U.S. patent number RE37,564 [Application Number 09/503,952] was granted by the patent office on 2002-02-26 for composition for contraception.
This patent grant is currently assigned to Schering Aktiengesellschaft. Invention is credited to Bernd Dusterberg, Frank Ludicke, Jurgen Spona.
United States Patent |
RE37,564 |
Spona , et al. |
February 26, 2002 |
Composition for contraception
Abstract
A combination product for oral contraception is disclosed
comprising an estrogen selected from 2.0 to 6.0 mg of
17.beta.-estradiol and 0.020 mg of ethinylestradiol; and a gestagen
selected from .[.0.25 to 0.30.]. .Iadd.2.5 to 3.0 .Iaddend.mg of
drospirenone and .[.0.1 to 0.2.]. .Iadd.1 to 2 .Iaddend.mg of
cyproterone acetate, followed by 5 or 4 pill-free or sugar pill
days.
Inventors: |
Spona; Jurgen (Vienna,
AT), Dusterberg; Bernd (Berlin, DE),
Ludicke; Frank (Geneva, CH) |
Assignee: |
Schering Aktiengesellschaft
(Berlin, DE)
|
Family
ID: |
6506206 |
Appl.
No.: |
09/503,952 |
Filed: |
February 15, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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268996 |
Jun 30, 1994 |
5583129 |
|
|
Reissue of: |
742147 |
Oct 31, 1996 |
05824667 |
Oct 20, 1998 |
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Foreign Application Priority Data
|
|
|
|
|
Dec 22, 1993 [DE] |
|
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43 44 462 |
|
Current U.S.
Class: |
514/170 |
Current CPC
Class: |
A61K
31/57 (20130101); A61K 31/58 (20130101); A61P
15/18 (20180101); A61K 31/565 (20130101); A61K
31/567 (20130101); A61P 43/00 (20180101); A61P
15/08 (20180101); A61K 31/565 (20130101); A61K
2300/00 (20130101); A61K 31/57 (20130101); A61K
2300/00 (20130101); A61K 31/58 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
31/565 (20060101); A61K 31/57 (20060101); A61K
31/58 (20060101); A61K 031/57 (); A61K
031/565 () |
Field of
Search: |
;514/170 |
References Cited
[Referenced By]
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Foreign Patent Documents
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DE |
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0 253 607 |
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Jan 1988 |
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EP |
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0 398 460 |
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Nov 1990 |
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EP |
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0 491 415 |
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Jun 1992 |
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EP |
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0 491 438 |
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Jun 1992 |
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EP |
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640 343 |
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Mar 1995 |
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EP |
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WO 95/26730 |
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Oct 1995 |
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WO |
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WO 98/04246 |
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WO |
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WO |
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WO 98/04267 |
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Feb 1998 |
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WO |
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WO 98/04268 |
|
Feb 1998 |
|
WO |
|
Other References
GB. Melis, et al., Contraception, "A Comparative Study on the
Effects of a Monophasic Pill Containing Desogestrel Plus 20 .mu.g
Ethinylestradiol, a Triphasic Combination Levonorgestrel and a
Monophasic Combination Containing gest odene on Coagulatory
Factors", vol. 43, No. 1, pp. 23-30 (Jan. 1991), [including
abstract]. .
A.R. Genazzani, et al. (Ed), Progress in Gynecology and Obstetrics,
"Multicenter Clinical Trial on the new Oral Contraceptive
Containing 20 .mu.g Ethinylestradiol", Chapter 1, pp. 747-756,
(1990). .
Parke Davis package insert for Loestrin, Jun., 1993. .
W. Oelkers et al., "Journal of Clinical Endocrinology and
Metabolism", p. 73, pp. 837-842, (1991). .
W. Oelkers et al., "Acta Endocrinologica", Suppl. 4, p. 71, #97,
(1992) (Abstract Only). .
W. Oelkers et al., "Journal of Clinical Endocrinology and
Metabolism", 80, pp. 1816-1821, (1995). .
Elstein et al., Zentralblatt fur Gynakologie, 117, pp. 559-565,
(1995). .
Schillinger et al., "Arzneim.-Forsch.", 26, pp. 2242-2245,
(Abstract only), (1976). .
Huempel et al., Contraception, 16, pp. 199-216 (Abstract only),
(1977). .
Dusterberg et al., "Acta Obstet Gynecol Scand. Suppl.", 88, pp.
