SK14612002A3 - Novel medical use of aldosterone synthase inhibitors alone or in combination with AT1-receptor antagonists - Google Patents

Abstract

The invention relates to a pharmaceutical composition, of (i) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof either alone or in combination with (ii) an AT1-receptor antagonist combined with a diuretic, or in each case, a pharmaceutically acceptable salt thereof and (iii) a pharmaceutically acceptable carrier.

Description

Technical field

The present invention relates to pharmaceutical compositions comprising an aldosterone synthase inhibitor alone or in combination with an AT 1 -receptor antagonist or an AT 1 -receptor antagonist combined with a diuretic.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising (i) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, alone or in combination with (ii) an α 1 -receptor antagonist or an AT 1 -receptor antagonist combined with a diuretic or, in any case, a pharmaceutically acceptable thereof a salt, and (iii) a pharmaceutically acceptable carrier.

The present invention further relates to a method of preventing, delaying the progression or treating a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, particularly chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery ;

(b) atherosclerosis, insulin resistance and syndrome X, type 2 diabetes mellitus, obesity, nephropathy, renal failure, e.g. chronic kidney failure, hypothyroidism, survival after myocardial infarction (MI), coronary heart disease, old age hypertension, congenital dyslipidemic hypertension, increased collagen production, fibrosis and remodeling after hypertension (antiproliferative effect of the combination) or all of these diseases and conditions without hypertension; and (c) endothelial dysfunction with or without hypertension, comprising administering the pharmaceutical composition of the present invention.

According to a preferred embodiment, the present invention relates to a method of preventing, delaying the progression or treating endothelial dysfunction with or without hypertension, comprising administering an effective amount of an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof to a warm-blooded animal, including a human in need thereof.

By AT1 receptor antagonists (also referred to as angiotensin II receptor antagonists) are meant those active compounds that bind to the angiotensin II receptor subtype but do not result in receptor activation. Due to the inhibition of the α-receptor, these antagonists can be used, for example, as antihypertensives or for the treatment of congestive heart failure.

The class of AT 1 -receptor antagonists includes compounds of different structural properties, particularly preferred are non-peptide antagonists. For example, compounds selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan, the compound designated E-1477 of the following formula

the compound designated SC-52458 of the following formula

and the compound designated ZD-8731 of the following formula

N NH \ /

N = N and, in each case, a pharmaceutically acceptable salt thereof.

Preferred alpha-receptor antagonists are those marketed, most preferably valsartan or a pharmaceutically acceptable salt thereof.

For example, the diuretic is a thiazide derivative selected from the group consisting of chlortiazide, hydrochlorothiazide, methylclothiazide, and chlortalidone. Most preferred is hydrochlorothiazide.

An aldosterone synthase inhibitor is an enzyme that converts corticosterone to aldosterone by hydroxylation of corticosterone to give 18-OH-corticosterone and 18-OH-corticosterone to aldosterone. The class of aldosterone synthase inhibitors known to be useful in the treatment of hypertension and primary aldosteronism includes both steroidal and non-steroidal aldosterone synthase inhibitors, the latter being most preferred.

Preferred are commercially available aldosterone synthase inhibitors or aldosterone synthase inhibitors that are approved by the health authorities.

The class of aldosterone synthase inhibitors includes compounds with different structural properties. For example, compounds selected from the group consisting of non-steroidal aromatase inhibitors anastrozole, fadrozole (including their (+) - enantiomer), as well as steroidal aromatase inhibitors exemestane or, in any case where applicable, pharmaceutically acceptable salts thereof.

The most preferred non-steroidal aromatase inhibitor is the (+) - enantiomer of fadrozole hydrochloride (US Patents 4617307 and

HCl

Surprisingly, the pharmaceutical compositions of the present invention exhibit favorable, particularly synergistic (i.e., higher than additive), therapeutic effect, as well as beneficial effects resulting from combination therapy, such as surprising prolongation of effect, broader spectrum of therapeutic treatment and surprising beneficial effects on diseases and conditions. associated with AT 1 -receptors or aldosterone synthase inhibitors.

The compositions of the present invention may be used to prevent, delay progression or to treat a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after surgery by coronary arterial bypass;

(b) atherosclerosis, insulin resistance and syndrome X, type 2 diabetes mellitus, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival after myocardial infarction (MI), coronary heart disease, old age hypertension, congenital dyslipidemic hypercension, increased collagen production, fibrosis and remodeling after hypertension (antiproliferative effect of the condition or combination), all of these without hypertension; and (c) endothelial dysfunction with or without hypertension.

