U.S. patent application number 10/207907 was filed with the patent office on 2002-12-26 for pharmaceutical combined preparation and its use in the treatment of gynaecological disorders.
This patent application is currently assigned to Schering Aktiengesellschaft. Invention is credited to Muhn, Peter, Stockemann, Klaus.
Application Number | 20020198155 10/207907 |
Document ID | / |
Family ID | 7784640 |
Filed Date | 2002-12-26 |
United States Patent
Application |
20020198155 |
Kind Code |
A1 |
Stockemann, Klaus ; et
al. |
December 26, 2002 |
Pharmaceutical combined preparation and its use in the treatment of
gynaecological disorders
Abstract
The invention relates to a pharmaceutical combined preparation
of LHRH analogues and anti-oestrogens having tissue-selective
oestrogen activity and also to its use for the treatment of
gynaecological disorders, especially for the treatment of
endometrioses and myomas.
Inventors: |
Stockemann, Klaus; (Berlin,
DE) ; Muhn, Peter; (Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
Schering Aktiengesellschaft
Berlin
DE
|
Family ID: |
7784640 |
Appl. No.: |
10/207907 |
Filed: |
July 31, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10207907 |
Jul 31, 2002 |
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09117357 |
Sep 22, 1998 |
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09117357 |
Sep 22, 1998 |
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PCT/EP97/00395 |
Jan 29, 1997 |
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Current U.S.
Class: |
514/10.2 ;
514/10.3; 514/10.4; 514/21.7; 514/317; 514/320 |
Current CPC
Class: |
A61K 38/09 20130101;
A61P 15/00 20180101; A61P 43/00 20180101; A61K 38/09 20130101; A61K
31/445 20130101; A61K 38/09 20130101; A61K 31/40 20130101; A61K
38/09 20130101; A61K 31/135 20130101; A61K 38/09 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/16 ; 514/317;
514/320 |
International
Class: |
A61K 038/09; A61K
031/453; A61K 031/445 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 29, 1996 |
DE |
196 04 231.3 |
Claims
1. Pharmaceutical combined preparation comprising two active
ingredients one of which is an LHRH analogue or a combination of
LHRH analogues and the other of which is an anti-oestrogen having
tissue-selective oestrogenic activity.
2. Combined preparation according to claim 1, characterised in that
the LHRH analogue is an LHRH agonist or an LHRH antagonist.
3. Combined preparation according to claim 1 or 2, characterised in
that the LHRH analogue is selected from the group of compounds
Leuprorelin, Cetrorelix, Buserelin, Antide,
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys- (Mor)-D-Ala-NH.sub.2,
Ramorelix, Zoladex and derivatives thereof.
4. Combined preparation according to any one of claims 1 to 3,
characterised in that the LHRH analogue or the combination of LHRH
analogues is orally bioavailable.
5. Combined preparation according to any one of claims 1 to 4,
characterised in that the LHRH analogue is a non-peptidergic LHRH
agonist or antagonist.
6. Combined preparation according to any one of claims 1 to 5,
characterised in that the anti-oestrogen is selected from the group
of compounds Raloxifen, Droloxifen, Centchroman and derivatives
thereof.
7. Combined preparation according to any one of claims 1 to 6,
characterised in that the anti-oestrogen is of the Raloxifen
type.
8. Combined preparation according to any one of claims 1 to 7,
characterised in that the two active ingredients are in separate
forms of administration.
9. Combined preparation according to any one of claims 1 to 7,
characterised in that the two active ingredients are in joint forms
of administration.
10. Process for the manufacture of a pharmaceutical combined
preparation, characterised in that an LHRH analogue or a
combination of LHRH analogues and an anti-oestrogen having
tissue-selective activity are formulated with customary
pharmaceutical carriers, excipients and/or additives, separately
from one another or together.
11. Process according to claim 10, characterised in that the LHRH
analogue or the combination of LHRH analogues and the
anti-oestrogen having tissue-selective activity are formulated
separately from one another.
12. Process according to claim 10, characterised in that the LHRH
analogue or the combination of LHRH analogues and the
anti-oestrogen having tissue-selective activity are formulated
together.
13. The use of an LHRH analogue or a combination of LHRH analogues,
and of an anti-oestrogen having tissue-selective oestrogenic
activity, for the treatment of gynaecological disorders, especially
for the treatment of endometrioses and myomas.
14. Use according to claim 13, characterised in that LHRH analogue
and anti-oestrogen are administered simultaneously and/or in
chronological sequence.
15. Packaging unit comprising two spatially separately packaged
active ingredients, one of which is an LHRH analogue or a
combination of LHRH analogues and the other of which is an
anti-oestrogen having tissue-selective oestrogenic activity, and
comprising as third component an information leaflet on the
simultaneous and/or chronologically sequential administration of
the forms of administration.
Description
[0001] 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 for the
treatment of gynaecological disorders, especially for the treatment
of endometrioses and myomas.
[0002] Gynaecological disorders and diseases considerably reduce
the quality of life of women and frequently result, in some cases
in addition to unbearable pain, in infertility. 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 (dysmenorrhoea) and/or
intermenstrual bleeding (metrorrhagia, menorrhagia) and each,
depending on the condition, may also result in limited fertility.
