CN101272791A - Stable composition of benzenesulfonic acid ammonia chlorine horizon and hydrochloric acid Benazepril - Google Patents
Stable composition of benzenesulfonic acid ammonia chlorine horizon and hydrochloric acid Benazepril Download PDFInfo
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- CN101272791A CN101272791A CNA2005800516885A CN200580051688A CN101272791A CN 101272791 A CN101272791 A CN 101272791A CN A2005800516885 A CNA2005800516885 A CN A2005800516885A CN 200580051688 A CN200580051688 A CN 200580051688A CN 101272791 A CN101272791 A CN 101272791A
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- amlodipine
- benazepril
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- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 title claims abstract description 38
- 229960004530 benazepril Drugs 0.000 title claims abstract description 38
- 239000000203 mixture Substances 0.000 title claims description 112
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title 2
- URPQIUWADDATAL-UHFFFAOYSA-N [Cl].N.C1(=CC=CC=C1)S(=O)(=O)O Chemical group [Cl].N.C1(=CC=CC=C1)S(=O)(=O)O URPQIUWADDATAL-UHFFFAOYSA-N 0.000 title 1
- 229960000528 amlodipine Drugs 0.000 claims abstract description 54
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 29
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims description 43
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 40
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 28
- 229960004005 amlodipine besylate Drugs 0.000 claims description 27
- 229960003619 benazepril hydrochloride Drugs 0.000 claims description 26
- 229960000913 crospovidone Drugs 0.000 claims description 26
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 26
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 26
- VPSRQEHTHIMDQM-FKLPMGAJSA-N benazepril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 VPSRQEHTHIMDQM-FKLPMGAJSA-N 0.000 claims description 25
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 25
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- 239000008108 microcrystalline cellulose Substances 0.000 claims description 24
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 24
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 24
- 239000008187 granular material Substances 0.000 claims description 21
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- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- 239000008107 starch Substances 0.000 claims description 15
- 229940032147 starch Drugs 0.000 claims description 15
- 235000019698 starch Nutrition 0.000 claims description 15
- 229920002472 Starch Polymers 0.000 claims description 14
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 13
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 13
- 238000005550 wet granulation Methods 0.000 claims description 13
- 229920003110 Primojel Polymers 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 12
- 239000008119 colloidal silica Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000005469 granulation Methods 0.000 claims description 12
- 230000003179 granulation Effects 0.000 claims description 12
- 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 claims description 11
- 229960001021 lactose monohydrate Drugs 0.000 claims description 11
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 11
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 11
- 229920000053 polysorbate 80 Polymers 0.000 claims description 11
- 229940068968 polysorbate 80 Drugs 0.000 claims description 11
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 6
- 239000011833 salt mixture Substances 0.000 claims description 5
- 238000007873 sieving Methods 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 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 abstract description 42
- 239000002775 capsule Substances 0.000 description 14
- 239000002552 dosage form Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000002131 composite material Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- 239000005541 ACE inhibitor Substances 0.000 description 4
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 4
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 4
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- -1 salt Benazepril Hydrochloride Chemical class 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
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- 239000001913 cellulose Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 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 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
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- 235000012222 talc Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- YQLPCBNEPNLCEP-UHFFFAOYSA-N 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethyl-5,6-dimethylpiperidine-3,5-dicarboxylic acid;benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCC1(C(O)=O)C(COCCN)NC(C)C(C)(C(O)=O)C1C1=CC=CC=C1Cl YQLPCBNEPNLCEP-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
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- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 1
- 206010019233 Headaches Diseases 0.000 description 1
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- 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
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- VCOYRKXQRUGBKS-UHFFFAOYSA-N N.[Cl] Chemical compound N.[Cl] VCOYRKXQRUGBKS-UHFFFAOYSA-N 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960004067 benazeprilat Drugs 0.000 description 1
- MADRIHWFJGRSBP-ROUUACIJSA-N benazeprilat Chemical compound C([C@H](N[C@H]1CCC2=CC=CC=C2N(C1=O)CC(=O)O)C(O)=O)CC1=CC=CC=C1 MADRIHWFJGRSBP-ROUUACIJSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium phosphate dihydrate Substances O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
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- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
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- 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
- 239000003605 opacifier Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229960005455 polacrilin Drugs 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Abstract
The present invention provides a pharmaceutical composition comprising benazepril and amlodipine wherein the benazepril and the amlodipine are in physical contact with one another, and methods for making the same.
