EP1227815A1

EP1227815A1 - Contraceptive medicament based on a progesterone and an oestrogen and method for producing the same

Info

Publication number: EP1227815A1
Application number: EP00971488A
Authority: EP
Inventors: Jacques Le Clos De Cimiez Paris; Jean-Louis Thomas
Original assignee: Laboratoire Theramex SAM
Current assignee: Laboratoire Theramex SAM
Priority date: 1999-10-25
Filing date: 2000-10-24
Publication date: 2002-08-07
Also published as: HK1048600A1; EP2020236A1; AP1707A; HK1129564A1; CN1382054A; CN1205936C; NZ518308A; KR20020073333A; ZA200203399B; IL149141A0; OA12071A; NO20021948D0; EP2020236B1; HUP0203443A2; CZ20021426A3; CR6627A; AU784478B2; RU2002113654A; MXPA02004083A; JP2003518013A

Abstract

The invention relates to the field of chemistry and more specifically, to the field of therapeutic chemistry. In particular, the invention relates to novel contraceptive compositions comprising a progesterone and an oestrogen, especially novel pharmaceutical compositions for contraceptive use which are characterised in that they contain an ester of nomegestrol and estradiol as their active agents in conjunction with or mixed with an inert, non-toxic, pharmaceutically compatible excipient or vehicle which is suitable for oral administration.

Description

NEW CONTRACEPTIVE MEDICINAL PRODUCT AND ITS PREPARATION METHOD

Among the most used and effective contraceptive means are hormonal associations which act by 3 different mechanisms which are, in order of importance:

- the inhibition of the gonadotropic function which slows down the secretion by the pituitary gland of FSH and LH and consequently prevents the maturation of the ovarian follicle and the occurrence of the ovulatory peak of LH essential for ovarian egg-laying; - changes in the secretion and physico-chemical properties of the cervical mucus, which make it impermeable to sperm;

- inhibition of the development of the uterine lining which becomes unfit for implantation.

Until now, in the estrogen-progestogen combinations used for contraception, the inhibition of gonadotropic function was mainly due to the estrogenic fraction constituted by a synthetic estrogen: ethinylestradiol. Thanks to the simultaneous use of 19-nor-testosterone derivatives, the progestogen fraction strengthens this inhibition of ovulation, and also provides peripheral contraceptive effects on cervical mucus and endometrium.

However, the use of estrogen-progestogen contraceptive combinations currently available has significant drawbacks. Ethinyl estradiol has a very strong impact on liver functions; this is essentially manifested by disorders in the synthesis of coagulation factors and by abnormalities in the plasma lipid profile (BONNAR et al, 1987; MEADE, 1,988; LINDBERG et al, 1989; VON SHOULTZ et al, 1,989; DALY & BONNAR, 1990; BURKMAN, 1997; SPITZER, 1997). As a result, the use of estrogen-progestogen contraceptives is problematic in women at risk (women with circulatory disorders, women in perimenopause, women who smoke ...). This is all the more important since the deleterious effect of ethinyl estradiol can be further increased by the progestogen fraction due to a frequently present residual androgenic activity (BONNAR, 1987; SABRA and BONNAR, 1983; BONNAR et al , 1987). The progestogenic response of currently available estrogen-progestogen contraceptives is most often made up of a 19-nortestosterone derivative which, like ethmv 1-estradιol, has a negative impact on liver function the lipid profile and the vessels Although this has not has been demonstrated definitively, the most modern 19-nor-testosterone derivatives, so-called 3rd generation progestins, are suspected of inducing an increase in thromboembolic accidents (O'BRIEN. 1999)

To avoid the disadvantages of ethinyl-estradiol, the derivatives of 19-nor-testosterone are sometimes used alone in contraception, in 2 different ways

-or at low doses and in this case 1 contraceptive action is ensured by the peripheral effects of the progestogen alone. 1 inhibition of ovulation is not constant because low doses of progestin very often allow the development of ovarian follicles and, in some cases, an increase in endogenous secretion of estradiol,

