KR20080031435A - Oral contraception with trimegestone - Google Patents

Abstract

The invention relates to a method for contraception comprising the administration of trimegestone in combination with ethinyloestradiol to a woman of child-bearing age on at least 21 successive days, beginning on day 1 of the menstrual cycle, wherein on at least one of the at least 21 successive days the daily dose of trimegestone is more than 500 mug.

Description

Oral contraception with trimegestone

The present invention relates to a method of contraception by administration of trimegestone. The present invention also relates to pharmaceutical compositions and dosage forms containing trimegstones.

Trimegeston (17β-[(S) -2-hydroxypropanoyl] -17α-methyl-estra-4,9-dien-3-one) is a known prior art gestagen. It can be regarded as a very potent progestin in terms of potent endometrial transformation effects and mild ovulation inhibition. The pharmacodynamic profile is very similar to progesterone, a natural progestin. In this regard, for example, European Patent Publication No. 007 823 may be cited by reference. Formulations of trimegestone and estrogens for contraception include, for example, WO 98/04246, WO 98/04265, WO 98/04268 and WO 98/04268. WO 98/04269. WO 01/37841 describes the administration of trimegestone in combination with estradiol for the treatment of menopausal signs and for the prevention of postmenopausal osteoporosis.

Most commercial oral contraceptive preparations contain a guestogen with estrogen as a hormonal active ingredient, with administration typically taking 21-25 days in each 28-day menstrual cycle. Thereafter, retrograde bleeding is initiated if placebo or none is administered for 3-7 days.

In addition to effective contraceptive methods, the contraceptive preparation should provide good cycle control on the one hand and, on the other hand, show no side effects or only slight side effects.

Periodic control is mainly influenced by estrogen. However, the cyclic modulating effect of the estrogen may be affected by gestagen, and as a result, the nature and dosage of the gestagen are also important consideration factors.

Good cycle control is characterized by the development of desirable (bleeding) bleeding, particularly with the following characteristics:

The time interval between the discontinuation of the active ingredient and the onset of bleeding,

-Bleeding period,

-Degree of bleeding and

Occurrence of menstrual bleeding (eg, drip bleeding or breakthrough bleeding).

The most commonly reported side effects are weight change, nausea, changes in menstruation, changes in the chest such as sensitivity, discomfort or bloating, depression or mood disorders, decreased libido or reactions, and acne. Rare but serious potential effects include cardiovascular disease (eg seizures) and increase the risk of breast cancer, liver tumors, and cholelithiasis. CA. Frye, Neurology, 2006, 66 (6 Suppl. 3), 29-36].

Since the introduction of oral contraceptive preparations, researchers have focused on developing formulations that reduce potential side effects without reducing the contraceptive effects or deviating from the 28-day natural menstrual cycle. Oral contraceptive preparations of the first generation were required to contain more gestagen and estrogen to ensure effective contraception. Adverse hemostasis and metabolic changes, clinical problems and side effects are associated with these high dose first generation agents. In 1978, WHO encouraged the pharmaceutical industry to develop formulations with the lowest possible amounts of gestagen and estrogen in the future.

First, the content of estrogens was reduced in the formulations because known side effects, in particular thromboembolism, could be attributed to estrogens. However, as it has become increasingly apparent that gestagen is also associated with certain side effects, especially cardiovascular complications, the content of gestagen in the formulations has also decreased. It was also recognized that establishing a balance between estrogen and gestagen may not adversely affect carbohydrate metabolism and lipid or lipoprotein levels. As a result, it has been found that there is a synergistic effect of inhibiting ovulation at relatively low doses of both estrogen and gestagen.

A number of therapeutic approaches have been developed to achieve the goal while maintaining good cycle control contraception and minimizing the side effects of the full dose of steroids. In this regard, the gestagen / estrogen combination is administered at a constant dosage (monophasic) or in a bi- or polyphasic regimen.

For example, International Publication No. WO 98/04269 describes monophasic regimens, including International Publication No. WO 98/04265, International Publication No. WO 98/04268, and International Publication No. WO 98/04246. The issue describes polymorphic regimens, in particular 40-500 μg of trimegestone in combination with estrogen and is administered daily. See A.E. According to Schindler et al., Maturitas, 2003, 46, S1, 7-16], the ovulation inhibitory dose of trimegestone is 0.5 mg per day by oral administration, but WO 98/04269, International Publication. According to WO 98/04265, WO 98/04268 and WO 98/04246, the daily dose of trimegston is preferably in the range of 40 to 250 μg. However, it is at least questionable whether a daily dose, for example 40 μg of trimegestone, is sufficient to provide and maintain a positive contraceptive effect.

Each time a large decrease in the amount of active ingredient cannot continue forever, and can often cause new problems.

Thus, the problem often arises that, due to the minimum amount of active ingredient, effective contraception and a stable menstrual cycle depend largely on being administered at the correct time so that the plasma concentration of the active ingredient in the blood remains maximally constant. All deviations from a constant dosing regimen, i.e. deviations occurring each day at the same time, should be avoided as much as possible.

However, it is difficult to ascertain the practical reasons for the overall constant administration. For example, it is known that a small percentage of women sometimes forget to take a dosage for a particular day and only supplement the next day. It may occur that the prescribed dose is administered one morning and not until the next evening. Similar problems may occur if a woman vomits after taking the pill but before the dose is fully absorbed.

The resulting variation in plasma concentration may be lowered to a value below the minimum threshold concentration necessary to ensure sure contraception as a result of the low dose of the active ingredient administered. In such cases, the effectiveness of contraception cannot always be guaranteed even with the minimum active ingredient dose. Regardless of the failure of contraceptive function, fluctuations in plasma concentration can furthermore also prematurely initiate (retrospective) bleeding (menstrual bleeding, eg drip bleeding or disruptive bleeding).

In addition, the metabolism of the active ingredient in the body may vary between individuals, for example due to gene arrangement. Thus, low doses of trimegestone may produce plasma concentrations above the minimum required for some women, but for the other women higher doses may be required to ensure effective contraception due to faster metabolism. have.

Regardless of the effectiveness of contraception, the progression of retrograde bleeding also plays an important role. In general, it is desirable that bleeding occur only to a small extent for a short time. This is desirable not only from the personal point of view of most women, but also for medical reasons. For example, short and minor bleeding is only associated with a small loss of iron.

It is an object of the present invention to provide an advantageous method of contraception over the methods of the prior art. Regardless of ensuring effective contraception, the method guarantees good cycle control and shows no or only minor adverse effects on, for example, depression and other adverse effects on carbohydrate metabolism and lipid or lipoprotein levels. These properties should be relatively insensitive to the administration of irregular active ingredients and interpersonal changes.

This object is achieved by the claims.

