Note: Descriptions are shown in the official language in which they were submitted.
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ph~m~ceutical combined preparation and its use in the
treatment of gynaecological disorders
The invention relates to a pharmaceutical combined
preparation of LHRH analogues and anti-oestrogens having
a tissue-selective oestrogenic activity, and also to its
use ~or the treatment of gynaecological disorders,
especially for the treatment o~ endometrioses and myomas
Gynaecological disorders and diseases considerably reduce
the quality of life of women and frequently result, in
some cases in addition to unbearable pain, in infer-
tility One of the most common diseases in women of
child-bearing age (5 ~ to 10 ~) is endometriosis
Associated with it are severe pain during menstruation
and a limited fertility rate to sterility In the case of
the myoma, a benign tumour in the muscle tissue of the
uterus, the incidence is high too (in 10 to 25 ~ of women
in their 30s). Myomas may cause heavy abnormal menstrual
bleeding (hypermenorrhoea), painful menstruation (dys-
menorrhoea) and/or intermenstrual bleeding (metrorrhagia,
menorrhagia) and each, depending on the condition, may
also result in limited fertility In addition to dys-
menorrhoea caused by endometriosis and by myomas,
dysmenorrhoea that is caused by functional disorders (by
hormonal and vegetative disorders) also occurs
The gonal steroids (oestrogens, gestagens), which are
under the control of the hypothalamic-pituitary system,
and growth ~actors (including also cytokines) play a
decisive role in the clinical syndromes described. Treat-
ment of such diseases and disorders is usually effected
with hormones, such as LHRH analogues (Lemay, A. et al ,
Fertil. Steril., 41, 863-871 (1984)). In some women,
however, these are not tolerated without side ef~ects
For example, it is known that treatment with LHRH
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agonists may result in side effects such as, for example,
hypo-oestrogenaemia (risk of osteoporosis) (Dawood, M.Y.
et al., Fertil. Steril. 52, 21-25, (1989)) and treatment
with danazol may result in androgenisation phenomena
(Dmowski, W.P. et al., Am. J. Obstet. Gynecol., 130, 41-
48 (1978)).
No established and proven long-term medicament treatment
has existed hitherto for myomas. The medicament treatment
currently used is associated with distinct side effects
For example, the use of LHRH agonists for more than six
months results in a hypo-oestrogenic state in women
(Matta, W H. et al., Br. Med J., 294, 1523-1525, (1987))
and, associated with that, a reduction in bone density,
which increases the risk of osteoporosis (Dawood, M Y
Int. J Gynecol. Obstet., 40, 29-42 (1993)) Other side
effects associated with oestrogen withdrawal (hot
flushes) are also described by Dawood
Studies for the treatment of gynaecological disorders
with LHRH analogues and oestrogens - so-called Add-Back
or HRT treatment regimes - are known for the purpose of
avoiding those side ef~ects. The discovery of an
oestrogen dose that completely prevents a reduction in
bone density using LHRH agonist therapy (Howell, R. et
al., Fertil, Steril. 64, 474-481, (1995)) without at the
same time stimulating endometriosis or stimulating the
endometrium, which may result in endometrium hyperplasia
and, associated with that, endometrium carcinomas, has
hitherto been unsuccessful, however.
The problem underlying the invention is therefore to
prepare a pharmaceutical combined preparation for the
treatment o~ gynaecological disorders, especially for the
treatment of endometrioses and myomas, with which a
reduction in bone density is prevented and the dis-
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advantages of previous hormone treatments are avoided.
The problem is solved in accordance with the invention by
a pharmaceutical combined preparation that comprises two
active ingredients, the ~irst of which is an LHRH
analogue or a combination o~ LHRH analogues and the
second o~ which is an anti-oestrogen having tissue-
selective oestrogenic activity.
The LHRH analogue is an LHRX agonist or antagonist.
