FR2823976A1 - NOVEL HORMONAL COMPOSITION AND ITS USE - Google Patents

Abstract

The invention relates to the field of therapeutic chemistry, more specifically to hormonal pharmaceutical techniques, especially to novel hormonal pharmaceutical compositions which are formed as a result of an estro-gestagenic association consisting of an estrogen compound and a gestagenic compound, associated with or mixed with one or several non-toxic excipients which are inert and pharmaceutically acceptable and which can be administered orally. The invention also relates to the use of an estro-gestagenic mixture wherein the estrogenic component and the gestagenic component are administered in a combined manner. Combined association can be prescribed in a continuous or intermittent manner with a view to providing a composition which can be used to treat estrogenic deficiency, and prevent osteoporosis and cardiovascular diseases in menopaused women. The invention further relates to a method for the production of said estro-gestagenic compositions.

Description

NEW HORMONAL COMPOSITION

AND ITS USE

  The present invention relates to the field of therapeutic chemistry and more particularly to the field of pharmaceutical technology. More specifically, it relates to new pharmaceutical compositions formed from an estroprogestative association with a view to the correction of estrogenic deficiencies.

  in women of all origins, and more especially in menopausal women.

  It relates in particular to an estroprogestative association, characterized in that it is constituted by intake units containing a combination of a progestogen and an estrogen, the two components of which are present simultaneously

in each unit outlet.

  It specifically relates to new pharmaceutical compositions intended for hormone replacement therapy for menopause, containing as active principles a progestogen chosen from nomegestrol and its esters and an estrogen agent

  chosen from estradiol and its esters and conjugated estrogens.

  This combination is intended to be administered orally, continuously or

discontinuous.

  As we know, women's life expectancy has gone up in less than a century from

  at 80, while the average age of menopause has remained unchanged.

  Thus, women spend almost a third of their lives in a state of estrogen deficiency, which

  which is responsible for the increased risk of osteoporosis and heart disease

  Vascular. Replacement therapy for menopause has therefore become very common. It is administered either orally or, at least for its estrogenic component, percutaneously. However, compliance appears to be better when treatment is

  administered orally (ETTINGER et al, 1998).

  Sequential replacement therapy for menopause cures climacteric symptoms. It prevents osteoporosis and the occurrence of cardiovascular disease. He creates artificial cycles which are followed by a hemorrhage of deprivation. This therapeutic regimen is particularly suitable for women whose menopause is recent but it is not always well accepted in the long term, which partly explains the poor compliance with treatment (DRAPIER FAURE E .; Gynecology, 1992 , 43: 271 280). To overcome this drawback, combinations have been developed where the two components are taken simultaneously, continuously or discontinuously, the progestogen having the effect of permanently opposing the proiferative action of estrogen on the endometrium, causing endometrial atrophy and, consequently, the absence of deprivation hemorrhage (HARGROVE JT, MAXSON WS, WENTZ AC, BURNETT LS, Obstet Gynecol, 1989, 73: 606-612). Indeed, under these conditions, the endometrial atrophy is strong (WOLFE and PLUNKETT, 1994; PIEGSA et al, 1997; AFFINITO et al, 1998), there is no endometrial hyperplasia (STADBERG et al, 1996) and the frequency of bleeding is low and decreases over time (PIEGSA et al, 1997; CARRANZA-LIRA, 1998; ETTINGER et al, 1998). With this type of treatment, compliance is. in general, good (EIKEN and KULTHOFF, 1995; DOREN et al, 1996), and better than with sequential treatment (EIKEN et al, 1996). Quality of life also appears to have improved (ULRICH et al, 1997). We also know that this type of treatment protects bone mass (EIKEN et al, 1996; EIKEN et al, 1997; HART and

al, 1998; RECKER et al, 1999).

  This "no rules" scheme is more particularly suitable for women whose menopause is already old. It can be prescribed in sequence with sequential combinations in order to improve long-term adherence to hormone therapy

menopause substitute.

  During sequential treatments, the dose of progestin chosen is that which leads to long-term less than 1% endometrial hyperplasia when the progestogen is administered discontinuously, more than 10 days per cycle, in postmenopausal women on estrogen replacement therapy ( WHITEHEAD et al., J. Reprod. Med. 1982, 27:

  539-548, PATERSON et al., Br Med J. 1980, 22 March: 822-824).

