CN1181019A - Combination compositions containing benazepril or beazeprilat and valsartan - Google Patents

Combination compositions containing benazepril or beazeprilat and valsartan Download PDF

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CN1181019A
CN1181019A CN96193111A CN96193111A CN1181019A CN 1181019 A CN1181019 A CN 1181019A CN 96193111 A CN96193111 A CN 96193111A CN 96193111 A CN96193111 A CN 96193111A CN 1181019 A CN1181019 A CN 1181019A
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milligrams
compositions
active component
valsartan
benazepril
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M·德加斯帕罗
R·L·维布
D·S·科恨
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Abstract

The invention relates to pharmaceutical combination compositions for the treatment of hypertension, congestive heart failure and renal failure, comprising (1) the ACE-inhibitor benazepril of formula (I) or benazeprilat of formula (II) or a pharmaceutically acceptable salt thereof, and (2) the AT1-antagonist valsartan of formula (III) or a pharmaceutically acceptable salt thereof, as weel as to methods for the treatment of hypertension, congestive heart failure and renal failure.

Description

The pharmaceutical composition that contains benazepril or benazeprilat and valsartan
There is different approach to carry out getting involved adjustablely, thereby might exerts an influence to blood pressure regulating by different way the different phase of renin angiotensin cascade reaction.
Proangiotensin is the huge glycoprotein of a kind of α 2-, and it is become the decapeptide angiotensin I by the feritin enzymatic lysis, and the latter only has very faint biological activity.Next step of cascade reaction is further to remove 2 aminoacid by the effect that mainly is combined in the Angiotensin-Converting (ACE) in the endothelium, forms Angiotensin II.The latter is considered to one of the strongest natural vasoconstrictor.
Is a kind of effective ways of blood pressure regulation with so-called ACE inhibitor blocking-up angiotensin I to the enzymatic degradation reaction of Angiotensin II, so it also makes the method for the treatment of congestive heart failure become possibility.
Typical conventional ACE inhibitor is following formula active component 3-[(1-(carbethoxyl group)-3-phenyl-(1S)-propyl group) amino]-2,3,4,5-tetrahydrochysene-2-oxo-1H-(3S)-benzazepine-1-acetic acid [benazepril (benazepril)]:
Figure A9619311100051
Or (seeing EP 72352) following formula (3S)-3-[[(1S)-(1-carboxyl-3-phenylpropyl) amino]-2,3,4,5-tetrahydrochysene-2-oxo-1H-1-benzazepine-1-acetic acid [benazeprilat (benazeprilat)] (seeing EP 72352):
And pharmaceutical salts.What be worth especially mentioning also has a hydrochloride (benazepril hydrochloride).
The vasoconstriction effect of Angiotensin II is because it acts on non-striated muscle cell, the stimulation of renal upper parathyrine generate hormone-epinephrine and norepinephrine-generation, and under the effect of the norepinephrine that produces, increase the activity of sympathetic nervous system.Angiotensin II also influences electrolyte balance, produces antinatriuresis effect and antidiuretic activity in kidney, promotes on the one hand that thus hypophysis discharges vasopressin peptide, promotes adrenal gland's glomerule to discharge aldosterone on the other hand.All these influences all play an important role to blood pressure regulating.
Angiotensin II can with the single-minded acceptor interaction on target cell surface.Now can identify and be called as AT 1And AT 2The receptor subtype of receptor.Be combined in AT for differentiating recently 1Material on the receptor has been done a large amount of research.This class active substance is commonly called the Angiotensin II antagonist.Because it is to AT 1The inhibitory action of receptor, this class antagonist can be used to for example resisting hypertension family treatment congestive heart failure.
Therefore the Angiotensin II antagonist is understood as that and is combined in AT 1The active component of receptor subtype.They comprise the chemical compound with different structure feature.
Typical A T 1Antagonist is following formula active component (S)-N-(1-carboxyl-2-methyl-third-1-yl)-N-valeryl-N-[2 ' (1H-tetrazolium-5-yl) biphenyl-4 bases-methyl] amine [valsartan (valsartan)]:
Figure A9619311100061
(seeing EP 443983) and pharmaceutical salts thereof.
