AU784478B2 - Contraceptive medicament based on a progesterone and an oestrogen and method for producing the same - Google Patents

Description

NEW CONTRACEPTIVE MEDICINAL PRODUCT AND METHOD FOR ITS PREPARATION Among the contraceptive means most widely and most effectively used, are hormone combinations which act by three different mechanisms, namely, in order of importance: inhibition of gonadotropic function, which stops the secretion of FSH and LH from the pituitary and thereby prevents maturation of the ovarian follicles and the occurrence of the ovulatory peak of LH which is essential for oviposition changes in the secretion and the physicochemical properties of the cervical glairy mucus, making it impermeable to spermatozoa; inhibition of the development of the uterine mucosa, which becomes unsuitable for egg-implantation.

In the oestro-progestative combinations used hitherto for contraception, the inhibition of gonadotropic function was due mainly to the oestrogenic fraction consisting of a synthetic oestrogen: ethinyloestradiol. By means of the simultaneous use of 19-nor-testosterone derivatives, the progestative fraction reinforces this inhibition of ovulation, and also ensures the peripheral contraceptive effects on the cervical glairy mucus and the endometrium.

However, the use of the oestro-progestative contraceptive combinations currently available has major drawbacks.

Ethinyloestradiol has a very strong impact on liver function; this is reflected essentially by disorders in the synthesis of clotting factors and by abnomalies in the lipid profile of the plasma (Bonnar, et al., 1987; Meade, 1988; Lindberg et al., 1989; von Shoultz et al., 1989; Daly and Bonnar, 1990; Burkman, 1997; Soitzer, 1997). Consequently, the use of oestro-progestative contraceptives is problematic in at-risk 2 women (women suffering from circulatory disorders, women in the perimenopause, women who smoke, etc.). This impact is all the more pronounced since the deleterious effect of ethinyloestradiol can be further increased by the progestative fraction on account of a residual androgenic activity which is often present (Bonnar, 1987; Sabra and Bonnar, 1983; Bonnar et al., 1987).

The progestative fraction of the oestro-progestative contraceptives currently available usually consists of a 19-nor-testosterone derivative which, like ethinyloestradiol, has a negative impact on liver function, the lipid profile and blood vessels. Although this has not been demonstrated definitively, the most modern 19-nor-testosterone derivatives, known as third generation progestatives, are suspected of inducing an increase in thromboembolic accidents (O'Brien, 1999).

To escape the drawbacks of ethinyloestradiol, 19-nor-testosterone derivatives are occasionally used alone in contraception, in two different modes: either at low doses, and in this case the contraceptive action is ensured by the peripheral effects of the progestative agent; the reason for this is that the inhibition of ovulation is not constant, since the low doses of progestative agent very often allow the development of ovarian follicles and, in certain cases, an increase in the endogenous secretion of oestradioi; or at high doses, so as to unequivocally inhibit ovulation, but at the risk of creating a hypooestrogenia, thus limiting their use in young women.

In summary, it appears to be very useful to have available an oestro-progestative combination which is at least as effective as those currently available, but which is free of their harmful side effects.

3 To do this, it was easy to do the following: Replace ethinyloestradiol (EE) with the hormone secreted by the ovaries, 17beta-oestradiol which is much less toxic than EE (Buckman et al., 1980; Bergink et al., 1981; Lindberg et al., 1989) but is weakly anti-gonadotropic (Hirvonen, 1995). Many attempts have been made, but none has resulted in a product made available to women. In general, the antiovulatory effect was clearly obtained, but the many failures were due, in most cases, to poor control of the menstrual cycle with the appearance of spotting and intermenstrual bleeding which made the method unacceptable.

Thus, combinations of natural oestrogens with desogestrel (Wenzl, 1993; Kivinen and Saure, 1996; Csemicsky et al., 1996), with cyproterone acetate (Hirvonen et al., 1988; Hirvonen et al., 1995), with norethisterone (Astedt et al., 1977; World Health Organization, 1980; Serup et al., 1981) were found to be contraceptive, but the intermenstrual bleeding, spotting and poor quality of the periods were unacceptable. For some, the reasons for these failures lay in an insufficient oestrogenic stimulation on account of the poor bioavailability of oestradiol or esters thereof; the excessively intense progestative effect led to a partial inhibition of endometrial proliferation and thus to anarchic bleeding (Hirvonen et al., 1995; Csemicsky et al., 1996). Only one combination gave satisfactory results in terms of controlling the menstrual cycle; this is the combination of oestradiol valerate and dienogest (Oettel et al., 1999; Hoffman et al., 1999). According to these authors, the positive results were thought to be due to a strong dissociation between central activity (anti-ovulatory activity) and peripheral activity (endometrial activity) to the benefit of this latter activity for dienogest. In summary, all of the data oublished show that the result depends closely on the anti-gonadotropic effect of the progestative agent, the 31- 1-06: 8:48 :WATERMARK PATENT ;61 3 98196010 5/ is 4 bioavailability of oestradiol or derivatives thereof in the formulation used and an optimum ratio between the oestrogenic and progestative stimulations.