Any LHRH antagonist or LHRH agonist may be used within
the scope of the invention. Pre~erred LHRH analogues are
selected ~rom the group o~ compounds Leuprorelin,
Cetrorelix, Antide, Buserelin, Ramorelix, Zoladex, 2-(4-
acetylaminophenyl)-4,7-dihydro-7-(2-methoxybenzyl)-3-(N-
methyl-N-benzylaminomethyl)-4-oxothienot2,3-b]pyridine-
5-carboxylic acid ethyl ester and 5-benzoyl-7-(2,6-
di~luorobenzyl)-4,7-dihydro-3-(N-methyl-N-benzylamino-
methyl)-2-(4-propionylamidophenyl)-4-oxothieno[2,3-
b]pyridine.
The active ingredients are generally in separate ~orms o~
administration or, in the case o~ orally bioavailable
LHRH antagonists, also in a joint ~orm o~ administration.
The LHRH analogues pre~erably used are known and are
described in the patent speci~ications US 4 005 063
(heuprorelin), EP-B1 0 299 402 (Cetrorelix), GB 1 523 623
(Buserelin), EP-A 0 451 791 (Ramorelix), WO-A 89/01944
(Antide), WO-A 92/20711 (Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-
Cit-Leu-Lys(Mor)-D-Ala-NH2), US 4 100 274 (Zoladex) and
WO-A 95/28405 (2-(4-acetylaminophenyl)-4,7-dihydro-7-(2-
methoxybenzyl)-3-(N-methyl-N-benzylaminomethyl)-4-
oxothieno[2,3-b]pyridine-5-carboxylic acid ethyl ester).
CA 0224467~ 1998-07-28
They are prepared and packaged according to processes
known E~E se and, depending on the desired use, are
available in oral or nasal form, in the form of an
injection, or in the form of a long-term preparation to
be administered topically or intravaginally. According to
the invention, the LHRH analogues may be administered as
individual doses or as depot forms.
A unit dose contains different amounts of active in-
gredient depending in each case on the form of admin-
istration. For example, in the case of oral administra-
tion usually ~rom 2 ~g to 20 mg of LHRH analogue is
administered per kg of body weight. The administration
may be in solid or liquid ~orm. For intravenous, sub-
cutaneous, intramuscular, intranasal or intravaginal
administration, the amounts of LHRH analogues are from
0 02 ~g to 2.5 mg per kg of body weight. For parenteral
administration there is preferably used an isotonic
sodium chloride or dextrose solution that optionally is
adjusted with a buffer to a pH value of from 5 to 9,
pre~erably to the pH value of the blood.
Leuprorelin is preferably used orally at a dose of from 2
to 100 ~g/kg of body weight (daily dose); one tablet
contains preferably ~rom 0.1 to 5.0 mg of Leuprorelin
The dose ~or parenteral administration is preferably ~rom
0 02 to 1 0 ~g/kg o~ body weight
Cetrorelix is used preferably in the form of a physio-
logical saline with an amount o~ active ingredient o~
from 0.1 to 2.5 mg/kg of body weight. In DE 43 42 092,
also slow-release formulations of Cetrorelix are des-
cribed.
Buserelin is administered preferably in the following
doses :
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from 0.02 to 1 ~g/kg of body weight (intravenous),
from 0.02 to 2 ~g/kg of body weight (subcutaneous),
from 0.02 to 10 ~g/kg o~ body weight (intramuscular),
from 0.1 to 50 ~g/kg of body weight (intranasal) and
from 10 to 200 ~g/kg o~ body weight (oral).
As in the case of Cetrorelix, slow-release formulations
are also possible. In the case of an implant, the implant
contains ~rom 1 to 6 mg of Cetrorelix.
Zoladex is preferably administered orally with a content
of from 50 ~g to 20 mg/kg of body weight and parenterally
with a content of from 0.02 ~g to 100 ~g/kg of body
weight or using a slow-release system (WO-A 93/24150).
