Note: Descriptions are shown in the official language in which they were submitted.
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Oral contraception with trimegestone
The invention relates to a method for contraception by the administration of
trimegestone. The invention further relates to pharmaceutical compositions and
dosage forms which contain trimegestone.
Trimegestone (17R-[(S)-2-hydroxypropanoyl]-17a-methyl-estra-4,9-dien-3-one) is
a
known prior art gestagen. It may be considered as a very potent progestin with
regard to strong endometrial transformation effect and moderate ovulation
suppression. The pharmacodynamic profile is very close to progesterone, the
natural
progestin. Reference may for example be made in this connection to EP-A 007
823.
Combinations of trimegestone with oestrogens for contraception are described,
for
example, in WO 98/04246, WO 98/04265, WO 98/04268 and WO 98/04269. WO
01/37841 discloses the administration of trimegestone in combination with
oestradiol
for treating the symptoms of the menopause and for preventing post-menopausal
osteoporosis.
The majority of commercially available oral contraceptive preparations
comprise a
gestagen in combination with an oestrogen as the hormonal active ingredients,
with
administration conventionally proceeding for 21-25 days in each 28-day
menstrual
cycle. Thereafter, either a placebo or nothing at all is administered for 3-7
days, so
initiating withdrawal bleeding.
In addition to effective contraception, a contraceptive preparation should, on
the one
hand, provide good cycle control and, on the other hand, exhibit no or only
slight
side-effects.
Cycle control is primarily effected by the oestrogen. However, the cycle
controlling
effect of the oestrogen in turn may be influenced by the gestagen and hence,
the
nature and the dose of the gestagen are also important factors to be taken
into
account.
CONFoRMATION COPY
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Good cycle control is in particular also distinguished by the occurrence of
the desired
(withdrawal) bleeding, which may inter alia be characterised by
- the time interval between cessation of administration of the active
ingredient and
the onset of bleeding,
- the duration of bleeding,
- the extent of bleeding and
- the occurrence of intermenstrual bleeding (for example spotting or
breakthrough
bleeding).
The most commonly reported side-effects are weight gain, nausea, variations in
menstrual flow, breast changes such as tenderness, discomfort, or swelling,
depression or mood disturbances, decreased sexual desire or response, and
acne.
Rare but serious potential effects include cardiovascular diseases, such as
stroke,
and an increased risk for breast cancer, liver tumors, and gallbladder disease
(cf. e.g.
C.A. Frye, Neurology, 2006, 66(6 Suppl. 3), 29-36).
Since the introduction of oral contraceptive preparations, research has
primarily
focussed on the development of preparations which minimise the potential side-
effects without in so doing exhibiting a reduced contraceptive action or
deviating from
the natural menstrual cycle of 28 days. The first generation of oral
contraceptive
preparations contained more gestagen and oestrogen than would per se have been
necessary in order to ensure effective contraception. Disadvantageous
haemostatic
and metabolic changes, clinical problems and side-effects were associated with
these high-dose first generation preparations. In 1978, the WHO recommended
that
the pharmaceutical industry should in future develop preparations with the
lowest
possible content of gestagen and oestrogen.
At first, the content of oestrogen was reduced in combination preparations
because it
was assumed that the side-effects known at that time, in particular thrombo-
embolic
disorders, were attributable to oestrogen. However, as it became increasingly
clear
that the gestagen was also associated with specific side-effects, in
particular with
cardiovascular complications, the content of gestagen in the combination
preparations was also reduced. It was also recognised that a balance between
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oestrogen and gestagen may be established in order to avoid disadvantageous
effects on carbohydrate metabolism and lipid or lipoprotein levels. It was
subsequently found that, at a comparatively low dose of both the oestrogen and
the
gestagen, there is a synergistic action which inhibits ovulation.
Numerous therapeutic approaches have been developed in order to achieve the
goal, while retaining contraceptive activity, of good cycle control and
minimising the
side-effects of the overall dose of steroids. In this connection, the
gestagen/
oestrogen combination is administered either at a constant dose (monophasic)
or in a
bi- or multiphasic regimen.
WO 98/04269, for example, discloses a monophasic regimen and WO 98/04265, WO
98/04268 and WO 98/04246 disclose multiphasic regimens, with inter alia 40-500
pg
of trimegestone being administered daily in combination with an oestrogen.
While
according to A.E. Schindler et al., Maturitas, 2003, 46, S1, 7-16 the
ovulation
inhibition dose of trimegestone is 0.5 mg per day p.o., according to WO
98/04269,
WO 98/04265, WO 98/04268 and WO 98/04246 the administered daily dose of
trimegestone is preferably in the range from 40 to 250 pg. However, it is at
least
doubtful whether a daily dose of e.g. 40 pg trimegestone is sufficient in
order to
provide and to maintain a reliable contraceptive effect.
An ever greater reduction in the quantity of active ingredient cannot continue
ad
infinitum and may sometimes also cause new problems.
Accordingly, the problem sometimes arises with a minimised quantity of active
ingredient that effective contraception and a stable menstrual cycle are more
highly
dependent on administration proceeding at the correct time so that a maximally
constant plasma concentration of the active ingredients in the blood is
maintained.
Any deviations from a regular administration regimen, i.e. deviations from
taking each
day at the same time, should then as far as possible be avoided.
Entirely regular administration is, however, difficult to guarantee for
practical reasons.
It is known, for example, that a not inconsiderable proportion of women
occasionally
forget to take the dose intended for a particular day and only catch up on the
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following day. It may also happen, that the intended dose is administered in
the
morning on one day and not until the evening on the following day. Similar
problems
may also arise if the woman vomits after having taken the contraceptive, but
before
the dose has been completely resorbed.
The consequent fluctuations in plasma concentration may, as a result of the
low dose
of the administered active ingredients, possibly fall to values below the
minimum
threshold concentration which would be necessary to ensure reliable
contraception.
In such cases, the effectiveness of the contraception cannot always be
guaranteed
with a minimised active ingredient dose. Apart from failure of the
contraceptive
action, the fluctuations in plasma concentration may furthermore also result
in
premature onset of (withdrawal) bleeding (intermenstrual bleeding, for example
as
spotting or breakthrough bleeding).
It is furthermore known that the metabolisation of active ingredients in the
body may
vary between individuals, for example due to a genetic disposition. It is
accordingly
possible that a low dose of trimegestone may in some women result in a plasma
concentration which is above the necessary minimum concentration, but in other
women, due to faster metabolisation, a higher dose would be necessary in order
to
ensure effective contraception.
Apart from the effectiveness of contraception, the course of withdrawal
bleeding also
plays an important role. It is in principle desirable for bleeding to occur
for only a
short time and to be only slight in extent. This is desirable not only from
the
subjective standpoint of most women, but also on medical grounds. Short and
light
bleeding, for example, is associated with only slight loss of iron.
The object of the invention is to provide a contraceptive method which
exhibits
advantages over prior art methods. Apart from ensuring effective
contraception, the
method should ensure good cycle control and exhibit no or at most only slight
side-
effects, for example no depressive mood effect and no disadvantageous effects
on
carbohydrate metabolism and lipid or lipoprotein levels. These properties
should be
relatively insensitive to irregularities in administration of the active
ingredients and to
interindividual variations.
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This object is achieved by the subject matter of the claims.
It has been surprisingly found that, when trimegestone is administered in
combination
with an oestrogen for oral contraception, the ratio of gestagen to oestrogen
may be
varied within relatively broad limits thereby providing a reliable
contraceptive effect
without consequently giving rise to increased side-effects, such as for
example
depressive mood effect and disadvantageous effects on carbohydrate metabolism
and lipid or lipoprotein levels. It has thus surprisingly been found that the
dose of
trimegestone may be increased within certain limits without simultaneously
also
having to increase the dose of the oestrogen in order to maintain the gestagen-
oestrogen balance. In this way, side-effects which would otherwise accompany
an
elevated dose of the oestrogen are prevented.
The invention relates to a method for contraception comprising preferably oral
administration of
- trimegestone,
- optionally in combination with at least one oestrogen, preferably
ethinyloestradiol,
or optionally in combination with two oestrogens, preferably ethinylestradiol
and
oestradiol, and/or
- optionally in combination with at least one further gestagen, and/or
- optionally in combination with at least one further physiologically active
substance,
to a woman of child-bearing age on at least 21, preferably 21 to 26, more
preferably 22 to 25 and most preferably 23 or 24 successive days of a
preferably
28-day menstrual cycle, beginning on day 1 or 5 of the menstrual cycle,
wherein on at least one, preferably at least on 2, more preferably at least on
5,
still more preferably at least on 8, most preferably at least on 14 and in
particular
on all of the at least 21 successive days, the daily dose of trimegestone is
more
than 500 pg.
In preferred embodiments of the method according to the invention, on at least
one of
the at least 21, preferably 24 successive days the daily dose of trimegestone
is in the
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range from more than 500 pg to less than 2,000 pg, or it is more than 2,000
pg.