In addition to dysmenorrhoea caused by endometriosis and by myomas,
dysmenorrhoea that is caused by functional disorders (by hormonal
and vegetative disorders) also occurs.
[0003] The gonal steroids (oestrogens, gestagens), which are under
the control of the hypothalamic-pituitary system, and growth
factors (including also cytokines) play a decisive role in the
clinical syndromes described. Treatment 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 effects. For
example, it is known that treatment with LHRH 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)).
[0004] 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.
[0005] 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 effects.
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.
[0006] The problem underlying the invention is therefore to prepare
a pharmaceutical combined preparation for the treatment of
gynaecological disorders, especially for the treatment of
endometrioses and myomas, with which a reduction in bone density is
prevented and the disadvantages of previous hormone treatments are
avoided.
[0007] The problem is solved in accordance with the invention by a
pharmaceutical combined preparation that comprises two active
ingredients, the first of which is an LHRH analogue or a
combination of LHRH analogues and the second of which is an
anti-oestrogen having tissue-selective oestrogenic activity.
[0008] The LHRH analogue is an LHRH agonist or antagonist.
[0009] Any LHRH antagonist or LHRH agonist may be used within the
scope of the invention. Preferred LHRH analogues are selected from
the group of compounds Leuprorelin, Cetrorelix, Antide, Buserelin,
Ramorelix, Zoladex, 2-(4-acetylaminophenyl)-4,
7-dihydro-7-(2-methoxybenzyl)-3-(N-methyl-N-be-
nzylaminomethyl)-4oxothieno [2,3-b]pyridine-5-carboxylic acid ethyl
ester and
5-benzoyl-7-(2,6-difluorobenzyl)-4,7-dihydro-3-(N-methyl-N-benzylamin-
o-methyl)
-2-(4-propionylamidophenyl)-4-oxothieno[2,3-b]pyridine.
[0010] The active ingredients are generally in separate forms of
administration or, in the case of orally bioavailable LHRH
antagonists, also in a joint form of administration.
[0011] The LHRH analogues preferably used are known and are
described in the patent specifications U.S. 4,005,063
(Leuprorelin), 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-NH.sub.2), U.S. 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-carboxyli- c acid ethyl ester).
[0012] They are prepared and packaged according to processes known
per 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.
[0013] A unit dose contains different amounts of active ingredient
depending in each case on the form of administration. For example,
in the case of oral administration usually from 2 .mu.g to 20 mg of
LHRH analogue is administered per kg of body weight. The
administration may be in solid or liquid form. For intravenous,
subcutaneous, intramuscular, intranasal or intravaginal
administration, the amounts of LHRH analogues are from 0.02 .mu.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, preferably to the pH value of the blood.
[0014] Leuprorelin is preferably used orally at a dose of from 2 to
100 .mu.g/kg of body weight (daily dose); one tablet contains
preferably from 0.1 to 5.0 mg of Leuprorelin. The dose for
parenteral administration is preferably from 0.02 to 1.0 .mu.g/kg
of body weight.
[0015] Cetrorelix is used preferably in the form of a physiological
saline with an amount of active ingredient of from 0.1 to 2.5 mg/kg
of body weight. In DE 43 42 092, also slow-release formulations of
Cetrorelix are described.
[0016] Buserelin is administered preferably in the following
doses:
[0017] from 0.02 to 1 .mu.g/kg of body weight (intravenous),
[0018] from 0.02 to 2 .mu.g/kg of body weight (subcutaneous),
[0019] from 0.02 to 10 .mu.g/kg of body weight (intramuscular),
[0020] from 0.1 to 50 .mu.g/kg of body weight (intranasal) and
[0021] from 10 to 200 .mu.g/kg of body weight (oral).
[0022] As in the case of Cetrorelix, slow-release formulations are
also possible. In the case of an implant, the implant contains from
1 to 6 mg of Cetrorelix.
[0023] Zoladex is preferably administered orally with a content of
from 50 .mu.g to 20 mg/kg of body weight and parenterally with a
content of from 0.02 .mu.g to 100 .mu.g/kg of body weight or using
a slow-release system (WO-A 93/24150).
[0024] Antide is, like Cetrorelix, administered in an amount of
from 0.1 to 2.5 mg/kg of body weight.
[0025] The administration of Ramorelix is carried out preferably in
liposomal form.
[0026] Depot formulations for peptides (microparticles, implants)
are described inter alia in EP 0 505 966 and EP 0 315 875.
[0027] According to the invention, the second active ingredient
component of the combined preparation is an anti-oestrogen having
tissue-selective oestrogenic activity.
[0028] Anti-oestrogenic substances are used inter alia in tumour
therapy.
[0029] Within the scope of the invention there are to be understood
by anti-cestrogens having tissue-selective oestrogenic activity
so-called SERMs (selective oestrogen-receptor modulators) which
exert their partial agonistic oestrogenic activity tissue- and
organ-selectively.
[0030] 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.
[0031] The anti-oestrogens mentioned are known. For example
Raloxifen is
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]th-
iophene. In combination with parathyroid hormone, Raloxifen and its
derivatives are used to increase bone mass (EP 0 635 270).
