Note: Descriptions are shown in the official language in which they were submitted.
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WO 97/33589 PCT/DE97/00580
Sequential Estrogen/Progesterone Antagonist Combination
for Hormone Replacement Therapy
This invention relates to a pharmaceutical agent that
contains in combination individual dosage units of an estrogen
and individual dosage units of a competitive progesterone
antagonist for separate, sequential administration thereof,
packaging for hormone replacement therapy that contains
individual dosage units of an estrogen and individual dosage
units of a competitive progesterone antagonist for its separate,
sequential administration, and the use of the above-mentioned
pharmaceutical agent for hormone replacement therapy.
With the onset of menopause in women, so-called menopausal
symptoms occur owing to altered hormone production. Because of
reduced estrogen production, the risk of osteoporosis increases
at the same time (reduction of bone tissue while retaining the
same bone structure, due to increased bone degradation and/or
reduced bone growth); likewise in postmenopausal women, a
myocardial infarction rate that is significantly increased
compared to premenopausal women and an increased incidence of
other cardiovascular diseases are observed, which also can be
attributed to reduced estrogen production.
Hormone replacement therapy (= HRT) with estrogens or with
an estrogen/gestagen combination is currently the standard method
for treating the symptoms that are associated with menopause
(Ernster, V. L. et al. (1988): Benefits and Risks of Menopausal
Estrogen and/or Progestin Hormone Use; Prev. Med. 17:201-223).
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Estrogen exerts a protective action on the cardiovascular
system, on the bones (reduction of the risk of osteoporosis), and
on the central nervous system (avoidance of so-called "hot
flashes"). However, the chronic use of estrogens in hormone
replacement therapy leads to an increased risk of endometrial
carcinoma (Ernster, V. L. et al. (1988): Benefits and Risks of
Menopausal Estrogen and/or Progestin Hormone Use; Prev. Med.
17:201-223).
By simultaneously using a gestagen for hormone replacement
therapy, the stimulating effect of estrogen on the endometrium is
suppressed (Gibbson, W. E., 1986, Biochemical and Histologic
Effects of Sequential Estrogen/Progestin Therapy on the
Endometrium of Postmenopausal Women; Am. J. Obstet. Gynecol:
154:46-61); in contrast, however, in the case of combined therapy
with an estrogen and gestagen, the protective effects of the
estrogenic components with respect to the plasma lipids can at
least be attenuated (Lobo, R. (1992): The Role of Progestins in
Hormone Replacement Therapy; Am. J. Obstet. Gynecol. 166: 1997-
2004).
In addition, with an estrogen/gestagen treatment based on a
hormone dosage that is lower than with an oral contraceptive
agent, undesirable intracyclic menstrual bleeding can occur
(Hillard, T. C. et al. (1992): Continuous Combined Conjugated
Equine Estrogen-Progestagen Therapy: Effects of
Medroxyprogesterone Acetate and Norethindrone Acetate on Bleeding
Patterns and Endometrial Histologic Diagnosis; Am. J. Obstet.
Gynecol. 167: 1-7).
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Finally, recent findings show that many gestagens can
increase the risk of breast cancer (Staffa, J. A. et al. (1992):
Progestins and Breast Cancer: An Epidemiologic Review; 57: 473-
491); King, R. J. B. (1991): A Discussion of the Roles of
Estrogen and Progestin in Human Mammary Carcinogenesis; J. Ster.
Biochem. Molec. Bio. 39: 8111-8118).
In summary, the picture that forms is that the known
estrogen-mono- and estrogen/gestagen combination therapies do not
represent any satisfactory options for treating the symptoms that
are associated with menopause.
Recently, the use of "true" antiestrogens for the production
of pharmaceutical agents for hormone replacement therapy (HRT)
has also been proposed (EP-A-O 178 862). "True" antiestrogens
refer, according to EP-A-O 178 862, for example, to tamoxifen,
nafoxidine, MER-25, as well as those antiestrogens which act in a
receptor-mediated manner and which at the same time also have an
estrogenic (agonistic) partial action. This estrogenic partial
action occurs in the uterus and in bone.
A disadvantage to such a pharmaceutical agent that contains
a "true" antiestrogen with a partial estrogenic action is that,
owing to the chronically estrogenic stimulation of the
endometrium, such as occurs with use of estrogens, an increased
risk of the development of an endometrial carcinoma exists
(Fornander, T. et al. (1989): Adjuvant Tamoxifen in Early Breast
Cancer: Occurrence of New Primary Cancers: Lancet 21: 117-119).
In contrast, positive effects on the bone are produced by
the partial estrogenic action of tamoxifen; in women, tamoxifen
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seems to partially prevent the degradation of the bone mass
(Love, R. R. et al. (1992): Effects of Tamoxifen on Bone Mineral
Density in Postmenopausal Women with Breast Cancer; N. Engl. J.