Description
Invention field
The present invention relates to the combined therapy field of amlodipine and benazepril.
Background technology
In resisting with cardiovascular disease, our present arm store comprises angiotensin converting enzyme inhibitor (ACEI) and calcium ion channel blockor (CCB).The combined therapy of ACEI and CCB comprises in the following various disease conditions in treatment can obtain effective synergy: hypertension, congestive heart failure, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, apoplexy and headache.U.S. Pat 6,162,802 (" described ' 802 patents ") have been described the combination of ACEI benazepril and CCB amlodipine.
Benazepril can be used as the benazepril hydrochloride administration, and it chemically is defined as 3-[[1-(carbethoxyl group)-3-phenyl-(1S)-propyl group] amino]-2,3,4,5-tetrahydrochysene-2-oxo-1H-1-(3S)-benzodiazepine
(benzazepine)-1-acetic acid mono-hydrochloric salts (C
24H
28N
2O
5HCl).Amlodipine can be used as the Amlodipine Besylate Tablet administration, and it chemically is defined as (R.S.) 3-ethyl-5-methyl-2-(2-amino ethoxy methyl)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate (C
20H
25ClN
2O
5AC
6H
6O
3S).Benazepril hydrochloride and Amlodipine Besylate Tablet be combined in the U.S. as the capsule that is used for oral administration by Novartis with trade name
Sell.Capsule is formulated into four kinds of varying strengths of the benazepril hydrochloride of the Amlodipine Besylate Tablet of the amount that contains the amlodipine free base that is equivalent to 2.5mg, 5mg or 10mg and 10mg or 20mg, provides following obtainable combination: 2.5/10mg, 5/10mg, 5/20mg and 10/20mg.
Indicated and be used for the treatment of hypertension.
Described ' " benazepril and amlodipine are the inconsistent materials of physics to the instruction of 802 patents.Therefore, if it is added in the single dosage form, they must keep physical separation " the 3rd hurdle, 48-50 is capable.
The inventor has found that surprisingly preparation comprises the method for the pharmaceutical composition of amlodipine and benazepril, does not wherein need these two kinds of drug components of physical separation.This paper provides such pharmaceutical composition and has prepared its method.
Summary of the invention
In one embodiment, the invention provides a kind of stable pharmaceutical composition, it comprises benazepril, its solvate, ester or officinal salt and amlodipine or its solvate, ester or officinal salt.This pharmaceutical composition is stable, that is, under about 75% relative humidity, at about 40 ℃, store about 3 months after, its comprise with respect to benazepril be no more than 2.5% weight (s, s)-binary acid and/or be no more than the impurity D of 0.3% weight with respect to amlodipine.Preferably, described benazepril is a benazepril hydrochloride, and described amlodipine is an Amlodipine Besylate Tablet.
In a preferred embodiment, described benazepril and amlodipine each other physics contact.
In another embodiment, described benazepril hydrochloride is to pass through wet granulation, and described Amlodipine Besylate Tablet is to prepare by dry process.
In another embodiment, the invention provides a kind of method, it comprises the steps: by wet granulation benazepril compositions; Prepare the amlodipine compositions by dry process; With make the benazepril compositions contact the pharmaceutical composition that obtains making up with the amlodipine compositions.
