KR19980703647A - Compositions Containing Benazepril or Benazefrillat and Valsartan - Google Patents

Abstract

The present invention relates to (a) benasepril of formula (I) or benazeprillat of formula (II) or a pharmaceutically acceptable salt thereof, and (2) valsartan of formula (III) which is an AT ₁ -antagonist or A pharmaceutical composition for treating hypertension, congestive heart failure and renal failure, containing a pharmaceutically acceptable salt thereof, as well as a method for treating hypertension, congestive heart failure and renal failure.

Formula I

Formula II

Formula III

Description

Benazepril or Benaziprilat and composition containing Valsartan

Different studies have been undertaken to regulate the different points of the Lenin-Angiotensin cascade and to develop the possibility of affecting the regulation of blood pressure in different ways.

Angiotensinogen, an α2-macrosaccharide protein, is degraded into 10 peptides of angiotensin I by the renin enzyme, which itself has very weak biological activity. In the next step of the cascade, angiotensin II is formed by removing two additional amino acids, mainly by the action of angiotensin-converting enzyme (ACE) bound to the endothelium. The latter is considered one of the strongest natural vasoconstrictors.

Inhibition of enzymatic degradation from angiotensin I to angiotensin II using so-called ACE-inhibitors is a successful variable of blood pressure control and thus also becomes an available treatment method for congestive heart failure.

One known representative of conventional ACE-inhibitors is the active ingredient 3-[(1- (ethoxycarbonyl) -3-phenyl- (1S) -propyl) amino] -2,3,4,5 of formula (I) -Tetrahydro-2-oxo-1H-1- (3S) -benzeazin-1-acetic acid [benazepril; European Patent No. 72352] or the active ingredient (3S) -3-[[(1S)-(1-carboxy-3-phenylpropyl] amino] -2,3,4,5-tetrahydro of formula II -2-oxo-1H-1-benzasepin-1-acetic acid [benazeprilat; see European Patent No. 72352] and their pharmaceutically acceptable salts. Monohydrochloride (benazepril hydrochloride) is particularly preferred. It is worth mentioning.

The vasoconstrictive action of angiotensin II is due to an increase in the activity of the sympathetic nervous system due to the formation of norepinephrine, as well as stimulation of the action on non-smooth muscle fibers, the formation of adrenergic hormones epinephrine and norepinephrine. Angiotensin II also affects electrolyte balance and, for example, exhibits antisodiumuria and antidiuretic effects on the kidney, thereby promoting release of vasopressin from the pituitary gland and, on the other hand, of aldosterone from the adrenal globules. Promote release. All these effects play an important role in the regulation of blood pressure.

Angiotensin II interacts with specific receptors on the surface of target cells. For example, it has been possible to identify receptor subtypes referred to as AT ₁ -and AT ₂ -receptors. Recently, much effort has been made to identify substances that bind to AT ₁ -receptors. Such active ingredients are often referred to as angiotensin II antagonists. By inhibition of the AT ₁ -receptor, such antagonists can be used, for example, as antihypertensive agents or for the treatment of congestive heart failure.

Thus, angiotensin II antagonists are understood as active ingredients that bind to the AT ₁ -receptor subtype. These include compounds with different structural properties.

Representatives selected as the AT ₁ -antagonist are the active ingredient (S) -N- (1-carboxy-2-methyl-prop-1-yl) -N-pentanoyl-N- [2 '(1H) -Tetrazol-5-yl) biphenyl-4-yl-methyl] amine [valsartan; European Patent No. 443983 and its pharmaceutically acceptable salts.

Pharmaceutically acceptable salts of benazepril and valsartan are typically acid addition salts. These acid addition salts can be substituted, for example, with inorganic strong acids, such as mineral acids, typically sulfuric acid, phosphoric acid or hydrofluoric acid, or with organic strong acids, for example, typically with halogens such as acetic acid. C ₁ -C ₄ alkancarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, such as unsaturated dicarboxylic acids, for example, ascorbic acid, Using hydroxycarboxylic acids such as glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, amino acids such as for example aspartic acid or glutamic acid, or for example using benzoic acid, or using, for example, for example, using a C ₁ -C ₄ alkanoic acid or arylsulfonic acid which may be substituted by halogen, for example, methoxy - or it is formed of a p- toluenesulfonic acid. Suitable salts with bases are typically metal salts such as, for example, alkali metal salts such as sodium, potassium or magnesium salts or alkaline earth metal salts, or ammonia or for example morpholine, thiomorpholine, piperidine , Pyrrolidine, or mono-, di- or tri-lower alkylamines typically such as ethylamine, tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine or dimethylpropylamine Or a salt with an organic amine, typically mono-, di- or trihydroxy-lower alkylamine, such as mono-, di- or triethanolamine. Corresponding internal salts may also be used.