Surprisingly, when trimegestone is administered in combination with estrogen for oral contraception, the ratio of gestagen to estrogen is varied in a relatively wide range, such as side effects such as depression and carbohydrate metabolism and lipid or lipoproteins. It was found that it provides a clear contraceptive effect without causing adverse effects on the level. Thus, it has surprisingly been found that in order to maintain a gestagen-estrogen balance, the dosage of trimegstonone can be increased within a certain range without simultaneously increasing the dosage of estrogen. In this way, side effects that may be accompanied by increased estrogen dosage are avoided.

The present invention preferably

-Trimegeston

Optionally in combination with at least one estrogen, preferably ethynylestradiol, or optionally in combination with two estrogens, preferably ethynylestradiol and estradiol,

Optionally combining with one or more additional gestagens, and / or

Optionally in combination with one or more additional bioactive substances

Starting from the first or fifth day of the menstrual cycle, preferably at least 21 consecutive days, preferably 21 to 26 days, more preferably 22 to 25 days, most preferably 23 or 24 days of the 28-day menstrual cycle. A method of contraception comprising oral administration to women of childbearing age for days, wherein at least one of 21 consecutive days or more, preferably two or more days, more preferably five or more days, even more preferably eight or more days Most preferably at least 14 days, in particular all 21 consecutive days, with a daily dose of trimegston of at least 500 μg.

In a preferred embodiment of the method according to the invention, at least 21 consecutive days, preferably at least one of 24 days, has a daily dosage range of trimegestone of at least 500 μg and less than 2,000 μg, or at least 2,000 μg. Preferably, at least 21 consecutive days, preferably at least one of the 24 days has a daily dosage range of trimegston

500 μg or more, preferably less than 1,000 μg, preferably 510 to 990 μg, more preferably 525 to 975 μg, even more preferably 550 to 950 μg, most preferably 575 to 925 μg, especially 600 To 900 μg;

1,000 μg or more, preferably less than 2,000 μg, preferably 1,010 to 1,990 μg, more preferably 1,025 to 1,975 μg, even more preferably 1,050 to 1,950 μg, most preferably 1,075 to 1,925 μg, especially 1,100 To 1,900 μg;

At least 2,000 μg, preferably at least 2,100 μg, more preferably at least 2,500 μg, even more preferably at least 3,000 μg, most preferably at least 4,000 μg, in particular at least 5,000 μg.

In a preferred embodiment of the method according to the invention, the trimegestone is combined with one or more estrogens and administered at least 21 consecutive days, preferably at least one of 24 days. The estrogens are preferably chlorotrianigen, dientrol, diethylstilbestrol, estradiol (17β-estradiol), estriol, estrone, ethynylestradiol, hexoestrol, mestranol, metalleno Estryl, methylestrenol, promestriene and conjugated estrogens, or pharmaceutically acceptable esters thereof. Particular preference is given to ethynylestradiol or a combination of ethynylestradiol and estradiol (17β-estradiol). Preferred pharmaceutically acceptable esters of the estrogens described above are acetates, propionates and valerates such as estradiol valerate.

The daily dosage of estrogen is preferably 5.0 to 55 μg, more preferably 10 to 50 μg, even more preferably 15 to 48 μg, most preferably 20 to 45 μg of the equivalent dose of ethynylestradiol. , In particular, 22 to 40 μg. 20 μg or 30 μg is particularly preferred. If two or more estrogens are used, their total daily dose preferably corresponds to the equivalent dose mentioned above, and the equivalent dose is preferably related to the ovulation inhibitory effect of the esterosterone.

Preferably, a daily dose of 1,000 to 3,000 μg trimegstonone is combined with ethynylestradiol at a daily dose of 20 ± 5 μg or 30 ± 5 μg for 24 or 25 consecutive days during the 28-day menstrual cycle. To be administered.

Particularly preferred embodiments of the combination of the daily dose X of trimegestone and the daily dose Y of ethynylestradiol are summarized in the table below.

According to a preferred embodiment of the present invention, ethynylestradiol is combined with trimegstonone at a daily dose of 20 ± 5 μg, preferably 20 ± 2.5 μg, with a daily dose of trimegston being ≧ 500. Μg, ≥625 μg, ≥750 μg, ≥875 μg, ≥1,000 μg, ≥1,125 μg, ≥1,250 μg, ≥1,375 μg, ≥1,500 μg, ≥1,625 μg, ≥1,750 μg, ≥1,875 μg, ≥2,000 μg, ≥2,125 μg, ≥2,250 μg, ≥2,375 μg, ≥2,500 μg, ≥2,625 μg, ≥2,750 μg, ≥2,875 μg, ≥3,000 μg, ≥3,125 μg, ≥3,250 μg, ≥3,375 μg, ≥3,500 μg, ≥3,625 μg Μg, ≧ 3,750 μg, ≧ 3,875 μg, ≧ 4,000 μg, ≧ 4,125 μg, ≧ 4,250 μg, ≧ 4,375 μg, ≧ 4,500 μg, ≧ 4,625 μg, ≧ 4,750 μg, ≧ 4,875 μg or ≧ 5,000 μg.

According to a preferred embodiment of the present invention, ethynylestradiol is combined with trimegstonone at a daily dose of 30 ± 5 μg, preferably 30 ± 2.5 μg, where the daily dose of trimegston is ≧ 500. Μg, ≥625 μg, ≥750 μg, ≥875 μg, ≥1,000 μg, ≥1,125 μg, ≥1,250 μg, ≥1,375 μg, ≥1,500 μg, ≥1,625 μg, ≥1,750 μg, ≥1,875 μg, ≥2,000 μg, ≥2,125 μg, ≥2,250 μg, ≥2,375 μg, ≥2,500 μg, ≥2,625 μg, ≥2,750 μg, ≥2,875 μg, ≥3,000 μg, ≥3,125 μg, ≥3,250 μg, ≥3,375 μg, ≥3,500 μg, ≥3,625 Μg, ≧ 3,750 μg, ≧ 3,875 μg, ≧ 4,000 μg, ≧ 4,125 μg, ≧ 4,250 μg, ≧ 4,375 μg, ≧ 4,500 μg, ≧ 4,625 μg, ≧ 4,750 μg, ≧ 4,875 μg or ≧ 5,000 μg.

In a preferred embodiment, the weight ratio of ethynylestradiol to trimegston is less than 1:45. According to another preferred embodiment, the daily dose of trimegstone corresponds to an equivalent dose of noethysterone acetate at a weight ratio of ethynylestradiol to noethysterone acetate of 1:45 or less, wherein the equivalent administration The amount is preferably related to the ovulation inhibitory effect of noethysterone acetate and trimegstone.

