HK1097185A - Extended use combination comprising estrogens and progestins - Google Patents

Description

Extended use combination comprising an estrogen and a progestin

Technical Field

The present invention relates to the prolonged use of a pharmaceutical preparation comprising an estrogen and a progestin, wherein an increasing dosage of estrogen and/or progestin achieves a sustained stimulation of the endometrium after a typical 28 day period. This may result in the desired endometrial stability and achieve a prolonged treatment regimen without bleeding.

More specifically, the invention relates to a pharmaceutical preparation for obtaining a sustained hormonal treatment over a desired period of time longer than 21-28 days, comprising a first composition containing a predetermined amount of at least one estrogen and/or at least one progestin for administration in the first 21-28 days and a second composition containing a predetermined amount of at least one estrogen and/or at least one progestin higher 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 of inhibiting ovulation in a mammal, in particular a human, so as to obtain a continuous hormonal treatment over a period of time longer than 21-28 days, comprising administering to said mammal a first composition comprising an amount of an estrogen alone or a combination of an estrogen and a progestin during 21-28 days, followed by further administration of a second composition comprising an estrogen and a progestin. The second composition comprises an estrogen and a progestin in an amount higher than the amount of the first composition. The second composition further comprises a single or multi-phase sequence of pharmaceutical dosages.

The use of said pharmaceutical preparation for the preparation of a medicament for inhibiting ovulation in a mammal, in particular a human being, inducing long-term amenorrhea and reducing the symptoms associated with hormonal withdrawal is also an object of the present invention.

The invention further relates to a pharmaceutical pack for use in medical treatment with an extended treatment regimen.

Background

Pharmaceutical contraceptive formulations containing multiple hormonal components are developed for very different dosing regimens depending on their stability.

The common contraceptive formulations on the market fall into two main groups. The first group is contraceptives containing a constant amount of estrogen and progestin and prepared, for example, in the form of 21 tablets with active agent and 7 tablets without active agent. The amount of active drug in each tablet was the same. They are known as multi-phase formulations.

The side effects (unforced effects) associated with these types of tablets depend to some extent on the balance between estrogen and progestin.

The second group of contraceptives includes preparations in which the level of estrogen or progestin changes over time. Depending on the amount of hormone level, biphasic or multiphasic formulations may be obtained. A typical pattern for this group of contraceptives involves estrogen and progestin administration with a relatively dominant estrogenic composition being administered at the beginning of the treatment cycle and increasing progestin activity until the end. This mode of administration appears to provide greater stability to the endometrium and thus limits breakthrough bleeding or spotting due to poor endometrial epithelialization. Contraceptive reliability is provided primarily by the progestogenic component being administered during the course of treatment. Therefore, at least the minimum progestogen dose should be provided in a daily dose to be effective in inhibiting ovulation. On the other hand, estrogen improves the ovulation inhibitory effect of progestogen and ensures cycle stability.

A typical hormonal contraceptive regimen has an interval of no administration of about 7 days in which withdrawal bleeding mimics the normal menstrual period and is thus similar to the normal course of the cycle. Thus, as described above, 21 days of hormone dosing intervals alternated with 7 days during which no hormone was administered.

Due to the psychological and physical limitations of women during the premenstrual phase, it is often desirable in some cases to delay the menstrual period in our daily lives. For example, a typical situation is a sports competition, especially a physical examination or a travel situation.

As reported in the literature, the retardation of menstruation in women treated with hormonal preparations such as those mentioned previously is readily available ("Kontrazepton mit Hormonen: ein Leitfaden fur Praxis", Hans-Dieter Taubert and Herbert Kuhl, 2)^nd edition 1995，GeorgThieme Verlag，pp.199-201)。

Such delay may be achieved, for example, by a monophasic formulation, simply by starting a new contraceptive kit on day 22 of treatment and maintaining the treatment for a period of up to 2-3 days required before the desired withdrawal bleed. When a multiphasic hormone formulation is used, only the dose of the last phase should be administered for delayed menstruation.