  The dose of progestogen to be used in combination replacement therapy is usually deducted from that usually prescribed in the sequential schedules. This is the example of micronized progesterone, didrogesterone (FOX H., BMK J.,

  VAN DE WEIJER P., AL-AZZAWI E., PATERSON M., JOHNSON A., MICHELL G.,

  BARLOW D., FRANCIS R., 7 th International Congress on the Menopause, Stockholm, -24 June 1993, abstr 119) and medroxyprogesterone acetate (BOCANERA R.,

  BEN J., COFONE M., GUINLE I., MAILAND D., SOSA M., POUDES G., ROBERTI A.,

  BISO T., EZPELETA D., PUCHE R., TOZZINI R., 7 th International Congress of the Menopause, StockNolm, 20-24 June 1993, abstr 40) which were used at the dosage of 100, 10 and 5 mg respectively / day, with encouraging results in terms of

cl in iq ue and e nd ométria l.

  Combination therapy is most often used continuously, that is, without interruption. Some therapists are however in favor of using it intermittently, for example 25 days per month (BIRKAUSER M et al; Hormonal substitution: a well-posed indication and individual treatment regimens are

  determinants for successful treatment, Med and Hyg, 1995, 53: 17701773).

  The aim of the therapeutic interruption is to eliminate the inhibition exerted by the progestogen on the synthesis of estradiol and progesterone receptors and to avoid

  thus the decrease in receptivity of hormone-dependent tissues.

  The progestin used according to the present invention is nomepestrol or one of its esters, in particular nomeestrol acetate. Nomegestrol acetate is a powerful progestogen, active by the oral route and which has an original pharmacological profile: - unlike 19nestestosterone derivatives, nomegestrol acetate does not exhibit any residual androgenic and estrogenic activity; -like derivatives of 17alphahydroxyprogesterone, it has a profile

  pure pharmacological, but unlike these, it has a powerful antigonadotropic effect.

  li It belongs to the category of progestins qualified as hybrids (OETTEL et al, 1999) which do not carry deleterious metabolic effects due to the lack of 17alpha-ethinyl function and which combine the advantages of progesterone derivatives with those

  more modern derivatives of 19-nortestosterone.

  Its use in sequential administration during menopause at a dose of mg / day, 12 days per cycle, in combination with different types of estrogens, makes it possible to prevent endometrial hyperplasia as shown by a multicentric study on women during 1 year (THOMAS JL, BERNARD AM, DENIS C, 7 th International

  Congress on the Menopause, Stockolm, 20-24 June 1993, abstr 372).

  The absence of hyperplasia was confirmed in a study where nomegestrol acetate was administered at the same dose, 14 days per cycle, in women treated with percutaneous estradiol (BERNARD AM et al. Comparative evaluation of two percutaneous estradiol gels in combination with nomegestrol acetate in hormone replacement therapy. XIV Worid Congress of Gynecology and Obstetrics, FIGO, Montreal, 24-30 September 1994). This use was the subject of French patent 2,737,411 in the name of the Applicant Company which claims a range of

  doses between 1.5 and 6 mg, preferably between 2.5 and 5 mg.

  The estrogen used is estradiol, free or esterified, and in particular estradiol valerate, or natural or synthetic conjugated estrogens or an alkynylated derivative such as ethynyl estradiol, which is presented according to an active formulation by oral route. It has been shown that a dose of estradiol of between 1 and 2 mg / day makes it possible to combat

  hypoestrogenism present in postmenopausal women.

  Nomegestrol acetate and free or esterified estradiol, or equine conjugated estrogens are administered in one of the forms allowing oral administration: capsules, capsules, pills, sachets of powder, tablets, coated tablets, dragees, etc. The present invention is characterized in that it constitutes a new estroprogestative association, active by the oral route, administered in a combined manner. The present invention also relates to the use of the compositions according to the invention in the correction of estrogenic deficiencies, in the prevention of

  osteoporosis and cardiovascular disease in postmenopausal women.

  The present invention is also defined by: a) the fact that it is a progestogen-specific association different from those

  described above for the same type of indications.