In a particularly preferred embodiment, for at least 21 consecutive days, preferably at least 1 of 24 days, preferably all of them

Ethynylestradiol is administered at a daily dose of 1.0 to 55 μg, preferably 20 ± 5 μg or 30 ± 5 μg

Estradiol (17β-estradiol) is administered at a daily dose of 1,000 to 10,000 μg, preferably 1,000 to 5,000 μg.

In another particularly preferred embodiment, the trigegestone is retained for at least 21 consecutive days, preferably at least one of 24 days, preferably all of them

Not administered with estradiol (17β-estradiol), or

Administered with a combination of estradiol (17β-estradiol) and ethynylestradiol.

Thus, according to this embodiment, when ethynylestradiol is also administered, it is preferred that only estradiol (17β-estradiol) is administered.

In a particularly preferred embodiment of the method according to the invention, no more than 21 consecutive days, preferably 24 days, no estrogen is administered without trimegestone administration.

Preferably, the trimegestone is combined with a daily dose of 10-20 μg of ethynylestradiol and a daily dose of 1,000-5,000 μg for estradiol for 24 or 25 consecutive days of the 28 menstrual cycle. The daily dose is 1,000 to 3,000 μg.

Particularly preferred embodiments of the combination of the daily dose X of trimegestone, the daily dose Y of ethynylestradiol and the daily dose Z of estradiol (17β-estradiol) are summarized in the table below :

In a preferred embodiment of the method according to the invention, trimegstone is administered in combination with one or more additional bioactive substances for at least 21 consecutive days, preferably at least 1 of 24 days, preferably all of them. Preferably, the additional bioactive material is selected from the group consisting of folic acid, folic acid, vitamin C, vitamin B preparation, iron (II) preparation, iron (III) preparation, calcium preparation and magnesium preparation.

Examples of vitamin B preparations include, but are not limited to, vitamin B ₁ preparations such as thiamine hydrochloride and thiamine nitrate; Vitamin B ₂ preparations such as riboflavin and riboflavin-5'-phosphate; Nicotinamide preparations; Vitamin B ₆ preparations, such as pyridoxine hydrochloride; Pantothenic acid preparations such as dexpanthenol; And vitamin B ₁₂ preparations, such as cyanocobalamin and hydroxylcobalamin acetate.

Examples of iron (II) preparations include iron (II) sulfate, iron carbonate (II), iron (II) chloride, iron tartrate (II), iron gluconate (II), iron aspartate (II), and glycine sulfate (II), iron fumarate (II), iron ascorbate (II), iron iodide (II), iron succinate (II) and ammonium iron sulfate (II).

Examples of iron (III) preparations include sodium iron citrate, iron (III) oxide / sucrose complex, sodium peredate, iron hydroxide (III), dextriferon, iron (III) citrate, chondroitin sulfate / iron ( III) complexes, iron (III) acetyltransferrin, iron (III) protein succinylate and potassium / iron phosphate (III) / citrate complexes.

Examples of calcium preparations include calcium carbonate, calcium citrate, calcium hydrogen phosphate, calcium phosphate, calcium aspartate, calcium bis aspartate, calcium hydrogen aspartate, calcium gluconate, calcium lactate, calcium lactogloconate, calcium glucoheptonate, acetic acid Calcium, calcium saccharide, calcium orte and calcium lactobate.

Examples of magnesium preparations include magnesium hydrogen aspartate, magnesium L-aspartate hydrochloride, magnesium oxide, magnesium hydrogen phosphate, magnesium citrate, magnesium hydrogen citrate, magnesium sulfate, magnesium hydrogen L-glutamate, magnesium magnesium D-gluconate It is magnesium, adipic acid and magnesium nicotinate.

In a preferred embodiment of the method according to the invention, each of the daily doses of trimegestone is at least 21 consecutive days, more preferably at least 22 days, even more preferably at least 23 days, most preferably at least 24 days , In particular the same for at least 25 days (= monophasic regimen), with administration preferably being combined with at least one estrogen, preferably in each case with 20 + 5 μg ethynylestradiol or 30 ± 5 μg ethynylestradiol Proceed.

In another preferred embodiment of the method according to the invention two, at least 21 consecutive days, more preferably at least 22 days, even more preferably at least 23 days, most preferably at least 24 days, in particular at least 25 days, It is divided into three or more daily groups, where the daily dose of trimegestone is the same as all of the days in the group, but the daily dosage of trimegeston differs from the consecutive days of the different groups (= polyphase regimen) Preferably in each case it proceeds in combination with at least one estrogen, preferably ethynylestradiol. Preferred regimens are listed in the following table, wherein the daily dose of trimegestone is A1, A2 or A3 and the daily dose of one or more estrogens, preferably ethynylestradiol, is B:

Specific ranges of dosage values for specific combinations of A1, A2, A3, and B for each one of these embodiment numbers 1, 2 ₁ , 2 ₂ , 3 ₁ , 3 ₂ , 3 ₃ , 4 ₁ and 4 ₂ are as follows: In the table, it can be seen as a, b, c and d, where dose B of one or more estrogens is expressed as equivalent dose for ethynylestradiol:

or

or

or

Thus, aspect numbers 1, 2 ₁ , 2 ₂ , 3 ₁ , 3 ₂ , 3 ₃ , 4 ₁ and 4 ₂ are administered at doses a, b1, b2, b3, b4, c1, c2, c3, c4, d1, d2 When combined with any one of, d3 and d4, the following preferred embodiments will be treated separately:

In the list above, an embodiment, eg, “3 ₂ ^b2 ” represents the triphasic regimen “3 ₂ ” and trimegestone and estrogen are administered at the daily dose, value “b2” according to Table b.

Equivalent dosages for ethynylestradiol can be carried out by the equivalent dosage of each suitable estrogen, the amount of which is selected so that the estrogen activity corresponds to the activity that can occur by administration of the stated amount of ethynylestradiol Ethinyl estradiol itself is a preferred estrogen. Ethinylestradiol in combination with two or more different estrogens, for example estradiol, may be used in an amount corresponding to the equivalent dosage mentioned, and is preferably related to the ovulation inhibitory effect. Suitable methods for determining equivalent dosages are known to those skilled in the art. Trimegeston is preferably used in combination with ethynylestradiol or in combination with ethynylestradiol and estradiol (17β-estradiol).

In di-, tri- and filamentous regimens, the daily doses of trimegstonone and estrogen are constant in each case one day before and different for two consecutive days in the different phases.

