Note: Descriptions are shown in the official language in which they were submitted.
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Mesoprogestins (Progesterone Receptor Modulators) as a component of female
contraceptives
The present invention relates to the field of contraception. More particularly
it relates to the
use of mesoprogestins for the production of a pharmaceutical for female
contraception, to a
pharmaceutical preparation for female contraception and to a method of female
contraception administering effective amounts of a mesoprogestin to a female
desiring
contraception.
For female oral contraception different pharmaceutical preparations are
available.
The most prevalent form of oral contraception is a pill that combines both an
estrogen and a
progestin, a so-called combined oral contraceptive preparation. Apparently,
the progestin
acts to block gonadotropin releases (inhibition of ovulation); the estrogen
component
provides endometrial control to diminish breakthrough bleeding.
Alternatively, there are contraceptive preparations that comprise progestin
only. However,
the progestin-only preparations (= progesterone-only pill = POP) have a more
varied
spectrum of side effects than do the combined preparations, especially more
breakthrough
bleeding. As a result, the combined preparations are the preferred oral
contraceptives in use
today (Sheth et al., Contraception, 25:243, (1982)).
Antiprogestins (also termed as "progesterone antagonits" or "antigestagens")
are a class of
compounds that block the progesterone receptor. For example, RU 486
(mifepristone) is a
progesterone receptor antagonist. RU 486 binds to the progesterone receptor
and produces
a blockade of the binding of progesterone to ist receptor. When administered
in the luteal
phase of the menstrual cycle, RU 486 induces vaginal bleeding.
The prior art has demonstrated either inhibition of the ovulatory menstrual
cycle or delayed
endometrial maturation. It has been demonstrated in primate models that both a
single
injection of the antiprogestin RU 486 (5 mg/kg i.m.) in the late follicular
phase or a once
weekly oral RU 486 dose of 25 mg prevented ovulation (Collins et al., J. Clin.
Endocrinol.
Metab. 1986, 63:1270-1276; Danforth et al., Contraception 1989, 40:195-200).
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Using various study protocols which differed in regimen and dose, it has been
demonstrated
by several groups of investigators that RU 486 inhibits ovulation in women as
well (Shoupe
et al., Am. J. Obstet. Gynecol. 1987, 157:1421-1426; Liu et al., J. Clin.
Endocrinol. Metab.
1987, 65:1135-1140; Luukkainen et al., Fertil. Steril. 1988, 49:961-963).
An ovulation inhibiting activity has also been demonstrated for other
progesteron
antagonists than RU 486 (Zelinski-Waoten, M.B., Slayden, O.D., Chwalisz, K.,
Hess, D.L.,
Brenner; R.M., Stouffer, R.L .(1998x) Chronic treatment of female cycling
rhesus monkeys
with !ow-doses of the antiprogestin ZK 137 316: Establishment of a regimen
that permits
normal menstrual cyclicity. Hum Reprod 13: 259-267).
Consequently, several approaches for antiovulatory strategies to achieve
contraception with
progesterone antagonists have been suggested.
Also contraceptive approaches in which the RU 486 acts via implantation
inhibition have
been described.
In the so-called "LH+2" treatment (Swahn et al., "The luteal effect of RU 486
administration
during the early luteal phase on bleeding pattern, hormonal parameters and
endometrium",
Human Reproduction 5, 4:402-408 (1990)) 2 days after occurrence of the LH peak
(LH =
Luteinizing Hormone) an ovulation-inhibiting dose of RU 486 is administered
one time. The
active compound is thus administered only after the time of ovulation in the
luteal phase of
the menstrual cycle (luteal contraception).
A contraception method using competitive progesterone antagonists is disclosed
in WO
93/23020. Below their ovulation inhibiting dose and the abortive dose
progesterone
antagonist, preferably after oral administration, achieve contraception in
females, by
inhibition of implantation. The method does not adversely affect the female's
menstrual
cycle and is without risk of aborting a previous implanted fertilized egg or a
fetus. The
application of the progesterone antagonist occurs at least once in the
follicular phase of the
female's menstrual cycle (i.e. before ovulation). The preferred frequency of
administration is
daily or it follows in regular intervals of some days, e.g. weekly or with a
distance of 3 or 4
days between the single administrations of active compound.