-or in large doses, so as to inhibit, for sure. ovulation, but at the risk of creating hypoestrogenia, which limits their use in young women

In summary, it seems very useful to have an estrogen-progestogen combination as effective as those which are currently available but which is devoid of their harmful side effects. To do this, it was easy to - replace ethinyl-estradiol (EE ) by 1 hormone secreted by 1 ovary, 17-beta estradiol (E2) much less toxic than EE (BUC MAN et al, 1980, BERGINK et al. 1981, LINDBERG et al. 1989) but weakly antigonadotropic (HIRVONEN, 1995) Attempts have been numerous but none have resulted in a product offered to women. In general, the anti-ovulatory effect was well obtained but the numerous failures were due. in most cases poor control of the menstrual cycle with the appearance of spotting and intermenstrual bleeding which made the method unacceptable Thus the associations of natural estrogens with desogestrel (WENZL, 1993, KIVINEN and S <\ URE. 1996, CSEMICZKY et al 1996), with cyproterone acetate (HIRVONEN et al, 1988 HIRVONEN et al 1995), with norethisterone (ASTEDT et al. 1 977; WORLD HEALTH ORGANIZATION. 1 980; S ERU P et al. 1 98 1) were found to be contraceptive but intercurrent bleeding, spotting and poor quality of the rules were not acceptable . For some, the reasons for these failures lay in insufficient estrogen stimulation due to the poor bioavailability of estradiol or its esters; the overly potent progestational effect led to partial inhibition of endometrial proliferation and therefore to uncontrolled bleeding (HIRVONEN et al, 1995; C SEMICSKY et al, 1 996). Only one association has given satisfactory results in terms of menstrual cycle control; it is the valerate association of estradiol and dienogest (OETTEL et al 1 999; HOFFMAN et al, 1 999). According to these authors, the positive results are due to a strong dissociation between central activity (anti-ovulatory) and peripheral activity (endometrial) in favor of the latter activity for dienogest. In summary, all of the published data show that the result depends closely on the antigonadotropic effect of the progestogen, on the bioavailability of estradiol or its derivatives in the formulation used and on an optimum ratio between estrogen and progestogen stimulation. .

- replace the derivative of 1 9-nortestosterone by a synthetic progestin strongly antigonadotropic and known to have no impact on liver function, the metabolism of glucose-lipid lipid and coagulation factors.

Contraceptive effect of the n omegestrol acetate / estradiol combination

The object of the present invention is a new oral contraceptive formulation in women of childbearing age (young or perimenopausal); this formulation is based on the combination:

l. a synthetic progestogen devoid of any secondary metabolic effect, nomegestrol or its esters, the antigonadotropic effect of which is unexpectedly potentiated by estradiol or its esters;

2. estradiol or one of its ether or ester derivatives to compensate for the hypoestrogenism induced by the progestogen administered for a prolonged period during the cycle; 3. and the use of an optimum weight ratio between the estrogenic fraction and the progestogenic fraction to ensure good control of the menstrual cycle. The estrogenic component uses estradiol or one of its esters such as, for example, valerianate, benzoate. ^the enanthate .... doses employed being calculated as estradiol equivalent. The doses range from 0.3 mg to 3 mg per day with a preference for the range 0.5 to 2 mg per day. According to the data in the literature (HIRVONEN, 1995), a dose of 4 mg is necessary to ensure inhibition of ovulation, but they correspond to the doses used to compensate for states of hypoestrogenism. For example, in postmenopausal women, the recommended dose to compensate for hypoestrogenic states is approximately 1.5 mg.

The progestin component uses nomegestrol or one of its esters. Preferably nomegestrol acetate will be used. The dose range is between 0.1 and 2.5 mg per day, preferably between 0.1 and 1.5 mg per day, and especially between 0.3 and 1.25 mg per day. At these very low doses, nomegestrol acetate combined with estradiol inhibits ovulation as well as follicular maturation in 100% of cases when the two active ingredients are administered together from the ^1st to the 21st day of the cycle, with frequencies acceptable withdrawal bleeding and intercurrent bleeding.