The daily dose of 20 ± 5 ethynylestrogens in combination with trimegston with daily doses A1, A2 and A3, defined as a, b, c and d in the table above, for 21 to 24 consecutive days. As administered in μg, particularly preferred regimens 1 ′, 2 ₁ ′, 2 ₂ ′, 3 ₁ ′, 3 ₂ ′, 3 ₃ ′, 4 ₁ ′ and 4 ₂ ′ can be seen in the following table:

The daily dose of 30 ± 5 ethynylestrogens in combination with trimegston with daily doses A1, A2 and A3, defined as a, b, c and d in the table above, for 21 to 24 consecutive days As administered at μg, further particularly preferred regimens 1 ", 2 ₁ ", 2 ₂ ", 3 ₁ ", 3 ₂ ", 3 ₃ ", 4 ₁ "and 4 ₂ " can be seen in the following table:

In a preferred embodiment of the method according to the invention, trimegestone is preferably not administered during all days of the 28-day menstrual cycle. Instead, for days of 21 or more consecutive days, preferably 24 days or more

-Placebo,

Pharmaceutically acceptable preparations containing iron,

Preparations containing folic acid, polyic acid and / or salts thereof

Preparations containing estrogens, preferably ethynylestradiol, are preferably administered in a daily dose corresponding to 10 μg or less of the equivalent dose of ethynylestradiol or not at all.

In this way, it is ensured that the menstrual cycle is terminated by retrograde bleeding, allowing a new menstrual cycle to begin. The menstrual cycle is preferably at least 28 days.

However, according to another preferred embodiment of the method according to the invention, the menstrual cycle may be at least 28 days. This is due to the suspension of trimegestone (and optionally one or more estrogens and / or one or more additional gestagens) which do not occur until a later time point, so that recurrent bleeding does not occur until this time point, so that the menstrual cycle Does not end until a later point in time, which can be achieved according to the invention. In such embodiments, the trimegestone is preferably administered for at least 28 consecutive days.

In this embodiment, the trimegestone (without interruption) is at least 42 or 56 consecutive days, more preferably at least 63 days, even more preferably at least 84 days, most preferably at least 105, 112 or 120 days , Especially if administered 126 days, 140 days, 150 days, 183 days, 184 days, 189 days or 365 days or more, will not initiate retroactive bleeding within this period. In a preferred embodiment, trimegeston is administered (without interruption) of at least 183 days but less than 365 days. According to the present invention, the continuous period during which trimegeston can be administered daily may be longer. Thus, trimegestone can generally be administered continuously for one year or longer without any regressive bleeding.

If the menstrual cycle extends beyond 28 days, for example 183 days, then trimegestone can be administered in a daily dose of 1,000 to 3,000 μg with a daily dose of 20 ± 5 μg or 30 ± 5 μg of ethynylestradiol. It is preferred that the dose be administered daily for at least 28 days, for example at least 183 days, without interruption.

Optionally, the trimegestone is combined with a daily dose of 10-20 μg ethynylestradiol and a daily dose of 1,000-5,000 μg estradiol for at least 28 days without interruption at a daily dose of 1,000-3,000 μg, For example, it is preferred to be administered daily for at least 183 days.

Preferably on days after 28 days or more, preferably for 28 consecutive days after 3 days, 4 days, 5 days, 6 days or 7 days

-Placebo,

Pharmaceutically acceptable preparations containing iron,

Preparations containing folic acid, polyic acid and / or salts thereof

Formulations containing estrogens, preferably ethynylestradiol, are preferably administered in a daily dose corresponding to up to 10 μg of equivalent dose of ethynylestradiol or not at all.

In a preferred embodiment of the method according to the invention, the trimegestone is combined with a daily dose of 20 ± 5 μg or 30 ± 5 μg of ethynylestradiol in a daily dose of 1,000 to 3,000 μg daily for at least 28 days, For example, it is administered uninterrupted for 84 consecutive days and for 7 consecutive days after the 28 or more consecutive days, and ethynylestradiol is administered at a daily dose of 5-10 μg in the absence of trimegston.

In a preferred embodiment of the method according to the invention, the trimegestone is administered together with one or more additional gestagens for at least 21 days, preferably at least one of 24 consecutive days. Further gestagens are preferably herein allylestrenol, chlormadinone, danazol, demegestone, desogestrel, dienogest, drospirenone, dydrogethrone, etisterone, ethino Diol, Gestosterone, Gestonolone, Hydroxyprogesterone, Levonogestrel, Linoestrenol, Medroxyprogesterone, Medrogestone, Megestrol, Methylestrenol, Methylnortestosterone, Nomegestrol, Noethysterone, noethinodrel, norgestel, norgestimate, progesterone, promegestone and tibolone, or pharmaceutically acceptable esters thereof. Preferred pharmaceutically acceptable esters of the aforementioned gestagens include acetates (e.g. chlormadinone acetate, nomegestrol acetate, methoxyprogesterone acetate, megestrol acetate, norethosterone acetate), caproate (e.g. Hydroxyprogesterone caproate) and enanthate such as noethysterone enanthate.

The daily dose of the additional gestagen is preferably 100 to 5,000 μg, more preferably 250 to 4,000 μg, even more preferably 500 to 3,500 μg, most preferably the equivalent dose of chlormadinone acetate Corresponding to 750 to 3,000 μg, in particular 1,000 to 2,500 μg, the equivalent dosage is preferably associated with the ovulation inhibitory effect of chlormadinone acetate or the endometrial effect of chlormadinone acetate.

The method according to the invention is carried out for one or more menstrual cycles. The method according to the invention is preferably carried out for at least two, in particular for three, four, five or six consecutive menstrual cycles.

The present invention furthermore comprises at least 500 μg, preferably at least 600 μg, even more preferably at least 700 μg, even more preferably at least 1,000 μg, most preferably at least 1,200 μg, in particular 1,000 to 3,000 It relates to a solid pharmaceutical composition comprising μg in combination with preferably 20 ± 5 μg or 30 ± 5 μg ethynylestradiol.

The invention also preferably comprises

500 μg or more, preferably less than 1,000 μg, preferably 510 to 990 μg, more preferably 525 to 975 μg, even more preferably 550 to 950 μg, most preferably 575 to 925 μg, especially 600 To 900 µg;

1,000 μg or more, preferably less than 2,000 μg, preferably 1,010 to 1,990 μg, more preferably 1,025 to 1,975 μg, even more preferably 1,050 to 1,950 μg, most preferably 1,075 to 1,925 μg, especially 1,100 To 1,900 µg; or

In a solid pharmaceutical composition comprising at least 2,000 μg, preferably at least 2,100 μg, more preferably at least 2,500 μg, even more preferably at least 3,000 μg, most preferably at least 4,000 μg, in particular at least 5,000 μg. It is about.

The invention also provides at least 500 μg of trimegonestone, preferably at least 750 μg, even more preferably at least 1,000 μg, most preferably at least 2,000 μg, in particular at least 3,000 μg, preferably at least 5 μg, more preferably Relates to a pharmaceutical composition comprising in combination with 20 ± 5 μg or 30 ± 5 μg ethynylestradiol.