Med. 26:852-856).
In addition, studies on tamoxifen have shown that its
antiestrogenic component is responsible for growth inhibition
when used in the treatment of breast cancer in postmenopausal
women (Buckley, M. M. T. et al. (1989); Tamoxifen: A Reappraisal
of its Pharmacodynamic and Pharmacokinetic Properties and
Therapeutic Use; Drugs 37: 451-490).
In addition, antiestrogens such as raloxifen for inhibiting
bone degradation and for treating perimenopausal syndrome have
become known (US Patent 5,393,763 or 5,391,557). Antiestrogens
of this type show a clearly reduced agonistic (estrogenic) action
on the endometrium, but exert a significantly estrogenic action
on the bone. Since these substances are also not completely
dissociated, however (i.e., they always have a residual
estrogenic action on the endometrium), they can also result in a
proliferation of the endometrium after long-term treatment.
Accordingly, the necessary chronic use of an antiestrogen
with a partial agonistic action in hormone replacement therapy
can be considered harmful since stimulation of the endometrium
can promote the development of endometrial carcinoma.
WO-EP 94/03408 proposes to avoid this permanent stimulation
of the endometrium by simultaneously using a compound with a
progesterone-antagonistic action as well as a compound with an
antiestrogenic action while at the same time there is a partial
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agonistic action for the production of a pharmaceutical agent for
hormone replacement therapy. In the case of such a
pharmaceutical agent, the component with a progesterone-
antagonistic action inhibits the changes that are caused by the
partial estrogenic action of the antiestrogen (stimulation of the
myometrium and endometrium) only in the uterus, while, however,
the other estrogenic effects, which are highly desired in hormone
replacement therapy, for example on bone and on the
cardiovascular system, remain unchanged.
The administration of an estrogen, optionally together with
a gestagen, both at very low dosages, which by themselves do not
ensure stable bleeding behavior, combined with a periodic, one-
time administration of an antiprogestin (progesterone antagonist)
for contraception and for hormone replacement therapy, is
described in WO-A 93/17686. The progesterone antagonist ensures
a reduction in breakthrough bleeding.
The joint, and preferably simultaneous use of a competitive
progesterone antagonist with an estrogen without gestagen is
described in WO-A 94/18983. The use of the estrogen according to
this publication is done entirely according to the conventional
principles of estrogen replacement therapy. The progesterone
antagonist is used in an amount that inhibits the endometrial
proliferation that is induced by estrogen.
In any case, chronic (e.g., daily) treatment with a
progesterone antagonist can lead to side-effects, for example in
the liver, because of the daily burden of the organism.
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The object of this invention is to provide a pharmaceutical
agent which is based on an estrogen and progesterone antagonist
for hormone replacement therapy and which has a stronger
antiproliferative action on the endometrium than the
pharmaceutical agent that is described according to WO-A 93/17686
and WO-A 94/18983.
This object is achieved by this invention, and specifically
by a pharmaceutical agent that contains in combination individual
dosage units of an estrogen and individual dosage units of a
competitive progesterone antagonist in its separate, sequential
administration.
This pharmaceutical agent can be used for hormone
replacement therapy.
In addition to the pharmaceutical agent, this invention also
relates to packaging that contains this pharmaceutical agent.
In the pharmaceutical agent according to the invention, the
dosage units that contain the progesterone antagonists are thus
used only after a specific length of time during which the
exclusively estrogen-containing dosage units were administered.
Over the period when the progesterone antagonist is administered,
no estrogen is provided. This sequential administration of the
progesterone antagonist inhibits proliferation of the endometrium
that is otherwise induced by estrogen and in addition reduces the
level of estrogen-dependent irregular bleeding. The use of the
progesterone antagonist thus results in protection of the
endometrium and ultimately induces amenorrhea. In this case, the
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protective effect of the estrogen on the bones remains fully
intact.
It has been found that such a pharmaceutical agent has,
surprisingly enough, a stronger antiproliferative action than the
pharmaceutical agents that are produced according to WO-A
93/17686 and WO-A 94/18983.
The stronger antiproliferative action of the pharmaceutical
agent according to the invention is due to the stronger
antiproliferative action of the progesterone antagonist in the
absence of estrogen than when a progesterone antagonist is used
simultaneously with an estrogen (WO-A 94/18983). The risk of an
"unopposed estrogen effect" is thus reduced.
Advantages of the pharmaceutical agent according to the
invention lie in the fact that, with the latter, the positive
effects of estrogen on the bones and the lipids are not inhibited
and no breakthrough bleeding is induced. This is achieved by
avoiding additional stress on the organism, as would be the case
with a combined treatment.