  Some patents claim the use of estrogen-progestogen combinations continuously for the replacement therapy of menopause. This is for example the case of US patents 5108995 or EP 309263. However, obviously, these patents claim multi-sequential treatments with changes in doses of the active ingredients. This is also the case for patents filed in the USA (US 4820831 A and RE 36247) and in Europe (EP 136 011) in the name of PLUNKETT. These patents claim the use of many estrogens and many progestogens in the treatment

  menopause substitute. However, it appears that these claims do not cover

  not the use of all progestins on the one hand for scientific reasons and on the other

  share for scientific and legal reasons related to the formulation of claims

  of these two patents: 1) The use of numerous progestogens is based on equivalences with one of them, in this case levonorgestrel. This approach does not appear acceptable because the different progestogens are characterized by very different pharmacological profiles and it is not possible to deduce the doses to be used by a simple and unique equivalence system. This impossibility becomes obvious if we consider the ranges of active doses of different progestogens proposed in 3 patents

different (Table 1).

  We note that the lower limit for the different progestogens varies in a ratio of 2.4 to 50 while the upper dose varies in a ratio of 1 to 50. Therefore, for indications of the same type, the dose ranges vary from one patent to another in a big way, which shows that the equivalence system does not bring

  credibility of the relationships that could be established between progestins.

  2) Beyond that, one can legitimately think that the doses claimed should be based on clinical pharmacology and / or clinical data previously published and commonly accepted. However, if we consider the doses defined as in the PLUNKETT patents, it is easy to see that, in most cases, the active doses published a long time ago, that is to say before these patents were filed ( NEUMANN, 1977) or at a more recent date (KUHL, 1996), are very consistent but are only rarely included in the dose ranges

  claimed in patents in the name of PLUNKETT (Table 2).

  This observation is also valid if we take into account, instead of the active doses as previously, the ratio between the active doses taking as

  reference (= 1) norgestrel (table 3).

Table 1

  Doses (, ug / d) of the various progestogens claimed according to the patents PROGESTATIVE PATENT DOSE (, ug / d) Mini Maxi Levonorgestrel WO 95/17194 60 125 Levonorgestrel EP 025607 A1 25 100 Levonorgestrel PLUNKETT 25 75 Gestodene WO 95/17194 50 75 Gestodene EP 025607 A1 10 70 Desogestrel WO 95/17194 60 150 Desogestrel EP 025607 A1 25 100 3-ketodesogestrel WO 95/17194 60 150 3-ketodesogestrel EP 025607 A 1 25 100 Noresthisterone WO 95/17194 350 750 Noresthisterone EP 025607 A1 85 350 Noresthisterone PLUNKETT 150 1000 Norethisterone Acét. PLUNKETT 100 1000 Norgestimate WO 95/17194 200 300 Norgestrel PLUNKETT 50 150 Ethynodiol diacetate PLUNKETT 100 1000 D ihydrogesterone PLUNKETT 5000 30000

MPA PLUNKETT 1000 15000

  Norethynodrel PLUNKETT 200 5000 1000 10000 Allylestrenol PLUNKETT Lynestrenol PLUNKETT 100 2000 quingestanol acetate medrogestone PLUNKETT PLUNKETT 50 1000 1000 10000 20 200 norgestrienone PLUNKETT dimethisterone PLUNKETT 500 15000 1000 25000 C ethisterone PLUNKETT iprotérone Acetate PLUNKETT 100 10000 WO 95/17194 Ciprotérone Acetate 100 200 - oo: at =

in 'r-

a '0 0 0 0 0 O

0 =, o j Id.

  Y Ng 'i ô so o A o ô o o o o o o o o o a' -00 0 0 0 a '> _._ O tr_ ô 0 0 0 0 O 1) r _ T À _ at, È_. lie. o ^ - o a '0 0 0 0 O ^ =, O oo O offs Oreo O or - ^ m ^ - ^ 0 To ç ^ To - ^ of To 0 ^ 0 0 - ^

ô C

n 0! ^ 9 9 -

Claims reasons

  1) In the aforementioned US patents, claims 1 and 2 are directed to the

  continuous processing; the progestogen thresholds claimed are dlnorgestrel and

  levonorgestrel. The following claims address discontinuous processing

  multi-sequential, that is to say a therapeutic regimen different from that proposed in the present patent application. For the latter type of therapeutic regimen, the progestogens claimed are more numerous, but the list is precise and limited as appears from the writing of the Markush type ofUites

  claims of the cited issue and it does not include nomegestrol and its esters.

