CN1120314A - Methods and compositions for treating osteoporosis - Google Patents
Methods and compositions for treating osteoporosis Download PDFInfo
- Publication number
- CN1120314A CN1120314A CN94191682A CN94191682A CN1120314A CN 1120314 A CN1120314 A CN 1120314A CN 94191682 A CN94191682 A CN 94191682A CN 94191682 A CN94191682 A CN 94191682A CN 1120314 A CN1120314 A CN 1120314A
- Authority
- CN
- China
- Prior art keywords
- estrogen
- potassium salt
- amount
- patient
- osteoporosis
- 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.)
- Pending
Links
- 208000001132 Osteoporosis Diseases 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims description 27
- 239000000203 mixture Substances 0.000 title description 24
- 229940011871 estrogen Drugs 0.000 claims abstract description 57
- 239000000262 estrogen Substances 0.000 claims abstract description 57
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 40
- 229940079593 drug Drugs 0.000 claims abstract description 35
- 210000002700 urine Anatomy 0.000 claims abstract description 18
- 235000015497 potassium bicarbonate Nutrition 0.000 claims abstract description 12
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims abstract description 12
- 239000011736 potassium bicarbonate Substances 0.000 claims abstract description 12
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical group [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- 230000001076 estrogenic effect Effects 0.000 claims description 25
- 230000029142 excretion Effects 0.000 claims description 17
- 229940088597 hormone Drugs 0.000 claims description 17
- 239000005556 hormone Substances 0.000 claims description 17
- 229940035811 conjugated estrogen Drugs 0.000 claims description 15
- 239000002552 dosage form Substances 0.000 claims description 15
- QTTMOCOWZLSYSV-QWAPEVOJSA-M equilin sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 QTTMOCOWZLSYSV-QWAPEVOJSA-M 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 claims description 12
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 10
- 229910052791 calcium Inorganic materials 0.000 claims description 10
- 239000011575 calcium Substances 0.000 claims description 10
- 102000008186 Collagen Human genes 0.000 claims description 8
- 108010035532 Collagen Proteins 0.000 claims description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 8
- 229920001436 collagen Polymers 0.000 claims description 8
- 239000011574 phosphorus Substances 0.000 claims description 8
- 229910052698 phosphorus Inorganic materials 0.000 claims description 8
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims description 7
- 238000004132 cross linking Methods 0.000 claims description 7
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 229960002591 hydroxyproline Drugs 0.000 claims description 7
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims description 7
- 230000003203 everyday effect Effects 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 238000001727 in vivo Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 230000002354 daily effect Effects 0.000 claims 2
- 235000012976 tarts Nutrition 0.000 claims 2
- 230000004927 fusion Effects 0.000 claims 1
- 159000000001 potassium salts Chemical class 0.000 abstract description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 abstract description 2
- -1 hydroxyl ions Chemical class 0.000 abstract description 2
- 230000003113 alkalizing effect Effects 0.000 abstract 1
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- 210000003722 extracellular fluid Anatomy 0.000 abstract 1
- 230000001009 osteoporotic effect Effects 0.000 description 16
- 230000000694 effects Effects 0.000 description 12
- 239000000583 progesterone congener Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 230000011164 ossification Effects 0.000 description 7
- 235000013305 food Nutrition 0.000 description 6
- 231100000206 health hazard Toxicity 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 201000003914 endometrial carcinoma Diseases 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 3
- 208000006386 Bone Resorption Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000004067 Osteocalcin Human genes 0.000 description 3
- 108090000573 Osteocalcin Proteins 0.000 description 3
- 230000024279 bone resorption Effects 0.000 description 3
- 210000003608 fece Anatomy 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000000737 periodic effect Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- 150000000307 17β-estradiols Chemical class 0.000 description 2
- ZAHDXEIQWWLQQL-IHRRRGAJSA-N Deoxypyridinoline Chemical compound OC(=O)[C@@H](N)CCCC[N+]1=CC(O)=C(C[C@H](N)C([O-])=O)C(CC[C@H](N)C(O)=O)=C1 ZAHDXEIQWWLQQL-IHRRRGAJSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- 241000287433 Turdus Species 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000002079 cooperative effect Effects 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229960003399 estrone Drugs 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229960003975 potassium Drugs 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229960001424 quinestrol Drugs 0.000 description 2
- PWZUUYSISTUNDW-VAFBSOEGSA-N quinestrol Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@]4(O)C#C)C)CC2=CC=3OC1CCCC1 PWZUUYSISTUNDW-VAFBSOEGSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000005728 strengthening Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYWZPRVUQHMJFF-BZSNNMDCSA-N (13s,14s,17s)-13-methyl-11,12,14,15,16,17-hexahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2C(CC[C@]3([C@H]4CC[C@@H]3O)C)=C4C=CC2=C1 RYWZPRVUQHMJFF-BZSNNMDCSA-N 0.000 description 1