It was shown that in the case of ovariectomized Cynomolgus
monkeys (as animal models for postmenopausal women), the
proliferation of the myometrium or endometrium that is stimulated
by estradiol is inhibited by a progesterone antagonist such as RU
486 that is administered over a period of 7 days -- after 28 days
when estrogen was administered by itself.
The pharmaceutical agents according to the invention are
suitable both for preventive use and for curative use in hormone
replacement therapy (HRT), since degradation of bone mass is
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prevented by the estrogen and simultaneously the estrogen exerts
a protective effect on the cardiovascular system and the
undesirable stimulating effect on the endometrium is prevented by
the antiproliferative action of the progesterone antagonist.
These pharmaceutical agents are thus especially suitable for
long-term use in HRT.
In the pharmaceutical agent according to the invention, the
dosage units of the estrogen are intended for administration
preferably over a period of 28 to 112 days.
In another embodiment of the pharmaceutical agent according
to the invention, the dosage units of the competitive
progesterone antagonist are provided for administration over a
period of at least 4 days and at most 30 days.
A special embodiment of the pharmaceutical agent according
to the invention contains the dosage units of the competitive
progesterone antagonist for administration over a period of 7
days.
The pharmaceutical agent according to the invention is
preferably designed in such a way that the dosage units of
estrogen and the dosage units of the competitive progesterone
antagonist are present together in the pharmaceutical agent in
such a number that the sum of the number of daily dosage units of
the estrogen and the dosage units of the competitive progesterone
antagonist is 28 or 28 plus 7 or 28 plus a multiple of 7.
The taking of this embodiment of the pharmaceutical agent
according to the invention thus leads to an administration cycle
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that lasts exactly a certain number of weeks, but at least four
weeks.
As examples, the following compositions can be used:
28 daily units of estrogen + 7 daily units of progesterone
antagonist, 28 daily units of estrogen + 14 daily units of
progesterone antagonist, 28 daily units of estrogen + 21 daily
units of progesterone antagonist, 56 daily units of estrogen + 21
daily units of progesterone antagonist, etc.
Compositions of the pharmaceutical agent according to the
invention that are preferred as well are also possible, however,
in which the number of the daily dosage units of estrogen and the
number of dosage units of the competitive progesterone
antagonists are not in each case 7 or a multiple of 7: it is
important only that the sum of these daily units can be divided
by 7, i.e., the taking of the pharmaceutical agent leads to an
exactly 4-week or multiple-week administration cycle.
According to another embodiment, estrogen is present in
dosage units that are intended for daily administration.
The progesterone antagonist can also be present in daily
oral dosage units.
If the dosage units of the competitive progesterone
antagonist 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.
In such a dosage unit that is to be administered once a
week, the progesterone antagonist should preferably be prepared
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in a formulation that results in a delayed release of the active
ingredient.
A delayed release of the competitive progesterone antagonist
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 competitive
progesterone antagonist 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. This principle is implemented
in, for example, the esters of 11B-[4-N,N-(dimethylamino)phenyl]-
17a-hydroxy-17B-(3-hydroxypropyl)-13a-methyl-4,9(10)-gonadien-3-
one (onapristone) that are described in EP-A 0 186 834.
The estrogenic aspect of this invention is analogous to
conventional estrogen replacement therapy. Consequently, any
compound that is effective as estrogen can be used in the known
doses and according to the methods that are known for estrogen
replacement therapy.
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, 178-estradiol as
well as its esters such as estradiol-3-benzoate, estradiol-17-
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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. Steroid Biochem. Molec. Biol., Vol. 55, No.
3/4, 395-403, 1995; DE 44 29 398 Al and DE 44 29 397 Al), can
also be used in the pharmaceutical agent according to the
invention.
Finally, the orally bioavailable derivatives of 173- and
17a-estradiol with a modified D-ring of the steroid skeleton are
also suitable.
The use of a natural estrogen (also conjugated estrogens) or
a prodrug of a natural estrogen is preferred according to the
invention.
