HK1077743B - Composition for contraception - Google Patents

Description

Contraceptive composition

The application is a divisional application of Chinese patent application with the filing date of 1994, 12-month and 22-day, the filing number of 94194888.9 and the title of the invention being "contraceptive composition".

The invention relates to the co-use of an estrogen and a progestogen in the preparation of an oral monophasic combination for contraception and a corresponding package containing the monophasic combination.

Oral combination preparations for contraception are known, for example from Femovan ® (DE-PS2546062) or Marvelon ® (DE-OS 2361120). The preparation consisted of 21 dosage units containing the active substance (estrogen/progestin) and 7 coated tablets (dragees; placebo) without active substance. The daily dose is the same (so-called monophasic preparation) and the desired contraceptive effect is achieved during the entire dosing and withdrawal phase or during placebo. Until recently it was thought necessary for most formulations to stop taking 7 days of active-containing dosage units in order to cause reliable withdrawal bleeding and thus achieve satisfactory menstrual control.

Other preparations have more than 21 dosage units of active substance containing estrogen and progestin and the withdrawal period of the preparation is bridged partly (Ijzerman, Pasquale) or completely (Kuhl) by the dosage units containing estrogen. In which the synthetic estrogen ethinyl estradiol normally contained in oral contraceptives may be partially or completely replaced by conjugated estrogens, preferably estradiol.

Low-dose triphasic combination preparations for hormonal contraception, containing 21 to 24 or 24 daily estrogen/progestin dosage units, are described in EP-AS 0491438 and 0491415. According to the teaching of EP-A0491438, administration is first started on the first day of the menstrual cycle to complement the placebo for the usual 28-day cycle or there is first a no-administration interval without any contraceptive steroid.

EP-A-0253607 describes ｃA combination for substitution therapy and contraception in premenopausal women (from about age 40). The combined preparation comprises an estrogen selected from the group consisting of

17 beta-estradiol in the form of a salt,

ethinyl estradiol and

ethinyl estradiol methyl ester

And a progestogen consisting of

The dosage of the levonorgestrel is as follows,

gestodene

Deoxynorethindrone

3-ketodeoxynorethindrone and

norethindrone.

The composition is selected to regulate the hormonal irregularities of the perimenopausal phase and to help relieve pain caused by hormonal adjustments in the body of women during this period. At the same time, the composition ensures that women need contraception in this age group before menopause.

The new oral contraceptives developed for women of childbearing age before menopause in the last 20 years are characterized above all by a reduced dosage of estrogen and progestin.

Reducing the daily hormone dose is intended to minimize the incidence of unwanted side effects. The epidemiological data presented during this period confirm the ideal trend of better tolerability of low-dose formulations in relation to Cardiovascular complications [ (1) thyroid m. organic contexts and Cardiovascular diseases: an epidemic overview; pharmacopepidemiology and Drug Safety, Vol.2: 3-16 (1993); (2.) Gerstman B, Piper J M, Tomita D K, Ferguson W J, Stadel B V, Lundin F E; oral contextual essence Dose and the Risk of Deep Venous Thromboembolic Disease, Am J E, Vol.133, No1, 32-36 (1991); (3.) Lidegaard O, Oral conjugation and rist of aceberbarl thrombo acid attack: a results of a case-control study; BMJVol 306, 956-63 (1993); (4.) Vessey M, Man D, Smith A, YeatesD, Oral concepts and venous thromboemolism: findings in individual productive study; BMJ, Vol 292, (1986); (5.) Mishell D R, Oralcontraception: past, Present, and Future Perspectives; int J Fertil, 36suppl., 7-18(1991) ].

It is recognized that, in the first place, the magnitude of estrogen dosage is correlated with the incidence of cardiovascular disease. However, achieving contraceptive efficacy is contradictory to a large reduction in daily estrogen dosage. Although the ovulation-inhibiting effect of low-dose oral contraceptives is mainly caused by the progestogenic component, the estrogenic component also plays an important role in central inhibition and ovulation inhibition. Furthermore, in order to ensure satisfactory menstrual control, the daily estrogen dose must not fall below the limit dose range (Der Frauenarrzt; 34, 7: 793 (1993)).

