030 mg of EE plus 2.00 mg of DNG for 21 (ref.) Days, plus 7 days of placebo 0.030 mg of EE plus 2.00 mg of DNG for 21 days , plus 7 days of placebo 0.030 mg of EE plus 2.00 mg of DNG for 21 days, plus 7 days of placebo 0.030 mg of EE plus 2.00 mg of DNG for 21 days, plus 7 days of placebo. The results obtained in the previous example are compared with those of the reference preparations, and the following observations were made: - Lower incidence of intermenstrual hemorrhage, shorter period of bleeding and lesser intensity of hemorrhage; - Lower incidence of symptoms related to the lack of hormones; - Greater well-being in women. The invention has been described with reference to preferred embodiments. Still, it is clear that numerous modifications to the invention can be made within the framework of technical equivalences.

Claims (5)

1. CLAIMS 1. A pharmaceutical preparation for obtaining a continuous hormonal treatment during a longer period of time than 21-28 days, comprising a first composition containing at least one estrogen and / or at least one progestin in a predetermined amount, which is administered in the first 21-28 days, and a second composition containing at least one estrogen and / or at least one progestin, in a predetermined amount greater than the amount of the first composition, and comprising a mono or multiphase sequence of dosages Pharmaceutical 2. A pharmaceutical preparation according to claim 1, CHARACTERIZED BECAUSE it comprises pharmaceutical dosages that are administered during a total time period of 56, 84, 112, 140 or 168 days. 3. A pharmaceutical preparation according to claims 1 and 2, CHARACTERIZED BECAUSE the second composition comprises a sequence of a pharmaceutical dosage phase. 4. A pharmaceutical preparation according to claims 1 and 2, CHARACTERIZED BECAUSE the second composition comprises a sequence of two phases of pharmaceutical dosages. 5. A pharmaceutical preparation according to claim 3, CHARACTERIZED BECAUSE the pharmaceutical dosage of at least one estrogen of the second composition is greater than the amount contained in the first composition. 5. A pharmaceutical preparation according to claim 3, CHARACTERIZED BECAUSE the pharmaceutical dosage of at least one progestin of the second composition is greater than the amount contained in the first composition. 7. A pharmaceutical preparation according to claim 4, CHARACTERIZED BECAUSE the pharmaceutical dosage of at least one estrogen and / or at least one progestin of the second composition is greater than the amount contained in the first composition. 8. A pharmaceutical preparation according to any of the preceding claims, CHARACTERIZED BECAUSE the at least one estrogen is selected from the group consisting of the following synthetic oestrogens: ethinylestradiol, mestranol, quinestranol, or a precursor capable of releasing said synthetic estrogen, and / or of the group consisting of the following biogenic estrogens: estradiol, estrena, estrano, estriol, estetrol, conjugated equine estrogens, or precursors capable of releasing said biogenic estrogens. 9. A pharmaceutical preparation according to claim 8, CHARACTERIZED BECAUSE the at least one estrogen is ethinylestradiol and / or estradiol. 10. A pharmaceutical preparation according to any of the preceding claims, CHARACTERIZED BECAUSE the daily hormonal units of estrogen preferably contain ethinylestradiol in an amount of 0.005-50 mg, more preferably in an amount of 0.005-0.030 mg, and / or estradiol in an amount of 0.1-5.0 mg. 11. A pharmaceutical preparation according to any of the preceding claims, CHARACTERIZED BECAUSE the at least one progestin is selected from the group consisting of levonorgestrel, norgestimate, norethisterone, dihydrogesterone, drospirenone, 3-beta-hydroxidesogestrel, 3-keto desogestrel (= etonogestrel), 17-deacetyl norges-thimate, 19-norprogesterone, acetoxipregnenolone , allyl-trenol, anagestone, chlormadinone acetate, ci-proterone acetate, demegestone, desogestrel, dienogest, dihydrogesterone, dimetisterone, ethisterone, ethinodiol diacetate, flurogestone acetate, gastrinon, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, linestrenol (= linoestrenol), medrogestone, medroxyprogesterone acetate, megestrol, melengestrol, nomegestrol, norethindrone (= norethisterone), norethynodrel, norgestrel (includes d-norgestrel and di norgestrel), norgestrienone, normetisterone, progesterone, quingestanol, (17-alpha) -17-hydroxy-ll-methylene-19-norpregna-4, 15-dien- 20-in-3-one, tibolone, algestone, acetophenide, nestorone, promegestone, esters of 17-hydro-iprogesterone, 19-nor-17-hydroxyprogesterone, 17-alpha-ethy-nil-testosterone, 17-alpha-ethynyl-19-nor-testosterone, oxime of d-17beta -acetoxy-13-beta-ethyl-17-alpha-ethynyl-gon-4-en-3-one, hydroxytriendione ((21S) -21-hydroxy-21-methyl-14, 17-ethan-19-nor-pregna -4,, 15-trien-3, 20-di ona), 5-. { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-trifluoromethyl-propionylamino) -phthalide, and precursors thereof. 12. A pharmaceutical preparation according to any of the preceding claims, CHARACTERIZED BECAUSE the at least one progestin is preferably selected from the group consisting of levonorgestrel, dienogest, gestodene, drospirenone, and precursors thereof. 13. A pharmaceutical preparation according to any of the preceding claims, CHARACTERIZED BECAUSE the daily hormonal units of at least one progestin to be used during the extended extended treatment preferably contain the progestin in an amount of 0.03-0.25 mg of levonorgestrel. , and / or 0.5-5 mg of dienogest, and / or 0.03-0.15 mg of gestodene, and / or 0.5-5 mg of drospirenone, or equivalent dosages of other progestins. 14. A pharmaceutical preparation according to any of the preceding claims, CHARACTERIZED BECAUSE the hormonal units are administered orally, parenterally, sublingually, transdermally, intravaginally, intrana-salt or buccally. 15. A pharmaceutical preparation according to any of the preceding claims, CHARACTERIZED BECAUSE the hormonal units are for oral administration. 16. A pharmaceutical preparation according to any of the preceding claims, CHARACTERIZED BECAUSE the hormonal units are daily units. 17. The use of a pharmaceutical preparation according to claims 1 to 16, for the manufacture of an agent for inhibiting ovulation in a mammal, in particular a human. 18. The use of a pharmaceutical preparation according to claim 17, CHARACTERIZED BECAUSE the administration of said preparation extends for a period of time of 56, 84, 112, 140 or 168 days. 19. The use of a pharmaceutical preparation according to claim 17 or 18, for the manufacture of an agent to reduce the symptoms related to the lack of administration of hormones, such as premenstrual symptoms, dysmenorrhea, endometriosis and migraine menstrual 20. The use of a pharmaceutical preparation according to claim 17 or 18, for the manufacture of an agent to reduce the symptoms related to acne. 21. A pharmaceutical set for an extended treatment regimen longer than 21-28 days, comprising: a first composition containing at least one estrogen and / or at least one progestin in a predetermined amount, which is administered in the first 21-28 days - a second composition containing at least one estrogen and / or at least one progestin, in a predetermined amount greater than the amount of the first composition, which is administered after treatment and which comprises a mono or multiphase sequence of pharmaceutical dosages. 22. The pharmaceutical composition according to claim 21, characterized in that said first composition and said second composition correspond to the first and second compositions - defined for the pharmaceutical preparation according to claims 1 to 16. 23. The pharmaceutical composition of according to claims 21 and 22, CHARACTERIZED BECAUSE the first and / or the second composition are administered in daily doses. 24. The pharmaceutical composition according to any of claims 21 to 23, CHARACTERIZED BECAUSE the first and / or the second composition are prepared to obtain a consecutive administration separately, for example, in separating ampoules. 25. The pharmaceutical composition according to any of claims 21 to 24, CHARACTERIZED BECAUSE the administration of the first and second compositions extends for a period of time of 56, 84, 112, 140 or 168 days.