  2) The European patent only claims continuous combined processing; the estrogens and progestins claimed are listed in the tables present

  in the body of the text and recalled in the claims. Again the

  nomegestrol and its esters are not included in the lists of progestins that may be used. However, nomegestrol acetate is characterized by a powerful progestogenic effect, an absence of residual androgenic and estrogenic effects as well as by a powerful anti-estrogenic power which results in the endometrium by a strong anti-mitotic activity and, as a result, a strong atrophying effect. Therefore, it can not be assimilated to other progestogens and to conceive a correspondence of doses compared to another progestogen taken as reference, can only be wrong. In addition, nomegestrol acetate is characterized by very good tolerance; it has no action on the lipid profile, the tolerance to carbohydrates, the blood pressure and the coagulation factors even when it is used in doses higher than those described in the present patent application and for treatment of long-term (BASDEVANT et al 1997). This is very important because the goal of using the least toxic replacement therapy possible using the lowest doses possible is common to all therapists. In this, nomegestrol acetate differs from many 19-nortestosterone derivatives cited in the PLUNKETT patents, they are progestins which carry androgenic and estrogenic effects which can have consequences for

  endometrial level, and which also have harmful metabolic effects.

  For the same reasons as those mentioned above, none of the numerous publications devoted to the continuous combined treatment of menopause can

: 11 2823976

  affect the present invention since none of these publications deals with a combination of nomepestrol acetate with an estrogen. This is for example the case of combinations of estradiol and norethisterone acetate (STADBERG et al, 1996; DOREN and SCHNEIDER, 1996; DOREN et al, 1997; EIKEN et al, 1997; PIEGSA et al, 1997; HART et al, 1998), estradiol and medrogestone (AFFINITO et al, 1998), estradiol and norgestrel (WOLFE and PLUNKETT, 1994), estradiol valerianate and chlormadinone acetate (RAUCH and TAUBERT , 1993), equine conjugated estrogens with medroxyprogesterone acetate (REUBINOFF et al, 1995; WOLFE and HUFF, 1995; MIZUNUMA et al, 1997) or medrogestone (RECKER and

al, 1999).

  b) the fact that it is an estroprogestative association which differs from the association previously patented by the Applicant Company French patent 2,754,179 in the name of the Applicant Company claims an association of estradiol and acetate of nomegestrol for the replacement, combined, treatment of menopause. The dose range claimed on the basis of previous experience with nomegestrol acetate in the sequential treatment ranged from 1.5 to 3.75 mg, and was preferably 2.5 mg. However, larger-scale clinical trials have unexpectedly shown that much lower doses of nomegestrol acetate, and in particular 0.1 mg to 1.00 mg, are

  capable of ensuring endometrial atrophy and very good control of bleeding.

  This observation is important since it allows to further reduce the doses of nomegestrol acetate and therefore to be able to use it with safety

further increased employment.

  The doses of estradiol sold in this patent ranged from 0.2 to 3 mg.

  The doses of estradiol used here are in the estrogen / progestin ratio as well

  significantly changed, from 0.5 / 2 instead of 6: 1.

  c) the method of manufacturing suitable pharmaceutical forms.

  The invention relates to a manufacturing method which enables a

  same pharmaceutical form the two active ingredients.

l

1 2 2823976

  The compositions according to the invention, based on nomegestrol acetate and free or esterified estradiol, or conjugated estrogens are administered continuously or

  intermittent (from 21 to 28 days per month).

  According to a particular embodiment of the invention, the compositions contain an amount of nomegestrol acetate ranging from 0.1 to 1.8 mg and an amount

  free or esterified estradiol, or conjugated estrogens ranging from 0.5 to 2 mg.

  Preferably, the optimal formulations contain from 0.125 to 1.0 mg of nomegestrol acetate combined with 0.5 to 1.0 mg of free estradiol or from 0.5 to 1 mg of estradiol ester or from 0.312 0.625 mg of conjugated estrogens or ethynyl estradiol,

per daily intake.

  This combined mode of administration is indicated in postmenopausal women, naturally or surgically; the estroprogestative combination is intended to compensate for the functional disorders caused by the hypoestrogenism of menopause, while maintaining an atrophy of the endometrium and avoiding in a

  majority of them the appearance of deprivation hemorrhage.

  The present invention also relates to a process for obtaining new pharmaceutical compositions which consists in mixing the active principles: nomegestrol or one of its esters and free or esterified or esterified or alkynylated estradiol, or estrogens conjugated with one or more excipients or inert vehicles , non-toxic,

pharmaceutically acceptable.

  Among the excipients, mention may be made of binding and solubilizing agents,

  compression, disintegrating agents and slip agents.

