SK133897A3 - Combination compositions containing benazepril or benazeprilat and valsartan - Google Patents

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

Pharmaceutical compositions comprising benazepril or benazeprilat and valsartan

Technical field

The invention relates to combined pharmaceutical compositions for the treatment of hypertension, congestive heart failure and renal failure, characterized in that it contains (1) the ACE-inhibitor benazepril or benazeprilat or a pharmaceutically acceptable salt thereof, and (2) _x AT-antagonist valsartan or a pharmaceutically an acceptable salt, and methods of treating hypertension, congestive heart failure, and kidney failure.

BACKGROUND OF THE INVENTION

There are various regulatory approaches that interfere with the renin-angiotensin cascade at different sites and thus allow different influences on blood pressure.

The α2-macrocycloprotein angiotensinogen is cleaved by the renin enzyme to the decapeptide angiotensin I, which alone is very poorly biologically active. The next step of the cascade is the cleavage of the other two amino acids by the action of the angiotensin-converting enzyme (ACE), mainly bound to the endothelium, to form angiotensin II. Angiotensin II is one of the strongest natural vasoconstrictors.

Disruption of the enzymatic degradation of angiotensin I to angiotensin II by the action of so-called ACE inhibitors is one of the successful variants of blood pressure regulation and also provides a therapeutic method for the treatment of congestive heart failure.

One known ACE-inhibitor is 3 - [(1- (ethoxycarbonyl) -3-phenyl- (1S) -propyl) amino] -2,3,4,5-tetrahydro-2-oxo-1H-1-acid. - (3S) -benzazepine-1-acetic (benazepril) of the formula

(see EP 72352) or (3S) -3 - [[(1S) - (1-carboxy-3-phenylpropyl) amino] -2,3,4,5-tetrahydro-2-oxo-1H-1 acid -benzazepine-1-acetic (benazeprilat) of the formula

(see EP 72352) and pharmaceutically acceptable salts thereof, among which deserves particular mention of monohydrochloride (benazepril hydrochloride).

The vasoconstrictive effects of angiotensin II are due to acting on smooth muscle cells, stimulating the production of epinephrine and norepinephrine adrenergic hormones, and increasing the activity of the sympathetic nervous system due to norepinephrine production. Angiotensin II also affects the electrolyte balance, for example causing antinatriuretic and antidiuretic effects in the kidneys, thereby promoting, on the one hand, the release of the vasopressin peptide from the pituitary gland and, on the other hand, the release of aldosterone from adrenal glomeruli. All of these effects play an important role in the regulation of blood pressure.

Angiotensin II interacts with specific receptors on the surface of target cells. They were identified subtypes of these receptors have been named for example _ΑΤ χ receptors _and AT receptors. At present, intensive research is under way on compounds that bind to the AT ₁ -receptor. These active ingredients are often called angiotensin II antagonists. Because they bind to the AT ₁ -receptor, they can be used, for example, as antihypertensives or in the treatment of congestive heart failure

Thus, angiotensin II antagonists are understood to be those active compounds that bind to receptors of the Αpu _χ subtype. These include compounds of different structural types.

(S) -N (Carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] was selected as a representative of N ₁ -antagonists. amine (valsartan) of formula ch,

CH, CH, \ /

CH

II T / ° /

CH,

CH, (see EP 443983) and pharmaceutically acceptable salts thereof.

The pharmaceutically acceptable salts of benazepril and valsartan are typical acid addition salts. These addition salts are formed, for example, with strong inorganic acids, typically with mineral acids such as sulfuric acid, phosphoric acid or hydrohalic acids, with strong organic acids, typically with 1-4 carbon atoms in the alkyl chain, which may be substituted, for example halogen, typically acetic acid, with dicarboxylic acids which may be unsaturated, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, with hydroxycarboxylic acids such as ascorbic acid, glycolic acid, acid lactic, malic acid, tartaric acid, citric acid, with amino acids such as aspartic acid or glutamic acid, benzoic acid, organic sulfonic acids such as alkanesulfonic acids with 1 to 4 carbon atoms in the alkyl chain or arylsulfonic acids which may be substituted, for example, by a halogen such as methanesulfonic acid or p-toluenesulfonic acid. Suitable base salts are typically metal salts, such as alkali metal or alkaline earth metal salts, typically sodium salts, potassium salts or magnesium salts, or ammonium salts, or salts with organic amines such as morpholine, thiomorpholine, piperidine, pyrrolidine , lower monoalkylamines or trialkylamines, typically ethylamine, dialkylamines t-butylamine, triethylamine, tributylamine, or diethylamine, diisopropylamine, dimethylpropylamine, or dihydroxyalkylamines or trihydroxyalkylamines, typically monoethanolamine, diethanolamine or triethanolamine or triethanolamine. Corresponding inner salts may also be used.