Replace the 19-nor-testosterone derivative with a highly anti-gonadotropic synthetic progestative agent which is known not to have any impact on liver function, sugar-lipid metabolism or clotting factors.

Contraceptive effect of the nomegestrol acetate/oestradiol combination In one aspect, the present invention relates to the use of a composition comprising from 0.3 mg to 3 mg of estradiol or an ester thereof, (il) from 0.1 mg to 2.5 mg of nomegestrol acetate and (iii) pharmaceutically acceptable excipients, in the manufacture of a contraceptive product.

Oestradiol or an ester thereof, such as, for example, the valerate, benzoate, enanthate, etc., is the oestrogenic component, the doses used being calculated as oestradiol equivalents. The doses range from 0.3 mg to 3 mg per day with a preference for a range from 0.5 mg to 2 mg per day. According to the literature data (Hirvonen, 1995), a dose of 4 mg is needed to ensure the inhibition of ovulation, but they correspond to the doses used to compensate for hypooestrogenic states. For example, in menopausal women, the dose recommended to compensate for hypooestrogenic states is about 1.5 mg.

The progestative component includes nomegestrol or an ester thereof.

Nomegestrol acetate is the progestative component. The range of doses is between 0.1 and 2.5 mg per day and preferably between 0.1 and 1.25 mg per day and more preferably between 0.3 and 1.25 mg day. At these very low doses, the nomegestrol acetate combined with oestradiol inhibits ovulation and follicle maturation in 100% of cases when the two active principles are administered 25 together from the 1 s to the 21 st day of the cycle, with acceptable frequencies of deprivational haemorrhage and intermenstrual bleeding.

The range of the weight ratio of the oestradiol doses to the nomegestroi acetate doses extends from about 0.5 to 5 and this ratio is preferably between about 1 and 3.

The combination of nomegestrol acetate and oestradiol is administered daily, at the same dose, from the 1 st day of the cycle, for a period which may range from 21 to 28 days. Next, the women receive a placebo tablet daily for the period of time required to complete the 28-day cycle (0 to 7 days).

COMS ID No: SBMI-02526912 Received by IP Australia: Time 09:06 Date 2006-01-31 31- 1-06: 8:48 :WATERMARK PATENT :139161 /1 6 1 3 9 8 1 9 6 0 1 0 6 1 8 Nomegestrol acetate is a powerful, orally-active progestative agent which has a novel pharmacological profile: like 19-nor-testosterone derivatives, nomegestrol acetate bears high anti-gonadotropic activity but, unlike these 19-nor-testosterone derivatives, it does not display any residual androgenic or oestrogenic activity and it has a strong anti-oestrogen activity.

COMS ID No: SBMI-02526912 Received by IP Australia: Time 09:06 Date 2006-01-31 6 like 17alpha-hydroxyprogesterone derivatives, it has a pure pharmacological profile, but, unlike the above derivatives, it has a powerful anti-gonadotropic effect.

It belongs to the category of progestative agents known as hybrids (Oettel et al., 1999) which do not bear deleterious metabolic effects on account of the absence of the 17a-ethinyl function, and which combine the advantages of progesterone derivatives with those of the more modern 19-nor-testosterone derivatives.

A clinical trial similar to the Kaufmann's trial, made it possible to show that the endometrial conversion is obtained with a daily dose of 1 mg of nomegestrol acetate, i.e. 10 mg for the entire cycle. It has previously been shown (Bazin et al., 1987) that the inhibition of ovulation and of follicle development were obtained in women with a daily dose of 2.5 mg of nomegestrol acetate. The ratio of the ovulation-inhibiting activity in women (in mg/day) to the endometrial luteinizing activity (in mg/cycle) as defined by Neumann (1977) is thus in the order of 0.2, i.e. close to those of cyproterone acetate and chlormadinone acetate; this indicates a strong central activity (Oettel et al., 1999). In this sense, it clearly differs from dienogest, whose activity is disequilibrated to the benefit of the peripheral activity. Consequently, the results observed with an oestradiol valerate/dienogest contraceptive combination do not in any way suggest and do not make obvious the results observed with the oestradiol/nomegestrol acetate combination according to the invention.