27-31, (1979). .
Leis et al., "Geburtshilfe Frauenheilkd", 39, pp. 54-57 (Abstract
only), (1979). .
Klebe et al, "Arch Gynecol", 234, pp. 113-120, (Abstract only)
(1983). .
Holdaway et al., "Acta Endocrinol", 109, 522-529, (Abstract only)
(1985). .
Kuhl et al., "Contraception", 30, pp. 467-482, (1985). .
Larsson-Cohn et al., "Acta Obstet Gynecol Scand", 65, pp. 125-128,
(Abstract only) (1986). .
Calaf-Alsina et al., "Obstet Gynecol", 69, pp. 255-258, (Abstract
only) (1987). .
Spona et al., "Gynecol Obstet Invest", 23, pp. 184-193, (1987).
.
Jandrain et al., "Am J. Obstet Gynecol", 163, pp. 378-381, (1990).
.
Porcile et al., "Fertility and Sterility", 55, pp. 877-881,
(Abstract only) (1991). .
Scheen et al., "Fertility and Sterility", 59, pp. 797-802,
(Abstract only) (1993). .
Kuhnz et al., "Contraception", 48, pp. 557-575, (1993). .
M. Elstein, "Advances in Contraception", 12, pp. 155-156, (1996).
.
Foidart et al., "Int'l J. Gynecol & Obstet", 46, Suppl. 3, p.
11, (1994). .
Oelkers et al., "Advances in Contraception", 7, Suppl. 3, pp.
195-206 (1991). .
Filshie and Guillebaud, eds., "Contraception: Science and
Practice", 69-93 (1989). .
J. Guillebaud, Br. J. Family Planning, 12 (Suppl.), 35-43 (1987).
.
Van Keep et al., eds. "The Controversial Climactoric", MTP Press
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German Pharmacopeia, 9th Edition, 1986--English Translation. .
PCT Search Report dated May 12, 1995..
|
Primary Examiner: Spivack; Phyllis G.
Attorney, Agent or Firm: Millen White Zelano &
Branigan
Parent Case Text
.[.This.]. .Iadd.This application is the parent of application Ser.
No. 09/504,084, both filed Feb. 15, 2000, both of which are
reissues of application Ser. No. 08/742,147, filed Oct. 31, 1996,
now U.S. Pat. No. 5,824,667, which .Iaddend.is a continuation of
the application Ser. No. 08/268,996 filed Jun. 30, 1994, now U.S.
Pat. No. 5,583,129.
Claims
We claim:
1. A combination product for oral contraception, comprising
(a) 23 or 24 dosage units, each containing an estrogen selected
from
>2.0 to 6.0 mg of 17.beta.-estradiol and
0.020 mg of ethinylestradiol;
and a gestagen selected from
.[.0.25 to 0.30.]. .Iadd.2.5 to 3.0 .Iaddend.mg of drospirenone
and
.[.0.1 to 0.2.]. .Iadd.1 to 2 .Iaddend.mg of cyproterone
acetate,
and
b) 5 or 4, respectively, active ingredient-free placebo pills or
other indications to show that the daily administration of the 23
or 24 dosage units respectively, is to be followed by 5 or 4,
respectively pill-free or placebo pill days.
2. A combination preparation for oral contraception according to
claim 1, wherein the estrogen is ethinylestradiol.
3. A combination preparation of claim 2, wherein the gestagen is
cyproterone acetate.
4. A combination preparation of claim 2, wherein the gestagen is
drospirenone..[.
5. A combination preparation according to claim 1, wherein the
estrogen is present in a dose of 20 .mu.g of ethinylestradiol or an
equivalent dose of 17.beta.-estradiol and the gestagen is present
in a dose equivalent to 75 .mu.g of gestadene..].
6. A combination preparation according to claim 1, which comprises
23 dosage units and 5 placebo pills or other indications to show
that no dosage unit or a placebo pill is administered during the
last 5 days of the menstrual cycle..[.
7. A combination preparation according to claim 1, which comprises
23 dosage units, each containing 20 .mu.g of ethinylestradiol and a
dose of cyproterone acetate or drospirenone equivalent to 75 .mu.g
of gestodene and 5 placebo pills or other indications to show that
no dosage unit or a placebo pill is administered during the last 5
days of the menstrual cycle..].
8. A combination preparation of claim 1, wherein the estrogen is
17.beta.-estradiol.