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 1
- AOPDRZXCEAKHHW-UHFFFAOYSA-N 1-pentoxypentane Chemical compound CCCCCOCCCCC AOPDRZXCEAKHHW-UHFFFAOYSA-N 0.000 description 1
- RYWZPRVUQHMJFF-KSZLIROESA-N 17alpha-Dihydroequilenin Chemical compound OC1=CC=C2C(CC[C@]3([C@H]4CC[C@H]3O)C)=C4C=CC2=C1 RYWZPRVUQHMJFF-KSZLIROESA-N 0.000 description 1
- RYWZPRVUQHMJFF-UHFFFAOYSA-N 17alpha-Dihydroequilenin Natural products OC1=CC=C2C(CCC3(C4CCC3O)C)=C4C=CC2=C1 RYWZPRVUQHMJFF-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- 150000000304 17α-estradiols Chemical class 0.000 description 1
- NLLMJANWPUQQTA-UBDQQSCGSA-N 7,8-didehydro-17beta-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4C3=CCC2=C1 NLLMJANWPUQQTA-UBDQQSCGSA-N 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- UYIFTLBWAOGQBI-BZDYCCQFSA-N Benzhormovarine Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4O)C)CC2=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-BZDYCCQFSA-N 0.000 description 1
- 208000018083 Bone metabolism disease Diseases 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010030247 Oestrogen deficiency Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 244000203593 Piper nigrum Species 0.000 description 1
- HLCFGWHYROZGBI-JJKGCWMISA-M Potassium gluconate Chemical compound [K+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O HLCFGWHYROZGBI-JJKGCWMISA-M 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- LCYXYLLJXMAEMT-SAXRGWBVSA-N Pyridinoline Chemical compound OC(=O)[C@@H](N)CCC1=C[N+](C[C@H](O)CC[C@H](N)C([O-])=O)=CC(O)=C1C[C@H](N)C(O)=O LCYXYLLJXMAEMT-SAXRGWBVSA-N 0.000 description 1
- VPMWDFRZSIMDKW-YJYMSZOUSA-N Salmefamol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 VPMWDFRZSIMDKW-YJYMSZOUSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000000680 avirulence Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003150 biochemical marker Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000002805 bone matrix Anatomy 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229950004783 cipionate Drugs 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- PDRGHUMCVRDZLQ-UHFFFAOYSA-N d-equilenin Natural products OC1=CC=C2C(CCC3(C4CCC3=O)C)=C4C=CC2=C1 PDRGHUMCVRDZLQ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 208000016018 endometrial polyp Diseases 0.000 description 1
- PDRGHUMCVRDZLQ-WMZOPIPTSA-N equilenin Chemical compound OC1=CC=C2C(CC[C@]3([C@H]4CCC3=O)C)=C4C=CC2=C1 PDRGHUMCVRDZLQ-WMZOPIPTSA-N 0.000 description 1
- WKRLQDKEXYKHJB-HFTRVMKXSA-N equilin Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 WKRLQDKEXYKHJB-HFTRVMKXSA-N 0.000 description 1
- NLLMJANWPUQQTA-SPUZQDLCSA-N estra-1,3,5(10),7-tetraene-3,17alpha-diol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@@H](CC4)O)[C@@H]4C3=CCC2=C1 NLLMJANWPUQQTA-SPUZQDLCSA-N 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229950002007 estradiol benzoate Drugs 0.000 description 1
- 229960001348 estriol Drugs 0.000 description 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 1
- VUCAHVBMSFIGAI-ZFINNJDLSA-M estrone sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 VUCAHVBMSFIGAI-ZFINNJDLSA-M 0.000 description 1
- 230000012173 estrus Effects 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 208000020694 gallbladder disease Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000004224 potassium gluconate Substances 0.000 description 1
- 229960003189 potassium gluconate Drugs 0.000 description 1
- 235000013926 potassium gluconate Nutrition 0.000 description 1
- 229940063238 premarin Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229950001879 salmefamol Drugs 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 206010046811 uterine polyp Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Inorganic Chemistry (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
用于治疗骨质疏松的下列活性成分的结合药物：(a)可药用的碱化钾盐，该盐能产生羟基离子，从而能降低组织液或尿液的酸性，且所述钾盐选自碳酸氢钾和羧酸的钾盐，所述羧酸的钾盐能转化成碳酸氢盐，从而在体内被碱化，以及(b)能有效治疗骨质疏松的雌激素，其用量为低至其标准推荐剂量的1/10；所存在的碱化钾盐的量为使得结合药物比单独给用相同量所述雌激素治疗骨质疏松时实质上更有效的量。A combination of the following active ingredients for the treatment of osteoporosis: (a) a pharmaceutically acceptable alkalinizing potassium salt capable of generating hydroxyl ions to reduce the acidity of interstitial fluid or urine, and said potassium salt is selected from Potassium bicarbonate and potassium salts of carboxylic acids which can be converted to bicarbonate and thus be alkalized in the body, and (b) estrogens effective in the treatment of osteoporosis in amounts as low as 1/10 of its standard recommended dose; the amount of alkalizing potassium salt present is such that the combined drug is substantially more effective in treating osteoporosis than the same amount of said estrogen alone.
Description
The application is that the application number that proposed on October 17th, 1989 is 420,597 patent applications, the United States Patent (USP) 5 that on November 15th, 1992 authorized, 171,583 continue, wherein above-mentioned patent are that the application number that proposed on October 21st, 1988 is 260,856, now resigned application for patent continues.
The present invention relates to the method for the human osteoporosis of a kind of new treatment, more particularly, comprise and utilize alkaline potassium salt and this type of is treated the method and composition of effective estrogen in conjunction with the drug treatment osteoporosis that this can reduce health risk and the side effect that common estrin treatment osteoporosis is followed in conjunction with administration.