One of ordinary skill in the art is fully able to select a relevant test animal model to demonstrate the therapeutic and therapeutic effects and benefits listed below.

These beneficial effects can be demonstrated, for example, in the test model described in G. Jeremic et al., J. Cardiovasc. Pharmacol. 27: p. 347-354, 1996.

Study plan

In the study performed, permanent coronary artery occlusion (CAO) in rats was used as a model for acute myocardial infarction. Experiments were performed with 5 treatment groups characterized by the following properties:

- falsely operated animals,

- CAO + vehicle,

- CAO + valsartan,

- CAO + aldosterone synthase inhibitor,

- CAO + AT 1 -receptor antagonist + aldosterone synthase inhibitor.

The following dosages and routes of administration could be used:

For example, for the AT 1 -receptor antagonist valsartan

a) -3d to + 2d: s.c. injection of 2.5 mg / kg BW / 12 hours,

b) + 3d to + 28d: s.c. osmotic minipump Alza 5 mg / kg / day.

For the (+) - enantiomer of fadrazole hydrochloride osmotic minipump Alza 0.4 mg / kg / day

The following parameters were measured during the study:

- size of heart attack,

- left ventricular chamber volume (LV),

- density of interstitial and perivascular collagen in the remaining LV myocardium,

- COL-I and COL-III protein content in the remaining LV myocardium by Western blot,

- cross-sectional area and length of cardiomyocytes on LV myocardial sections,

- plasma concentrations of Ang II and aldosterone,

- blood pressure in waking animals,

- LV and carotid blood pressure in anesthetized animals.

methodics

Infarct size

Left ventricular transverse sections of 6 μπι were stained with nitroblue-tetrazolium and scanned with a B / W XC-77CE CCD (Sony). The resulting image was processed on a KS 300 image analysis system (Carl Zeiss Vision) using specifically developed software (Porzio et al., 1995). A single operator, uninformed about treatment, interactively defined the boundaries of the interventricular septum and the infarct area at each section was semi-automatically identified as the unstained ventricular tissue area. The software automatically calculated a set of geometric parameters for each of the ventricular section components defined as ventricular, septum, infarct area, LV affected wall and viable LV wall, (Porzio et al., 1995).

histology

The heart was post-diastolic by i.v. injection of 0.5 M KCl fixed in situ, by retrograde perfusion buffered with 4% formaldehyde. After fixation, the left ventricle (LV) and the free wall of the right ventricle were weighed separately; a longer diameter LV was measured by caliper. LV histological sections were stained with hematoxylin and eosin for qualitative analysis and for quantifying the cross-sectional area of cardiomyocytes using a routine semi-automatic image analysis. Interstitial collagen deposition in LV was assessed on sections stained with Sirius red using routine semi-automatic image analysis (Masson et al., 1998).

Collagen content in the remaining LV myocardium

The remaining LV tissue myocardium was homogenized, subjected to PAGE-SDS electrophoresis and electroblotted onto a nitrocellulose membrane. The blots were exposed to primary antibodies, i.e. rabbit antisera against rat type Z or type III collagen (Chemicon). Primary antibodies were recognized by secondary antibodies conjugated to alkaline phosphatase (for type I collagen) or peroxidase (for type III collagen).

Left ventricular chamber volume

The LV ventricular volume was determined on diastolic arrested hearts (KCl) and formalin fixed at a hydrostatic pressure equivalent to that measured by LV at the end of the diastole. A metric gauge was introduced into the LV to measure the inner length of the LV. The LV transversal diameters were measured in two cross sections near the base and the 1 mm thick chamber tip (Jeremic et al., 1996). The ventricular volume was calculated using a computer from the equation integrating the transverse diameters and the internal length.

Systemic and left ventricular haemodynamics

A micro-point pressure sensor (Millar SPC-320) coupled to a recording device (Windograf, Gould Electronics) was inserted into the right carotid artery to record systolic and diastolic blood pressure. The pressure sensor was inserted into LV to determine LV systolic pressure (LVSP) and diastolic end LV pressure (LVEDP), the first derivative of LV pressure by time (+ dP / dt) and heart rate.

Non-invasive blood pressure determination

Systolic blood pressure and heart rates were determined using the tail cuff method (Letica LE 5002) in alert rats.