Preferably, on at least one of the at least 21, preferably 24 successive days
the daily
dose of trimegestone is
in the range from more than 500 pg to preferably less than 1,000 pg,
preferably
from 510 to 990 pg, more preferably from 525 to 975 pg, still more preferably
from 550 to 950 pg, most preferably from 575 to 925 pg and in particular from
600 to 900 pg; or
- in the range from _ 1,000 pg to preferably less than 2,000 pg, preferably
from
1,010 to 1,990 pg, more preferably from 1,025 to 1,975 pg, still more
preferably
from 1,050 to 1,950 pg, most preferably from 1,075 to 1,925 pg and in
particular
from 1,100 to 1,900 pg; or
_ 2,000 pg, preferably at least 2,100 pg, more preferably _ 2,500 pg, still
more
preferably at least 3,000 pg, most preferably at least 4,000 pg and in
particular at
least 5,000 pg.
In a preferred embodiment of the method according to the invention,
trimegestone is
administered in combination with at least one oestrogen at least on one,
preferably
on all of the at least 21, preferably 24 successive days. The oestrogen is
preferably
selected from the group consisting of chlorotrianisene, dienestrol,
diethylstilbestrol,
oestradiol (17p-oestradiol), oestriol, oestrone, ethinyloestradiol,
hexoestrol,
mestranol, methallenoestril, methyloestrenol, promestriene and conjugated
oestrogens or the pharmaceutically acceptable esters thereof.
Ethinyloestradiol or a
combination of ethinyloestradiol and oestradiol (170-oestradiol) are
particularly
preferred. Preferred pharmaceutically acceptable esters of the above listed
oestrogens are acetates, propionates and valerates (for example oestradiol
valerate).
The daily dose of the oestrogen preferably corresponds to an equivalent dose
of 5.0
to 55 pg, more preferably of 10 to 50 pg, still more preferably of 15 to 48
pg, most
preferably of 20 to 45 pg and in particular of 22 to 40 pg of
ethinyloestradiol. 20 pg or
30 pg are particularly preferred. If two or more oestrogens are used, the
daily overall
dose thereof preferably corresponds to the above-stated equivalent doses, the
equivalent dose preferably being related to the ovulation inhibition effect of
the
oestrogen.
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Preferably, trimegestone in a daily dose of 1,000 to 3,000 pg is administered
in
combination with ethinyloestradiol in a daily dose of 20 5 pg or 30 5 pg, on
24 or 25
successive days of a 28-day menstrual cycle.
Particularly preferred embodiments of combinations of the daily dose X of
trimegestone with the daily doses Y of ethinyloestradiol are summarised in the
following table:
Trimegestone Ethinyloestradiol
1,000:5 X:5 3,000 10 :5 Y:5 30
1,000 5 X<_ 3,000 7.5 5 Y<_ 12.5
1,000 <_ X s 3,000 12.5 <_ Y< 17.5
1,000 :5 X<_ 3,000 17.5 5 Y<_ 22.5
1,0005 X5 3,000 22.5 <_Y<_27.5
1,000 s X<_ 3,000 27.5 <_ Y<_ 32.5
510 <_X<_ 1,990 10 :5 Y5 50
510 <_X<_ 1,900 12 :5 Y:5 48
525 <_ X<_ 1,500 15 <_ Y<_ 45
525 :5 X:5 975 18 :5 Y:5 42
550 <_ X<_ 950 20 <_ Y_ 40
2,000 < X 10 <_ Y<_ 50
2,100 <X 10 :5 Y:5 50
2,500 < X 10 pg:5 Y<_ 50
According to a preferred embodiment of the present invention,
ethinyloestradiol is
adminstered in a daily dose of 20 5 pg, preferably 20 2.5 pg, in combination
with
z
trimegestone, the daily dose of trimegestone being > 500 pg, _ 625 pg, _ 750
pg,
875 pg, _ 1,000 pg, 21,125 pg, ? 1,250 pg, 21,375 pg, ? 1,500 pg, _ 1,625 pg,
_
?
1,750 pg, ? 1,875 pg, ? 2,000 pg, ? 2,125 pg, ? 2,250 pg, ? 2,375 pg, ? 2,500
pg,
2,625 pg, 2,750 pg, ? 2,875 pg, 3,000 pg, ? 3,125 pg, ? 3,250 pg, 3,375 pg,
3,500 pg, ? 3,625 pg, ? 3,750 pg, 3,875 pg, 4,000 pg, _ 4,125 pg, ? 4,250 pg,
4,375 pg, 4,500 pg, 4,625 pg, 4,750 pg, 4,875 pg or ? 5,000 pg.
According to a preferred embodiment of the present invention,
ethinyloestradiol is
adminstered in a daily dose of 30 5 pg, preferably 30 2.5 pg, in combination
with
trimegestone, the daily dose of trimegestone being > 500 pg, z 625 pg, ? 750
pg, 875 pg, _ 1,000 pg, 21,125 pg, z 1,250 pg, 21,375 pg, 21,500 pg, _> 1,625
pg, ~
1,750 pg, ? 1,875 pg, - 2,000 pg, _ 2,125 pg, _ 2,250 pg, z 2,375 pg, ~ 2,500
pg, 7
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2,625 pg, - 2,750 pg, > 2,875 pg, _ 3,000 pg, > 3,125 pg, _ 3,250 pg, _ 3,375
Ng,
3,500 pg, 3,625 pg, > 3,750 pg, _ 3,875 pg, > 4,000 pg, _ 4,125 pg, > 4,250
pg,
4,375 pg, 4,500 pg, > 4,625 pg, >_ 4,750 pg, > 4,875 pg or _ 5,000 pg.
According to a prefered embodiment, the weight ratio of ethinyloestradiol to
trimegestone is below 1:45. According to another preferred embodiment, the
daily
dose of trimegestone corresponds to an equivalent dose of norethisterone
actetate in
a weight ratio of ethinyloestradiol to norethisterone acetate of below 1:45,
the
equivalent dose preferably being related to the ovulation inhibition efficacy
of
norethisterone acetate and trimegestone, respectively.
In a particularly preferred embodiment, on at least one, preferably on all, of
the at
least 21, preferably 24 successive days
- ethinyloestradiol is administered in a daily dose of 1.0 to 55 pg,
preferably 20 5
or 30 5 pg, and/or
- oestradiol (17R-oestradiol) is administered in a daily dose of 1,000 to
10,000 pg,
preferably 1,000 to 5,000 pg.
In another particu{arly preferred embodiment on at least one, preferably on
all, of the
at least 21, preferably 24 successive days trimegestone is administered
- either not together with oestradiol (17p-oestradiol)
- or together with a combination of oestradiol (170-oestradiol) and
ethinyloestradiol.
According to this embodiment, oestradiol (17R-oestradiol) is thus preferably
only
administered when ethinyloestradiol is also administered.
In a particularly preferred embodiment of the method according to the
invention, on
none of the at least 21, preferably 24 successive days is an oestrogen
administered
without trimegestone being administered.
Preferably, trimegestone is administered in a daily dose of 1,000 to 3,000 pg
in
combination with ethinyloestradiol in a daily dose of 10 to 20 pg and
oestradiol in a
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daily dose of 1,000 to 5,000 pg, on 24 or 25 successive days of a 28-day
menstrual
cycle.
Particularly preferred embodiments of combinations of the daily dose X of
trimegestone with the daily doses Y of ethinyloestradiol and the daily dose Z
of
oestradiol (17p-oestradiol) are summarised in the following table:
Trimegestone Ethinyloestradiol Oestradiol
1,000 < X<_ 3,000 1.0 5 Y<_ 25 1,000 s Z<_ 5,000
1,000 _< X<_ 3,000 1.0 <_ Y<_ 20 1,000 pg:s Z<_ 5,000
1,000<_X<_3,000 1.0 <_Y<_ 15 1,000 <_Z<_5,000
1,000<_X<_3,000 1.0 <_Y510 1,000 :5 Zs5,000
510 5 X<_1,990 1.0 5 Y<_10 1,000 <_Z<_10,000
510 <_X<_ 1,900 2.0 5Y<_ 10 1,100 <_Z5 9,000
525 5 X_ 1,500 3.0 5 Y5 9.5 1,200 5 Z<_ 8,000
525 S X_ 975 4.0 <_ Y<_ 9.5 1,300 5 Z<_ 7,000
550 5 X_ 950 5.0 <_ Y<_ 9.0 1,400 5 Z<_ 6,000
575 5 X<_ 925 6.0 <_ Y<_ 9.0 1,500 <_ Z<_ 5,000
2,000 < X 1.0 <_ Y<_ 10 1,000 <_ Z 5 10,000
2,100 <-X 1.0 <_Y510 1,000 <_Z<_ 10,000
2,500 < X 1.0 <_ Y<_ 10 1,000 <_ Z<_ 10,000
In a preferred embodiment of the method according to the invention,
trimegestone is
administered in combination with at least one further physiologically active
substance
at least on one, preferably on all of the at least 21, preferably 24
successive days.