Osteoporosis is a kind of bone metabolism disease, shows as bone quantity on its feature pathology and definitely reduces, and shows as fracture sensitivity clinically and strengthens.Riggs etc., N, Engl.J.Med. (1986), 314:1676; Rusbach etc., Textbook ofEndocrinology, Ed (s) Williams, (1981), p.922; Riggs, Cecil Textbook of Medicine, Ed (s) Wyngaarden etc., (1985), p.1456; Riggs etc., Am.J.Med., (1983), 75:899.
Existing a few class biochemical markers together are considered for diagnosing osteoporotic patient, perhaps are used for the osteoporotic effectiveness of research treatment.For example, urine hydroxyproline excretion rate is widely used as the labelling of bone resorption.Metabolism such as Klein 2, Vol.13, No.3, March 1964,272-285; Charles etc., J.Clin.Invest., Vol, 76, December 1985 2254-2258; And Deacon etc., Clin.Chim.Acta., 1987,297-306.Pyridinoline and Deoxy-Pyridinoline are two kinds of collagen cross-linking agents that exist in the bone, they can detect in urine, equally also can be used as the labelling of bone resorption.Robins, etc., European Journal of Clinical Investigation (1991), 21:310-315.
The concentration of serum bone protein is as the biochemical marker of bone formation rate.Bone protein is by the integral protein of the synthetic organic bone matrix of bone formation cell (osteoblast) in the bone formation process.A small amount of new synthetic osteocalcin escapes into blood circulation, thereby the blood labelling of bone formation rate is provided.The concentration of osteocalcin increases along with the increase of bone formation rate, reduces along with the reduction of bone formation rate.Broun etc., TheLancet, May 19,1984, p.1091, " Serum Bone GLA-Pro-tein:A Specific Marker For Bone Formation in Post-menopausal Osteoporosis ".Another is reflected as variation (positive or negative) with phosphorus balance bone resorption/osteoplastic, and this variation is measured by the difference between the suction volume of measuring total excretion (feces and urine) and regulation food or phosphonium ion.(this balance is positive when total excretion is less than the suction volume of regulation food).
For postmenopausal women, oestrogen deficiencies has been confirmed as osteoporotic key element because of sexual factor.Existing report claims that long-term controversies in hormone replacement in the elderly may cause that postmenopausal women's osteoporosis is more serious.Johansen waits (1990) Metabolism Vol.39, No.11, pp.1122-1126; Ettinger, Ob-stetrics ﹠amp; Gynecology, (1988), 72:125-175:Ettinger etc., Annals of Internal Medicine (1985), 102:319-324.
Ratified by FDA and to osteoporotic control or to treat effective estrogenic minimum dose be the 0.625mg conjugated estrogen hormone, or other estrogenic dose,equivalent.Yet, take estrogen with this level for a long time and can cause serious health hazard.Independently study for three groups and shown that the danger that postmenopausal women is taken the carcinoma of endometrium of exogenesis estrogen trouble for a long time with above-mentioned dosage level increases.Siel waits (1975) New England Journal of Medicine, 293:1167-1170; Smith etc. (1975) New England Journal ofMedicine, 293:1164-1167; Mack etc. (1976) New EnglandJournal of Medicine, 294:1262-1267.These three groups research has reported that danger that the estrogen user suffers from carcinoma of endometrium is greater than user not 4.5 to 13.9 times.This danger was both relevant with the persistent period of treatment seemingly, and Ziel etc. are the same, relevant with estrogenic dosage again, and Mack etc. are the same.
In the estrin treatment of proof, the danger of carcinoma of endometrium, also have a kind of postmenopausal women that studies show that to take estrogen the danger that increases the trouble mastocarcinoma is arranged at least.New?England?Journal?of?Medicine(1974)290：15-19。Reported that in addition accepting estrogenic women after the menopause suffers from fixedly two to three times of the danger increases of gallbladder disease of surgery.Ditto.In addition, the menopausal women of accepting estrin treatment is suffered from thromboembolism and thrombosis angiopathy and hypertensive dangerous increasing.Pfeffer etc., (1976) Am.J.Epidemiology103:445-456.Thereby under the dosage level that effectively the treatment osteoporosis needs, estrogen may cause serious health hazard and side effect.
One class studies show that progestogen are attached to and the protective effect of exempting to suffer from the carcinoma of endometrium that estrogen brings out can be provided in the controversies in hormone replacement in the elderly and can improve bone metabolism.Williams etc. (1990) Am.J.Obstet.Gynecol., Vol.162, pp.438-446.Yet the adding of progestational agents can cause the high rate of side effect, and to comprise every month once hemorrhage and through preceding symptom in these side effect.Ditto.Although above-mentionedly studies show that these side effect can slow down by following administering mode: with connect the preface periodic mode and give with adopt opposite of estrogen and continue the every day mode and combine with estrogen to the dispenser of using progestogen with progestogen.But above-mentioned studies show that among 65 patients that accept to continue dosage estrogen and progestin dosage has 3 people growth that endometrial polyp is arranged.Ditto.
Another research, Ettinger, (1988), Obstetrics ﹠amp; Gynecology72:125-175, suggestion is arrived 1500mg/ days at least by the calcium suction volume that increases patient, and Dou is used for the treatment of osteoporotic estrogenic common dosage, and the above-mentioned conjugated estrogen hormone of promptly about 0.6mg reduces half.Yet, even half of the common dosage of this research hint estrogen also probably causes menstrual bleeding and other unwanted secondary use.
