CN105106962A - Compound antihypertensive preparation and application thereof - Google Patents
Compound antihypertensive preparation and application thereof Download PDFInfo
- Publication number
- CN105106962A CN105106962A CN201510543339.0A CN201510543339A CN105106962A CN 105106962 A CN105106962 A CN 105106962A CN 201510543339 A CN201510543339 A CN 201510543339A CN 105106962 A CN105106962 A CN 105106962A
- Authority
- CN
- China
- Prior art keywords
- metolazone
- mix homogeneously
- pharmaceutical composition
- angiotensin
- recipe quantity
- 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
- 238000002360 preparation method Methods 0.000 title claims description 54
- 230000003276 anti-hypertensive effect Effects 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 title description 26
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 claims abstract description 61
- 229960002817 metolazone Drugs 0.000 claims abstract description 60
- 206010020772 Hypertension Diseases 0.000 claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 230000006378 damage Effects 0.000 claims abstract description 12
- 239000002671 adjuvant Substances 0.000 claims abstract description 8
- 201000004239 Secondary hypertension Diseases 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims abstract description 4
- 208000007530 Essential hypertension Diseases 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 127
- 239000011248 coating agent Substances 0.000 claims description 79
- 238000000576 coating method Methods 0.000 claims description 79
- 239000003814 drug Substances 0.000 claims description 53
- 239000000543 intermediate Substances 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000000843 powder Substances 0.000 claims description 30
- 239000008213 purified water Substances 0.000 claims description 30
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 29
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 29
- 229960004699 valsartan Drugs 0.000 claims description 29
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 29
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 23
- 239000005557 antagonist Substances 0.000 claims description 22
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 21
- 229910001424 calcium ion Inorganic materials 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 229960000528 amlodipine Drugs 0.000 claims description 19
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims description 19
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims description 18
- GKQPCPXONLDCMU-CCEZHUSRSA-N lacidipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C GKQPCPXONLDCMU-CCEZHUSRSA-N 0.000 claims description 18
- 229960003580 felodipine Drugs 0.000 claims description 17
- 229960004340 lacidipine Drugs 0.000 claims description 17
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 16
- 238000013019 agitation Methods 0.000 claims description 16
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 claims description 16
- 239000005480 Olmesartan Substances 0.000 claims description 15
- -1 fluidizer Substances 0.000 claims description 15
- 229960005117 olmesartan Drugs 0.000 claims description 15
- 239000011230 binding agent Substances 0.000 claims description 11
- 230000001631 hypertensive effect Effects 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 10
- 210000003734 kidney Anatomy 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 6
- 206010002383 Angina Pectoris Diseases 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000000945 filler Substances 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 4
- 229960002198 irbesartan Drugs 0.000 claims description 4
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 3
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims description 3
- 229960005187 telmisartan Drugs 0.000 claims description 3
- 239000002080 C09CA02 - Eprosartan Substances 0.000 claims description 2
- 229960004563 eprosartan Drugs 0.000 claims description 2
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 229960004773 losartan Drugs 0.000 claims description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 claims 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 claims 1
- 229960004916 benidipine Drugs 0.000 claims 1
- QZVNQOLPLYWLHQ-ZEQKJWHPSA-N benidipine Chemical compound C1([C@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@H]2CN(CC=3C=CC=CC=3)CCC2)=CC=CC([N+]([O-])=O)=C1 QZVNQOLPLYWLHQ-ZEQKJWHPSA-N 0.000 claims 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 claims 1
- 229960001783 nicardipine Drugs 0.000 claims 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims 1
- 229960001597 nifedipine Drugs 0.000 claims 1
- 229960000715 nimodipine Drugs 0.000 claims 1
- 229960000227 nisoldipine Drugs 0.000 claims 1
- 229960005425 nitrendipine Drugs 0.000 claims 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 abstract description 20
- 239000002934 diuretic Substances 0.000 abstract description 16
- 230000001882 diuretic effect Effects 0.000 abstract description 14
- 229940127291 Calcium channel antagonist Drugs 0.000 abstract description 7
- 239000000480 calcium channel blocker Substances 0.000 abstract description 7
- 230000002195 synergetic effect Effects 0.000 abstract description 6
- 108050000824 Angiotensin II receptor Proteins 0.000 abstract description 3
- 102000008873 Angiotensin II receptor Human genes 0.000 abstract description 3
- 206010067484 Adverse reaction Diseases 0.000 abstract 1
- 230000006838 adverse reaction Effects 0.000 abstract 1
- 239000003087 receptor blocking agent Substances 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 239000008187 granular material Substances 0.000 description 22
- 229960002003 hydrochlorothiazide Drugs 0.000 description 22
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 21
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 19
- 235000019359 magnesium stearate Nutrition 0.000 description 19
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 19
- 239000008108 microcrystalline cellulose Substances 0.000 description 19
- 229940016286 microcrystalline cellulose Drugs 0.000 description 19
- 229920002472 Starch Polymers 0.000 description 16
- 230000036772 blood pressure Effects 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 238000009472 formulation Methods 0.000 description 16
- 238000005516 engineering process Methods 0.000 description 15
- 239000008107 starch Substances 0.000 description 15
- 235000019698 starch Nutrition 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 229940097420 Diuretic Drugs 0.000 description 12
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 description 11
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 description 11
- 241000700159 Rattus Species 0.000 description 11
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 11
- 239000007779 soft material Substances 0.000 description 11
- 229960001199 olmesartan medoxomil Drugs 0.000 description 10
- 229920000881 Modified starch Polymers 0.000 description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 7
- 239000001768 carboxy methyl cellulose Substances 0.000 description 7
- 238000007906 compression Methods 0.000 description 7
- 230000006835 compression Effects 0.000 description 7
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 7
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 7
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 7
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 7
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 7
- 230000002269 spontaneous effect Effects 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 6
- 238000004132 cross linking Methods 0.000 description 6
- 230000001077 hypotensive effect Effects 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 5
- 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 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- 239000004141 Sodium laurylsulphate Substances 0.000 description 5
- 229960000932 candesartan Drugs 0.000 description 5
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 5
- 229960001375 lactose Drugs 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 5
