Note: Descriptions are shown in the official language in which they were submitted.
CA 0221~382 1997-09-1~
Once-A-Month Injection a~ a Depot Contraceptive and
for Hormone Replacement Therapy for
Perimenopausal and Premenopausal Women
This invention relates to the use of a once-a-month
injection (once-a-month injectable composition) that contains an
estrogenic and gestagenic component as an active ingredient for
the production of a pharmaceutical agent for contraception and
simultaneous hormone replacement therapy for perimenopausal and
premenopausal women.
A once-a-month injection as defined, by this invention means
a hormone preparation that is injected in women of child-bearing
age once a month for contraception. In this hormone preparation,
a gestagenic as well as an estrogenic component are contained as
active substances, each with a sufficiently long action to
achieve a contraceptive effect for a one-month period.
So-called progestogen-only injectables are also available,
which ensure longer-lasting contraceptive protection, but with
poor cycle control.
The best known representatives of such a once-a-month
injection are Cyclofem (HRP 112; Cycloprovera) and Mesigyna (HRP
102). The former contains 25 mg of medroxyprogesterone acetate
as a gestagenic component and 5 mg of estradiol cyprionate as an
estrogenic component in a microcrystal suspension, while the
latter contains 50 mg of norethisterone enanthate as a gestagenic
component and 5 mg of estradiol valerate as an estrogenic
component in an oily solution. Although the women that select
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these methods of prevention have to visit a family planning
center or a physician each month to have the injection
administered, these once-a-month injections are readily used for
contraception. Vaginal bleeding occurs like menstruation more or
less regularly and predictably, which is of tremendous importance
for ensuring broad acceptance of these reliable methods in many
cultural groups. (Biennial Report 1988-1989, Research in Human
Reproduction, WHO).
A method for hormonal treatment of menopausal, including
perimenopausal and postmenopausal, disorders is already described
in US Patent 4,826,831, which especially relates to a treatment
during continuous use of a gestagen in connection with an
estrogen. In this case, the estrogen can also be used
continuously or else cyclically, i.e., with pauses in intake.
A considerable number of estrogens and gestagens are known
that are suitable for the purpose of this invention, i.a., even
norethisterone acetate and medroxyprogesterone acetate as
gestagens as well as estradiol valerate. In principle, all
estrogens and gestagens that also are conceivable in oral
contraceptives should be usable. Adequate contraceptive
protection is not expressly provided by the described treatments.
In addition, norethisterone acetate/estradiol valerate is
disclosed as a possible combination. The quantities of gestagen
and estrogen that are used are low: the gestagen corresponds to
a daily quantity that corresponds to a quantity of 0.025 mg to
0.075 mg of levonorgestrel, and the estrogen corresponds to a
CA 0221~382 1997-09-1~
daily quantity that corresponds to a quantity of 0.5 to 2.0 mg of
estradiol.
In the case of oral administration of active ingredients,
the quantity of estradiol valerate that is to be administered
daily is in a range of O.S mg to 2.0 mg; a daily quantity of 0.1
mg to 1.0 mg is indicated for norethisterone acetate, and a
quantity of from 1.0 mg to 15.0 mg is indicated for
medroxyprogesterone acetate. US-PS 4,826,831 also comprises the
non-oral administration of the indicated active ingredients using
implants or by intramuscular injection. The required "daily"
dosages are then somewhat lower than in the case of oral
administration because of the direct transition of the active
ingredients into the blood stream.
20 mg to 100 mg of estradiol valerate is indicated for an
estrogen implant. A gestagen depot formulation for 3 months is
to contain S0 to 500 mg of medroxyprogesterone acetate or 20 to
400 mg of norethisterone enanthate.
This patent also relates to pharmaceutical compositions for
implementing this method.
With this method, the symptoms that are associated with the
natural removal of estrogen, which begins as early as in
premenopause, such as, for example, hot flashes, dryness of the
vagina, the risk of osteoporosis, and the increasing risk in
women over age 60 of suffering myocardial infarction
(cardiovascular complications), are effectively counteracted,
whereby based on the gestagenic components, however, induction of
CA 022l~382 l997-09-l~
bleeding is suppressed, but the risk of endometrial carcinomas
forming is not increased.
US-PS 4,826,831 expressly mentioned that in the case of oral
administration, this is not a method of contraception.
In terms of this invention, perimenopause and premenopause
are to be defined with their conventional meanings, as is
indicated in "The Controversial Climacteric," P. A. van Keep et
al., Ed., MTP Press (1981) on page 9.
The object of this invention is to make available a depot
pharmaceutical agent that is suitable for women in perimenopause
and premenopause equally for still necessary contraception and
for hormonal substitution therapy (Hormone Replacement Therapy =
HRT) that is advisable already in this phase of life.