Wet granulation preferably includes the salt-mixture Benazepril Hydrochloride and one or more preferably are selected from the step of following pharmaceutical excipient: pregelatinized Starch, lactose monohydrate, starch, crospovidone and microcrystalline Cellulose; Add granulation solution, obtain wet granular, wherein said granulation solution comprises water and randomly polysorbate80, polyvidone or both; Dry this wet granular obtains dried granule; And this dried granule of grinding.
Dry process preferably includes sieve Amlodipine Besylate Tablet and one or more and preferably is selected from the step of the mixture of following pharmaceutical excipient: calcium hydrogen phosphate, primojel, microcrystalline Cellulose and colloidal silica; With this mixture of blend.
In one embodiment, dry process further comprises one or more other pharmaceutical excipients that sieve, preferred crospovidone and/or magnesium stearate and with described other pharmaceutical excipient and described mixture blend.
In another embodiment, described method comprises the step of the pharmaceutical composition of sealing this combination.
In one embodiment, the invention provides a kind of benazepril compositions, it comprise with respect to about 5% weight of total benazepril compositions to the benazepril hydrochloride of about 20% weight, about 15% weight to the pregelatinized Starch of about 20% weight, about 25% weight to the lactose monohydrate of about 35% weight, about 10% weight to the starch of about 15% weight, the crospovidone of about 5% weight, about 15% weight to the microcrystalline Cellulose of about 25% weight, about 0.1% weight to the polysorbate80 of about 2% weight and the polyvidone of about 5% weight.
In another embodiment, the invention provides a kind of amlodipine compositions, it comprise with respect to about 2% weight of total amlodipine compositions to the Amlodipine Besylate Tablet of about 10% weight, about 25% weight to the calcium hydrogen phosphate of about 30% weight, about 1% weight to the primojel of about 2% weight, about 50% weight to the microcrystalline Cellulose of about 60% weight, the colloidal silica of about 1% weight, about 5% weight crospovidone and about 0.2% weight to the magnesium stearate of about 2% weight.
Description of drawings
Fig. 1 has illustrated the capsular method flow diagram that is used to prepare the mixture that comprises benazepril and amlodipine.
Detailed Description Of The Invention
In one embodiment, the invention provides a kind of stable pharmaceutical composition, its bag Draw together benazepil, its solvate, ester or officinal salt and Amlodipine, its solvate, Ester or officinal salt. The general terms Amlodipine refers to free alkali form as used herein. At this In the stable pharmaceutical composition of invention, described benazepil preferred salt Benazepril Hydrochloride, described The preferred Amlodipine Besylate Tablet of Amlodipine.
This pharmaceutical composition is stable, that is, this pharmaceutical composition comprises low-level degraded and produces Thing. Partly, described composition slows down and/or has avoided the degraded of active component, thereby reduces Be present in impurity level in the active component after storing. The main degradation products of benazepil is (s, s)-binary acid (Benazeprilat), it is the active metabolite of benazepil. The master of Amlodipine Wanting catabolite is impurity D (ethyl 5-methyl 2-[(2-amino ethoxy) methyl]-4-(2-chlorobenzene Base)-and 6-picoline-3, the 5-dicarboxylic ester). The catabolite explanation of benazepil and Amlodipine is general State in table 1.
Table 1: to the restriction of the catabolite of benazepil and Amlodipine
In one embodiment, at described pharmaceutical composition under about 75% relative humidity, About 40 ℃, store about 3 months after, this pharmaceutical composition comprises with respect to benazepil and is no more than (s, the s) of 2.5% weight-binary acid and/or be no more than the impurity of 0.3% weight with respect to Amlodipine D.
In a preferred embodiment, described benazepil and Amlodipine each other physics connect Touch. The example of physical contact be included in the interface of no dressing between the tablet layer physical contact, Physical contact in the liquid medium of liquid oral or injectable formulation and these two active components The mixture of blend in physical contact. In a preferred embodiment, comprise described The mixture of the blend of two kinds of active components uses as capsule filling.