Generally, a withdrawal bleeding delay of at least 7 days can be readily achieved using the methods described previously.

Hormonal therapy is used not only to prevent pregnancy but also to avoid all the derived symptoms associated with hormonal withdrawal, such as premenstrual syndrome, dysmenorrhea, endometriosis, menstrual headache and acne.

Under these circumstances, the long-term inhibition of ovulation obtained by hormonal contraception allows overcoming the problems associated with hormonal changes, which is well accepted and is particularly effective over a period of three months (84 days).

This treatment longer than 21-28 days is also referred to as extended use regimen (extended useregimen).

WO03/049744 describes oral contraceptives for women which prevent pregnancy and treat premenstrual syndrome (PMS), including premenstrual dysphoric disorder (PMDD). The document also describes a method of preventing pregnancy and treating PMS, including PMDD, by avoiding complete withdrawal of estrogen at the end of the treatment period or between treatment periods by administering an oral contraceptive in an extended regimen without interruption. According to the above documents, premenstrual syndrome is less common when menstruation is infrequent, and therefore users of oral contraceptives have a lower chance of developing premenstrual syndrome when exposed to peaks and troughs of endogenous progestagens that have a protective effect on PMDD.

WO03/049744 also describes a method of preventing pregnancy which comprises administering an oral contraceptive regimen or a combination of two oral contraceptive regimens. The hormone treatment is performed over a continuous period of 110 days.

The main drawback of the method reported in WO03/049744 is the change in hormone levels during prolonged treatment. Increased and decreased estrogen and progestin dosages determine endometrial instability, leading to increased side effects such as breakthrough bleeding.

Another standard 21 day/7 day oral contraceptive regimen is known in the art that utilizes monophasic pills containing 30 to 35 μ g ethinylestradiol and a different type of progestin to delay menses and reduce hormone withdrawal symptoms (PJ Sulak et al, Am J Obstet Gynecol, 2002; 186: 1142-. Also, one of the major side effects in this case involves the high incidence of breakthrough bleeding, which is a common cause of interruption of the treatment regimen.

WO99/09993 describes an oral contraceptive regimen comprising the sequential administration of two or more progestational agents having different effects on human endometrium in combination with an estrogen. In particular, prolonged use oral contraceptive regimens are reported which include the sequential administration of two or more progestational agents in combination with an estrogen. Again, the extended regimen is based on modulating the progestational agent in a fluctuating pattern while the estrogen dose remains constant.

This is clearly advantageous because prolonged application regimens both inhibit ovulation and avoid menses and premenstrual syndrome for extended periods of time. Such extended application regimens also have advantageous therapeutic uses in premenstrual-type symptoms, dysmenorrhea, menstrual headache. Continuous use of oral contraceptives also has a beneficial effect on acne, since acne usually recurs during withdrawal. This method, which is particularly useful for achieving a purposely long bleedings period, should not lead to the occurrence of abnormal bleeding, such as spotting or breakthrough bleeding, while having a favourable effect on the morphology of the endometrium.

Disclosure of Invention

The present invention aims to eliminate the drawbacks associated with the prior art and, in particular, to provide a pharmaceutical preparation for obtaining a sustained hormonal treatment over a period of time longer than 21-28 days, comprising a first composition containing a predetermined amount of at least one estrogen and/or at least one progestin for administration in the first 21-28 days and a second composition containing a predetermined amount of at least one estrogen and/or at least one progestin higher than the amount of the first composition and comprising a mono-or multiphase sequence of pharmaceutical dosages.

The use of said pharmaceutical preparation for the manufacture of a medicament for inhibiting ovulation and for reducing symptoms associated with hormonal withdrawal in mammals, in particular humans, is also an object of the present invention.

