Title of Invention	"A PHARMACEUTICAL COMPOSITION FOR STOPPING OVULATION"
Abstract	A pharmaceutical composition for stopping ovulation which comprises (i) from 0.5 to 3 mg of an estrogen selected from the group consisting of free estradiol, esterified estradiol and equine conjugated estrogens, (ii) from 1.5 to 3.75 mg of nomegestrol acetate and (iii) pharmaceutical excipients suitable for an oral administration.

Full Text

The present invention relates to the field of therapeutic chemistry and more particularly to the field of hormonal pharmaceutical techniques. A more precise subject of the invention is new pharmaceutical compositions formed by an estroprogestative combination with a view to the correction of estrogenic deficiencies in natural or artificial menopauses or in order to stop ovulation in women during their period of ovarian activity. In particular a subject of the invention is an estroprogestative combination, characterized in that it is constituted by unit doses containing the combination of a progestative and an estrogen, the two components being present simultaneously in each medicinal dose. This combination is intended to be administered by oral route. As is known, the life expectancy of women has passed in less than a century from 50 to 80 years, whilst the average age for the onset of the menopause has remained unchanged. Therefore, women spend a third of their life in a state of estrogenic deficiency which is the origin of the increase in risk of osteoporosis and cardiovascular illnesses. Sequential replacement treatment for the menopause cures the climateric symptomology and prevents osteoporosis and the onset of illnesses. It creates artificial cycles which are followed by a withdrawal bleeding. This therapeutic schema quite particularly suits women for whom the menopause is recent but it is not always well accepted in the long term, which in part explains the poorer observance of treatment (DRAPIER FAURE E.; Gynecologic. 1992, 43: 271-280). In order to overcome this drawback, combined combinations have been perfected where the two components are taken simultaneously, the progestative having the effect of permanently opposing the proliferative action of the estrogen on the endometrium. In order to overcome this drawback, combined combinations hav«! been perfected where the two components are taken simultaneously, the progestative having the effect of permanently opposing the proliferate action of the estrogen on the endometrium, by creating an atrophy of the endometrium and as a consequence, the absence of withdrawal bleeding (HARGROVE J.T., MAXSON W.S., WENTZ A.C-, BURNETT L.S.. Obstet Gynecol, 1989, 73: 606-612). This "no periods" schema more particularly suits women for whom the menopause is already well in the past. It can be prescribed in courses of sequential combinations in order to improve the long-term observance of replacement hormone Treatment for the menopause. The dose of progestative to be used in a combined replacement treatment is in general deduced from that. Which is usually prescribed in sequential schemata In the latter the dose chosen is that which gives over the long term less than 1% endometrial hyperplasia when the progestative is administered discontinuously, more than 10 days per cycle, in post-menopasual women under replacement strogenotherapy (WHTTEHEAD et al., J. reprod. Med, 1982. 27; 539-548, PATERSON et al, Br Med J 1980, 22 March: 822-824). In the combined treatment, these same progestatives were used at half the dose judged to be effective during a sequential treatment: this is the example cf the micronized progesterone, didrogestcrone (POX H., BAAK J., VAN DE V^EIJER P., AL-AZZAWT E, PATERSON M, JOHNSON A.. MJCHELL G., BARLOW D., FRANCIS R . 