- 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 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 206010027525 Microalbuminuria Diseases 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 229920003081 Povidone K 30 Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960001021 lactose monohydrate Drugs 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000008327 renal blood flow Effects 0.000 description 3
- 108090000312 Calcium Channels Proteins 0.000 description 2
- 102000003922 Calcium Channels Human genes 0.000 description 2
- 102000003846 Carbonic anhydrases Human genes 0.000 description 2
- 108090000209 Carbonic anhydrases Proteins 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 208000019025 Hypokalemia Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- 206010030124 Oedema peripheral Diseases 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 206010061481 Renal injury Diseases 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000024924 glomerular filtration Effects 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 208000037806 kidney injury Diseases 0.000 description 2
- 238000009533 lab test Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 239000003605 opacifier Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 208000024896 potassium deficiency disease Diseases 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000002889 sympathetic effect Effects 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 230000002618 waking effect Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- QWCYQCQLAZCPHO-FTBISJDPSA-N 3-o-ethyl 5-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 QWCYQCQLAZCPHO-FTBISJDPSA-N 0.000 description 1
- UIYUUEDFAMZISF-FTBISJDPSA-N 6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 UIYUUEDFAMZISF-FTBISJDPSA-N 0.000 description 1
- OZCVMXDGSSXWFT-UHFFFAOYSA-N 6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide;2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoic acid Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O.CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O OZCVMXDGSSXWFT-UHFFFAOYSA-N 0.000 description 1
- 101150059573 AGTR1 gene Proteins 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 235000019890 Amylum Nutrition 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010015856 Extrasystoles Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000000857 Hepatic Insufficiency Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229940121792 Thiazide diuretic Drugs 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
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229940043531 amlodipine / olmesartan Drugs 0.000 description 1
- 229940051123 amlodipine / valsartan Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008081 blood perfusion Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229940003871 calcium ion Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 1
- 229960001826 dimethylphthalate Drugs 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 229940124567 diuretic antihypertensive agent Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960000519 losartan potassium Drugs 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000001452 natriuretic effect Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 230000004873 systolic arterial blood pressure Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a pharmaceutical composition for treating hypertension. The pharmaceutical composition is characterized by comprising (1) angiotensin II receptor blocker, (2) diuretic metolazone, (3) calcium channel blocker and (4) pharmaceutically acceptable adjuvant materials, wherein the weight ratio among the angiotensin receptor blocker, the metolazone and the calcium channel blocker is 2-200:0.5-5:2-50. The pharmaceutical composition for treating hypertension has the advantages that the pharmaceutical composition combines the angiotensin receptor blocker, the metolazone and the calcium channel blocker, and accordingly, synergetic antihypertensive effect is enhanced, adverse reaction is reduced and compliance of patients is improved; the pharmaceutical composition is wide in application range and can be also used for patients suffering from severe renal damage; the pharmaceutical composition is applicable to mild and moderate essential hypertension, particularly secondary hypertension caused by renal damage.
Description
Technical field
The present invention relates to drug world, be specifically related to pharmaceutical composition that Angiotensin Ⅱ receptor antagonist, metolazone and calcium ion antagonist are effective ingredient and application thereof.
Background technology
Along with the quick growth of China's economy, the drastic change of people life style, cardiovascular diseases has become the maximum killer threatening human health.Hypertension is one of current modal cardiovascular disease, has become the great public health problem in global range.According to the statistics display of national hygiene department, to the end of the year 2010, China patients with hypertension crowd will have reached 200,000,000 people, and annual newly-increased more than 3,000,000.Hypertension is a kind of clinical syndrome being feature with body circulation systolic arterial pressure (SBP) and (or) diastolic pressure (DBP) rising, especially the infringement of the target organ such as the heart, brain, kidney that excites of hypertension, has a strong impact on life-span and the quality of life of patient.
The hypertensive medicine of current treatment has a variety of, relatively more conventional has calcium ion antagonist (CCBs), beta-blocker, angiotensin-convertion enzyme inhibitor (ACEI), Angiotensin Ⅱ receptor antagonist (ARBs), diuretic five class medicine, but single medicine treatment hypertension is more difficult up to standard in a short time, Most patients needs to take two or more antihypertensive drug can reach blood pressure lowering target, and especially blood pressure exceedes the patient of desired value 20/10mmHg.Drug combination is the preferred option of hypertension therapeutic, by different machine-processed blood pressure lowerings, complements one another, and prevents the cancellation mechanism after single medicine dosage; The medication combined of different peaks Effect time can extend the hypotensive effect time, reduces untoward reaction, thus strengthens the protective effect to target organ.But several drugs is taken simultaneously, patient compliance is poor, and the collocation of the dosage of several drugs is due to the problem of formulation dosage and the degree of awareness of doctor, is not often optimized proportioning.In order to meet the needs of hyperpietic and improve drug compliance, be the Main way that compound preparation has become domestic and international medicine and looks forward to competitively chasing by the drug development of different mechanism of action.
Angiotensin Ⅱ receptor antagonist (ARB) is a class novel antihypertensive medicament, is described as a milestone of 20th century the nineties cardiovascular drugs.Side effect angle, it has higher safety than antihypertensive drug in the past.Renin-angiotensin system (RAS) excessive activation during hypertension, just starts to play illeffects after the angiotensinⅡ (Ang II) too much generated and angiotensin-ii-receptor combine.Research proves that angiotensin-ii-receptor is divided into AT1, AT2 two kinds, and Ang II mainly acts on AT1 receptor, causes blood pressure to raise, damages target organ.For this link, scientist develops Angiotensin Ⅱ receptor antagonist, and ARB fights for AT1 with Ang II competitiveness, by blocking the combination of angiotensinⅡ and AT1, thus plays the effect of blood pressure lowering protection target organ.And ARB also can indirect activation AT2, causes vasodilation, alleviates heart burden.Angiotensin Ⅱ receptor antagonist medicine can be used in early days while injury of kidney; the effect of protection kidney can be played; decrease glomerule inner high voltage height filtration state; its mechanism of action makes urine volume increase; row's sodium row chlorine increases; and improve the blood perfusion of kidney, improve protein in nephropathy, lipid and carbohydrate metabolism disturbance, to a certain degree decrease urine protein.Such as: valsartan, telmisartan, irbesartan etc.