Preferably, said further physiologically active substance is selected from the
group
consisting of folic acid, folinic acid, vitamin C, vitamin B preparations,
iron(II)
preparations, iron(III) preparations, calcium preparations and magnesium
preparations.
Examples of vitamin B preparations are vitamin B, preparations, such as
thiamine
hydrochloride and thiamine nitrate; vitamin B2 preparations, such as
riboflavin and
riboflavin-5'-phosphate; nicotinamid preparations; vitamin B6 preparations,
such as
pyridoxine hydrochloride; panthotenic acid preparations, such as dexpanthenol;
and
vitamin B12 preparations, such as cyanocobalamin and hydroxocobalamin acetate.
Examples of iron(II) preparations are iron(II) sulfate, iron(il) carbonate,
iron(II)
chloride, iron(II) tartrate, iron(II) gluconate, iron(II) aspartate, iron(II)
glycine sulfate,
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iron(II) fumarate, iron(II) ascorbate, iron(II) iodate, iron(II) succinate and
ammonium
iron(II) sulfate.
Examples of iron(III) preparations are iron(III) sodium citrate, iron(III)
oxide/sucrose
complex, sodium feredetate, iron(III) hydroxide, dextriferron, iron(III)
citrate,
chondroitin sulfate/iron(III) complex, iron(III) acetyltransferrin, iron(III)
protein
succinylate and potassium/iron(III) phosphate/citrate complex.
Examples of calcium preparations are calcium carbonate, calcium citrate,
calcium
hydrogenphosphate, calcium phosphate, calcium aspartinate, calcium
bisaspartate,
calcium hydrogenaspartate, calcium gluconate, calcium lactate, calcium
lactogluconate, calcium glucoheptonate, calcium acetate, calcium saccharate,
calcium orotate and calcium lactobionate.
Examples of magnesium preparations are magnesium hydrogenaspartate,
magnesium L-aspartate hydrochloride, magnesium oxide, magnesium
hydrogenphosphate, magnesium citrate, magnesium hydrogencitrate, magnesium
sulfate, magnesium L-hydrogenglutamate, magnesium D-gluconate, magnesium
orotate, mgnesium adipate and magnesium nicotinate.
In a preferred embodiment of the method according to the invention, the daily
dose of
trimegestone is identical on each of the at least 21, more preferably at least
22, still
more preferably at least 23, most preferably at least 24 and in particular at
least 25
successive days (= monophasic regimen), wherein administration preferably
proceeds in each case in combination with at least one oestrogen, preferably
20 5
pg ethinyloestradiol or 30 5 pg ethinyloestradiol.
In another preferred embodiment of the method according to the invention, the
at
least 21, more preferably at least 22, still more preferably at least 23, most
preferably
at least 24 and in particular at least 25 successive days are divided into
two, three or
more groups of days, wherein the daily dose of trimegestone is identical on
all the
days within a group, but the daily dose of trimegestone is different on
successive
days of different groups (= multiphasic regimen), and wherein administration
preferably proceeds in each case in combination with at least one oestrogen,
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preferably ethinyloestradiol. Preferred regimens are listed in the following
table, the
daily dose of trimegestone being Al, A2 or A3 and the daily dose of the at
least one
oestrogen, preferably ethinyloestradiol, being B:
Number of phases
1 2 2 3 3 3 4 4
Embodiment no. 1 21 22 31 32 33 41 42
Total duration 21-25 21-25 21-25 21-25 21-25 21-25 21-25 21-25
da s of 28]
1 Duration da s 21-25 7-13 7-13 3-8 3-8 3-8 3-8 3-8
Trimegestone dose Al A2 Al A2 A2 Al A2 A2
Oestrogen dose
(equivalent dose to B B B B B B B B
ethin loestradiol
2 Duration da s 12-18 12-18 4-15 4-15 4-15 4-15 4-15
Trime estone dose Al A2 A2 Al A2 Al A2
Oestrogen dose
(equivalent dose to B B B B B B B
ethin loestradiol
3 Duration da s 4-15 4-15 4-15 4-15 4-15
Trime estone dose Al A2 A2 A2 Al
Oestrogen dose
(equivalent dose to B B B B B
ethin loestradiol
4 Duration da s 2-5 2-5
Trime estone dose A3 A3
Oestrogen dose
(equivalent dose to B B
ethin loestradiol
The particular ranges of values of the doses for the particular combinations
of Al, A2,
A3 and B for each one of these embodiments no. 1, 21, 22, 31, 32, 33, 41 and
42 may
be found in the following tables a, b, c and d, the dose B of the at least one
oestrogen being stated as the equivalent dose to ethinyloestradiol:
a a
Al > 500
A2 ? 40
A3 ? 0
B 5.0-55
or
b b1 b2 b3 b4
preferably more still more in particular
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preferably preferably
Al 510-990 525-975 550-950 550-750
A2 40-990 40-750 120-750 260-500
A3 0-990 0-750 0-500 260-500
B 5.0-55 10-50 20-45 25-40
or
c c1 c2 c3 c4
preferably more still more in particular
preferably preferably
Al 1,010-1,990 1,025-1,975 1,050-1,950 1,050-1,750
A2 40-1,990 40-750 120-750 260-500
A3 0-1,990 0-750 0-500 260-500
B 5.0-55 7.5-50 10-45 15-40
or
d dl d2 0 d4
preferably more still more in particular
preferably preferably
Al > 2,000 > 2,500 23,000 >_ 4,000
A2 40-5,000 40-750 120-750 260-500
A3 0-5,000 0-750 0-500 260-500
B 5.0-55 7.5-50 jig 10-45 15-40
Thus, when combining the embodiments no. 1, 21, 22, 31, 32, 33, 41 and 42 with
any
one of the doses a, b1, b2, b3, b4, c1, c2, c3, c4, d 1, d2, d3 and d4,
respectively, the
following preferred embodiments may be individualized: 1a, 21a, 22a, 31a, 32a,
33a, 41a
and 42a; 1 b1 , 21 b1 , 22b1 , 31b1 , 32b1 , 33b1 , 41b1 and 42b1; 1 b221b2,
22b2, 31b2, 32b2, 33b2,
41b2 and 42b2; 1b321b3, 22b3, 31b3, 32b3, 33b341b3 and 42b3; 1b421b422b431b47
32b433b441b4 and 42b4; 1 c1 , 21c1 , 22c1 , 31c1 , 32c1 , 33c1 , 41c1 and 42c1
; 1 c2, 21c2, 22c23ic232c2 33~2, 41~2 and 42~; 1~, 21~, 22~ 31~, 32~, 33~, 41~
and 42~. 1~, 21~, 22c4,
, 32c4, 33'4, 41'A and 42c4; 1d1, 2id122d131d132d1, 33d1, 41d1 and 42d1;
1d221d2
31c4 22d2, 31d232d2, 33d2, 41d2 and 42d2; 1d3210 22d3, 31d3320 , 33d3410 and
420 ; and
1d421d422d4v 31d49 .32d49 33d49 41d4 and 42d4. In the preceding list the
embodiment e.g.
1132b2" refers to the triphasic regimen "32", wherein trimegestone and the
oestrogen
are administered in daily dosages according to table b, values "b2".
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The equivalent dose to ethinyloestradiol may be effected by an equivalent
quantity of
each suitable oestrogen, the quantity here being selected such that the
oestrogenic
activity corresponds to that which would be brought about by the
administration of
ethinyloestradiol in the stated quantity, ethinyloestradiol itself being the
preferred
oestrogen. Two or more different oestrogens, for example ethinyloestradiol in
combination with oestradiol, may also be used in a quantity which corresponds
overall to the stated equivalent dose, preferably being related to the
ovulation
inhibition effect. Suitable methods for determining the equivalent dose are
known to
the person skilled in the art. Trimegestone is preferably used in combination
with
ethinyloestradiol or in combination with ethinyloestradiol and oestradiol
(17(3-
oestradiol).
In the bi-, tri- and tetraphasic regimens, the daily dose of trimegestone and
of the
oestrogen is in each case constant on all days within a phase and different on
two
successive days of different phases.