The pharmaceutical salts of typical benazepril and valsartan is an acid-addition salts.These acid-addition salts can generate with following acid, and for example strong inorganic acid typically has mineral acid such as sulphuric acid, phosphoric acid or halogen acids; Strong organic acid typically might be by for example C of halogen replacement 1-C 4Alkanoic acid typically has acetic acid; May be undersaturated dicarboxylic acids, oxalic acid for example, malonic acid, succinic acid, maleic acid, Fumaric acid, phthalic acid or p-phthalic acid; Hydroxy carboxylic acid, as ascorbic acid, glycolic, lactic acid, malic acid, tartaric acid or citric acid; Aminoacid such as aspartic acid or glutamic acid; Benzoic acid or organic sulfonic acid; The C that may be replaced by halogen 1-C 4Alkanoic acid or aryl sulfonic acid; Methane-or right-toluenesulfonic acid.The suitable salt that is generated by alkali is slaine typically, as alkali metal salt or alkali salt, sodium is arranged typically, potassium or magnesium salt, or ammonium salt or organic amine are as morpholine, thiomorpholine, piperidines, pyrrolidine, single, double or three rudimentary alkanamines typically have ethamine, tert-butylamine, diethylamine, diisopropylamine, triethylamine, tri-n-butylamine or dimethyl propylamine; Or the single, double or rudimentary alkanamine of trihydroxy, single, double or triethanolamine is typically arranged.Also can use corresponding inner salt.
Many tests also try hard to develop the compositions of different activities composition, to be used for the treatment of hypertension and congestive heart failure.The advantage that this based composition has is, the effective dose that each dose of components of for example using in the compositions obviously is less than each composition when using separately.For example, if used antihypertensive drug in the compositions with different mechanism of action, can be added usually and curative effect.Yet, the objective of the invention is to provide on the one hand to have synergistic compositions, make the drug effect time lengthening on the other hand.
PCT application WO 94/28924 discloses the compositions of ACE inhibitor and Angiotensin II antagonist.At enalapril (enalapril, ACE inhibitor) and Losartan (losartan, AT 1In the clinical experiment of compositions antagonist), the hypotensive activity of the compositions of given dose is compared with the Enalapril on Lowering Blood Pressure effect and is not demonstrated the obvious synergistic effect, only can define addition.And in above-mentioned patent application with the prolongation that does not demonstrate drug effect after Losartan and the enalapril combination treatment.Therefore, in fact this patent application can not illustrate such powerful ACE inhibitor and AT 1The compositions of antagonist can produce collaborative hypotensive activity in human body.Therefore it does not claim evident in efficacy.Yet disclosed WO 94/28924 shows that the applied in any combination of these two kinds of active component of indicating but plays a part to increase renal blood flow speed.Similarly, people such as Azizi (Circulation 1995; 92:825-834) discovery is with inhibitory action and the AT of ACE 1Antagonism combine (compositions of captopril and Losartan) blood pressure lowering had add and effect, and use the compositions of captopril and Losartan not make average blood pressure lowering time lengthening.
More beat all is that co-administered ACE inhibitor-benazepril or its pharmaceutical salts are found in experiment, and AT 1Antagonist-valsartan or its pharmaceutical salts not only have collaborative antihypertensive function, and unexpectedly observe the prolongation of effective drug duration.
The advantage of these unexpected effects is the frequency that can reduce dosage and reduce medication.This meets by treatment needs of patients and requirement.
In addition, the side effect that occurs in some patients is dropped to minimum.
Jointly nervous plain invertase of sealing blood vessels and AT 1Receptor, also advantageously significantly reduced the Angiotensin II that the vasoconstrictive effect is arranged increase circulation.
Synergism should be understood that to occur in the following cases, promptly two kinds of active component are used together, use in the unit dosage form of a combination such as both, or a kind of composition is used after another kind of composition, or both use individually, and the combined effect of compositions is than the algebraical sum height of the independent result of use of two compositions, promptly reach be higher than add and drug effect.
Synergism can be by for example following remote measurement (telemetering) experiment confirm:
The spontaneous hypertension rat (SHR) in 22 to 25 ages in week is prepared in experiment for this reason.Such rat can be available from Taconic Farms, Germantown, New York (Tac:N (SHR) fBR).Before experiment begins at least one month, telemetering gear is implanted the low ventral aorta of whole animal subjects.Transmitting set is fixed on the musculus ventralis interni with silk thread.Cardio-vascular parameters is constantly spread out of by transmitting set, makes in not influencing big mouse cage gather data under the active situation.Animal encages under controlled temperature and atmospheric humidity, alternate round the clock 12 hours.Measure rat body weight weekly.Common 5 rats are one group.Wherein only accept valsartan for one group; Another winding is subjected to benazepril; Also have a winding to be subjected to the compositions of valsartan and benazepril; The 4th winding is subjected to different valsartan of dosage and benazepril compositions; Last group is only accepted excipient (0.15N sodium hydroxide) in contrast.With the subcutaneous successive administration of micro pump 14 days at interval more than.In these experiments, (DataSciences Inter. Inc.) measures mean arterial pressure and heart beating with the computer data detection system.Also keep a record per ten minutes measurement mean arterial pressure and ten seconds of heart beating.The 24 hourly average values of every rat of report every day comprise 144 data points.The blood pressure baseline is determined by implanting the meansigma methods that records for three days on end before the micro pump.The value of using during the active component is calculated by 24 hourly average values.When fortnight, remove micro pump, after stopping to use active component, continue to observe drug effect 7 days.
Studies show that the benazepril of 1.5 milligrams/kg/day of the non-combined administration of 1.5 milligrams/kg/day and valsartan can make blood pressure reduce about 20mm Hg.In contrast, the valsartan of the benazepril of 1.5 milligrams/kg/day of combined administration and 1.5 milligrams/kg/day can make blood pressure significantly reduce about 50mm Hg.In addition, the constant time lengthening to 16 of drug effect hour, descend but still significantly effective drug duration reach at least 21 hours.
Estimate the long-term drug effect of medicine to the mean arterial pressure of spontaneous hypertension rat with radio telemetry, the additional result of experiment of being carried out is as follows:
Chemical compound Dosage [milligram/kg/day] AUC[mmHg] SEM
Benazepril 0.5(N＝7) -64 6
0.75(N＝6) -136 11
1.0(N＝7) 244 30
1.5(N＝5) 213 28
3.0(N＝7) 341 20
10.0(N＝7) 581 18
Valsartan 0.5(N＝7) 62 16
0.75(N＝7) 107 6
1.0(N＝7) 115 19
1.5(N＝6) 195 8
3.0(N＝7) 226 21
10.0(N＝7) 425 38
Benazepril/valsartan 0.5(N＝6) 221 21
0.75(N＝6) 329 20
1.0(N＝5) 470 31
1.5(N＝5) 609 23
0.15N NaOH excipient (N＝6) (N＝7) (N＝6) (N＝7) (N＝4) 1 10 23 4 11 11 9 16 13 14
1N?NaCO 3 (N＝7) 61 15
[area value under the AUC=curve (mmHg), because all values all are 14 days records, so natural law (time) is disallowable]
[SEM=standard error of the mean]
Experimental result clearly demonstrates the AUC value, and for example the AUC value of the compositions of the benazepril of 1 milligram/kg/day and valsartan is significantly higher than the benazepril of 0.5 milligram/kg/day and adding and value of valsartan.Correspondingly, from other measured value, also can find out effect same.
In residual kidney rat model, the compositions of valsartan and benazepril is proved to be than any independent treatment wherein has better kidney protective effect.The cut right kidney of this animal pattern, the 2-3 of a left renal artery branch is connected together, and is equivalent to 1/6 kidney on the function.Be characterized in albuminuria, lose the heavy absorbability of renal tubules electrolyte and follow systolic pressure sharply to rise.Operation one week of back, this moment, animal was in the chronic renal failure of carrying out property through subcutaneous administration (with the infiltration micro pump).Animal is carried out the treatment of 6 weeks.Valsartan and benazepril (Val+Bz) are by 1.0 milligrams/kg/day of each medicament and 3.0 milligrams/kg/day combination medicine-feeding., be of no curative effect when individually dosed by above-mentioned dosage or only have slight renal function to improve to the excipient ratio with only.Then almost make systolic pressure reach the preceding normal level of excision with the Val+Bz administration, reduced albuminuria and significantly improved renal tubular function (showing as the excretory variation of classification of sodium).