The range of the weight ratio of estradiol doses on the doses ^of nomegestrol acetate ^extends about 0.5 to 5 and this ratio is preferably between 1 and 3 approximately.

The combination of nomegestrol acetate and estradiol is administered daily, at the same dose, from the ^1st day of the cycle, for a period ranging from 21 to 28 days. Then, women receive a placebo tablet daily for the time necessary to complete the 28-day cycle (0 to 7 days).

Nomegestrol acetate is a powerful progestin, orally active and which has an original pharmacological profile:

- like 19-nortestosterone derivatives. nomegestrol acetate carries a strong antigonadotropic activity but unlike the former, it does not manifest no residual androgenic and estrogenic activity and it has a strong anti-estrogenic activity.

- like the derivatives of 1 7alpha-hydroxyprogesterone, it presents a pure pharmacological profi le, but unlike these, it has a powerful antigonadotropic effect.

It belongs to the category of progenitors qualified as hybrids (OETTEL et al.

1,999) which do not carry deleterious metabolic effects due to the lack of 1 7α-ethinyl function and which combine the advantages of progesterone derivatives with those of the more modern derivatives of 1 9-nortestosterone.

A clinical trial similar to the KAUFMANN trial has shown that endometrial transformation is obtained with a daily dose of 1 mg of nomegestrol acetate, or 10 mg for the whole cycle. It had previously been shown (BAZIN et al, 1,987) that the inhibition of ovulation and the absence of follicular development were obtained in women with a daily dose of 2.5 mg of nomegestrol acetate. The ratio of ovulation inhibiting activity in women (in mg / day) to endometrial luteinization activity (in mg / cycle) as defined by NEUMANN (1 977) is therefore of the order of 0.2, c ' that is to say close to those of cyproterone acetate and chlormadinone acetate; it shows strong central activity (OETTEL et al, 1,999). In this sense, it is clearly distinguished from dienogest whose activity is unbalanced in favor of peripheral activity. Therefore the results observed with a contraceptive combination of estradiol valerate / dienogest not suggest in any way and do not make obvious those observed with the combination estradiol / nomegestrol acetate according to ^the invention.

The study of the anti-ovulatory power of the nomegestrol acetate / estradiol association shows an unexpected potentiation of the antigonadotropic effects of nomegestrol acetate by estradiol since the inhibition of ovulation and follicular development are obtained with a low dose, is 0.625 mg. This result cannot come from an antigonadotropic effect of estradiol or even from an addition of effects between the two active ingredients insofar as the doses of estradiol used are much lower than the doses known to inhibit ovulation ( HIRVONEN et al. 1995). Accordingly, this unexpected finding is the sign ^of a real i nnovation as it allows the use of lower doses of progestin and therefore better tolerance it differs from 1 ob _j and from the French patent and 2,754 1,79 belonging to the Applicant company, in which the range of doses of nomegestrol acetate could range from 1.5 at 5 mg The present invention therefore relates to an estrogen-progestogen agent administered in a monophasic manner from the ^1st day of the cycle for 2 1 to 28 days. It is distinguished from the claims of numerous patents which describe the association of estradiol or of estradiol ester administered in polyphasic modalities with modified doses of estrogen and / or progestogen from one phase to another and, sometimes even, change of progestogen from one phase to another. in this regard by way of example the patents EP 770338, WO 974 1 868, WO 9909993. WO 9835682. WO US98 1 7288, WO 9602486, WO 9707074. WO 9707083, WO 9707084, WO 9707085, WO 9707089. WO 971 2785 , WO 9712785, WO 9712786, WO 9712787, WO 9712788, WO 9 712789, WO 23228, WO 9741 868, WO 991 3882, EP 491438, EP 49141 5. WO 9004330, EP 3092263, US 462805 1, EP 091 1029 A2, EP0770388 A1 and DE 3229612, as well as the publications of HIRVONEN et al (1988, 1 995) which describe a biphasic contraceptive method with the valerate estradiol / cyproterone acetate association or that of HOFFMANN et al (1998) which describes a biphasic contraceptive method with the valerate estradiol / dienogest association