lower monohydroxyalkylamines,

Much attention has also been paid to combinations of different active ingredients for the treatment of, for example, hypertension or congestive heart failure. An envisaged advantage is, for example, that smaller doses of individual components may be used in such a combination than would be necessary for a single component. For example, when antihypertensives that act by different mechanisms are combined, an additive effect is usually expected. The aim, however, is to find combinations which, on the one hand, have a synergistic effect and, on the other hand, have a prolonged effectiveness.

WO 94/28924 discloses a combination of an ACE-inhibitor and an angiotensin II antagonist. As demonstrated by clinical trials, the combination of enalapril (ACE inhibitor) and losartan (AT ₁ -antagonist) at the indicated doses showed no significant synergistic blood pressure lowering effect compared to the reduction caused by enalapril and only an additive effect was observed. Nor is there any mention of the prolonged effect of the mixture of losartan and enalapril in said patent application. Therefore, it is not a priori predicted that the combination of a potent ACE-inhibitor and a N -antagonist will have a synergistic effect in lowering blood pressure in humans. It is not possible to talk about group effect. Rather, patent application WO 94/28924 shows that the combined administration of the two active ingredients causes an increase in renal blood flow. Azizi et al. (Circulation 1995; 92, 825-834) also invented additive effects on blood pressure in a combination of ACE-inhibition and AT-antagonist (combination of captopril and losartan). They also observed that the mean decrease in blood pressure did not prolong with the combination of captopril and losartan.

It has surprising is the experimental finding that the combined administration of the ACE inhibitor benazepril or a pharmaceutically acceptable salt thereof, and at _X-antagonist valsartan or a pharmaceutically acceptable salt thereof has a synergistic antihypertensive effect and the same time there is even a surprising prolongation of the effect.

The advantage of these unexpected effects is that often dosages can be not only lower but also less frequent, which is beneficial for patients.

In addition, the incidence of side effects may be reduced in some patients.

Combined blocking the enzyme ACE and _ΑΤ χ-receptor positive way, also significantly reduces the increased circulation of vasoconstrictor angiotensin II.

A synergistic effect occurs when two active ingredients administered together, for example, in one combined dosage form or sequentially, or independently in two separate dosage forms, together produce an effect greater than the algebraic sum of the individual effects of these ingredients, i. j. when the resulting effect is greater than the additive.

The synergistic effect can be determined experimentally, for example, by the telemetry method described below.

Spontaneous hypertensive rats (SHR), 22-25 weeks of age, obtained from Taconic Farms, Germantown, New York (Tac: N (SHR) fBR), are used for these experiments. All test animals are implanted with a radiotelemetry device in the lower abdominal aorta at least one month prior to the tests and a radio transmitter is attached to the inner abdominal muscle. Cardiovascular parameters are continuously transmitted, allowing data to be collected without disturbing the animals in the cages. Rats are housed in cages at constant temperature and atmospheric humidity for twelve hour light and dark cycles. Their weight is measured once a week. Usually groups of five animals are used. One group receives only valsartan, the other only benazepril. Another group receives a mixture of valsartan and benazepril, a fourth group a mixture of valsartan and benazepril at other doses, and finally the last group, which is a control, is administered only vehicle (0.15 N NaOH). Drugs are administered continuously subcutaneously for 14 days using a minipump. In these experiments, a computerized data detection system (Data Sciences Inter., Inc.) is used to measure mean arterial blood pressure and pulse. Mean arterial blood pressure and pulse are measured every 10 minutes for 10 seconds and recorded. Values for each rat are delivered as mean values over 24 hours and contain 144 data per day. Baseline blood pressure lines are determined as the average over three consecutive days prior to minipump implantation. Values during application of the active substances are 24-hour mean values. On the fourteenth day, the minipump is removed and the observation is continued for 7 days after the end of the active compound application.