Particularly preferred regimens 1', 21', 22, 31', 32', 33', 41' and 42' may be
found in the
following table, according to which ethinyloestradiol is administered on 21-24
successive days in a daily dose of 20 5 pg in combination with trimegestone in
daily
doses Al, A2 and A3, respectively, as defined in tables a, b, c and d supra:
Number of phases
1 2 2 3 3 3 4 4
Embodiment no. 1' 21' 22 31' 32' 33 41' 42
Total duration 21-24 21-24 21-24 21-24 21-24 21-24 21-24 21-24
da s of 28]
1 Duration da s 24 7-13 7-13 3-8 3-8 3-8 3-8 3-8
Trimegestone dose Al A2 Al A2 A2 Al A2 A2
ethinyloestradiol 20 5 20 5 20 5 20 5 20 5 20 5 20 5 20 5
dose
2 Duration da s 12-18 12-18 4-15 4-15 4-15 4-15 4-15
Trimegestone dose Al A2 A2 Al A2 Al A2
ethinyloestradiol 20 5 20 5 20 5 20 5 20 5 20 5 20 5
dose [N
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3 Duration da s 4-15 4-15 4-15 4-15 4-15
Trimegestone dose Al A2 A2 A2 Al
ethinyloestradiol 20 5 20 5 20 5 20 5 20 5
dose
4 Duration da s 2-5 2-5
Trimegestone dose A3 A3
ethinyloestradiol 20 5 20 5
dose
Further particularly preferred regimens 1", 21", 22", 31", 32", 33", 41" and
42" may be
found in the following table, according to which ethinyloestradiol is
administered on
21-24 successive days in a daily dose of 30 5 pg in combination with
trimegestone in
daily doses Al, A2 and A3, respectively, as defined in tables a, b, c and d
supra:
Number of phases
1 2 2 3 3 3 4 4
Embodiment no. 1" 21" 22" 31" 32" 33' 41" 42"
Total duration 21-24 21-24 21-24 21-24 21-24 21-24 21-24 21-24
da s of 28
1 Duration da s 24 7-13 7-13 3-8 3-8 3-8 3-8 3-8
Trimegestone dose Al A2 Al A2 A2 Al A2 A2
ethinyloestradiol 30 5 30 5 30 5 30 5 30 5 30 5 30 5 30 5
dose
2 Duration da s 12-18 12-18 4-15 4-15 4-15 4-15 4-15
Trime estone dose Al A2 A2 Al A2 Al A2
ethinyloestradiol 30 5 30 5 30 5 30 5 30 5 30 5 30 5
dose Ng]
3 Duration da s 4-15 4-15 4-15 4-15 4-15
Trimegestone dose Al A2 A2 A2 Al
ethinyloestradiol 30 5 30 5 30 5 30 5 30 5
dose [pg] W/
4 Duration da s 2-5 2-5
Trimegestone dose A3 A3
ethinyloestradiol 30 5 30 5
dose pg] //////I I I
In a preferred embodiment of the method according to the invention,
trimegestone is
not administered on all the days of the preferably 28-day menstrual cycle.
Instead, it
is preferred that, on the days which follow the at least 21, preferably 24
successive
days,
- a placebo,
- a pharmaceutically acceptable preparation containing iron,
- a preparation containing folic acid, folinic acid and/or a salt thereof, or
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- a preparation containing an oestrogen, preferably ethinylestradiol,
preferably in a
daily dose corresponding to an equivalent dose of <_ 10 pg of
ethinyloestradiol is
administered;
- or nothing at all is administered.
In this manner, it is ensured that the menstrual cycle is terminated by the
withdrawal
bleeding, such that a new menstrual cycle may begin. The menstrual cycle
preferably
lasts 28 days.
According to another preferred embodiment of the method according to the
invention,
it is, however, also possible for the menstrual cycle to be longer than 28
days. This
may be achieved according to the invention, by the cessation of trimegestone
(and
optionally at least one oestrogen and/or at least one further gestagen) not
occurring
until a later point in time, such that the withdrawal bleeding also does not
occur until a
later point in time and thus the menstrual cycle also does not end until a
later point in
time. In this embodiment, trimegestone is preferably administered on more than
28
successive days.
In this embodiment, (uninterrupted) administration of trimegestone proceeds on
at
least 42 or 56, more preferably at least 63, still more preferably at least
84, most
preferably at least 105, 112 or 120 and in particular at least 126, 140, 150,
183, 184,
189 or 365 successive days, such that it is not intended to initiate
withdrawal
bleeding within this period. According to a preferred embodiment,
(uninterrupted)
administration of trimegestone proceeds on more than 183 but less than 365
days.
According to the invention, the continuous period for which trimegestone may
be
administered daily may also be still longer. In principle, it is accordingly
possible to
administer trimegestone on all successive days over one or more years, without
any
withdrawal bleeding occurring.
When the menstrual cycle is extended to more than 28 days, e.g. more than 183
days, trimegestone is preferably administered in a daily dose of 1,000 to
3,000 pg in
combination with ethinyloestradiol in a daily dose of 20 5 pg or 30 5 pg on
every day
of said more than 28 days, e.g. more than 183 days, without interruption.
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Alternatively, trimegestone is preferably administered in a daily dose of
1,000 to
3,000 pg in combination with ethinyloestradiol in a daily dose of 10 to 20 pg
and
oestradiol in a daily dose of 1,000 to 5,000 pg on every day of said more than
28
days, e.g. more than 183 days, without interruption.
Preferably, on the days which follow the more than 28 days, preferably on the
consecutive 3, 4, 5, 6 or 7 days which follow the more than 28 days,
- a placebo,
- a pharmaceutically acceptable preparation containing iron,
- a preparation containing folic acid, folinic acid and/or a salt thereof, or
- a preparation containing an oestrogen, preferably ethinyloestradiol,
preferably in a
daily dose corresponding to an equivalent dose of <_ 10 pg of
ethinyloestradiol is
administered;
- or nothing at all is administered.
In a preferred embodiment of the method according to the invention,
trimegestone is
administered in a daily dose of 1,000 to 3,000 pg in combination with
ethinyloestradiol in a daily dose of 20 5 pg or 30 5 pg on every day of said
more
than 28 days, e.g. at least 84 consecutive days, without interruption, and the
7
consecutive days following said more than 28 days, ethinyloestradiol is
administered
in a daily dose of 5 to 10 pg in the absence of trimegestone.
In a preferred embodiment of the method according to the invention,
trimegestone is
administered in combination with at least one further gestagen at least on one
of the
at least 21, preferably 24 successive days. The further gestagen is here
preferably
selected from the group consisting of allyloestrenol, chlormadinone, danazol,
demegestone, desogestrel, dienogest, drospirenone, dydrogesterone,
ethisterone,
etynodiol, gestodene, gestonorone, hydroxyprogesterone, levonorgestrel,
lynoestrenol, medroxyprogesterone, medrogestone, megestrol, methyloestrenol,
methylnortestosterone, nomegestrol, norethisterone, norethynodrel, norgestrel,
norgestimate, progesterone, promegestone and tibolone, or the pharmaceutically
acceptable esters thereof. Preferred pharmaceutically acceptable esters of the
above
listed gestagens are acetates (for example chlormadinone acetate, nomegestrol
acetate, medroxyprogesterone acetate, megestrol acetate, norethisterone
acetate),
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caproates (for example hydroxyprogesterone caproate) and enantates (for
example
norethisterone enantate).
The daily dose of the further gestagen preferably corresponds to an equivalent
dose
of 100 to 5,000 pg, more preferably of 250 to 4,000 pg, still more preferably
of 500 to
3,500 pg, most preferably of 750 to 3,000 pg and in particular of 1,000 to
2,500 pg of
chlormadinone acetate, the equivalent dose preferably being related to the
ovulation
inhibition effect of chlormadinone acetate or the endometrial effect of
chlormadinone
acetate.
The method according to the invention is carried out for at least one
menstrual cycle.
The method according to the invention is preferably carried out for two or
more, in
particular for at least 3, 4, 5 or 6 successive menstrual cycles.
The present invention also relates to a, preferably solid, pharmaceutical
composition
comprising trimegestone in a quantity of more than 500 pg, preferably at least
600
pg, still more preferably at least 700 pg, yet more preferably at least 1,000
pg, most
preferably at least 1,200 pg and in particular 1,000 to 3,000 pg, in
combination with
ethinyloestradiol, preferably in a quantity of 20 5 pg or 30 5 pg.
The present invention also relates to a, preferably solid, pharmaceutical
composition
comprising trimegestone in a quantity
- of more than 500 pg and preferably less than 1,000 pg, preferably of 510 to
990
pg, more preferably of 525 to 975 pg, still more preferably of 550 to 950 pg,
most
preferably of 575 to 925 pg and in particular of 600 to 900 pg; or
- of ? 1,000 pg and preferably less than 2,000 pg, preferably of 1,010 to
1,990 pg,
more preferably of 1,025 to 1,975 pg, still more preferably of 1,050 to 1,950
pg,
most preferably of 1,075 to 1,925 pg and in particular of 1,100 to 1,900 pg;
or
- of ? 2,000 pg, preferably at least 2,100 pg, more preferably more than 2,500
pg,
still more preferably at least 3,000 pg, most preferably at least 4,000 pg and
in
particular at least 5,000 pg.