[0032] The active ingredient content of the anti-oestrogen used in
accordance with the invention is in the case of daily
administration from 0.1 .mu.g to 10 mg of antioestrogen per kg of
body weight, depending on the form of administration. The
anti-oestrogens may be administered intravenously, subcutaneously,
intramuscularly, orally, intranasally or intravaginally.
Slow-release formulations are also possible, in which case the
amount released daily lies also within the above-mentioned
range.
[0033] The administration of the LHRH analogue and of the
antio-estrogen to the patient may be simultaneous and/or
chronologically sequential. Various treatment regimes are possible
:
[0034] 1. The LHRH analogue is administered simultaneously with the
tissue-selective anti-oestrogen over the same period of time.
Administration 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.
[0035] In the case of monthly administration a depot formulation is
preferred.
[0036] 2. The LHRH analogue is first of all administered
simultaneously with the tissue-selective anti-oestrogen over a
particular period of 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.
[0037] 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 administered. For each
component, the period and frequency of administration may be
selected as indicated in 1.
[0038] 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, inhibited in its growth, is not stimulated
again, and the growth of the normal endometrium in the uterus also
is not stimulated.
[0039] The pharmaceutical combined preparation according to the
invention is suitable especially for long-term treatment of
endometrioses and myomas and other steroid (sex)-hormone-dependent
disorders, since on the one hand the side effects that normally
occur with an LHRH analogue (agonist or antagonist) treatment are
avoided and on the other hand lost bone mass is rebuilt (for
example in the case of administration of the tissue-selective
antioestrogen after completion of an LHRH analogue treatment). At
the same time the growth inhibition of the endometriosis is
maintained without the endometrium in the uterus being
stimulated.
[0040] Variant 1 has proved especially preferred for long-term
therapy.
[0041] The pharmaceutical combined preparation according to the
invention is prepared, for example, by formulating the LHRH
analogues and the anti-oestrogens having tissue-selective
oestrogenic activity separately from one another with the customary
pharmaceutical carriers, excipients and/or additives; the forms of
administration of the individual active ingredients do not have to
be identical. It is wholly possible, for example, for one active
ingredient of the combined preparation to be administered orally
while the other active ingredient is administered subcutaneously or
nasally.
[0042] In the case of orally bioavailable LHRH analogues, it is
also possible for the two active ingredients (LHRH analogues plus
anti-oestrogen) to be formulated together for oral administration.
Separate oral forms of administration are also possible.
[0043] The invention relates also to a packaging unit which, in the
case of peptidergic LHRH analogues, comprises at least three
components. The unit contains two spatially separately packaged
active ingredients, one of which is an LHRH analogue or a
combination of LHRH analogues, and the other of which is an
anti-oestrogen having tissue-selective oestrogenic activity. The
third component is an information leaflet for the simultaneous
and/or chronologically sequential administration of the forms of
administration.
[0044] The invention relates also to the use of an LHRH analogue 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.
[0045] The invention is illustrated further in the following by
Examples without, however, being limited to those Examples.
EMBODIMENT EXAMPLES
Example 1
Effect of LHRH Administration and Raloxifen Administration on
Experimentally Produced Endometriosis in the Rat
[0046] 1.1 Comparison of the Administration of Each of the Active
Ingredient Components Alone With the Simultaneous Administration of
the Active Ingredients (Combined Preparation)
[0047] Method:
[0048] Fragments of endometrium were transplanted into different
regions of the abdominal cavity of 60 animals.
[0049] Four weeks later the development of the endometriosis
(cystic endometriosis foci) was examined.
[0050] 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.
[0051] The combination of LHRH antagonist plus Raloxifen 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 the uterus (no stimulation of the endometrium) were
observed.
[0052] By comparison, although treatment with the LHRH antagonists
alone resulted in a complete regression of the endometriosis foci,
at the same time it caused a reduction in endogenous oestrogen
levels corresponding to an ovariectomy. The result was a distinct
reduction in bone density and an increase in osteoclast
activity.
[0053] Administration of Raloxifen alone resulted in a partial
regression of the endometriosis.
[0054] 1.2 LHRH antagonist Antide and Raloxifen for simultaneous
and chronologically sequential administration
[0055] 60 animals received the LHRH antagonist Antide and Raloxifen
in parallel for the first 2 weeks and Raloxifen alone for the
following 2 weeks. The doses were selected as in 1.1.
[0056] As with the simultaneous administration of 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 effects on the uterus.
[0057] 1.3. Chronologically sequential administration of the
combined preparation
[0058] 60 animals received the LHRH antagonist Antide for 2 weeks.
On completion of the LHRH administration Raloxifen was then
administered for 2 weeks.
[0059] This sequential treatment also resulted in 100% regression
of the endometriosis without a reduction in bone density.
EXAMPLE 2
[0060] Analogously to Example 1, treatment with LHRH antagonists
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys(Mor)-D-Ala-NH.sub.2 and
Droloxifen was carried out on 40 animals.
[0061] The same results could be achieved as in Example 1.
* * * * *