Calcium ion antagonist (CCBs) refers to the medicine reduced blood pressure by retardance calcium channel.It can enter in cell by the calcium channel of Selective depression Ca2+ on cell membrane, has blood vessel dilating and negative inotropic action, and sliding flesh, reduce peripheral vascular resistance, thus reduce blood pressure, but brain, coronary artery and renal blood flow does not reduce.In addition, calcium ion antagonist also has suppression myocardial contraction, reduce myocardial oxygen consumption, lax vascular smooth muscle, cause the effect of the cardiovascular system aspects such as hemodynamics variation, but also there is anticoagulant, suppress neural and the excitation-secretion coupling of hormonal system and reduce the effect such as release of SNE mediator.Untoward reaction is slight, and long-term taking, without toleration, has no significant effect lipid, sugar, carbamide and electrolyte.
Within 2009, Japanese Hypertension Guideline, " Chinese hypertension prevention and control guide 2010 " are all recommended, Angiotensin Ⅱ receptor antagonist (ARB) and diuretic are as conbined usage, there is blood pressure lowering synergism, the untoward reaction such as ARB can make serum potassium slightly rise, the hypokalemia caused by energy antagonist/diuretic agent life-time service.The compound preparation of the ARB associating diuretic of current listing has valsartan/hydrochlorothiazide, telmisartan/hydrochlorothiazide, Losartan Potassium/hydrochlorothiazide, irbesartan/hydrochlorothiazide, olmesartan medoxomil/hydrochlorothiazide etc.Angiotensin Ⅱ receptor antagonist and dihydropyridine type calcium antagonists conbined usage, calcium antagonist has the effect of direct expansion artery, and ARB is expansion artery both, again expansion of veins, therefore two medicines share and have Synergistic Hypotensive Effects.The common untoward reaction of dihydropyridine type calcium antagonists has ankle edema, can be offset by ARB.Separately there are some researches show, ARB can increase and the untoward reaction of increased heart rate by sympathetic reflex tension force caused by part blocks calcium antagonist.The compound preparation of the ARB associating dihydropyridine type calcium antagonists of current listing has valsartan/amlodipine.Dihydropyridine type calcium antagonists and diuretic conbined usage, can reduce the risk that hyperpietic's apoplexy occurs.Due to ARB+ diuretic+dihydropyridine type calcium antagonists conbined usage, there is obvious Synergistic Hypotensive Effects, and untoward reaction each other can be offset, therefore common in three kinds of combination therapies schemes clinically.
Three compound recipes that current FDA ratifies ARB+ diuretic+dihydropyridine type calcium antagonists have amlodipine/olmesartan medoxomil/hydrochlorothiazide, amlodipine/valsartan/hydrochlorothiazide, and wherein diuretic is all hydrochlorothiazide.And hydrochlorothiazide can disturb tubular excretion uric acid, minority can bring out gout outbreak; To severe renal hypothyroid, heavy dose of can cause drug accumulation when using, toxicity increases, should careful use, thus clinically in the urgent need to a kind of new diuretic to reduce its untoward reaction.
Metolazone (Metolazone) is a kind of Thiazoling type derivant, have diuretic antihypertensive effect, drug effect is similar with thiazide diuretic, and its natriuretic diuretic effect is 10 times of hydrochlorothiazide, but the effect of unrestraint carbonic anhydrase, significant to the acid-base balance in body.This product oral absorption is rapid, but not exclusively (about 64%), some cardiac's absorbance is 40%.Extensively and plasma protein and erythrocyte binding, plasma half-life is about 8h.After taking medicine there is diuresis in 1h, continues 12 ~ 24h.The untoward reaction of metolazone is similar to hydrochlorothiazide, occurs individually cardiopalmus, chest pain, room quivers, but be different from hydrochlorothiazide, and renal blood flow and glomerular filtration rate can not be made to reduce, and severe renal functional lesion person still can apply.
One section of Chinese invention patent (publication number: CN101132770A) being entitled as " Nanoparticulate candesartan formulations " discloses a kind of pharmaceutical composition of Candesartan, said composition comprises one or more compounds being used for the treatment of hypertension or related cardiovascular sufferer, wherein relates to metolazone
the compositions mentioned in the document, mainly utilizes the feature of Candesartan nanoparticle, improves dissolution and the bioavailability of Candesartan, and then improves its effect.Do not mentioned medication crowd in patent, we know, the patient of Candesartan to hepatic insufficiency likely makes deterioration of liver function, and Clinical practice should be very careful, also should be cautious use of the patient of severe renal functional lesion.Rational prescription should improve the curative effect of medicine, reduces toxic and side effects again, therefore seeks suitable Angiotensin Ⅱ receptor antagonist and dihydropyridine type calcium antagonists, combines make compound preparation with metolazone, be clinical application in the urgent need to.So it is diuretic with metolazone that the present invention develops a kind of, the compound preparation formed with Angiotensin Ⅱ receptor antagonist and dihydropyridine type calcium antagonists, is used for the treatment of hypertension complicated with angina pectoris, the secondary hypertension particularly caused by kidney damage.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of reasonable recipe, the composite antihypertensive preparation of ratio optimization, to increase its synergism, reduces untoward reaction and toxic action.
The present invention finds through a large amount of tests, and Angiotensin Ⅱ receptor antagonist, dihydropyridine calcium ion antagonist and metolazone, in the ratio range of doses, have good synergism and blood pressure lowering effect.Be applicable to hypertension complicated with angina pectoris, the secondary hypertension particularly caused by kidney damage.
Therefore, technical scheme of the present invention is a kind of hypertensive pharmaceutical composition for the treatment of containing Angiotensin Ⅱ receptor antagonist, dihydropyridine calcium ion antagonist and metolazone.
Pharmaceutical composition of the present invention, containing Angiotensin Ⅱ receptor antagonist, dihydropyridine calcium ion antagonist, metolazone and pharmaceutically acceptable adjuvant.
Wherein, count by weight, Angiotensin Ⅱ receptor antagonist: metolazone: dihydropyridine calcium ion antagonist is 5 ~ 500:0.1 ~ 10:1-100.
Preferably, count by weight, Angiotensin Ⅱ receptor antagonist: metolazone: dihydropyridine calcium ion antagonist is 10 ~ 200:0.5 ~ 5:2 ~ 50.
Preferred further, count by weight, Angiotensin Ⅱ receptor antagonist: metolazone: dihydropyridine calcium ion antagonist is 20 ~ 160:0.5 ~ 1:2 ~ 40.
Described Angiotensin Ⅱ receptor antagonist is one or more mixture of losartan, valsartan, telmisartan, irbesartan, Olmesartan, eprosartan and physiologically acceptable salt or ester.
