CA2244675A1 - Pharmaceutical combined preparation and its use in the treatment of gynaecological disorders - Google Patents
Pharmaceutical combined preparation and its use in the treatment of gynaecological disorders Download PDFInfo
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- CA2244675A1 CA2244675A1 CA 2244675 CA2244675A CA2244675A1 CA 2244675 A1 CA2244675 A1 CA 2244675A1 CA 2244675 CA2244675 CA 2244675 CA 2244675 A CA2244675 A CA 2244675A CA 2244675 A1 CA2244675 A1 CA 2244675A1
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Abstract
A combined pharmaceutical preparation contains LHRH-analogous substances and anti-estrogens with tissue-selective estrogenic effect. Also disclosed is the use of this combined pharmaceutical preparation to treat gynaecological disorders, in particular endometriosis and myomas.
Description
CA 0224467~ 1998-07-28 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
CA 0224467~ 1998-07-28 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-CA 0224467~ 1998-07-28 ~ .
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 :
CA 0224467~ 1998-07-28 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.
CA 0224467~ 1998-07-28 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.
CA 0224467~ 1998-07-28 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-CA 0224467~ 1998-07-28 ~ .
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 :
CA 0224467~ 1998-07-28 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.
CA 0224467~ 1998-07-28 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 CA 0224467~ 1998-07-28 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 CA 0224467~ 1998-07-28 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.
~ .
-~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.
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 CA 0224467~ 1998-07-28 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 CA 0224467~ 1998-07-28 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.
~ .
-~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.
Claims (9)
1. Use of a LHRH analog or a combination of LHRH analogs and an antiestrogen with tissue-selective estrogenic effect which is selected from the group of compounds Raloxifen, Droloxifen, Centchroman, or their derivatives, for treatment of gynecological conditions, especially for treatment of endometrioses and myomas.
2. Use as claimed in claim 1, wherein the LHRH analog is a LHRH agonist or LHRH antagonist.
3. Use as claimed in claim 1 or 2, wherein the LHRH analog is selected from the group of compounds Leuprorelin, Centrorelix, Buserelin, Antide, Ac-D-Nal-D-Cpa-D-Pal-Ser-Try-D-Cit-Lan-Lys(Nor)-Pro-D-Ala-NH2, Ramorelix, Zoladex or their derivatives,
4. Use as claimed in one of claims 1 to 3, wherein the LHRH
analog or combination of LHRH analogs is orally bioavailable.
analog or combination of LHRH analogs is orally bioavailable.
5. Use as claimed in one of claims 1 to 4, wherein the LHRH
analog is a non-peptidergic LHRH agonist or antagonist.
analog is a non-peptidergic LHRH agonist or antagonist.
6. Use as claimed in one of claims 1 to 5, wherein the antiestrogen is of the Raloxifen type.
7. Use as claimed in one of claims 1 to 6, wherein the two active ingredients are present in separate forms of administration.
8. Use as claimed in one of claims 1 to 6, wherein the two active ingredients are present in common forms of administration.
9. Use as claimed in claim 7 or 8, wherein the LHRH analog and antiestrogen are used at the same time and/or sequentially in time.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19604231.3 | 1996-01-29 | ||
DE19604231A DE19604231A1 (en) | 1996-01-29 | 1996-01-29 | Combined pharmaceutical preparation and its use for the treatment of gynecological disorders |
PCT/EP1997/000395 WO1997027863A1 (en) | 1996-01-29 | 1997-01-29 | Combined pharmaceutical preparation containing lhrh-analogous substances and anti-estrogens for treating gynaecological disorders |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2244675A1 true CA2244675A1 (en) | 1997-08-07 |
Family
ID=29421547
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA 2244675 Abandoned CA2244675A1 (en) | 1996-01-29 | 1997-01-29 | Pharmaceutical combined preparation and its use in the treatment of gynaecological disorders |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA2244675A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011156908A1 (en) * | 2010-06-16 | 2011-12-22 | Endorecherche, Inc. | Methods of treating or preventing estrogen-related diseases |
-
1997
- 1997-01-29 CA CA 2244675 patent/CA2244675A1/en not_active Abandoned
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011156908A1 (en) * | 2010-06-16 | 2011-12-22 | Endorecherche, Inc. | Methods of treating or preventing estrogen-related diseases |
CN103037862A (en) * | 2010-06-16 | 2013-04-10 | 恩多研究公司 | Methods of treating or preventing estrogen-related diseases |
EA026675B1 (en) * | 2010-06-16 | 2017-05-31 | Эндорешерш, Инк. | Methods of treating or preventing estrogen-dependent diseases |
CN107693794A (en) * | 2010-06-16 | 2018-02-16 | 恩多研究公司 | The method for treating or preventing estrogen relative diseases |
US11576891B2 (en) | 2010-06-16 | 2023-02-14 | Endorecherche, Inc. | Methods of treating or preventing estrogen-related diseases |
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