WO 94/18982 teaches a method of inhibiting fertilization of an oocyte which
comprises
administering a fertilizing inhibitory amount of an antiprogestin to an
ovulatory mammal. The
amount is insufficient either to prevent ovulation or to interfere with the
regularity of the
ovarian menstrual cycle of the mammal. The preferred frequency of
administration is daily.
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According to one aspect of the present invention mesoprogestins are used as a
component
for the production of a pharmaceutical for female contraception.
They can be used either as single pharmaceutically active principle in female
contraceptives
or they can be used together with an estrogen.
According to one aspect of the invention the mesoprogestins, either alone or
in combination
with estrogens, are used in a regular, cyclical administration regime. This
shall mean that
the mesoprogestins are administered in identical and repeating administration
cycles as
long as contraception is desired.
A cycle starts with the administration of a mesoprogestin or mesoprogestin /
estrogen
containing dosage unit followed daily by further dosage units thereof. Each
cycle is
completed by a period in which no active dosage units ("pill-free" days) or in
which placebos
are administered.
Alternatively in case of mesoprogestin / estrogen administration the
administration cycle can
be completed by further administration of estrogen only containing dosage
units.
A new application cycle starts on the first day after completion of the "pill
free" or placebo
phase, respectively or after the phase in which estrogen only containing
dosage units have
been administered.
In all cases day 1 in the first administration cycle is the first day of
bleeding in the female's
menstrual cycle in which the contraceptive treatment starts.
One embodiment of the mesoprogestin only administration provides for
administering the
mesoprogestin containing dosage units up to day 180 at the maximum. Under the
continuos
daily treatment (1 to 25 mg mesoprogestin/day) a reversible amenorrhoea is
induced and
maintained. The contraceptive effect is due to endometrial effects
(endometrial suppression)
of the mesoprogestin. Consequently the endometrium is not prepared for
implantation of a
fertilized egg. To achieve the contraceptive effect it is sufficient to
administer the
mesoprogestin in dosages to prevent nidation. The dose of the mesoprogestin
can also be
ovulation inhibiting but this is not essential to achieve the contraceptive
effect and to induce
and maintain amenorrhoea.
Preferably the mesoprogestin only administration takes place for 3 months at
the maximum
(this allows to check the contraceptive reliability of the method).
Compared to other contraceptive regimes which use progestins only the above
described
administration regime leads to a better bleeding behavior. Compared to the
minipill
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(progesterone only pill) and to subcutaneous implants loaded with a progestin
(Norplant)
less breakthrough bleedings are observed.
With the methods using a progesterone antagonist as disclosed in WO 93/23020
and WO
94/18982 the normal cycle was maintained.
A next embodiment of the mesoprogestin only administration takes place
continuously for
more than 3 months, for example, 1-3 years. Since a mesoprogestin suppresses
endometrial growth and prevents endometrial vessel fragility it can be used
chronically. In
addition a condition of chronic but reversible amenorrhea is achieved.
A next embodiment of the mesoprogestin only administration provides for
administering the
mesoprogestin containing dosage units up to day 21, 22, 23, 24 or 25 either
followed by a
period of 7, 6, 5, 4 or 3 days during which no active compound is administered
or followed
by the administration of 7, 6, 5, 4 or 3 placebo pills so as to complete a 28
day long cycle.
On the next day the next cycle starts with the administration of a
mesoprogestin containing
dosage unit, etc.
In this last mentioned administration regime the mesoprogestin acts like a
progestin by
blocking the ovulation and inducing amenorrhoea and triggering withdrawal
bleeding.
Breakthrough bleedings are not induced. The withdrawal bleeding is due to
endometrial
transformation induced by the mesoprogestin. Consequently, in this embodiment
the
mesoprogestin has to be administered, at least in the luteal phase of the
female's menstrual
cycle, in an ovulation-inhibiting dose.
A variant of the last mentioned embodiment (not yet claimed) is to administer
dosage units
containing mesoprogestin in an ovulation inhibiting dose exclusively during
the luteal phase
of the female's menstrual cycle (no administration in the follicular phase).