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The present invention also relates to a pharmaceutical composition comprising
trimegestone in a quantity of more than 500 pg, preferably of at least 750 pg,
still
more preferably of at least 1,000 pg, most preferably of at least 2,000 pg and
in
particular of at least 3,000 pg, in combination with ethinyloestradiol in a
quantity of
preferably at least 5 pg, more preferably 20 5 pg or 30 5 pg.
The present invention also relates to a pharmaceutical composition comprising
trimegestone in a quantity of more than 500 pg, preferably of at least 750 pg,
still
more preferably of at least 1,000 pg, most preferably of at least 2,000 pg and
in
particular of at least 3,000 pg, in combination with ethinyloestradiol in a
quantity of
preferably at least 5 pg, more preferably 20 5 pg or 30 5 pg, and oestradiol
in a
quantity of preferably 1,000 to 10,000 pg, more preferably 1,000 to 5,000 pg.
The pharmaceutical composition according to the invention is preferably
formulated
for oral administration. It preferably assumes the form of (film coated)
tablets, sugar
coated tablets or multiparticulate form, preferably the form of microtablets,
microcapsules, micropellets, accretion pellets, granules, extrudates,
spheroids,
beads or pellets, which may optionally be packaged in capsules or press-
moulded to
form (film coated) tablets. Dry-compacted formulations are also possible.
The present invention also relates to a dosage form comprising the
pharmaceutical
composition as described above, preferably for once daily, preferably oral
administration.
The dosage form according to the invention comprises trimegestone in a
quantity of
more than 500 pg; preferably of at least 510 pg; more preferably of at least
525 pg, at
least 1,000 pg, at least 1,500 pg or at least 2,000 pg; still more preferably
of 550 to
950 pg; most preferably of 575 to 925 pg and in particular of 600 to 900 pg,
wherein
the dosage form is preferably selected from the group consisting of film
coated
tablets, sugar coated tablets and capsules.
In a preferred embodiment of the dosage form it comprises trimegestone in a
quantity
of _ 1,000 pg and less than 2,000 pg or of ? 2,000 pg. The dosage form
according to
the invention may assume multiparticulate form, preferably the form of
microtablets,
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microcapsules, micropellets, accretion pellets, granules, extrudates,
spheroids,
beads or pellets, optionally packaged in capsules or press-moulded to form
(film
coated) tablets. Dry-compacted formulations are also possible.
In a preferred embodiment, the dosage form according to the invention is
selected
from the group consisting of film coated tablets, sugar coated tablets and
capsules
and comprises the pharmaceutical composition according to the invention.
The preferred embodiments described below relate both to the pharmaceutical
composition according to the invention and to the dosage form according to the
invention.
The pharmaceutical composition or dosage form according to the invention
preferably
additionally contains at least one oestrogen, preferably ethinyloestradiol.
The at least
one oestrogen is here preferably selected from the group consisting of
chlorotrianisene, dienestrol, diethylstilbestrol, oestradiol (17(3-
oestradiol), oestriol,
oestrone, ethinyloestradiol, hexoestrol, mestranol, methallenoestril,
methyloestrenol,
promestriene and conjugated oestrogens or the pharmaceutically acceptable
esters
thereof. Preferred pharmaceutically acceptable esters are valerates (for
example
oestradiol valerate).
The quantity of the oestrogen preferably corresponds to an equivalent dose of
5.0 to
55 pg, more preferably of 10 to 50 pg, still more preferably of 15 to 48 pg,
most
preferably of 20 to 45 pg and in particular of 22 to 40 pg of
ethinyloestradiol,
ethinyoestradiol itself being the preferred oestrogen. If two or more
oestrogens are
used, the overall quantity thereof preferably corresponds to the above-stated
equivalent doses, which are preferably related to the ovulation inhibition
effect.
In a preferred embodiment of the pharmaceutical composition or dosage form
according to the invention, said composition or dosage form contains
- either no oestradiol (17R-oestradiol) or
- oestradiol (17R-oestradiol) in combination with ethinyloestradiol.
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In a preferred embodiment, the pharmaceutical composition or dosage form
according to the invention additionally contains at least one further gestagen
apart
from trimegestone. The further gestagen is here preferably selected from the
group
consisting of allyloestrenol, chlormadinone, danazol, demegestone,
desogestrel,
dienogest, drospirenone, dydrogesterone, ethisterone, etynodiol, gestodene,
gestonorone, hydroxyprogesterone, levonorgestrel, lynoestrenol, medroxy-
progesterone, medrogestone, megestrol, methyloestrenol, methylnortestosterone,
nomegestrol, norethisterone, norethynodrel, norgestrel, norgestimate,
progesterone,
promegestone and tibolone, or the pharmaceutically acceptable esters thereof.
Preferred pharmaceutically acceptable esters are acetates (for example
chlormadinone acetate, medroxyprogesterone acetate, megestrol acetate,
norethisterone acetate), caproates (for example hydroxyprogesterone caproate)
and
enantates (for example norethisterone enantate).
The quantity of the further gestagen preferably corresponds to an equivalent
dose of
100 to 5,000 pg, more preferably of 250 to 4,000 pg, still more preferably of
500 to
3,500 pg, most preferably of 750 to 3,000 pg and in particular of 1,000 to
2,500 pg of
chlormadinone acetate, the equivalent dose preferably being related to the
ovulation
inhibition effect of chlormadinone acetate or the endometrial effect, i.e.
endometrial
transformation effect, of chlormadinone acetate.
If, apart from trimegestone, the pharmaceutical composition or dosage form
according to the invention contains further active ingredients, in particular
at least one
oestrogen (such as ethinyloestradiol) and/or a further gestagen, these are
preferably
present as a mixture within the same administration unit. Such dosage forms
may be
produced with the assistance of conventional methods and auxiliary substances.
Suitable auxiliary substances are known to the person skilled in the art. In
this
connection, reference may be made, for example, to H.P. Fiedler, Lexikon der
Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor
Aulendorff, 2002; and R.C. Rowe et al., Handbook of Pharmaceutical Excipients,
APhA Publications, 4th edition, 2003 in their entirety.
Examples of auxiliary substances are salt formers, buffers, emulsifiers,
solubilising
agents (solubilisers), wetting agents, antifoaming agents, gel formers,
thickeners, film
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formers, surfactants, binders, slip agents, lubricants, embedding agents,
mould
release agents, flow-control agents, disintegration accelerators
(disintegrants),
chelating agents, sorbents, fillers, pharmaceutical solvents, antioxidants
(for example
a-tocopherol), preservatives, plasticizers, flavour and odour correctives and
colorants.
Examples of extenders are lactose, mannitol, calcium diphosphate, starch,
microcrystalline cellulose, calcium carbonate (E170) and magnesium carbonate.
Examples of disintegration accelerators (disintegrants) are starch, for
example maize
starch, potato starch, crosslinked polyvinylpyrrolidone and low substituted
sodium
carboxymethylcellulose.
Examples of binders are starch (e.g. potato starch, maize starch), gelatin,
polyvinylpyrrolidone, cellulose ethers, sugars, for example sucrose and
glucose
syrup.
Examples of slip agents are talcum, sodium stearyl fumarate, fatty acid esters
and
macrogol.
Examples of lubricants are stearic acid, magnesium stearate, calcium stearate
and
zinc stearate.
An example of a flow-control agent is colloidal silicon dioxide.
Examples of pharmaceutical solvents are propylene glycol and glycerol.
One example of a surfactant is polyoxyethylene/sorbitan fatty acid ester (for
example
Polysorbate 80).
Examples of colorants are indigo carmine (E132), titanium dioxide (E171) and
quinoline yellow (E104).
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Examples of film formers are shellac, methylcellulose, hypromellose
(hydroxypropyl-
methylcellulose, HPMC), hydroxypropylcellulose, hydroxyethylcellulose,
ethyicellulose, polyacrylates and polymethacrylates. Plasticizers, such as
propylene
glycol and/or polyethylene glycol may additionally be contained in the film
coating
composition.
Examples of embedding agents are carnauba wax, montan glycol wax, stearic/
paimitic acid, glycerol trioleate and cetylstearyl alcohol.
Examples of chelating agents are citric acid, phenylaianine, sodium calcium
edetate
and disodium edetate (EDTA-Na2).
Examples of preparations containing iron are iron(II) preparations, such as
for
example iron(II) sulfate, iron(II) carbonate, iron(II) chloride, iron(II)
tartrate, iron(II)
gluconate, iron(II) aspartate, iron(II) glycine sulfate, iron(II) fumarate,
iron(II)
ascorbate, iron(II) iodate, iron(II) succinate and ammonium iron(II) sulfate;
and
iron(III) preparations, such as for example iron(III) sodium citrate,
iron(III)
oxide/sucrose complex, sodium feredetate, iron(ill) hydroxide, dextriferron,
iron(III)
citrate, chondroitin sulfate/iron(III) complex, iron(III) acetyltransferrin,
iron(III) protein
succinylate and potassium/iron(III) phosphate/citrate complex.