It has now been found that such a pharmaceutical agent for
premenopausal and perimenopausal women can be produced,
surprisingly enough, based on a once-a-month injection. While
bleeding of the women under treatment is to be especially avoided
by the methods that are described in US-PS 4,826,831, monthly
bleeding occurs in perimenopausal or premenopausal women after
administration of the once-a-month injection according to the
invention at the end of the treatment period; thus no amenorrhea
is induced.
Once-a-month injections in terms of this invention are to be
defined both as the already initially mentioned products and all
other conceivable combinations of a natural estrogen with a
gestagen. In this case, the two active components have to be
present in a depot formulation, whereby the depot effect is
CA 022l~382 l997-09-l~
achieved either by the special type of galenical formulation (for
example, a microcrystal suspension) or else, more likely, by the
chemical structure of the gestagen and/or estrogen (for example,
by the esterification of free hydroxy groups).
In principle, all natural estrogens and all gestagens are
considered that are suitable for use in oral contraceptives, and
they can be converted in the above-mentioned way into a galenical
formulation or a chemical form can be derived that produces a
depot effect, and the dosage form that is to be administered
intramuscularly can be produced. As estrogens, primarily 17B-
estradiol, estradiol-3-benzoate, estradiol-17-valerate,
-cypionate, -undecylate, -enanthate and/or other estradiol esters
are suitable here (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).
The gestagenic component is preferably selected from the
groups of compounds norethisterone acetate, norethisterone
enanthate, medroxyprogesterone acetate, and cyproterone acetate.
Selected estrogens or gestagens that are to be used
according to this invention are listed in the following tables lA
and 2A with indication of the preferred quantity range. The
especially preferred quantities of the respective estrogen or
gestagen, which are to be contained in a once-a-month injection
according to this invention, are described in Tables lB and 2B.
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Table lA
Ninimum Do~age Maximum Dosage
(mg) (mg)
17B-Estradiol 4 10
Estradiol valerate 4 10
Estradiol cipionate 4 10
Table lB
Dosage
(mg)
Estradiol 17B 5
Estradiol valerate 5
Estradiol cipionate 5
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Table 2A
Minimum Dosage Maximum Dosage
(mg) (mg)
Norethisterone 20 60
acetate
Norethisterone 20 60
enanthate
Medroxyprogesterone 12.5 30
acetate
Cyproterone acetate 40 100
Table 2B
Dosage
(mg)
Norethisterone acetate 50
Norethisterone enanthate 50
Medroxyprogesterone acetate 25
Cyproterone acetate 50
According to the invention, the combination of
medroxyprogesterone acetate/estradiol cypionate is preferred for
the production of a once-a-month injection for perimenopausal and
premenopausal contraception; the norethisterone
enanthate/estradiol valerate combination is especially preferred.
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As special advantages of the once-a-month injection that is
produced according to the invention, which can be used on
premenopausal women, surprisingly enough, both for contraception
and for hormone replacement therapy, the following can primarily
be mentioned:
~ a more reliable contraceptive effect without
ethinylestradiol with "natural" estrogen;
~ accompanying active therapy of the beginning estrogen-
loss symptoms (elimination of menopausal symptoms);
~ simultaneous optimum osteoporosis prevention;
~ outstanding tolerance and cycle control;
~ virtually no change in blood pressure;
~ very low, almost nonexistent undesirable side-effects
and influences on metabolic and hemostatic parameters;
~ avoidance of burdening the liver, as well as of
gastrointestinal disorders based on the parenteral
method of application;
~ preserving the advantageous side effects of oral
contraceptives (protection from ovarial and endometrial
carcinomas and pelvic inflammatory disease tPID]).
All these properties were documented by a 3-year clinical
study with Mesigyna, whereby 17- to 35-year-old women
participated in the group of patients.
The especially preferred embodiment based on the
gestagen/estrogen combination of norethisterone
enanthate/estradiol valerate offers not only a prophylactic
effect with respect to osteoporosis, but even a bone build-up
CA 0221~382 1997-09-1
effect caused by norethisterone enanthate is observed in this
combination owing to the bone-degradation-inhibiting action of
the estrogen.
CA 02215382 1997-09-15
Formulation Examples
Me~Ygina
An ampoule contains
50 mg of norethisterone enanthate +
S mg of estradiol valerate
in 1 ml of castor oil/benzyl benzoate 6/4 (V/V).
Formul~tion with cYproterone Acetate
An ampoule contains
50 mg of cyproterone acetate +
5 mg of estradiol valerate
in 1 ml of castor oil/benzylbenzoate 6/4 (V/V).