Urinary electrolytes, hormones

Rats were housed individually in metabolic cages and urine was collected for 24 hours (1 mL HCl 6N). Water intake was measured. Urinary catecholamines were extracted using Bondelut Cis columns (Varian), separated by high resolution liquid chromatography, i.e. HPLC, (Apex-II C18, 3 µm, 50 x 4.5 mm analytical column, Jones Chromatographs) and quantified by electrochemical detector. (Coulochem II, ESA) (Goldstein et al., 1981). Plasma and urinary aidosterone and plasma angiotensin II were determined using specific radioimmunoassay methods (Aldoctk-2, DiaSorin and Angiotensin II, Nichols Diagnostics). Urinary sodium and potassium were determined by flame photometry.

Sample size

Ten analysable animals in each treatment group were sufficient to detect biologically significant differences. Only rats with infarct size representing at least 10% LV cut area were included in the resulting analysis.

Therefore, the compositions of the present invention can be used to prevent, delay progression and treat survival after myocardial infarction.

Endothelial dysfunction has been confirmed to be a critical factor in vascular diseases. Endothelium plays a dual role as a source of various hormones or by-products with opposite effects: vasodilation and vasoconstriction, growth inhibition or growth, fibrinolysis or thrombogenesis, production of antioxidants or oxidizing agents. Animals with a genetic predisposition to hypertension with endothelial dysfunction represent the right model for assessing the effectiveness of cardiovascular therapy.

Endothelial dysfunction is characterized, for example, by increased oxidative stress, causing reduced nitric oxide content, increased factors involved in coagulation or fibrinolysis, such as plasminogen 1 (PAI-1) activation inhibitor, tissue factor (TF), plasminogen activator tissue (tPA), increased adhesion molecules such as ICAM and VCAM, increased growth factors such as bEGE, βΕβ, PDGF, VEGE, all factors causing cell growth, inflammation and fibrosis.

Treatment of, for example, endothelial dysfunction can be demonstrated in the following pharmacological assay:

Materials and methods

Male 20-24 week old SHR rats, obtained from RCC Ltd (Fullingsdorf, Switzerland), were housed in a temperature and light control room with free access to rat food (Nafag 9331, Gossau, Switzerland) and tap water. The experiment was conducted in accordance with the NIH guidelines and approved by the Canton Veterinary Office (Bew 161, Kantonales Veterinäramt, Liestal, Switzerland). All rats were treated with a NO synthase inhibitor L-NAME (Sigma Chemicals) administered in drinking water (50 mg / L) for 12 weeks. The average daily dose of L-NAME calculated from the water consumption was 2.5 mg / kg / day (range 2.1 to 2.7).

Rats were divided into five groups: group 1 - control (n = 40); Group 2 - valsartan (5 mg / kg / day; n = 40); 3 - (+) - enantiomer of fadrozole hydrochloride (n = 30); Group 4 combination of the (+) - enantiomer of fadrozole hydrochloride and valsartan (5 mg / kg / day; n = 30) and Group 5 - valsartan (50 mg / kg / day; n = 30). Drugs were administered in drinking fluid. The peroral effect of mg / kg Ang II obtained in control normotensive rats was reduced by 49% and 73%, respectively, after treatment with valsartan 5 and 50 mg / kg / day, respectively (Gervais et al., 1999). The response to Ang I injected Wistar Kyoto rats pretreated with the (+) - enantiomer of fadrozole hydrochloride or valsartan at 5 mg / kg / day was similar.

Body weight was measured every week. Systolic blood pressure and heart rate were recorded using tail cuff plethysmography 3 and 2 weeks prior to study initiation and weeks after drug administration. Urine was collected within 24 hours of rats housed in individual (metabolic) cages the week before treatment and at weeks 4 and 12 to determine volume and protein, creatinine, sodium and potassium using standard laboratory methods. At the same time, blood samples were taken from the retro-orbital plexus (maximum 1 ml) for creatinine, Na ⁺ and K ^{+ determination} .

Ten rats from each group were sacrificed at 4 weeks for kidney and heart collection for morphological analysis. The remaining rats were sacrificed at 12 weeks. Heart and kidney weights were recorded. Terminal blood sampling was performed in 5% ethylenediaminetetraacetic acid (EDTA) at 4 (morphometric study) and 12 (end of study) weeks for aldosterone, as determined by radioimmunoassay using the DPC coat-a-count aldosterone-RIA kit (Buhlmann, Switzerland).

Statistical analysis

All data were expressed as mean ± standard measurement error (SEM). Statistical analysis was performed using a one-way ANOVA, followed by Duncan's multiple rank test and the Newman-Keuls test, to compare between different groups. Results with a probability value less than 0.05 were considered statistically significant.