The present invention also aims to provide a method of inhibiting ovulation in a mammal, in particular a human, comprising administering to said mammal a first composition comprising an amount of at least one estrogen and/or at least one progestin for 21-28 days comprising the further administration of a second composition comprising a predetermined amount of at least one estrogen and at least one progestin for a desired period of time longer than 21-28 days for obtaining a continuous hormonal treatment. The second composition comprises a predetermined amount of at least one estrogen and/or at least one progestin in an amount higher than the amount of the first composition, and the second composition comprises a mono-or multi-phasic sequence of pharmaceutical dosages.

The method may further advantageously be used in symptoms associated with hormone withdrawal to reduce premenstrual syndrome, dysmenorrhea, endometriosis, menstrual headache. Since acne usually recurs during periods of contraceptive inactivity, continued use of oral contraceptives according to the above method also has a beneficial effect on acne.

The invention also relates to a pharmaceutical pack for an extended regimen of treatment longer than 21-28 days, comprising a first composition containing a predetermined amount of at least one estrogen and/or at least one progestin for administration in the first 21-28 days and a second composition containing a predetermined amount of at least one estrogen and/or at least one progestin higher than the amount of the first composition for administration in a subsequent treatment and comprising a mono-or multiphase sequence of pharmaceutical dosages.

The concept of prolonged hormonal treatment for inhibiting ovulation, for example over a period of three months, stems from the finding that abnormal bleeding is rarely observed during pregnancy. Furthermore, the levels of estrogen and progestin gradually increase over time during pregnancy.

According to the invention, the escalation of the estrogen and/or progestin dosage results in a continuous and stepwise increase in the stimulation of the endometrium, which leads to the desired endometrial stability and to a prolonged treatment regime without bleeding.

According to the invention, a pharmaceutical preparation for obtaining a sustained hormonal treatment over a desired period of time longer than 21-28 days comprises a first composition containing a predetermined amount of at least one estrogen and/or at least one progestin for administration in the first 21-28 days. The first composition is followed by a second composition comprising a predetermined amount of at least one estrogen and/or at least one progestin higher than the amount of the first composition and comprising a mono-or multiphasic sequence of pharmaceutical dosages.

More specifically, in the second composition of the pharmaceutical preparation, the amount of estrogen only or the amount of progestin only or the amount of both estrogen and progestin is higher than the respective amount comprised in the first composition.

The estrogen used in the first and/or second composition may be at least one synthetic estrogen, at least one biogenic estrogen or a mixture thereof.

According to the present invention, the synthetic estrogen may be selected from the group consisting of: ethinyl estradiol, mestranol, quinestranol, precursors that release these estrogens when used in the pharmaceutical formulations of the present invention, and mixtures thereof. Most preferably, the synthetic estrogen is ethinyl estradiol or a precursor from which ethinyl estradiol may be released. The daily hormone unit used throughout the extended treatment preferably contains an amount of synthetic oestrogen equivalent to 0.005 to 0.050mg of ethinyloestradiol, most preferably an amount equivalent to 0.005 to 0.030mg of ethinyloestradiol.

The biogenic estrogen is preferably selected from the group consisting of: estradiol, estrone, estrane, estriol, estetrol, conjugated equine estrogens, precursors which when used in the pharmaceutical preparations according to the invention release these estrogens and mixtures thereof. The most preferred biogenic estrogen is estradiol or a precursor that can release estradiol, the term estradiol encompassing 17 β -estradiol. Most preferably, the biogenic estrogen is estradiol or a precursor thereof.

The daily oral hormone units used throughout the extended treatment preferably contain biogenic estrogens in an amount equivalent to 0.1-5mg estradiol, most preferably in an amount equivalent to 0.1-3.0mg estradiol.