Study of the anti-ovulatory power of the nomegestrol acetate/oestradiol combination shows an unexpected potentiation of the anti-gonadotropic effects of nomegestrol acetate by oestradiol, since the inhibition of ovulation and 31- 1-06; 8:48 :WATERMARK PATENT 61 3 9 8 19 60 10 7 1 8 7 of follicle development are obtained with a low dose, in the order of 0.625 mg.

This results cannot result from an anti-gonadotropic effect of oestradiol, nor even from an addition of effects between the two active principles since the doses of oestradiol used are very much lower than the doses known to inhibit ovulation (Hirvonen et al., 1995). Consequently, this unexpected observation Is a sign of a real innovation, since it allows the use of lower doses of progestative agent and thus better tolerance; it differs from the subject of French Patent 2,754,179 (to the Applicant), in which the range of nomegestrol acetate doses could extend from to 5 mg.

The present invention, in another aspect, thus relates to a contraceptive product comprising 21 to 28 formulations each containing from 0.3 mg to 3 mg of estradiol or an ester thereof, (ii) from 0.1 mg to 2.5 mg of nomegestrol acetate and (iii) pharmaceutically acceptable excipients. It differs from the claims of many patents which describe the combination of oestradiol or of an oestradiol ester administered in multi-stage modes with modified doses of oestrogenic and/or of the progestative agent from one stage to another and, even occasionally, a change of the progestative agent from one stage to another. Mention should be made in this respect, for example of patents EP 770338, WO 9741868, WO 9909993, WO 9835682, WO US9817288, WO 9602486, WO 9707074, 20 WO 9707083, WO 9707084, WO 9707085, WO 9707089, WO 9712785, WO 9712785, WO 9712786, WO 9712787, WO 9712788, WO 9712789, WO 23228, WO 9741868, WO 9913882, EP 491,438, EP 491,415, WO 9004330, EP 3092263, US 4628051, EP 0911029 A2, EP 0770388 Al and DE 3229612, as well as the publications by Hirvonen et al. (1998, 1995) which describe a 25 two-stage contraceptive method with the oestradiol valerate/cyproterone acetate combination or that by Hoffmann et al. (1988) which describes a two-stage contraceptive method with the oestradiol valerate/dienogest combination.

The present invention, in another aspect, relates to a method of contraception in women, which comprises administering a composition comprising from 0.3 mg to 3 mg of estradiol or an ester thereof, (ii) from 0.1 mg to 2.5 mg of nomegestrol acetate and (iii) pharmaceutically acceptable excipients.

This method of contraception is novel with respect to the patents and publications devoted to oestro-progrestative combinations of oestradiol (or of one of the esters COMS ID No: SBMI-02526912 Received by IP Australia: Time 09:06 Date 2006-01-31 31- 1-06; 8:48 :WATERMARK PATENT 6 1 561 bu I a U/ I t 8 or ethers thereof) and of a progestative agent administered in single-stage mode, since the literature as a whole shows that ht eoverall clinical result is entirely dependent on the nature of the progestative agent used, its pharmacological profile, its effects on the hypothalamo-hypophyseal axis of the "central" power/"peripheral" power ratio and the ratio of oestrogenic and progestative activity. For these reasons, the single-stage methods of contraception described in some patents, such as, for example, WO 95/17194, WO 99/12531 and EP 0,253,607, and in some publications, such as, for example, those which deal with norethisterone/oestradiol combinations (Astedt et al., 1977; Task force on oral contraception, 1980; Serup et al., 1981), those which deal with desogestrel/oestradiol combinations (Wenzl et al., 1993; Csemicsky et al., 1996) or combinations of dienogest and oestradiol (Hoffmann et al., 1998) cannot be applied to the combination of nomegestrol acetate/oestradiol since they are validated only for the oestrogen and the progestative agent claimed. Added to this is the fact that the potentiation observed between oestradiol and nomegestrol acetate renders any extrapolation of doses from the pharmacological profile unnecessary. Furthermore, nomegestrol acetate is never cited as a progestative agent which can be used. Patents EP 309,263 and WO 90/04330 cited the possibility of using 17alpha-19-nor-progesterone and esters thereof, but it should 20 be pointed out, on the one hand, that nomegestrol acetate is not a 17alpha-19-nor-progesterone ester, and, on the other hand, that 17alpha-19-nor-progesterone esters bear antidiuretic properties which render then unsuitable for use on women (Paris et al., 1987).