For example, many analyzes have also been attempted to develop combinations of different active ingredients for treating hypertension and congestive heart failure. The advantage of such a combination is that, for example, in such combinations, the dosage of the individual components is used significantly less than the effective dosage for a single component. For example, using antihypertensive agents with different mechanisms of action in such combinations, an additive effect is generally expected. However, it is an object of the present invention to provide such formulations which on the one hand have a synergistic effect and on the other hand have an extended duration of action.

PCT application WO 94/28924 discloses a combination of an ACE-inhibitor and angiotensin-II antagonist. Clinical trials of a combination of enalapril (ACE-inhibitor) and losartan (AT ₁ -antagonist) at the indicated dosages indicated that the significant synergistic effect of blood pressure lowering compared to the lowering of blood pressure achieved with enalapril It did not happen, only the additive effect was confirmed. Moreover, the patent application did not dictate any prolongation of the duration of action after treatment with a combination of losartan and enalapril. Thus, such a combination of potent ACE-inhibitors and AT ₁ -antagonists cannot be presumed to synergistically lower blood pressure in humans. Thus, no species effect can be mentioned. In contrast, the disclosure of WO 94/28924 shows that a mixed administration of the two indicated active ingredients rather increases the neovascularization. Similarly, Azizi et al. [Circulation, 1995; 92: 825-834, found an additive effect of combined ACE inhibition and AT ₁ antagonism (a combination of captopril and losartan) on blood pressure, and the duration of mean blood pressure drop was determined in the combination of captopril and losartan. Was not extended by

More surprisingly, the combination of the ACE-inhibitor Benazepril or its pharmaceutically acceptable salts with the AT ₁ -antagonist valsartan or its pharmaceutically acceptable salts not only shows synergistic antihypertensive action, but the efficacy is surprising. Lasting to a degree is the experimental finding observed.

The advantage of these unexpected effects is that the required dosage is often smaller and less frequent. This is consistent with what the patient to be treated wants and needs.

Thus, in addition, the occurrence of any side effects can be minimized in some patients.

Mixed blocking of angiotensin-converting enzymes and AT ₁ -receptors also greatly reduces the increased circulation of vasoconstrictive angiotensin II in a good manner.

When the two active ingredients are administered together, for example together in one complex unit dosage form, or separately, or in two separate unit dosage forms, the combined effect of the combinations is the logarithm of the two individual effects. It will be understood that a synergistic effect has occurred when greater than the sum, ie when an effect beyond the additive effect is achieved.

Synergistic effects can be experimentally demonstrated, for example, by telemetry as follows:

For this experiment, 22-25 week old spontaneous hypertension rats (SHR) were used. Such rats were purchased from Taconic Farms, Germantown, New York (Tac: N (SHR) fBR). At least one month before the experiment, a radiotelemetry device was implanted into the lower abdominal aorta of all test animals. The radio transmitter was fixed to the intraabdominal muscle with silk sutures. Cardiovascular parameters were continuously transmitted via a radio transmitter to collect data while keeping the animals in cages. Animals were kept in cages at controlled temperature and atmospheric humidity and with day and night alternation alternately for 12 hours. Body weights were measured at weekly intervals. Usually five groups of rats were formed. One group of animals received valsartan alone; In the other group, benazepril is administered alone; In the other group, a combination of valsartan and benazepril; Group 4 is administered a combination of valsartan and benazepril in different dosages; In the last group, vehicle (0.15N NaOH) alone was used as a control. Minipumps were used for continuous subcutaneous drug delivery over 14 day intervals. In these experiments, average arterial blood pressure and heart rate were examined by a computerized data sensing system (Data Sciences Inter., Inc.). Mean arterial blood pressure and heart rate were recorded and measured every 10 minutes for 10 seconds. The values for each rat were recorded as averaged over 24 hours and included 144 data points daily. Baseline for blood pressure was determined as the average of three consecutive days prior to implantation of the minipump. The value during administration of the active ingredient is an average value of 24 hours. On day 14, the minipump was removed and the effect was observed for 7 days after stopping the administration of the active ingredient.

