CN101002766A - Pharmaceutical combination of angiotensin ii antagonists and ace inhibitors - Google Patents

Abstract

A method of treatment of indications which can be positively influenced by inhibition of AT<SUB>1 </SUB>mediated effects with maintenance of AT<SUB>2 </SUB>receptor mediated effects of angiotensin II and by ACE inhibition, thus also increasing bradykinin mediated effects, e.g., to reduce the incidence of stroke, acute myocardial infarction or cardiovascular death, or of indications associated with the increase of AT<SUB>1 </SUB>receptors in the subepithelial area or increase of AT<SUB>2 </SUB>receptors in the epithelia, comprising coadministration of effective amounts of an angiotensin II antagonist and an ACE inhibitor, pharmaceutical compositions containing an angiotensin II antagonist together with an ACE inhibitor and the use of an angiotensin II antagonist and an ACE inhibitor for the manufacture of corresponding pharmaceutical compositions.

Description

The drug conjugates of angiotensin and ace inhibitors

The application is the Chinese patent application (applying date: August 16 calendar year 2001; Application number: 01814414.4;

Denomination of invention: the dividing an application drug conjugates of Angiotensin II antagonist and ACEI inhibitor).

Invention field

The invention relates to treatment sign (A) or sign (B) method, sign (A) may determine to be subjected to AT ₁The inhibitory action of mediation effect influences, and keeps the AT of Angiotensin II (ANG II) ₂The mediation effect of receptor, and be subjected to the influence of ACE inhibitory action, and therefore also increase bradykinin mediation effect, for example reduce the incidence rate of apoplexy, acute myocardial infarction or cardiovascular death, particularly the people of rising risk with cardiovascular event or apoplexy, and sign B with at last subcutaneous area AT ₁Receptor increases, or in epithelium AT ₂Receptor increases relevant, and this method comprises the people to this class treatment of needs, the ANG II antagonist and the ACE inhibitor of common-effective quantity of administration,

Suitable pharmaceutical composition comprises ANG II antagonist and ACE inhibitor, with the form of combination preparation, and when this sign of treatment, use simultaneously, separately or continuously, and

When ANG II antagonist and ACE inhibitor are used in combination, the purposes of ANG II on the pharmaceutical composition of making this sign of treatment.

As if the favourable effectiveness of the method according to this invention mainly be Organoprotective, organization protection and the vascular protection effect based on combined therapy.

Background of invention

ANG II plays an important role on pathophysiology, particularly at the most effective blood pressure dose of the conduct mankind.Therefore, ANG II antagonist is adapted in the mammal, is used for treating hypertension, and congestive heart failure.At No. 253 310, No. 502 314, European patent-A-0, European patent-A-0, No. 324 377, No. 323 841, European patent-A-0, European patent-A-0, United States Patent (USP)-A-4,355, No. 040 and United States Patent (USP)-A-4 have described the example of ANG II antagonist in 880, No. 804.Specific ANGII antagonist is Sha Tan (sartan) class, for example Kan Teshatan (candesartran), eprosartan (eprosartan), Irb (irbesartan), Losartan (losartan), temisartan (telmisartan) or Wa Ershatan (valsartan), also has RNH 6270 (olmesartan) and WAY-ANA 756 (tasosartan).

Also known a series of angiotensin i-converting enzyme (ACE) inhibitor as antihypertensive, be used in combination and treat congestive heart failure, for example Benazepril, captopril, ceronapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, ramipril, trandolapril, Perindopril.At No. 079 022, European patent-A-0, United States Patent (USP)-A-4,046, No. 889 and 4,374, example has been described in No. 829.

Known ANG II, except it increases the effect of blood pressure, the extra growth-promoting effect that is characterized as impels that left ventricular hypertrophy, blood vessel thicken, atherosclerosis, renal failure and apoplexy.Bradykinin plays vasodilation and organization protection on the other hand, as following open in announcement:

People such as W Wienen: after the rat long-term treatment of hypertensive cerebral diabetes (D), the resisting hypertension of temisartan and kidney protection effect, 2 ^Nd.Int.Symposium on Angiotensin IIAntagonism, February 15-18,1999, The Queen Elizabeth II Conference Center, London, UK, Book of Abstracts, Abstract No.50;

People such as J Wagner: in the spontaneous hypertensive rat that apoplexy tendency strain is arranged, AT ₁The effect of receptor blocking blood pressure and renin-angiotensin system, Clin Exp Hypertens 1998,20:205-221; With

People such as M Bohm: in TGR (mREN2) 27, block angiotensin-ii receptor: the influence and the cardiovascular function of renin angiotensin-system's gene expression, J Hypertens 1995,138:891-899.

In primary clinical trial, find that Losartan and Irb provide kidney protection effect, as what in following disclosing, disclose:

People such as S Andersen: in suffering from the type i diabetes patient of diabetic nephropathy, the kidney protection effect of blocking-up angiotensin-ii receptor, Kidney Int 57 (2), 601-606 (2000);

LM Ruilope: blocking-up kidney protective effect and renin-angiotensin system in diabetes, Am J Hypertens 10 (12 PT 2) suppl, 325S-331S (1997);

JFE Mann: Wa Ershatan and kidney: present and future, J Cardiovasc Pharmacol 33suppl 1, S37-S40 (1999);

People such as EL Schiffrin: in human essential hypertension, by the dysfunction that the angiotensin receptor antagonist Losartan is corrected artery structure and endothelium, Circulation 101 (14), 1653-1659 (2000);

People such as RM Touyz: Angiotensin II is deriving from the vascular smooth muscle cell moderate stimulation DNA and the protein synthesis of human tremulous pulse: extracellular signal-regulate kinase whose effect, and J Hypertens 17 (7), 907-916 (1999);

EL Schiffrin: reconstructing blood vessel in the hyperpietic and endothelial function: the effect of antihypertensive treatment, Scand Cardiovasc J 32 suppl 47,15-21 (1998); And

A Prasad: acute and chronic angiotensin-1 receptor antagonism has reversed the dysfunction of endothelium in atherosclerosis, Circulation 2000; 101:2349 cont..

In addition, have been found that in suffering from the normotensive patient of diabetic nephropathy, can strengthen the anti-albuminuria effectiveness of enalapril through Losartan, as at Am J Hypertens 13 (4, part2), disclosed among the 117A Abstr A017 (2000), with reference to 15th Sci Mtg of the American Societyof Hypertension, 16-20 May 2000.

Result (the New Engl J Med 432/3 of heart prevention achievement assessment (HOPE) research, on January 20th, 2000, the 145-153 page or leaf) points out, utilize the treatment of ACE inhibitor ramipril, reduced the risk 22% of mixing constitutional cardiovascular consequence significantly, and reduce the risk of Secondary cases terminal point consequence all the time, comprise general mortality rate.The most of influence that reduces with blood pressure of shown cardiovascular benefit has nothing to do, and thinks that ramipril plays independently vascular protection and organ pipe protective effect.

Yet, also confirm to utilize the chronic treatment of ACE inhibitor, can not constrain the level of ANG II effectively, be because other produce the compensation activation of the enzyme (for example human Chymosin, cathepsin G) of ANG II, it may have injurious effects, particularly ongoing terminal organ's injury is owing to the AT of the ANG II that continues ₁(for example, Willenheimer, Eur.Heart are J.1999 for the receptor regulating action; 20, its mechanism is described) in the survey article of 997-1008.

ANG II antagonist is optionally blocked AT ₁Receptor stays AT ₂Receptor, it is played a role in anti--growth and playing the part of on of tissue regeneration, the unmanned opposition.As if the clinical trial that utilizes ANG II antagonist to finish show and reduce with the similar blood pressure of ACE inhibitor and organization protection is renderd a service, as following open in announcement:

People such as DHG Smith: in hypertensive treatment, temisartan is once a day compared with enalapril, and Adv.Ther 1998,15:229-240;

People such as BE Karlberg: the effectiveness of temisartan and safety, selectivity AT ₁Receptor antagonist is compared with enalapril in old primary hypertension patient, J Hypertens 1999,17:293-302; And

People such as JM Neutel: suffering from gentleness-to-medium hypertensive patient, relatively temisartan and lisinopril, Am J Ther 1999,6,161-166.

Recently, during congestive heart failure, be primarily focused on two kinds of medicines of combination in principle, be based on potentiality, and via AT inhibiting interests of ACE and bradykinin in treatment ₁Receptor blocking, and with the effect of remaining ANG II from AT ₁Convert AT to ₂The theoretical basis that the more effective inhibitory action of the renin angiotensin aldosterone system of receptor is combined (M Burnier, IDrugs 3 (3): 304-309, (2000)).On the pharmacology, this is highly tempting method, and at present a large amount of research (VAL-HeFT, Cardiology 1999,91 (supplI)), 19-22 is being carried out in congestive heart failure; CHARM, J Cardiac Failure 1999,5:276-282), so that confirm this hypothesis.

In No. 527 879, European patent-A-0, combined therapy and corresponding compositions have been disclosed, it comprises that at least two are selected from the therapeutic preparation that comprises renin inhibitor, ACE inhibitor and ANG II antagonist, to be enough to the causing quantity that brings high blood pressure down and treat the synergistic therapeutic effect of congestive heart failure in mammal.Instructing preferred ACE inhibitor is captopril, enalapril, lisinopril and ramipril.Disclosing Losartan is preferred ANG II antagonist.The dosage range that discloses ACE inhibitor comprises 40 mg/day to 450 mg/day, and oral and 20 mg/day are in the parenteral mode.The dosage range that discloses ANG II antagonist then comprises 0.5 to 500 mg/kg, and is oral, 2 to 80 mg/kg preferably, oral and 3 mg/kg, intravenous.

European patent-A-1 discloses AT 013 No. 273 ₁Receptor antagonist or AT ₂Receptor suppresses regulator, increases AT in treatment and in last subcutaneous area ₁Receptor, or in epithelium, increase AT ₂Purposes in the receptor related disease particularly is used for treating serious pneumonopathy.

Brief summary of the invention

Have been found that the co-administered of ANG II antagonist and ACE inhibitor, determining to be subjected to AT ₁The inhibitory action of mediation effect influences, and keeps the AT of ANG II ₂Therefore the mediation effect of receptor, and be subjected to ACE inhibitory action influence also increases in sign (indication) treatment (A) of mediation effect of bradykinin,

In addition, with increase AT in last subcutaneous area ₁Receptor, or in epithelium, increase AT ₂In receptor related sign (indication) treatment (B), provide unexpected advantage,

This advantage has higher efficient for to compare with individually dosed ANG II antagonist or ACE inhibitor, and is irrelevant with the known hypotensive activity of these preparations.

These signs comprise the sign of determining to be subjected to the advantage Organoprotective, tissue-protection and the vascular protection function influence that are provided by the combined therapy that uses ANG II antagonist with ACE inhibitor, and for example sign (A) can comprise

For example reduce the incidence rate of apoplexy, acute myocardial infarction or cardiovascular death, especially in the people of rising risk with cardiovascular event or apoplexy,

The kidney protective effect, for example in renal failure or diabetic nephropathy,

Left ventricular hypertrophy, blood vessel thicken, and for example prevent vessel wall thickening after vascular surgery, and art prevents the restenosis of tremulous pulse after angioplasty, prevention or treatment atherosclerosis, and the prevention of diabetic vascular disease,

The ischemic peripheral circulatory disturbance, myocardial ischemia (angina pectoris), the progress of after myocardial infarction, preventing cardiac dysfunction,

With at last subcutaneous area AT ₁Receptor increases, or in epithelium AT ₂Receptor increases relevant sign (B), can comprise

For example obstructive airway diseases, chronic obstructive pulmonary disease, for example bronchitis or chronic bronchitis, emphysema, asthma, cystic fibrosis of the pancreas, interstitial lung disease, pulmonary carcinoma, lungs angiopathy, and during forced expiration, air-flow is built up one's resistance to disease,

The formation of adult's respiratory distress syndrome (ARDS), the epitheliogenetic ability that in pulmonary carcinoma and breast carcinoma, reduces, treatment sepsis syndrome, lungs injury, for example detour art, O of the aspiration pneumonitis of gastric content, thoracic cavity wound, shock, burn, fat embolism, cardiopulmonary ₂Toxicity, hemorrhagic pancreatitis, a matter and bronchovesicular inflammation, epithelium and Interstitial cell propagation, collagen protein are piled up and fibre modification.

Unexpected advantages mentioned above is attributable to more effectively to block the AT of ANG II ₁The mediation effect, and owing to the AT of ANG II ₂Receptor-mediated effect, the influence that keeps not being subjected to ANG II antagonist is together with the increase of the bradykinin mediation effect that is caused by ACE inhibitor.

According to a first aspect of the invention, provide the method for treatment sign (A) or disease (B), sign (A) can determine to be subjected to AT ₁Mediate the inhibiting influence of effect, and keep the AT of ANG II ₂Therefore receptor-mediated effect, and be subjected to the inhibiting influence of ACE has also increased the joint effect of bradykinin, disease B with at last subcutaneous area AT ₁Receptor increases, or in epithelium AT ₂Receptor increases relevant, and this method comprises ANG II antagonist and the ACE inhibitor to the human or non--mankind's of this class treatment of needs the effective quantity of mammalian body co-administered.

The details that can use the medicable sign of the method according to this invention is provided hereinbefore.

Have been found that the common-administration of ANG II antagonist and ACE inhibitor, when with individually dosed the comparing of ANG II antagonist or ACE inhibitor, provide tangible prevention for cardiovascular death and general mortality rate, especially about the generation of apoplexy and acute myocardial infarction.

Therefore, preferred version according to the present invention is by co-administered ANG II antagonist and ACE inhibitor, reduce the incidence rate of apoplexy and acute myocardial infarction in the human or non--human mammalian body need this treatment, especially in having the people who increases cardiovascular event or stroke risk.

In addition, have been found that combined therapy and particularly including the quantity of ACE inhibitor ramipril, with the corresponding compositions of the quantity of ANG II antagonist temisartan, in mammal, for bringing high blood pressure down and treating the activity that congestive heart failure has height.Expection shockingly surpasses corresponding combination well known in the prior art by the synergy that this particular combinations provided.Be used for reducing hypertension according to the present invention, or the synergistic combination of treatment congestive heart failure means the quantity that comprises ramipril and the quantity of temisartan, the therapeutic effect that the independent lazy weight of wherein indivedual preparations can reach with the combination that reaches through the administration said preparation, and the combined effect of the quantity of therapeutic agent wherein, Billy is bigger with the sum total of the therapeutic effect that the quantity of individualized treatment agent can reach.

From different aspect of the present invention, also about in order to treat the sign that preamble is mentioned, be used for treating the pharmaceutical composition of human or non--human mammalian body, it comprises ANG II antagonist and ACE inhibitor, optional pharmaceutically acceptable diluent and/or the carrier of being included in, make when this sign of treatment, simultaneously, separately or continuously the mix preparation of use.

From another aspect of the present invention, ANG II is provided antagonist, when using jointly, be used for treating purposes in the pharmaceutical composition of the sign that preamble mentions in manufacturing with ACE inhibitor.

Detailed description of the invention

About all aspects of the present invention, any ANG II antagonist may be fit to, except as otherwise noted, for example husky smooth class, Kan Teshatan for example mentioned above, eprosartan, Irb, Losartan, temisartan, Wa Ershatan, RNH 6270 and WAY-ANA 756, preferably Losartan or temisartan, best is temisartan 4 '-[2-just-propyl group-4 methyl-6-(benzimidazole-1-ylmethyl of 1-methyl-benzimidazolyl-2 radicals-yl)] xenyl-2-carboxylic acid }, in addition, about all aspects of the present invention mentioned above, can use any ACE inhibitor, except as otherwise noted, Benazepril for example, captopril, ceronapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, ramipril, trandolapril and Perindopril, captopril preferably, enalapril, lisinopril and ramipril, most preferably ramipril.

In the preferred embodiment aspect Therapeutic Method, co-administered ramipril and any ANG II antagonist.

In second embodiment preferred aspect Therapeutic Method, any ACE inhibitor of co-administered and temisartan.

In the 3rd embodiment preferred aspect Therapeutic Method, co-administered ramipril and temisartan.

The co-administered of ANG II antagonist and ACE inhibitor means and comprises in time administration in succession or administration simultaneously, preferably administration simultaneously.About administration in succession, can be before or after the administration ACE inhibitor, administration ANG II antagonist.

By oral, cheek, parenteral, suction spraying, per rectum or partial mode, administration reactive compound, preferably oral administration.That parenteral administration can comprise is subcutaneous, intravenous, intramuscular and breastbone inner injection, and infusion techn.

The reactive compound of the various dosage form of Orally-administrable, just can utilize variously, they are deployed into forms such as lozenge, capsule, tablet, lozenge, hard sugar, powder, spray, aqueous suspension, elixir, syrup at pharmaceutically acceptable inert carrier.This class carrier comprises solid-state diluent or filler, aseptic water-bearing media and various avirulent organic solvent, or the like.In addition, available for this classification and all types of additive that often uses suitably increases sweet this class oral drug preparation and/or seasoning.Generally speaking, chemical compound of the present invention can be by the weight of total composition, providing from about 0.5% this class oral dosage form in about 90% the concentration range, will be enough to provide the unit dose of wanting with this quantity.For chemical compound of the present invention, other suitable dosage forms comprise the preparation and the device of sustained release well known to those skilled in the art.

For oral administration, can use the tablet that contains various excipient, excipient has sodium citrate, calcium carbonate and calcium phosphate, together with various disintegrating agents, similarly be starch, preferably Rhizoma Solani tuber osi or cassava starch, alginic acid and some compound silicate, with binding agent, for example polyvinylpyrrolidone, sucrose, gelatin and Radix Acaciae senegalis.In addition, also can use, or the lubricant of the compositions of similar type and so on such as magnesium stearate, sodium lauryl sulphate and Talcum, as soft hard-fill the filler of gelatine capsule; Comprise lactose or toffee, and high-molecular weight Polyethylene Glycol.When wishing oral administration aqueous suspension and/or elixir, wherein necessary active ingredient can be mixed with various sweeteners or flavoring agent, coloring matter or dyestuff, if need, also have emulsifying agent and/or water, ethanol, propylene glycol, glycerol and various similar combination thereof.

For parenteral administration, can use at Oleum sesami or Oleum Arachidis hypogaeae semen, or the compound solution in aqueous propylene glycol, and corresponding sterile water solution in the pharmaceutically acceptable salt class.If need suitably cushion this class aqueous solution, and utilize competent normal saline or glucose, it is saturating that liquid diluent is become etc.The aqueous solution that these are specific is particularly suitable for intravenous, intramuscular and hypodermic purpose.About this point, available standard technique well known to those skilled in the art promptly obtains employed sterilization water-bearing media.For example, use distilled water usually, and make last goods by suitable bacterial filter, for example sintered glass filter, or kieselguhr or unglazed porcelain filter as liquid diluent.Preferred this type filter comprises Berkefeld, Chamberland and Asbestos Disk-MetalSeitz filter, wherein uses suction pump, fluid is pumped in the container of sterilization.In the whole preparation of these injection solutions, should adopt necessary step, under aseptic condition, obtain end-product so that guarantee.For percutaneous dosing, the dosage form of specific compound or several chemical compounds can comprise, for example the preparation and the device thereof that discharge of the delay of solution, lotion, ointment, cream, gel, suppository, limiting speed.This class dosage form comprises specific chemical compound or several chemical compound, and can comprise ethanol, water, penetration enhancer and inert carrier, for example produces material, mineral oil, emulsifying agent, benzyl alcohol of gel etc.

Existing several ANG II inhibitor listings, and can supply with medicine use, for example Micardis ^_, Lorzaar ^_, Cozaar ^_, Lortaan ^_, Losaprex ^_, Neo-Lotan ^_Or Oscaar ^_, Approvel ^_, Karvea ^_, Diovan ^_, Atacand ^_, Blopress ^_And Teveten ^_

Also existing several ACE inhibitor listings, and can supply with medicine use, for example Briem ^_, Cibacen ^_, Cibacne ^_, Lotensin ^_, Dynacil ^_, Elidiur ^_, Fosinorm ^_, Fositen ^_, Fozitec ^_, Monopril ^_, Staril ^_, Tensozide ^_, Novaloc ^_, Tanapril ^_, Fempress ^_, Perdix ^_, Univasc ^_, Accupril ^_, Accuprin ^_, Accupro ^_, Acequin ^_, Acuitel ^_, Korec ^_, Quinazil ^_, Xanef ^_, Pres ^_, Acerbon ^_, Lopirin ^_, Tensobon ^_, Delix ^_Or Vesdil ^_

Can 1.25 milligrams of (or 0.018 mg/kg, artificial basis with 70 kilograms) oral to 450 milligrams (0.571 mg/kg), and dosage every day of about 20 milligrams (0.286 mg/kg) parenterals, preferably 5 milligrams (0.071 mg/kg) is to 100 milligrams of (1.429 mg/kg) oral administration ACE inhibitor.Particularly preferably be 5 (0.071 mg/kg) to 30 milligrams (0.429 mg/kg) or particularly about 10 milligrams (0.143 mg/kg) oral every day dosage.

Can 10 milligrams of (or 0.143 mg/kg, artificial basis with 70 kilograms) oral to 500 milligrams (7.143 mg/kg), and about 20 milligrams (0.286 mg/kg) parenterals, administration ANG II antagonist, preferably 20 milligrams (0.286 mg/kg) is to 100 milligrams of dosage every day that (1.429 mg/kg) is oral.Particularly preferably be 40 milligrams (0.571 mg/kg) to 80 milligrams (1.143 mg/kg), or oral every day of the dosage of particularly about 80 milligrams (1.143 mg/kg).

In administering mode and dosage that all preambles are mentioned, preferred ACE inhibitor is a ramipril, and preferred ANG II antagonist is a temisartan.In the most preferred embodiment, via oral, administration simultaneously about 10 milligrams every day dosage ramipril and about 80 milligrams every day dosage temisartan.

Pharmaceutical composition of the present invention, in single dose unit, contain a kind of ACE inhibitor, content is 1.25 milligrams to 450 milligrams, and a kind of ANG II antagonist, content is 10 milligrams to 500 milligrams, choose wantonly and contain one or more at pharmaceutically acceptable diluent and/or carrier, for example, pharmaceutical composition of the present invention, in single dose unit, contain a kind of being selected from and comprise Benazepril, captopril, ceronapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, ramipril, the ACE inhibitor of trandolapril and Perindopril, content is 1.25 milligrams to 100 milligrams, and a kind of being selected from comprises Kan Teshatan, eprosartan, Irb, Losartan, temisartan and Wa Ershatan, the ANG II antagonist of RNH 6270 and WAY-ANA 756, content is 20 to 100 milligrams, except the combination of captopril and Losartan, chooses wantonly and contains one or more at pharmaceutically acceptable diluent and/or carrier.

The preferred subgroup of pharmaceutical composition of the present invention, in single dose unit, the ACE inhibitor ramipril that contains 1.25 milligrams to 100 milligrams of content, with a kind of ANG II antagonist that comprises Kan Teshatan, eprosartan, Irb, Losartan, temisartan and Wa Ershatan that is selected from of 20 milligrams to 100 milligrams of content, choose wantonly and contain one or more at pharmaceutically acceptable diluent and/or carrier.

Second kind of preferred subgroup of pharmaceutical composition of the present invention, in single dose unit, a kind of ACE inhibitor that comprises Benazepril, captopril, ceronapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, ramipril and trandolapril that is selected from that contains 1.25 milligrams to 100 milligrams of content, with the ANG II antagonist temisartan of 20 milligrams to 100 milligrams of content, choose wantonly and contain one or more at pharmaceutically acceptable diluent and/or carrier.

Third preferred subgroup of pharmaceutical compositions of the present invention, in single dose unit, contain a kind of ACE inhibitor that is selected from enalapril, lisinopril and ramipril, content is 1.25 milligrams to 100 milligrams, with a kind of ANG II antagonist that is selected from Losartan and temisartan, content is 20 to 100 milligrams, chooses wantonly to contain one or more at pharmaceutically acceptable diluent and/or carrier.

The most preferred pharmaceutical composition of the present invention, in single dose unit, the ACE inhibitor ramipril that contains 1.25 milligrams to 100 milligrams of content, with the ANG II antagonist temisartan of 20 milligrams to 100 milligrams of content, choose wantonly and contain one or more at pharmaceutically acceptable diluent and/or carrier.

The special preferred pharmaceutical composition of the present invention, in single dose unit, contain the about 80 milligrams ANG II antagonist temisartan of about 10 milligrams ACE inhibitor ramipril of content and content, choose wantonly and contain one or more at pharmaceutically acceptable diluent and/or carrier.

As what above mentioned, the present invention also provides in order to treat the sign that preamble is mentioned, when being used in combination with ACE inhibitor, ANG II antagonist can be used to treat purposes in the pharmaceutical composition of human or non--human mammalian body in manufacturing.This purposes comprises the manufacturing of all pharmaceutical compositions that preamble is mentioned according to the present invention.

Claims (5)

1. a pharmaceutical composition comprises the ACE inhibitor ramipril of effective dose and the ANG II antagonist temisartan of effective dose.

2. the pharmaceutical composition of claim 1 is characterized in that, ramipril content in single dosage unit is 1.25 milligrams to 100 milligrams, and temisartan content in single dose unit is 20 to 100 milligrams.

3. the compositions of claim 1 is used for preventing or treating the purposes of fibrotic medicine in preparation.

4. the compositions of claim 1 is used for preventing or treat the purposes of the medicine of apoplexy, myocardial infarction or cardiovascular death in preparation.

5. the compositions of claim 1 is used for preventing or treat the purposes of the medicine of hypertension or congestive heart failure in preparation.