The present invention includes a contraceptive method associating 17β-estradiol or one of its esters and nomegestrol or one of its esters, preferably nomegestrol acetate This method of contraception is innovative compared to patents and publications devoted to associations estradiol estrogen-progestogens (or one of its esters) and a progestogen administered in a monophasic manner, because all of the literature shows that the overall clinical result is totally dependent on the nature of the progestogen used, on its pharmacological profile , its effects on the hypothalamic-pituitary axis of the "central" V "peripheral" power ratio and of the estrogenic and progestogenic activity ratio For these reasons, the monophasic contraceptive methods described in patents, such as for example WO 95 / 1 7 1 94, WO 991253 1 and EP 0253607 and publications such as for example those which deal with norethisterone / estrad associations iol (ASTEDT e al. 1 977: Task force on oral contraception. 1980; SERUP et al. 1 98 1), those which deal with desogestrel / estradiol combinations (WENZL et al. 1 993; CS EMICSKY et al. 1996) or combinations of dienogest and estradiol (HOFFMANN et al, 1 998) cannot 'apply to the combination of nomegestrol acetate / estradiol insofar as they are validated only for the estrogen and for the progestogen claimed. Added to this is the fact that the potentiation observed between estradiol and nomegestro acetate makes it unnecessary to extrapolate doses from the pharmacological profile. In addition, nomegestrol acetate is never mentioned as a progestin that can be used. The patents EP 309263 and WO 9004330 cite the possibility of using 1 7alpha-1 9-nor progesterone and its esters but it should be noted on the one hand that nomegestrol acetate is not an ester of 17alpha-9 -norprogesterone. and that on the other hand the esters of 17alpha-1 9-norprogesterone carry antidiuretic properties which make them unsuitable for use in women (PARIS et al, 1987).

A preferred composition will be one which contains 0.312 mg of nomegestrol acetate per 1 mg of estradiol or 0.625 mg of nomegestrol acetate and 1 mg of estradiol or 0.625 mg of nomegestrol acetate and 1.5 mg estradiol or 0.625 mg of nomegestrol acetate and 2 mg of estradiol.

The pharmaceutical compositions according to ^the invention are those suitable for the digestive tract, especially in the form of plain or coated tablets, dragees, capsules, capsules, pills, cachets or powders flavored or not. They contain a diluting agent and / or a filler and / or a compression aid and / or a lubricating agent and / or a bursting agent. As coating agent, there may be mentioned ^{hydroxypropyl} methylcellulose (Hypromellose) or cellulose acetate phthalate.

Polyvinylpyrolidone, carboxymethylcellulose, crosslinked carboxymethylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose or a chemically or unmodified starch may be used as the binding agent. As filler, mention may be made of calcium carbonate, magnesium carbonate, magnesium phosphate, clays, zeol ites. of diatomaceous earth. etc. As compression adjuvant, mention may be made of lactose or powdered sugar. Mention may be made, as lubricating agent, of talc, calcium stearate, magnesium stearate, and silica neck. Mention may be made, as bursting agent, of mannitol, carboxymethyl starch or polyvinylpolypyrolidone.

Generally speaking, the weight of the compositions according to the invention ^s' ranges from 40 to 1 00 mg and the composition contains from 80 to 99% of diluents and excipients for from 1 to 20% of active ingredients. Nomegestrol acetate and estradiol can be administered simultaneously combined in a single formulation or on the contrary presented in two pharmaceutical forms to be successively or simultaneously ingested.

The daily dosage will be 1 to 2 doses and the duration of treatment will be exercised for the entire month. In total, the average monthly dose ^of nomegestrol acetate s' stages between 8 mg to 75 mg. The doses are perfectly tolerated.

EXAMPLE I: Examples of Formulations

The combination of nomegestrol acetate and estradiol is presented in the form of bare tablets or dandruff.