These studies showed that 1.5 mg / kg / day unblended administration of benazepril and valsartan lowered blood pressure by about 20 mm Hg. In contrast, a mixed dose of Benazepril 1.5 mg / kg / day and Valsartan 1.5 mg / kg / day effectively lowered the blood pressure to about 50 mmHg. In addition, although the constant duration of efficacy is extended to 16 hours or less and reduced to at least 21 hours or less, significant duration of action is still achieved.

Additional experiments conducted with spontaneous hypertension rats using radiotelemetry to evaluate the sustained effect on mean arterial blood pressure showed the following results.

compound Dose [mg / kg / day] AUC [mmHg] SEM Benazefril 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 Benazefril / 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 Vehicle (N = 6) (N = 7) (N = 6) (N = 7) (N = 4) 110-234-11 119161314 1N NaHCO ₃ (N = 7) -61 15 AUC = area under curve (mmHg), all values were recorded over 14 days, so days (hours) were factored. SEM = standard error of the mean.

These results clearly show that the AUC value for the combination of benazepril and valsartan, for example 1 mg / kg / day, is much greater than the combined value of 0.5 mg / kg / day of both benazepril and valsartan. . Correspondingly, the same result can be obtained from other values.

In the rat's remnant kidney model, a combination of valsartan and benazepril has been demonstrated to be more kidney protective than each individual treatment. In these models, the right kidney was excised and two to three capillaries of the left renal artery were ligated, effectively making the functional kidney mass 1/6. There is a pronounced proteinuria, loss of vascular electrolyte resorption capacity and a dramatic rise in systolic blood pressure. The drug (s) were administered subcutaneously (via an osmotic minipump) for one week after surgery in which the animal had advanced chronic renal failure. Animals were treated for 6 weeks. A combination of valsartan + benazepril (Val + Bz) was administered at doses of 1.0 mg / kg / day and 3.0 mg / kg / day of each agent. Benazepril or Valsartan slightly improves or is ineffective at renal function as compared to vehicle treated animals at these doses individually. Val + Bz almost normalized systolic blood pressure to pre-ablation levels, reduced proteinuria, and greatly enhanced vascular function (as indicated by the change in fractional excretion of sodium).

Similarly, in animal models of congestive heart failure, which may be induced by, for example, atrial pacing, the synergistic effect of the combination of valsartan and benazepril on congestive heart failure can be assessed. Sustained rapid cardiac paced pigs are a well-recognized model of congestive heart failure. Dosezeprilat (0.15 mg / kg / day) or valsartan (2.4 mg / kg / day) was selected to block Ang I and Ang II blood pressure responses by 50% without altering resting blood pressure. For the combination treatment (benazepril / valsartan 0.04 / 2.4 mg / kg / day), the dose of benazeprillat from monotherapy should be reduced to prevent a significant decrease in resting blood pressure. For comparison, pigs of the same age as well as mock controls were sustained faced without treatment. After 21 days of treatment and pacing palpitation, a final study was performed to perform the function and geometry of the left ventricle (LV) and to examine neurohormonal profiles, isolated myocyte contractile function, β adrenergic response and electrophysiology. Continuous rapid pacing and simultaneous ACE inhibition reduced LV and dilator size, significantly improved LV pump function, and reduced levels of circulating catecholamines. Blocking Ang II receptors with valsartan improves cardiac output and decreases lung and systemic vascular resistance. In contrast, the mixing of benazeprillat and valsartan further benefits the neurohormonal activation, including LV geometry and function, and endothelin plasma concentrations. Moreover, such mixing reduces the critical index of LV wall stress and lung and vascular resistance, myocardial oxygen consumption, and LV postload to a greater extent than when using only the inhibition of ACE. It also enhances myocyte β β adrenergic neurons and calcium response compared to the treatment with benazeprillat alone.