The progesterone antagonist is preferably selected for this
invention from the group of compounds
118-[4-(dimethylamino)phenyl]-17B-hydroxy-l7a-(1-
propinyl)estra-4,9-dien-3-one (RU 38 486)
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11B-[4-(dimethylamino)phenyl]-17B-hydroxy-17a-(1-propinyl)-
18a-homoestra-4,9-dien-3-one
118-[4-(dimethylamino)phenyl]-17aB-hydroxy-17aa-(1-
propinyl)-17a-homoestra-4,9,16-trien-3-one
17a-ethinyl-17B-hydroxy-11B-(4-methoxyphenyl)estra-4,9-dien-
3-one
11B-(4-acetylphenyl)-17B-hydroxy-17a-(1-propinyl)estra-4,9-
dien-3-one
the 19,118-bridged steroids from EP-A 0283 428,
the 10B-H steroids from EP-A 0 404 283, especially
(Z)-118-[4-(dimethylamino)phenyl]-17B-hydroxy-17a-(3-
hydroxy-l-propenyl)estr-4-en-3-one
118-[4-(dimethylamino)phenyl]-17a-hydroxy-17B-(3-
hydroxypropyl)-13a-estra-4,9-dien-3-one (onapristone)
(Z)-118-(4-acetylphenyl)-17B-hydroxy-17a-(3-hydroxy-l-
propenyl)estra-4,9-dien-3-one
(Z)-6'-(4-cyanophenyl)-9,lla-dihydro-17B-hydroxy-17a-(3-
hydroxy-l-propenyl)-4'H-naphth[3',2',1':10,9,11]estra-4,9(11)-
dien-3-one
(Z)-9,lla-dihydro-17B-hydroxy-17a-(3-hydroxy-l-propenyl)-6'-
(3-pyridinyl)-4'H-naphth[3',2',1':10,9,11]estra-4,9(11)-dien-3-
one
4',5'-dihydro-11B-[4-(dimethylamino)phenyl]-68-
methylspiro[estra-4,9-diene-17B,2'(3'H)-furan]-3-one
4',5'-dihydro-11B-[4-(dimethylamino)phenyl]-78-
methylspiro[estra-4,9-diene-17B,2'(3'H)-furan]-3-one
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118-(.4-acetylphenyl)-19,24-dinor-17,23-epoxy-17a-chola-
4,9,20-trien-3-one.
Especially preferred for the purposes of this invention are
the progesterone antagonists
11B-[4-(dimethylamino)phenyl]-17A-hydroxy-17a-(1-
propinyl)estra-4,9-dien-3-one (RU 38 486)
(Z).-11B-[4-(dimethylamino)phenyl]-17B-hydroxy-17a-(3-
hydroxy-l-propenyl)estr-4-en-3-one
4',5'-dihydro-11B-[4-(dimethylamino)phenyl]-68-
methylspiro[estra-4,9-diene-178-2'(3'H)-furan]-3-one
4',51-dihydro-11B-[4-(dimethylamino)phenyl]-78-
methylspiro[estra-4,9-diene-178,2'(3'H)-furan]-3-one
118-(4-acetylphenyl)-19,24-dinor-17,23-epoxy-17a-chola-
4,9,20-trien-3-one.
For the purposes of this.invention, the formulation of the
estrogen and progesterone antagonist is. done in a completely
conventional manner, as is already known for the formulation of
these compounds for their individual use in hormone replacement
therapy for estrogen, for example Cyclo-Progynova, or in tumor
therapy or for abortion for progesterone antagonists, for'example
mifepristones.
In particular, reference is also made to the information
that is contained in WO-A 93/17686 and WO-A 94/18983.
In addition to oral administration of the estrogen and the
progesterone antagonist, it is equally possible to administer one
or both of the components transdermally, for example with a.skin
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patch, which is best known for the administration of estrogen
:;, = .
(Climara Patch).
In addition, administration can be done using an
intrauterine release system, 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. .
The estrogen is contained per daily dosage unit according to
the invention in'an amount of 1 to 2 mg of estradiol or. a
bioequivalent amouht of another estrogen.
As bioequivalent amounts of other estrogens for the purposes
of this invention, the following amounts can be considered:
ethinylestradiol 5-35 g
conjugated estrogens 0.625 to 1.25 mg.
In the case of transdermal administration'of the estrogen,
the transdermal administration system should release daily
approximately 50 g of estradiol or a bioequivalent amount of
another estrogen.
The administration of the estrogen using a.vaginal. cream or
vaginal ring is also possible. The daily amounts.are about 1.25
mg or 0.2 mg in the case of estradiol. In this case, these are
only approximate values. .
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M1 .
In the pharmaceutical agent according to the invention, the
competitive progesterone antagonist 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 especially preferred embodiment of the pharmaceutical
agent according to the invention, the competitive progesterone
antagonist is contained in each daily dosage unit in an amount
that is equivalent to 0.5 mg to 10 mg, preferably 1 mg to 5 mg of
RU 486.
=
The packaging that contains the pharmaceutical agent
according ta the invention is prepared in such a way that, in
addition to the two components estrogen,or an antiestrogen
with partical agonistic action, and progesterone
antagonist 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 estrogen and/or progesterone
antagonists, or the estrogen as a skin patch and the progesterone
antagonist 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). Particularly, said
packaging contains instructions for administration of the dosage
units of estrogenl)or antiestrogen with a partial agonistic action5'
in the absence of dosage units of the competitive progesterone antagonist.