The smallest estrogen dose currently marketed for inclusion in oral contraceptives is 20 μ g ethinylestradiol mixed with 150 μ g deoxynorethindrone (Mercilon). Although the menstrual control effect of this formulation is less than ideal compared to formulations with large estrogen doses, the widespread acceptance of Mercilon suggests that the clinical effect of this disadvantage is minimal. However, it is a consistent conclusion from many experiments that the ovulation inhibitory effect of a preparation containing 20. mu.g of ethinylestradiol is low, which is a significant clinical problem. It is clear that if very low estrogen doses are used this will lead to follicle maturation in many women, as can be confirmed by ultrasound or hormonal tests. * (6.) Lunell N O, Carlstrom K, Zador G, insulation inhibition with a combined organic confinement 20 μ G ethinylRadiationand 250 μ G levonorgestrel; acta Obstet Gynecol Scand supply.88: 17-21 (1979); (7.) Mau-Haefeli M, Werner-Zodorw, I, Huber P R, Klinische Erfahrung nit Mercilon und Marvelon unit besonderer Berucksichting der Ovar-Funktion, Gebursh. und Frauenheilk.51, 35-38, Georg Thieme Verlag, Stuttgart-New York (1991); (8.) Strobel E, Behandlung mit oralen Kontrazeptiva; fortschr.med.110jg.nr.20 (1992); (9.) Letter to Editor, content 45: 519-; (10.) Teichmann A T, Brill K, Can Dose Reduction of Ethyl esterradiol in OCs joperadidze Ovarian depression and Cycle Con-trolAbstract Book, Vlllh World consistency on Human Reproduction, Bali, lndonsia (1993).

Hormone tests performed showed that follicle granules secreting 17 β -estradiol were involved. In those women with significant ovulatory activity, i.e. follicle maturation, every medication error accelerates the increase in gonadotropin secretion. Therefore, the conditions for ovulation are met. It is estimated that oral contraceptives are irregular in about one third of women during the year of use (Gynpress, i.jahrging, nr.3, 1990). The risk of pregnancy is therefore great, in particular in the case of administration errors when 20 μ g of the ethinylestradiol preparation is administered.

The object of the present invention is to provide an improved monophasic combination preparation for women of childbearing age who are not yet in the perimenopause phase, which preparation contains an estrogen and a progestogen in each individual dosage unit, the estrogen content in each dosage unit being as low as possible and the total hormone content in each dosage cycle being as low as possible.

It was found that significant ovulation inhibition without frequent follicular maturation can be achieved with a low daily estrogen dose and low total estrogen and low total hormone levels per dosing cycle using a composition comprising an estrogen selected from the group consisting of:

2.0 to 6.0mg of 17 beta-estradiol and

0.015 to 0.020mg ethinyl estradiol;

the composition contains a progestogen selected from the group consisting of

0.05 to 0.075mg of gestodene

0.075 to 0.125mg of Levonorgestrel (Levonorgestrel),

0.06 to 0.15mg of deoxynorethindrone,

0.06 to 0.15mg of 3-ketodeoxynorethindrone (3-Ketodesogestrel),

1 to 3mg Drospirenone (Drospirenone),

1 to 2mg of cyproterone,

0.2 to 0.3mg of norgestimate,

> 0.35 to 0.75mg norethindrone,

a dosage form for contraception is prepared from the composition for a woman of child bearing age who has not yet reached the pre-menopause stage, the dosage form having a dosing period of 23 or 24 days in a 28 day dosing cycle, starting on the first day of the cycle (first day of menstrual bleeding) and taking no pills or dragees for the next 5 or 4 days.

The amount of estrogen/progestin in each dosage form should be constant throughout the 23 or 24 days.

The concepts "pre-menopause" and "menopause" as used in The present invention are defined generally, see "The contextual clinical", p.a. van Keep et al, ed., MTP Press (1981), z.b.s, 9.

