US20020198155A1 - 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
- Publication number
- US20020198155A1 US20020198155A1 US10/207,907 US20790702A US2002198155A1 US 20020198155 A1 US20020198155 A1 US 20020198155A1 US 20790702 A US20790702 A US 20790702A US 2002198155 A1 US2002198155 A1 US 2002198155A1
- Authority
- US
- United States
- Prior art keywords
- lhrh
- combined preparation
- oestrogen
- tissue
- analogue
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 30
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical class C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000000262 estrogen Substances 0.000 claims abstract description 31
- 201000009273 Endometriosis Diseases 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 230000000694 effects Effects 0.000 claims abstract description 12
- 201000004458 Myoma Diseases 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims description 18
- AUYLVPGDOVEOML-UHFFFAOYSA-N [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(piperidin-1-ylmethoxy)phenyl]methanone Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 AUYLVPGDOVEOML-UHFFFAOYSA-N 0.000 claims description 14
- 230000001076 estrogenic effect Effects 0.000 claims description 14
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 claims description 10
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 claims description 9
- 102100024028 Progonadoliberin-1 Human genes 0.000 claims description 9
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 claims description 9
- 108700008462 cetrorelix Proteins 0.000 claims description 8
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical compound C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 claims description 8
- 229960003230 cetrorelix Drugs 0.000 claims description 8
- QRYFGTULTGLGHU-NBERXCRTSA-N iturelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CCCCNC(=O)C=1C=NC=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)CCCNC(=O)C1=CC=CN=C1 QRYFGTULTGLGHU-NBERXCRTSA-N 0.000 claims description 8
- 108010083551 iturelix Proteins 0.000 claims description 8
- 239000000556 agonist Substances 0.000 claims description 7
- 239000002474 gonadorelin antagonist Substances 0.000 claims description 6
- 108010000817 Leuprolide Proteins 0.000 claims description 5
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 5
- 229960004338 leuprorelin Drugs 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- WDYSQADGBBEGRQ-APSDYLPASA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-[(2r,3r,4r,5r,6s) Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)O[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O WDYSQADGBBEGRQ-APSDYLPASA-N 0.000 claims description 4
- 108010037003 Buserelin Proteins 0.000 claims description 4
- 108010069236 Goserelin Proteins 0.000 claims description 4
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 4
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 claims description 4
- 229960002719 buserelin Drugs 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 108010092834 ramorelix Proteins 0.000 claims description 4
- 229950000277 ramorelix Drugs 0.000 claims description 4
- 229940033942 zoladex Drugs 0.000 claims description 4
- 239000005557 antagonist Substances 0.000 claims description 3
- -1 Droloxifen Chemical compound 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- XZEUAXYWNKYKPL-URLMMPGGSA-N ormeloxifene Chemical compound C1([C@@H]2[C@H](C3=CC=C(C=C3OC2(C)C)OC)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 XZEUAXYWNKYKPL-URLMMPGGSA-N 0.000 claims description 2
- 229960003327 ormeloxifene Drugs 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 230000002263 peptidergic effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000037396 body weight Effects 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 12
- 208000035475 disorder Diseases 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 230000037182 bone density Effects 0.000 description 6
- 210000004696 endometrium Anatomy 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 210000004291 uterus Anatomy 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 4
- 206010013935 Dysmenorrhoea Diseases 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 206010027514 Metrorrhagia Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010067572 Oestrogenic effect Diseases 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- VXYFNFAJVNPWCT-UHFFFAOYSA-N ethyl 2-(4-acetamidophenyl)-3-[[benzyl(methyl)amino]methyl]-7-[(2-methoxyphenyl)methyl]-4-oxothieno[2,3-b]pyridine-5-carboxylate Chemical compound C1=2SC(C=3C=CC(NC(C)=O)=CC=3)=C(CN(C)CC=3C=CC=CC=3)C=2C(=O)C(C(=O)OCC)=CN1CC1=CC=CC=C1OC VXYFNFAJVNPWCT-UHFFFAOYSA-N 0.000 description 2
- 230000035558 fertility Effects 0.000 description 2
- 208000000509 infertility Diseases 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 208000007106 menorrhagia Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 206010061692 Benign muscle neoplasm Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010060800 Hot flush Diseases 0.000 description 1
- 206010030247 Oestrogen deficiency Diseases 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000011292 agonist therapy Methods 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 description 1
- 229960000766 danazol Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- 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.
- 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.
- 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.
- dysmenorrhoea caused by endometriosis and by myomas
- dysmenorrhoea that is caused by functional disorders (by hormonal and vegetative disorders) also occurs.
- gonal steroids oestrogens, gestagens
- growth factors including also cytokines
- LHRH analogues Lemay, A. et al., Fertil. Steril., 41, 863-871 (1984)
- LHRH agonists may result in side effects such as, for example, hypo-oestrogenaemia (risk of osteoporosis) (Dawood, M. Y.