Antide is, like Cetrorelix, administered in an amount of
from 0.1 to 2.5 mg/kg of body weight.
The administration o~ Ramorelix is carried out preferably
in liposomal ~orm.
Depot ~ormulations for peptides (microparticles,
implants) are described inter alia in EP 0 505 966 and
EP 0 315 875.
According to the invention, the second active ingredient
component of the combined preparation is an anti-
oestrogen having tissue-selective oestrogenic activity.
Anti-oestrogenic substances are used inter alia in tumour
therapy.
Within the scope o~ the invention there are to be
understood by anti-oestrogens having tissue-selective
oestrogenic activity so-called SERMs (selective
oestrogen-receptor modulators) which exert their partial
CA 0224467~ 1998-07-28
agonistic oestrogenic activity tissue- and organ-selec-
tively.
Any antioestrogen having tissue-selective oestrogenic
activity may be used in accordance with the invention.
Preferably used are those selected from the group
Raloxifen, Droloxifen, Centchroman and derivatives
thereof. Anti-oestrogens of the Raloxifen type are
especially preferred
The anti-oestrogens mentioned are known. For example
Raloxifen is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-
piperidinoethoxy)benzoyl]benzo[b]thiophene. In combina-
tion with parathyroid hormone, Raloxifen and its deriva-
tives are used to increase bone mass (EP 0 635 270).
The active ingredient content of the anti-oestrogen used
in accordance with the invention is in the case of daily
administration from 0.1 ~g to 10 mg o~ antioestrogen per
kg of body weight, depending on the form of administra-
tion The anti-oestrogens may be administered intraven-
ously, subcutaneously, intramuscularly, orally, intra-
nasally or intravaginally. Slow-release formulations are
also possible, in which case the amount released daily
lies also within the above-mentioned range.
The administration of the LHRH analogue and of the anti-
oestrogen to the patient may be simultaneous and/or
chronologically sequential. Various treatment regimes are
possible :
1. The LHRH analogue is administered simultaneously with
the tissue-selective anti-oestrogen over the same period
of time ~m; n; stration is possible daily, every three
days, weekly or once monthly over a period of from 1 to 6
months. Longer administration is also readily possible.
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In the case of monthly administration a depot formulation
is preferred.
2. The LHRH analogue is first of all administered
simultaneously with the tissue-selective anti-oestrogen
over a particular period o~ time. The information given
in 1 applies in respect of period and frequency of
administration (daily or at greater intervals). Treatment
is then continued with the anti-oestrogen only.
Here, too, the information given in 1 applies in respect
of period and frequency of administration.
3. The treatment with the LHRH analogue is conducted over
a particular period of time and terminated Following
this the tissue-selective anti-oestrogen is then admin-
istered. For each component, the period and frequency of
administration may be selected as indicated in 1.
It was established that the treatment with the combined
preparation according to the invention surprisingly
prevents the hitherto observed LHRH analogue-induced
reduction in bone density, and the endometriosis, inhib-
ited in its growth, is not stimulated again, and the
growth of the normal endometrium in the uterus also is
not stimulated.
The pharmaceutical combined preparation according to the
invention is suitable especially ~or long-term treatment
o~ endometrioses and myomas and other steroid(sex)-
hormone-dependent disorders, since on the one hand the
side ef~ects that normally occur with an LHRH analogue
(agonist or antagonist) treatment are avoided and on the
other hand lost bone mass is rebuilt (~or example in the
case o~ administration o~ the tissue-selective anti-
oestrogen after completion of an LHRH analogue treat-
ment). At the same time the growth inhibition of the
CA 0224467~ 1998-07-28
endometriosis is maintained without the endometrium in
the uterus being stimulated.
Variant 1 has proved especially preferred for long-term
therapy.
