Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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CONTRACEPTIVE PHARMACEUTICAL PREPARATION
Description
Field of the invention
The invention relates to a pharmaceutical composition
comprising dienogest in an amount which on
administration of the composition corresponds to a
daily dose unit of 1.5 mg or 2.0 mg and comprising
ethinylestradiol in an amount which on administration
of the composition corresponds to a daily dose unit of
0.015 mg or 0.020 mg, together with one or more
pharmaceutically acceptable carriers for at least 21
daily dose units.
The invention further relates to a pharmaceutical
product for oral contraception comprising 1.5 mg of
17a-cyanomethyl-l7-(3-hydroxyestra-4,9-dien-3-one
(dienogest) and 0.015 or 0.020 mg of 17a-
ethinylestradiol (ethinylestradiol) or 2.0 mg of
dienogest and 0.015 mg of ethinylestradiol, together
with one or more pharmaceutically acceptable carriers
for at least 21 daily dose units of a 28-day menstrual
cycle.
General prior art
Oral contraceptive compositions consisting of a
progestogen component and of an oestrogen component
were marketed for the first time in the early 1960s.
Three essential properties characterize the profile of
the "contraceptive pill": contraceptive reliability,
very good cycle control and a minimum of side effects.
The contraceptive reliability derives primarily from
the progestogen component. The effect of this is to
inhibit gonadotropin release in the pituitary and to
inhibit ovulation. In addition, the peripheral effect
of the progestogen on the endometrium results in a
reduced probability of implantation of the fertilized
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ovum; on the cervix results in secretion of viscous
secretion which reduces the sperm in the uterus. A
peripheral effect on the fallopian tubes should also be
noted.
The oestrogen component enhances the anovulatory effect
of the progestogen and is responsible for acceptable
cycle control. Since the introduction of hormonal
contraceptives, research has been directed to
developing products which, while the contraceptive
reliability and cycle control remain good, reduces
unwanted side effects such as, for example, arterial
and venous thromboses and effects on carbohydrate and
lipid metabolism. Such side effects are known in
particular for first-generation oral contraceptives
which comprised a higher content of progestogen and
oestrogen than was necessary for contraception.
WO 98/004269 discloses inter alia the oral
administration of a combination of 250 pg-4 mg of
dienogest and 10 pg-20 pg of ethinylestradiol for
contraception. In order to achieve the substantial
reduction in the total contraceptive steroid
administered per cycle, while retaining a good cycle
control, the low-dose progestogen/oestrogen combination
is administered for 23 to 25 days of a 28-day menstrual
cycle. However, the patent does not disclose results
and information proving that the inventive idea is also
successful.
WO 01/015701 claims a pharmaceutical composition also
for oral administration on 21 days of a 28-day
menstrual cycle, which comprises drospirenone and
ethinylestradiol, inter alia also in low dose, the
drospirenone being present in micronized form.
Particular attention is directed in this case to rapid
release of the steroids.
It is known from the specialist and patent literature
that steroidal active ingredients are metabolized by
the cytochrome P 450 enzyme system which is also at the
same time responsible for the breakdown of a number of
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medicinal products. Certain medicinal products, such as
barbiturates, antiepileptics and selected virostatics,
induce this enzyme system and reduce the concentration
of the steroid active ingredients in the blood. In
order to compensate for this, it would really be
necessary for the progestogen content to be increased
or at least maintained, and not reduced, which induces
the side effects identified above, however.
Detailed disclosure of the invention
The invention is based on the object of indicating a
pharmaceutical composition based on dienogest and
ethinylestradiol, in which the total steroidal dosage
is reduced, at the same time the balance between
dienogest and ethinylestradiol is retained, the
contraceptive efficacy and a good cycle control is
attained and side effects such as, for example,
additional reduction in the active ingredient levels in
the blood on concomitant intake of further medicinal
products is compensated.
This object is achieved according to the invention by a
pharmaceutical composition comprising dienogest in an
amount which on administration of the composition
corresponds to a daily dose unit of 1.5 mg or 2.0 mg
and comprising ethinylestradiol in an amount which on
administration of the composition corresponds to a
daily dose unit of 0.015 mg or 0.020 mg, together with
one or more pharmaceutically acceptable carriers for at
least 21 daily dose units.