These studies show that uncontrolled administration of benazepril and valsartan at 1.5 mg / kg / day results in a decrease in blood pressure of about 20 mm Hg. In contrast, the combined administration of benazepril at doses of 1.5 mg / kg / day and valsartan at doses of 1.5 mg / kg / day may reduce blood pressure by about 50 mm Hg. In addition, the steady effect is prolonged up to 16 hours and the weaker but still significant effect persists for at least 21 hours.

The results of further experiments performed in spontaneously hypertensive rats by radiotelemetric measurement of the effect on mean arterial blood pressure are shown in the following table.

Table 1

substance dose fmg / mm / day] AUC fmmHg] PULL benazeDril 0.5 (N = 6) - 64 6 0.75 (N = 6) -136 11 1.0 (N = 6) -244 30 1.5 N = 5 -213 28 3.0 (N = 6) -341 20 10.0 (N = 6) -581 18 valsartan 0.5 (N = 6) - 62 16 0.75 (N = 6) -107 6 1.0 (N = 6) -115 19 1.5 (N = 5) -195 8 3.0 (N = 6) -226 21 10.0 (N = 6) -425 38 benazepril / valsartan 0.5 (N = 5) -221 21 0.75 (N = 5) -329 ' 20 1.0 (N = 4) -470 31 1.5 N = 5 -609 23 0.15N (N = 6) 1 11 NaOH (N = 7) 10 9 vehicle (N = six) -23 16 (N = 7) 4 13 (N = 4) -11 14 1N NaHCO ₃ (N = 7) -61 15

(AUC = area under the curve (mm Hg). Since all values are measured over 14 days, days (time) are multiplied) (SEM = standard deviation of the mean)

The results clearly show that the AUC, for example at doses of 1 mg / kg / day of the combination of benazepril and valsartan, is dramatically higher than the additive values for 0.5 mg / kg / day of benazepril and 0.5 mg / kg / day of valsartan. The same conclusion can be drawn from other values.

In experiments in rats with renal rest, the combination of valsartan and benazepril has been shown to have a higher renal protective effect than when administered with individual agents. In these experiments, the rat's right kidney is removed and ligated 2-3 branches of the lava in the renal artery to ensure that only 1/6 of the kidney mass works. This results in significant proteinuria, loss of tubular electrolyte reuptake capacity and a dramatic increase in systolic blood pressure. The drug (or drugs) is administered subcutaneously (osmotic minipump) a week after surgery. At this time, the animals are in a state of progressive chronic renal failure. Drug administration lasts 6 weeks. The combination of valsartan + benazepril (Val + Bz) is administered at doses of 1.0 mg / kg / day and 3.0 mg / kg / day for each drug. Benazepril or valsartan alone is ineffective at these doses or only slightly improves renal function compared to vehicle control animals. The Val + Bz mixture almost normalizes systolic blood pressure to preoperative values, decreases proteinuria and greatly improves tubular function (as evidenced by changes in fractional sodium excretion).

The synergistic effect of the combination of valsartan and benazepril on congestive heart failure can also be demonstrated. A model in which local heart failure is induced by ventricular pacing may be used. Sustained rapid heart pacing in pigs is a recognized model for congestive heart failure. A dose of benazeprilat (0.15 mg / kg / day) or valsartan (2.4 mg / kg / day) is selected which blocks 50% Ang I and Ang II pressure responses without altering resting blood pressure. When a combination of drugs (benazeprilat / valsartan 0.04 / 2 mg / kg / day) is administered, the benazeprilat dose should be reduced over the monotherapy dose to avoid a significant reduction in resting blood pressure. For comparison, pigs of the same age are subjected to continuous pacing without treatment as a control. After 21 days of concomitant drug administration and stimulated tachycardia, left ventricular function (LV), neurohormonal profiles, contractile functions of isolated myocytes, β-adrenergic response, and electrophysiology are studied. Continuous rapid pacing and concomitant ACE-inhibition reduce LV and diastolic volume, significantly improve LV pumping function, and reduce circulating catecholamine levels. Blockade of Ang II receptors with valsartan improves cardiac performance and reduces pulmonary and systemic vascular resistance. In contrast, the combined administration of benazeprilat and valsartan has a significant beneficial effect on the geometry, function and neurohormonal activation of LV, including endothelin plasma levels. In addition, LV wall congestion and pulmonary and vascular resistance, important indicators of myocardial oxygen consumption and LV afterload, are reduced more than the ACE inhibition by said combination of drugs. There is also an increased β-adrenergic and calcium response of myocytes compared to benazeprilat monotherapy.