*aia *oe g o COMS ID No: SBMI-02526912 Received by IP Australia: Time 09:06 Date 2006-01-31 9 A preferred composition will be one which contains 0.312 mg of nomegestrol acetate per 1 mg of oestradiol or 0.625 mg of nomegestrol acetate and 1 mg of oestradiol or 0.625 mg of nomegestrol acetate and 1.5 mg of oestradiol or alternatively 0.625 mg of nomegestrol acetate and 2 mg of oestradiol.

The pharmaceutical compositions according to the invention are those which are suitable for the digestive route, in particular in the form of plain or film-coated tablets, sugarcoated tablets, gelatine capsules, wafer capsules, pills, cachets or powders, which may or may not contain flavourings.

They contain a diluent and/or a filling substance and/or a tabletting adjuvant and/or a lubricant and/or a splitting agent. Film-forming agents which may be mentioned are hydroxypropylmethylcellulose (Hypromellose) and cellulose acetophthalate.

Binders which may be used are polyvinylpyrrolidone, carboxymethylcellulose, crosslinked carboxymethylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose or a starch which may or may not have been chemically modified. Filling substances which may be mentioned are calcium carbonate, magnesium carbonate, magnesium phosphate, clays, zeolites, infusorial earth, etc.

Tabletting adjuvants which may be mentioned are powdered sugar or lactose. Lubricants which may be mentioned are talc, calcium stearate, magnesium stearate and colloidal silica.

Splitting agents which may be mentioned are mannitol, carboxymethylstarch and polyvinylpyrrolidone.

In general, the weight of the compositions according to the invention ranges between 40 and 100 mg and the composition contains from 80 to 99% of diluents and excipients per 1 to of active principles.

10 Nomegestrol acetate and oestradiol can be administered simultaneously, combined in a single formulation, or, on the contrary, may be present in two pharmaceutical forms to be ingested successively or simultaneously.

The daily dosage will be 1 or 2 intakes and the duration of the treatment will be exerted throughout the entire month. In total, the mean monthly dose of nomegestrol acetate will range from 8 mg to 75 mg. The doses are fully tolerated.

EXAMPLE I: examples of formulations The combination of nomegestrol acetate and oestradiol is presented in the form of plain or film-coated tablets.

In these compositions, oestradiol is advantageously introduced into the final mixture in the form of a premix containing from 2 to 5% of oestradiol in povidone (10 to 25%) and lactose (qs 100%), such as, for example: FORMULATIONS IN MG/1 TABLET IN Oestradiol 1.00 2.50 Povidone 6.00 15.00 Lactose 33.00 82.50 Isopropyl alcohol 6.14 15.35 Demineralized water 1.06 2.67 TOTAL ON DRY 40.00 100.00 This premix is introduced into the final mixture in order to obtain a tablet by direct tabletting.

The plain finished tablets generally weigh from 60 to 90 mg and have the overall formulation below: FORMULATIONS OF THE PLAIN TABLETS 11 Composition in mg/ tablet Oestradiol premix qs Nomegestrol acetate Colloidal silica Crosoovidone Lactose Cellulose Stearic acid Talc 0.5 to 0.300 to 2.500 0.300 to 1.500 2.500 to 5.000 4.000 to 40.000 6.000 to 40.000 0.900 to 3.00 0.450 to 1.500 mg By way of example, mention may be made of tablets weighing 90 mg and having the formulation below: Examples of formulations (UF unit formulation) 90 mg tablets

FORMULATIONS

UF mg/l 90 mg tablet Premix containing 2.5% oestradiol Nomegestrol acetate Colloidal silica (Aerosil 200) Crospovidone (Polyplasdone XL) Lactose Microcrystalline cellulose (Avicel PH 101) Stearic acid AC68/50VG Talc