Described pharmaceutical composition preferably comprises about 10mg to the benazepril hydrochloride of about 20mg, More preferably from about 10mg or about 20mg. Preferably, the amount of Amlodipine Besylate Tablet is equivalent to about 2.5 Mg is to the amlodipine free base of about 10mg. More preferably, the amount phase of Amlodipine Besylate Tablet When in the amlodipine free base of about 2.5mg, about 5mg or about 10mg. Preferably, shellfish that The ratio of Puli and Amlodipine is equivalent to about 2: 1 to about 4: 1 weight ratio, more preferably from about 2: 1 Or about 4: 1.
In one embodiment, described benazepril hydrochloride prepares by wet granulation, Described Amlodipine Besylate Tablet prepares by dry process. Wet granulation and dry process exist Hereinafter further describe in detail.
In one embodiment, the invention provides and comprise benazepil and ammonia chlorine ground a kind of the preparation The method of flat pharmaceutical composition. The described pharmaceutical composition that comprises benazepil and Amlodipine The pharmaceutical composition that is called as combination. Described method comprises the steps: by wet granulation system Standby benazepil composition; Prepare the Amlodipine composition by dry process; With make Bei Napu Sharp composition contacts the pharmaceutical composition that obtains making up with the Amlodipine composition. Fig. 1 describes The preferred embodiment of the method.
Wet granulation preferably includes salt-mixture Benazepril Hydrochloride and one or more pharmaceutical excipients Step; Add granulation solution to obtain wet granular, wherein said granulation solution preferably includes Water and one or more other excipient randomly; Dry this wet granular obtains dried particle; With this dried particle of grinding. Pharmaceutical excipient describes in further detail hereinafter. For benazepil Composition, preferred pharmaceutical excipient comprise pregelatinized starch, lactose monohydrate, starch, Crospovidone, microcrystalline cellulose, polysorbate80 and PVP.
Dry process preferably includes the step of the mixture of sieve Amlodipine Besylate Tablet and one or more pharmaceutical excipients; With this mixture of blend.If necessary, sieve step to avoid comprising agglomerate and impurity.For the amlodipine compositions, preferred pharmaceutical excipient comprises calcium hydrogen phosphate, primojel, microcrystalline Cellulose and colloidal silica.Preferably, the described mixture that sieves passes 30 purpose sizes.
In one embodiment, dry process further comprises sieve one or more other pharmaceutical excipients and the described other pharmaceutical excipient of blend and described mixture, i.e. amlodipine compositions.In a preferred embodiment, with other pharmaceutical excipient with after the benazepril compositions is mixed, again with itself and the blend of amlodipine compositions.Preferred other pharmaceutical excipient comprises crospovidone and magnesium stearate.Preferably, crospovidone sieves and passes 30 purpose sizes.Preferably, magnesium stearate is sieved and is passed 50 purpose sizes.
In one embodiment, described method comprises the step of the pharmaceutical composition of sealing this combination.
In a preferred embodiment, this method comprises that salt-mixture Benazepril Hydrochloride and one or more are selected from the step of following pharmaceutical excipient: pregelatinized Starch, lactose monohydrate, starch, crospovidone and microcrystalline Cellulose; Add granulation solution to obtain wet granular, wherein said granulation solution comprises water, polysorbate80 and polyvidone; Dry this wet granular is to obtain dried granule; Grind this dried granule; The Amlodipine Besylate Tablet that sieves passes 30 mesh sieves with one or more mixture that are selected from following pharmaceutical excipient: calcium hydrogen phosphate, primojel, microcrystalline Cellulose and colloidal silica; This mixture of blend and dried granule are to form the pharmaceutical composition that merges; The crospovidone that sieves passes 30 mesh sieves; The pharmaceutical composition of blend crospovidone and merging; The magnesium stearate of sieving is passed 50 mesh sieves; The pharmaceutical composition of blend magnesium stearate and merging; With the pharmaceutical composition of sealing this merging.