The progestogen contained in the pharmaceutical preparation according to the invention is especially selected from the group consisting of: levonorgestrel, norgestimate, norethindrone, dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (═ etonogestrel), 17-deacetylnorgestimate, 19-norgestrel, acetoxypregnenolone, allylestrenol, anagesterone, chlormadestone acetate, cyproterone acetate, demegestone, desogestrel, dienogest, demegestone, ethisterone, norgestrel diacetate, fluogesteron acetate, gastrinon, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenone (═ lynestrenol), medroxyprogesterone acetate, megestrol, melengestrol, nomegesterone, norethindrone (═ norethindrone), norethindrone (including d-norethindrone and dl-norgestrel), pregnenone, norethindrone (norethindrone), Progesterone, quingestrol, (17 alpha) -17-hydroxy-11-methylene-19-norpregn-4, 15-dien-20-yn-3-one, tibolone, algesten (algestone acetophenide), nersterone (nestorone), promegestrol, 17-hydroxyprogesterone ester, 19-nor-17 hydroxyprogesterone, 17 alpha-ethynyl-testosterone, 17 alpha-ethynyl-19-nor-testosterone, d-17 beta-acetoxy-13 beta-ethyl-17 alpha-ethynyl-st-4-en-e-3-one oxime, hydroxytriedione ((21S) -21-hydroxy-21-methyl-14, 17-ethano-19-nor-pregn-4, 9, 15-triene-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 progestogenic precursors that may be used in accordance with the invention include: anagesterone acetate, gestodene acetate, hydroxymethyl progesterone acetate, hydroxyprogesterone caproate, hydroxyprogesterone heptanoate, megestrol acetate, melengestrol acetate, nomegestrol acetate, norethindrone heptanoate, quinigestrol acetate, (17 alpha) -17-hydroxy-11-methylene-19-norpregn-4, 15-diene-20-yne-3-one, tibolone, antiprogestrel, nerolidone, promegestrol, 17-hydroxyprogesterone ester, 19-nor-17 hydroxyprogesterone ester, and 17 alpha-ethynyl-testosterone.

Preferably, the progestogen is selected from the group consisting of: levonorgestrel, dienogest, gestodene, drospirenone, and their precursors.

The daily hormone unit used throughout the prolonged treatment preferably contains at least one progestin in the following amounts: 0.03-0.25mg levonorgestrel and/or 0.5-5mg dienogest and/or 0.03-0.15mg gestodene and/or 0.5-5mg drospirenone or equivalent doses of other progestogens.

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 the progestin is selected from the group consisting of levonorgestrel, dienogest, gestodene, drospirenone and precursors thereof.

In a preferred embodiment, therefore, the pharmaceutical preparation according to the invention for obtaining a sustained hormonal treatment over a desired period of time longer than 21-28 days comprises a first composition containing ethinylestradiol and/or estradiol or precursors thereof in a therapeutically effective amount for ovulation inhibition and/or a progestin preferably selected from the group consisting of levonorgestrel, dienogest, gestodene, drospirenone and precursors thereof in a predetermined therapeutically effective amount for administration within the first 21-28 days. The first composition is followed by a second composition comprising a predetermined therapeutically effective amount of at least one estrogen and/or at least one progestin, respectively selected from the group of estrogens and progestins mentioned above, higher than the amount of the first composition.

According to a particularly advantageous embodiment of the invention, the second composition comprises a monophasic or multiphasic pharmaceutical dosage sequence, so that the hormone concentration of estrogen and progestin can be gradually increased over time.

The previously reported hormonal doses of estrogen and progestin are particularly relevant for oral compositions. The estrogen and the progestogen used for preparing the combined preparation according to the invention are formulated by mixing with a conventional oral contraceptive known for having an active ingredient administration period of 21 days, such as Femovan^®、Meliane^®And Mirelle^®(ethinylestradiol/gestodene) or Miranova^®And Microgynon^®(ethinylestradiol/levonorgestrel) or Yasmin^®And Yaz^®(ethinylestradiol/drospirenone) or Valette^®(ethinylestradiol/dienogest) in a completely similar manner.

The progestogen-only unit dose may also be formulated in combination with a progestogen-containing drug such as Microlut containing 0.03mg LN for oral administration that is already available^®In a completely similar manner.