The object is also achieved according to the invention
by a pharmaceutical product for oral contraception
comprising 1.5 mg of 17a-cyanomethyl-17-R-hydroxyestra-
4,9-dien-3one (dienogest) and 0.015 mg or 0.020 mg of
17a-ethinylestradiol (ethinylestradiol) or 2.0 mg of
dienogest and 0.015 mg of ethinylestradiol, together
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with one or more pharmaceutically acceptable carriers
to form at least 21 daily dose units of a 28-day
menstrual cycle.
It is clear in this connexion from the wording of Claim
2 that the pill users take the pill for at least 21
days and interpolate 7 pill-free days. The statement
"21 days of a 28-day menstrual cycle" is to be equated
in its significance and extent in the field of hormonal
contraception with the statement "21 days of hormone
pill + 7 pill-free days" in the field.
The dienogest/ethinylestradiol active ingredient
combination is incorporated together with one or more
pharmaceutically acceptable carriers or medicinal
product carriers in the pharmaceutical product.
Embodiments are pharmaceutical products in the form of
tablet preparations. The pharmaceutical product in this
case is a film-coated tablet is consisting of a tablet
core with a dienogest content and of an active
ingredient-containing film coating with a dienogest
content and a total ethinylestradiol content.
In a particular embodiment of the pharmaceutical
product according to the invention, there is delayed
dissolution of the proportion of dienogest of at least
30%, preferably 50%, of dienogest from the tablet core
after more than 30 min, and dissolution of the
proportion of dienogest and of the total
ethinylestradiol content of at least 75% in a maximum
of 45 min, preferably 70% in 30 min, from the film
coating, as determined by the dissolution test using
water at 37 C as dissolution medium and a stirring
speed of 50 rpm.
It is also conceivable that, together with the
proportion of dienogest, there is delayed release of a
proportion of ethinylestradiol from the total
ethinylestradiol content, preferably from the tablet
core.
The number of daily dose units in suitable embodiments
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of the pharmaceutical product according to the
invention can amount to 22, 23, 24 or 25 daily dose
units, and the number of active ingredient-free daily
dose units then amounts to 6, 5, 4 or 3 in the 28-day
menstrual cycle.
It has been found that surprisingly the partial delayed
dissolution (release) of the dienogest from the tablet
preparations enables the dosage of the
dienogest/ethinylestradiol active ingredient
combination to be in the low range according to the
invention.
The appended figure 1 shows curves according to the
corresponding release profiles of a film-coated tablet
with the total dose of 1.5 mg of dienogest and 0.015 mg
of ethinylestradiol. The release of proportions of
dienogest in two phases is clearly evident, i.e. a slow
(delayed) release and a non-slow (rapid) release - in
this regard, see the broken-line markings at 30 min and
45 min. It is furthermore evident further that after 30
min and 45 min have elapsed, the proportion of
dienogest which has undergone slow (delayed) release is
greater than 30%, preferably 50%, as already explained.
A release behaviour of at least 75% of the active
ingredient dose within 45 min, preferably 70% in
30 min, is called rapid release.
It has also emerged that the active ingredient
combination in the pharmaceutical product according to
the invention has, besides the contraception,
antiandrogenic properties and can therefore be used for
the prophylaxis and therapy of androgen-induced
disorders, especially of acne.
It is possible to use the combination of 1.5 mg to
2.0 mg of dienogest and 0.015 mg to 0.020 mg of
ethinylestradiol for producing a pharmaceutical product
or for the preparation of a pharmaceutical composition
according to the invention for inhibiting ovulation.
Contraceptive efficacy of formulations which comprise
dienogest and ethinylestradiol.
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In a randomized, open clinical study, 40 women between
18 and 35 years of age, who had given their written
consent to take part in the study, were treated with 2
different formulations which contained dienogest and
ethinylestradiol. The first formulation (A)
corresponded to a combination of 2 mg of dienogest
(release not delayed) and 0.02 mg of ethinylestradiol.
The second formulation (B) consisted of a combination
of 1.5 mg of dienogest (delayed release of 50%
=
0.75 mg) and 0.02 mg of ethinylestradiol.