Amenorrhoea inducing doses of mesoprogestins can be determined by methods
known to a
person skilled in the art for example in clinical studies.
Generally the daily dose of the mesoprogestin will be in the range of 1 to 25
mg.
If an estrogen is administered in addition to the mesoprogestin both active
components are
administered from day 1 (see above) to day 21, 22, 23, 24 or 25 of the
female's menstrual
cycle either followed by a period of 7, 6, 5, 4 or 3 days during which no
active compound is
administered or followed by the administration of 7, 6, 5, 4 or 3 only
estrogen containing
dosage units or followed by the administration of 7, 6, 5, 4 or 3 placebo
pills, respectively so
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as to complete a 28 day long administration cycle. On the next day the next
cycle starts with
the administration of a mesoprogestin/estrogen containing dosage unit, etc.
The estrogen is used in a daily amount of 10 to 30 Ng ethinyl estradiol or a
bioequivalent
amount thereof.
Mesoprogestins can be used sequentially with a progestin. In this
contraceptive regimen the
mesoprogestin component prevents breakthrough bleeding which is usually
associated with
chronic progestin treatment. The progestin component at a dose used in so
called "mini pill
regimen" is administered for a period of 30-180 days, whereas the
mesoprogestin
component is administered for a period of 1-30 days.
During mesoprogestin treatment menstrual bleeding may or may not occur. As a
result of
sequential progestin/mesoprogestin treatment the number of unscheduled
bleeding is,
however, markedly reduced.
The regular, cyclical administration regimes of a mesoprogestin, optionally in
combination
with an estrogen, are illustrated in detail in Figure 2.
The use of a mesoprogestin in a discontinuous, non-cyclical administration
regime is the use
as a so-called demand pill which has to be administered only around the time
point of sexual
intercourse for which contraception is desired. Preferably the administration
is before
sexual intercourse ("medicinal condom"). For details c.f. WO 93/23020.
A further aspect of the invention refers to a pharmaceutical combination
product
(composition) containing a mesoprogestin together with an estrogen.
A further aspect of the invention refers to a pharmaceutical combination
product
(composition) containing a mesoprogestin together with a progestin.
Yet another aspect of the invention deals with pharmaceutical preparations for
female
contraception comprising daily dosage units of a mesoprogestin.
All the aspects of the pharmaceutical preparation according to the invention
are apparent
from claims 25 to 38.
As mesoprogestins i.a. compounds disclosed in DE 43 32 283 and in DE 43 32 284
are
suitable for the purposes of the invention.
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These aforementioned compounds, for instance J 867 [4-[17(3-Methoxy-17a-
(methoxymethyl)-3-oxoestra-4,9-dien-11 f3-yl]benzaldehyd-(1 E)-oxim] and J 912
[4-[17[3-
Hydroxy-17a-(methoxymethyl)-3-oxoestra-4,9-dien-11 f3-yl]benzaldehyd-(1 E)-
oxim] ( both
DE 43 32 283) and J 900 [4-[17(3-Methoxy-17a-(methoxymethyl)-3-oxoestra-4,9-
dien-11 f3-
yl]benzaldehyd-(1 E)-[O-(ethoxy)carbonylJoxim], J 914 [4-[17[3-Methoxy-17a-
(methoxymethyl)-3-oxoestra-4,9-dien-11 f3-yl]benzaldehyd-(1 E)-(O-acetyl)oxim]
and J 956
[4-[17~-Methoxy-17a-(methoxymethyl)-3-oxoestra-4,9-dien-11 f3-yl]benzaldehyd-
(1 E)-[O-
(ethylamino)carbonyl]oxim] (all DE 43 32 284) are described as compounds
having strong
antiprogestagenic and compared to RU 486 having markedly reduced
antiglucocorticoid
activity. Moreover these compounds are mentioned to have (indirect)
antiestrogenic
properties reflected by reduced uterine weights in cyclic guinea pigs.
These effects should promise the exertion of a particularly favorable
influence on
pathologically modified tissues in which estrogens stimulate growth
(endometriotic focuses,
myomas, etc.).
The disclosure of these applications does not pertain to the use of the new
compounds for
female contraception or to pharmaceutical preparations for this purpose.