In a particularly preferred embodiment, a preparation containing iron is
administered
in combination with folic acid, folinic acid and/or a salt thereof. The
following iron
preparations are particularly suitable for this embodiment: iron/amino acid
complex,
iron(II) fumarate, iron(II) sulfate, dextriferron, ammonium iron(II) sulfate,
iron(II)
glycine sulfate and iron(II) gluconate. The folic acid and the folinic acid,
respectively,
is here preferably present in free form or as its calcium salt.
When folic acid, folinic acid and/or a salt thereof is administered, its daily
dose is
preferably within the range of from 0.1 to 7.5 mg, more preferably from 0.2 to
5.0 mg,
still more preferably from 0.3 to 3.0 mg, most preferably from 0.4 to 2.5 mg
and in
particular from 0.5 to 2 mg.
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Examples of particularly preferred auxiliary substances are talc, long chain
fatty
acids, magnesium stearate, stearic acid, calcium stearate, polyethylene
glycol,
palmitic acid, and hydrogenated vegetable oils, such as hydrogenated castor
oil.
In a preferred embodiment, the pharmaceutical composition or dosage form
according to the invention contains a buffer with a pH value in the range from
2.0 to
5.5. The buffer is preferably formed by a mixture of citric acid and disodium
hydrogenphosphate.
In a preferred embodiment, the pharmaceutical composition or dosage form
according to the invention contains a cyclodextrin, such as R-cyclodextrin or
y-cyclodextrin, preferably 0-hydroxypropyl-cyclodextrin (P-HP). Preferably,
the
cyclodextrin forms a complex with trimegestone and/or an oestrogen, e.g. with
ethinyloestradiol.
In a preferred embodiment, apart from trimegestone and optionally at least one
oestrogen and/or at least one further gestagen, the pharmaceutical composition
or
dosage form according to the invention contains a further physiologically
active
substance, such as folic acid, folinic acid or a suitable derivative or salt,
for example
the calcium salt, vitamin C, vitamin B preparations, iron(II) preparations,
iron(III)
preparations, calcium preparations and magnesium preparations.
In a preferred embodiment, apart from trimegestone and optionally at least one
oestrogen and/or at least one further gestagen, the pharmaceutical composition
or
dosage form according to the invention contains the following auxiliary
substances in
the following preferred quantities (percentages are relative to the total
weight of the
dosage form):
Constituent preferably more preferably in particular
Wf.% V11t.% Wt.%
HPMC 1.0 to 7.5 2.5 to 5.0 3.0 to 5.0
Titanium dioxide 0.1 to 2.0 0.5 to 1.5 0.7 to 1.2
Starch 10 to 60 20 to 40 25 to 35
Lactose monohydrate 25 to 80 40 to 70 50 to 65
Stearic acid 0.1 to 2.5 0.2 to 1.5 0.3 to 1.0
Talcum 0.1 to 5.0 0.5 to 2.5 0.9 to 1.5
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In another preferred embodiment, apart from trimegestone and optionally at
least one
oestrogen and/or at least one further gestagen, the pharmaceutical composition
or
dosage form according to the invention contains the following auxiliary
substances in
the following preferred quantities (percentages are relative to the total
weight of the
dosage form):
Constituent preferably more preferably in particular
wt. % wt.001 wt. %
PVP 0.1 to 10 0.5 to 7.5 1.0 to 5.0
Stearic acid 0 to 7.5 0.1 to 5.0 0.5 to 2.0
Starch 1.0 to 50 2.5 to 25 5.0 to 15
Colloidal silicon dioxide 0 to 7.5 0.1 to 5.0 0.5 to 2.0
a-Tocopherol 0 to 1.0 0.001 to 0.5 0.05 to 0.2
Lactose monohydrate 10 to 95 25 to 92 50 to 90
Magnesium stearate 0 to 1.0 0.001 to 0.5 0.05 to 0.2
The pharmaceutical composition or dosage form according to the invention may,
for
example, contain the following substances in the following preferred
quantities:
Constituent m 1-A 1-B 1-C 1-D 1-E 1-F
Trimegestone 0.525 0.575 0.600 0.750 1.100 1.500
Ethinyloestradiol 0.020 0.020 0.020 0.020 0.020 0.020
PVP 2.400 2.400 2.400 2.400 2.400 2.400
Stearic acid 0.800 0.800 0.800 0.800 0.800 0.800
Starch 8.000 8.000 8.000 8.000 8.000 8.000
Colloidal silicon dioxide 0.800 0.800 0.800 0.800 0.800 0.800
a-Tocopherol 0.080 0.080 0.080 0.080 0.080 0.080
Lactose monohydrate 67.295 67.245 67.220 67.070 66.720 66.320
Magnesium stearate 0.080 0.080 0.080 0.080 0.080 0.080
E 80.000 80.000 80.000 80.000 80.000 80.000
Film-coated tablets may, for example, have the following composition:
Constituent [mg] 2-A 2-B 2-C 2-D 2-E 2-F
Trimegestone 0.525 0.575 0.600 0.750 1.100 1.500
Ethinyloestradiol 0.020 0.020 0.020 0.020 0.020 0.020
Potato Starch 8.000 8.000 8.000 8.000 8.000 8.000
Lactose monohydrate 67.290 67.240 67.215 67.065 66.715 66.315
Stearic acid 0.800 0.800 0.800 0.800 0.800 0.800
a-Tocopherol 0.080 0.080 0.080 0.080 0.080 0.080
Colloidal silicon dioxide 0.800 0.800 0.800 0.800 0.800 0.800
Povidone K30 2.400 2.400 2.400 2.400 2.400 2.400
Quinoline Yellow E104 0.005 0.005 0.005 0.005 0.005 0.005
Magnesium stearate 0.080 0.080 0.080 0.080 0.080 0.080
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HPMC (film coating) 0.750 0.750 0.750 0.750 0.750 0.750
PEG 6000 0.220 0.220 0.220 0.220 0.220 0.220
Propylene glycol 0.030 0.030 0.030 0.030 0.030 0.030
E 81.000 81.000 81.000 81.000 81.000 81.000
Constituent [mg] 3-A 3-B 3-C 3-D 3-E 3-F
Trimegestone 0.525 0.575 0.600 0.750 1.100 1.500
Ethinyloestradiol 0.030 0.030 0.030 0.030 0.030 0.030
Potato Starch 8.000 8.000 8.000 8.000 8.000 8.000
Lactose monohydrate 67.285 67.235 67.210 67.060 66.710 66.310
Stearic acid 0.800 0.800 0.800 0.800 0.800 0.800
a-Tocopherol 0.080 0.080 0.080 0.080 0.080 0.080
Colloidal silicon dioxide 0.800 0.800 0.800 0.800 0.800 0.800
Polyvidone K30 2.400 2.400 2.400 2.400 2.400 2.400
Magnesium stearate 0.080 0.080 0.080 0.080 0.080 0.080
HPMC (film coating) 0.750 0.750 0.750 0.750 0.750 0.750
PEG 6000 0.220 0.220 0.220 0.220 0.220 0.220
Propylene glycol 0.030 0.030 0.030 0.030 0.030 0.030
E 81.000 81.000 81.000 81.000 81.000 81.000
The storage stability of the pharmaceutical composition or dosage form
according to
the present invention meets international standards (cf. European, Japanese
and
U.S. Pharmacopoeia).
The present invention also relates to a kit comprising at least one of the
above-
described dosage forms according to the invention.
The kit according to the invention is preferably designed for in each case
once daily
administration of the dosage forms contained therein.
The kit preferably comprises all the dosage forms containing trimegestone
which are
necessary for administering trimegestone for at least one menstrual cycle. The
kit is
preferably made up such that the above-described method for contraception
according to the invention may be carried out without entailing the
acquisition of
further dosage forms containing trimegestone which are not contained in the
kit. The
kit preferably contains one dosage form for each day, as administration
preferably
proceeds once daily.
If the menstrual cycle is 28 days long, the kit according to the invention
preferably
comprises at least as many dosage forms containing trimegestone as are
necessary
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for administering trimegestone on at least 21, preferably 24 successive days
of the
28-day menstrual cycle. If trimegestone is administered on fewer than 28 days,
for
the remaining days up to the end of the 28 days of the menstrual cycle, the
kit
according to the invention may contain either no dosage forms at all, or
preparations
containing iron, preparations containing folic acid, folates, folinic acid,
folinates or
placebos, preferably a preparation containing iron. It is necessary here for
at least
one of the dosage forms containing trimegestone of the kit according to the
invention
to be a dosage form according to the invention as described above.
If the menstrual cycle is extended, i.e. is more than 28 days long, the number
of
dosage forms containing trimegestone contained in the kit according to the
invention
is correspondingly increased, wherein preferably again at least one of the
dosage
forms containing trimegestone is a dosage form according to the invention as
described above.