TOTAL

40.000 0.300 0.495 3.240 26.000 17.265 1.800 0.900 90.000 UF 44.45 0.33 0.55 3.60 28.89 19.18 2.00 1.00 100.00 12 FORMULATIONS UF mg/l 90 mg tablet UF Premix containing 2.5% 40.000 44.45 oestradiol Nomegestrol acetate 2.500 2.77 Colloidal silica 0.495 0.55 (Aerosil 200) Crospovidone 3.240 3.60 (Polyplasdone XL) Lactose 24.900 27.67 Microcrystalline cellulose 16.165 17.96 (Avicel PH 101) Stearic acid AC68/50VG 1.800 2.00 Talc 0.900 1.00 TOTAL 90.000 100.00 FORMULATIONS UF mg/1 90 mg tablet UF Premix containing 2.5% 60.000 66.67 oestradiol Nomegestrol acetate 0.300 2.77 Colloidal silica 0.495 0.55 (Aerosil 200) Crospovidone 3.240 3.60 (Polyplasdone XL) Lactose 12.215 8.91 Microcrystalline cellulose 13.050 14.50 (Avicel PH 101) Stearic acid AC68/50VG 1.800 2.00 Talc 0.900 1.00 TOTAL 90.000 100.00 13 FORMULATIONS UF mg/1 90 mg tablet UF Premix concaining 2.5% 60.000 66.67 oestradiol Nomegestrol acetate 0.625 0.69 Kollidon 25 9.000 10.00 Colloidal silica 0.495 0.55 (Aerosil 200) Crospovidone 3.240 3.60 (Polyplasdone XL) Microcrystalline cellulose 13.050 14.50 (Avicel PH 101) Stearic acid AC68/50VG 1.800 2.00 Talc 0.900 1.00 Lactose 0.890 0.99 TOTAL 90.000 100.00 Plain tablets weighing 60 mg and having the formula below, can also be prepared: Examples of formulations (UF unit formulation) 60 mg tablets FORMULATIONS UF mg/1 60 mg tablet UF Premix containing 4.0% 25.000 41.67 oestradiol Nomeaestrol acetate 0.300 0.50 Colloidal silica (Aerosil 200) 0.324 0.54 Crospovidone (Polyplasdone XL) 3.000 5.00 Lactose 16.076 26.779 Microcrystalline cellulose 13.500 22.50 (Avicel PH 101) Stearic acid AC68/50VG 1.200 2.00 Talc 0.600 1.00

TOTAL

60.000 100.00 14 FORMULATIONS UF mg/1 60 mg tablet UF Premix containing 4.0% 25.000 41.67 oestradiol Nomegestrol acetate 2.5000 4.17 Colloidal silica (Aerosii 200) 0.324 0.54 Crospovidone (Polyplasdone XL) 3.000 5.00 Lactose 14.976 24.96 Microcrystalline cellulose 12.400 20.66 (Avicel PH 101) Stearic acid AC68/50VG 1.200 2.00 Talc 0.600 1.00 TOTAL 60.000 100.00 FORMULATIONS UF mg/l 60 mg tablet UF Premix containing 4.0% 37.500 62.50 oestradiol 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 8.213 13.69 (Avicel PH 101) Stearic acid AC68/50VG 1.200 2.00 Talc 0.600 1.00 Lactose 1.538 2.56

TOTAL

60.000 100.00 15 FORMULATIONS UF mg/l 60 mg tablet UF Premix containing 4.0% 37.500 62.50 oestradiol Nomegestrol acetate 0.300 4.17 Colloidal silica 0.324 0.54 (Aerosil 200) Crospovidone 3.000 5.00 (Polyplasdone XL) Lactose 7.076 16.08 Microcrystalline cellulose 10.000 8.71 (Avicel PH 101) Stearic acid AC68/50VG 1.200 2.00 Talc 0.600 1.00 TOTAL 60.000 100.00 FORMULATIONS UF mg/1 60 mg tablet UF Premix containing 4.0% 25.000 41.67 oestradiol Nomegestrol acetate 2.500 4.17 Colloidal silica (Aerosil 0.324 0.54 200) Crospovidone (Polyplasdone 3.000 5.00

XL)

Lactose 14.976 24.96 Microcrystalline cellulose 12.400 20.66 (Avicel PH 101) Stearic acid AC68/50VG 1.200 2.00 Talc 0.600 1.00 TOTAL 60.000 100.00 These tablets can be film-coated with, for example: film-forming agents based on polyvinyl alcohol, of the type OPADRY PVA "moisture barrier" (polyvinyl alcohol, titanium dioxide, purified talc, lecithin, xanthan gum, pigments, lacquers), 16 or film-forming agents based on cellulose, of the type SEPIFILM L.P. [HPMC (hydroxypropylmethyl cellulose)], microcrystalline cellulose, stearic acid, pigments, lacquers.

EXAMPLE II: potentiation of the anti-gonadotropic effect of nomegestrol acetate with oestradiol The anti-ovulatory action of the oestradiol/nomegestrol acetate combination was evaluated in a randomized double-blind study on 38 female volunteers, in good health, aged 18 to in the period of ovarian activity, for whom it was checked beforehand, by means of an assay of the progesterone in the plasma and the establishment of a temperature curve, that they had ovulatory menstrual cycles.