9. A combination preparation of claim 8, wherein the gestagen is
cyproterone acetate.
10. A combination preparation of claim 8, wherein the gestagen is
drospirenone..Iadd.
11. A combination preparation of claim 4, which comprises 23 dosage
units and 5 placebo pills or other indications to show that no
dosage unit or placebo pill is administered during the last 5 days
of the menstrual cycle..Iaddend..Iadd.
12. A combination preparation of claim 4, which comprises 24 dosage
units and 4 placebo pills or other indications to show that no
dosage unit or placebo pill is administered during the last 4 days
of the menstrual cycle..Iaddend..Iadd.
13. A combination product for oral contraception, comprising
(a) 23 or 24 daily dosage units, each containing
0.020 mg of ethinylestradiol, and
2.5 to 3.0 mg of drospirenone,
and
(b) 5 or 4, respectively, active ingredient-free placebo pills or
other indications to show that the daily administration of the 23
or 24 dosage units, respectively, is to be followed by 5 or 4,
respectively, pill-free or placebo pill days,
wherein each of the dosage units containing drospirenone contains
the same amount of drospirenone..Iaddend..Iadd.
14. A combination preparation of claim 13, which comprises 23
dosage units and 5 placebo pills or other indications to show that
no dosage unit or placebo pill is administered during the last 5
days of the menstrual cycle..Iaddend..Iadd.
15. A combination preparation of claim 13, which comprises 24
dosage units and 4 placebo pills or other indications to show that
no dosage unit or placebo pill is administered during the last 4
days of the menstrual cycle..Iaddend.
Description
DESCRIPTION
This invention relates to the common use of estrogen and gestagens
for the production of a combination preparation for oral
contraception and a corresponding pack containing this combination
preparation.
Combination preparations for oral contraception are already known,
for example, Femovan.RTM. [DE-PS 2 546 062] or Marvelon.RTM. [DE-OS
2 361 120]. These preparations consist of 21 active
ingredient-containing (estrogen/gestagen) dosage units and 7 active
ingredient-free coated tablets (sugar pills; placebos). The dose to
be administered daily is uniformly high in each case (so-called
single-phase preparations) and produces the desired contraceptive
effect in the entire intake period and in the intake pause or
during the intake of the placebos. In most preparations, a 7-day
interruption of the intake of active ingredient-containing dosage
units was considered necessary until quite recently to trigger a
reliable withdrawal bleeding and thus to achieve a satisfactory
cycle control.
Other preparations, which exhibit more than 21 dosage units
containing an estrogenic and progestational active ingredient, and
in which the intake pause is partially (Ijzerman, Pasquale) or
completely (Kuhl) bridged over by estrogen-containing dosage units.
In this case, it is possible that the synthetic estrogen
ethinylestradiol otherwise contained in oral contraceptives is
replaced partially or completely by a conjugated estrogen,
preferably estradiol.
A combination preparation for substitution therapy and
contraception for females before menopause (approximately starting
from the 40th year of life) is known from EP-A-0 253 607. This
combination preparation contains an estrogen from the group
17.beta.-Estradiol,
ethinylestradiol and
mestranol
as well as a gestagen from the group
levonorgestrel,
gestodene,
desogestrel,
3-ketodesogestrel and
norethindrone.
A thus selected composition is to offset hormonal irregularities in
the transition phase of premenopause and to help alleviate the
symptoms caused by the hormonal changeover of the female organism
in this phase. Such a composition simultaneously assures a
premenopausal female the contraceptive protection still necessary
at this age.
The development of new oral contraceptives for females of
reproductive age before premenopause was characterized during the
last twenty years above all by the reduction of the estrogen and
gestagen dosages.
The reduction of the daily hormone dose was connected with the
expectation to minimize the frequency of undesired side effects.
Epidemiological data collected in the meantime confirm the desired
trend toward better compatibility of lower-dosed preparations
relative to cardiovascular complications [(1.) Thorogood, M., Oral
Contraceptives and Cardiovascular Disease: An Epidemiologic
Overview; Pharmaceoepidemiology and Drug Safety, Vol. 2: 3-16
(1993); (2.) Gerstman, B. B.; Piper, J. M.; Tomita, D. K.;
Ferguson, W. J.; Stadel., B. V.; Lundin, F. E.; Oral Contraceptive
Estrogen Dose and the Risk of Deep Venous Thromboembolic Disease,
Am. J. E., Vol. 133, No. 1, 32-36 (1991); (3.) Lidegaard, O., Oral
contraception and risk of a cerebral thromboembolic attack: results
of a case-control study; BMJ Vol. 306, 956-63 (1993); (4.) Vessey,
M.; Mant, D.; Smith, A.; Yeates, D.; Oral contraceptives and venous
thromboembolism: findings in a large prospective study; BMJ, Vol.