The present invention also provides at least 500 μg of trimegestone, preferably at least 750 μg, even more preferably at least 1,000 μg, most preferably at least 2,000 μg, especially at least 3,000 μg, preferably at least 5 μg, more Preferably in combination with ethynylestradiol in an amount of 20 ± 5 μg or 30 ± 5 μg and estradiol in an amount of preferably 1,000 to 10,000 μg, more preferably 1,000 to 5,000 μg. It is about.

The pharmaceutical composition according to the invention is preferably formulated for oral administration. Preferably in the form of (membrane coated) tablets, sugar coated tablets or multiparticulates, preferably microtablets, microcapsules, myopellets, accretion pellets, granules, extrudates, spheroids, beads or Estimated in pellet form, it may optionally be filled or press-moulded in capsules to form (membrane coated) tablets. Anhydrous compressed formulations are also possible.

The invention also relates to a dosage form comprising the pharmaceutical composition described above, preferably once daily, preferably orally.

Dosage forms according to the invention may comprise at least 500 μg of trimegston; Preferably at least 510 μg; More preferably 525 μg or more, 1,000 μg or more, 1,500 μg or more or 2,000 μg or more; Even more preferably 550 to 950 µg; Most preferably in an amount of 575 to 925 μg, in particular 600 to 900 μg, wherein the dosage form is preferably selected from the group consisting of membrane coated tablets, sugar coated tablets and capsules.

In a preferred embodiment of the dosage form, trimegeston is included in an amount of at least 1,000 μg and less than 2,000 μg, or at least 2,000 μg. Dosage forms according to the invention are presumed to be in the form of multiparticulates, preferably in microtablets, microcapsules, myelopellets, additional pellets, granules, extrudates, spheroids, beads or pellets, optionally filled or pressurized in capsules. Can be shaped to form (membrane coated) tablets. Anhydrous compressed formulations are also possible.

In a preferred embodiment, the dosage form according to the invention is selected from the group consisting of membrane coated tablets, sugar coated tablets and capsules and comprises a pharmaceutical composition according to the invention.

Preferred embodiments described below relate to both pharmaceutical compositions according to the invention and dosage forms according to the invention.

The pharmaceutical composition or dosage form according to the invention preferably further contains one or more estrogens, preferably ethynylestradiol. The one or more estrogens are preferably chlorotrianigen, dientrol, diethylstilbestrol, estradiol (17β-estradiol), estriol, estrone, ethynylestradiol, hexoestrol, mestranol, Metalrenostryl, methylestrenol, promestriene and conjugated estrogens or pharmaceutically acceptable esters thereof. Preferred pharmaceutically acceptable esters are valerates (eg estradiol valerate).

The amount of estrogen is preferably 5.0 to 55 μg, more preferably 10 to 50 μg, even more preferably 15 to 48 μg, most preferably 20 to 45 μg, especially 22 to the equivalent dose of ethynylestradiol. Corresponding to 40 μg, etiniestradiol itself is the preferred estrogen. If two or more estrogens are used, the total amount thereof preferably corresponds to the equivalent dosage described above, which is preferably related to the ovulation inhibitory effect.

In a preferred embodiment of the pharmaceutical composition or dosage form according to the invention, the composition or dosage form

Contains no estradiol (17β-estradiol), or

Contains estradiol (17β-estradiol) together with ethynylestradiol.

In a preferred embodiment, the pharmaceutical composition or dosage form according to the present invention further contains one or more additional gestagens, independent of trimegstones. Further gestagens are preferably allylestrenol, chlormadinone, danazol, demegestone, desogestrel, dienogest, drospirenone, dydrogestrone, etisterone, ethinodiol, crab Stodene, Gestonolone, Hydroxyprogesterone, Levonorgestrel, Linoestrenol, Medoxyprogesterone, Medrogstone, Megestrol, Methylestrenol, Methylnortestosterone, Nomegestrol, Noretis Theron, noethinodrel, norgestrel, norgestimate, progesterone, promegestone and tibolone, or pharmaceutically acceptable esters thereof. Preferred pharmaceutically acceptable esters include acetates (e.g. chlormadinone acetate, methoxyprogesterone acetate, megestrol acetate, noethysterone acetate), caproates (e.g. hydroxyprogesterone caproate) and enanthates (e.g. Noreosterone enanthate).

The amount of additional gestagen is preferably 100 to 5,000 μg, more preferably 250 to 4,000 μg, even more preferably 500 to 3,500 μg, most preferably 750 to 3,000 μg of the equivalent dose of chlormadinone acetate. , In particular corresponding to 1,000 to 2,500 μg, the equivalent dosage is preferably associated with the ovulation inhibitory effect of chlormadinone acetate or the endometrial effect of chlormadinone acetate, ie the endometrial deforming effect.

Irrespective of trimegeston, if the pharmaceutical composition or dosage form according to the invention contains further active ingredients, in particular one or more estrogens (eg ethynylestradiol) and / or additional gestagens, the same dosage unit It is preferred to exist as a mixture within. Such dosage forms can be prepared with the usual methods and with the aid of an adjuvant. Suitable auxiliary substances are known to those skilled in the art. In this regard, see, for example, H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendorff, 2002; and R.C. Rowe et al., Handbook of Pharmaceutical Excipients, APhA Publications, 4th edition, 2003].

Examples of auxiliary substances include salt formers, buffers, emulsifiers, solubilizers, wetting agents, defoamers, gel formers, thickeners, membrane formers, surfactants, binders, slip agents, lubricants, embedding agents , Release agents, flow regulators, disintegration accelerators (disintegrants), chelating agents, adsorbents, fillers, pharmaceutical solvents, antioxidants (e.g. α-tocopherol), preservatives, plasticizers, flavoring agents and colorants.

Examples of extenders are lactose, mannitol, calcium diphosphate, starch, microcrystalline cellulose, calcium carbonate (E170) and magnesium carbonate.

Examples of disintegration accelerators (disintegrants) are starches such as corn starch, potato starch, crosslinked polyvinylpyrrolidone and less substituted sodium carboxymethylcellulose.

Examples of binders are starch (eg potato starch, corn starch), gelatin, polyvinylpyrrolidone, cellulose ethers, sugars such as sucrose and glucose syrup.

Examples of slip agents are talc, sodium stearyl fumarate, fatty acid esters and macrogols.

Examples of lubricants are stearic acid, magnesium stearate, calcium stearate and zinc stearate.

An example of a flow-regulator is colloidal silicon dioxide.

Examples of pharmaceutical solvents are propylene glycol and glycerol.

One example of a surfactant is polyoxyethylene / sorbitan fatty acid esters such as polysorbate 80.