In a preferred embodiment, the kit according to the invention comprises all
the
dosage forms containing trimegestone which are necessary for administering
trimegestone for at least two, more preferably at least three, still more
preferably at
least four, most preferably at least five and in particular at least six
menstrual cycles.
In a preferred embodiment, the kit according to the invention is designed for
mono- or
multiphasic administration of trimegestone in combination with an oestrogen,
preferably ethinyloestradiol. The menstrual cycle is here preferably 28 days
long. In
the bi-, tri- and tetraphasic regimens, the daily dose of trimegestone and of
the
oestrogen is in each case constant on all days within a phase and different on
two
successive days of different phases.
Trimegestone is preferably used in the dosage forms in combination with
ethinyloestradiol or in combination with ethinyloestradiol and oestradiol (170-
oestradiol).
Preferred embodiments no. 1, 21, 22, 31, 32, 33, 41 and 42 of the kit
according to the
invention comprise in total 21-25, preferably 24 dosage forms, containing
trimegestone, wherein, depending on the number of phases, these contain
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trimegestone in doses Al, A2, A3 and at least one oestrogen, preferably
ethinyloestradiol, in dose B according to the following table:
Number of phases
1 2 2 3 3 3 4 4
Embodiment no. 1 21 22 31 32 33 41 42
Totaf dosage forms 21-25 21-25 21-25 21-25 21-25 21-25 21-25 21-25
1 Number of 21-25 7-13 7-13 3-8 3-8 3-8 3-8 3-8
administration units
Trimegestone dose Al A2 Al A2 A2 Al A2 A2
Oestrogen dose
(equivalent dose to B B B B B B B B
ethin loestradiol
2 Number of 12-18 12-18 4-15 4-15 4-15 4-15 4-15
administration units
Trimegestone dose Al A2 A2 Al A2 Al A2
Oestrogen dose
(equivalent dose to B B B B B B B
ethin loestradiol
3 Number of 4-15 4-15 4-15 4-15 4-15
administration units
Trimegestone dose Al A2 A2 A2 Al
Oestrogen dose
(equivalent dose to B B B B B
ethin loestradiol
4 Number of 2-5 2-5
administration units
Trimegestone dose A3 A3
Oestrogen dose
(equivalent dose to B B
ethin loestradiol
The particular ranges of values of the doses for the particular combinations
of Al, A2,
A3 and B for each one of these embodiments no. 1, 21, 22, 31, 32, 33, 41 and
42 may
be found in the following tables, the dose B of the at least one oestrogen
being stated
as the equivalent dose to ethinyloestradiol:
a a
Al > 500
A2 ? 40
A3 _ 0
B 5.0-55
or
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b b1 b2 b3 b4
preferably more still more in particular
preferably referabl
Al 510-990 525-975 550-950 550-750
A2 40-990 40-750 120-750 260-500 LJO
A3 0-990 0-750 0-500 260-500
B 5.0-55 10-50 20-45 25-40
or
c c1 c2 c3 c4
preferably more still more in particular
preferably preferably
Al 1,010-1,990 1,025-1,975 1,050-1,950 1,050-1,750
A2 40-1,990 40-750 120-750 260-500
A3 0-1,990 0-750 0-500 260-500
B 5.0-55 7.5-50 10-45 p 15-40
or
d dl d2 d3 d4
preferably more still more in particular
preferably preferably
Al > 2,000 > 2,500 23,000 24,000
A2 40-5,000 40-750 120-750 260-500
A3 0-5,000 0-750 p 0-500 260-500
10-45 15-40
B 5.0-55 7.5-50 pgq
The following preferred embodiments may be individualized: 1 a, 21a, 22a, 31a,
32a, 33a,
41a and 42a; 1b121b1, 22b13ib1, 32b1, 33b141b1 and 42b1; 1b221b222b231b232b2,
33b2,
41b2 and 42b2; 1b321b322b3, 31b3, 32b3, 330 410 and 42b3; 1b421b422b431b4,
32b4,
33b4, 41b4 and 42b4; 1 c1 , 21c1, 2201 , 31c1 , 32c1 , 33c1 , 41c1 and 42c1 ;
1 c2, 21c2, 22c2, 3ic2,
32c233c2~ 41c2 and 42c2; 1c3 21c322c331c3, 32c333c3, 41~ and 42~; 1~, 21~,
22c4,
314, 32c4, 33c4, 41c4 and 42c4; 1d1, 21d1, 22d1, 31d132d1, 33d141d1 and 42d1;
1d221d2,
22d2, 31d2, 32d233d241d2 and 42d2; 1d3210 220 31d3P 32d39 33d37 41d3 and 42d3;
and
1d421d422d431d4, 32d433d441d4 and 42d4
A particularly preferred kit according to the invention contains all dosage
forms that
are necessary in order to allow for the administration of trimegestone in
combination
with ethinyloestradiol on 21-24 successive days of the menstrual cycle,
thereby
following any of regimens 1', 21', 22', 31', 32', 33', 41' and 42' as
described above in
connection with the method according to the invention.
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Another particularly preferred kit according to the invention contains all
dosage forms
that are necessary in order to allow for the administration of trimegestone in
combination with ethinyloestradiol on 21-24 successive days of the menstrual
cycle,
thereby following any of regimens 1", 21", 22", 31", 32", 33", 41" and 42" as
described
above in connection with the method according to the invention.
Further preferred embodiments of the kit according to the invention comprise
84
dosage forms containing 1,000-3,000 pg trimegestone in combination with 20 5
pg
or 30 5 pg ethinyloestradiol and 7 dosage forms containing 10 5 pg
ethinyloestradiol
alone, i.e. in the absence of trimegestone.
Trimegestone, optionally in combination with an oestrogen and/or a further
gestagen,
may also be taken optionally for a period of more than 28 days for therapeutic
reasons, such as for example for the treatment and/or prevention of at least
one of
the complaints or conditions selected from the group consisting of bleeding
disorders;
dysmenorrhoea; conditions dependent on the menstrual cycle, such as
endometriosis, polycystic ovarian syndrome (PCOS), uterus myomatosus,
functional
cysts, premenstrual syndrome and headaches/migraine; conditions influenced by
the
menstrual cycle, such as epilepsy, multiple sclerosis, diabetes mellitus,
depression,
schizophrenia, asthma and Parkinson's disease; and androgen-induced disorders,
such as seborrhoea, acne, androgenetic alopecia and hirsutism.
The present invention accordingly also relates to the use of trimegestone,
optionally
in combination with an oestrogen (such as ethinyloestradiol) and/or a further
gestagen, for the production of a medicine (e.g. an oral contraceptive),
preferably
with a dose of trimegestone of more than 500 pg and preferably less than 2,000
pg,
for the treatment and/or prevention of at least one of the complaints or
conditions
selected from the group consisting of bleeding disorders; dysmenorrhoea;
conditions
dependent on the menstrual cycle, such as endometriosis, polycystic ovarian
syndrome (PCOS), uterus myomatosus, functional cysts, premenstrual syndrome
(PMS), premenstrual dysphoric disorder (PMDD) and headaches/migraine; and
androgen-induced disorders, such as seborrhoea, acne, androgenetic alopecia
and
hirsutism.
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The dosage forms according to the invention may be prepared by conventional
processes. The following examples are not to be considered as limiting the
scope of
the invention:
Example 1:
a) Composition
Per tablet Per batch
Ethinyloestradiol 0.020 mg 0.002 kg
Trimegestone 2.000 mg 0.200 kg
Povidone K30 3.000 mg 0.300 kg
Lactose monohydrate 31.980 mg 3.198 kg
Maize starch 12.000 mg 1.200 kg
Magnesium stearate 0.500 mg 0.050 kg
Colloidal silicon dioxide 0.500 mg 0.050 kg
b) Composition
Per tablet Per batch
Ethinyloestradiol 0.015 mg 0.0015 kg
Trimegestone 2.000 mg 0.2000 kg
Povidone K30 3.000 mg 0.300 kg
Lactose monohydrate 32.985 mg 3.2985 kg
Maize starch 12.000 mg 1.2000 kg
Magnesium stearate 0.500 mg 0.0500 kg
Colloidal silicon dioxide 0.500 mg 0.0500 kg
Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved
in 600
ml of ethanol. Trimegestone (particle size 90% <50pm), lactose and maize
starch are
mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened
thoroughly
and mixed with the ethanolic EE/PVP solution. The moist composition is forced
through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular
product is disagglomerated through a 0.6 mm screen, mixed with magnesium
stearate and colloidal silicon dioxide and pressed on a tablet press with 5 mm
punches into tablets with a weight of 50 mg.
The tablets of composition a) are coated with a hypromellose-based coating
(e.g.
Opadry YS-1 -2184 made by Colorcon), coating composition 2 mg per tablet, and
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packaged into a packaging comprising 24 hormone-containing daily units and 4
hormone-free daily units with the same composition but without hormones.
The tablets of composition b) are coated with a hypromellose-based coating
(e.g.