In one embodiment, the invention provides a kind of benazepril compositions, it comprise with respect to about 5% weight of total benazepril compositions to the benazepril hydrochloride of about 20% weight, about 15% weight to the pregelatinized Starch of about 20% weight, about 25% weight to the lactose monohydrate of about 35% weight, about 10% weight to the starch of about 15% weight, the crospovidone of about 5% weight, about 15% weight to the microcrystalline Cellulose of about 25% weight, about 0.1% weight to the polysorbate80 of about 2% weight and the polyvidone of about 5% weight.
In another embodiment, the invention provides a kind of amlodipine compositions, it comprise with respect to about 2% weight of total amlodipine compositions to the Amlodipine Besylate Tablet of about 10% weight, about 25% weight to the calcium hydrogen phosphate of about 30% weight, about 1% weight to the primojel of about 2% weight, about 50% weight to the microcrystalline Cellulose of about 60% weight, the colloidal silica of about 1% weight, about 5% weight crospovidone and about 0.2% weight to the magnesium stearate of about 2% weight.
Preparation of compositions of the present invention can be become for example medicine of oral administration.The suitable form that is used for oral administration comprises solid form, such as tablet, powder, granule, capsule.
Except active component, compositions of the present invention can comprise one or more excipient or adjuvant.Excipient is an inert component, and it is added pharmaceutical composition is in order to dilute this pharmaceutical composition or to give its form or robustness.The effect of adjuvant auxiliary activity composition.The selection of excipient and adjuvant and consumption can easily be determined based on standard method and list of references in experience and this area by formulation science man.
Diluent has increased the volume of solid composite medicament, and can prepare the pharmaceutical dosage form that comprises described compositions that is easy for patient and nursery work person's operation.The diluent that is used for solid composite comprises that for example microcrystalline Cellulose (for example
), particle cellulose, lactose, starch, pregelatinized Starch, calcium carbonate, calcium sulfate, sugar, dicalcium phosphate dihydrate, tricalcium orthophosphate, mannitol, powdery cellulose and Sorbitol.
Be pressed into dosage form and can comprise that such as the solid composite medicament of tablet its function is included in the excipient that helps after the compacting in conjunction with active component and other excipient.The bonding agent that is used for solid composite medicament (for example comprises sodium carboxymethyl cellulose, ethyl cellulose, gelatin, hydroxyethyl-cellulose, hydroxypropyl cellulose
), hydroxypropyl emthylcellulose (for example
), methylcellulose, polyvidone (for example
), pregelatinized Starch and starch.
The dissolution rate of solid composite medicament in patient's stomach of compacting can increase by adding disintegrating agent to described compositions.Disintegrating agent (for example comprises carboxymethylcellulose calcium, cross-linked carboxymethyl cellulose sodium
), crospovidone (for example
), microcrystalline Cellulose, bohr Acree woods (polacrilin) potassium, pregelatinized Starch, primojel (for example
) and starch.
Can add fluidizer with flowability that increases non-compacted solid composition and the accuracy of improving dosed administration.The excipient that can play the fluidizer effect comprises colloidal silica, magnesium trisilicate, powdery cellulose, starch and Talcum.
When dosage form is during by the pressed powder preparation of compositions such as tablet, said composition for example stands the pressure from drift and punch die.Some excipient and active component have the trend on the surface that adheres to drift and punch die, and it can cause that described product has indenture and other surface imperfection.Can in compositions, add lubricant to reduce adhesion and to make things convenient for product from punch die, to discharge.Lubricant comprises magnesium stearate, calcium stearate, glyceryl monostearate, palmitostearate, castor oil hydrogenated, hydrogenated vegetable oil, mineral oil, Polyethylene Glycol, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, Talcum and zinc stearate.
Dosage form of the present invention can be the capsule that contains the present composition, and preferred pulverous and/or granular solid composite of the present invention is included in hard or the soft shell.Described shell can be prepared by gelatin, and can randomly comprise plasticizer such as glycerol and Sorbitol, and opacifier or coloring agent.
