MXPA99003291A - Hormonal composition consisting of an oestrogen compound and of a progestational compound - Google Patents

Abstract

The invention concerns the field of chemical therapy and more particularly the field of pharmaceutical hormonal technique. More precisely it concerns novel pharmaceutical hormonal compositions characterised in that they are formed by an oestroprogestational combination consisting of an oestrogen compound and a progestational compound, associated or mixed with one or several non-toxic, inert and pharmaceutically acceptable excipients, for oral administration. The invention also concerns the use of the oestroprogestational mixture in which the oestrogenic constituent and the progestational constituent are administered in combination. The combined association can be prescribed continuously or intermittently, for producing a composition for treating oestrogenic deficiencies, preventing osteoporosis and cardiovascular diseases in the menopausal woman, or still for blocking ovulation in a woman during the period of ovarian activity. The invention also concerns a method for preparing these novel pharmaceutical oestroprogestational compositions.

Description

HORMONAL COMPOSITION CONSTITUTED OF. A COMPOSITE STROGEN AND A PROGESTATIONAL COMPOUND DESCRIPTION OF THE INVENTION The present invention relates to the field of therapeutic chemistry and more particularly to the field of hormonal pharmaceutical technology. More specifically, its object is novel pharmaceutical compositions formed from a estroprogestative association, with a view to correcting estrogenic deficiencies in natural or artificial menopause, or in order to prevent ovulation in women during periods of ovarian activity. In particular, it has as an object a estroprogestative association characterized in that it is constituted by dosage units that contain the combination of a progestative and an estrogen, both components being present at the same time in each drug intake. Said association is intended to be administered orally. As is known, the life expectancy of women has passed in less than a century from 50 to 80 years, while the average age of arrival of menopause has remained unchanged. Thus, women spend a third of their lives in a state of estrogenic deprivation, which causes an increased risk of osteoporosis and cardiovascular diseases. Sequential replacement therapy for menopause cures climacteric symptomatology, and prevents osteoporosis and the onset of cardiovascular diseases. It creates artificial cycles that are followed by a hemorrhage of deprivation. This therapeutic scheme is particularly suitable for women whose menopause is recent, but is not always accepted in the long term, which partly explains the poor adherence to treatment (E. DRAPIER FAURE, Gyn ecol ogi e 43, 1992, pages 271- 280). To alleviate this drawback, combined associations have been prepared in which the two components are taken at the same time, with the progestative having the effect of permanently opposing the proliferative action of estrogen on the endometrium, generating an atrophy of the endometrium and therefore lack of deprivation haemorrhage (JT HARGROVE, WS MAXSON, AC WENTZ, SL BURNETT, Obs tet Gynecol. 73, 1989 pages 606-612).

This scheme "without rules" is more particularly suited to women whose menopause is already long-standing. It can be prescribed as a relay of sequential associations, to improve the prolonged adherence to hormone replacement therapy for menopause. The dose of progestative to be used in a combined substitution treatment is generally deduced from that usually prescribed in the sequential schemes. In the latter, the chosen dose is that in the long term of less than 1% of endometrial hyperplasia, when the progestative is administered discontinuously, more than 10 days per cycle, in menopausal women undergoing substitute trogen therapy (WHITEHEAD et al. al., J. Reprod. Med. 27, 1982, pages 539-548; PATERSON et al., Br. Med. J. March 22, 1980, pages 822-824). In the combined treatment, these same progestatives have been used in doses equal to half of what is considered effective in the case of a sequential treatment; is the example of the progesterone icroni zada of the didgroges terona (H. FOX, J. BAAK, P. VAN DE WEIJER, E. AL-AZZAWI, M. PATERSON, A. JOHNSON, G., MICHELL, DE. BARLOW, R FRANCIS, VII International Congress on Menopause, Stockholm, June 20-24, 1993, Extract 119) and acetate of medroriproges terona (R. BOCANERA, J. BEN, M. COFONE, I. GUINLE, D. MAILAND, M SOSA, G. POUDES, A. ROBETI, T, BISO, D. EXPELETA,. PUCHE, R. TOZZINI, VII International Congress on Menopause, Stockholm, 20-24 June 199.3, Extract 40), which have been used respectively in doses of 100, 10 and 5 mg daily with encouraging results in the clinical and endometrial planes. Among proges tatives, nomegestrol acetate has seemed one of the most effective. Nomegestro acetate: is a non-androgenic progestative derived from 19 nor-progesterone; Its use in sequential administration in menopause period with different types of estrogens, allows to prevent endometrial hyperplasia, as a multicenter study has shown in 150 women during 1 year (JL THOMAS, AM BERNARD, C. DENIS, VIII International Congress on the Menopause, Stockholm, June 20-24, 1993, Excerpt 372). The absence of hyperplasia has been confirmed in a study in which nomegestrol acetate was administered in the same dose, 14 days per cycle, in women treated with estradiol percutaneously (AM BERNAD et al., "Comparative Evaluation of two Percutaneous Estradiol Gels in combination with Nomegestrol Acétate in Hormone Replacement Therapy ", XIV World Congress of Gynecology and Obstetrics, FIGO, Montreal September 24-30, 1994. Combination treatment is the most frequently used continuously, ie However, some advocate using it intermittently, for example, 25 days per month (M. BIRKAUSER et al., "Hormone subsitution: an indication is well-known, and the traits of individual traits are decisive for success. du traitement ", Med. Et Hyg. 53, 1995 pages 1770-1773) The therapeutic interruption is aimed at the inhibition that the progestative exerts on the synthesis of the estradiol and progesterone receptors, and thus avoid the low receptivity of hormone-dependent tissues. The progestative used according to the present invention is nomegestrol acetate, which is active orally.