The United States Patent (USP) 5 that on October 15th, 1992 authorized, 171,583 (content of this application can be listed in herein as a reference) disclose improvement or the Therapeutic Method that evil is had or suffers from osteoporosis patient's osteoporosis, comprise to the compositions with the pharmaceutically useful Alkalinizing potassium salt mixture that contains treatment or prevention effective dose.Wherein the effective dose of disclosed Alkalinizing potassium salt is 40-400mmoles/70kg patient body weight/sky, preferred 40-250mmdes/70kg/ days.
One of purpose of the present invention provides a kind of ratio and uses the osteoporotic method and composition of the more effective treatment of estrin treatment separately.
Another object of the present invention provides the osteoporotic method and composition of a kind of treatment, and it can alleviate otherwise then eliminate harm and the side effect of supervening with estrin treatment.
The present invention relates to a kind of new improvement or the harmful osteoporotic method that has or suffer from the osteoporosis patient of treatment, this method comprises to the compositions with following active ingredients:
(a) pharmaceutically useful Alkalinizing potassium salt, this salt can produce hydroxyl ion and thereby can reduce the acidity (by strengthening alkalescence) of tissue fluid or urine, and described salt is selected from potassium bicarbonate and can transforms (burning) in vivo and becomes bicarbonate also so the potassium salt of alkalifiable carboxylic acid; With
(b) to the effective estrogen of osteoporotic treatment, described estrogen can be with little 1/10 amount to its normal recommended dosage, preferably with about 1/10 normal recommended dosage to recommended dose or more substantial dosed administration;
Alkalization potassium is with following amount administration: this dosage can make the more effective in fact in conjunction with administration of two kinds of medicines, and more effective 10% to up to 50% during usually than the individually dosed treatment osteoporosis of the estrogen of usefulness same amount, perhaps higher.
The pharmaceutically useful Alkalinizing potassium salt of the present invention is with estrogenic to combine cooperative effect that administration produced during osteoporosis in treatment be non-obvious to those skilled in the art before the present invention.Therefore, the invention provides than the more effective Therapeutic Method of conventional estrin treatment osteoporosis.In addition, if desired, according to the present invention, the estrogenic amount of being used in the drug combination can be low to moderate 1/10 as the estrogenic normal recommended dosage of giving a definition.The present invention is more effective to osteoporotic treatment than the estrogen and the bonded compositions of Alkalinizing potassium salt of low dosage.And can bring and alleviate otherwise then eliminate the health hazard supervened with the estrogen conventional therapy and the obvious benefit of side effect.Alkalinizing potassium salt and estrogenic together use can be avoided the harm of estrogen and the shared medicine of progestogen; On the other hand, sodium---the retention properties that the short natruresis characteristic of Alkalinizing potassium salt can the balance progestogen, thereby can improve the result of conjugated estrogen hormone-progestogen-alkalization potassium treatment gained.
The active component of bound drug of the present invention, i.e. (a) pharmaceutically useful Alkalinizing potassium salt and (b) can be with independent dosage form (the Seperate doseage form) administration that mutually combines to the effective estrogen of osteoporosis therapy is promptly with identical or by different timetable administrations.On the other hand, following description more fully preferably is mixed into unit dosage form with Alkalinizing potassium salt and estrogen, and this dosage form needing have been avoided giving respectively to the time spent and used these active component.
Used herein term " treatment " or " treatment " comprise the treatment of any osteoporosis, and comprise: (1) prevention of osteoporosis is the host who does not suffer from osteoporosis or be not diagnosed with yet in the host of osteoporosis and occur; (2) suppress or stop advancing of disease; Or degenerate or reverse osteoporosis state (3).
Term as herein described " normal recommended dosage " when being used for estrogen, meaning and gives with effectively treating osteoporotic estrogenic amount suffering from osteoporotic patient, and promptly it can cause column effect down in human body:
(a) reduce urine hydroxyproline excretion rate;
(b) reduce urine collagen cross-linking excretion rate; With
(c) strengthen calcium and phosphorus balance, even they are the more weak negative and stronger positive.For example, in osteoporotic treatment, known estrogenic normal recommended dosage as conjugated estrogen hormone (being defined as follows) is 0.625mg, by the periodic manner administration, i.e. and three weeks of administration, one week of drug withdrawal.Referring to Pysicians Desk Reference, 1993 editions, P2624 ... 25.(whether above-mentioned effect no matter give simultaneously with all producing with progestogen by estrogen).
As used herein, " the described estrogen of same dose when individually dosed " is meant identical estrogenic same amount in the bound drug of the present invention, only gives with estrogen and no longer to the Alkalinizing potassium salt composition with bound drug of the present invention in this case.
As used herein, term " collagen cross-linking thing " is meant Pyridenoline and deoxy-pyridinoline cross-linking agent.
As used herein, term " calcium balance " is meant the difference between calcium total excretion (feces and urine) and regulation food calcium suction volume.Equally, term " phosphorus balance " is meant the difference between phosphorus total excretion (feces and urine) and regulation food phosphorus suction volume.