In these compositions, the estradiol is advantageously introduced into the final mixture in the form of a premix containing from 2 to 5% of estradiol in povidone (1 0 to 25%) and lactose (qs 1 00%) as for example :

This premix is introduced into the final mixture to obtain a tablet by direct compression.

The finished, naked tablets generally weigh 60 to 90 mg and have the following general formula:

BARE TABLET FORMULATIONS Composition in mg / per tablet

- Estradiol premix qs 0.5 to 1.5

- Nomegestrol acetate 0.300 to 2.500

- Colloidal silica 0.300 to 1.500

- Crospovidone 2,500 to 5,000

- Lactose 4,000 to 40,000

- Cellulose 6,000 to 40,000

- Stearic acid 0.900 to 3.00

- Talc 0.450 to 1.500 mg

By way of example, mention may be made of tablets weighing 90 mg, of the following formula:

Example formulations (FU = unit formulation) 90 mg tablets

FORMULATIONS FU mg / 1 tablet 90 mg FU%

2.5% estradiol premix 40,000 44.45 Nomegestrol acetate 0.300 0.33

Colloidal silica (Aerosil 200) 0.495 0.55

Crospovidone (Polyplasdone XL) 3,240 3.60

Lactose 26,000 28.89

Microcrystalline cellulose (Avicel PH 101) 17,265 19.18 Stearic acid AC68 / 50VG 1,800 2.00

Talc 0.900 1.00

TOTAL 90,000 100.00 FORMULATIONS FU mg / 1 tablet 90 mg FU%

2.5% estradiol premix 40,000 44.45 Nomegestrol acetate 2,500 2.77 Colloidal silica (Aerosil 200) 0.495 0.55 Crospovidone (Polyplasdone XL) 3.240 3.60

Lactose 24,900 27.67

Microcrystalline cellulose (Avicel PH 101) 16,165 17.96 Stearic acid AC68 / 50VG 1,800 2.00 Talc 0.900 1.00 TOTAL 90,000 100.00

FORMULATIONS FU mg / 1 tablet 90 mg FU%

2.5% estradiol premix 60,000 66.67

Nomegestrol acetate 0.300 2.77 Colloidal silica (Aerosil 200) 0.495 0.55

Crospovidone (Polyplasdone XL) 3,240 3.60

Lactose 12,215 8.91

Microcrystalline cellulose (Avicel PH 101) 13,050 14.50

Stearic acid AC68 / 50VG 1,800 2.00 Talc 0.900 1.00

TOTAL 90,000 100.00

FORMULATIONS FU mg / 1 tablet 90 mg FU%

2.5% estradiol premix 60,000 66.67 Nomegestrol acetate 0.625 0.69

Kollidon 25 9,000 10.00

Colloidal silica (Aerosil 200) 0.495 0.55

Crospovidone (Polyplasdone XL) 3,240 3.60

Microcrystalline cellulose (Avicel PH 101) 13,050 14.50 Stearic acid AC68 / 50VG 1,800 2.00

Talc 0.900 1.00

Lactose 0.890 0.99

TOTAL 90,000 100.00 Bare tablets weighing 60 mg can also be produced with the following formula Example formulations (FU = unit formulation) 60 mg tablets

FORMULATIONS FU mg / 1 tablet 60 mg FU%

4.0% estradiol premix 25,000 4 1.67 Nomegestrol acetate 0.300 0.50

Colloidal silica (Aerosil 200) 0.324 0.54

Crospovidone (Polyplasdone XL) 3,000 5,00

Lactose 16,076 26.79

Microcrystalline cellulose (Avicel PH 1 0 1) 13, 500 22.50 Stearic acid AC68 / 50VG 1, 200 2.00