The unit dose of the first composition of the pharmaceutical preparation of the invention can also be in the form of a paste (transdermal application), an implant, a vaginal ring or other depot form and thus be administered continuously.

The hormone unit according to the invention may also be administered parenterally, for example sublingually, transdermally, intravaginally, intranasally or buccally in a daily dose of 0.01-0.10mg estradiol or an equivalent amount of other biogenic estrogens. The daily hormone units may suitably be administered orally, transdermally or intravaginally.

For this mode of administration, which avoids the first pass effect, lower hormone units can be administered, e.g., lower dosages of biogenic estrogens equivalent to 0.005-0.030mg ethinylestradiol can be used.

A particularly advantageous form of embodiment of the invention relates to a formulation for transdermal administration, for example in the form of an ointment comprising said first or second composition suitably formulated therein, for example dissolved in a suitable percentage in a non-flowing, physiologically acceptable gel microdispersed in a cross-linked silicone elastomer.

For the determination of equivalent amounts of ethinylestradiol and estradiol on the one hand and of different progestogens such as levonorgestrel, dienogest, gestodene and drospirenone on the other hand reference may be made to the information provided in EP- ｃA-0253607. More detailed information for determining equivalent amounts of different progestagen active ingredients can be found, for example, in "protocol der dossisfindung: sexualhorrone "(dose determination problem: sex hormone); neumann et al, "Arzneimitelforkung" (Drug Research)27, 2a, 296-318(1977) and "Aktuelle Entwicklung in der Hormonalen Kontrazezation" (current progress in hormonal contraception), H.Kuhl, "Gynakologe" 25: 231-240(1992).

According to the present invention, the pharmaceutical formulation may comprise a pharmaceutical dose for administration over a total time period of 56, 84, 112 or 140, 168 days. The preferred dosing regimen covers a total time period of 84 and 112 days.

Between two successive administrations of the pharmaceutical preparation, a period of hormone-free administration of 1-7 days may be provided. The period of time may thus be a particular form of embodiment of the invention which is a period of 4 to 7 days.

The invention further relates to a method of inhibiting ovulation in a mammal, in particular a human, comprising administering to said mammal said first composition comprising an amount of at least one estrogen and/or at least one progestin for 21-28 days and further administering said second composition comprising a predetermined amount of at least one estrogen and at least one progestin for a desired period of time longer than 21-28 days, for obtaining a continuous hormonal treatment.

As previously mentioned, the second composition contains a predetermined amount of at least one estrogen and/or at least one progestin higher than the amount of the first composition and comprises a mono-or multiphasic sequence of pharmaceutical dosages.

According to the invention, the method can also be advantageously used for reducing symptoms associated with hormonal withdrawal, such as premenstrual syndrome, dysmenorrhea, endometriosis and menstrual headache. Since acne typically recurs during withdrawal, the continued use of oral contraceptives may also have a beneficial effect on acne.

The method of the invention with stepwise increased hormone uptake shows an optimal combination of contraceptive reliability, cycle control and minimal side effects throughout the extended treatment regimen.

According to a particular form of embodiment of the method of the invention, the user of this unique extended regimen begins to ingest the lowest dose on the first day of menstruation. The lowest dose corresponds to the first composition. The individual takes the first dose uninterrupted for a typical minimum of 28 days until early symptoms of spotting (e.g., brown vaginal discharge) occur. On the day of the first appearance of punctate bleeding symptoms, the user switches to ingest the next higher dosage form corresponding to said second composition, or according to a particular embodiment of the invention, to one of the multiphase sequences of said second composition.

The user follows this increasing intake regimen until spotting occurs at the time of ingestion of the highest dose tablet. At this point, the intake period ended and a 7 day off interval would allow withdrawal bleeding. After this week, the treatment period is restarted.

Kits for use in extended treatment regimens longer than 21-28 days are also part of the invention, comprising:

-a first composition containing a predetermined amount of at least one estrogen and/or at least one progestin for administration on the first 21-28 days;

-a second composition containing at least one estrogen and/or at least one progestin in a predetermined amount higher than the amount of the first composition and comprising a mono-or multiphasic sequence of pharmaceutical dosages for administration in a subsequent treatment.