Daily hormone doses are kept to a minimum while the usual 21 day dosing period is extended by 2 or 3 days. To avoid dosing errors, the remaining 5 or 4 days of a cycle were bridged with placebo or 5 or 4 days were left undrawn.

According to a preferred embodiment of the invention, this relates to the use of a composition comprising an estrogen selected from the group consisting of estrogen for the preparation of the above-mentioned contraceptive dosage forms.

> 2.0 to 6.0mg of 17 beta-estradiol and

0.020mg of ethinyl estradiol;

the composition comprises a progestogen selected from the group consisting of,

More than 0.06 to 0.075mg of gestodene,

0.100 to 0.125mg of levonorgestrel,

> 0.10 to 0.15mg of deoxynorethindrone,

> 0.1 to 0.15mg of 3-ketodeoxynorethindrone,

2.5 to 3.0mg of drospirenone,

1 to 2mg of cyproterone,

0.2 to 0.3mg of norgestimate and

0.50 to 0.75mg norethindrone.

In a preferred embodiment of the invention the estrogen is ethinyl estradiol at a dose of 20 μ g or an equivalent dose of 17 β -estradiol and the progestin is gestodene at a dose of 75 μ g or an equivalent dose of levonorgestrel, cyproterone or drospirenone.

Furthermore, the invention relates to a monophasic mixed product for oral contraception, which comprises

(a)23 or 24 dosage units, each containing an estrogen > 2.0 to 6.0mg 17 beta-estradiol and a pharmaceutically acceptable carrier selected from the group consisting of

0.020mg of ethinyl estradiol;

and contains a progestogen selected from

More than 0.06 to 0.075mg of gestodene,

0.100 to 0.125mg of levonorgestrel,

> 0.10 to 0.15mg of deoxynorethindrone,

> 0.10 to 0.15mg of 3-ketodeoxynorethindrone,

2.5 to 3.0mg of drospirenone,

1 to 2mg of cyproterone,

0.2 to 0.3mg of norgestimate and

0.50 to 0.75mg norethindrone and

(b) 5-granule or 4-granule dragees or other indicia to indicate that no or no pills are taken for the next 5 or 4 days after daily dosing of 23 or 24 dosage units.

In a preferred embodiment of the invention the estrogen contained in the monophasic combination preparation is ethinyl estradiol at a dose of 20 μ g or an equivalent dose of 17 β -estradiol and the progestogen is gestodene at a dose of 75 μ g or an equivalent dose of levonorgestrel, cyproterone or drospirenone.

In another preferred embodiment of the invention, the monophasic combination contains 23 dosage units and 5 dragees or other indicia to indicate that no dosage units or dragees are taken on the last 5 days of the menstrual cycle.

In a further preferred embodiment of the invention, the monophasic combination preparation contains 23 dosage units each containing 20 μ g of ethinylestradiol and 75 μ g of gestodene and contains 5 dragees or other indication that no dosage units or dragees are to be taken during the last 5 days of the menstrual cycle.

Particularly preferred combination preparations according to the invention have 23 dosage units.

Particularly preferred is a single phase combination preparation comprising 23 dosage units, each dosage unit of the preparation containing 20g ethinylestradiol and 75g gestodene, and 5 dragees or other indicia to indicate that no dosage units or dragees are to be taken during the last 5 days of the menstrual cycle.

The clinical studies outlined below were performed using ethinyl estradiol as the estrogen and gestodene as representative of the possible progestogenic species of the present invention.

Administration of 20 μ g ethinylestradiol mixed with 75g gestodene for 23 days will achieve a stronger ovulation inhibitory effect than administration on 21 days. In a double-blind, randomized study of healthy, anovulatory women, the women receiving the study were divided into 30 groups and the groups were given the combination either once daily for 21 days or once daily for 23 days and placebo for 7 or 5 days (to ensure the double-blind nature of the study).

Treatment was initiated on the first day of menstrual bleeding following the previous cycle of untreated ovulation and continued for a total of 3 treatment cycles. Finally, the test was terminated with an untreated cycle.

