Note: Descriptions are shown in the official language in which they were submitted.
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1
Use of estradiol valerate or estradiol combined with
dienogest for the oral therapy of dysfunctional uterine
bleeding in the form of oral contraceptives
(Description)
Technical field of the invention
The present invention relates to the use of oestradiol
valerate or oestradiol in combination with 17a-
cyanomethyl-17(3-hydroxyoestra-4,9-diene-3-one (dieno-
gest), comprising a first stage, with two daily doses
of 3 mg of oestradiol valerate or of less than 3 mg of
oestradiol, a second stage, consisting of two sets of
daily doses, where the first set comprises five daily
doses of a combination of 2 mg of oestradiol valerate
or of less than 2 mg of oestradiol and 2 mg of
dienogest, and the second set comprises 17 daily doses
of a combination of 2 mg of oestradiol valerate or of
less than 2 mg of oestradiol and 3 mg of dienogest, a
third stage, with two daily doses of 1 mg of oestradiol
valerate or of less than 1 mg of oestradiol, and
another stage, with two daily doses of a
pharmaceutically acceptable placebo, in order to obtain
a multi-stage combined system with a total of 28 daily
doses for the oral treatment of dysfunctional uterine
bleeding in conjunction with oral contraception.
The total number of daily doses of this multi-stage
drug combination and pharmaceutically acceptable
placebo corresponds to 28 days.
Prior art
Dysfunctional uterine bleeding (DUB) is a frequent
clinical problem in gynaecology and accounts for up to
33% of outpatient gynaecological consultations [see
J.T. Awwad, T.L. Toth and I. Schiff: Abnormal uterine
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bleeding in the perimenopause, Int. J. Fertil., 38
(1993) pp. 261-269].
The symptoms of dysfunctional uterine bleeding are as
follows:
- menstrual periods lasting for more than seven
days
- menstrual periods occurring at intervals of 21
days or less, and
- abnormally intense menstrual bleeding, with a
discharge of 80 ml or more.
Dysfunctional uterine bleeding should only be diagnosed
as such after ruling out organic causes, such as myoma,
polyps and cancer.
DUB may occur both in ovulating and in non-ovulating
women. It is basically caused by an imbalance between
oestrogen-stimulated endometrial proliferation and the
gestagen-promoted conversion of the endometrium. If
the symptoms of dysfunctional uterine bleeding are due
to prolonged anovulation, the problem is often that the
endometrium is exposed to excessive oestrogenic
proliferation. This can lead not only to abnormal
bleeding but also to endometrial hyperplasia [see
Speroff et al., Clinical Gynecologic Endocrinology and
Infertility, 6th ed., Lippincott Williams & Wilkins,
1999].
Endometrial hyperplasia is a risk factor for cancer of
the endometrium.
In a previous trial, dysfunctional uterine bleeding was
treated with norethisterone in a daily dose of 3 x 5 mg
or with medroxyprogesterone acetate in a daily dose of
3 x 10 mg as a sole high-dose gestagen, each drug being
administered for 14 days from day 12 to day 25 of the
cycle in the case of six non-ovulating women, and for
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20 days from day 5 to day 25 of the cycle in the case
of ten ovulating women [see I.S. Fraser: Aust. N.Z. J.
Obstet. Gynaecol., 30, No. 4 (1990), pp. 353-356]. The
duration of the bleeding was reduced in both groups,
but the patients were not covered by reliable
contraception here.
A review article states that women have a low tolerance
to irregular and intense menstrual bleeding (see M.
Hickey, J. Higham and I.S. Fraser The Cochrane Library,
No. 3, 2004 M. Hickey, J. Higham and I.S. Fraser:
Progestogens versus oestrogens and progestogens for
irregular uterine bleeding associated with anovulation
(Cochrane Review) In: The Cochrane Library, No. 3,
2004, John Wiley & Sons Ltd., Chichester, England).