  This mixture can be subjected to direct compression or in several stages to form tablets which can be protected on the surface, if desired, by film-coating, coating or coating. The production of tablets by direct compression makes it possible to reduce as much as possible the proportion of agents

  dilution, binding agents, disintegrating agents and slip agents.

  The production of capsules can be done by mixing the active ingredients with a

  inert diluent and a slip agent.

  - The tablets contain, in particular, mass diluting agents such as lactose, sorbitol for direct compression, marketed under the name NEOSORB 60, Palatinite which is the registered trademark for designating an equimolar mixture of [D ] glucopyranosido 1,6-mannitol and [D] glucopyranosido 1,6-glucitol crystallized with two molecules of water, mannitol,

  sorbitol or the lactose / PVP mixture sold under the name Ludipress.

  The compression binding agents are generally microcrystalline celluloses

  like those sold under the name AVICEL PH 101 or AVICEL PH 102.

  Polyvinylpyrrolidone also plays an important role and facilitates the agglomeration of powders and the compressibility of the mass. Polyvinylpyrrolidones of molecular weight between 10,000 and 30,000 are used for this purpose, such as

  Povidone, the Kollidon grade between 12 and 30.

  The mixture also contains slip or anti-electrostatic agents which prevent the powder from clumping together in the feed hoppers. Mention may be made, in this regard, of colloidal silicas sold under the name Aerosil 100

or AEROSIL 200.

  The mixture also contains disintegrating agents which allow disintegration or disintegration in accordance with pharmaceutical standards. Mention may be made, as useful disintegrating agents, of crosslinked vinylpyrrolidone polymers such as those sold under the names Polyplasdone or Polyclar AT, carboxymethyl starches such as those sold under the names Amijel or Explotab, crosslinked carboxymethylcelluloses such as the compound

  sold under the name AC-DI-SOL.

  In addition, the preparation contains lubricants which facilitate the compression and ejection of the tablet on the compressing machines. Mention may be made, as lubricating agents, of glycerol palmitostearate sold under the

  name Precirol, magnesium stearate, stearic acid or Talc.

  After compression, the tablets can be coated to ensure their

  conservation or facilitate their swallowing.

  The coating agents are either cellulosic, for example cellulose phthalate (Sepifilm, Pharmacoat), or polyvinyl, of the OPADRY PVA or Sepifilm ECL type, or saccharose, like sugar for coating of the Sepisperse DR, AS type,

AP, OR K (colored).

  The coated or uncoated tablets can, in addition, be colored on the surface or in the mass, by mineral, vegetable or synthetic dyes (eg.

  quinoline yellow or E 104 or iron oxides).

  The proportions of the various constituents vary according to the nature of the tablet to be produced. The diluting agents vary from 20 to 75% of the total mass, the slip agents from 0.1 to 2% of the total mass, the compression binding agents vary from 2 to 20%, the polyvinylpyrrolidone from 0.5 to 15%, the disintegrating agents vary from 2 to 5.5% for the crosslinked polyvinylpyrrolidone or for the

  carboxymethyl starch, from 2.0 to 3.0% for croscarmellose.

  The amounts of lubricants vary depending on the nature of the lubricant.

0.1 to 3.0%.

  The compositions according to the invention are intended to be administered once a day. However, depending on the therapeutic needs, the administration can be fragmented (twice a day) or on the contrary, repeated (two tablets

per day).

  The following examples illustrate the invention. They do not limit it in any way.

  EXAMPLE 1: Examples of Formulations The combination of nomegestrol acetate and estradiol is presented in the form of

bare or film-coated tablets.

  We can either subject the mixture of ingredients to direct compression, or make a premix of estradiol beforehand and then incorporate nomegestrol acetate and the rest of the excipients in dry form. The estradiol premix is made by dissolving the estradiol in an alcoholic solution of microcrystalline cellulose, PVP and lactose, then drying, grinding and sizing. This process is advantageous because the tablets made from an estradiol premix have a significantly improved estradiol dissolution profile compared to

  those produced in direct compression.

  The final mixture may contain 1.5 to 5% of estradiol in povidone (5 to%), microcrystalline cellulose (5 to 15%) and lactose (qs 100%). He will be able to

  be advantageous to introduce an antioxidant such as for example alpha-

  tocopherol or ascorbic acid, when making the premix.