The results obtained show an unexpected beneficial effect of the combination on blood pressure, renal blood flow and congestive heart failure. The existence of alternative pathways leading to the production of Ang II in tissues may limit the effectiveness of treatment with ACE inhibitors. On the other hand, inhibition of ACE by its effect on bradykinin degradation improves endothelium-dependent muscle reactivity. Therefore, the combination of ACE inhibition and Ang II antagonism results in a more complete blockade of RAS and the anti-regulatory mechanism mediated by Ang II itself. As a result, dose reductions and thus side effects can be expected. This may be important in situations where renal function is extremely dependent on renin.

The present invention is a combination pharmaceutical composition for the treatment of hypertension, congestive heart failure and renal failure, comprising (1) the ACE-inhibitor bena10 ZEPRIS or benazeprilat or a pharmaceutically acceptable salt thereof, and (2) _x AT-antagonist valsartan or a pharmaceutically acceptable salt thereof . In this formulation, components (1) and (2) may be present and administered together, one after the other or separately in a single unit dose or in two separate unit doses.

The pharmaceutical preparations of the invention may be administered enterally, for example orally, as well as rectally or parenterally to warm-blooded animals, the active ingredient being contained therein in pure form or in admixture with conventional pharmaceutical vehicles. These pharmaceutical preparations contain the active ingredient in an amount of, for example, from about 0.1% to 100%, especially from about 1% to about 80%. Pharmaceutical preparations for enteral, parenteral, or also ophthalmic administration are typically administered in unit dosage form, such as in dragees, tablets, capsules or suppositories, but also in ampoules. These dosage forms are prepared by known methods, for example by conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. Pharmaceutical preparations for oral use can be obtained by mixing the active ingredient with solid carriers and, if necessary, granulating the mixture. If desired or necessary, the mixture or granulate is mixed with suitable vehicles and processed into tablets or dragee fillings.

Suitable carriers are fillers, typically sugars such as lactose, sucrose, mannitol or sorbitol, cellulose blends and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, typically corn starch, wheat starch, rice starch or potato starch. gelatin, tragacanth gum, methylcellulose and / or polyvinylpyrrolidone, if desired, disintegrants such as the aforementioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof, typically sodium alginate. In particular, liquefiers and lubricants, typically silica gel, talc, stearic acid or salts thereof, typically magnesium stearate or calcium stearate, and / or polyethylene glycol are used as vehicles. The dragee filling is coated with suitable materials which, if desired, are resistant to gastric juices. Among others, concentrated sugar solutions are used, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, solutions in suitable organic solvents or solvent mixtures. Solutions of suitable cellulose derivatives, typically acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used to prepare gastric juice-resistant coatings. Dyestuffs or pigments may be added to the tablets or coatings, for example, to identify or indicate different doses of the active ingredient.

Another type of pharmaceutical preparation for oral administration is a gelatin capsule filled with a dry substance or a closed soft capsule prepared from gelatin and a plasticizer such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in granular form, typically with an admixture of fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid such as fatty oils, paraffin oil or liquid polyethylene glycols, optionally with the addition of stabilizers.

Suitable pharmaceutical compositions for rectal administration are typically suppositories containing a mixture of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons and higher alkanols. Gelatin rectal capsules containing a mixture of the active ingredient and the base may also be used. Suitable bases are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Suitable formulations for parenteral administration are, in particular, aqueous solutions of the active ingredient in its water-soluble form, typically in the form of a water-soluble salt, and also suspensions of the active ingredient, such as appropriate oily injection suspensions in suitable solvents or vehicles, typically in fatty oils, e.g. or in synthetic fatty acid esters, typically in ethyl oleate or triglycerides, or an injectable aqueous suspension containing thickeners, for example sodium carboxymethylcellulose, sorbitol and / or dextran. Stabilizers may also be added to the suspensions as necessary.