Described Angiotensin Ⅱ receptor antagonist is preferably one or more mixture of valsartan, Olmesartan and physiologically acceptable salt or ester.
Described dihydropyridine calcium ion antagonist is preferably one or more mixture of amlodipine, lacidipine, felodipine and physiologically acceptable salt or ester.
Wherein, described pharmaceutically acceptable adjuvant is selected from one or more mixture of binding agent, filler, disintegrating agent, lubricant, fluidizer, coating material and other adjuvants etc.
Described binding agent can be distilled water, ethanol, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose, polyvidone, syrup, rubber cement etc.
Described filler can be starch, Icing Sugar, dextrin, lactose, amylum pregelatinisatum, microcrystalline Cellulose, inorganic salts and mannitol etc.
Described disintegrating agent can be dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, gas-producing disintegrant etc.
Described lubricant can be magnesium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycols and magnesium laurylsulfate etc.
Described fluidizer can be micropowder silica gel, Pulvis Talci etc.
Described coating material can be hydroxypropyl emthylcellulose, hydroxypropyl cellulose, No. VI, acrylic resin, polyvinylpyrrolidone, ethyl cellulose, cellulose acetate etc.
Other described adjuvants can be plasticizer, opacifier etc., and plasticizer is as propylene glycol, Oleum Ricini, Polyethylene Glycol, silicone oil, glycerol, dimethyl phthalate or dibutyl ester etc., and opacifier is as titanium dioxide etc.
Another object of the present invention is the preparation method providing pharmaceutical composition.
The preparation method of pharmaceutical composition involved in the present invention, its preparation method includes but not limited to following steps: pulverize, sieve, weigh, add the processes such as binding agent, granulation, drying, total mixed, tabletting or filling.Wherein binding agent can be additional, Nei Jia or interior additional; Granulation can be dry granulation or wet granulation; Drying can be vacuum drying, spraying dry, lyophilization, pneumatic conveying drying or airpillow-dry; Tabletting can be direct compression or pelletizing press sheet.
Preferably, preparation method of the present invention, comprises the following steps:
(1) take the Angiotensin Ⅱ receptor antagonist of recipe quantity, metolazone, dihydropyridine calcium ion antagonist, cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the filler of recipe quantity, disintegrating agent, cross 60 mesh sieves, mix homogeneously;
(3) by (1) and (2) mix homogeneously, then add fluidizer and lubricant, mix homogeneously, obtain intermediate;
(4) check intermediates content, calculate sheet weight, tabletting;
(5) take purified water in prescription ratio, under agitation, slowly add the coating powder of recipe quantity;
(6) tablet is placed in high-efficiency coating machine coating, obtains final product.
Another object of the present invention is the purposes providing pharmaceutical composition of the present invention.
Pharmaceutical composition of the present invention for the preparation for the treatment of hypertensive medicine in application.
Pharmaceutical composition of the present invention for the preparation for the treatment of hypertension complicated with the application in angina drug.
Wherein, described hypertension is light, moderate essential hypertension, the secondary hypertension particularly caused by kidney damage.
Pharmaceutical composition of the present invention, by selecting the drug regimen of suitable Angiotensin Ⅱ receptor antagonist, dihydropyridine calcium ion antagonist and metolazone, strengthen Synergistic Hypotensive Effects, reduce untoward reaction, improve the compliance of patient, medication crowd is wide, all can use with anginal patient the patient of renal function grievous injury and hypertension complicated.Pharmaceutical composition of the present invention is particularly useful for hypertension complicated with angina pectoris, the secondary hypertension particularly caused by kidney damage.
The untoward reaction such as Angiotensin Ⅱ receptor antagonist (ARB) and diuretic conbined usage are preferred option, have blood pressure lowering synergism, and ARB can make serum potassium slightly rise, the hypokalemia caused by energy antagonist/diuretic agent life-time service.Angiotensin Ⅱ receptor antagonist (ARB) and dihydropyridine type calcium antagonists conbined usage, calcium antagonist has the effect of direct expansion artery, and ARB is expansion artery both, again expansion of veins, and two medicines share has Synergistic Hypotensive Effects; ARB can offset the untoward reaction of dihydropyridine type calcium antagonists ankle edema, also can increase and the untoward reaction of increased heart rate by sympathetic reflex tension force caused by part blocks calcium antagonist.Dihydropyridine type calcium antagonists and diuretic conbined usage, can reduce the risk that hyperpietic's apoplexy occurs.Three kinds of Drug combinations, have obvious Synergistic Hypotensive Effects, and can offset untoward reaction each other.In addition, metolazone (Metolazone) as diuretic, the effect of unrestraint carbonic anhydrase, significant to the acid-base balance in body; Renal blood flow and glomerular filtration rate can not be made to reduce, and severe renal functional lesion person still can apply.Therefore Angiotensin Ⅱ receptor antagonist, dihydropyridine calcium ion antagonist and metolazone coupling is selected.
Accompanying drawing explanation
Fig. 1 is the impact of different pharmaceutical combination on spontaneous hypertensive rat blood pressure.
Fig. 2 is the impact of different pharmaceutical combination on spontaneous hypertensive rat Microalbuminuria
Detailed description of the invention
The present invention is further illustrated below by embodiment.It should be understood that; the product of the embodiment of the present invention and preparation method are only used for the present invention is described; instead of limitation of the present invention, under concept thereof of the present invention, all the scope of protection of present invention is belonged to the simple modifications of product of the present invention and preparation method.Except as otherwise noted, " % " in the present invention is all quality criterias.
The active constituents of medicine playing therapeutical effect due to valsartan or its pharmaceutically useful salt or ester is identical, and therefore in the following example, valsartan can be regarded as valsartan or its pharmaceutically useful salt or ester.Equally, Olmesartan, amlodipine, lacidipine, felodipine also should be understood like this.
Embodiment 1: three drug regimen resists effect experimental to hypertension in spontaneous hypertensive rats
1, laboratory animal and experiment grouping
Male spontaneously hypertensive rat 190, body weight 250g ± 20g, adapts to raising after one week, is divided into 19 groups at random, often organize 10.