  As an example of a premix, the following may be cited: FORMULATIONS in mg / 1 Tablet in% Estradiol 1.50 1.82

PVP K25 13.50 16.36

  Lactose 8195 60.00 72.73 Microcrystalline cellulose 7.50 9.09

TOTAL DRY 82.50 100.00

  This premix is introduced into the final mixture to obtain a tablet by direct compression. The finished, naked tablets generally weigh 60 to 200 mg and have the following general formula:

BARE TABLET FORMULATIONS

  Composition in mg / per tablet - Estradiol (premix qs) 0.2 to 2.0 Nomegestrol acetate 0.100 to 1,000 - Colloidal silica 0.400 to 2,000 Crospovidone 2,500 to 4,000 - Lactose 60,000 to 80,000 - Cellulose 10,000 to 25,000 - Acid stearic 0.900 to 3.00 - Talc 0.450 to 1.500 By way of example, mention may be made of tablets weighing 185 mg, of the following formula: Example of formulations (FU = unit formulation) tablets of 185 m FORMULATIONS FU mg / 1 tab 185 mg FU% Estradiol 1,500 0.811 Nomegestrol acetate 0.125 0.038 Lactose 131.790 71.238 Celluiose (Avicel PH 101) 27.810 15.032 Povidone (K25) 13.500 7.297 Precirol AT05 2.780 1.503 Colloidal silica (Aerosil 200) 1.000 0.540 Crospovidone 2 6,000 3,243

TOTAL 185.00 1,000.00

  Example of formulations (FU = unit formulation) 185 m tablets FORMULATIONS FU mgl1 cp 185 mg FU% Estradioi 0.500 0.270 Nomegestrol acetate 0.125 0.039 Lactose 136.787 73.934 Cellulose (Avicel PH 101) 32.813 17.736 Povidone (K25) 4.500 2.432 Precirol AT05 2.7500 Colloidal silica (Aerosil 200) 1,000 0.540 Crospovidone (Polyplasdone XL) 6,000 3.243

TOTAL 185.00 100.00

  Example of formulations (FU = unit formulation) 120 m tablets FORMULATIONS FU mgl1 cp 120 mg FU% Estradiol 1,500 1,250 Nomegestrol acetate 0.250 1.042 Lactose 84,000 70,000 Cellulose (Avicel PH 101) 11,250 9,375 Povidone (K25) 13,500 11,250 Silica colloTdale (Aerosil 200) 1,000 0.833 Crospovidone (Polyplasdone XL) 3,000 2,500 Magnesium stearate 1,000 0.833 Talc 1,000 0.833 Stearic acid AC / 50VG 2,500 2,083

TOTAL 120.00 100.00

  Example of formulations (FU = unit formulation) 120 m tablets FORMULATIONS FU mgl1 cp 120 mg FU% Estradiol 0.500 0.417 Nomegestrol acetate 0.250 0.021 Lactose 89,000 74,167 Cellulose (Avicel PH 101) 16,875 14,062 Povidone (K25) 4,500 3,750 Collodal silica (Aerosil 200) 1,000 0.833 Crospovidone (Polyplasdone XL) 3,000 2,500 Magnesium stearate (vegetable) 1,000 0.833 Talc 1,000 0.833 Stearic acid AC / 50VG (vegetable) 2,500 2,083

TOTAL 120.00 100.00

  Example of formulations (FU = unit formulation) tablets of 80 m FORMULATIONS FU mg / 1 tablet 80 mg FU% Estradiol 0.500 0.625 Acetate denomegestrol 0.250 0.081 Kollidon 25 4,500 5,625 Lactose M 59,735 74,669 Cellulose (Avicel PH 101) 12,000 15,000 Crospovidone (Polyplasdone XL ) 0.800 1,000 Talc 0.700 0.875 Collodal silica (Aerosil 200) 0.440 0.550 Magnesium storate (vegetable) 0.700 0.875

TOTAL 80.0 100.00

  : Example of formulations (FU = unit formulation) containing 80 m FORMULATIONS FU mg / 1 tablet 80 mg FU% Estradiol 1,000 1,250 Nomegestrol acetate 0.250 1,563 Kollidon 25 9,000 11,250 Lactose M 54,110 67,637 Cellulose (Avicel PH 101) 12,000 15,000 Crospovidone ( Polyplasdone XL) 0.800 1,000 Talc 0.700 0.875 Collordal silica (Aerosil 200) 0.440 0.550 Magnesium stearate (vegetable) 0.700 0.875

TOTAL 80.00 10.00, 00

  These tablets can be film-coated with, for example: - film-coating agents based on polyvinyl alcohol of the OPADRY PVA type "moisture barrier" (polyvinyl alcohol, titanium dioxide, purified taic, lecithin, xanthan gum, pigments, lacquers), or

  - cellulose film-based agents of the SEPIFILM L.P. type

  [H.P.M.C. (hydroxypropylmethylcellulose)], microcrystalline cellulose, acid

stearic, pigments, lacquers).