7th International Congress on the Menopause, Stockholm, 20-24 June 1991 abstr 119) and nedroxyprogesterone acetate (BOCANEFA R., BEN J., COFONT- M., GUINLE I. MAIL AND D.. SOSA M., POUDES G, ROBERTI A., BISO T , EZPELF.TA D., PUCHE R. TOZ2INI R, 7th International Congress on the Menopause, Stockholm, 2C-24 June 1993, abstr 40) which were use;! at doses of 100, 10 and 5 mg/day respectively, with encouraging results on the clinical and endometnal level .Among the progesratives. r.omegestrol acetate appeared to be one of the most effective Nomegestrol acetate is a ncn-androgenic progestative deiived from 19-nor progesterone, its use in sequential administration during the menopause at the dose of 5 mg/day, 12 days per cycle, in combination with different types of estrogens, allows endometrial hyperplasia to be prevented as shown by a multicenje study on 150 women for one year (THOMAS J.L., BERNARD AM., DENIS C., 7th International Congress on the Menopause, Stckholm, 20-24 June 1993, abstr 372). The absence of hyperplasia was confirmed in a study where the nonegestrol acetate was administered at the same dose, 14 days per cycle, in worrcn treated with percutaneous estradiol (BERNARD A.M. et al. Comparative evaluation of two percutaneous estradiol gels in combination with nomegestrol aceiate in hormone replacement therapy. XIV World Congress of Gynecology and Obstetrics, FIGO, Montreal, 24-30 September 1994). The combined treatment is more often used in a continuous fashion, i.e. without interruption. However some people are in favour of using it in an intermittent fashion, for example 25 days per month (BIRKAUSER M. ET AL; Substitution hormonale: une indication bien posee et des schemas de traitemem individuels sont determinants pour le succes du traitement, Med. et Hyg., 1995, 53: 1770-1773). The aim of the therapeutic interruption is to remove the inhibition exercised by the progestative on the synthesis of the estradiol and progesterone receptors and in this way to avoid the lowering of receptivity of the hormono-dependant tissues. The progesterone used according to the present invention is nomegestrol acetate which is active hy oral route. The estrogen used is free or es:erified estradiol, or equine conjugates estrogens which are presented according to a formulation which is active by oral route and in particular estradiol valerate. Nomepp.srrol acetate and free or esterified estradiol or equine conjugated estrogens are administered in one of the forms which permit administration by oral route- gelatine capsules, capsules, pills, sachets of powder, tablets, coated tablets, sugar-coated tablets etc The present invention is characterized in that it is constituted by s. new estroprogestative combination, which is active by oral route and administered in a combined manner A subject of the present invention is also its use ir the correction of estrogenic deficiencies, in the prevention of osteoporosis and cardiovjiscular illnesses in post-menopausal women, or in stopping ovulation in women durim; their period of ovarian activity The compositions according to the invention based on nomegesirol and free or csterified estradiol or equine conjugated estrogens are administered ir a continuous or intermittent fashion, from 21 to 25 days per month. According to a particular implementation of the invention the compositions contain a quantity of nomegestrol acetate ranging form 1.5 to 3.75 mg and a qjantity of free or esterified estradiol or equine conjugated estrogens ranging from 0.5 to 3 mg. Preferably, the optimal formulations contain 2.5 mg of nomegestrol acetate combined with eiiher 1 5 mg of free estradiol or 2 mg of estradiol ester or 0.625 mg of equine conjugated estrogens, per daily dose. This combined administration method can have several therapeutic indications. In post-menopausal women, the estroprogestative combination is intended to compensate for the functional disorders brought about by hypoestrogenism of the menopause, while maintaining an atrophy of the endometrium and avoiding in a majority of them the appearance of withdrawal bleeding. In women during the period of ovarian activity, young or in the years preceding the menopause, the cyclic administration cf the hormonal combination is capable of stopping ovu'.aticn and of exercising a contraceptive effect insofitf as it has been proved that nomegestrol is capable of stopping the ovulation peak of LH and FSH, starting from ' 2:5 mg/day (BAZIN B et el, Effect cf nomegestrol a:etate, a new 19-norprogesterone derivative on pituitary ovarian function in women. Br 1 Obstet Gynaecol. 