Examples of colorants are indigo carmine (E132), titanium dioxide (E171) and quillin yellow (E104).

Examples of membrane forms are shellac, methylcellulose, hydromellose (hydroxypropyl-methylcellulose, HPMC), hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, polyacrylates and polymethacrylates. Plasticizers such as propylene glycol and / or polyethylene glycol may be further contained in the membrane coated composition.

Examples of sunscreens are carnauba wax, montan glycol wax, stearic acid / palmic acid, glycerol trioleate and cetylstearyl alcohol.

Examples of chelating agents are citric acid, phenylaniline, sodium calcium edetate and disodium edetate (EDTA-Na ₂ ).

Examples of iron-containing preparations include iron (II) preparations, for example iron (II) sulfate, iron (II) carbonate, iron (II) chloride, iron tartrate (II), iron gluconate (II), aspartic acid. Iron (II), glycine sulfate (II), iron fumarate (II), iron ascorbate (II), iron iodide (II), iron succinate (II) and ammonium iron (II); And iron (III) preparations, such as sodium iron citrate, iron (III) oxide / sucrose complex, sodium peredate, iron hydroxide (III), dextriferon, iron (III) citrate, chondroitin sulfate Iron (III) complex, iron (III) acetyltransferrin, iron (III) protein succinylate and potassium / iron phosphate (III) / citrate complex.

In a particularly preferred embodiment, the iron containing formulation is administered with folic acid, polylinic acid and / or salts thereof. The following iron formulations are particularly suitable for this embodiment: iron / amino acid complexes, iron (II) fumarate, iron (II) sulfate, dextrinferon, ammonium iron (II) sulfate, glycine iron (II) and iron gluconate (II). Folic acid and folic acid are respectively present here in free form or as calcium salts thereof.

When folic acid, folic acid and / or salts thereof are administered, their daily dosage is preferably 0.1 to 7.5 mg, more preferably 0.2 to 5.0 mg, even more preferably 0.3 to 3.0 mg, most preferably Preferably 0.4 to 2.5 mg, especially 0.5 to 2 mg.

Examples of particularly preferred auxiliary substances are talc, long chain fatty acids, magnesium stearate, stearic acid, calcium stearate, polyethylene glycol, palmitic acid, hydrogenated vegetable oils such as hydrogenated castor oil.

In a preferred embodiment, the pharmaceutical composition or dosage form according to the invention contains a buffer having a pH value in the range of 2.0 to 5.5. The buffer is preferably formed by a mixture of citric acid and disodium hydrogen phosphate.

In a preferred embodiment, the pharmaceutical composition or dosage form according to the invention contains a cyclodextrin, for example β-cyclodextrin or γ-cyclodextrin, preferably β-hydroxypropyl-cyclodextrin (β-HP) do. Preferably, the cyclodextrins form complexes with trimegstones and / or estrogens such as ethynylestradiol.

In a preferred embodiment, irrespective of trimegestone and optionally one or more estrogens and / or one or more additional gestagens, the pharmaceutical compositions or dosage forms according to the invention may be further bioactive substances such as folic acid, foline Acids or suitable derivatives, or salts, such as calcium salts, vitamin C, vitamin B preparations, iron (II) preparations, iron (III) preparations, calcium preparations and magnesium preparations.

In a preferred embodiment, irrespective of trimegestone and optionally one or more estrogens and / or one or more additional gestagens, the pharmaceutical compositions or dosage forms according to the invention may comprise the following auxiliary substances in Based on the total weight of the dosage form).

In another preferred embodiment, irrespective of trimegestone and optionally one or more estrogens and / or one or more additional gestagens, the pharmaceutical compositions or dosage forms according to the invention may comprise the following auxiliary substances in the following preferred amounts: % Is based on the total weight of the dosage form).

Pharmaceutical compositions or dosage forms according to the invention may contain, for example, the following substances in the following preferred amounts:

Membrane-coated tablets may, for example, have the following composition:

The storage stability of the pharmaceutical compositions or dosage forms according to the invention meets international standards (see European, Japanese and American Pharmacopoeia).

The present invention relates to a kit comprising one or more of the aforementioned dosage forms according to the present invention.

The kit according to the invention is preferably designed once daily in each case in the dosage form contained therein.

The kit preferably includes all dosage forms containing the trimegestone necessary for administering trimegestone for one or more menstrual cycles. The kit is preferably prepared such that the above contraceptive method according to the invention is carried out without acquiring additional dosage forms containing trimegestone, which are not contained in the kit. The kit preferably contains one dosage form daily, since the administration preferably proceeds once daily.

If the menstrual cycle is longer than 28 days, the kit according to the invention contains at least trimegestones, since it is necessary to administer trimegeston for at least 21 consecutive days of the 28-day menstrual cycle, preferably 24 days. It is preferable to include the dosage form of. If trimegeston is administered for less than 28 days, during the remaining days until the end of the 28 menstrual cycle, the kit according to the invention contains no dosage form at all, or iron-containing preparations, folic acid, folate, polyacid, polyate Or placebo, preferably iron-containing formulations. Herein, one or more of the dosage forms containing the trimegestone of the kit according to the invention need to be the dosage form according to the invention described above.

If the menstrual cycle is extended, i.e. longer than 28 days, the number of dosage forms containing trimegestone contained in the kit according to the invention increases correspondingly, where one of the dosage forms containing trimegestone is present. The above is preferably the dosage form according to the present invention described above.

In a preferred embodiment, the kits according to the invention all comprise a dosage form containing trimegestone, which comprises at least 2, more preferably at least 3, even more preferably at least 4, enteric It is preferably necessary for administration at least 5, in particular at least 6 menstrual cycles.

In a preferred embodiment, the kits according to the invention are designed for the monophasic or polyphasic administration of the combination of trimegestone with estrogen, preferably ethynylestradiol. The menstrual cycle herein is preferably at least 28 days. In di-, tri- and filamentous regimens, the daily doses of trimegstonone and estrogen are constant in each case one day before and different for two consecutive days in the different phases.

Trimegestone is preferably used in a dosage form in combination with ethynylestradiol or in a dosage form in combination with ethynylestradiol and estradiol (17β-estradiol).