Particularly advantageous forms of particular embodiments of the present invention include blister packs (blisters) as the packaging form of the pharmaceutical formulation; however, other forms of packaging for this purpose may also be applied.

Examples

Other characteristics and advantages of the invention will become apparent from the following description of some advantageous forms of embodiment, provided purely as non-limiting examples:

example 1

The following clinical study was conducted to test the efficacy of the proposed incremental dosage regimen for prolonged application of hormonal contraception. This study was designed to test the following assumptions: a phasic regimen with increasing dosages of, for example, estrogen and progestin, can result in an interval of 84 days without bleeding while maintaining contraceptive protection.

Two different episodic regimens and a conventional 21-day regimen were evaluated in this study based on the number of bleeding days over an observation period of 84 days.

The number and type of adverse events were compared and the number of pregnancies recorded.

A three-factor, multicenter, randomized, open test was designed with a study population of 18-35 years old fertile young women with regular menstrual cycles. Exclusion criteria constitute contraindications for hormonal contraceptives.

Test treatment (EE ═ ethinylestradiol, DRSP ═ drospirenone)

Preparation A0.015 mg EE plus 2.0mg DRSP for 28 days

0.020mg EE plus 2.5mg DRSP for 28 days

0.030mg EE plus 3.0mg DRSP for 28 days

Preparation B0.020 mg EE plus 2.0mg DRSP for 28 days

0.020mg EE plus 2.5mg DRSP for 28 days

0.020mg EE plus 3.0mg DRSP for 28 days

Formulation C (reference) 0.020mg EE plus 3.0mg DRSP for 21 days plus 7 days placebo

0.020mg EE plus 3.0mg DRSP for 21 days plus 7 days placebo

0.020mg EE plus 3.0mg DRSP for 21 days plus 7 days placebo

The primary efficacy variable was the number of bleeding days (mild and severe bleeding) over the entire observation period of 84 days.

Secondary efficacy variables are the number of adverse events and pregnancies. The number of subjects was initially determined by biometrics as approximately 200 subjects per test group.

Example 2

Another clinical study was performed following the protocol of example 1 but using the following test treatments (EE ═ ethinylestradiol, GSP ═ gestodene):

preparation A0.015 mg EE plus 0.060mg GSD for 28 days

0.020mg EE plus 0.075mg GSD for 14 days

0.030mg EE plus 0.075mg GSD for 14 days

0.030mg EE plus 0.100mg GSD for 14 days

Preparation B0.030 mg EE plus 0.060mg GSD for 28 days

0.030mg EE plus 0.075mg GSD for 28 days

0.030mg EE plus 0.100mg GSD for 28 days

Formulation C (reference) 0.015mg EE plus 0.060mg GSD plus 24 days plus 4 days placebo

0.015mg EE plus 0.060mg GSD, 24 days plus 4 days placebo

0.015mg EE plus 0.060mg GSD, 24 days plus 4 days placebo

Example 3

Another clinical study was conducted following the protocol of example 1 but using the following test treatments (EE ═ ethinylestradiol, LNG ═ levonorgestrel):

preparation A0.020 mg EE plus 0.080mg LNG for 28 days

0.030mg EE plus 0.100mg LNG for 28 days

0.030mg EE plus 0.125mg LNG for 28 days

0.030mg EE plus 0.150mg LNG for 28 days

Preparation B0.030 mg EE plus 0.080mg LNG for 28 days

0.030mg EE plus 0.100mg LNG for 28 days

0.030mg EE plus 0.125mg LNG for 28 days

0.030mg EE plus 0.150mg LNG for 28 days

Formulation C (reference) 0.020mg EE plus 0.100mg LNG, 21 days plus 7 days placebo