(1) model control group: gavage gives same volume normal saline;
(2) metolazone group: 0.05mg/kg/d
(3) hydrochlorothiazide: 1.2mg/kg/d
(4) valsartan group: 7.5mg/kg/d
(5) Olmesartan group: 4mg/kg/d
(6) amlodipine group: 1mg/kg/d
(7) lacidipine group: 0.4mg/kg/d
(8) felodipine group: 0.5mg/kg/d
(9) metolazone+valsartan+amlodipine: 0.05mg/kg/d+7.5mg/kg/d+1mg/kg/d
(10) metolazone+valsartan+lacidipine: 0.05mg/kg/d+7.5mg/kg/d+0.4mg/kg/d
(11) metolazone+valsartan+felodipine: 0.05mg/kg/d+7.5mg/kg/d+0.5mg/kg/d
(12) metolazone+Olmesartan+amlodipine: 0.05mg/kg/d+4mg/kg/d+1mg/kg/d
(13) metolazone+Olmesartan+lacidipine: 0.05mg/kg/d+4mg/kg/d+0.4mg/kg/d
(14) metolazone+Olmesartan+felodipine: 0.05mg/kg/d+4mg/kg/d+0.5mg/kg/d
(15) metolazone+valsartan: 0.05mg/kg/d+7.5mg/kg/d
(16) metolazone+Olmesartan: 0.05mg/kg/d+4mg/kg/d
(17) metolazone+amlodipine: 0.05mg/kg/d+1mg/kg/d
(18) metolazone+lacidipine: 0.05mg/kg/d+0.4mg/kg/d
(19) metolazone+felodipine: 0.05mg/kg/d+0.5mg/kg/d
2, test method: once, totally 4 weeks, receptacle temperature controlled at about 25 DEG C each group every gastric infusion every day, humidity 45% ~ 65%.Tail arterial blood pressure under BP-2006A intelligence non-invasive blood pressure measuring (Beijing is soft grand) measurement rat waking state, measures blood pressure three times, averages after administration surrounding.The results are shown in Table 1.
3, experimental result:
Impact (X ± S, n=10) (mmHg) of table 1 different pharmaceutical combination on spontaneous hypertensive rat blood pressure
| Group | Before treatment | After treatment surrounding |
| 1 | 174±8.9 | 180±11.3 |
| 2 | 172±7.3 | 150±8.2 |
| 3 | 175±9.0 | 155±7.5 |
| 4 | 172±11.3 | 152±6.8 |
| 5 | 175±6.9 | 151±8.8 |
| 6 | 172±9.5 | 152±4.9 |
| 7 | 171±5.7 | 154±6.4 |
| 8 | 172±9.6 | 152±7.1 |
| 9 | 173±9.1 | 121±5.4 |
| 10 | 170±7.6 | 122±4.1 |
| 11 | 169±7.4 | 119±2.6 |
| 12 | 174±10.7 | 120±5.8 |
| 13 | 171±8.8 | 122±7.5 |
| 14 | 168±7.1 | 121±3.4 |
| 15 | 177±6.9 | 135±4.1 |
| 16 | 171±7.0 | 137±5.7 |
| 17 | 174±8.9 | 131±2.8 |
| 18 | 172±9.4 | 134±3.9 |
| 19 | 170±8.6 | 133±4.4 |
As can be seen from table 1 result, three drug regimens have stronger antihypertensive effect relative to folk prescription and bigeminy drug regimen.
Embodiment 2: the present invention three drug regimen is tested compared to containing hydrochlorothiazide three drug regimen hypertension in spontaneous hypertensive rats antagonism effect and kidney injury
1, laboratory animal and experiment grouping
Male spontaneously hypertensive rat 120, body weight 250g ± 20g, adapts to raising after one week, is divided into 12 groups at random, often organize 10.
(1) metolazone+valsartan+amlodipine: 0.05mg/kg/d+7.5mg/kg/d+1mg/kg/d
(2) metolazone+valsartan+lacidipine: 0.05mg/kg/d+7.5mg/kg/d+0.4mg/kg/d
(3) metolazone+valsartan+felodipine: 0.05mg/kg/d+7.5mg/kg/d+0.5mg/kg/d
(4) metolazone+Olmesartan+amlodipine: 0.05mg/kg/d+4mg/kg/d+1mg/kg/d
(5) metolazone+Olmesartan+lacidipine: 0.05mg/kg/d+4mg/kg/d+0.4mg/kg/d
(6) metolazone+Olmesartan+felodipine: 0.05mg/kg/d+4mg/kg/d+0.5mg/kg/d
(7) hydrochlorothiazide+valsartan+amlodipine: 1.2mg/kg/d+7.5mg/kg/d+1mg/kg/d
(8) hydrochlorothiazide+valsartan+lacidipine: 1.2mg/kg/d+7.5mg/kg/d+0.4mg/kg/d
(9) hydrochlorothiazide+valsartan+felodipine: 1.2mg/kg/d+7.5mg/kg/d+0.5mg/kg/d
(10) hydrochlorothiazide+Olmesartan+amlodipine: 1.2mg/kg/d+4mg/kg/d+1mg/kg/d
(11) hydrochlorothiazide+Olmesartan+lacidipine: 1.2mg/kg/d+4mg/kg/d+0.4mg/kg/d
(12) hydrochlorothiazide+Olmesartan+felodipine: 1.2mg/kg/d+4mg/kg/d+0.5mg/kg/d
2, test method: once, totally 4 weeks, receptacle temperature controlled at about 25 DEG C each group every gastric infusion every day, humidity 45% ~ 65%.Tail arterial blood pressure under BP-2006A intelligence non-invasive blood pressure measuring (Beijing is soft grand) measurement rat waking state, measures blood pressure three times, averages after surrounding after administration.The results are shown in Table 2.Each group of rat before administration one day and experiment terminates last day and is placed in metabolic cage respectively to raise, and collects 12h urine overnight and detects microdose urine protein (MA) using as kidney injury mark with immunoturbidimetry, the results are shown in Table 3.
Impact (X ± S, n=10) (mmHg) of table 2 different pharmaceutical combination on spontaneous hypertensive rat blood pressure
| Group | Before treatment | After treatment surrounding |
| 1 | 173±9.1 | 121±5.4 |
| 2 | 170±7.6 | 122±4.1 |
| 3 | 169±7.4 | 119±2.6 |
| 4 | 174±10.7 | 120±5.8 |
| 5 | 171±8.8 | 122±7.5 |
| 6 | 168±7.1 | 121±3.4 |
| 7 | 171±8.8 | 122±4.2 |
| 8 | 174±10.2 | 123±5.0 |
| 9 | 169±5.7 | 123±2.9 |
| 10 | 172±10.9 | 121±4.9 |
| 11 | 173±8.0 | 124±4.7 |
| 12 | 175±8.3 | 120±3.8 |
As can be seen from table 2 result, the present invention three drug regimen is relative to suitable containing hydrochlorothiazide three drug regimen antihypertensive effect.