Also, a progestagenic activity of the compounds which is advantageous for the
herein
claimed indication contraception is not mentioned in these applications at
all.
Further, the mentioned applications are silent about any active dose to be
used to treat any
of the therein mentioned conditions.
According to the invention mesoprogestins are defined as compounds possessing
both
agonistic and antagonistic activities at the progesterone receptor (PR) in
vivo. As progestins
and antiprogestins, mesoprogestins show high binding affinity to PR. However,
mesoprogestins exhibit different pharmacodynamic properties compared to either
progestins
or antiprogestins. The presence of progesterone agonistic activity in
mesoprogestins
measured in commonly used biological tests in vivo represents the key property
of this novel
class of PRMs. This activity remains, however, below that of progesterone in
the plateau of
the dose response curve. Mesoprogestins fail to maintain pregnancy in
ovariectomized
pregnant rodents as mice and rats.
In the classical bioassay, the McPhail test, assessing progestagenic and
antiprogestagenic
effects in rabbits (Selye H., Textbook of Endocrinology, 1947, pp. 345-346),
progesterone
produces a maximum McPhail score of 4 (by definition). Treatment with a
mesoprogestin in
the absence of progesterone leads, however, to a McPhail score which is higher
than that
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under any dose of RU 486, i.e. above 0.5 - 1.0, preferentially 2.0 - 3.0, but
to distinctly lower
score than 4 at the plateau of the dose response curve at the clinically
relevant doses for
the claimed indications (i.e. 0.01 mg - 30 mg/rabbit).
The capacity of mesoprogestins to antagonize progesterone function is also
tested in the
McPhail test using a progesterone dose which induces a McPhail score ranging
between 3
and 4. A mesoprogestin inhibits the effect of progesterone to a significant
degree, but the
maximum inhibition is below that which is inducible with RU 486 or other pure
antiprogestins
(e.g. onapristone).
The mesoprogestins stabilize, therefore, the function of PR at an intermediate
activity level
providing the rationale for the novel clinical applications in gynecological
therapy.
Corresponding functional states cannot be achieved with progestins or
antiprogestins.
Pharmacological results demonstrating the utility of the mesoaroaestins in the
claimed
indications
The PR antagonistic and agonistic properties of mesoprogestins were assessed
in estrogen-
primed rabbits in the McPhail test according to Selye (Textbook of
Endocrinology, 1947, pp.
345-346).
A) Assessment of PR agonistic properties of mesoprogestins in rabbits (Figure
1 A)
The progestagenic activity of J867, J956, J1042 [4-[17(3-Methoxy-17a-
(methoxymethyl)-3-
oxoestra-4,9-dien-11 f3-yl]benzaldehyd-(1 E)-[O-(ethylthio)carbonyl]oxim
(German Patent
Application 198 09 845.6)] and RU 486 (dose range: 0.003-100 mg/rabbit) was
evaluated in
estradiol-primed juvenile rabbits after 4 days of subcutaneous (s.c.)
treatment in the
absence of progesterone). The progestagenic effect of the mesoprogestins was
observed at
doses equal to or higher that 0.03 mg/rabbit. Progesterone induced endometrial
transformation at doses equal to or higher that 0.1 mg reaching a maximum
effect at 1
mg/rabbit (approximately McPhail score 4). Neither mesoprogestin tested
(J1042, J867,
J956) reached the maximum effect of progesterone. J956 showed a biphasic
response in
this test with a maximum effect of McPhail score 1.5 at 0.3-1 mg/rabbit.
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8
B) Assessment of PR antagonistic properties of mesoprogestins in rabbits
(Figure 1 B)
Similarly, the antiprogestagenic activity of J867, J956, J1042 and RU 486
(dose range:
0.001-100 mg/rabbit) was evaluated in estradiol-primed juvenile rabbits after
4 days of
subcutaneous (s.c.) treatment in the presence of progesterone (1 mg/rabbit
s.c.). The first
antiprogestagenic effect of the mesoprogestins and RU 486 was observed with a
dose of
0.3-1 mg mg/rabbit (McPhail index 0 = no transformation; 4 = complete
transformation).