The estrogen used is free or esterified estradiol. or conjugated equine estrogens that are presented according to an orally active formulation and, more particularly, estradiol valerate. gestrol acetate and free or esterified estradiol, or conjugated equine estrogens, are administered in one of the forms that allow their oral administration: wafers, capsules, pills, pouches with powder, tablets, coated tablets, dragees, etc . The present invention is characterized in that it constitutes a novel troprogestative association, active orally, administered in combination. The present invention also has as an object its use in correcting estrogenic deficiencies, in preventing osteoporosis and cardiovascular diseases in the menopausal woman, or in preventing the ovulation of the woman in period of ovarian activity. The compositions according to the invention, based on sgestrol acetate and free or esterified estradiol, or equine conjugated estrogens, are administered continuously, or intermittently 21-25 days per month. According to a particular embodiment of the invention, the compositions contain an amount of stepped gestrol acetate of 1.5 to 3.75 mg, and an amount of free or esterified estradiol, or equine conjugated estrogens staggered from 0.5 to 3 mg. Preferably, the optimal formulations contain, per day, 2.5 mg of gestrol acetate associated with either 1.5 mg of free estradiol or 2 mg of estradiol ester, and 0.625 mg of conjugated equine estrogens. This combined mode of administration may have various therapeutic indications. In menopausal women, the troproges tativa combination is intended to compensate for the functional alterations caused by the menopause hypoestrogenia, while maintaining an atrophy of the endometrium and avoiding, at the same time, the appearance of hemorrhage of most men. deprivation. In women in periods of ovarian activity, young or in the years preceding menopause, the cyclic administration of the hormonal combination is capable of inhibiting ovulation and exerting a contraceptive effect, inasmuch as it was proved that of gestrol was able to inhibit the maximum ovulatory luteinizing hormone (LH) and follicle stimulating hormone (FSH), from 1.25 mg daily (B. BAZIN et al., "Effect of gestrol Acétate, a new 19-norproges terone Derivate on pituitary ovarian Function in lomen ", Br. J. Obs tet Gyna ecol ogy 94, 1987, pages 1199-1204). When the hormonal combination is administered for a contraceptive purpose, the gestrol acetate is intended to prevent ovulation, and the estrogenic component is intended to compensate for hypoestrogenia and to ensure better control of the cycle. The present invention also has as its object a method for obtaining the novel pharmaceutical compositions. The method of obtaining according to the invention consists in mixing the active ingredients: gestrol acetate and free or esterified estradiol, or equine conjugated estrogens, with one or more inert, non-toxic, pharmaceutically acceptable excipients.