- 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.
- 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.
- the LHRH analogue is an LHRH agonist or antagonist.
- 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-benzylaminomethyl)-4oxothieno [2,3-b]pyridine-5-carboxylic acid ethyl ester and 5-benzoyl-7-(2,6-difluorobenzyl)- 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 forms of administration or, in the case of orally bioavailable LHRH antagonists, also in a joint form of administration.
- 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 2 ), 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-
- LHRH analogues 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.
- the LHRH analogues may be administered as individual doses or as depot forms.
- a unit dose contains different amounts of active ingredient depending in each case on the form of administration.
- oral administration usually from 2 ⁇ g to 20 mg of LHRH analogue is administered per kg of body weight.
- the administration may be in solid or liquid form.
- the amounts of LHRH analogues are from 0.02 ⁇ g to 2.5 mg per kg of body weight.
- 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.
- Leuprorelin is preferably used orally at a dose of from 2 to 100 ⁇ 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 ⁇ g/kg of body weight.
- 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.
- DE 43 42 092 also slow-release formulations of Cetrorelix are described.
- Buserelin is administered preferably in the following doses:
- the implant contains from 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.
- Ramorelix is carried out preferably in liposomal form.
- 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.
- SERMs selective oestrogen-receptor modulators
- 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.
- Raloxifen is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene.
- Raloxifen and its derivatives 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 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.
- 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 :
- 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.
- 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.
- the information given in 1 applies in respect of period and frequency of administration.
- 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.
- LHRH analogue agonist or antagonist
- Variant 1 has proved especially preferred for long-term therapy.
- 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.
- LHRH analogues 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.
- 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.
- 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.
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.
Description
- 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.
- 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.
- 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)).
- 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 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.
- 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.
- 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.
- The LHRH analogue is an LHRH agonist or antagonist.
- 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-benzylaminomethyl)-4oxothieno [2,3-b]pyridine-5-carboxylic acid ethyl ester and 5-benzoyl-7-(2,6-difluorobenzyl)-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 forms of administration or, in the case of orally bioavailable LHRH antagonists, also in a joint form of administration.
- 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-NH2), 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-carboxylic acid ethyl ester).
- 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.
- 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 μg 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 μg 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.
- Leuprorelin is preferably used orally at a dose of from 2 to 100 μg/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 μg/kg of body weight.
- 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.
- Buserelin is administered preferably in the following doses:
- from 0.02 to 1 μg/kg of body weight (intravenous),
- from 0.02 to 2 μg/kg of body weight (subcutaneous),
- from 0.02 to 10 μg/kg of body weight (intramuscular),
- from 0.1 to 50 μg/kg of body weight (intranasal) and
- from 10 to 200 μg/kg of body weight (oral).
- 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.
- Zoladex is preferably administered orally with a content of from 50 μg to 20 mg/kg of body weight and parenterally with a content of from 0.02 μg to 100 μg/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 of Ramorelix is carried out preferably in liposomal form.
- Depot formulations for peptides (microparticles, implants) are described inter alia in EP 0 505 966 and EP0 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 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.
- 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 combination with parathyroid hormone, Raloxifen and its derivatives 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 μg 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.
- 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 :
- 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.
- 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 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.
- 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.
- 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.
- 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.
- Variant 1 has proved especially preferred for long-term therapy.
- 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.
- 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.
- 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.
- 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.
- The invention is illustrated further in the following by Examples without, however, being limited to those Examples.
- 1.1 Comparison of the Administration of Each of the Active Ingredient Components Alone With the Simultaneous 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 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.
- 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.
- Administration of Raloxifen alone resulted in a partial regression of the endometriosis.
- 1.2 LHRH antagonist Antide and Raloxifen for simultaneous and chronologically sequential administration
- 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.
- 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.
- 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 Raloxifen was then administered for 2 weeks.
- This sequential treatment also resulted in 100% regression of the endometriosis without a reduction in bone density.
- 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 Droloxifen was carried out on 40 animals.
- The same results could be achieved as in Example 1.
Claims (15)
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-NH2, 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.