The antiprogestagenic activity of mesoprogestins at higher clinically relevant
doses doses
(i.e. 3-30 mg/rabbit) was lower that that of RU 486.
In the guinea pig model which allows a good prediction of the effects in
humans with respect
to the abortifacient activity (Elger W, Beier S., Chwalisz K, Fahnrich M,
Hasan SH,
Henderson D, Neef G, Rohde R (1986): Studies on the mechanism of action of
progesterone antagonists. J Steroid Biochem 25: 835-845) the mesoprogestins J
867, J
912, J 956, J 1042 lead up to 100 mg/kg/day to a maximal abortion rate of 20%.
C) Evaluation of abortifacient effects
Physiological background:
The guinea pig is considered as relevant model of human gestation and
parturition (Elger W,
Fahnrich M, Beier S, Quing SS, Chwalisz K (1987). Endometrial and myometrial
effects of
progesterone antagonists in pregnant guinea pigs. Am J Obstet Gynecol 157:
1065-1074;
Elger W, Neef G, Beier S, fahnrich M, Grundel M, Heermann J, Malmendier A,
Laurent D,
Puri CP, Singh MM, Hasan SH, Becker H (1992). Evaluation of antifertility
activities of
antigestagens in animal model. In: Puri CP and Van Look PFA (eds), Current
Concepts in
Fertility Regulation and Reproduction. Wiley Eastern Limited, New Delhi, pp.
303-328; Elger
W, Faehnrich M, Beier S, Qing SS, Chwalisz K (1986). Mechanism of action of
progesterone
antagonists in pregnant guinea pigs. Contraception 6: 47-62; Elger W, Chwalisz
K,
Faehnrich M, Hasan SH, Laurent D, Beier S, Ottow E, Neef G, Garfield RE
(1990). Studies
on labor-conditioning and labor-inducing effects of antiprogesterones in
animal model. In:
Garfield RE (eds), Norwell, pp. 153-175.) The mechanism of abortion of
antiprogestins in
this species is the initiation of labor and finally the expulsion of the
conceptus. Abortifacient
effects in the rat during very early pregnancy reflect inhibitory effects on
nidation rather than
initiation of uterine contractions. Studies in the rat model lead to
"overestimation" of the
potential of antiprogestins to terminate pregnancy in humans. Conversely, in
the guinea pig
model, irrespective of the antiprogestin doses, there were high rates of
ongoing pregnancies
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9
similar to the situation in humans (Elger et al., Current Concepts in
Fertility Regulation and
Reproduction cited above). Furthermore, in both humans and guinea pigs, there
is a strong
synergism between antiprogestins and prostaglandins with respect the induction
of labor
(see the articles cited above and Elger W, Beier S (1983). Prostaglandine and
Antigestagene fur den Schwangerschaftsabbruch (Prostaglandins and
antigestagens for
pregnancy termination). German Patent DE 3337450 12; Van Look P, Bygdeman M
(1989).
Antiprogestational steroids: a new dimension in human fertility regulation.
Oxford reviews of
reproductive medicine 11: 2-60).
Assessment of labor inducing activity: Figure 3.
Pregnant guinea pigs were treated on days 43 and 44 of pregnancy and observed
until day
50 of gestation. For the effects of various treatments see table 1 and figure
3. It is typical for
this model that expulsions occur with a delay of several days after treatment.
It can be seen
that Mesoprogestins have a much reduced abortifacient activity compared to
RU486. The
following ranking of abortifacient activity was found: RU486>J956>J867,
J912>J1042. The
differences with respect to abortifacient activity seem qualitative ones. It
is not possible to
overcome the low abortifacient activity of a Mesoprogestin by the use of a
higher dose.
Table 1: Studies of relative binding activity (RBA) and ED5° of
abortifacient activity in
pregnant rats and guinea pigs.
RBA (%) # abortifacient
compound activity
EDSO (mg/animal/day,
s.c.)