Among the excipients, mention may be made of the binders and solubilizers, the compression agents, the disintegrants and the glidants. This mixture can be subjected to direct or multi-stage compression to form tablets that can be surface-protected, if desired with a film, lacquer layer or other coating. The production of tablets by direct compression allows to reduce to the maximum the proportion of diluents, binders, disintegrants and glidants. The production of wafers can be done by mixing the active ingredients with an inert diluent and a slip agent. The tablets contain, in particular, mass diluents such as lactose, sorbitol for direct compression marketed under the name NEOSORB 60, Palatino, which is the brand name for an equimolar mixture of D-glucopyranoside 1,6-mannitol isomer and of 1,6-glucitol D-glucopyranoside crystallized with two water molecules, mannitol, sorbitol or the lactose / PVP mixture sold under the name "Ludipress".

The compression binding agents are generally mcrystalline celluloses such as those sold under the name AVICEL PH 101 or AVICEL PH 102. The polyvinylpyrrolidone PVP also plays an important role in facilitating the agglomeration of the powders and the compressibility of the dough. For this purpose, PVPs with a molecular weight between 10,000 and 30,000 are used, such as Povidone and Kollidon with a grade between 12 and 30. The mixture also contains slip or anti-electrostatic agents, which prevent the powder from agglomerating in the feeder hoppers. In this regard, mention may be made of colloidal silicas * sold under the name AEROSIL 100 or AEROSIL 200. The mixture also contains disintegrants which allow a disintegration or a suppression according to pharmaceutical standards. Useful disintegrants are crosslinked vinylpyrrolidone polymers such as those sold under the names Polyplasdone or Polycral AT, carboxymethylamidones such as those sold under the names Amigel or Explotab, the crosslinked carboxyt and ilcelluloses or croscarmellose as the compound sold under the name AC-DI-SOL In addition, the preparation contains lubricants that facilitate compression and ejection of the tablet on the compressor machines. As lubricants, mention may be made of glycerol palmito stearate sold under the name Precirol, magnesium stearate, stearic acid or talc. After compression, the tablets can be coated, to ensure their preservation or facilitate their swallowing. Coating agents are either cellulosic such as cellulose phthalate (Sepifilm, Pharmacoat), or polyvinyl septifilm type.

ECL, now saccharotic as the sugar for dragee formation of type Sépisperse DR, AS, AP, OUK (colored). The tablets, whether coated or not, can also be colored superficially or massively with vegetable or synthetic dyes (for example, lacquer in yellow quinoline or E 104). The proportions of the different constituents vary according to the tablet to be produced.

The content of active ingredients may vary from 1.5 to 3.75 mg for nomegestrol acetate, and from 0.5 to 3 mg for free or esterified estradiol or for conjugated equine estrogens. The diluents vary from 20 to 75%; the slip agents vary from 0.1 to 2%; Compression binders vary from 2 to 20%; polyvinylpyrrolidone varies from 0.5 to 15%; the disintegrants vary from 2 to 5.5% for the cross-linked polyvinylpyrrolidone or for the carboxymetalamidon, from 2.0 to 3.0% for the croscarmellose (per hundreds all referred to the total mass). The quantities of lubricants vary from 0.1 to 3.0% according to their nature. The compositions according to the invention are intended to be administered once a day. However, depending on the therapeutic needs, the administration can be divided (twice a day) or, on the contrary, repeated (with two tablets per day). The following examples illustrate the invention; they do not limit it in any way.

EXAMPLE 1 Tablets with 4 mg of active ingredients Active ingredients: estradiol 1.5 mg nomegestrol acetate 2.5 mg Mcrystalline cellulose (AVICELMRPH 102) 22.5 mg Lactose 60 mg Polyvinyl pyrrolidone 8.4 mg Colloidal silica 1.2 mg glycerol palmitostearate 3.6 mg Colorant E. 104 0.4 mg for a final tablet with an average weight of 100 mg.

EXAMPLE II Study of clinical tolerance in the cases of two continuous combined schedules of hormone replacement therapy for menopause.

E.1 pilot study is carried out for 24 weeks, in two parallel groups subjected to treatments A and C.

Treatment A Every day: 2.5 mg / d of nomesgestrol acetate + 1.5 mg / d of 17ß-is tradiol percutaneously Nomegestrol acetate is administered in the form of tablets and 17β-is tradiol percutaneously, in the form of gel.