Preferred embodiments Nos. 1, 2 ₁ , 2 ₂ , 3 ₁ , 3 ₂ , 3 ₃ , 4 ₁ and 4 ₂ of the kit according to the invention are in total 21 to 25, preferably 24 dosage forms containing trimegston And according to the following table, according to the number of phases, the trimegestone contains doses A1, A2 and A3 and at least one estrogen, preferably ethynylestradiol, at dose B:

The specific range of dosage values for a particular combination of A1, A2, A3 and B for each one of these embodiment numbers 1, 2 ₁ , 2 ₂ , 3 ₁ , 3 ₂ , 3 ₃ , 4 ₁ and 4 ₂ is As can be seen in the following table, Dose B of one or more estrogens is expressed in equivalent doses for ethynylestradiol:

or

or

or

The following preferred embodiments will be treated separately:

Particularly preferred kits according to the invention are the combinations of trimegestones with ethynylestradiol for 21 to 24 days in a continuous menstrual cycle for the regimen 1 ', 2 ₁ ', 2 described above in connection with the method according to the invention. _{Any one of 2} ′, 3 ₁ ′, 3 ₂ ′, 3 ₃ ′, 4 ₁ ′ and 4 ₂ ′ contains all dosage forms necessary to be accepted.

Another particularly preferred kit according to the invention is the regimen 1 ", 2 ₁ ", described above in connection with the method according to the invention, by administering trimegestone together with ethynylestradiol for 21 to 24 consecutive days of the menstrual cycle. Any one of 2 ₂ ", 3 ₁ ", 3 ₂ ", 3 ₃ ", 4 ₁ "and 4 ₂ " contains all dosage forms necessary to be accepted.

Further preferred embodiments of the kits according to the invention are 84 dosage forms containing from 1,000 to 3,000 μg of trimegestone with 20 ± 5 μg or 30 ± 5 μg of ethynylestradiol and ethynylestradiol alone, ie 7 dosage forms containing 10 ± 5 μg in the absence of trimegestone.

Trimegestone, optionally in combination with estrogen and / or additional gestagen, optionally for a treatment period for a period of at least 28 days, eg, bleeding disorders; Dysmenorrhea; Symptoms dependent on the menstrual cycle, such as endometriosis, polycystic ovary syndrome (PCOS), fibroids, cysts, premenstrual syndrome and headache / migraine headaches; Symptoms affected by the menstrual cycle, such as epilepsy, multiple sclerosis, diabetes, depression, schizophrenia, asthma and Parkinson's disease; And androgen-induced disorders such as seborrhea, acne, androgen alopecia and hirsutism, for the treatment and / or prevention of one or more of the diseases or symptoms selected from the group.

Thus, the present invention is directed to bleeding disorders; Dysmenorrhea; Symptoms dependent on the menstrual cycle, such as endometriosis, polycystic ovary syndrome (PCOS), fibroids, cysts, premenstrual syndrome (PMS), premenstrual unpleasant mood disorder (PMDD) and headache / migraine headaches; And a trimegestone dose of at least 500 μg, preferably for treating and / or preventing one or more of the diseases or conditions selected from the group consisting of androgen-induced disorders such as seborrhea, acne, androgen alopecia and hirsutism. It also relates to the use of trimegestone, optionally formulated with estrogen (eg ethynylestradiol) and / or additional gestagens, for the manufacture of a drug of less than 2,000 μg (eg oral contraceptives).

Dosage forms according to the invention may be prepared by conventional processes. The following examples are not to be considered as limiting the scope of the invention.

Example  One:

a) composition

b) composition

Ethinylestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved in 600 ml of ethanol. Trimegestone (particle size 90% <50 μm), lactose and corn starch were mixed in a mixer / pelletiser (Diosna P25) for 5 minutes, thoroughly wetted, and then ethanolized. Mix with EE / PVP solution. The wettable composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granulated product was separated into masses through a 0.6 mm screen, mixed with magnesium stearate and colloidal silicon dioxide, and pressed into a tablet press of 5 mm punch to prepare a 50 mg weight tablet.

The tablets of composition (a) were coated with a hydromelose-based coating (e.g. Opadry YS-1-2184, manufactured by Colorcon) having a 2 mg tablet coating composition, having the same composition but containing no hormones. Packaging into packaging containing 24 hormone-containing daily units and 4 hormone-free daily units.

The tablet of the composition (b) is coated with a hydromelon-based coating (for example, Opadry YS-1-2184 manufactured by Colon) of the following composition (coating composition 2 mg per tablet).

24 hormone-containing tablets and 4 hormone-free tablets were packed in one packaging as each daily dosage unit.

Example  2:

a) composition

b) composition

Ethinylestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved in 950 ml of ethanol. Trimegeston (particle size 90% <50 μm), lactose and corn starch were mixed in a mixer / pelletizer [Dios or P25] for 5 minutes, thoroughly wetted and then mixed with ethanol EE / PVP solution do. The wettable composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granulated product was separated into masses through a 0.6 mm screen, mixed with magnesium stearate, and pressed into a tablet press of 6 mm punch to produce 80 mg weight tablets.

Tablets of composition (a) were coated with a 2 mg hydrogel-based coating (e.g. Opadry YS-1-2184 from Colon), with a 24 hormone-containing daily unit and 4 hormone ratios. Package into packaging containing containing daily unit.

The tablets of the composition (b) were coated with a hydromelon-based coating of the following composition (1 mg of the coating composition per tablet) (e.g. Opadry YS-1-2184 from Colon).

24 hormone-containing tablets and 4 hormone-free tablets were packed in one packaging as each daily dosage unit.

Example  3:

Two-phase contraceptive

a) one-phase composition

Ethinylestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved in 600 ml of ethanol. Trimegeston (particle size 90% <50 μm), lactose and corn starch were mixed in a mixer / pelletizer [Dios or P25] for 5 minutes, thoroughly wetted and then mixed with ethanol EE / PVP solution do. The wettable composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granulated product was separated into masses through a 0.6 mm screen, mixed with magnesium stearate and colloidal silicon dioxide, and pressed into a tablet press of 5 mm punch to prepare a 50 mg weight tablet.

b) two-phase compositions

As shown in a), a 50 mg by weight hormone-free, folic acid-containing tablet was prepared, wherein the sodium salt of folic acid was dissolved in 600 ml of aqueous ethanol.

Some tablets are prepared as described in a).

The tablets under a) and b) are coated with a hydromelon-based coating (e.g. Opadry YS-1-2184 from Colonon) with a 2 mg tablet coating composition. 12 hormone-containing daily units prepared according to a), 12 hormone-containing daily units and 4 hormone-free daily units prepared according to b) were packed into commercially available packaging for daily administration.

Example  4:

a) Ethinylestradiol (EE), povidone K30 (polyvinylpyrrolidone) and sodium folate are dissolved in 600 ml of ethanol. Trimegeston (particle size 90% <50 μm), lactose and corn starch were mixed in a mixer / pelletizer [Dios or P25] for 5 minutes, thoroughly wetted and then mixed with ethanol EE / PVP solution do. The wettable composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granulated product was separated into masses through a 0.6 mm screen, mixed with magnesium stearate and colloidal silicon dioxide, and pressed into a tablet press of 5 mm punch to prepare a 50 mg weight tablet.

b) As shown in a), a hormone-free, folic acid-containing tablet weighing 50 mg is prepared by dissolving sodium folate in 600 ml of aqueous ethanol.