The ovulation inhibition is determined by the endogenous 17 beta-estradiol content and the size of the follicle structure. The results of the measurements show that the 17 β -estradiol content was significantly reduced (p < 0.05) when the test preparation was taken on day 23 compared to the case of the 21-day administration (fig. 1).

In accordance with the examination results, the number of women with mature follicles was much larger than that of the women with 21 administrations (FIG. 2).

The significantly enhanced ovulation inhibition can be achieved by a 2-day prolongation of the dosing period with the daily dose remaining low. The combined preparation of the invention can thus achieve the effects known hitherto for preparations with a daily content of 30 μ g ethinylestradiol, despite a daily ethinylestradiol dose that is 33% lower and a total dose per cycle that is 27% lower.

The advantages of the 23-day combination formulation for oral contraception compared to the usual 21-day formulation with less than 30 μ g of ethinyl estradiol are as follows:

1. the probability of follicular maturation in the subject is significantly lower (maximum 13% in women taking the preparation for 23 days and maximum 40% in women taking the preparation for 21 days). This means that the contraceptive reliability of the 23-day formulation is high, especially in the presence of the above-mentioned medication errors. The risk of "breakthrough ovulation" is low.

2. The appearance of large ova with a diameter of more than 30mm is extremely rare. In contrast to the 21-day preparation, the formation of oocysts was not possible with the 23-day preparation.

3. The supplementation of the dominant ova is also inhibited during a short intermittent period of administration.

4. The suppression of endogenous 17 β -estradiol levels is better controlled in the vast majority of women taking the 23-day formulation. In the case of the 23-day preparation, the incidence of clinical symptoms such as chest distension, premenopausal syndrome and menstrual disorder, which are caused by increased and fluctuating estradiol levels, is significantly reduced.

In summary, an extended period of 2 (or 3) days for the administration of a formulation containing 20 μ g of ethinylestradiol per daily dosage unit would provide the advantages described above without having to increase the daily dosage to the extent of 30 μ g of ethinylestradiol which has been widely used to date.

The above advantages, in particular a more effective suppression of follicular maturation, are achieved with a single phase combined preparation according to the invention. Compared to multi-phase formulations, single-phase formulations are characterized by various advantages:

1. simple and convenient to manufacture

2. The pill confusion caused by the unnoticed taking sequence can be avoided.

3. Delay of menstrual period is easily achieved.

4. The user can easily understand the description of the administration

5. The package or housing containing the dosage units need not be provided with a label to give notice of the order of administration.

The formulation of the estrogen and progestin for use in the formulations of the invention or combinations of the invention is exactly the same as is known for general purpose oral contraceptives such as Femovan ® (ethinylestradiol/gestodene) or Microgynon ® (ethinylestradiol/levonorgestrel) for a 21 day active agent dosing cycle.

The packaging containing the combination of the invention is likewise similar in construction to known, commercially available packages for oral contraceptives, with the difference that instead of the usual 21 dosage units containing the active ingredient, 23 or 24 of these dosage units are mixed with 5 or 4 pellets or other suitable instructions which do not necessarily require bridging of the 5 or 4 pellets before further administration of the active-containing dosage unit.

Furthermore, reference is made to the description made in EP-A0253607, in particular to the description for determining, on the one hand, an equivalent amount of ethinylestradiol and 17 β -estradiol and, on the other hand, an equivalent amount of a variety of progestogens, such as levonorgestrel, deoxynorethindrone, 3-ketodeoxynorethindrone and gestodene.

For the determination of equivalent dosages of different progestagen active substances, see "protermeder dossisfindung: sexualhormon "; neumann et al in "Arzneimittelforkung" (Drug Research)27, 2a, 296-activated 318(1977) wind auf "Aktuelle Entwhickengen in der hormonen Kontzeptop", H.Kuhlin "Gynn-kologe" 25: 231-240(1992).

