Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-03-17
2004-12-14
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S170000, C514S171000, C514S177000, C514S178000, C514S182000, C552S625000
Reexamination Certificate
active
06831073
ABSTRACT:
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.; Gynècologie. 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, 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 estrogenotherapy (WHITEHEAD et al., J. reprod. Med, 1982, 27: 539-548, PATERSON et al, Br Med J, Mar. 22, 1980, 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 of the micronized progesterone, didrogesterone (FOX H., BAAK J., VAN DE WEIJER P., AL-AZZAWI E., PATERSON M., JOHNSON A., MICHELL G., BARLOW D., FRANCIS R., 7th International Congress on the Menopause, Stockholm, Jun. 20-24, 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., 7th International Congress on the Menopause, Stockholm, Jun. 20-24, 1993, abstr 40) which were used at doses of 100, 10 and 5 mg/day respectively, with encouraging results on the clinical and endometrial level. Among the progestatives, nomegestrol acetate appeared to be one of the most effective. Nomegestrol acetate is a non-androgenic progestative derived 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 multicentre study on 150 women for one year (THOMAS J. L., BERNARD A. M., DENIS C., 7th International Congress on the Menopause, Stckholm, Jun. 20-24, 1993, abstr 372).
The absence of hyperplasia was confirmed in a study where the nomegestrol acetate was administered at the same dose, 14 days per cycle, in women treated with percutaneous estradiol (BERNARD A. M. et al. Comparative evaluation of two percutaneous estradiol gels in combination with nomegestrol acetate in hormone replacement therapy. XIV World Congress of Gynecology and Obstetrics, FIGO, Montreal, Sep. 24-30, 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 (BLRKAUSER M. ET AL; Substitution hormonale: une indication bien posèe et des schèmas de traitement individuels sont dèterminants pour le succès du traitement, Mèd. 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 by oral route. The estrogen used is free or esterified estradiol, or conjugated equine estrogens which are presented according to a formulation which is active by oral route and in particular estradiol valerate. Nomegestrol acetate and free or esterified estradiol or conjugated equine 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 a 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 in the correction of estrogenic deficiencies, in the prevention of osteoporosis and cardiovascular illnesses in post-menopausal women, or in stopping ovulation in women during their period of ovarian activity.
The compositions according to the invention based on nomegestrol and free or esterified or equine conjugated estrogens are administered in a continuous fashion 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 quantity of free or esterified estradiol or conjugated estrogens ranging from 0.5 to 3 mg. Preferably, the optimal formulations contain 2.5 mg of nomegestrol acetate combined with: either 1.5 mg of free estradiol or 2 mg of estradiol ester or 0.625 mg of conjugated equine 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 of the hormonal combination is capable of stopping ovulation and of exercising a contraceptive effect insofar as it has been proved that nomegestrol is capable of stopping the ovulation peak of LH and FSH, starting from 1.25 mg/day (BAZIN B. et al, Effect of nomegestrol acetate, a new 19-norprogesterone derivative on pituitary ovarian function in women. Br. J. Obstet. Gynaecol., 1987, 94: 1199-1204). When the hormonal combination is given for a contraceptive purpose, the aim of nomegestrol acetate is to stop ovulation and for the estrogenic compound to compensate for hypoestrogenia and ensure a 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 mi
Lanquetin Michel
Paris Jacques
Thomas Jean-Louis
Dennison Schultz Dougherty & MacDonald
Laboratoire Theramex
Qazi Sabiha
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