The impact (X ± S, n=10) (unit: ug/mL) of table 3 different pharmaceutical combination on spontaneous hypertensive rat Microalbuminuria
| Group | Before treatment | After treatment |
| 1 | 90.5±7.3 | 67.3±7.6 |
| 2 | 91.5±6.9 | 71.0±7.2 |
| 3 | 93.7±10.2 | 69.4±5.6 |
| 4 | 95.8±7.7 | 68.2±8.5 |
| 5 | 95.3±6.4 | 72.4±6.7 |
| 6 | 94.6±5.9 | 71.1±6.2 |
| 7 | 92.9±6.9 | 108.3±8.3 |
| 8 | 94.1±8.2 | 107.8±8.1 |
| 9 | 91.2±7.1 | 113.6±7.3 |
| 10 | 92.6±8.6 | 111.2±6.7 |
| 11 | 91.7±5.2 | 109.4±5.9 |
| 12 | 88.1±7.3 | 113.6±7.1 |
Can find out according to table 3 result; the present invention three drug regimen obviously reduces rat Microalbuminuria before treatment and containing hydrochlorothiazide three drug regimen; point out it not only can not cause damage to kidney over the course for the treatment of; also can play certain protective effect; and within 4 weeks, all finding that Microalbuminuria raises after the treatment containing the drug regimen of hydrochlorothiazide, prompting hydrochlorothiazide life-time service has certain damage to renal function.
Need to further illustrate, in above-mentioned experiment, the present invention only enumerates section Example, and in fact the pharmaceutical composition of other proportionings of the present invention also has identical or close beneficial effect, does not just enumerate at this.
Embodiment 1: the preparation (in 1000) of compound medicament composition 1 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation method:
(1) take the valsartan of recipe quantity, metolazone, amlodipine, cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, pregelatinized Starch, vertical compression mannitol, cross-linking sodium carboxymethyl cellulose, cross 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, then add micropowder silica gel and magnesium stearate, mix homogeneously, obtain intermediate.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness and be about 8kg.
(5) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(6) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 2: the preparation (in 1000) of compound medicament composition 2 (tablet)
Core formulation:
Coating prescription:
Opadry coating powder 9g
Purified water 60g
Preparation method:
(1) take the valsartan of recipe quantity, metolazone, amlodipine, cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, starch, cross-linking sodium carboxymethyl cellulose, cross 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, soft material made by the ethanol adding 95%, and 18 mesh sieves are granulated, dry at 50 DEG C.
(4) after granule is dried, 20 mesh sieve granulate, then add micropowder silica gel, magnesium stearate, mix homogeneously, obtain intermediate.
(5) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 7kg.
(6) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(7) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
The preparation (in 1000) of embodiment 3, compound medicament composition 3 (tablet)
Core formulation:
Coating prescription:
Opadry coating powder 9g
Purified water 60g
Preparation method:
(1) take the valsartan of recipe quantity, metolazone, amlodipine, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, starch, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, soft material made by the ethanol adding 95%, and 18 mesh sieves are granulated, dry at 50 DEG C.
(4) after granule is dried, 20 mesh sieve granulate, then add magnesium stearate, mix homogeneously, obtain intermediate.
(5) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 7kg.
(6) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(7) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
The preparation (in 1000) of embodiment 4 compound medicament composition 4 (capsule)
Prescription:
Preparation method:
(1) get the valsartan of recipe quantity, metolazone, lacidipine, cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the meglumine of recipe quantity, microcrystalline Cellulose, pregelatinized Starch cross 60 mesh sieves, mix homogeneously.
(3) get PVP K30 appropriate, the ethanol adding 95% is about 20ml, is made into binding agent, for subsequent use.
(4) by (1) and (2) mix homogeneously, add binding agent and make soft material, 18 eye mesh screens are granulated, dry at 50 DEG C.
(5) after granule is dried, 20 eye mesh screen granulate.Add magnesium stearate again, mix homogeneously, obtain intermediate.
(6) detect intermediates content, calculate loading amount, fill.
The preparation (in 1000) of embodiment 5 compound medicament composition 5 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) take the valsartan of recipe quantity, metolazone, lacidipine, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the hydroxypropyl methylcellulose of recipe quantity, microcrystalline Cellulose, pregelatinized Starch, carboxymethyl starch sodium, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, soft material made by the ethanol adding 95%, and 18 mesh sieves are granulated, dry at 50 DEG C.
(4) after granule is dried, 20 mesh sieve granulate, then add magnesium stearate, mix homogeneously, obtain intermediate.
(5) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 7kg.
(6) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(7) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
The preparation (in 1000) of embodiment 6 compound medicament composition 6 (capsule)
Prescription:
Preparation technology:
(1) take the valsartan of recipe quantity, metolazone, lacidipine, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the hydroxypropyl methylcellulose of recipe quantity, microcrystalline Cellulose, pregelatinized Starch, carboxymethyl starch sodium, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, soft material made by the ethanol adding 95%, and 18 mesh sieves are granulated, dry at 50 DEG C.
(4) after granule is dried, 20 mesh sieve granulate, then add magnesium stearate, mix homogeneously, obtain intermediate.
(5) check intermediates content, calculate loading amount, fill.
Embodiment 7: the preparation (in 1000) of compound medicament composition 7 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the valsartan of recipe quantity, metolazone, felodipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the anhydrous vertical compression lactose of recipe quantity, microcrystalline Cellulose, polyvinylpolypyrrolidone cross 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, add micropowder silica gel and magnesium stearate, mix homogeneously, obtain intermediate.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 7kg.
(5) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(6) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 8: the preparation (in 1000) of compound medicament composition 8 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the valsartan of recipe quantity, metolazone, felodipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the anhydrous vertical compression lactose of recipe quantity, microcrystalline Cellulose, polyvinylpolypyrrolidone cross 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, add micropowder silica gel and magnesium stearate, mix homogeneously, obtain intermediate.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 8kg.