0.020mg EE plus 0.100mg LNG for 21 days plus 7 days placebo

0.020mg EE plus 0.100mg LNG for 21 days plus 7 days placebo

0.020mg EE plus 0.100mg LNG for 21 days plus 7 days placebo

Example 4

Another clinical study was performed according to the protocol of example 1 but with the following test treatments (EE ═ ethinylestradiol, DNG ═ dienogest):

formulation A0.010 mg EE plus 1.50mg DNG for 28 days

0.015mg EE plus 2.00mg DNG for 28 days

0.020mg EE plus 2.50mg DNG for 28 days

0.030mg EE plus 2.50mg DNG for 28 days

Formulation B0.010 mg EE plus 2.00mg DNG for 28 days

0.015mg EE plus 2.00mg DNG for 28 days

0.020mg EE plus 2.00mg DNG for 28 days

0.030mg EE plus 2.00mg DNG for 28 days

Formulation C (reference) 0.030mg EE plus 2.00mg DNG plus 7 days placebo

0.030mg EE plus 2.00mg DNG, 21 days plus 7 days placebo

0.030mg EE plus 2.00mg DNG, 21 days plus 7 days placebo

0.030mg EE plus 2.00mg DNG, 21 days plus 7 days placebo

The results obtained from the above examples were compared with the results obtained from the reference formulation and are commented on as follows:

lower rate of intermenstrual bleeding, shorter bleeding period and lower bleeding intensity;

-lower rates of symptoms associated with hormone withdrawal;

-improved female health status.

The invention has been described with reference to the preferred forms of embodiment. It is clear that the invention is susceptible to numerous variations within the framework of technical equivalents.

Claims (25)

1. A pharmaceutical preparation for obtaining a sustained hormonal treatment over a desired period of time longer than 21-28 days, comprising a first composition containing a predetermined amount of at least one estrogen and/or at least one progestin for administration in the first 21-28 days and a second composition, characterized in that said second composition contains a predetermined amount of at least one estrogen and/or at least one progestin which is higher than the amount of the first composition and comprises a mono-or multiphase sequence of pharmaceutical dosages.

2. The pharmaceutical formulation of claim 1, comprising a dosage of the drug for administration over a total period of 56, 84, 112, 140 or 168 days.

3. The pharmaceutical formulation of claim 1 or 2, wherein said second composition comprises a monophasic pharmaceutical dosage sequence.

4. The pharmaceutical formulation of claim 1 or 2, wherein said second composition comprises a biphasic pharmaceutical dosage sequence.

5. The pharmaceutical formulation according to claim 3, wherein the pharmaceutical dosage of the at least one estrogen of the second composition is higher than the amount contained in the first composition.

6. A pharmaceutical formulation according to claim 3, characterized in that the pharmaceutical dosage of the at least one progestin of the second composition is higher than the amount comprised in the first composition.

7. A pharmaceutical preparation according to claim 4, characterized in that the pharmaceutical dosage of the at least one estrogen and/or the at least one progestin of the second composition is higher than the amount comprised in the first composition.

8. A pharmaceutical formulation according to any of the preceding claims, wherein said at least one estrogen is selected from the group of synthetic estrogens consisting of: ethinyl estradiol, mestranol, quinestranol, or a precursor capable of releasing the synthetic estrogen, and/or a biogenic estrogen selected from the group consisting of: estradiol, estrone, estrane, estriol, estetrol, conjugated equine estrogens, precursors which can release this biogenic estrogen.

9. The pharmaceutical formulation according to claim 8, wherein the at least one estrogen is ethinyl estradiol and/or estradiol.

10. Pharmaceutical preparation according to any of the preceding claims, characterized in that the daily hormone units of estrogen comprise ethinylestradiol in an amount of 0.005-50mg, most preferably in an amount of 0.005-0.030mg and/or estradiol in an amount of 0.1-5.0 mg.