Adoptable in the methods of the invention Alkalinizing potassium salt is meant when being present in the human body fluid can produce hydroxyl ion, thereby can reduce the Alkalinizing potassium salt of tissue fluid or uric acid (strengthening alkalescence).A large amount of pharmaceutically useful Alkalinizing potassium salts are known, wherein severally see Berg etc., and described in J.pharmaceut.Sci (1977) 66:1, the document can be incorporated this paper into as a reference.If above-mentioned document is disclosed in this, those skilled in the art is easy to can be used in the osteoporotic pharmaceutically useful alkalization salt of treatment by adopting the known method and the choice of technology and filtering out.Best selected salt should have therapeutic activity, and is easily received and have a tolerance relatively preferably in the human body.Can select different salt according to specific route of administration and preferred preparation way.
So the Alkalinizing potassium salt of administration is preferably selected from potassium bicarbonate (KHCO
3) and pharmaceutically acceptable, nontoxic carboxylic acid potassium salt such as potassium gluconate (C
6H
11KO
7) and potassium citrate (C
6H
5K
3O
7).Especially preferably use potassium bicarbonate.The preparation of these salt, for example they use in the purposes with numerous treatment backgrounds but not aspect the purposes described herein usually.The special aspects method for preparing this class salt is usually seen Remington ' s Pharmaceutical Sciences, Mack PublishingCompany, and Easton, Pennsylvania, 16th Ed., 1982, this data can be listed in this paper as a reference.
Used herein, this language " estrogen " is meant to have the bioactive any natural or synthetic of energy postpartum estrus hormone, and is used for the treatment of osteoporosis.Useful estrogen preferably includes and has following structure in the present invention's practice, comprises the estrogen of its pharmaceutically useful salt and ester:
R wherein
1Be hydroxyl and R
2Be selected from H ,-C=C, and-C ≡ C, perhaps
R
1And R
2Together the oxygen of two keys and molecular linkage is passed through in expression,
R
3Perhaps be hydrogen or for hydroxyl, and
R
4Be selected from H, methyl, and cyclopenta and
Wherein said estrogen or have two keys at 6-7 and 8-9 position has two keys in the 7-8 position, perhaps 6,7, and the unparalleled key in 8 and 9 position.
For example the present invention's estrogen that can give usefulness is including, but not limited to all following estrogen and their mixture: estrone (3-hydroxyl female-1,3,5 (10)-triolefins-17-ketone); 17 beta estradiols (17 β-female-1,3,5 (10)-triolefins-3,17-glycol); 17 alpha-estradiols (female-1,3,5 (10)-triolefins-3,17 salmefamol); Ethinylestradiol (17 α-acetenyl-1,3,5 (10)-estratriene-3,17-isoallopregnane-3); 1,3,5,7-estratetraen-3-ol-17-one (3-hydroxyl female-1,2,5 (10), 7-tetraene-17-ketone); Equilenin (3-hydroxyl female-1,2,3,5,7,9-pentaene-17-ketone); 17 α-dihydroequilin (17 α-female-1,3,5 (10), 7-tetraene-3,17-glycol); 17 β-dihydroequilin (17 β-female-1,3,5 (10), 7-tetraene-3,17-glycol); 17 α-dihydro equilenin (17-female-1,3,5,7,9-pentaene-3,17-glycol); 17 β-dihydro equilenin (17 β-female-1,3,5,7,9-pentaene-3,17-glycol); Quinestrol methyl ether (17-α-acetenyl-3-methoxyl group-1,3,5 (10)-estratriene-17 β-alcohol); Q1 (estriol 3-cyclopenta ether); Quinestrol (the female alcohol ring of 17 alpha-acetylenes amyl ether); Estradiol benzoate (17 β-female-1,3,5 (10)-triolefins-3,17-glycol 3-benzoate); 17 β-estradiol cypionate (17 β-female-1,3,5 (10)-triolefins-3,17-glycol 17-cipionate); And conjugated estrogen hormone.
As described herein, this language " conjugated estrogen hormone " is meant the mixture of the conjugated estrogen hormone that is existed by the sodium-salt form with water solublity estrogen sulfuric ester that obtains in the natural resources, described sulfuric ester is the mixing average composition of representative from the material in the pregnant mare urine, and its main component is the estrone sulfuric ester.Conjugated estrogen hormone is to be sold with " PREMARIN " trade mark by Wyeth-Ayerst Laboratories.Referring to Physicians Desk Reference, 1993 Edition, P2624-26.
Aforementioned various estrogenic preparation separates and purification is known for those skilled in the art.Existing lot of documents has described how to prepare these estrogen, and these documents are drawn record with aforementioned estrogenic title by Merck Index (11th Ed.1989).Merk Index and the narration of being quoted thereof prepare these estrogenic documents and can be incorporated herein as a reference.
The administration of pharmaceutically useful Alkalinizing potassium salt of the present invention or estrogenic component can and can be given by any acceptable administering mode of the medicament that uses in the known osteoporosis therapy and use for described Pharmaceutical composition form hereinafter.For Alkalinizing potassium salt, these methods comprise a mouthful newspaper, parenterai administration, and other mode that is administered systemically.Different Alkalinizing potassium salts can mix and give usefulness simultaneously, perhaps in some situation, separates, and may be obtained some benefits with them in order.For estrogen, these methods comprise oral, parenterai administration, percutaneous dosing, and other mode that is administered systemically.