1987, 94: 1195-1204). When the hormonal combination is given for a contraceptive purpose, the aim of nomegestrol acetate is to stop ovulation and for the estrogenic compcund to compensate for hypoestrogenia and ensure i, better control of the cycle A subject of the present invention is also a process for obtaining new pharmaceutical compositions. The obtaining process according to the invention consists of m.xing the active ingredients: nomegestrol acetate and free or esterified estradiol or equine conjugated estrogens with one or more pharmaceutically acceptable, non-toxic, irert excipients. Among the excip;ents which can be mentioned are binding and soiubilizing agents, compression agents, disintegration agents and slip agents This mixture can be subjected to direct compression or to several stages of compression in order to form tablets which, if desired, can have their surface protected by a film, by lacquering or coating. The production of tablets by di -ect compression allows a maximum reduction in the proportion of diluting agents, binding agents, disintegration agents and slip agents. The production of gelatine capsules can be carried out by mixing the active ingredients with an inert diluant 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 a registered trademark for designating an equimolar mixture of the isomer of -D- glucopyranosido 1,6-mannitol and -D-glucopyranosido 1,6-glucitol crystallized with two molecules of water, mannitol, sorbitol or the mixture lactose/P\P sold under the name Ludipress. The compression binding agents are in general microcrystalline cellule ses such as those sold under the name AVICEL PH 101 or AVICEL PH 102. The polyvinylpyrrolidone plays an important role and facilitates the E gglomerarion of the powders and the compressibility' of the mass. To this end polyvinylpyrrolidon^s are u«ftd with a molecular weight comprised between 10COO and 30000 such as Povidone. Kollidon of a grade comprised between 12 and 30 The mixture also co-tains slip or anti-electrostatic agents so that the powder does not agglomerate in the feed hoppers. In this respect, colloidal silicas can be mentioned which are sold under the name AEROSIL IOC or AEROSIL 200. The mixture aUo contains disintegration agents which allow disintegration or crumbling which conforms to pharmaceutical standards. There can be mentioned as useful disintegrate agents, polymers of cross-linked vinylpyrrolido nes such as those sold under the names Polyplasdone or Polyclar AT, carboxymethylamidons such as those sold under the names Anigel or Explotab, cross-linked carboxymethylcelluloses or croscarmelloses such as the compound sold under the name AC-DI-SOL> In addition, the preparation contains lubrication agents which facilitate the compression and ejection of the tablet from the tablet compressing machine. There can be mentioned as lubrication agents, glycerol palmitostcarate sold under the name Precirol, magnesium stearate, stearic acid or talc. After compression the tablets can be coated in order to ensure their storage or to facilitate their deglutination. The coating agents are either of cellulose origin such as cellulose ph- halate (Sepifilm, Pharmacoat), or of polyvinyl origin of Sepifilm ECL type, or of sacclurose origin such as the sugar for sugar-coating of Sepisperse DR, AS, AP OR K (coloured) type. The tablets, whether coated or not, can, in addition, be surface or bulk coloured, by plant or synthetic colouring agents (for example chinolin yellow lacquer or E 104), The proportions of the different constituents varies according to the type of tablet to be produced. The content of active ingredients can van- from 1.5 to 3.75 mg for nomegestrol acetate and from 0.5 to 3 mg for free or esterified estradiol or for equine conjugated estrogens. The dilution 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 polyvinylpyrrolidc-ne from 0.5 to 15%, the disintegration agents vary from 2 to 5.5% for the cross-linked polyvinylpyrrolidone or the carboxymethylamic on, from 2.0 to 3 0% for the croscarmellose. The quantities of lubricating agents vary as function of the type of agents from 0.1 to 3.0% The compositions according to the invention are intended to be acmnistered once per day. However, depending on the therapeutic requirements, administration can be split up (twice per day) or on the other hand, repeated (two tablets per day) The following examples illustrate the invention. They in no way limit it EXAMPLE 1 Tablets with 4 mg of active ingredient Active ingredient s: - estradiol 1.5 mg - nomegestrol acetate 25 mg Microcrystallme cellulose 22 4 mg (marketed under the name AV1CEL PH 102) Lactose 60 mg Polyvmylpyrrolidone 8.4 mg Colloidal silica 1.2 mg Glycerol palmitostearate 3 6 mg Colouring