Oral dosage forms, preferably in tablets or capsules, are preferred.

The dose of the active ingredient may depend on various factors, for example, the mode of administration, the species of warm-blooded animal, its age and / or individual condition. A normal dose for oral administration to a patient weighing about 75 kg is estimated to be about 5 mg to about 40 mg of active ingredient (1) (benazepril or a pharmaceutically acceptable salt thereof) and about 20 mg to about 160 mg of active ingredient (2) (valsartan or its pharmaceutically acceptable salts), preferably once or twice daily.

The weight ratio of active ingredient (1) to active ingredient (2) may be, for example, about 1 to 8, but also 1 to 4 or 1 to 2.

The novel combination medicament compositions of the invention may, preferably, contain about 10 mg to about 40 mg of the active ingredient (1), in particular 10 mg to about 20 mg, and most preferably 10 mg.

The novel combination medicament compositions of the invention may contain preferably about 20 mg to about 80 mg of the active ingredient (2), especially about 40 mg to about 80 mg, and most preferably about 40 mg or 80 mg.

In a preferred embodiment of the invention, pharmaceutically acceptable combination medicaments comprising benazepril monohydrochloride and valsartan are used in unit doses. The preferred amount of the ACE inhibitor is 10 mg and preferred amounts _x AT-antagonist is 40 mg or 80 mg.

In the pharmaceutical compositions of the invention, the active ingredients (1) and (2) may be available together, one after the other or separately in a single combined single dose or in two separate single doses. Co-administration in the form of a single combined single dose is preferred.

The novel pharmaceutical combination of the invention can be used to treat hypertension and congestive heart failure.

A method of treating hypertension, congestive heart failure, and kidney failure is characterized by administering to the patient a corresponding combination pharmaceutical composition of the invention, comprising (1) an ACE-inhibitor benazepril or benazeprilat or a pharmaceutically acceptable salt thereof, and (2) the N 2 -antagonist valsartan. or a pharmaceutically acceptable salt thereof.

The present invention also relates to the preparation of novel combination pharmaceutical preparations.

Claims (3)

PATENT CLAIMS A combination pharmaceutical composition for the treatment of hypertension, congestive heart failure and kidney failure, comprising or benazeprilat of the formula or a pharmaceutically acceptable salt thereof, and (2) the valsartan N 2 -antagonist of formula ^C 2 or ^CH 2 or a pharmaceutically acceptable salt thereof salt. Composition according to claim 1, characterized in that the active ingredient (1) is benazepril monohydrochloride and the active ingredient (2) is valsartan. Composition according to claim 1 or 2, characterized in that it contains about 5 mg to about 40 mg of the active ingredient (1). s a (1). 4. The composition according to by containing approx Claim 3 10 mg to approx characterized by 40 mg of active ingredient 5. The composition according to Claim 3 characterized ú c a s a by containing approx 10 mg to approx 20 mg active ingredients d). 6. The composition according to Claim 3 characterized ú c a s a by containing approx 10 mg of active ingredient (1). 7. The composition according to anybody of claims 1 to 6, v y tagging containing about 20 mg to ca. 160 mg of active ingredient (2). 8. The composition according to Claim 7 characterized ú c a comprising about 20 mg to about 80 mg of the active ingredient (2). The composition of claim 7, comprising about 40 mg or about 80 mg of the active ingredient (2). The composition of any one of claims 1 to 9, comprising about 10 mg of active ingredient (2) and about 40 mg or about 80 mg of active ingredient (1). Composition according to claim 1, characterized in that the components (1) and (2) are present together, one after the other or separately in one combined or in two separate individual doses. 12. A method of treating hypertension, congestive heart failure and renal failure, characterized in that the patient in need of such treatment a combination or benazeprilat of formula or a pharmaceutically acceptable salt thereof, and (2) _the AT-antagonist valsartan of formula Method according to claim 12, characterized in that the components (1) and (2) are administered together, one after the other or separately in one combined or in two separate individual doses.