According to predetermined administering mode, the Alkalinizing potassium salt composition can be solid, semisolid or liquid dosages form, and as, tablet, capsule, pill, powder, granule, crystal, liquid, dosage forms such as suspending agent preferably are fit to have the unit dosage form of relatively accurate dosed administration.Equally, estrogenic component can be a solid tablet, and the form of capsule or pill is preferably the unit dosage form that is fit to have relatively accurate dosed administration.
Preferably will alkalize salt and estrogenic component is combined into tablet, the unit solid dosage of capsule or pill, thereby eliminated the needs of giving respectively with these compositions.The solid-state bond dosage form can comprise conventional pharmaceutical carrier or excipient, but also can comprise other medicament.Thereby unit dosage forms can combine with conventional non-toxic solid carrier, and described carrier for example is other mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, Talcum, fine little element, glucose, sucrose, magnesium carbonate or the like.This compositions can contain the 50-90% that has an appointment active component of the present invention, preferred 70-90%.
On the other hand, the Alkalinizing potassium salt composition can with the bonded individually dosed form administration of estrogen activity composition administration.Thereby two kinds of medicines can be with identical planning chart or different planning chart administrations according to their common administering modes.Give usefulness when the Alkalinizing potassium salt composition with independent dosage form, it can be a tablet, pill, and capsule, powder, granule, crystal, sustained release formses etc. also contain the form of any aforementioned excipients, and perhaps the composition forms that pharmaceutically can use with liquid state is given and is used.This fluid composition can be dissolved in as water as potassium bicarbonate and optional pharmaceutical adjuvant by for example with salt, and D/W prepares in the carriers such as glycerol, thereby forms solution or suspension.If desired, independent alkalization salt dosage form also can contain a small amount of avirulence auxiliary substance such as pH buffer agent etc., for example, and Sorbitan list lemon palmitic acid acid esters, triethanolamine, sodium acetate, triethanolamine oleate etc.The current methods for preparing this dosage form is known, is conspicuous to those skilled in the art perhaps; Referring to aforesaid Remington ' s Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pennsylvania, 16th Ed., 1982.The active potassium salt composition of bound drug such as potassium bicarbonate for example can pills, and being applied directly to the granule of food and food arbitrary way that powder is supplied with provides, or are dissolved in that the form with conventional medication provides in the drinking water.
The estrogenic component of bound drug of the present invention can be as small as the amount of 1/10 normal recommended dosage and gives usefulness.The Alkalinizing potassium salt composition of bound drug of the present invention is given with following dosage and is used.To be bound drug when giving with same amount estrin treatment osteoporosis separately more effective 10% for this dosage, perhaps up to 50% or higher.
As preferably, the oral amount of usefulness of giving of estrogenic component is equivalent to (based on dosage every day) 0.06 to 1.25mg, preferred 0.06 to 0.625mg conjugated estrogen hormone.Alkalinizing potassium salt is 30-120 to consumption in the bound drug, preferred 30 to 60 milliequivalents.Under these levels, the result when giving separately with same amount estrogen compares, and can be observed following relative result:
(a) reduction of urine hydroxyproline excretion rate (press Klein, method is measured described in the above-mentioned document of Charles etc. and Deacon etc.) is above 10%;
(b) reduction of urine collagen cross-linking excretion rate (the described method of above-mentioned document of press Robins etc. is measured) is above 10%; And
(c) increase of calcium and phosphorus balance (measuring according to a conventional method) is for example high to 10%, or higher.
As what see from the front, the conjugate of active component of the present invention demonstrates cooperative effect in the treatment osteoporosis, and promptly the binding ratio of two kinds of medicines is given with same amount estrogen more effective in fact separately.Most preferably estrogen can be oral to using the amount administration that is low to moderate the 0.06mg conjugated estrogen hormone to be equal to.When using in the present invention's combination, estrogenic lowest dose level is effectively to the treatment osteoporosis not only, and can significantly reduce health hazard and the side effect of using routine dose estrogen to be supervened.
Amount according to the estrogenic component of administration of the present invention depends on employed specific estrogenic effectiveness and administering mode certainly.Various estrogenic relative and equal effectiveness are that those skilled in the art is known.For example, according to osteoporotic effectiveness of estrin treatment and ability, the 0.6mg conjugated estrogen hormone is equivalent to micronized 17 beta estradiols of 2.0mg.These are openly listed in herein, and those skilled in the art is easy to select to be equivalent to the estrogen and the dosage level of estrogen as herein described and dosage level.
Bound drug of the present invention can perhaps replace administration in a periodic manner with continuation mode administration every day, i.e. three all medications, all drug withdrawals.Same those skilled in the art is appreciated that except that giving with the bound drug described in the invention, preferably also should replenish patient's calcium suction volume, if desired, keeps sucking 1500mg calcium every day.
Following embodiment has illustrated more of the present invention preferred especially, nonrestrictive aspect
Example I
Preparation contains the bound drug tablet of following active component: 0.156mg conjugated estrogen hormone and 1.5g potassium bicarbonate.Be fit to every day give with four tablets of these class tablets.
Example II
Preparation contains with the bound drug tablet of example I identical component and by the same approach administration, only contains 0.08mg conjugated estrogen hormone and 0.75g potassium bicarbonate in being every.