Improvement of atherosclerosis regression without affecting serum lipid levels can be demonstrated, for example, by the animal model as described by H. Kano et al., In Biochemical and Biophysical Research Communications 259, p. 414-419 (1999).

The fact that the compounds or combinations of the present invention can be used for regression of cholesterol diet-induced atherosclerosis can be demonstrated using the test model described, for example, by C. Jiang et al. in Br. J. Pharmacol. (1991), 104, p. 1033 to 1037.

The fact that the compounds or combinations of the present invention can be used to treat renal failure, particularly chronic renal failure, can be demonstrated using the test model described, for example, by D. Cohen et al., In Journal of Cardiovascular Pharmacology, 32: p. 87-95 (1998).

Other beneficial effects of administering the compositions of the present invention are the fact that lower doses of the individual drugs combined according to the present invention can be used to reduce dosages, for example, dosages may not only be often lower, but may also be administered less frequently, or reduce the occurrence of side effects. This is in accordance with the requirements of the treated patients.

Even more surprising is the experimental finding that the combined administration of the combination of the present invention results in a beneficial, particularly synergistic (i.e., greater than additive) effect, as well as beneficial effects resulting from the combination therapy and other surprising beneficial effects compared to monotherapy in during which only one of the pharmaceutically active compounds used in the combination described herein is administered.

Even more surprising is the experimental finding that the combination of the present invention results in a beneficial, especially synergistic, therapeutic effect, but also in the beneficial effects resulting from the combination therapy, such as surprising prolongation of efficacy, broader spectrum of therapeutic treatment and surprising beneficial effects on diseases. and conditions specified before and on.

Another beneficial effect of administering the composition of the present invention is that lower doses of the individual drugs combined according to the present invention can be used to reduce dosages, for example, dosages may not only be lower, but may also be administered less frequently, or reduce the occurrence of side effects. This is in accordance with the requirements of the treated patients.

The results of the study clearly show that the composition of the present invention can be used to prevent, delay progression or to treat a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after surgical treatment with coronary arterial bypass;

(b) atherosclerosis, insulin resistance and syndrome X, type 2 diabetes mellitus, obesity, nephropathy, renal failure, e.g. chronic kidney failure, hypothyroidism, survival after myocardial infarction (MI), coronary heart disease, old age hypertension, congenital dyslipidemic hypertension, increased collagen production, fibrosis and remodeling after hypertension (antiproliferative effect of the combination) or all of these diseases and conditions without hyperten13 zie; and (c) endothelial dysfunction with or without hypertension.

The compositions of the present invention can also be used to prevent and delay progression, and preferably to treat other diseases.

A preferred composition comprises the (+) - enantiomer of fadrozole hydrochloride and valsartan or valsartan combined with hydrochlorothiazide.

Advantageously, a therapeutically effective amount of an α 1 -receptor antagonist or an AT 1 -receptor antagonist combined with a diuretic, in each case in free or pharmaceutically acceptable salt form, and an aldosterone synthase inhibitor in free or pharmaceutically acceptable salt form may be administered concurrently or sequentially in in any order, separately or in a fixed combination.

The present invention further relates to a method of preventing, delaying the progression or treating a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, particularly chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery ;

(b) atherosclerosis, insulin resistance and syndrome X, type 2 diabetes mellitus, obesity, nephropathy, renal failure, e.g. chronic kidney failure, hypothyroidism, survival after myocardial infarction (MI), coronary heart disease, old age hypertension, congenital dyslipidemic hypertension, increased collagen production, fibrosis and remodeling after hypertension (antiproliferative effect of the combination) or all of these diseases and conditions without hypertension; and (c) endothelial dysfunction with or without hypertension;

comprising administering a therapeutically effective amount of an aldosterone synthase inhibitor in free form or in the form of a pharmaceutically acceptable salt, either alone or in combination with an AT 1 receptor antagonist or an AT 1 receptor antagonist combined with a diuretic, in each case in free form or a pharmaceutically acceptable salt , a warm-blooded animal, including a human.