(5) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(6) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 9: the preparation (in 1000) of compound medicament composition 9 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the valsartan of recipe quantity, metolazone, felodipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the lactose monohydrate of recipe quantity, microcrystalline Cellulose, carboxymethyl starch received 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, add appropriate 95% ethanol and make soft material, granulated by 18 mesh sieves, dry at 50 DEG C.
(4), after granule is dried, with 18 mesh sieve granulate, add magnesium stearate mix homogeneously, obtain intermediate.
(5) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 8kg.
(6) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(7) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 10: the preparation (in 1000) of compound medicament composition 10 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the olmesartan medoxomil of recipe quantity, metolazone, amlodipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the anhydrous vertical compression lactose of recipe quantity, microcrystalline Cellulose, polyvinylpolypyrrolidone cross 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, add micropowder silica gel and magnesium stearate, mix homogeneously, obtain intermediate.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 6kg.
(5) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(6) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 11: the preparation (in 1000) of compound medicament composition 11 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the olmesartan medoxomil of recipe quantity, metolazone, amlodipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the anhydrous vertical compression lactose of recipe quantity, microcrystalline Cellulose, polyvinylpolypyrrolidone cross 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, add micropowder silica gel and magnesium stearate, mix homogeneously, obtain intermediate.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 7kg.
(5) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(6) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 12: the preparation (in 1000) of compound medicament composition 12 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the olmesartan medoxomil of recipe quantity, metolazone, amlodipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the microcrystalline Cellulose of recipe quantity, starch, polyvinylpolypyrrolidone, cross 60 mesh sieves, mix homogeneously.
(3) get PVP K30 appropriate, the ethanol adding 95% is about 30ml, is made into binding agent, for subsequent use.
(4) by (1) and (2) mix homogeneously, add binding agent and make soft material, 18 eye mesh screens are granulated, dry at 50 DEG C.
(5) after granule is dried, 20 eye mesh screen granulate.Add magnesium stearate again, mix homogeneously, obtain intermediate.
(6) detect intermediates content, calculate sheet weight, tabletting, control tablet hardness is 8kg.
(7) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(8) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 13: the preparation (in 1000) of compound medicament composition 13 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the olmesartan medoxomil of recipe quantity, metolazone, lacidipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the vertical compression mannitol of recipe quantity, microcrystalline Cellulose, pregelatinized Starch, sodium lauryl sulphate, carboxymethyl starch sodium, cross 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, add micropowder silica gel and magnesium stearate, mix homogeneously, obtain intermediate.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 7kg.
(5) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(6) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 14: the preparation (in 1000) of compound medicament composition 14 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the olmesartan medoxomil of recipe quantity, metolazone, lacidipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the vertical compression mannitol of recipe quantity, microcrystalline Cellulose, pregelatinized Starch, sodium lauryl sulphate, carboxymethyl starch sodium, cross 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, add micropowder silica gel and magnesium stearate, mix homogeneously, obtain intermediate.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 7kg.
(5) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(6) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 15: the preparation (in 1000) of compound medicament composition 15 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the olmesartan medoxomil of recipe quantity, metolazone, lacidipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the microcrystalline Cellulose of recipe quantity, pregelatinized Starch, sodium lauryl sulphate, polyvinylpolypyrrolidone, cross 60 mesh sieves, mix homogeneously.
(3) get PVP K30 appropriate, the ethanol adding 95% is about 30ml, is made into binding agent, for subsequent use.
(4) by (1) and (2) mix homogeneously, add binding agent and make soft material, 18 eye mesh screens are granulated, dry at 50 DEG C.
(5) after granule is dried, 20 eye mesh screen granulate.Add micropowder silica gel and magnesium stearate again, mix homogeneously, obtain intermediate.
(6) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 8kg.
(7) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(8) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 16: the preparation (in 1000) of compound medicament composition 16 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 9g
Purified water 60g
Preparation technology:
(1) get the olmesartan medoxomil of recipe quantity, metolazone, felodipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the microcrystalline Cellulose of recipe quantity, lactose monohydrate, starch, cross-linking sodium carboxymethyl cellulose, cross 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, soft material made by the ethanol adding 95%, granulated by 18 mesh sieves, dry at 50 DEG C.
(4) after granule is dried, 20 eye mesh screen granulate.Add micropowder silica gel and magnesium stearate again, mix homogeneously, obtain intermediate.
(5) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 6kg.
(6) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(7) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
Embodiment 17: the preparation (in 1000) of compound medicament composition 17 (capsule)
Prescription:
Preparation technology:
(1) get the olmesartan medoxomil of recipe quantity, metolazone, felodipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the microcrystalline Cellulose of recipe quantity, lactose monohydrate, starch, cross-linking sodium carboxymethyl cellulose, cross 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, soft material made by the ethanol adding 95%, granulated by 18 mesh sieves, dry at 50 DEG C.
(4) after granule is dried, 20 eye mesh screen granulate.Add micropowder silica gel and magnesium stearate again, mix homogeneously, obtain intermediate.
(5) check intermediates content, calculate loading amount, fill.
Embodiment 18: the preparation (in 1000) of compound medicament composition 18 (capsule)
Prescription:
Preparation technology:
(1) get the olmesartan medoxomil of recipe quantity, metolazone, felodipine cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) get the meglumine of recipe quantity, microcrystalline Cellulose, starch, polyvinylpolypyrrolidone, cross 60 mesh sieves, mix homogeneously.
(3) by above-mentioned (1) and (2) mix homogeneously, soft material made by the ethanol adding 95%, granulated by 18 mesh sieves, dry at 50 DEG C.
(4) after granule is dried, 20 eye mesh screen granulate.Add magnesium stearate again, mix homogeneously, obtain intermediate.
(5) check intermediates content, calculate loading amount, fill.
Claims (10)
1. treat a hypertensive pharmaceutical composition, it is characterized in that, containing Angiotensin Ⅱ receptor antagonist, metolazone, dihydropyridine calcium ion antagonist and pharmaceutically acceptable adjuvant.
2. pharmaceutical composition as claimed in claim 1, it is characterized in that, described Angiotensin Ⅱ receptor antagonist is selected from: one or more mixture of losartan, valsartan, telmisartan, irbesartan, Olmesartan, eprosartan and physiologically acceptable salt or ester.
3. pharmaceutical composition as claimed in claim 1, it is characterized in that, described Angiotensin Ⅱ receptor antagonist is selected from: one or more mixture of valsartan, Olmesartan and physiologically acceptable salt or ester.