292, (1986); (5.) Mishell, D. R., Oral Contraception: Past, Present
and Future Perspectives; Int. J. Fertil., 36 Suppl., 7-18
(1991)].
It is assumed that a correlation exists above all between the level
of the estrogen dose and the incidence of cardiovascular diseases.
But the maintenance of the contraceptive effectiveness stands in
the way of an extreme reduction of the daily estrogen dose.
Although the ovulation-inhibiting effect of the low-dosed oral
contraceptives is caused mainly by the gestagenic component, the
estrogenic component also makes a significant contribution to the
central inhibition action and to the ovarian suppression (ovulation
inhibition). Moreover, the daily estrogen dose must not fall below
the minimum dose ranges, so that a satisfactory cycle control can
be assured (Der Frauenarzt [The Gynecologist]; 34, 7: 793
(1993)].
The lowest estrogen dose contained in an oral contraceptive on the
market at this time is 20 .mu.g of ethinylestradiol, combined with
150 .mu.g of desogestrel (Mercilon). Although the cycle control of
this preparation is, as expected, somewhat poorer in comparison to
preparations with a higher estrogen dose, the high acceptance rate
of Mercilon indicates a small clinical relevance of this drawback.
But the observation, made identically in several studies, of a
lesser ovarial suppression of the preparation containing 20 .mu.g
of ethinylestradiol represents a clinically important problem.
Obviously with this very low estrogen dose, in the case of many
females, the maturation of follicles, which could be detected with
ultrasonic studies or hormonal studies, results [(6.) Lunell, N.
O.; Carstrom, K.; Zador, G.; Ovulation inhibition with a combined
oral contraceptive containing 20 .mu.g of ethinylestradiol and 250
.mu.g of levonorgestrel; Acta. Obstet. Gynecol. Scand. Suppl. 88:
17-21 (1979); (7.) Mall-Haefeli, M.; Werner-Zodrow, I.; Huber, P.
R.; Klinische Erfahrungen mit Mercilon und Marvelon unter
besonderer Berucksichtigung der Ovar-Funktion [Clinical Experience
with Mercilon and Marvelon under special consideration of the ovary
function]; Geburtsh. und Frauenheilk. [Obstetrics and Gynecology]
51, 35-38, Georg Thieme Verlag, Stuttgart-New York (1991); (8.)
Strobel, E., Behandlung mit oralen Kontrazeptiva [Treatment with
Oral Contraceptives]; Fortschr. Med. Vol. 110, No. 20 (1992); (9.)
Letter to Editor, Contraception 45: 519-521 (1992); (10.)
Teichmann, A. T.; Brill, K.; Can Dose Reduction of Ethinylestradiol
in OCs Jeopardize Ovarian Suppression and Cycle Control? Abstract
Book, VIIIth World Congress on Human Reproduction, Bali, Indonesia
(1993)].
The hormone determinations performed showed that functional
granulosa cells that secrete 17.beta.-estradiol are involved. Each
intake error in the case of females with clear ovarian activity,
thus with follicular maturations, can result in a quick increase of
gonadotropin production. The requirements for an ovulation would
thus be present. It is estimated that approximately one third of
females take oral contraceptives irregularly within one year of use
(Gynpress, Volume 1, No. 3, 1990). The risk of a pregnancy is
therefore high especially in the case of intake errors with the 20
.mu.g ethinylestradiol preparations.
The object of this invention is an improved single-phase
combination preparation for a female of reproductive age, who is
not yet in premenopause, containing an estrogen and gestagen in
each individual dosage unit, with the lowest possible estrogen
content in each individual dosage unit, but also with a low total
hormone content per administration cycle.