Example II

  Dissociation of the antimitotic and differentiating effects of nomegestrol acetate on the endometrial cell Menopausal women, naturally or surgically, have been subjected to a sequential estrogen-progestogen treatment. They received from D1 to D12, 30 g of ethinyl estradiol then from the 13th to the 22nd day the same dose of ethinyl estradiol associated with different doses of nomagestrol acetate or chlormadinone acetate. The doses were as follows: nomepestrol acetate in mg: 0.1 0.25 0.5 1 2.5 5 and 10 _ _ chlormadinone acetate in mg: 0.1 0, 5 1 2 5 and 10 i

  : The number of women was between 2 and 11 depending on the group.

  There was then a 7-day therapeutic pose, followed by a 2nd cycle treated.

  The parameters taken into account were: - the period of onset of menstruation after stopping treatment after the 1st and 2nd treatment cycles; The histological aspect of the endometrium recovered during a biopsy performed between the 1st and the 20th day of the second cycle The results show that: the period of onset of menstruation is a function of the dose and similar for the 2 products. The dose necessary so that menstruation does not appear before the end of treatment is between 0.2 and 0.3 mg / d for the 2 products (tab 1); 15. The transformation of the endometrium into secretory endometrium is complete with the 2 products from 1 mg / day; it decreases for the highest doses (10 mg / day); The proliferation activity, expressed by the number of mitoses in the glandular cells appears to be more strongly inhibited by nomegestrol acetate than by chlormadinone acetate. There is no longer mitosis in women treated with a dose of 0.5 nng / d or more of nomagestrol acetate while mitosis is still present with a dose

  daily of 1 mg / d of chlormadinone acetate (tab 2).

  It can therefore be concluded that at the endometrial level, nomegestrol acetate and chlormadinone acetate are not comparable: the secretory transformation activity is comparable but nomegestrol acetate is characterized by a very

  strong antimitotic and antiproliferative activity.

  Table 1: Period for onset of menstruation days) after stopping treatment Progestin Dose (mg / day) 0,] 0.25 0.5 l, 0 2.0 2.5 5 10 Acetate - 0.5 - 0.5 1.5 2.7 3.2 4.3 3.8 nomegestrol 1.5 0.5 0.5 0.2 0.2 0.4 0.8 _ Acetate - 2.3 2, 0 3.0 3.8 5.5 5.5 Chlormadinone 0.5 0.6 0.3 1.5 0.5

_ _

  Table 2: Evaluation of the number of mitoses (% of section with presence of mitoses) Dose (mg / day)

I 0.1 Q, 25 C 5 1 2.5 5 10

  Nomegestrol acetate 50 50 0 0 0 0 0 30 Glands Chlormadinone acetate 90 50 0 0 0

EXAMPLE lil

  A study has been conducted to test the effects on the endometrium of the continuous combination combination of an oral estradiol dose, equivalent to 1.5 mg and several

doses of nomegestrol acetate.

21 2823976

  It consisted in treating for 6 consecutive months 179 female renopausoes for at least 3 years, with 1.5 mg per day of estradiol combined continuously with 5 different doses of nomegestrol acetate: 5 mg / day (n = 47) ; 2.5 mg / day (n = 42);

  1.25 mg / day (n = 43); 0.625 mg / day (n = 47) and 0.125 mg / day (n = 47).

  The impact of these 5 associations on the endometrium was evaluated by collecting the characteristics of genital bleeding, by measuring the thickness of the endometrium by endovaginal ultrasound before and at the end of treatment and by performing a

  endometrial biopsy before and at the end of treatment.

  The percentage of women who had no genital bleeding during the entire course of treatment was 40 - 42.5 - 58.1 - 52.4 and 68.1%, respectively, with

  doses of 0.125 - 0.625 - 1.25 - 2.5 and 5 mg of nomegestrol acetate per day.

  The percentages observed are not statistically different between groups,

  but the relationship between dose and incidence of bleeding is significant.

  The attached tables indicate for each dose of nomegestrol acetate the results of the ultrasound examination and endometrial biopsy performed at the end

of the 6 m o is of tra item ent.