Equally, valsartan and benazepril compositions also can obtain proof from the congestive heart failure animal model that for example atrial pacing method is brought out to the synergism of congestive heart failure.The chronic quick cardiac pacing of pig is good congestive heart failure model.Select potion benazeprilat (0.15 milligram/kg/day) or valsartan (2.4 milligrams/kg/day) capable of blocking 50% angiotensin I and the stress reaction of Angiotensin II for use and do not change the tranquillization blood pressure.When using compositions (benazeprilat/valsartan 0.04/2.4 milligram/kg/day) treatment, be necessary to reduce the dosage of benazeprilat, to prevent the obvious decline of tranquillization blood pressure than single therapy.For comparing, agematched pig is carried out chronic pace-making, but do not treat, contrast as vacation.21 days follow treatment and pace-making tachycardia after, to left ventricular function and geometry, and to neuro hormone distribution, isolating myocyte's contractile function, the β adrenal gland can reply with electric physiology and study.Chronic rapid pacing and follow the ACE inhibitory action to reduce left ventricle and vasodilative degree has obviously promoted the pumping function of LV, has reduced the level of catecholamine in the blood circulation.Angiotensin-ii receptor is sealed by valsartan, has improved cardiac output and has reduced pulmonary circulation and body circulation resistance.By contrast, be used in combination function and the neurohormonal activation of benazeprilat and valsartan, comprise that the Endothelin blood plasma level all has further improvement effect LV geometry, LV.And, this pressure that reduces the LV wall that is combined and used in, the resistance of lung and blood vessel, important indicator aspects such as myocardial oxygen consumption and LV afterload are than using ACE inhibitor that stronger effect is arranged separately.And when and benazeprilat folk prescription treatment relatively, also increased myocardial cell β adrenal gland and can reply with calcium and reply.
Existing result shows this compositions to blood pressure, and kidney blood flow and congestive heart failure have beyond thought therapeutic effect.Other approach that the Angiotensin II that produces in the tissue causes may limit the effect of ACE.On the other hand, ACE inhibitor has promoted the activity of endothelium-dependent relaxation blood vessel by the effect to the degraded of bradykinin.Therefore, the combination medicine of ACE inhibitor and Angiotensin II makes RAS more complete with the blocking effect of the reverse regulatory mechanism that regulated by Angiotensin II.Correspondingly, also wish to reduce dosage and also therefore reduce side effect.When renal function is under the dependent situation of strong feritin, this may be important.
The purpose of this invention is to provide the pharmaceutical composition for the treatment of hypertension, congestive heart failure and renal failure, said composition comprises (1) ACE inhibitor-benazepril or benazeprilat, or its pharmaceutical salts; (2) AT 1Antagonist-valsartan or its pharmaceutical salts.In this compositions, component (1) and (2) can provide simultaneously and administration together, administration successively or a combination or two independent unit dosage forms in administration respectively.
Aforementioned pharmaceutical compositions is used for the digestive tract administration of homoiothermic animal such as oral, rectally or parenteral administration.But active constituents of medicine individualism or combine with common drug excipient.Contain in the pharmaceutical composition for example about 0.1% to 100%, preferred about active component of 1% to 80%.The pharmaceutical composition that digestive tract or non-digestive tract are used with ocular administration generally is a unit dosage form, as dragee, tablet, capsule or suppository and injection ampoule.The preparation method of these medicines all is known, for example Chang Gui mixing, granulating, sugar coating, dissolving or lyophilization.Being used for oral medicine can be by combining preparation with active component with solid carrier.But if the mixture that the words granulating that needs obtains, if need, can be adding suitable excipient post-treatment mixture or granule, to obtain the core of tablet or dragee.