It has now been found that a pronounced ovarian suppression without
frequent follicular maturations with low daily estrogen dosage, low
total estrogen as well as low total hormone amount per
administration cycle can be achieved by the use of a composition
comprising an estrogen selected from
2.0 to 6.0 mg of 17.beta.-estradiol and
0.015 to 0.020 mg of ethinylestradiol,
and a gestagen selected from
0.05 to 0.075 mg of gestodene,
0.075 to 0.125 mg of levonorgestrel,
0.06 to 0.15 mg of desogestrel,
0.06 to 0.15 mg of 3-ketodesogestrel,
.[.0.1 to 0.3.]. .Iadd.1 to 3 .Iaddend.mg of drospirenone,
.[.0.1 to 0.2.]. .Iadd.1 to 2 .Iaddend.mg of cyproterone
acetate,
0.2 to 0.3 mg of norgestimate and
>0.35 to 0.75 mg of norethisterone.
for the production of a form of dosage for contraception for a
female of reproductive age, who has not yet reached premenopause,
by administration of the form of dosage for 23 or 24 days,
beginning on day one of the menstrual cycle (first day of menstrual
bleeding), followed by 5 or 4 pill-free or sugar pill days, during
a total of 28 days in the administration cycle.
The terms "premenopause" and "menopause" are used within the scope
of this invention in the meaning of the conventional definition,
see, for example, "The Controversial Climacteric," P. A. of Keep et
al., Ed., MTP press (1981), e.g., p. 9.
The daily hormone dose is kept to a very low level here, while the
usual 21-day intake is extended by two or three days. The remaining
5 or 4 days of a cycle are preferably bridged over by placebos, to
avoid intake errors, or by 5 or 4 intake-free days.
According to a preferred embodiment of this invention, this relates
to the use of a composition comprising an estrogen selected
from
>2.0 to 6.0 mg of 17.beta.-estradiol and
0.020 mg of ethinylestradiol;
and a gestagen selected from
>0.06 to 0.075 mg of gestodene,
>0.100 to 0.125 mg of levonorgestrel,
>0.10 to 0.15 mg of desogestrel,
>0.10 to 0.15 mg of 3-ketodesogestrel,
.[.0.25 to 0.30.]. .Iadd.2.5 to 3.0 .Iaddend.mg of
drospirenone,
.[.0.1 to 0.2.]. .Iadd.1 to 2 .Iaddend.mg of cyproterone
acetate,
0.2 to 0.3 mg of norgestimate and
0.50 to 0.75 mg of norethisterone
for the production of a form of dosage for contraception as
described above.
In addition, this invention relates to a combination product for
oral contraception, which comprises
a) 23 or 24 dosage units, each containing an estrogen selected
from
>2.0 to 6.0 mg of 17.beta.-estradiol and
0.020 mg of ethinylestradiol;
and a gestagen selected from
>0.06 to 0.075 mg of gestodene,
>0.100 to 0.125 mg of levonorgestrel,
>0.10 to 0.15 mg of desogestrel,
>0.10 to 0.15 mg of 3-ketodesogestrel,
.[.0.25 to 0.30.]. .Iadd.2.5 to 3.0 .Iaddend.mg of
drospirenone,
.[.0.1 to 0.2.]. .Iadd.1 to 2 .Iaddend.mg of cyproterone
acetate,
0.2 to 0.3 mg of norgestimate and
0.50 to 0.75 mg of norethisterone
and
b) 5 or 4 sugar pills or other indications to show that the daily
administration of 23 or 24 dosage units is to be followed by 5 or 4
pill-free or sugar pill days are to be followed.
Further embodiments according to the invention follow from the
features of the subclaims.
An especially preferred combination preparation according to this
invention comprises 23 dosage units, each containing 20 .mu.g of
ethinylestradiol and 75 .mu.g of gestodene and 5 sugar pills or
other indications to show that no dosage unit or a sugar pill is
administered during the last 5 days of the menstrual cycle.
The clinical study briefly described below was performed with
ethinylestradiol as estrogen and gestodene as representative of the
substance class of the gestagens possible according to the
invention. All possible combinations of ethinylestradiol or
estradiol according to the invention in the indicated dosages with
one of the selected gestagens in the indicated dosages as 23- or
24-day preparations exhibit the advantages according to the
invention.
The 23-day administration of 20 .mu.g of ethinylestradiol in
combination with 75 .mu.g of gestodene results, in comparison to
the 21-day administration, in a stronger ovarian suppression. In a
double-placebo, randomized study on healthy females with normal
ovarian function, groups of 30 test subjects each received the
combination preparation either once daily over 21 or 23 days as
well as placebos on 7 or 5 days (to assure the double-placebo
nature of the study).