Although optimal administration will be depended on the character and the seriousness of the disease that will treat under any given situation, most preferred route of the present invention is oral.Described dosage form can be present in the unit dosage forms easily, and can prepare by any method that drug world is known.
The compositions that is used for tablet or filled capsules can be passed through wet granulation.In wet granulation, some of blended powder shape form or all active component and excipient causing that powder agglomates becomes particulate liquid, typically are water then, existence under, further mix.Sieve and/or grind, dry this granule, sieve and/or be ground to the particle diameter of expectation.Then, this granule randomly can be filled in the capsule with other composition.This method is the preferable methods of preparation benazepril component of the present invention.
Usually can prepare granular composition by dry granulation.For example, the blended composition compacting slivering or the sheet material of activating agent and excipient can be ground into granule closely then.Granule is pressed into tablet or is filled in the capsule closely subsequently.This technology is more suitable for amlodipine component of the present invention, but more preferably is to use the powder composition of the blend of amlodipine and excipient.
Capsule filling of the present invention can comprise each aforesaid blend and granule, promptly aforesaid, yet, most preferably comprise the blended capsule of powder composition of the dried blend of benazepril granule by wet granulation and amlodipine and excipient.
So far, described the present invention with reference to some embodiment preferred, the present invention will further set forth by following non-restrictive example now.
Embodiment
Embodiment 1: Amlodipine Besylate Tablet/benazepril hydrochloride capsule
The capsule that comprises benazepril hydrochloride and Amlodipine Besylate Tablet prepares by following method.
The particulate preparation of benazepril hydrochloride-part I:
In the pelletize mixer, mix following substances: pregelatinized Starch (Starch STA-RX-1500), lactose monohydrate NF (100 order), benazepril hydrochloride, starch NF, crospovidone NF and microcrystalline Cellulose NF (Avicel PH 101).By preparing granulation solution in the mixture that pure water USP is added polysorbate80 NF and PVP K-30 (polyvidone USP), mix simultaneously and mix up to dissolving continuously.Then, join in the pelletize mixer this granulation solution and mixing, up to obtaining granule.Then, dry this granule in fluid-bed drier.Then, in oscillating granulator, grind this dried granules, and put it in the container.
Dry blending (amlodipine)-part II:
The following substances of sieving: Amlodipine Besylate Tablet, calcium phosphate dibasic anhydrous USP (powder) and primojel NF.Then, with the substance transfer of sieving in the blending machine and blend.Sieve microcrystalline Cellulose and colloidal silica are added in it in the mixture in blending machine, and mix.Then, this mixture is transferred in the container.
Combination-part the III of amlodipine and benazepril hydrochloride
Be placed in the blending machine granule of part I and the dry mixture of part II and blend.The crospovidone that sieves, and it is added in the described blending machine this mixture of blend.Then, the magnesium stearate of sieving, and it is added in the described blending machine this mixture of blend.
Seal-part IV:
The final blend of part III is filled in the capsule.Be described in the table 2 concrete the composition.
Table 2: Amlodipine Besylate Tablet/benazepril hydrochloride capsule
*Only be used for the processing of granulating
*3.465mg, the Amlodipine Besylate Tablet of 6.93mg and 13.86mg is equivalent to the amlodipine free base of 2.5mg, 5mg and 10mg respectively.
Embodiment 2: stability study
During 3 months under 40 ℃ and 75% relative humidity, measure the capsular catabolite of Amlodipine Besylate Tablet/benazepril hydrochloride with HPLC.The result is summarized in the following table 3.
Claims (22)
1. pharmaceutical composition, it comprises:
A) benazepril or its solvate or its officinal salt and
B) amlodipine or its solvate or its officinal salt,
Make benazepril and amlodipine not have physical separation each other, wherein at about 75% relative humidity, at about 40 ℃, after about 3 months, this pharmaceutical composition comprises:
I) with respect to benazepril be no more than 2.5% weight (s, s)-binary acid; And/or
Ii) be no more than the impurity D of 0.3% weight with respect to amlodipine.