4. pharmaceutical composition as claimed in claim 1, it is characterized in that, dihydropyridine calcium ion antagonist is selected from: one or more mixture of nifedipine, amlodipine, nimodipine, nicardipine, nitrendipine, nisoldipine, felodipine, benidipine, lacidipine and physiologically acceptable salt or ester.
5. pharmaceutical composition as claimed in claim 1, it is characterized in that, dihydropyridine calcium ion antagonist is selected from: one or more mixture of amlodipine, lacidipine, felodipine and physiologically acceptable salt or ester.
6. pharmaceutical composition as claimed in claim 1, it is characterized in that, count by weight, the ratio of three kinds of components is Angiotensin Ⅱ receptor antagonist: metolazone: dihydropyridine calcium ion antagonist is 10 ~ 500:0.1 ~ 10:1-100; Be preferably Angiotensin Ⅱ receptor antagonist: metolazone: dihydropyridine calcium ion antagonist is 2 ~ 200:0.25 ~ 5:2 ~ 50.
7. chemicals compositions as claimed in claim 1, it is characterized in that, described pharmaceutically acceptable adjuvant is selected from: one or more mixture of binding agent, filler, disintegrating agent, lubricant, fluidizer, coating material and other adjuvants.
8. the preparation method of chemicals compositions according to claim 1, comprises the following steps:
(1) take the Angiotensin Ⅱ receptor antagonist of recipe quantity, metolazone, dihydropyridine calcium ion antagonist, cross 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the filler of recipe quantity, disintegrating agent, cross 60 mesh sieves, mix homogeneously;
(3) by (1) and (2) mix homogeneously, then add fluidizer and lubricant, mix homogeneously, obtain intermediate;
(4) check intermediates content, calculate sheet weight, tabletting;
(5) take purified water in prescription ratio, under agitation, slowly add the coating powder of recipe quantity;
(6) tablet is placed in high-efficiency coating machine coating, obtains final product.
9. pharmaceutical composition as claimed in claim 1 for the preparation for the treatment of hypertension complicated with the application in angina drug.
10. apply as claimed in claim 9, it is characterized in that, described hypertension is light, moderate essential hypertension, the secondary hypertension particularly caused by kidney damage.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510543339.0A CN105106962A (en) | 2015-08-29 | 2015-08-29 | Compound antihypertensive preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510543339.0A CN105106962A (en) | 2015-08-29 | 2015-08-29 | Compound antihypertensive preparation and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105106962A true CN105106962A (en) | 2015-12-02 |
Family
ID=54655225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510543339.0A Pending CN105106962A (en) | 2015-08-29 | 2015-08-29 | Compound antihypertensive preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105106962A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1652777A (en) * | 2002-05-17 | 2005-08-10 | 诺瓦提斯公司 | Combination of organic compounds |
| CN101478956B (en) * | 2006-06-27 | 2013-03-20 | 诺瓦提斯公司 | Solid dosage form of valsartan, amlodipine and hydrochlorothiazide and method for preparing the solid dosage form |
| CN104324377A (en) * | 2014-06-19 | 2015-02-04 | 西安力邦肇新生物科技有限公司 | Compound antihypertensive preparation and application of compound antihypertensive preparation |
-
2015
- 2015-08-29 CN CN201510543339.0A patent/CN105106962A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1652777A (en) * | 2002-05-17 | 2005-08-10 | 诺瓦提斯公司 | Combination of organic compounds |
| CN101478956B (en) * | 2006-06-27 | 2013-03-20 | 诺瓦提斯公司 | Solid dosage form of valsartan, amlodipine and hydrochlorothiazide and method for preparing the solid dosage form |
| CN104324377A (en) * | 2014-06-19 | 2015-02-04 | 西安力邦肇新生物科技有限公司 | Compound antihypertensive preparation and application of compound antihypertensive preparation |
Non-Patent Citations (1)
| Title |
|---|
| 陆恒主编: "《高血压病人最关心的349个问题》", 30 April 2015 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2310443C2 (en) | Renin inhibitor-containing synergetic compositions designated for treatment of cardiovascular disease | |
| JP5968927B2 (en) | Drug composition used for the treatment of hypertension and metabolic syndrome and its application | |
| JP2020534347A (en) | A pharmaceutical composition comprising an SGLT-2 inhibitor and an angiotensin receptor antagonist | |
| JP2017122115A (en) | Angiotensin II receptor antagonist for the prevention or treatment of systemic diseases in cats | |
| JP6068765B2 (en) | Pharmaceutical combination preparation | |
| WO2022036506A1 (en) | Composition and use of sglt-2 inhibitor and angiotensin receptor blockers | |
| JP2011507973A (en) | Pharmaceutical composition of amlodipine and valsartan | |
| CN108289850B (en) | Drug combination formulation containing amlodipine, losartan, and chlorthalidone | |
| US20150352048A1 (en) | Valsartan-amlodipine compound solid preparation and preparation method therefor | |
| WO2006034631A1 (en) | Composition comprising amlodipine and angiotensin ii receptor blocker | |
| CN102370965A (en) | Pharmaceutical composition containing pharmaceutically acceptable salts of levoamlodipine and pharmaceutically acceptable salts of perindopril | |
| WO2008148359A1 (en) | The therapeutic uses of imidazol-5-carboxylic acid derivatives | |
| CN104324377B (en) | A kind of composite antihypertensive preparation and its application | |
| CN101416966A (en) | Medical composition capable of treating hypertension | |
| EP2948142B1 (en) | Combinations with 2-aminoethanesulfonic acid | |
| CN102485228B (en) | Pharmaceutical composition and purpose thereof | |
| CN104740636B (en) | A kind of composite antihypertensive preparation and its application | |
| TW202313072A (en) | Pediatric formulations of ferric citrate | |
| CN105106962A (en) | Compound antihypertensive preparation and application thereof | |
| CN102397278A (en) | Antihypertensive medicine composition | |
| WO2011144724A1 (en) | A pharmaceutical controlled release composition of losartan | |
| CN104758290A (en) | A compound antihypertensive composition and applications thereof | |
| CN107072977B (en) | NEP inhibitor drug combination and its application | |
| CN104758289B (en) | A kind of compound antihypertensive drug combination and its application containing medetofazone | |
| JP5982715B2 (en) | Antihypertensive composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20151202 |