PR' GRz rata guinea pig4
RU 486 506 685 0.98* 3.8
Ona~~ristone 22 39 1.71 * ca 3
J867 302 78 0.65* > 100
J956 345 154 0.64* 20
J912 162 16 0.36 > 100
J1042 164 42 > 10 100
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# by Kaufmann; 'progesterone = 100%, Zdexamethasone = 100%
3treatment days 5 - 7 of pregnancy, autopsy day 9, 4treatment day 43 - 44 of
pregnancy,
autopsy day 50, *SAS, probit procedure.
The mesoprogestin is preferably selected for this invention from the group of
the
compounds J867, J912, J956, J1042.
Further preferred mesoprogestins are
4-[17~-Hydroxy-17a-(ethoxymethyl)-3-oxoestra-4,9-dien-11 f3-yl]benzaldehyd-(1
E)-oxim;
4-[17~-Methoxy-17a-(ethoxymethyl)-3-oxoestra-4,9-dien-11 f3-yl]benzaldehyd-(1
E)-oxim;
4-[17~-Hydroxy-17a-(chlormethyl)-3-oxoestra-4,9-dien-11 f3-yl]benzaldehyd-(1
E)-oxim;
4-[17(3-Methoxy-17a-(methoxymethyl)-3-oxoestra-4,9-dien-11 (3-yl]benzaldehyd-
(1 E)-(O-
methyl)oxim (all DE 43 32 283)
and
4-[17a-Methoxy-17a-(methoxymethyl)-3-oxoestra-4,9-dien-11 f3-yl]benzaldehyd-(1
E)-[O-
(phenylamino)carbonyl]oxim;
4-[17[3-Methoxy-17a-(methoxymethyl)-3-oxoestra-4,9-dien-11 f3-yl]benzaldehyd-
(1 E)-
[propionyl]oxim;
4-(17[3-Methoxy-17a-(methoxymethyl)-3-oxoestra-4,9-dien-11 !3-yl]benzaldehyd-
(1 E)-
[benzoyl]oxim (all DE 43 32 284).
The amount per daily dosage is in the range of 1 to 25 mg of mesoprogestin.
As estrogens, all estrogenically active compounds are suitable for the
purposes of this
invention.
~ Estrogens that can be used within the scope of this invention are, for
example,
ethinylestradiol, 17(3-estradiol as well as its esters such as estradiol-3-
benzoate,
estradiol-17-valerate, -cypionate, -undecylate, -enanthate and/or other
estradiol esters
(US-PS 2,611,773, US-PS 2,990,414, US-PS 2,054,271, US-PS 2,225,419 and US-PS
2,156,599) and conjugated estrogens.
~ Estradiol-, ethinylestradiol- and estrone-3-sulfamates, for example estrone-
N,N-
dimethylsulfamate, estrone-N,N-diethylsulfamate, ethinylestradiol-3-N,N-
dimethylsulfamate, ethinylestradiol-3-N,N-diethylsulfamate, ethinylestradiol-3-
N,N-
tetramethylenesulfamate, estrone sulfamate, estradiol-3-sulfamate, estradiol-3-
N,N-
dimethylsulfamate, estradiol-3-N,N-diethylsulfamate, ethinylestradiol-3-
sulfamate, which
all represent prodrugs for the corresponding 3-hydroxy compounds (W. Elger et
al., in J.
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Steroid Biochem. Molec. Biol., Vol. 55, No. 3/4, 395-403, 1995; DE 44 29 398
A1 and
DE 44 29 397 A1 ), can also be used in the pharmaceutical agent according to
the
invention.
As progestins useful in the invention, all compounds are suitable that are
suitable for use in
oral contraceptives because of their progestin activity. An exemplary list of
such
compounds is found in B. Runnebaum et al., "Female Contraception: Update and
Trends,"
Springer-Verlag, Berlin, 1988, pages 64-90, 109-121, 122-128 and 129-140.
Preferred
progestins within the scope of this invention are gestodene, progesterone,
levonorgestrel,
cyproterone acetate, chlormadinone acetate, drospirenone (dihydrospirorenone),
norethisterone, norethisterone acetate, norgestimate, desogestrel or 3-
ketodesogestrel.