Treatment C - Every day: 2.5 mg / d of nomegestrol acetate + 2 mg / d of estradiol valerate. - The valerate is administered in the form of tablets. The pilot study is intended to evaluate endometrial clinical tolerance when using the two menopausal hormone replacement therapy schemes called "no rules", associating the A or C treatment in a continuous combined manner. The endometrial clinical tolerance is evaluated based on the presence or absence of vaginal bleeding and the intensity or frequency of these, from the data of endovascular ultrasound examination, etcetera. Another purpose of this study is to also appreciate the general clinical tolerance (weight, blood pressure, breast reactions), biological tolerance (numerical expression of blood formula, glycemia, cholesterol, etc.), as well as the observance of treatment. The selection of people is based on "inclusion" criteria. These criteria are related: with menopause: it includes women over 50 years who have had a natural menopause clinically expressed by amenorrhea greater than 12 months and less than 10 years, having women had a natural menopause biologically confirmed by administering doses of FSH (follicle-s t imulating-hormone) and of estradiol (say plasma FSH >); 20 IU / liter, E-plasmatic < 0.11 nmol / liter). with women: including non-hysterectomy women whose Quetelet Index (weight in kg / (height in m) ~) is < 27 and who had regular cycles before menopause, who never received hormone replacement therapy (HRT) during the menopause, or who received a well-tolerated hormone replacement therapy (without abnormal bleeding) that was interrupted after more than 6 weeks. an endometrial thickness < 5 mm measured by endovaginal ultrasound, who accept the idea of a hormone replacement therapy for menopause, who are desirous of hormone therapy without rules, willing to accept a hormonal therapy is tproproductive during min. 6 months and to cooperate according to the imperatives of the study, whose psychic or intellectual profile allows to suppose a good observance of the treatment, and who have a mammography taken less than a year before the date of inclusion in the study. At the beginning of the treatment, the patients undergo a consultation for inclusion (Ci), which aims to verify compliance with the inclusion criteria, the normality of the endovaginal ultrasound, and to receive in writing the patient's consent to take part. The intermediate consultation (C_) takes place between the 9th and the 11th week of treatment, and aims to verify the good endometrial and mammary clinical tolerance of the treatment. Finally, a final consultation takes place, (C- in the 24th week of treatment.

Patients wishing to continue the trial may receive estroprogestative treatment again, according to the same therapeutic scheme, for a further 24 weeks. Thus, the extension of the trial allows a total follow-up of the trial of 48 weeks.

STUDY ANALYSIS RESULTS I Tables I and II below show a difference in terms of amenorrhea results (ie, no bleeding in 0-24 weeks), and of mammary and / or endometrial tolerance, depending on the estrogen.

TABLE I: Treatment A nomegestrol acetate + estradiol-17beta percutaneously TABLE I: Treatment A nomegestrol acetate + estradiol-17beta percutaneously OR TABLE I: Treatment A nomegestrol acetate + estradiol-17beta percutaneous route O TABLE II: Treatment C nomegestrol acetate + estradiol valerate, orally TABLE II: Treatment C nomegestrol acetate + estradiol valerate, by oral route KJ TABLE II: Treatment C nomeggstrol acetate + estradiol valerate, orally CONCLUSION Of 16 patients treated: 1 (= 6%) out of trial 15 (= 94%) completed the trial, in 24 weeks 13 (= 81%) repeated the treatment (24 additional weeks) Two patients did not repeat the treatment for reasons unrelated to that, but they continued it out of protocol.

CONCLUSION Of 14 patients treated: 6 (= 43%) out of trial 8 (= 57%) completed the trial, in 24 weeks 7 (= 50%) repeated the treatment (24 additional weeks% of amenorea (this is no bleeding in 24 weeks) = 43% RESULTS II A - OBSERVANCE Although there is no significant difference between the two treatment groups A and C, with treatment A a smaller number of days of forgetting is observed in the total of 24 weeks of the study.

B - TOLERANCE The most considerable percent of absolute amenorrhea is again in group A, with the difference being significant in stage II (13th to 24th week of treatment). As described in the literature, the percent amenorrhea increases with time; thus, for group C it is 35.3% in the first 12 weeks of treatment and 46.1% in the last 12 weeks. The following Tables III, IV and V illustrate the results obtained.