  At the end of treatment, the average thickness of the endometrium is not different between the groups. The increase in endometrial thickness under treatment is 0.39 mm on average with the lowest dose of nomegestrol acetate. This increase increases logically with the dose, reaching 1.56 mm in the group of women receiving 5 mg / day of progestin, but the relationship between variation

  thickness and dose variation does not reach the level of statistical significance.

  The endometrial blops examined at the end of the study revealed no proliferative or hyperplastic aspect of the uterine lining. The highest percentage of secretory endometers was observed in women who received the highest dose of progestin; it decreases in a progressive and statistically significant manner with the dose. On the contrary, the highest percentage of atrophic endometers was

  found with the lowest dose of progestin and it decreases with the dose.

22 2823976

  These results are unexpected since they show that very low doses of nomepestrol acetate administered in a continuous combination with an estrogen are capable of preventing the growth of the uterine mucosa and of maintaining it in a state atrophic whereas, unlike the higher doses, they are insufficient to cause a secretory transformation of

the end ometer.

  This study thus highlights a surprising decoupling of the anti-

  estrogen and the progestin effect of nomegestrol acetate, administered

  continuous combination with estrogens.

  The anti-estrogen effect is predominant since it is detectable when the progestogen, administered continuously with an estrogen, is given in low doses. These doses are insufficient to cause secretory changes in the uterine lining. At higher doses and with the same therapeutic regimen, the secretory effect

  predominates, without however allowing an excessive proliferation of the endometrium.

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Claims (18)

  1. Hormonal pharmaceutical compositions characterized in that they are formed from a combined estrogen-progestogen combination intended for oral administration and making it possible to simultaneously administer an estrogenic component at a dose ranging from 0.5 to 2 mg, and a progestin component derived from 19-norprogesterone in a dose ranging from 0.1 to 1.8 mg, in combination or in mixture with one or more non-excipients   toxic, inert, pharmaceutically acceptable.   2. Estroprogestative compositions according to claim 1, in which the estrogenic component is free, esterified or alkynylated 1-7-estradiol or conjugated estrogens.   3. estroprogestative compositions according to claim 2, in which the   estrogenic component is 170-estradiol.   4. Estroprogestative compositions according to claim 2, in which the estrogenic component is an estradiol ester, such as for example estradiol valerate. 5. Estroprogestative compositions according to claim 2, in which the estrogenic component consists of natural conjugated estrogens or of synthesis.   6. estroprogestative compositions according to claim 2, in which the   estrogenic component is ethynyl estradiol.   7. Estroprogestative compositions according to one of claims 1 to 6, in   which estradiol, the estradiol ester, or conjugated estrogen, is present at   a dose ranging from 0.5 to 2 mg per unit dose.   8. Estroprogestative compositions according to claim 3, in which the free estradiol is preferably present in a dose of 0.5 to 1.0 mg per unit dose. 9. Estroprogestative compositions according to claim 4, in which the ester   estradiol is preferably present at a dose of 0.5 to 1 mg per unit dose.   10. Estroprogestative compositions according to claim 5, in which the natural or synthetic conjugated estrogen is preferably present at a   dose of 0.312 to 0.625 mg per unit dose.   11.Eroprogestative compositions according to claims 1 to 10, in which   the progestin component is nomagestrol or one of its esters, 12. estroprogestative compositions according to claim 11, in which the   progestogen component is nomegestrol acetate.   13. estroprogestative compositions according to claims 11 and 12, in   which nomegestrol acetate is present in a dose ranging from 0.1 to 1.0 mg per unit outlet.   14. The estroprogestative composition according to claims 11 to 13, in which   nomegestrol acetate is present at a dose between 0.125 and 1.00 mg per unit outlet.   15.Use of the estroprogestatif mixture according to one of claims 1 to 14,   view of the production of a drug to treat deficiencies   estrogen in postmenopausal women.   16.Use of the estroprogestatif mixture according to one of claims 1 to 14,   view of the production of a drug to prevent osteoporosis and   cardiovascular disease in menopausal women. 27 2823976   : 17.Use of the estroprogestative mixture Solon one of claims 1 to 14, in   view of the production of a medicament for administration continuous or intermittent.   18. Process for the preparation of new estroprogestative compositions Solon rune   of claims 1 to 14, in which the estrogenic active principle and the principle   progestogen active are mixed or incorporated into one or more inert excipients,