According to aforementioned content, be to be understood that to the invention provides a kind of new effective treatment/osteoporotic method and composition of prevention people, and compare with conventional hormone therapy osteoporosis method and to have lower health hazard and side effect incidence rate.
Understand the present invention for clear, although the present invention quite at length is described by explanation and embodiment, some changes and improvements of carrying out in additional claim scope all are conspicuous.
Claims (14)
1. be used for the treatment of two kinds of medicine bound drugs of the osteoporosis of suffering from the osteoporosis patient, comprise
(a) can reduce the tart pharmaceutically useful Alkalinizing potassium salt of tissue fluid or urine, described alkaline potassium salt is selected from potassium bicarbonate and alkalifiable in vivo carboxylic acid potassium salt; With
(b) to the effective estrogen of osteoporosis therapy, its amount is for lacking to 1/10 of its standard recommendation amount;
Alkalinizing potassium salt exists with following amount: more effective in fact when this consumption makes bound drug than to use same amount separately described estrin treatment osteoporosis.
2. the bound drug of claim 1, wherein said estrogen comprises the chemical compound with following general formula, comprises its pharmaceutically useful salt and ester:
R wherein
1Be hydroxyl, R
2Be selected from H ,-C=C, and-C ≡ C, perhaps
R
1And R
2Together the oxygen of two keys and molecular linkage is passed through in expression,
R
3Or be hydrogen or for hydroxyl,
R
4Be selected from H, methyl and cyclopenta, and
Wherein estrogen or have two keys at 6-7 and 8-9 position has two keys in the 7-8 position, perhaps 6,7, and 8 and 9 unparalleled keys.
3. the bound drug of claim 2, wherein Alkalinizing potassium salt and estrogen are with following proportional quantities fusion: the Alkalinizing potassium salt daily dose is that 30-120 milliequivalent and estrogenic daily dose are equivalent to 0.06 to 1.25mg conjugated estrogen hormone.
4. the bound drug of claim 3, wherein Alkalinizing potassium salt exists with following amount, this amount make bound drug can:
A. patient's urine hydroxyproline excretion rate is compared when giving separately with the described estrogen of same amount, can reduce the patient and urinate the hydroxyproline excretion rate above 10%;
B. patient's urine collagen cross-linking thing excretion rate is compared when giving separately with the described estrogen of same amount, can reduce the patient and urinate collagen cross-linking thing excretion rate above 10%; And
C. increase patient's calcium and phosphorus balance.
5. the bound drug of claim 4, wherein said Alkalinizing potassium salt and estrogen are mixed into the unit dosage forms that can further comprise its pharmaceutically suitable carrier.
6. the bound drug of claim 5, wherein said Alkalinizing potassium salt is a potassium bicarbonate.
7. treatment suffers from the method for osteoporosis disease patient's osteoporosis, comprises to the bound drug with following active ingredients:
(a) can reduce the tart pharmaceutically acceptable Alkalinizing potassium salt of tissue fluid or urine, described potassium salt is selected from the potassium salt that potassium bicarbonate reaches the carboxylic acid that can alkalize in vivo; With
(b) to the effective estrogen of osteoporosis therapy, its amount is for lacking to 1/10 of its standard recommendation amount;
Alkalinizing potassium salt is given with following amount and used: this amount makes bound drug than using the described estrin treatment osteoporosis more effective at least 10% of same amount separately.
8. the method for claim 7, wherein said estrogen comprises the chemical compound of following general formula, and pharmaceutically useful salt and ester:
R wherein
1Be hydroxyl, R
2Be selected from H ,-C=C and-C ≡ C, or R
1And R
2Together expression is by the oxygen of two keys and molecular linkage, R
3Or be hydrogen or for hydroxyl,
R
4Be selected from H, methyl and cyclopenta, and
Wherein estrogen or have two keys at 6-7 and 8-9 position has two keys in the 7-8 position, or 6,7, goes up unparalleled keys for 8 and 9.
9. the method for claim 8, wherein estrogen is to be equivalent to the amount administration of 0.06 to 1.25mg conjugated estrogen hormone with the millinormal amount administration of 30-120 every day for Alkalinizing potassium salt.
10. the method for claim 9, wherein Alkalinizing potassium salt is with following amount administration, and this medicine makes the administration of bound drug of active component have:
A. with separately compared with the described estrogen patient's of same amount urine hydroxyproline excretion rate, can reduce the patient and urinate the hydroxyproline excretion rate above 10%;
B. with separately compared with the described estrogen patient's of same amount urine collagen cross-linking thing excretion rate, can reduce the patient and urinate collagen cross-linking thing excretion rate above 10%; And
C. with the equilibrium phase ratio of giving separately with the described estrogen patient of same amount, can increase patient's calcium and phosphorus balance and surpass 10%.
11. the method for claim 9, wherein Alkalinizing potassium salt and estrogen are with independent dosage form administration.
12. the method for claim 9, wherein Alkalinizing potassium salt and estrogen are with the unit dosage form administration.
13. the method for claim 11, wherein unit dosage form also further comprises pharmaceutically useful carrier.