The results available indicate the unexpected beneficial effects of such combinations on blood pressure, renal blood flow and congestive heart failure. The presence of alternative production pathways of Ang II in tissues may limit the effectiveness of ACE inhibitor treatment. In contrast, ACE inhibition through effects on bradykinin degradation improved endothelial dependent vascular activity. Thus, the mixing of ACE inhibition and Ang II antagonism makes the blockade of RAS and the blocking of the backregulatory mechanism mediated by Ang II itself. Thus, a reduction in dosage and thereby a reduction in the likelihood of side effects is also expected. This may be important when renal function is extreme renin dependence.

It is an object of the present invention to provide hypertension, comprising (1) an ACE-inhibitor benazepril or benaziprilat or a pharmaceutically acceptable salt thereof and (2) an AT ₁ -antagonist valsartan or a pharmaceutically acceptable salt thereof It is to provide a pharmaceutical composition for treating congestive heart failure and renal failure. In this composition, components (1) and (2) can be present and administered together, continuously, or separately in one complex unit dosage form or in two separate unit dosage forms.

The pharmaceutical composition is for internal use, such as oral, and also for rectal or parenteral administration to warm-blooded animals, wherein the pharmacologically active ingredient is present alone or in combination with conventional pharmaceutical excipients. The pharmaceutical composition contains, for example, about 0.1% to 100%, and preferably about 1% to about 80% of the active ingredient. Pharmaceutical compositions for internal or parenteral administration and also for eye drop administration are typically in unit dosage forms such as dragees, tablets, capsules or suppositories and also ampoules. They are prepared by known methods, for example by conventional mixing, granulating, sugar-coating, dissolving or lyophilizing methods. Thus, pharmaceutical compositions for oral administration are obtained by mixing the active ingredient with a solid carrier, granulating the mixture obtained if desired, adding suitable excipients if desired or processing and processing the mixture or granules to provide tablets or dragee nuclei. Can be.

Suitable carriers are preferably fillers, for example, sugars such as lactose, saccharose, mannitol or sorbitol, cellulose compositions and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and further Furnace binders, for example, starch pastes typically using for example corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth gum, methylcellulose and / or polyvinylpyrrolidone, and desired Disintegrating agents, for example starch mentioned above, further carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or salts thereof, typically sodium alginate. Excipients are mainly flow regulators and lubricants, for example silica gel, talc, stearic acid or salts thereof, typically magnesium stearate or calcium stearate, and / or polyethylene glycol. Preparation of dragee nuclei, in particular, concentrated sugar solutions containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures, or gastric juice resistant coatings To this end, a solution of a suitable cellulose composition, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, is typically used to provide a suitable coating that is resistant to gastric juice, if desired. For example, colorants or pigments may be added to the tablets or dragee coatings to indicate or indicate different doses of the active ingredient.

Other pharmaceutical compositions for oral administration are not only dry-filled gelatin capsules, but also soft closed capsules consisting of gelatin and a plasticizer such as, for example, glycerol or sorbitol. Dry-filled capsules may typically comprise the active ingredient in granular form in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate. In soft capsules, the active ingredient may preferably be dissolved or suspended in a suitable liquid such as, for example, fatty oils, paraffin oils or liquid polyethylene glycols, and also stabilizers may be added.

Pharmaceutical compositions suitable for rectal administration are typically suppositories consisting of a combination of the active ingredient and suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons or higher alkanols. Moreover, gelatin rectal capsules containing a mixture of the active ingredient and the base substance can also be used. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Compositions suitable for parenteral administration are mainly aqueous solutions of the active ingredient in water-soluble form, typically in the form of water-soluble salts, and also suitable lipophilic solvents or vehicles, typically fatty oils such as, for example, sesame oil, or typically Suitable oily infusion suspensions using synthetic fatty acid esters such as ethyl oleate, or triglycerides, or aqueous infusion suspensions containing thickeners and optionally stabilizers, for example, sodium carboxymethylcellulose, sorbitol and / or dextran; It is a suspension of the same active ingredient.