AMENORREA Analysis with intent to treat TABLE III: Stage I / week 1 to 12 TOTAL GROUP AGRUPO CP TABLE III: Stage I / week 1 to 12 TOTAL GROUP AGRUPO CP TABLE IV: Stage 11 / weeks 13 to 24 TABLE V S.G.T.P. = Serum Glutamic Peripheral Transaminase (or Alanine Transaminase Aminotransferase = A.L.A.T.) F.S.H. = Follicle Stimulating Hormone The relative variation in the two groups (? = 567% in group A and 609% in group C), p = 0.04 Table VI illustrates another study carried out. In this other study, it is interesting to observe that with nomegestrol acetate the percentage of patients in absolute amenorrhea (including all forms of estrogen therapy) is greater since the 3rd month of treatment: 42.5% versus 33.3%. In the study cited above, we must wait for the 12th month of treatment to obtain this 42% of patients in amenorrhea obtained here from 3 months, with comparable populations in terms of age, weight and age of menopause. In addition, in the previous study there is an estrogenic effect that is not found in this other study. In contrast, this study has shown a dose effect of the progestative during the last 9 months of treatment (the lower the dose of progestative, the greater the control of the cycle). Finally, it is interesting to observe that there is no correlation between the existence of an amenorrhea and the endometrial thickness at 6 months, measured by endovaginal ultrasound, and varying this thickness by an average of + 1.6 mm over the course of 6 months, in the two treatment groups.

TABLE VI TABLE VI PA = Systolic blood pressure PAD = Diastolic blood pressure TSH = Substituted Hormone Treatment

Claims (15)

1. Pharmaceutical hormonal compositions, characterized by having formed a combined estroprogestativa association that allows to simultaneously administer an estrogenic component and a progestative component, derived from the 19-norprogesterone associated or mixed with one or several non-toxic, inert, pharmaceutically acceptable excipients, destined to the oral administration.

2. Compositions are troprogestatives according to claim 1, characterized in that the estrogen is free or esterified estradiol, or equine conjugated estrogens.

3. Stroprogestative compositions according to claim 1 or 2, characterized in that the estrogen in them is an estradiol ester, and more particularly estradiol valerate.

4. Stroprogestative compositions according to one of claims 1 to 3, characterized in that the free or -esterified oestradiol, or an equine conjugated estrogen, is present in a dose ranging from 0.5 to 3 mg per unit dose.

5. Compositions estroprogestati as according to claim 4, characterized in that in them the free estradiol is present preferably in doses of 1.5 mg per unit dose.

6. Stroprogestative compositions according to claim 4, characterized in that in them the estradiol ester is preferably present in doses of 2 mg per unit dose.

7. Stroprogestative compositions according to claim 4, characterized in that in them equine conjugated estrogen is preferably present in doses of 0.625 mg per unit dose.

8. Stroprogestative compositions according to claim 1, characterized in that the progestative is nomegestrol acetate.

9. Stroprogestative compositions according to claim 1 and 8, characterized in that in them the nomegestrol acetate is present in a dose ranging from 1.5 to 3.75 mg per unit dose.

10. Stroprogestative compositions according to claim 9, characterized in that nomegestrol acetate is preferably present in a dose of 2.5 nm per unit dose.

11. Use of the estroprogestative mixture according to one of claims 1-10, characterized in that it is intended for the production of a medicament intended to treat estrogenic deficiencies in the menopausal woman.

12. Use of the estroprogestative mixture according to one of claims 1-10, characterized in that it is intended for the production of a medicament intended to prevent osteoporosis and cardiovascular diseases in menopausal women.

13. Use of the estroprogestative mixture according to one of claims 1-10, characterized in that it is intended for the production of a medicament intended to be administered to the woman during the period of ovarian activity and thus prevent ovulation.

14. Use of the estroprogestative mixture according to one of claims 1-10, characterized in that it is intended for the production of a medicament intended to be administered continuously or intermittently.

15. A method for the preparation of the new estroprogestative compositions according to one of claims 1-10, characterized in that it consists in mixing the active estrogenic ingredient and the progestative active principle with one or more inert, non-toxic, pharmaceutically acceptable excipients.