These authors have described the rationale for using
gestagens in order to promote the conversion of the
endometrium and therefore bring about more stable
menstrual cycles. The conclusion is however that the
efficacy of these treatments has not been confirmed in
randomized studies.
According to R. Steiner, dysfunctional uterine bleeding
can be treated inter alia with large doses of
gestagens, oestrogens or a combination of both [see. R.
Steiner: Schweiz. Rundsch. Med. Prax., 91, No. 46
(2000), pp. 1967-1974] . This author recommends the
oral use of 0.01 mg of ethinyl oestradiol and 2 mg of
norethisterone acetate for eight days in a decreasing
dose of 6, 5, 4, 3, 3, 3, 3, 3 per day. In addition to
this hormone treatment, Steiner advocates the treatment
of acute bleeding with tranexamic acid in a daily dose
of 4 x 2 tablets.
A. Davis has treated dysfunctional uterine bleeding by
the three-stage administration of ethinyl oestradiol
(EE) and norgestimate (NGM), followed by the
administration of a hormone-free placebo, over three
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28-day cycles [see A. Davis, Obstet. gynecol., 96, No.
6 (2000), pp. 913-920]. The regimen was such that the
ethinyl oestradiol dose remained constant at 0.035 mg
for 21 days, while the norgestimate dose was raised
over the 21 days (from 0.180 mg for the first seven
days to 0.215 for the next seven days, and then to
0.250 mg for the last seven days), and this was
followed by a seven-day hormone-free placebo course.
In this placebo-controlled study, 45% of the women
presented with excessive menstrual bleeding
(metrorrhagia, menometrorrhagia and polymenorrhoea)
and about 55% had diminished menstrual bleeding
(oligomenorrhoea). This second group showed the best
results in comparison with the placebo, with regular
withdrawal bleeding being induced. Oligomenorrhoea is
not necessarily a symptom of dysfunctional uterine
bleeding but is known to require treatment.
In its description, US Patent No. 6,797,282 discloses
in general that the long-term administration of oral
contraceptives over three months is suitable for the
treatment of menorrhagia, which is a type of
dysfunctional uterine bleeding.
Detailed description of the invention
The aim of the present invention is to offer a means
for the treatment of dysfunctional uterine bleeding
that in general reduces the amount of bleeding,
prevents the recurrence of dysfunctional uterine
bleeding, and provides reliable and well-tolerated oral
contraception at the same time.
The term "dysfunctional uterine bleeding" is used here
to denote one of the following conditions without an
organic cause: a menstrual period lasting for more
than seven days, uterine bleeding at intervals of 21
days or less, or intensified bleeding with a menstrual
discharge of 80 ml or more.
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The aim of the invention is achieved by the use of
oestradiol valerate or oestradiol in combination of
17a-cyanomethyl-173-hydroxyoestra-4,9-diene-3-one (die-
nogest) to provide a multi-stage combined preparation
for the oral treatment of dysfunctional uterine
bleeding, in conjunction with oral contraception. The
use of the oestradiol valerate - dienogest combination
comprises here a first stage, with two daily doses of
3 mg of oestradiol valerate or of less than 3 mg,
preferably 2.25 mg, of oestradiol, a second stage, with
two different sets of daily doses, where the first set
comprises five daily doses of a combination of 2 mg of
oestradiol valerate or of less than 2 mg, preferably
1.5 mg, of oestradiol and 2 mg of dienogest, and the
second set comprises 17 daily doses of a combination of
2 mg of oestradiol valerate or of less than 2 mg,
preferably 1.5 mg, of oestradiol and 3 mg of dienogest,
a third stage, with two daily doses of 1 mg of
oestradiol valerate or of less than 1 mg, preferably
0.75 mg, of oestradiol, and another stage, with two
daily doses of a pharmaceutically acceptable placebo.
The total number of daily doses of the multi-stage drug
combination and pharmaceutically acceptable placebo
corresponds to 28 days.
This regime is employed for at least one cycle, the
length of the treatment depending on the patient's
contraceptive requirements.