It is typically preferred to use unit dosage forms that can be used for oral administration, such as tablets or capsules.

The dosage of the active ingredient may vary depending on various factors, such as the route of administration, warm-blooded animal species, age and / or individual condition. When orally administered to a patient weighing about 75 kg, the estimated general dosage is preferably from about 5 mg to about 40 mg of the active ingredient (1) [benazepril or a pharmaceutical thereof, preferably once or twice a day. Acceptable salt] and from about 20 mg to about 160 mg of the active ingredient (2) [valsartan or a pharmaceutically acceptable salt thereof].

The weight ratio of the active agent component (1) to the active agent component (2) can be, for example, about 1: 8, and also 1: 4 or 1: 2.

The novel formulation composition may preferably contain about 10 mg to about 40 mg, more preferably 10 mg to about 20 mg, most preferably 10 mg of the active ingredient component (1).

The novel formulation composition may preferably contain about 20 mg to about 80 mg, more preferably about 40 mg to about 80 mg, most preferably about 40 mg or 80 mg of the active ingredient component (2).

In a preferred embodiment of the invention, a pharmaceutically acceptable combination composition is used which contains benzapril monohydrochloride and valsartan in unit dosage forms. The amount of its ACE-inhibitor is preferably 10 mg and the amount of AT ₁ -antagonist is preferably 40 mg or 80 mg.

In the compositions of the invention, the active ingredients (1) and (2) can be obtained together, continuously or separately in one complex unit dosage form or in two separate unit dosage forms. They are preferably obtained together in one complex unit dosage form.

The novel pharmaceutical compositions can be used in methods of treating hypertension and congestive heart failure.

Methods of treating hypertension, congestive heart failure and renal failure include (1) ACE-inhibitor Benazepril or Benaziprilat or their pharmaceutically acceptable salts, and (2) AT ₁ -antagonist Valsartan or a pharmaceutically acceptable salt thereof. Administration of a corresponding pharmaceutical composition according to the invention containing a salt to a patient in need of treatment of hypertension, congestive heart failure and renal failure.

The present invention also relates to the formulation of the novel pharmaceutical composition.

Claims (13)

(1) Benazepril of Formula (I) or Benaziprilat of Formula (II) or a pharmaceutically acceptable salt thereof, which is an ACE-inhibitor, and (2) A pharmaceutical composition for treating hypertension, congestive heart failure and renal failure, containing an valsartan of formula III or an pharmaceutically acceptable salt thereof, which is an AT ₁ -antagonist. Formula I Formula II Formula III A composition according to claim 1, wherein the active ingredient component (1) is benazepril monohydrochloride and the active ingredient component (2) is valsartan. The composition according to claim 1 or 2, containing from about 5 mg to about 40 mg of the active ingredient component (1). 4. The composition of claim 3 containing from about 10 mg to about 40 mg of the active ingredient component (1). 4. A composition according to claim 3, containing about 10 mg or about 20 mg of active ingredient component (1). 4. A composition according to claim 3, containing about 10 mg of active ingredient component (1). 7. Composition according to any one of claims 1 to 6, containing from about 20 mg to about 160 mg of the active ingredient component (2). 8. A composition according to claim 7, which contains about 20 mg to about 80 mg of the active ingredient component (2). 8. A composition according to claim 7, which contains about 40 mg or about 80 mg of the active ingredient component (2). 10. A composition according to any one of the preceding claims, containing about 10 mg of the active ingredient component (2) and about 40 mg or about 80 mg of the active ingredient component (1). The composition of claim 1, wherein components (1) and (2) are present together, continuously or separately in one complex unit dosage form or two separate unit dosage forms. (1) Benazepril of Formula (I) or Benaziprilat of Formula (II) or a pharmaceutically acceptable salt thereof, which is an ACE-inhibitor, and (2) hypertension, congestive heart failure and renal failure, comprising administering a combination of valsartan of formula III, or a pharmaceutically acceptable salt thereof, as an AT ₁ -antagonist to a patient in need of treatment of hypertension, congestive heart failure and renal failure Method of treatment. Formula I Formula II Formula III 13. A method according to claim 12, wherein the components (1) and (2) are administered together, continuously or separately in one complex unit dosage form or in two separate unit dosage forms.