Appropriate carriers is preferably used filler, saccharide such as lactose, sucrose, mannitol or sorbitol are typically arranged, cellulose composition and/or calcium phosphate such as tricalcium phosphate or calcium hydrogen phosphate, also has binding agent such as starch cream, for example corn starch, wheaten starch, rice starch or potato starch are typically arranged, gelatin, Tragacanth, methylcellulose and/or polyvinylpyrrolidone, if the as noted above starch of the also available dispersant of words that needs, also have carboxymethyl starch, crospolyvinylpyrrolidone, agar in addition, alginic acid or its salt, typical in sodium alginate.Excipient mainly is regulator and lubricant, and commonly used have silica gel, Pulvis Talci, stearic acid or its salt, and commonly used have magnesium stearate, calcium stearate or a polyethylene glycol.The coating of dragee core is the anti-gastric juice of energy preferably, ad hoc proposal is with dense sugar juice, wherein can randomly contain arabic gum, Pulvis Talci, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, with the coating solution of organic solvent or solvent mixture preparation.The coating for preparing anti-gastric juice can typically have phthalic acid ethyl cellulose or phthalic acid hydroxypropyl cellulose with the solution of suitable cellulose composition.For for example distinguishing or indicating the active component of various dose can in the coating of tablet or dragee, add toner or pigment.
Other combination of oral medication is an exsiccant fill-type gelatine capsule and by the pliable-closure capsule of gelatin and plastic agent (as glycerol and sorbitol) preparation.Dry capsule charge can contain the graininess active component, wherein is mixed with filler such as lactose, binding agent such as starch, and/or lubricant such as Pulvis Talci or magnesium stearate.In soft capsule, active component preferably is dissolved in or is suspended in the suitable solution as oil, paraffin oil, liquid polyethylene glycerol and can add stabilizing agent.
The pharmaceutical composition that is fit to rectally is typically suppository, and it is made up of in compositions active component and suppository base.Suitable suppository base is for example natural or synthetic triglyceride, alkane and high triacontanol.Also can use the gelatin rectal capsule that contains active component and substrate.Suitable substrate is liquid triglycerides for example, polyethylene glycerol or alkane.
The pharmaceutical composition that is fit to parenteral administration mainly contains the aqueous solution of active component, and active component can exist with water-soluble form, and the form of water soluble salt is typically arranged; Also can be the suspension of active component, as injection oils suspension.This suspension uses lipophilic solvent or carrier, and for example Oleum sesami or synthetic fatty acid ester such as ethyl oleate or triglyceride are typically arranged.Or water for injection dissolubility suspension, it contains toughness enhancing substance such as sodium carboxymethyl cellulose, sorbitol and/or glucosan and optional stabilizing agent.
The oral medicine of preferred applying unit dosage form.Tablet or capsule are typically arranged.
Absorption of active ingredient depends on various factors, as application method, and homoiothermic animal kind, age and/or individual state.Estimation is approximately for the patient's of 75 kg body weight normal oral dose: about 5 milligrams to 40 milligrams of active component (1) benazepril or its pharmaceutical salts, and about 20 milligrams to 160 milligrams of (2) valsartan or its pharmaceutical salts, and preferred medication every day one is to twice.
Active component (1) can be about 1 to 8 and 1 to 4 or 1 to 2 with the weight ratio of active component (2).
New compositions can preferably contain about 10 to 40 milligrams of active component (1), more preferably 10 to 20 milligrams, most preferably 10 milligrams.
New compositions can preferably contain about 20 to 80 milligrams of active component (2), more preferably from about 40 to 80 milligrams, most preferably from about 40 milligrams or 80 milligrams.
In a preferred embodiment of the invention, the pharmaceutical composition of being made up of benazepril one hydrochloride and valsartan uses in a unit dosage form.Preferably 10 milligrams and AT of the amount of ACE inhibitor herein 1Preferably 40 or 80 milligrams of the amounts of antagonist.
In pharmaceutical composition of the present invention, active component (1) and (2) administration together, also administration in succession, or a combination or two independent unit dosage forms in administration respectively.Preferably administration in the unit dosage form of a combination.
This new pharmaceutical composition can be used for treating hypertension and congestive heart failure.
Treatment hypertension, the method for congestive heart failure and renal failure comprises that the patient to this treatment of needs uses pharmaceutical composition of the present invention, said composition comprises (1) ACE inhibitor-benazepril or benazeprilat, or its pharmaceutical salts and (2) AT 1Antagonist-valsartan or its pharmaceutical salts.
The invention still further relates to new preparation of drug combination method.

Claims (13)

1. pharmaceutical composition that is used for the treatment of hypertension, congestive heart failure and renal failure, it comprises:
(1) benazepril of ACE inhibitor-following formula:
Figure A9619311100021
Or the benazeprilat of following formula:
Figure A9619311100022
Or its pharmaceutical salts; And
(2) AT 1The valsartan of antagonist-following formula:
Or its pharmaceutical salts.
2. the compositions of claim 1, wherein active component (1) is benazepril one hydrochloride, active component (2) is a valsartan.
3. the compositions of claim 1 or claim 2, it contains has an appointment 5 milligrams to about 40 milligrams active component (1).
4. the compositions of claim 3, it contains has an appointment 10 milligrams to about 40 milligrams active component (1).
5. the compositions of claim 3, it contains have an appointment 10 milligrams or about 20 milligrams active component (1).
6. the compositions of claim 3, it contains 10 milligrams the active component (1) of having an appointment.
7. the compositions of arbitrary claim in the claim 1 to 6, it contains has an appointment 20 milligrams to about 160 milligrams active component (2).
8. the compositions of claim 7, it contains has an appointment 20 milligrams to about 80 milligrams active component (2).
9. the compositions of claim 7, it contains have an appointment 40 milligrams or about 80 milligrams active component (2).
10. the compositions of arbitrary claim in the claim 1 to 9, it comprises the active component (1) of about 10 milligrams active component (2) and about 40 milligrams or 80 milligrams.
11. the compositions of claim 1, wherein composition (1) and (2) can provide together, successively provide, a combination or two independent unit dosage forms in provide respectively.
12. a method for the treatment of hypertension, congestive heart failure and renal failure, it comprises that the patient to this treatment of needs uses following compositions:
(1) benazepril of ACE inhibitor-following formula:
Figure A9619311100031
Or the benazeprilat of following formula:
Or its pharmaceutical salts; And
(2) AT 1The valsartan of antagonist-following formula:
Or its pharmaceutical salts.
13. the method for claim 12, wherein composition (1) and (2) administration together, administration successively, or a combination or two independent dosage unit forms in administration respectively.
CN96193111A 1995-04-07 1996-04-02 Combination compositions containing benazepril or beazeprilat and valsartan Pending CN1181019A (en)

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CH101295 1995-04-07

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CN101869710A (en) * 2009-04-24 2010-10-27 北京奥萨医药研究中心有限公司 Antihypertensive medical composite
CN105939728A (en) * 2014-01-31 2016-09-14 詹森药业有限公司 Methods for the treatment and prevention of renal disorders and fatty liver disorders
CN113144204A (en) * 2014-01-31 2021-07-23 詹森药业有限公司 Method for treating and preventing renal and fatty liver diseases

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BR9604818A (en) 1998-06-09
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TR199701121T1 (en) 1998-03-21
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NO974400L (en) 1997-09-23
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HUP9801593A2 (en) 1999-01-28

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