The women were monitored for two consecutive cycles: the first was a control cycle without treatment; during the following cycle (cycle under treatment), they received a hormonal treatment administered orally daily from the 1 st to the 21" day of the cycle.

According to the randomization: 9 women received 1.5 mg of oestradiol 0.625 mg of nomegestrol acetate (group A), 10 others received 1.5 mg of oestradiol 1.25 mg of nomegestrol acetate (group B), another 10 received 1.5 mg of oestradiol 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 significantively different among the four groups.

17 Table I indicates the mean concentrations observed for each hormonal parameter in the course of the 21 days of treatment.

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

Comparison of the hormonal parameters in groups C and D made it possible to show that the combination of oestradiol with nomegestrol acetate not only significantly increased the oestradiol level in the plasma, but also reinforced the antigonadotropic effect of the progestative agent. Specifically, in the presence of oestradiol, the LH and FSH levels were found to be statistically lower than those observed when nomegestrol acetate was administered alone.

When nomegestrol acetate is combined with oestradiol, it exerts anti-gonadotropic effects, even at low doses (0.625 and 1.25 mg), since the hormonal parameters were not found to be significantively different in groups A, B and C.

This synergistic effect of oestradiol is confirmed by comparing the results of this study with those of another clinical trial performed according to the same methodology, but with the progestative agent alone. This comparison in fact shows that, at a dose of 1.25 mg of nomegestrol acetate, the addition of oestradiol has no appreciable influence on the levels of progesterone and of gonadotrophins (LH and FSH) in the plasma. On the other hand, the addition of oestradiol lowers the plasmatic levels of oestradiol, assayed 24 hours after taking the medicinal product, by about 300%; this parameter is a good reflection of the endogenous secretion of the ovaries (Table II).

18 It is known 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 at the same time resulting in an increase in the level of oestradiol in the plasma, which is evidence of follicle development without ovulation, as is encountered with the progestative micropill.

This study has thus shown that the addition of a dose of oestradiol, which is insufficient to block ovulation by itself, reinforces the anti-ovulatory effects of the progestative agent and also inhibits folliculogenesis, and maintains oestradiol levels markedly below 100 pg/ml an appreciable time after taking the medicinal product. It is thus possible to observe anti-ovulatory effects with lower doses of nomegestrol acetate than those initially used when it is combined with oestradiol; this confirms, in the new study, the results obtained with 0.625 mg of nomegestrol acetate (NOMAC) per day, combined with oestradiol.

In this study, the reading of the genital bleeding allows to evaluate the effect of the oestradiol/nomegestrol acetate combination on the cycle. In all of the women treated with the oestro-progestative combination, it was thus observed that the duration of the cycle did not exceed 1 month in 50% of cases, that spotting was totally absent from one woman in two and that the deprivational haemorrhage after stopping the treatment was on average 5.4 days and did not exceed 7 days in 86% of the women. These data did not differ among the groups.

As regards the first treatment cycle, they reflect a satisfactory level of tolerance; in point of fact, it is known that the quality of the cycles obtained with this type of combination improves after a few cycles of treatment.

1.9 Table I: Mean concentrations in the plasma (m sein) of gonadotrophins (LH and FSH) and of ovarian steroids (cestradiol and progesterone) in the course of a cycle under treatment with 3 oestradiol /nomegestrol acetate (E2/ NOMAC) combinations. Comparison with the treatment with nomegestrol acetate alone Hormonal Group A Group B (n=10) Group C (n=10) Group D (n=9) Parameter 1.5 mg E2 1.5 mg E2 1.5 mg E2 p (ANOVA) 0.625 mg NOMAC 1.25 mg NOMAC 2.5 mg NOMAC 2.5 mg NOMAC Comparison Comparison B, C C and D L11 4.1 0.51 3.0 0.51 2.7 0.49 5. 6 0 .62 0.135 0.002 FSH 6.2 0.42 6.6 0.52 5.4 0.75 7.6 0.28 0.318 0.019 (ml U/mi) Progesterone 0.11 0.031. 0.07 0.024 0 03 0. 0 09 0 .0 7 0 014 0.068 0.056 n g /ml Qestradiol 62 .0 7 90 57.6 4.53 4 7 .2 5. 61 31.9 3.91 0.225 0.043 pg/mi 20 Table II: Mean concentrations (m sem) of gonadotrophins (LH and FSH) and of oestradiol in the plasma with 1.25 mg of nomegestrol acetate combined or not combined with oestradiol.