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US10/207,907 US20020198155A1 (en) | 1996-01-29 | 2002-07-31 | Pharmaceutical combined preparation and its use in the treatment of gynaecological disorders |
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DE19604231A DE19604231A1 (en) | 1996-01-29 | 1996-01-29 | Combined pharmaceutical preparation and its use for the treatment of gynecological disorders |
US09/117,357 US7309691B2 (en) | 1996-01-29 | 1997-01-29 | Combined pharmaceutical preparation containing LHRH-analogous substances and anti estrogens for treating gynaecological disorders |
US10/207,907 US20020198155A1 (en) | 1996-01-29 | 2002-07-31 | Pharmaceutical combined preparation and its use in the treatment of gynaecological disorders |
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US09/117,357 Continuation US7309691B2 (en) | 1996-01-29 | 1997-01-29 | Combined pharmaceutical preparation containing LHRH-analogous substances and anti estrogens for treating gynaecological disorders |
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US6863891B2 (en) * | 1993-02-19 | 2005-03-08 | Zentaris Ag | Oligopeptide lyophilisate, their preparation and use |
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US6096764A (en) * | 1997-08-21 | 2000-08-01 | Eli Lilly And Company | Methods for inhibiting detrimental side-effects due to GnRH of GnRH agonist administration |
HU228736B1 (en) * | 1998-04-23 | 2013-05-28 | Zentaris Ivf Gmbh | Use of lhrh atnagonists in the production of pharmaceutical compostion for the treatment of fertility disorders |
PE20010578A1 (en) * | 1999-08-31 | 2001-06-04 | Schering Ag | MESOPROGESTINES (MODULAR PROGESTERONE RECEPTORS) FOR THE TREATMENT AND PREVENTION OF BENIGN HORMONE-DEPENDENT GYNECOLOGICAL DISORDERS |
US8193252B1 (en) | 1999-08-31 | 2012-06-05 | Bayer Pharma AG | Mesoprogestins (progesterone receptor modulators) for the treatment and prevention of benign hormone dependent gynecological disorders |
RU2255759C2 (en) * | 1999-09-23 | 2005-07-10 | Центарис Гмбх | Method for therapeutic treatment of extrauterine proliferation of endometrial tissue chronic pain in pelvis region caused by thereof and fallopian tubes impenetrability |
US7005418B1 (en) | 1999-09-23 | 2006-02-28 | Zentaris Gmbh | Method for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and fallopian tube obstruction |
EP1297850B1 (en) * | 2000-07-05 | 2015-08-19 | Takeda Pharmaceutical Company Limited | Medicinal preparations for treating sex hormone-dependent diseases |
DE10050831A1 (en) | 2000-10-05 | 2002-05-02 | Veyx Pharma Gmbh | Procedure for starting the cycle in female breeding animals |
IL145838A (en) * | 2000-10-16 | 2008-11-03 | Pfizer Prod Inc | Use of an estrogen agonist/antagonist for the manufacture of a medicament for treating vaginitis |
WO2002056903A2 (en) * | 2001-01-17 | 2002-07-25 | Praecis Pharmaceuticals Inc. | Methods for treating hormone associated conditions using a combination of lhrh antagonists and specific estrogen receptor modulators |
CA2458452C (en) * | 2001-08-10 | 2011-04-19 | Takeda Chemical Industries, Ltd. | Gnrh agonist combination drugs |
JP5020811B2 (en) * | 2005-03-16 | 2012-09-05 | 五十嵐 正雄 | Therapeutic and preventive agents for endometriosis and adenomyosis |
EP2266567A1 (en) | 2009-05-26 | 2010-12-29 | Æterna Zentaris GmbH | Use of cetrorelix in combination with PDE V inhibitors for the treatment of sex hormone dependent disorders |
EP2266568A1 (en) | 2009-05-26 | 2010-12-29 | Æterna Zentaris GmbH | Use of LHRH antagonists in combination with PDE V inhibitors for the treatment of sex hormone dependent disorders |
US11576891B2 (en) * | 2010-06-16 | 2023-02-14 | Endorecherche, Inc. | Methods of treating or preventing estrogen-related diseases |
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US5395842A (en) * | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
US5457116A (en) * | 1993-10-15 | 1995-10-10 | Eli Lilly And Company | Methods of inhibiting uterine fibrosis |
US5451589A (en) * | 1993-12-21 | 1995-09-19 | Eli Lilly And Company | Methods of inhibiting ovarian dysgenesis, delayed puberty, or sexual infantilism |
US5451590A (en) * | 1993-12-21 | 1995-09-19 | Eli Lilly & Co. | Methods of inhibiting sexual precocity |
US5593987A (en) * | 1993-12-21 | 1997-01-14 | Eli Lilly And Company | Methods of inhibiting breast disorders |
US6096764A (en) * | 1997-08-21 | 2000-08-01 | Eli Lilly And Company | Methods for inhibiting detrimental side-effects due to GnRH of GnRH agonist administration |
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US6863891B2 (en) * | 1993-02-19 | 2005-03-08 | Zentaris Ag | Oligopeptide lyophilisate, their preparation and use |
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HUP9901288A3 (en) | 2000-03-28 |
JP2000505422A (en) | 2000-05-09 |
HUP9901288A2 (en) | 1999-08-30 |
MX9806082A (en) | 1998-10-31 |
US7309691B2 (en) | 2007-12-18 |
IL125557A0 (en) | 1999-03-12 |
WO1997027863A1 (en) | 1997-08-07 |
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US20020032156A1 (en) | 2002-03-14 |
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