The treatment began after an ovulatory, untreated preliminary cycle
on the first day of the menstrual bleeding of the subsequent cycle
and extended altogether over three treatment cycles. The study was
concluded with an untreated follow-up cycle.
The ovarian suppression was measured based on the level of the
endogenous 17.beta.-estradiol level and the size of follicular
structures. The results show that the 17.beta.-estradiol levels
with 23-day intake of the test preparation were significantly lower
(p<0.05) in comparison to the 21-day administration (FIG.
1).
In accordance with this finding, the number of females with
follicular maturations was also clearly higher in the 21-time
administration relative to the 23-time administration (FIG. 2).
The intake interval extended only by two days surprisingly produces
a significantly greater ovarian suppression with unchangingly low
daily doses. The combination preparation according to the invention
thus achieves the effectiveness previously known for preparations
with a daily content of 30 .mu.g of ethinylestradiol, although the
daily ethinylestradiol dose is 33% lower and also the total dose
per cycle is 27% lower.
The advantages of a combination preparation for oral contraception
to be administered over 23 days relative to the usual 21-day
preparations with less than 30 .mu.g of ethinylestradiol can be
characterized as follows:
1. A significantly lower frequency of follicular developments in
the user (maximum of 13% in females who received the 23-day
preparation relative to a maximum of 40% among those who received
the 21-day preparation). This means a greater contraceptive
reliability of the 23-day preparation, especially in the case of
previous intake errors. The danger of "breakthrough ovulations" is
smaller.
2. The occurrence of large follicles of more than a 30 mm diameter
is extremely rare. The development of ovarian cysts is improbable
with the 23-day preparation in comparison to the 21-day
preparation.
3. The recruitment of dominant follicles is suppressed in the
shortened intake-free pause.
4. The endogenous 17.beta.-estradiol levels are suppressed easily
controllably in the case of the majority of the users of the 23-day
preparation. Clinical symptoms such as breast tenseness,
premenstrual syndrome and menstrual disorders, which can be
attributed to increased and greatly fluctuating estrogen levels,
are observed with the 23-day preparation with clearly lower
frequency.
In summary, an intake, extended by two (or three) days, of
preparations containing 20 .mu.g of ethinylestradiol in each daily
dosage unit can produce the above-mentioned advantages, without the
daily dose having to be raised to the previously largely used level
of 30 .mu.g of ethinylestradiol.
The formulation of an estrogen and gestagen for the use according
to the intention or for a combination preparation according to the
invention takes place completely analogously as it is already known
for usual oral contraceptives with 21-day intake period of the
active ingredients, such as, for example, Femovan.RTM.
(ethinylestradiol/gestodene) or Microgynon.RTM.
(ethinylestradiol/levonorgestrel).
A pack containing a combination preparation according to the
invention is also designed analogously to packs for already known
oral contraceptives on the market with the variation that instead
of the usual 21 dosage units containing the active components, now
23 or 24 such dosage units and 5 or 4 sugar pills are present or
else contain other suitable indications that 5 or 4 days are to be
bridged over until continuation of the intake of active
ingredient-containing dosage units.
Moreover, reference is made to the statements made in EP-A 0 253
607, especially also to the statements there for determination of
equivalent amounts of ethinylestradiol and 17.beta.-estradiol, on
the one hand, and various gestagens, such as levonorgestrel,
desogestrel, 3-ketodesogestrel and gestodene, on the other
hand.
For further details for the determination of dose equivalents of
various gestagenic active ingredients, reference is made to
"Probleme der Dosisfindung: Sexualhormone" [Problems of
Dose-Finding: Sex Hormones]; F. Neumann et al. in
"Arzneimittelforschung" (Pharmaceutical Agent Research) 27, 2a,
296-318 (1977), as well as to "Aktuelle Entwicklungen in der
hormonalen Kontrazeption" [Current Developments in Hormonal
Contraception]; H. Kuhl in Gyn akologe" [Gynecologist) 25: 231-240
(1992).
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: Area with the 17.beta.-estradiol level in groups of 30
females, who are treated with an oral contraceptive (75 .mu.g of
gestodene+20 .mu.g of ethinylestradiol) in 21- or 23-day
administration interval over three cycles.
FIG. 2: Number of females in %, who showed follicular developments
(>13 mm diameter) with 21- or 23-day treatment with an oral
contraceptive (75 .mu.g of gestodene+20 .mu.g of
ethinylestradiol).
* * * * *