Hormonal Cycle NOMAC 1.25 mg NOMAC 1.25 E2 1.5 mg (n=10) 2 Pa rameter LH Control 4.5 7.1 0.82 (mIU/ml) Treated 3.1 3.0 0.51 FSH Control. 4.3 6.6 0.28 (mIU/nl-) Treated 3.3 6 .9 ±0 48 Oestradiol Control 112.0 (64.8-203.8) 132.9 10.57 pg/m. Treated 158.8 (99.5-201.7) 47.2 5.61 E2 =oestradiol; NOMAC =nomegestrol acetate I m (breadti) 2 m ±sem 21 EXAMPLE III effect of the nomegestrol acetate /oestradiol combination on the endometrium A study was carried out to test the effects on the endometrium of several doses of nomegestrol acetate combined with an oral dose of oestradiol equivalent to mg.

In the course of this study, 179 women who had been menopausal for at least 3 years received continuously every day 2 mg of oestradiol valerate combined with four different doses of nomegestrol acetate: 5 mg 2.5 mg 1.25 mg (n=43) and 0.625 mg (n=47).

The effect of these four combinations on the endometrium was evaluated by measuring the thickness of the endometrium by endovaginal echography and by carrying out a biopsy on the endometrium before and after the treatment.

Table IV indicates the results of the echographic examination. At the end of the treatment, the mean thickness of the endometrium remains less than or in the order of 4 mm. The increase in thickness under treatment is 0.39 mm on average with the lowest dose of nomegestrol acetate (0.625 mg/day). It increases slightly as the dose increases, but remains less than mm with 2.5 mg/day.

The biopsies examined at the end of the study (Table V) revealed no proliferative or hyperplasic appearance of the uterine mucosa after 6 months of treatment. The 22 greatest number of atrophic endometria were observed with the lowest doses of nomegestrol acetate.

These results indicate that low doses of nomegestrol acetate administered continuously with oestradiol are capable of sufficiently impregnating the endometrium and of ultimately preventing the growth of the uterine mucosa.

Table III: Endometrial thickness after 6 months of treatment with several continuous combined combinations based on oestradiol (2 mg of oestradiol valerate) and nomegestrol acetate (NOMAC) at several doses Doses of NOMAC 0.625 1.25 2.5 (mg/day) (n 35) (n 33) (n 34) (n 41) Mean thickness at 3.18 4.05 3.93 3.83 the end (2.10) of treatment (mm) (1.65) (3.75) (2.72) Mean increase in 0.39 1.12 1.36 1.57 thickness under treatment (mm) (1.67) (3.67) (1.54) (2.39) standard deviation Table IV: Histological appearance of the endometrium after 6 months of treatment with several continuous combined combinations based on oestradiol (2 mg of oestradiol valerate) and nomegestrol acetate (NOMAC) at several doses 23 Doses ofL' NOMAC 0. 625 1.25 2.5 (mg/day) (n =32) (n 33) (n 34) (n Absence of b 10 3 3 endometrium (15.6) Atrophic 19 10 8 3 endometrium (59.4) (30.3) (23.5) Secretory 8 12 22 34 endornetrium (25.0) (36.4) (64.7) (85.0) Polyp 0 1 1(2.9) 0 percentage No endometrium was proliferative or hyperplasic

Claims (15)