11. A pharmaceutical preparation according to any one of the preceding claims, characterized in that the at least one progestogen is selected from the group consisting of: levonorgestrel, norgestimate, norethindrone, dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (═ etonogestrel), 17-deacetylnorgestimate, 19-norgestrel, acetoxygestrel, allylestrenol, anagesterone, chlormadestone acetate, cyproterone acetate, demegestone, desogestrel, dienogest, demegestone, ethisterone diacetate, norgestrel acetate, gastrinon, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenone (═ lynestrenol), medroxyprogesterone acetate, megestrol, melengestrol, nomegesterone, norethindrone (═ norethindrone), norethindrone (including d-norgestrel and dl-norgestrel), norethindrone methyl, norethindrone, Progesterone, quingestrol, (17 alpha) -17-hydroxy-11-methylene-19-norpregna-4, 15-dien-20-yn-3-one, tibolone, alistipen, nersterone, prometrone, 17-hydroxypregnanolone ester, 19-nor-17 hydroxyprogesterone, 17 alpha-ethynyl-testosterone, 17 alpha-ethynyl-19-nor-testosterone, d-17 beta-acetoxy-13 beta-ethyl-17 alpha-ethynyl-4-en-3-one oxime, hydroxytrienedione ((21S) -21-hydroxy-21-methyl-14, 17-ethano-19-nor-pregn-4, 9, 15-triene-3, 20-dione), 5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -phthalide and precursors thereof.

12. Pharmaceutical preparation according to any of the preceding claims, characterized in that the at least one progestogen is preferably selected from the group consisting of: levonorgestrel, dienogest, gestodene, drospirenone, and precursors thereof.

13. Pharmaceutical preparation according to any of the preceding claims, characterized in that the daily hormone units of at least one progestogen for use throughout the prolonged treatment preferably contain the following amounts of progestogen: 0.03-0.25mg levonorgestrel and/or 0.5-5mg dienogest and/or 0.03-0.15mg gestodene and/or 0.5-5mg drospirenone or an equivalent dose of other progestins.

14. A pharmaceutical formulation according to any of the preceding claims, wherein the hormone unit is administered orally, parenterally, sublingually, transdermally, intravaginally, intranasally or buccally.

15. A pharmaceutical formulation according to any of the preceding claims, wherein the hormone unit is for oral administration.

16. A pharmaceutical formulation according to any of the preceding claims, characterized in that the hormone units are daily units.

17. Use of a pharmaceutical formulation according to claims 1 to 16 for the manufacture of a medicament for inhibiting ovulation in a mammal, in particular a human.

18. Use of a pharmaceutical formulation according to claim 17 wherein the administration of the formulation is extended for a period of 56, 84, 112, 140 or 168 days.

19. Use of a pharmaceutical preparation according to claims 17 to 18 for the preparation of a medicament for reducing symptoms associated with hormonal withdrawal, such as premenstrual syndrome, dysmenorrhea, endometriosis, menstrual headache.

20. Use of a pharmaceutical formulation according to claims 17 to 18 for the manufacture of a medicament for reducing the symptoms associated with acne.

21. A pharmaceutical pack for extended therapy treatment longer than 21-28 days comprising:

-a first composition containing a predetermined amount of at least one estrogen and/or at least one progestin for administration in the first 21-28 days;

-a second composition containing at least one estrogen and/or at least one progestin in a predetermined amount higher than the amount of the first composition and comprising a mono-or multiphasic sequence of pharmaceutical dosages for administration in a subsequent treatment.

22. Pharmaceutical package according to claim 21, characterised in that the first composition and the second composition correspond to the first and second composition as defined in the pharmaceutical preparation according to claims 1 to 16.

23. Pharmaceutical package according to claims 21 and 22, characterised in that the first and/or the second composition is administered in daily doses.

24. Pharmaceutical package according to any of claims 21 to 23, characterised in that the first and/or second composition is/are arranged for separate sequential administration, e.g. in separate blister packs.

25. Pharmaceutical package according to one of claims 21 to 24, characterised in that the administration of the first and second composition is extended to a period of 56, 84, 112, 140 or 168 days.