Talc 0.600 1.00

TOTAL 60,000 100.00

FORMULATIONS FU mg / 1 tab 60 mg FU% Premix 4.0% estradiol 25,000 41, 67

Nomegestrol acetate 2,500 4,17

Colloidal silica (Aerosil 200) 0.324 0.54

Crospovidone (Polyplasdone XL) 3,000 5.00

Lactose 14.976 24.96 Microcrystalline cellulose (Avicel PH 1 01) 12.400 20.66

Stearic acid AC68 / 50VG 1, 200 2.00

Talc 0.600 1.00

TOTAL 60,000 100.00

FORMULATIONS FU mg / 1 tablet 60 mg FU%

4.0% estradiol premix 37,500 62.50

Nomegestrol acetate 0.300 4, 17

Colloidal silica (Aerosil 200) 0.324 0.54

Crospovidone (Polyplasdone XL) 3,000 5.00 Lactose 7.076 1 6.08

Microcrystalline cellulose (Avicel PH 1 01) 10,000 8.71

Stearic acid AC68 / 50VG 1, 200 2.00

Talc 0.600 1.00

TOTAL 60,000 100.00 FORMULATIONS FU mg / 1 tablet 60 mg FU%

4.0% estradiol premix 25,000 41.67

Nomegestrol acetate 2,500 4.17

Colloidal silica (Aerosil 200) 0.324 0.54 Crospovidone (Polyplasdone XL) 3,000 5.00

Lactose 14.976 24.96

Microcrystalline cellulose (Avicel PH 101) 12,400 20.66

Stearic acid AC68 / 50VG 1,200 2.00

Talc 0.600 1.00 TOTAL 60,000 100.00

FORMULATIONS FU mg / 1 tablet 60 mg FU%

4% estradiol premix 37,500 62.50

Nomegestrol acetate 0.625 1.04 Kollidon 25 7,000 11.67

Colloidal silica (Aerosil 200) 0.324 0.54

Crospovidone (Polyplasdone XL) 3,000 5.00

Microcrystalline cellulose (Avicel PH 101) 8.213 13.69

Stearic acid AC68 / 50VG 1,200 2.00 Talc 0.600 1.00

Lactose 1.538 2.56

TOTAL 60,000 100.00

These tablets can be dandruff with for example: - film-coating agents based on polyvinyl alcohol of the OPADRY type

PVA "moisture barrier" (polyvinyl alcohol, titanium dioxide, purified talc, lecithin, xanthan gum, pigments, lacquers), or

- cellulose-based film-coating agents of the SEPIFILM L.P. type [H.P.M.C. (hydroxypropylmethylcellulose)], microcrystalline cellulose, stearic acid, pigments, lacquers).

EXAMPLE II Potentiation of the Antigonadotropic Effect of Nomegestrol Acetate by Estradiol The anti-ovulatory action of the estradiol-acetate combination of nomegestrol was evaluated in a randomized double-blind trial in 38 women in period of ovarian activity, volunteers, in good health, aged 18 to 35 years, including we had previously verified by a dosage of plasma progesterone and the establishment of a temperature curve that they had ovulatory menstrual cycles.

The women were followed for two consecutive cycles: the first was a control cycle without treatment; during the next cycle (cycle under treatment), they received a hormonal treatment administered orally daily from 1 ^st to 21 ^th j ^me our cycle. According to randomization:

• 9 women received 1.5 mg of estradiol + 0.625 mg of nomegestrol acetate (group A) • 10 others received 1.5 mg of estradiol + 1.25 mg of nomegestrol acetate (group B) ,

The other 10, 1.5 mg of estradiol + 2.5 mg of nomegestrol acetate (group C),

• and the other 9 were treated with nomegestrol acetate alone at a dose of 2.5 mg (group D).

During the control cycle, the hormonal parameters were not significantly different in the four groups.

Table I indicates for each hormonal parameter the average concentrations observed during the 2 1 days of treatment.

In all women and whatever the doses administered, the cycles under treatment were all anovulatory, with a disappearance of the mediocyclic LH peak and a plasma progesterone level of less than 1 ng / ml.

Comparison of hormonal parameters in groups C and D showed that the combination of estradiol with nomegestrol acetate not only significantly increased plasma estradiol levels, but also enhanced the antigonadotropic effect of progestin. Indeed, in presence of estradiol. LH and FSH levels were found to be statistically lower than those seen with nomegestrol acetate alone.