17- 2-06:10:44 ;WATERMARK PATENT ;61 3 98196010 3/ 9 24 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. Use of a composition comprising from 0.3 mg to 3 mg of estradiol or an ester thereof, (ii) from 0.1 mg to 2.5 mg of nomegestrol acetate and (iii) pharmaceutically acceptable excipients, in the manufacture of a contraceptive product. 2. The use according to claim 1, in which the composition comprises from 0.3 mg to 1.25 mg of nomegestrol acetate. 3. The use according to claim 1 or 2, in which the composition comprises from 0.5 mg to 2 mg of estradiol or an ester thereof. 4. The use according to claim 1, in which the composition comprises 1.5 mg estradiol. The use according to claim 1, in which the composition comprises 2.5 mg nomegestrol acetate. 6. The use according to claim 1, in which the composition comprises 1.5 mg estradiol and 2.5 mg nomegestrol acetate. 7. The use according to one of claims 1 comprises 0.5 mg of estradiol, 0.625 mg pharmaceutically acceptable excipients. 8. The use according to one of claims 1 comprises 1 mg of estradiol, 0.625 mg pharmaceutically acceptable excipients. 9. The use according to one of claims 1 comprises 1.5 mg of estradiol, 0.625 mg pharmaceutically acceptable excipients. to 3, in which the composition of nomegestrol acetate and to 3, in which the composition of nomegestrol acetate and to 3, in which the composition of nomegestrol acetate and COMS ID No: SBMI-02706394 Received by IP Australia: Time 10:59 Date 2006-02-17 17- 2-06:10:44 :WATERMARK PATENT 6 1 9 8 19 60 10 4/ 9 The use according to one of claims 1 to 3, in which the composition comprises 2 mg of estradiol, 0.625 mg of nomegestrol acetate and pharmaceutically acceptable excipients. 11. The use according to one of claims 1 to 7, in which the pharmaceutically acceptable excipients are suitable for administration via the digestive route. 12. The use according to one of claims 1 to 8, in which the composition is in the form of tablets, capsules, pills, cachets or powders. 13. The use according to one of claims 1 to 9, in which the composition is administered, from the first day of the cycle, from 21 to 28 days. 15 14. A contraceptive product comprising 21 to 28 formulations each containing from 0.3 mg to 3 mg of estradiol or an ester thereof, (ii) from 0.1 mg to 2.5 mg of nomegestrol acetate and (iii) pharmaceutically acceptable excipients when used in a method of contraception in women. 20 15. The product according to claim 11, in which each formulation contains from 0.3 mg to 1.25 mg of nomegestrol acetate when used in a method of contraception in women. o 16. The product according to claim 11 or 12, in which each formulation S 25 contains from 0.5 mg to 2 mg of estradiol or an ester thereof when used in a method of contraception in women. 17. The product according to claim 14, wherein the formulation comprises mg estradiol.

18. The product according to claim 14, wherein the formulation comprises mg nomegestrol acetate. COMS ID No: SBMI-02706394 Received by IP Australia: Time 10:59 Date 2006-02-17 17- 2-06:10:44 :WATERMARK PATENT ;61 3 98196010 5/ 9 26

19. The product according to claim 14, wherein the formulation comprises mg estradiol and 2.5 mg of nomegestrol acetate. The product according to one of claims 11 to 13, further comprising up to 7 formulations each containing a placebo when used in a method of contraception in women.

21. A method of contraception in women, which comprises administering a composition comprising from 0.3 mg to 3 mg of estradiol or an ester thereof, (ii) from 0.1 mg to 2.5 mg of nomegestrol acetate and (iii) pharmaceutically acceptable excipients.

22. The method according to claim 15, in which the composition comprises from 0.3 mg to 1.25 mg of nomegestrol acetate. S o: 23. The method according to claim 15 or 16, in which the composition comprises from 0.5 mg to 2 mg of estradiol or an ester thereof.

24. The method according to claim 15, wherein the composition comprises S 20 mg estradiol.

25. The method according to claim 15, wherein the composition comprises mg of nomegestrol acetate.

26. The method according to claim 15, wherein the composition comprises mg estradiol and 2.5 mg of nomegestrol acetate.

27. The method according to one of claims 15 to 17, in which the composition comprises 0.5 mg of estradiol, 0.625 mg of nomegestrol acetate and pharmaceutically acceptable excipients. COMS ID No: SBMI-02706394 Received by IP Australia: Time 10:59 Date 2006-02-17 17- 2-06:10:44 :WATERMARK PATENT :61 3 98195010 9 27

28. The method according to one of claims 15 to 17, in which the composition comprises 1 mg of estradiol, 0.625 mg of nomegestrol acetate and pharmaceutically acceptable excipients.

29. The method according to one of claims 15 to 17, in which the composition comprises 1.5 mg of estradiol, 0.625 mg of nomegestrol acetate and pharmaceutically acceptable excipients. The method according to one of claims 15 to 17, in which the composition comprises 2 mg of estradiol, 0.625 mg of nomegestrol acetate and pharmaceutically acceptable excipients.

31. The method according to one of claims 15 to 21, in which the pharmaceutically acceptable excipients are suitable for administration via the digestive route.

32. The method according to one of claims 15 to 22, in which the composition is in the form of tablets, capsules, pills, cachets or powders.

33. The method according to one of claims 15 to 23, in which the composition is administered, from the first day of the cycle, from 21 to 28 days.

34. A contraceptive product, substantially as hereinbefore described with reference to any one of the formulation examples when used in a method of contraception in women. A method of contraception in women, substantially as hereinbefore described with reference to example II. DATED this 15th day of February 2006 LABORATOIRE THERAMAX WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 (OUR REF: P21234AU00) COMS ID No: SBMI-02706394 Received by IP Australia: Time 10:59 Date 2006-02-17