agent E 104 0.4 mg for a tablet completed at an average weight of 100 mg. EXAMPLE n Study of the clinical tolerance during two continuous combined schemata of hormone replacement therapy for the menopause The pilot study is carried out over 24 weeks on two parallel grojps subjected to treatments A and C: Treatment A • Nomegestrol f.cetate 2.5 mg'day even,- day - percutaneous 173-estradiol 1.5 mg/day every day • The nomegestrol acetate is administered in the form of tablets and :he percutaneous 173-estradiol in the form of a eel Treatment C' • Nomegestrol acetate 2.5 mg'day every day T estradiol valerate 2 m#da> every day. • The estradiol valerate is administered in the form of tablets The pilot study is intended to evaluate the endometria! clinical tolerance during the use of the two hormone replacement therapy schemata for the menopause so-called '"without periods" combining in a continuous combined fashion treatr-rem A or C The endometriftl clinical tolerance is evaluated from the presence or not of occurences of vagina bleeding, their intensity, their frequency, from data acquired from endovaginal echographical examination etc . Also, another airr. of this study is to assess the general clinical tolerance (weight, blood pressure, mammfiry symptoms), biological tolerance (Formule Numeration Sanguine (blood count), glycemia, cholesterol...), as well as the observance of treatment The selection of subjects is carried out as a function of "inclusion" criteria. These criteria are to do. - with the menopause: women over 50 years old are included who have had a natural menopause expressed clinically by an amenorrhea greater than 12 months and less than 10 years, the women having had a natural menopause confirmed biologically by quantitative analysis of FSH (Follicle stimulating hormone) and estradiol (i.e. plasmatic FSH > 20 ]U/I, plasmatic E3 £ 0 11 nmol/1) - with women: women who have not had hysterectomies are included, whose Quetelct's index (weight in kg/(height in m)2 )is z 27, having had regular cycles before the menopause, having never received hormone replacement therapy for the menopause or having had a clinically weli-tolerated hormone replacement therapy (absence of abnormal bleeding)., interrupted tor more than 6 weeks, presenting an endometria! thickness measured by endovagina! echography 5 mm, accepting the idea of hormone rep acement therapy for the menopause, who would like a hormone therapy without periods justifying an estroprogestative hormone therapy for at least 6 months, cooperative' accepting to conform to the requirements of the study, whose psychic and intellectual profile would allow one to suppose a good observance of the treatment, having a mammograph dating from less than a year from the date of inclusion At the start of treatment the patients undergo ar. inclusion consultation (CO the purpose of which is to verify that the inclusion criteria have been respected, that the endovagmal echograph is normal and to obtain the written consent of the patient as regards participation. The intermediate consultation (C?) takes place between the 9th and llth week of treatment, the purpose of which is to verify mammary and er.dometrial clinical tolerance is good as regards the treatment. Lastly, a final consultation (C3) takes place during the 24th week of treatment The patients who wish to continue the study can receive, for 24 additional weeks, the estroprogestative treatment received during the study according to the same therapeutic schema. The extension of the study thus allows a complete monitoring of the study over 48 weeks. ANALYSTS OF THE STUDY RESULTS 1 The attached Tables I and II, reveal a difference in terms of the amer.orrhea results (le no bleeding from 0 to 24 weeks) and of mammary and/or endometiial tolerance as a function of the estrogen (Table Removed) CONCLUSION Of the 16 patients treated. • 1 left the study, i.e. 6% • 15 finished the study after 24 weeks, i e 94% • 13 extensions of treatment (24 additional weeks) 81% The two extensions which did not take place whee due to reajons which were independent of the treatment, the patients continued the same treatment outside the treatment protocol. (Table Removed) CONCLUSION Of the 14 patients treated • 6 left the study i.e. 43% • 8 finished the study after 24 weeks, i.e. 57% • 7 extensions of treatment (24 additional weeks), i.e. 