When nomegestrol acetate is associated with ^estradiol it exerts antigonadotrophic effects even at low doses (0.625 and 1.25 mg), since the hormonal parameters were not found significantly different in groups A, B and vs.

This synergistic effect of estradiol is confirmed by the comparison of the results of this study with those of another clinical trial carried out according to the same methodology but with the progestogen alone. This comparison indeed shows that at the dose of 1.25 mg of nomegestrol acetate, the addition of estradiol has no significant influence on the plasma levels of progesterone and gonadotropins (LH and FSH ). On the other hand, the addition of estradiol lowers the plasma estradiol level dosed 24 hours after taking the medication by around 300%, a parameter which is a good reflection of endogenous secretion from the ovary (Table II).

We know that nomegestrol acetate given alone at a rate of 1.25 mg per day abolishes ovulation and prevents the formation of the corpus luteum, while causing an increase in plasma estradiol, which indicates follicular development. without ovulation, as encountered with the progestogen micropill.

Studies have therefore shown that the addition of a dose of estradiol, insufficient to block ovulation alone, strengthens the anti-ovulatory effects of the progestin and also inhibits folliculogenesis, and maintains significantly lower estradiol levels. 100 pg / ml away from the medication. When combined with estradiol, it is possible to observe anti-ovulatory effects with doses of nomegestrol acetate lower than those initially used; this confirms, in the new study, the results obtained with 0.625 mg of nomegestrol acetate (NOMAC) per day, combined with estradiol. In this study, the survey of genital bleeding made it possible to assess the influence of the estradiol / nomegestrol acetate association on the cycle. Of all the women treated with the estroprogestative combination, it was thus found that the duration of the cycle did not exceed 1 month in 50% of the cases. that spotting was completely absent in one in two women and that the ^withdrawal hemorrhage after stopping treatment was on average 5, 4 days and did not exceed 7 days in 86% of women. These data did not differ between groups. As regards the first cycle of treatment, they reflect a satisfactory tolerance; it is indeed known that the quality of the cycles obtained with this type of association improves after a few treatment cycles.

Table I: Average plasma concentrations (m ± wk) of gonadotropins (LH and FSH) and ovarian steroids (estrad iol and progesterone) during a cycle treated with 3 estradiol / nomegestrol acetate combinations (E2 / NOMAC ). Comparison to treatment with nomegestrol acetate alone.

Table II: Average concentrations (m ± wk) of gonadotropins (LH and FSH) and of estradiol in plasma with 1.25 mg of nomegestrol acetate associated or not with estradiol

E2 = estradiol; NOMAC = nomegestrol acetate m (range) m ± wk

EXAMPLE III Effect of the combination of nomegestrol acetate / estradiol on the endometrium

A study was conducted to test the effects on the endometrium of several doses of nomegestrol acetate associated with a dose ^of oral estradiol equivalent to 1.5 mg.

In this study, 179 postmenopausal women for at least 3 years received daily 2 mg of estradiol valerate daily combined with four different doses of nomegestrol acetate: 5 mg (n = 47), 2.5 mg ( n = 42), 1.25 mg (n = 43) and 0.625 mg (n = 47).

The impact of these four associations on the endometrium was evaluated by measuring the thickness of the endometrium by endovaginal ultrasound and by performing an endometrial biopsy before and at the end of treatment.

Table IV shows the results of the ultrasound examination. At the end of treatment, the average thickness of the endometrium remains less than or close to 4 mm. The increase ⁱⁿ thickness under therapy is 0.39 mm on average with the smallest nomegestrol acetate dose (0.625 mg / day). It increases slightly with the dose but remains less than 1.5 mm with 2.5 mg / d.

The biopsies examined at the end of the study (Table V) revealed no proliferative or hyperplastic aspect of the uterine lining after 6 months of treatment. With the lower doses of nomegestrol acetate was observed the largest number ^of endometrium atrophic.