Claims (16)

1. Use of a composition for the manufacture of a dosage form for contraception in a woman of childbearing age not yet described to the pre-menopause stage, the composition comprising an estrogen selected from the group consisting of,

2.0 to 6.0mg of 17 beta-estradiol and

0.015 to 0.020mg ethinyl estradiol;

and contains a progestogen selected from

0.05 to 0.075mg of gestodene,

0.075 to 0.125mg of levonorgestrel,

0.06 to 0.15mg of deoxynorethindrone,

0.06 to 0.15mg of 3-ketodeoxynorethindrone,

1 to 3mg of drospirenone,

1 to 2mg of cyproterone,

0.2 to 0.3mg of norgestimate and

> 0.35 to 0.75mg norethindrone,

the dosage forms are administered for 23 or 24 days in a total of 28 days of the dosing cycle, starting on the first day of menstruation and then for 5 or 4 days without taking pills or dragees.

2. Use according to claim 1 wherein the estrogen is ethinyl estradiol.

3. Use according to claim 1, wherein the estrogen is 17 β -estradiol.

4. Use according to claim 1, 2 or 3, wherein the progestogen is a gestodene.

5. Use according to claim 1, 2 or 3, wherein the progestogen is levonorgestrel.

6. Use according to claim 1, 2 or 3, wherein the progestogen is cyproterone or drospirenone.

7. Use according to claim 1, wherein the dosage form contains an estrogen selected from the group consisting of > 2.0 to 6.0mg 17 β -estradiol and

0.020mg of ethinyl estradiol;

and contains a progestogen selected from,

More than 0.06 to 0.075mg of gestodene,

0.100 to 0.125mg of levonorgestrel,

> 0.10 to 0.15mg of deoxynorethindrone,

> 0.10 to 0.15mg of 3-ketodeoxynorethindrone,

2.5 to 3.0mg of drospirenone,

1 to 2mg of cyproterone,

0.2 to 0.3mg of norgestimate and

0.50 to 0.75mg norethindrone.

8. Use according to claim 1, wherein the estrogen is ethinylestradiol at a dose of 20 μ g or an equivalent dose of 17 β -estradiol and the progestin is gestodene at a dose of 75 μ g or an equivalent dose of levonorgestrel, cyproterone or drospirenone.

9. Monophasic mixed preparations for oral contraception comprising

(a)23 or 24 dosage units, each dosage unit containing an estrogen selected from the group consisting of > 2.0 to 6.0mg 17 beta-estradiol and

0.020mg of ethinyl estradiol;

and a progestogen selected from

More than 0.06 to 0.075mg of gestodene,

0.100 to 0.125mg of levonorgestrel,

> 0.10 to 0.15mg of deoxynorethindrone,

> 0.1 to 0.15mg of 3-ketodeoxynorethindrone,

2.5 to 3.0mg of drospirenone,

1 to 2mg of cyproterone,

0.2 to 0.3mg of norgestimate and

0.50 to 0.75mg norethindrone.

And comprises

(b)5 or 4 dragees or other designations to indicate that no or no pills are taken for the next 5 or 4 days after the daily administration of 23 or 24 dosage units.

10. Monophasic combination preparation for oral contraception according to claim 9, wherein the estrogen is ethinyl estradiol.

11. A single-phase combination preparation according to claim 9 or 10, wherein the progestogen is a gestodene.

12. A single-phase combination preparation according to claim 9 or 10, wherein the progestogen is levonorgestrel.

13. A single-phase combination preparation according to claim 9 or 10, wherein the progestogen is cyproterone or drospirenone.

14. A monophasic combination preparation according to claim 9, wherein the estrogen is ethinylestradiol at a dose of 20 μ g or an equivalent dose of 17 β -estradiol and the progestin is gestodene at a dose of 75 μ g or an equivalent dose of levonorgestrel, cyproterone or drospirenone.

15. A single phase combination preparation according to any one of claims 9 to 13, which contains 23 dosage units and 5 dragees or other designations to indicate that no dosage units or dragees are to be taken on the last 5 days of the menstrual cycle.

16. A single phase combination preparation according to claim 9, which preparation comprises 23 dosage units each comprising 20 μ g of ethinylestradiol and 75 μ g of gestodene and contains 5 dragees or other indication indicating that no dosage unit or dragee was taken during the last 5 days of the menstrual cycle.