Tablets a) and b) are each coated with a hydromelon-based coating (eg, Opadry YS-1-2184, produced from Colon), which has a 2 mg tablet coating composition.

21 hormone-containing daily units prepared according to a) and 7 hormone-free daily units prepared according to b) were packed into commercially available packaging for daily administration.

Example  5:

120 tablets according to example 1 a) are packed in blowing agents and sold for daily administration for 120 consecutive days.

Example  6:

Composition

Ethinylestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved in 600 ml of ethanol. Trimegeston (particle size 90% <50 μm), lactose and corn starch were mixed in a mixer / pelletizer [Dios or P25] for 5 minutes, thoroughly wetted and then mixed with ethanol EE / PVP solution do. The wettable composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granulated product was separated into masses through a 0.6 mm screen, mixed with magnesium stearate and colloidal silicon dioxide, and pressed into a tablet press of 5 mm punch to prepare a 50 mg weight tablet.

The tablets were coated with a hydromelose based coating of the following composition (2 mg of the coating composition per tablet):

Tablets are packed in blowing agents containing 189 daily units and sold for daily administration for 189 consecutive days.

Example  7:

Composition

Ethinylestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved in 950 ml of ethanol. Trimegeston (particle size 90% <50 μm), lactose and corn starch were mixed in a mixer / pelletizer [Dios or P25] for 5 minutes, thoroughly wetted and then mixed with ethanol EE / PVP solution do. The wettable composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granulated product was separated into masses through a 0.6 mm screen, mixed with magnesium stearate, and pressed into a tablet press of 6 mm punch to produce 80 mg weight tablets.

The tablets were coated with a hydromelose based coating of the following composition (2 mg of the coating composition per tablet):

Tablets are packed in blowing agents containing 365 daily units and sold for daily administration for 365 consecutive days.

Example  8:

Composition

Ethinylestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved in 950 ml of ethanol. Trimegeston (particle size 90% <50 μm), lactose and corn starch were mixed in a mixer / pelletizer [Dios or P25] for 5 minutes, thoroughly wetted and then mixed with ethanol EE / PVP solution do. The wettable composition is forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granulated product was separated into masses through a 0.6 mm screen, mixed with magnesium stearate, and pressed into a tablet press of 6 mm punch to produce 80 mg weight tablets.

The tablets were coated with a hydromelose based coating of the following composition (1 mg of the coating composition per tablet):

The tablets are packed in blowing agents containing 150 daily units and sold for daily administration for 150 consecutive days.

Claims (20)

Trimetheston in combination with ethynylestradiol, starting from day 1 of the menstrual cycle, for at least 21 consecutive days (wherein the daily dose of trimegston for at least 1 day of at least 21 consecutive days is at least 500 μg) A method of contraception comprising administering to a woman of childbearing age. 2. The method of claim 1, wherein trimegeston is administered with a combination of ethynylestradiol and estradiol for at least one of 21 consecutive days. The method of contraception according to claim 1 or 2, wherein the daily dose of ethynylestradiol or a combination of ethynylestradiol and estradiol corresponds to an equivalent dose of 5.0 to 55 μg of ethynylestradiol. The daily dose of trimegestone according to any one of claims 1 to 3, for at least one of 21 consecutive days. At least 500 μg and less than 2,000 μg or A method of contraception, in the range of at least 2,000 μg. The method of contraception according to any one of claims 1 to 4, which is administered orally. The contraceptive method according to any one of claims 1 to 5, wherein the menstrual cycle is at least 28 days. The method of contraception according to any one of claims 1 to 6, wherein the daily dose of trimegestone is the same as each of 21 or more consecutive days. 8. The treatment according to claim 1, wherein the trimegestone is not administered during the entire 28-day menstrual cycle and for days following at least 21 consecutive days. 9. Placebo is administered, -Iron-containing preparations are administered, -An agent containing folic acid, foline acid and / or salts thereof is administered, -Preparations containing estrogens, preferably ethynylestradiol, are administered, or A method of contraception that is not administered at all. The method of contraception according to claim 1, which is carried out for at least six consecutive menstrual cycles. A pharmaceutical composition comprising at least 500 μm of trimegonestone in combination with ethynylestradiol. The pharmaceutical composition of claim 10 which contains a combination of ethynylestradiol and estradiol. The pharmaceutical composition of claim 10 or 11, wherein the amount of ethynylestradiol or a combination of ethynylestradiol and estradiol corresponds to an equivalent dose of 5.0 to 55 μg of ethynylestradiol. The method of claim 10, wherein the salt forming agent, buffer, emulsifier, solubilizer, wetting agent, antifoaming agent, gel forming agent, thickener, membrane former, surfactant, binder, slip agent, One or more auxiliaries independently selected from the group comprising lubricants, embedding agents, mold release agents, flow control agents, disintegrants, chelating agents, adsorbents, fillers, pharmaceutical solvents, antioxidants, preservatives, plasticizers, flavoring agents and colorants A pharmaceutical composition further comprising a substance. The pharmaceutical composition according to any one of claims 10 to 13, for contraception. A dosage form comprising the pharmaceutical composition according to claim 10, which is selected from the group consisting of membrane coated tablets, sugar coated tablets and capsules. 16. A kit comprising one or more compositions or dosage forms according to any of claims 10-15. 17. A total of 21 to 25 dosage forms for administration once daily for 21 to 25 consecutive days, wherein ethynylestradiol or a combination of ethynylestradiol and estradiol is equivalent to estradiol, respectively. A kit containing an amount corresponding to a dosage of 5.0 to 55 μg and trimegestone in an amount of at least 500 μg. 17. A total of 28 or more dosage forms for administration once daily in succession, wherein at least one dosage form comprises ethynylestradiol or a combination of ethynylestradiol and estradiol equivalent of estradiol. A kit containing an amount corresponding to a dosage of 5.0 to 55 μg and trimegestone in an amount of at least 500 μg. The method of claim 18, wherein the dosage forms are present in at least 84 dosage forms for once daily administration for 84 consecutive days, each dosage form comprising ethynylestradiol or a combination of ethynylestradiol and estradiol equivalent of estradiol. A kit containing an amount corresponding to a dosage of 5.0 to 55 μg and trimegestone in an amount of at least 500 μg. The method of claim 19, wherein the dosage forms are present in at least 7 dosage forms for once daily administration for 7 consecutive days, each dosage form containing ethynylestradiol in an amount of 5.0 to 15 μg in the absence of trimegestone. Kit.