2. the pharmaceutical composition of claim 1, wherein said benazepril and described amlodipine physics each other contact.
3. the pharmaceutical composition of claim 1, wherein said pharmaceutical composition is entrapped.
4. the pharmaceutical composition of claim 1, wherein said benazepril is a benazepril hydrochloride.
5. the pharmaceutical composition of claim 1, wherein said amlodipine is an Amlodipine Besylate Tablet.
6. the pharmaceutical composition of claim 1, wherein said benazepril are for by wet granulation, and described amlodipine be to prepare by dry process.
7. method comprises:
A) by wet granulation benazepril compositions;
B) prepare the amlodipine compositions by dry process; With
C) the benazepril compositions is contacted with the amlodipine compositions, randomly add excipient, obtain the composition of medicine compositions.
8. the method for claim 7, wherein said benazepril compositions comprise benazepril hydrochloride and one or more pharmaceutical excipients.
9. the method for claim 8, wherein the benazepril compositions comprises that one or more are selected from following pharmaceutical excipient: pregelatinized Starch, lactose monohydrate, starch, crospovidone, microcrystalline Cellulose, polysorbate80 and polyvidone.
10. the method for claim 9, wherein said benazepril compositions comprises with respect to total benazepril compositions:
A) about 5% weight is to the benazepril hydrochloride of about 20% weight;
B) about 15% weight is to the pregelatinized Starch of about 20% weight;
C) about 25% weight is to the lactose monohydrate of about 35% weight;
D) about 10% weight is to the starch of about 15% weight;
E) crospovidone of about 5% weight;
F) about 15% weight is to the microcrystalline Cellulose of about 25% weight;
G) about 0.1% weight is to the polysorbate80 of about 2% weight; With
H) polyvidone of about 5% weight.
11. the method for claim 7, wherein by wet granulation benazepril compositions, it comprises:
A) salt-mixture Benazepril Hydrochloride and one or more are selected from following pharmaceutical excipient: pregelatinized Starch, lactose monohydrate, starch, crospovidone and microcrystalline Cellulose;
B) add granulation solution obtaining wet granular, wherein said granulation solution comprises water and randomly, polysorbate80, polyvidone or both;
C) dry this wet granular obtains dried granule; With
D) grind this dried granule.
12. the method for claim 7, wherein said amlodipine compositions comprise Amlodipine Besylate Tablet and one or more pharmaceutical excipients.
13. the method for claim 7, wherein said amlodipine compositions comprise that one or more are selected from following pharmaceutical excipient: calcium hydrogen phosphate, primojel, microcrystalline Cellulose, colloidal silica.
14. the method for claim 13, wherein said amlodipine compositions comprise with respect to total amlodipine compositions:
A) about 2% weight is to the Amlodipine Besylate Tablet of about 10% weight;
B) about 25% weight is to the calcium hydrogen phosphate of about 30% weight;
C) about 1% weight is to the primojel of about 2% weight;
D) about 50% weight is to the microcrystalline Cellulose of about 60% weight;
E) colloidal silica of about 1% weight.
15. the method for claim 7, wherein the excipient that randomly adds comprises crospovidone and magnesium stearate.
16. the method for claim 7, wherein the excipient that randomly adds comprises with respect to the magnesium stearate of about 1% weight of total amlodipine compositions to the crospovidone of about 5% weight and about 0.2% weight to about 2% weight.
17. the method for claim 7 wherein prepares the amlodipine compositions by dry process, it comprises:
A) sieve Amlodipine Besylate Tablet and one or more are selected from the mixture of following pharmaceutical excipient: calcium hydrogen phosphate, primojel, microcrystalline Cellulose and colloidal silica; With
B) this mixture of blend.