The trial included a pretreatment cycle (washout
phase), 3 treatment cycles and an after-treatment cycle
(follow-up phase).
At fixed times (before the start of the first treatment
cycle, at the end of the third treatment cycle),
various biochemical and function-testing investigations
are carried out.
To detect the ovulation-inhibiting effect, FSH, LH,
oestradiol, progesterone, "spinnbarkeit" and ferning
were investigated. Follicle maturation was examined by
means of an ultrasound investigation. In addition,
SHBG, CBG, total testosterone, triglycerides,
cholesterol, HDL, LDL, glucose in serum were
determined, and blood pressure, heart rate, body weight
and bleeding behaviour were recorded.
The results of the study prove that both formulations
reliably inhibit ovulation, as proved by the fall in
LH, FSH, progesterone and estradiol during the
treatment cycles. Follicle growth was detectable in
both groups by the accompanying ultrasound
investigation, that led, however, to follicle rupture
and thus to ovulation in no participant in the study.
So-called LUFs (luteinized unruptured follicles), which
represent evidence that follicle maturation has taken
place, but ovulation has not, were detectable in
treatment cycle 2 and 3 in 3 women treated with
formulation A. The increases in SHBG and CB were
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comparable in the two treatment groups. The
"spinnbarkeit" and ferning parameters which are
principally influenced by the progestogen component of
the products showed a tendency to be reduced more in
the group treated with formulation B than in the
comparison group. However, the difference did not reach
statistical significance. The increase in HDL-
cholesterol and the fall in LDL-cholesterol was
significantly greater in treatment group B than in
group A. Triglycerides and total cholesterol showed
comparable changes in the two groups. The glucose
tolerance remained substantially unaffected in the two
groups. Total testosterone decreased in a comparable
way and significantly in both treatment groups. The
subjective and objective tolerability of formulation B
was assessed as more favourable. Less irregular
bleeding occurred, especially in the first treatment
cycle. The intensity of the regular progestogen
withdrawal bleeding (in the pill break) was also less.
In addition, women treated with formulation B reported
fewer premenstrual symptoms (headaches, abdominal
pain). No differences were found between the groups and
in the time course in relation to blood pressure, heart
rate and body weight.
The study which was carried out showed that both
products reliably prevented ovulation in all the
volunteers. There was found to be a tendency for there
to be enhanced peripheral anticontraceptive effects
with formulation B. A few unfavourable side effects
(bleeding irregularities, premenstrual symptoms)
occurred significantly less often with formulation B. A
more favourable lipid profile was found for formulation
B.
The results show that a delayed dissolution (release)
of dienogest enables the dosage both of dienogest and
of ethinylestradiol to be low (formulation B), i.e. the
total steroidal dosage is reduced and, at the same
time, the requirement for a balance between dienogest
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and ethinylestradiol is met. Likewise, good
contraceptive efficacy and cycle control is achieved,
and such side effects such as, for example, additional
reduction in the active ingredient levels in the blood
on concomitant intake of further medicinal products is
compensated.
On reduction of the progestogen (dienogest) content
with the same estrogen (ethinylestradiol) content
different effects it is to be expected from the outset
that the contraceptive efficacy will deteriorate, good
cycle control will not be achieved, and the side
effects will intensify, because a shift in the balance
between dienogest and ethinylestradiol will be
expected.
Contrary to this view, the results show that a delayed
dissolution (release) of dienogest enables the dosage
both of dienogest and of ethinylestradiol to be low
(formulation B = 1.5 mg), i.e. the total steroidal
dosage is reduced and, at the same time, the
requirement for a balance between dienogest and
ethinylestradiol is met. Likewise, good contraceptive
efficacy and cycle control is achieved, and such side
effects such as, for example, additional reduction in
the active ingredient levels in the blood on
concomitant intake of further medicinal products is
compensated.
Formulation A = 2.0 mg of dienogest having the same
ethinylestradiol content as in formulation B = 0.02 mg
of ethinylestradiol, which comprises a low dosage of
ethinylestradiol compared with conventional products,
also shows a detectable ovulation-inhibiting effect,
but not so comprehensive as formulation B which has a
lower dose both in the dienogest content and in the
ethinylestradiol content.