50% % of amenorrhea (i.e no occurrence of bleeding for 24 weeks) = 43% RESULTS II A - OBSERVANCE While no significant difference exists between the two groups A and C, a lower number of days when treatment lapsed over all the 24 weeks of the study was observed with treatment A B - ENDOMETRIAL CLINICAL TOLERANCE The most significant absolute percentage of amenorrhea is found in group A, the difference being significant in phase IT (13th to 24th week of treatment) As has been described in the literature, the percentage of amenorrhea increases wiih time, therefore, for group C, it is 35 3% during the first 12 weeks of treatment, and 46.1% during the last 12 weeks The attached tables III. IV and V illustrate the results obtained AM6NORRHEA Analysis regarding treatment (Table Removed) A.L.A.T. — Alanine Aminotransferase Transaminase F.S.H. - Follicle Stimulating Hormone The relative variation in estradiol level is quite important in the two groups (A% = 567% in group A and 609% in group c), p » 0 04 Table VI illustrates another study which was carried out In this other study, it is interesting to no-e that with nomegestrol acetate, the percentage of patients with absolute amenorrhea (including all forms of estrogenotherapy) is greater from the 3rd month of treatment: 42 5% against 33 3% In the treatment ment oned above, one must wait until the 12th month of treatment to obtain this percentage of 42% of patients with amenorrhea which was obtained here from 3 mr.nths. whilst the populations are comparable in terms of age, weight and length cf time since the menopause In addition, there exists in the previous study, an estrog»n effect which is not found in this nther studv On the other hand, this study reveals i dosage effect of proeestative c'urirg the last 9 months of treatment (the lower the do;e of progestative the better thr cycle is controlled) Finally, it is interesting to note that no correlation exists between tie existence of an amenorrhea at 6 months and the endometrial thickness measured by endovaginal echography; this thickness varying by + 1.6mm on average over € months in the 2 treatment groups TABLE VI Characteristics of the patients (Table Removed) claim: 1. A pharmaceutical composition for stopping ovulation which comprises (i) from 0.5 to 3 mg of an estrogen selected from the group consisting of free estradiol, esterified estradiol and equine conjugated estrogens, (ii) from 1.5 to 3.75 mg of nomegestrol acetate and (iii) pharmaceutical excipients suitable for an oral administration. 2. The pharmaceutical composition as claimed in claim 1 wherein the estrogen is an ester of estradiol. 3. The pharmaceutical composition as claimed in claim 2, wherein the ester of estradiol valerate. 4. The pharmaceutical composition as claimed in one claim 1, wherein the said composition comprises 1.5 mg of free estradiol. 5. The pharmaceutical composition as claimed in one claim 1, wherein the said composition comprises 2 mg of ester of estradiol. 6. The pharmaceutical composition as claimed in one claim 1, wherein the said composition comprises 0.625 mg of equine conjugated estrogen. 7. The pharmaceutical composition as claimed in one claim 1, wherein the said composition comprises 2.5 mg of nomegestrol acetate. 8. The pharmaceutical composition as claimed in claim 1 , wherein the said composition comprises 1.5 mg estradiol and 2.5 mg nomegestrol acetate. 9. The pharmaceutical composition substantially as herein described with reference to foregoing examples.

Documents:

2575-DEL-1997-Correspondence-Others-(06-01-2009).pdf

2575-DEL-1997-Form-1-(06-01-2009).pdf

2575-DEL-1997-Petition-137-(06-01-2009).pdf

2575-DEL-1997-Petition-138-(06-01-2009).pdf

2875-DEL-1997-Abstract-(06-01-2009).pdf

2875-DEL-1997-Abstract-(19-01-2009).pdf

2875-del-1997-abstract.pdf

2875-DEL-1997-Claims-(06-01-2009).pdf

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2875-DEL-1997-Correspondence-Others-(06-01-2009).pdf

2875-DEL-1997-Correspondence-Others-(19-01-2009).pdf

2875-del-1997-correspondence-others.pdf

2875-DEL-1997-Description (Complete)-(06-01-2009).pdf

2875-del-1997-description (complete).pdf

2875-DEL-1997-Form-1-(06-01-2009).pdf

2875-del-1997-form-1.pdf

2875-del-1997-form-13-(06-01-2009).pdf

2875-del-1997-form-18.pdf

2875-DEL-1997-Form-2-(06-01-2009).pdf

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