In the embodiment containing a progestin according to this invention, the
progestin is
present in a dosage form that is suitable for oral administration, namely as a
tablet, coated
tablet, capsule or pill. In this case, the formulation of the progestin is
done in a way
analogous to preparing progestins for hormonal contraception with use of the
adjuvants that
are commonly used for this purpose. A daily dosage unit of the progestin
contains the latter
at a dose of 0.6-6.0 mg of levonorgestrel, 2-20 mg of cyproterone acetate, 0.3-
3.0 mg of
gestodene or 0.2-2.0 mg of desogestrel or an amount of another progestin that
is equivalent
in action to these dosages.
Determining equivalent-action dose amounts of various progestins is done
according to
known methods; further details are found in, for example, the two articles
"Probleme der
Dosisfindung: Sexualhormone [Problems of Dose-Finding: Sex Hormones]"; F.
Neumann
et al. in "Arzneimittelforschung [Drug Research]" 27, 2a, 296-318 (1977) as
well as "Aktuelle
Entwicklungen in der hormonalen Kontrazeption [Current Developments in
Hormonal
Contraception]"; H. Kuhl in "Gynakologe [Gynecologists]" 25: 201-240 (1992).
According to all embodiments, mesoprogestin can be present in dosage units
that are
intended for daily oral administration.
The estrogen can also be present in daily oral dosage units.
If the dosage units of the mesoprogestin are provided for administration over
a period of 7
days, these dosage units can advantageously be present in the form of a dosage
unit that
can be administered once a week.
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In such a dosage unit that is to be administered once a week, the
mesoprogestin should
preferably be prepared in a formulation that results in a delayed release of
the active
ingredient.
A delayed release of the mesoprogestin can be achieved, for example, by
formulating the
dosage unit that is to be administered orally as a composite tablet or by
providing the
dosage unit that is to be administered orally with a timed-disintegration
coating, as is readily
known to one skilled in the art.
By derivatization, for example by esterification of a free hydroxy group in an
effective
precursor, the mesoprogestin that is used for the production of the
pharmaceutical agent
according to the invention can also have a longer half-life than this
precursor. As a result, a
longer-lasting action is also achieved.
For the purposes of this invention, the formulation of the mesoprogestin and
optionally the
estrogen is done in a completely conventional manner, as is already known for
the
formulation of these compounds for their individual use as described for J867
in DE 43 32
283 and for estrogen therapy, for example Cyclo-Progynova.
In particular, reference is also made to the information that is contained in
the mentioned
prior art documents.
In addition to oral administration of the estrogen and the mesoprogestin, it
is equally
possible to administer one or both of the components transdermally, for
example with a skin
patch, which is best known for the administration of estrogen (Climara Patch).
In addition, administration can be done using an intrauterine release system
(c.f. Mirena),
but this variant is not preferred within the scope of this invention.
The administration of one or both components as a depot formulation is also
possible.
Finally, all above-mentioned types of administration can be combined. For
example, the
estrogen can be administered transdermally with a skin patch, and the
progesterone
antagonist can be administered daily orally or one or more times as a depot
formulation.
CA 02383650 2002-02-27
WO 01/26603 PCT/IB00/02053
13
The estrogen is contained per daily dosage unit according to the invention in
an amount of
to 30 pg of ethinylestradiol or a bioequivalent amount of another estrogen.
In the pharmaceutical agent according to the invention, the mesoprogestin is
contained in
each dosage unit preferably in an amount such that, when used over the
intended length of
time, it is sufficient for amenorrhea to occur.
In an preferred embodiment of the pharmaceutical agent according to the
invention, the
mesoprogestin is contained in each daily dosage unit in an amount that is
equivalent to 1 to
25 mg of J 867.
The bioequivalent doses of a mesoprogestin can be assessed in the McPhail
test.
The packaging that contains the pharmaceutical preparation according to the
invention is
prepared in such a way that, in addition to the one or two components
mesoprogestin and
estrogen in the respectively intended form of administration (orally in the
form of pills,
coated tablets, etc. in a blister pack, as may be appropriate for
mesoprogestin and/or
estrogen, or the estrogen as a skin patch and the mesoprogestin in the form of
pills, coated
tablets, etc. in a blister or in a capsule as a depot that is to be
administered once), said
packaging also contains instructions for the use of the pharmaceutical agent
(package
insert).