Opadry YS-1-2184 made by Colorcon) of the following composition (coating
composition 2 mg per tablet).
Composition of the coatin
Hypromellose 6 mPas 0.1351 kg
Polyethylene glycol 6000 0.0395 kg
Propylene glycol 0.0054 kg
Purified water 1.6200 kg
24 hormone-containing tablets and 4 hormone free tablets, each as daily dosage
unit, are packed into one packaging.
Example 2:
a) Composition
Per tablet Per batch
Ethinyloestradiol 0.015 mg 0.0015 kg
Trimegestone 3.000 mg 0.3000 kg
Povidone K30 4.000 mg 0.4000 kg
Lactose monohydrate 63.485 mg 6.3485 kg
Maize starch 10.000 mg 1.0000 kg
Magnesium stearate 0.500 mg
b) Composition
Per tablet Per batch
Ethinyloestradiol 0.025 mg 0.0025 kg
Trimegestone 5.000 mg 0.5000 kg
Povidone K30 4.500 mg 0.4500 kg
Lactose monohydrate 59.975 mg 5.9975 kg
Maize starch 10.000 mg 1.0000 kg
Magnesium stearate 0.500 mg 0.0500 kg
Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved
in 950
ml of ethanol. Trimegestone (particle size 90% <50Nm), lactose and maize
starch are
mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened
thoroughly
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and mixed with the ethanolic EE/PVP solution. The moist composition is forced
through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular
product is disagglomerated through a 0.6 mm screen, mixed with magnesium
stearate and pressed on a tablet press with 6 mm punches into tablets with a
weight
of 80 mg.
The tablets of composition a) are coated with a hypromellose-based coating
(e.g.
Opadry YS-1 -2184 made by Colorcon), coating composition 2 mg per tablet, and
packaged into a packaging comprising 24 hormone-containing daily units and 4
hormone-free daily units.
The tablets of composition b) are coated with a hypromellose-based coating
(e.g.
Opadry YS-1-2184 made by Colorcon) of the following composition (coating
composition 1 mg per tablet).
Composition of the coating
Hypromellose 6 mPas 0.068 kg
Polyethylene glycol 6000 0.020 kg
Propylene glycol 0.002 kg
Purified water 1.810 kg
24 hormone-containing tablets and 4 hormone free tablets, each as daily dosage
unit, are packed into one packaging.
Example 3:
2-phase contraceptive
a) Composition of the 1. phase
Per tablet
Ethinyloestradiol 0.020 mg
Trimegestone 2.000 mg
Povidone K30 3.000 mg
Lactose monohydrate 31.980 mg
Maize starch 12.000 mg
Magnesium stearate 0.500 mg
Colloidal silicon dioxide 0.500 mg
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Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved
in 600
ml of ethanol. Trimegestone (particle size 90% <50Nm), lactose and maize
starch are
mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened
thoroughly
and mixed with the ethanolic EE/PVP solution. The moist composition is forced
through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular
product is disagglomerated through a 0.6 mm screen, mixed with magnesium
stearate and colloidal silicon dioxide and pressed on a tablet press with 5 mm
punches into tablets with a weight of 50 mg.
b) Composition of the 2. phase
As indicated under a), hormone-free, folic acid-containing tablets with a
weight of 50
mg are produced, wherein the sodium salt of the folic acid is dissolved in 600
ml of
aqueous ethanol.
Per tablet
Ethinyloestradiol 0.020 mg
Trimegestone 3.000 mg
Povidone K30 3.000 mg
Lactose monohydrate 31.000 mg
Maize starch 12.000 mg
Magnesium stearate 0.500 mg
Colloidal silicon dioxide 0.500 mg
Some tablets are produced as disclosed under a)
The tablets under a) and b) are coated with a hypromellose-based coating (e.g.
Opadry YS-1 -2184 made by Colorcon), coating composition 2 mg per tablet. 12
hormone-containing daily units produced according to a) and 12 hormone-
containing
daily units produced according to b) and 4 hormone-free daily units are packed
in a
package marked for a daily administration.
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Example 4:
Composition a) b)
Per tablet Per tablet
Ethinyloestradiol 0.020 mg
Trimegestone 2.000 mg
Sodium folate 0.050 mg 3.000 mg
Povidone K30 3.000 mg 3.000 mg
Lactose monohydrate 31.930 mg 31.000 mg
Maize starch 12.000 mg 12.000 mg
Magnesium stearate 0.500 mg 0.500 mg
Colloidal silicon dioxide 0.500 mg 0.500 mg
a) Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) and sodium
folate
are dissolved in 600 ml of ethanol. Trimegestone (particle size 90% <50Nm),
lactose
and maize starch are mixed in a mixer/pelletiser (Diosna P25) for 5 mins and
then
moistened thoroughly and mixed with the ethanolic EE/PVP solution. The moist
composition is forced through a 3 mm screen and dried in a vacuum drying
cabinet.
The dried granular product is disagglomerated through a 0.6 mm screen, mixed
with
magnesium stearate and colloidal silicon dioxide and pressed on a tablet press
with 5
mm punches into tablets with a weight of 50 mg.
b) As set forth under a), hormon-free, folic acid containing tablet having a
weight of
50 mg are prepared by dissolving sodium folate in 600 ml aqueous ethanol.
The tablets a) and b), respectively, are coated with a coating based on
hypromellose
(e.g. Opadry YS-1-2184, Colorcon); coating composition 2 mg per tablet.
21 hormone-containing daily units produced according to a) and 7 hormone-free
daily
units produced according to b) are packed in a package marked for a daily
administration.
Example 5:
120 tablets according to Example 1 a) are packed in a blister and marketed for
daily
administration on 120 successive days.
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Example 6:
Composition
Per tablet
Ethinyloestradiol 0.030 mg
Trimegestone 2.000 mg
Povidone K30 3.000 mg
Lactose monohydrate 31.970 mg
Maize starch 12.000 mg
Magnesium stearate 0.500 mg
colloidal silicon dioxide 0.500 mg
Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved
in 600
ml of ethanol. Trimegestone (particle size 90% <50Nm), lactose and maize
starch are
mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened
thoroughly
and mixed with the ethanolic EE/PVP solution. The moist composition is forced
through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular
product is disagglomerated through a 0.6 mm screen, mixed with magnesium
stearate and colloidal silicon dioxide and pressed on a tablet press with 5 mm
punches into tablets with a weight of 50 mg.
The tablets are coated with a hypromellose-based coating of the following
composition (coating composition 2 mg per tablet):
Composition of the coating
Hypromellose 6 mPas 0.1351 kg
Polyethylene glycol 6000 0.0395 kg
Propylene glycol 0.0054 kg
Purified water 1.6200 kg
The tablets are packed into a blister containing 189 daily units and marketed
for daily
administration on 189 successive days.
Example 7:
Composition
Per tablet
Ethinyloestradiol 0.015 mg
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Trimegestone 2.000 mg
Povidone K30 4.000 mg
Lactose monohydrate 63.485 mg
Maize starch 10.000 mg
Magnesium stearate 0.500 mg
Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved
in 950
ml of ethanol. Trimegestone (particle size 90% <50Nm), lactose and maize
starch are
mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened
thoroughly
and mixed with the ethanolic EE/PVP solution. The moist composition is forced
through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular
product is disagglomerated through a 0.6 mm screen, mixed with magnesium
stearate and pressed on a tablet press with 6 mm punches into tablets with a
weight
of 80 mg.
The tablets are coated with a hypromellose-based coating of the following
composition (coating composition 2 mg per tablet):
Composition of the coatin
Hypromellose 6 mPas 0.1351 kg
Polyethylene glycol 6000 0.0395 kg
Propylene glycol 0.0054 kg
Purified water 1.6200 kg
The tablets are packed into a blister containing 365 daily units and are
marketed for
daily administration on 365 successive days.
Example 8:
Composition
Per tablet
Ethinyloestradiol 0.030 mg
Trimegestone 5.000 mg
Povidone K30 4.500 mg
Lactose monohydrate 60.470 mg
Maize starch 10.000 mg
Magnesium stearate 0.500 mg
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Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) are dissolved
in 950
ml of ethanol. Trimegestone (particle size 90% <50pm), lactose and maize
starch are
mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened
thoroughly
and mixed with the ethanolic EE/PVP solution. The moist composition is forced
through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular
product is disagglomerated through a 0.6 mm screen, mixed with magnesium
stearate and pressed on a tablet press with 6 mm punches into tablets with a
weight
of 80 mg.
The tablets are coated with a hypromellose-based coating of the following
composition (coating composition I mg per tablet):
Composition of the coatin
Hypromellose 6 mPas 0.068 kg
Polyethylene glycol 6000 0.020 kg
Propylene glycol 0.002 kg
Purified water 0.810 kg
The tablets are packed into a blister containing 150 daily units and are
marketed for
daily administration on 150 successive days.
37