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Thus in one aspect, the present invention provides a multi-
stage combined preparation with a total of 28 daily doses
of oestradiol valerate in combination with 17a-cyanomethyl-
17(3-hydroxyoestra-4,9-diene-3-one (dienogest), comprising
a first stage, with two daily doses of 3 mg of
oestradiol valerate,
a second stage, with two sets of daily doses, where
the first set comprises five daily doses of a combination
of 2 mg of oestradiol valerate and 2 mg of dienogest, and
the second set comprises 17 daily doses of a
combination of 2 mg of oestradiol valerate and 3 mg of
dienogest,_
a third stage, with two daily doses of 1 mg of
oestradiol valerate, and another stage of two daily doses
of a pharmaceutically acceptable placebo,
for use in the oral treatment of dysfunctional uterine
bleeding, which is to be understood as meaning intensified
menstrual bleeding in which the blood loss is not less than
80 ml, without an organic cause, in conjunction with oral
contraception.
In another aspect, the present invention provides use of
oestradiol valerate in combination with 17a-cyanomethyl-
17(3-hydroxyoestra-4,9-diene-3-one (dienogest) in the
manufacture of a multi-stage combined preparation with a
total of 28 daily doses for use in the oral treatment of
dysfunctional uterine bleeding, which is to be understood
as meaning intensified menstrual bleeding in which the
blood loss is not less than 80 ml, without an organic
cause, in conjunction with oral contraception, wherein said
multi-stage combined preparation comprises:
a first stage, with two daily doses of 3 mg of
oestradiol valerate,
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a second stage, with two sets of daily doses, where
the first set comprises five daily doses of a combination
of 2 mg of oestradiol valerate and 2 mg of dienogest, and
the second set comprises 17 daily doses of a
combination of 2 mg of oestradiol valerate and 3 mg of
dienogest,
a third stage, with two daily doses of 1 mg of
oestradiol valerate, and another stage of two daily doses
of a pharmaceutically acceptable placebo.
In another aspect, the present invention provides a
commercial package comprising a multi-stage combined
preparation with a total of 28 daily doses of oestradiol
valerate in combination with 17a-cyanomethyl-17(3-
hydroxyoestra-4,9-diene-3-one(dienogest), comprising
a first stage, with two daily doses of 3 mg of
oestradiol valerate,
a second stage, with two sets of daily doses, where
the first set comprises five daily doses of a combination
of 2 mg of oestradiol valerate and 2 mg of dienogest, and
the second set comprises 17 daily doses of a
combination of 2 mg of oestradiol valerate and 3 mg of
dienogest,
a third stage, with two daily doses of 1 mg of
oestradiol valerate, and another stage of two daily doses
of a pharmaceutically acceptable placebo,
together with instructions for use thereof the oral
treatment of dysfunctional uterine bleeding, which is to be
understood as meaning intensified menstrual bleeding in
which the blood loss is not less than 80 ml, without an
organic cause, in conjunction with oral contraception.
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Investigation of the effect of the claimed formulation
A randomized double-blind placebo-controlled clinical study
was carried out in 180 women, aged 18-50, who had given
with their written informed consent to participate in the
study, presented with symptoms of dysfunctional uterine
bleeding, and in the case of whom
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an organic cause had been ruled out with the aid of
appropriate diagnostic methods, namely a transvaginal
ultrasound scan and the determination of the blood
hormone levels. In this group, 120 women were given
oestradiol valerate and dienogest in accordance with
the claimed combination, while 60 women received a
placebo instead.
The study comprised a 90-day run-in stage, in which the
severity of the bleeding irregularity was established,
then treatment proper over six menstrual cycles, and
finally a follow-up stage.
The bleeding intensity was determined quantitatively
with the aid of the alkaline haematin method, using
sanitary towels and the like, which the women collected
over the whole duration of the study and handed in at
the study centre. The duration of bleeding and the
length of the non-bleeding interval were determined
from daily entries made in an electronic diary.