18. the method for claim 7, it further comprises:
A) sieve that one or more are selected from the other pharmaceutical excipient of crospovidone and magnesium stearate; With
B) this other pharmaceutical excipient of blend and described mixture.
19. the method for claim 7, it further comprises the pharmaceutical composition of sealing described combination.
20. the method for claim 7, it comprises:
A) salt-mixture Benazepril Hydrochloride and one or more are selected from following pharmaceutical excipient: pregelatinized Starch, lactose monohydrate, starch, crospovidone and microcrystalline Cellulose;
B) add granulation solution to obtain wet granular, wherein said granulation solution comprises water, polysorbate80 and polyvidone;
C) dry this wet granular obtains dried granule;
D) grind this dried granule;
E) sieve Amlodipine Besylate Tablet and one or more mixture that are selected from following pharmaceutical excipient pass 30 mesh sieves: calcium hydrogen phosphate, primojel, microcrystalline Cellulose and colloidal silica;
F) this mixture of blend and described dried granule form the pharmaceutical composition that makes up;
G) crospovidone that sieves passes 30 mesh sieves;
H) pharmaceutical composition of blend crospovidone and described combination;
I) magnesium stearate of sieving is passed 50 mesh sieves;
J) pharmaceutical composition of blend magnesium stearate and described combination; With
K) seal the pharmaceutical composition of described combination.
21. a benazepril compositions, it comprises with respect to total benazepril compositions:
A) about 5% weight is to the benazepril hydrochloride of about 20% weight;
B) about 15% weight is to the pregelatinized Starch of about 20% weight;
C) about 25% weight is to the lactose monohydrate of about 35% weight;
D) about 10% weight is to the starch of about 15% weight;
E) crospovidone of about 5% weight;
F) about 15% weight is to the microcrystalline Cellulose of about 25% weight;
G) about 0.1% weight is to the polysorbate80 of about 2% weight; With
H) polyvidone of about 5% weight.
22. an amlodipine compositions, it comprises with respect to total amlodipine compositions:
A) about 2% weight is to the Amlodipine Besylate Tablet of about 10% weight;
B) about 25% weight is to the calcium hydrogen phosphate of about 30% weight;
C) about 1% weight is to the primojel of about 2% weight;
D) about 50% weight is to the microcrystalline Cellulose of about 60% weight;
E) colloidal silica of about 1% weight;
F) crospovidone of about 5% weight; With
G) about 0.2% weight is to the magnesium stearate of about 2% weight.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102600173A (en) * | 2012-03-02 | 2012-07-25 | 海南美兰史克制药有限公司 | Amlodipine/benazepril medicament composition liposome solid preparation |
CN102781430A (en) * | 2010-02-24 | 2012-11-14 | 赛诺菲-安万特德国有限公司 | Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation |
CN117538462A (en) * | 2024-01-10 | 2024-02-09 | 地奥集团成都药业股份有限公司 | Method for detecting related substances of amlodipine benazepril capsules |
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2005
- 2005-09-28 CN CNA2005800516885A patent/CN101272791A/en active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102781430A (en) * | 2010-02-24 | 2012-11-14 | 赛诺菲-安万特德国有限公司 | Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation |
CN102781430B (en) * | 2010-02-24 | 2015-09-09 | 赛诺菲-安万特德国有限公司 | The solid pharmaceutical preparation of ramipril and Amlodipine Besylate Tablet and preparation thereof |
CN102600173A (en) * | 2012-03-02 | 2012-07-25 | 海南美兰史克制药有限公司 | Amlodipine/benazepril medicament composition liposome solid preparation |
CN117538462A (en) * | 2024-01-10 | 2024-02-09 | 地奥集团成都药业股份有限公司 | Method for detecting related substances of amlodipine benazepril capsules |
CN117538462B (en) * | 2024-01-10 | 2024-03-26 | 地奥集团成都药业股份有限公司 | Method for detecting related substances of amlodipine benazepril capsules |
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