The pharmaceutical combined preparation according to the
invention is prepared, ~or example, by formulating the
LHRH analogues and the anti-oestrogens having tissue-
selective oestrogenic activity separately ~rom one
another with the customary pharmaceutical carriers,
excipients and/or additives; the forms o~ administration
o~ the individual active ingredients do not have to be
identical. It is wholly possible, ~or example, for one
active ingredient o~ the combined preparation to be
administered orally while the other active ingredient is
administered subcutaneously or nasally.
In the case o~ orally bioavailable LHRH analogues, it is
also possible ~or the two active ingredients (L ~H
analogues plus anti-oestrogen) to be ~ormulated together
~or oral administration. Separate oral ~orms o~ admin-
istration are also possible.
The invention relates also to a packaging unit which, in
the case o~ peptidergic LHRH analogues, comprises at
least three components. The unit contains two spatially
separately packaged active ingredients, one o~ which is
an LHRH analogue or a combination o~ LHRH analogues, and
the other o~ which is an anti-oestrogen having tissue-
selective oestrogenic activity. The third component is an
in~ormation lea~let ~or the simultaneous and/or chrono-
logically sequential administration o~ the ~orms o~
administration.
The invention relates also to the use o~ an LHRH analogue
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or a combination of LHRH analogues and an anti-oestrogen
having tissue-selective oestrogenic activity for the
treatment of gynaecological disorders, especially for the
treatment of endometrioses and myomas.
The invention is illustrated further in the following by
Examples without, however, being limited to those
Examples.
Embo~; ~n t Examples
Example 1
Bffect of LHRH administration and Raloxifen administra-
tion on experimentally produced endometriosis in the rat
1 1 Comparison of the ~mi ni stration of each of the
active ingredient components alone with the simul-
taneous administration of the active ingredients
(combined preparation)
Method:
Fragments of endometrium were transplanted into different
regions of the abdominal cavity of 60 animals.
Four weeks later the development of the endometriosis
(cystic endometriosis foci) was examined
The animals were then treated for 4 weeks with the LHRH
antagonists Antide (0.5 mg/animal every 3 days s.c.) and
Raloxifen (3 mg/animal per day p.o.) in each case alone,
or in a combination of the two compounds At the end the
size of the endometriosis foci before the beginning of
the treatment was compared with the values after 4 weeks'
treatment
The combination of LHRH antagonist plus Raloxifen
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resulted in a complete regression of the endometriosis
without there being a significant reduction in bone mass.
At the same time no oestrogenic effects on ~he uterus (no
stimulation of the endometrium) were observed.
By comparison, although treatment with the LHRH antagon-
ists alone resulted in a complete regression of the
endometriosis foci, at the same time it caused a reduc-
tion in endogenous oestrogen levels corresponding to an
ovariectomy. The result was a distinct reduction in bone
density and an increase in osteoclast activity.
A~lm;n- stration of Raloxifen alone resulted in a partial
regression of the endometriosis.
1.2 LHRH antagonist Antide and Raloxifen for simul-
taneous and chronologically sequential admini~tra-
tion
60 ~n;m~l s received the LHRH antagonist Antide and
Raloxifen in parallel ~or the first 2 weeks and Raloxifen
alone for the following 2 weeks The doses were selected
as in 1.1.
As with the simultaneous administration o~ the active
ingredients, the result to be recorded was a complete
regression of the endometriosis without a significant
reduction in bone mass. At the same time there were no
oestrogenic e~ects on the uterus.
1.3. Chronologically sequential administration of the
combined preparation
60 animals received the LHRH antagonist Antide for 2
weeks. On completion of the LHRH administration Ral-
oxi~en was then administered for 2 weeks.
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~his sequential treatment also resulted in 100 ~regression o~ the endometriosis without a reduction in
bone density.
~xam~le Z
Analogously to Example 1, treatment with LHRH antagonists
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys(Mor)-D-Ala-
NH2 and Droloxi~en was carried out on 40 animals.
The same results could be achieved as in Example 1.