These results indicate that low doses of nomegestrol acetate administered continuously with estradiol are capable of sufficiently impregnating the endometrium and ultimately preventing the growth of the uterine lining. Table III: Endometrial thickness after 6 months of treatment with several continuous combined combinations based on estradiol (2 mg of estradiol valerate) and nomegestrol acetate (NOMAC) at several doses

() = standard deviation

Table IV: Histological appearance of the endometrium after 6 months of treatment with several continuous combined combinations based on estradiol (2 mg estradiol valerate) and nomegestrol acetate (NOMAC) at several doses

() = percentage No endometrium was proliferative or hyperplastic

Claims

1. New contraceptive compositions in women of childbearing age, based on nomegestrol and / or one of its esters, and estradiol or one of its esters, according to an optimum weight ratio "dose of the estrogenic fraction" on "dose of the progestogen fraction" allowing good control of the menstrual cycle, varying from 0.5 to 5, in combination or in mixture with a diluent or an inert non-toxic, pharmaceutically acceptable vehicle.

2. New contraceptive compositions according to claim 1 based on estradiol or one of its esters and nomegestrol or one of its esters, characterized in that the weight ratio "dose of the estrogenic fraction" to "dose of the progestin fraction "ranges from about 1 to 3.

3. New contraceptive compositions according to claim 1 in which the doses of nomegestrol in the form of acetate range from 0.1 mg to 2.5 mg per unit form.

4. New contraceptive compositions according to claim 1 or claim 2 in which the doses of nomegestrol in the form of acetate range from 0.3 to 1.25 mg per unit form.

5. New contraceptive compositions according to one of claims 1 to 4 in which the doses of estradiol or one of its esters or ethers expressed as estradiol, range from 0.3 to 3 mg.

6. New contraceptive compositions according to one of claims 1 to 5 in which the doses of estradiol or of one of its esters range from

0.5 mg to 2 mg expressed as estradiol.

7. New contraceptive compositions according to one of claims 1 to 6 which contain a combination of 0.625 mg of nomegestrol acetate and 0.5 mg of estradiol in mixture or in association with an inert non-toxic excipient or diluent, pharmaceutically acceptable.

8. New contraceptive compositions according to one of claims 1 to 7 which contain a combination of 0.625 mg of nomegestrol acetate and

1 mg of estradiol in mixture or in combination with an inert nontoxic diluent, pharmaceutically acceptable.

9. New contraceptive compositions according to one of claims 1 to 8 which contain a combination of 0.625 mg of nomegestrol acetate and 1.5 mg of estradiol in mixture or in association with an inert non-toxic excipient or diluent, pharmaceutically acceptable.

10. New contraceptive compositions according to one of claims 1 to 9 which contain a combination of 0.625 mg of nomegestrol acetate and

2 mg of estradiol in mixture or in combination with an inert non-toxic, pharmaceutically acceptable excipient or diluent.

1 1. New contraceptive compositions according ^to one of claims 1 to 1 0, which contain a combination of 0.3 mg of nomegestrol acetate and 1 mg of estradiol in admixture or association with a nontoxic pharmaceutically acceptable inert diluent.

12. New contraceptive compositions according to one of claims 1 to 10 which contain a combination of 0.3 mg of Nomegestrol acetate and 1.5 mg of estradiol in admixture or in combination with an inert nontoxic pharmaceutically acceptable diluent .

1 3. New contraceptive compositions according to one of claims 1 to 12 in which the vehicle or diluent is one of those which are suitable for administration by the digestive route.

14. New contraceptive compositions according to one of claims 1 to 1 3 in the form of bare tablets or dandruff, dragees, capsules, capsules, pills, cachets or powders.

1 5. Method for preparing the contraceptive pharmaceutical compositions according to one of claims 1 to 14 wherein there is incorporated into the active principles progestogen and estrogen, a diluent and / or a filler and / or a compression adjuvant and / or a lubricating agent and / or a bursting agent.

16. Use of the contraceptive pharmaceutical compositions according to one of claims 1 to 1 4 in the form of a packaging article containing from 21 to 28 tablets containing the active ingredients and from 0 to 7 tablets containing only a placebo.