14. the method for claim 9, wherein Alkalinizing potassium salt is a potassium bicarbonate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4234993A | 1993-04-02 | 1993-04-02 | |
| US08/042,349 | 1993-04-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1120314A true CN1120314A (en) | 1996-04-10 |
Family
ID=21921399
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94191682A Pending CN1120314A (en) | 1993-04-02 | 1994-03-29 | Methods and compositions for treating osteoporosis |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0692965A4 (en) |
| JP (1) | JPH08508502A (en) |
| KR (1) | KR960701642A (en) |
| CN (1) | CN1120314A (en) |
| AU (1) | AU692155B2 (en) |
| BR (1) | BR9406101A (en) |
| CA (1) | CA2159354A1 (en) |
| WO (1) | WO1994022457A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106132912A (en) * | 2014-04-02 | 2016-11-16 | 国际壳牌研究有限公司 | For separating monoethylene glycol and the method for 1,2 butanediols |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA03008366A (en) * | 2001-03-16 | 2004-11-12 | Wyeth Corp | Estrogen replacement therapy. |
| AU2004264899A1 (en) * | 2003-08-06 | 2005-02-24 | Innophos, Inc. | Method for promoting bone growth |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3608077A (en) * | 1969-11-13 | 1971-09-21 | Syntex Corp | Stabilization of metal steroid alcohol sulfates |
| US4078060A (en) * | 1976-05-10 | 1978-03-07 | Richardson-Merrell Inc. | Method of inducing an estrogenic response |
| US4261985A (en) * | 1978-11-22 | 1981-04-14 | Ciba-Geigy Corporation | Novel diuretics |
| US4617298A (en) * | 1985-10-22 | 1986-10-14 | University Of Florida | Method and compositions for weight control |
| US4814177A (en) * | 1986-03-18 | 1989-03-21 | Board Of Regents, University Of Texas System | Ultradense and more soluble and bioavailable preparations of calcium citrate |
| US5171583A (en) * | 1988-10-21 | 1992-12-15 | The Regents Of The University Of California | Treatment of osteoporosis using potassium bicarbonate |
-
1994
- 1994-03-29 JP JP6522294A patent/JPH08508502A/en active Pending
- 1994-03-29 BR BR9406101A patent/BR9406101A/en not_active Application Discontinuation
- 1994-03-29 EP EP94913970A patent/EP0692965A4/en not_active Withdrawn
- 1994-03-29 AU AU66219/94A patent/AU692155B2/en not_active Ceased
- 1994-03-29 WO PCT/US1994/003402 patent/WO1994022457A1/en not_active Application Discontinuation
- 1994-03-29 KR KR1019950704281A patent/KR960701642A/en not_active Application Discontinuation
- 1994-03-29 CA CA002159354A patent/CA2159354A1/en not_active Abandoned
- 1994-03-29 CN CN94191682A patent/CN1120314A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106132912A (en) * | 2014-04-02 | 2016-11-16 | 国际壳牌研究有限公司 | For separating monoethylene glycol and the method for 1,2 butanediols |
Also Published As
| Publication number | Publication date |
|---|---|
| AU6621994A (en) | 1994-10-24 |
| CA2159354A1 (en) | 1994-10-13 |
| BR9406101A (en) | 1995-12-19 |
| EP0692965A1 (en) | 1996-01-24 |
| EP0692965A4 (en) | 1998-08-12 |
| AU692155B2 (en) | 1998-06-04 |
| KR960701642A (en) | 1996-03-28 |
| JPH08508502A (en) | 1996-09-10 |
| WO1994022457A1 (en) | 1994-10-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1137691C (en) | heterogeneous contraception preparation based on natural estrogen | |
| JP3208482B2 (en) | Contraceptive preparation | |
| AU680239B2 (en) | Hormone replacement therapy | |
| US5382573A (en) | Hormone preparation and method | |
| ES2247054T3 (en) | PHARMACEUTICAL COMBINATION OF MICRONIZED DROSPIRENONE AND A STROGEN FOR HORMONAL REPLACEMENT THERAPY. | |
| CN1611222A (en) | Composition for contraception | |
| JPH04290830A (en) | Prescribed contraceptive | |
| EA005592B1 (en) | Hormone replacement therapy | |
| KR100782638B1 (en) | Hormonal composition consisting of an oestrogen compound and of a progestational compound | |
| Bainton | Interaction between antibiotic therapy and contraceptive medication | |
| JP2942560B2 (en) | Composition for treating estrogen deficiency | |
| CN1120314A (en) | Methods and compositions for treating osteoporosis | |
| CN1672685A (en) | New contraception medicine | |
| CN1382054A (en) | Novel contraceptive medicament and method for producing the same | |
| WO1999025360A2 (en) | Progestogen-antiprogestogen regimens | |
| JPH10506638A (en) | Prevention of tooth loss by administration of alendronate or its salt | |
| WO2003022292A1 (en) | Oral pharmaceutical formulation containing active carbon and use of the same | |
| CN1047974A (en) | Compositions and methods for effecting contraception | |
| AU729898B2 (en) | Transdermal therapeutic system having an active compound combination comprising oestriol | |
| JP3507515B2 (en) | Ointment with high blood concentration of estriol | |
| CN1057207C (en) | Method and composition for treatment of osteoporosis | |
| CN1111512A (en) | Medical composition for prevention of early pregnancy | |
| JPH11501649A (en) | Injection for January as a sustained release contraceptive for women in peri-menopause and pre-menopause and for hormone replacement therapy | |
| ZA200106689B (en) | Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding. | |
| MXPA99001793A (en) | Transdermal therapeutical approach involving a combination of active substances containing oestriol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |