CN101757004A - Novel compound antihypertensive preparation - Google Patents

Abstract

The invention discloses a novel compound antihypertensive preparation which comprises 50-200mg of irbesartan and 5-30mg of fosinopril. Aiming at solving the problem that currently when only one of irbesartan and fosinopril is used clinically, in order to ensure the curative effect, the dosage of the drug is increased, which leads to obvious increase of the side effects, the invention provides a novel compound preparation. Irbesartan and fosinopril are used together, so synergic and complementary curative effect can be produced. The novel compound antihypertensive preparation enhances the tolerance of the patient, improves the compliance and reduces the dosage and the adverse reaction, and is convenient to take and cheap in price.

Description

A kind of new compound antihypertensive preparation

Technical field

The present invention relates to medical technical field, disclose a kind of new compound antihypertensive preparation.

Background technology

Hypertension is modal cardiovascular disease, is the great public health problem in the global range.China has 100,000,000 hypertensive patients at present approximately.The Epidemiological study result showed in 1991, and China city and rural area hypertension awareness are respectively 36% and 13%, and treatment rate is respectively 17% and 5%, and the form of hypertension prevention and control is quite severe.According to the WTO prediction, will account for 79% of China's cause of death to the year two thousand twenty noninfectious, wherein the cardiovascular diseases will account for the first place.

Treatment hypertension drug commonly used has angiotensin receptor antagonist irbesartan and angiotensin converting enzyme inhibitor fosinopril.

Irbesartan (Irbesartan), chemistry 2-butyl-3-[4-[2-(1H-tetrazolium-5-yl) phenyl by name] benzyl-1, in 3-diaza spiro-[4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone, molecular formula is C ₂₅H ₂₈N ₆O, molecular weight: 428.53, shown in the structural formula:

The irbesartan structural formula

Candesartan is used for the treatment of hypertension, this product is Angiotensin II (AngiotensinII, AngII) acceptor inhibitor, can suppress Ang I and be converted into AngII, enzyme 1 receptor (AT1) of the nervous plain conversion of antagonizing vessel specifically, to the antagonism of AT1 doubly greater than AT28500, by optionally blocking combining of Ang II and AT1 receptor, suppress the release of vasoconstriction and aldosterone, produce hypotensive effect.This product does not suppress Angiotensin-Converting (ACE), feritin, other hormone receptor, does not suppress the ion channel relevant with blood pressure regulating and sodium balance yet.

According to foreign data, can absorb rapidly after this product is oral, bioavailability is 60～80%, the influence of unable to take food thing.The blood plasma peak time is 1～1.5 hour, and eliminating the half-life is 11～15 hours.Reach stable state in three days.Irbesartan is by glucuronidation or oxidative metabolism, and in vitro study shows mainly by cytochrome enzyme P4502C9 oxidation.This product and metabolite are through biliary tract and renal excretion.The plasma protein binding rate of irbesartan is 90%.According to domestic document announcement, behind the oral this product 300mg of health volunteer, about 1.9 hours blood drug level peakings, peak concentration is about 4058 μ g/L, and elimination phase half-life (t1/2 β) is about 10.2 hours.

Fosinopril (fosinoprilat), chemistry (2 α, 4 β)-4-cyclohexyl-1-[[[2-methyl isophthalic acid by name-(1-oxopropoxy) propoxyl group] (4-benzene butyl) phosphinyl] acetyl]-the L-proline, molecular formula is C ₃₀H ₄₆NO ₇P, molecular weight: 563.66, shown in the structural formula:

The fosinopril structural formula

Fosinopril is the plain converting enzyme inhibitor (ACE inhibitor) of a kind of phosphorated novel hypertension

Suppress Angiotensin-Converting:

Fosinopril is the precursor medicine, to the ACE direct repression a little less than, but oral back slowly and not exclusively absorbs, and changes active stronger diacid metabolite fosinoprilat (fosinoprilat) rapidly into.Fosinoprilat suppresses the ACE activity by the combination of zinc ion in next phosphate group and the ACE active site.This medicine produces column effect down to the inhibitory action of ACE: 1. Angiotensin II content obviously reduces.The aldosterone secretion is reduced, and water-sodium retention is reduced.3. reduce Catecholamine matter and discharge, reduce sympathetic tone.In addition, fosinopril slows down the Kallidin I inactivation by the inhibitory action to kininase II, and the vasodilator effect of Kallidin I is strengthened.In all ACE inhibitor, the characteristics of fosinopril are: 1. the inhibitory action to ACE is strong.2. acting duration is long, can make behind the once oral fosinopril more than the ACE activity inhibited 24h.3. can drain from kidney and liver sausage simultaneously, be difficult for accumulating.After fosinopril was used, plasma renin and angiotensin I concentration increased, and Angiotensin II and aldosterone concentration descend.

To hemodynamic effects:

Can produce favourable influence to systemic blood flow kinetics to hyperpietic's fosinopril.Once oral fosinopril 10～40mg can make patient's tranquillization mean arterial pressure descend 10%～14%, and systolic pressure descends 10%～14%, and diastolic pressure descends 6%～17%, and total peripheral vascular resistance descends 14%～27%.Fosinopril still can be kept hemodynamic effect after motion.It occurs in the back 5～7h that takes medicine to hemodynamic ceiling effect behind the oral fosinopril, and effect can be kept 24h.This medicine does not have obvious influence to heart rate, and whenever the amount of fighting and cardiac output slightly rise, and is respectively 6%～10% and 6%～9%, and fosinopril only has slight negative inotropic action, but it is favourable to improving left chamber diastolic function.

Influence to myocardial hypertrophy:

Fosinopril can postpone or reverse the left ventricular hypertrophy that hypertension causes.The oral fosinopril 20mg/d of hyperpietic, behind 3～December, left ventricular mass descends 5%～15%, meanwhile interventricular septum and left chamber sidewall, the rear wall end-diastolicthickness descends 6%～15%.Therefore, fosinopril is the same with other ACE inhibitor, reducing the cardiac damage that hypertension causes, prevents from and alleviate in the left ventricular remodeling to play a significant role.

Influence to cerebral blood flow:

The present known local renin-angiotensin system that discharges is brought into play important regulating action in easypro the contracting of local vascular, fosinopril can make the partial Angiotensin II of cerebrovascular produce minimizing.Though oral fosinopril 4～12 all backs arterial pressures obviously reduce, cerebral blood flow still remains unchanged.

Influence to renal blood flow and renal function:

Fosinopril does not have obvious influence to renal function.Use fosinopril 10～40mg/d, after 1～June, glomerular filtration rate, filtration fraction all increase to some extent, and the renal tubules resistance descends 14%.

Double blinding in a large number at random,, multicenter study show that fosinopril all has significant hypotensive effect to hypertension in various degree.After 5～80mg took for 8～12 weeks, systolic pressure, diastolic pressure all obviously descended; After taking December, its hypotensive effect still can be kept.(n=113 example) oral fosinopril 10～20mg/d in a research, 6 weeks back diastolic pressure decline, 12～21mmHg, the 16～26mmHg that descends after 12 weeks, 62% patient's diastolic pressure is reduced to＜90mmHg.Comprise in 2518 routine patients' the research that at another fosinopril 10～20mg is after oral 6 weeks, the diastolic pressure 9～14mmHg that descends, the 12 week back diastolic pressures 12～19mmHg that descend, 89% patient's diastolic pressure drops to＜90mmHg[7].One comprises the oral fosinopril 10～20mg/d of studies show that of 26992 routine hyperpietics, and after 4～12 weeks, 55% patient's diastolic pressure is reduced to＜90mmHg.

Single treat hypertension than the strong dose thing and bring some untoward reaction sometimes with a kind of; blood pressure reduces the compensation response that triggers during as single therapy; take medicine after weak, dizzy, drowsiness, tinnitus, nauseating, vomiting, epigastric discomfort, constipation appear in regular meeting; sometimes also phenomenons such as postural hypotension, muscular spasm, insomnia can appear; though these phenomenons mostly dying away in the drug administration process continuously, also can be brought inconvenience to the patient.

Goal of the invention

Product of the present invention has overcome when using irbesartan and fosinopril clinically now, is to guarantee that curative effect increases drug dose during singly with a medicine, causes side effect obviously to increase; During drug combination,, and use clinical medicine dose inaccurate, influence the defective of curative effect of medication because of nothing meets the pharmaceutical preparation of drug combination dosage.Irbesartan and fosinopril two medicines share, collaborative, complementary action that curative effect has; Reduce consumption, alleviate untoward reaction, taking convenience, cheap.

Summary of the invention

The objective of the invention is to defective, a kind of compound preparation is provided at the prior art existence.

The present invention is achieved by the following technical solutions:

The hypertensive compound preparation of a kind of treatment, contain the component of following dosage:

Irbesartan 50-200mg

Fosinopril 5-30mg

A kind of preferred as technique scheme, a kind ofly treat the component that hypertensive compound preparation contains following dosage:

Irbesartan 100-200mg

Fosinopril 10-30mg

As the hypertensive compound preparation of a kind of more excellent treatment, it contains the component of following dosage:

Irbesartan 150mg

Fosinopril 20mg

Beneficial effect of the present invention is: the present invention is that two kinds of antihypertensive drugs of low dose of use in conjunction are treated hypertensive, better and untoward reaction is less than single with heavy dose of wherein a kind of medicine antihypertensive effect, the treatment of associating lattice can improve efficacy of antihypertensive treatment, in and the untoward reaction that causes of different pharmaceutical, be applicable to that hyperpietic in various degree takes for a long time.

This preparation also contains a certain amount of adjuvant except that containing above two kinds of active drug; In pharmacy procedure, the addition of adjuvant can be determined according to actual needs.

The adjuvant that this preparation is commonly used has: microcrystalline Cellulose, pregelatinized Starch, low-substituted hydroxypropyl cellulose, silicon dioxide, Pulvis Talci, lactose, dextrin, magnesium stearate, carboxymethylstach sodium, calcium sulfate etc.

Compound preparation of the present invention can have multiple mode, as compound recipe irbesartan-fosinopril sheet (ordinary tablet, slow releasing tablet and other special tablets), compound recipe irbesartan-fosinopril capsule dosage forms such as (conventional capsule, slow releasing capsule and other special capsule preparations).

Embodiment 1

A kind of compound preparation, contain following component:

Irbesartan 150mg

Fosinopril 20mg

Starch 20mg

Calcium sulfate 8mg

Pulvis Talci 2mg

Present embodiment can be made into compound recipe irbesartan-fosinopril sheet, and preparation method can adopt the preparation method of common pharmaceutical preparation.

Claims (3)

1. treat hypertensive compound preparation for one kind, contain the component of following dosage:

Irbesartan 50-200mg

Fosinopril 5-30mg.

2. the hypertensive compound preparation of treatment according to claim 1 is characterized in that compound preparation contains the component of following dosage:

Irbesartan 100-200mg

Fosinopril 10-30mg.

3. the hypertensive compound preparation of treatment according to claim 2 is characterized in that compound preparation contains the component of following dosage:

Irbesartan 150mg

Fosinopril 20mg.