The present invention further relates to the use of (a) a pharmaceutical composition comprising (i) an AT 1 -receptor antagonist or an AT 1 -receptor antagonist combined with a diuretic or, in any case, a pharmaceutically acceptable salt thereof, (ii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof; iii) a pharmaceutically acceptable carrier; or (b) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing, delaying progression or treating a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after surgical treatment with coronary arterial bypass;

(β) atherosclerosis, insulin resistance and syndrome X, type 2 diabetes mellitus, obesity, nephropathy, renal failure, e.g. chronic kidney failure, hypothyroidism, survival after myocardial infarction (MI), coronary heart disease, hyper15 tension in old age, congenital dyslipidemic hypertension, increased collagen production, fibrosis and remodeling after hypertension (antiproliferative effect of the combination), all of these diseases or without hypertension; and (χ) endothelial dysfunction with or without hypertension.

The present invention also relates to a kit of parts, for example in the sense that the components of the combined stage of the invention can be dosed independently or by different fixed combinations with different amounts of components, i.e. simultaneously or at different times. For example, the kit of parts may be administered concurrently or equally spaced over time, i.e., at different times and with equal or different intervals for any portion of the kit of parts. Preferably, the intervals are selected such that the effect on the disease or condition being treated is greater than the effect that can be achieved by using only one of the components when used in combination.

The invention further relates to a commercial package comprising a combination according to the present invention together with instructions for simultaneous, separate or sequential administration.

These pharmaceutical preparations are for enteral, such as oral, as well as rectal or parenteral administration to warm-blooded animals, and include formulations comprising a pharmacologically active compound, either alone or together with conventional pharmaceutical excipients. The pharmaceutical preparations contain, for example, from about 0.1% to 90%, preferably from about 1% to about 80%, of the active compound. Pharmaceutical preparations for enteral or parenteral administration, as well as for ophthalmic administration, are, for example, in unit dosage forms such as coated tablets, capsules or suppositories as well as ampoules. These are prepared by known methods, for example by means of conventional mixing, granulating, coating, solubilizing or lyophilizing processes. Thus, pharmaceutical preparations for oral administration can be obtained by mixing the active compound with solid excipients, if desired, granulating the resulting mixture and, if desired or necessary, processing the mixture or granulate into tablets or coated tablet cores, after adding suitable excipients. substances.

The dose of the active compound may depend on various factors, such as the route of administration, the species of warm-blooded animal, age and / or the particular condition.

Preferred doses of the active ingredient in the pharmaceutical combination of the invention are therapeutically effective doses, especially those commercially available.

For oral administration, the approximate daily dose is pre-determined, for example, from about 1 mg to about 360 mg in a patient weighing about 75 kg.

The dose of the active compound may depend on various factors such as the mode of administration, the species of warm-blooded animal, age and / or the particular condition.

Valsartan, as a representative of the class of AT 1 receptor antagonists, will be administered in a suitable unit dosage form, for example, a capsule or tablet, and will contain a therapeutically effective amount, for example from about 20 to about 320 mg, of valsartan that can be administered to patients. The active ingredient can be administered up to three times a day, initially, for example, at a daily dose of 20 mg or 40 mg valsartan, via an increase to 80 mg daily and further to 160 mg daily to 320 mg daily. Preferably, valsartan is administered twice daily at a dose of 80 mg and 160 mg, respectively. Appropriate doses may be taken, for example, in the morning, lunch or evening.

The following examples illustrate the invention described above, but do not limit the scope of the present invention. .

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Film-coated tablets

ingredients Quantity per unit (mg) standards granulation Valsartan [= active substance] 80.00 Microcrystalline cellulose / Avicel PH 102 54,00 NF, Ph. Eur crospovidone 20.00 NF, Ph. ' Eur Colloidal anhydrous silica / colloidal silica / Aerosil 200 0.75 Ph. Eur / NF Magnesium stearate 2.5 NF, Ph. Eur mixing Colloidal anhydrous silica / colloidal silica / Aerosil 200 0.75 Ph. Eur / NF Magnesium stearate 2.00 NF, Ph. Eur coating Purified water - DIOLACK pale red 00F34899 7.00 Total tablet weight 167.00

'Removed during processing.

For example, a film-coated tablet is prepared as follows:

Mixture of valsartan, microcrystalline cellulose, crospovidone, a portion of colloidal anhydrous silica / colloidal silica / Aerosil 200, silica and stearate. Magnesium is premixed in a diffusion mixer and then sieved using a sieve mill. The resulting mixture is premixed in a diffusion mixer, compacted in a roller compact, and then sieved using a sifting mill. The remainder of the colloidal anhydrous silica / colloidal silica / Aerosil 200 was added to the resulting mixture, and the resulting mixture was formed in a diffusion mixer. The whole mixture is compressed in a rotary tabletting machine and the tablets are film-coated using Diolack pale red in a perforated pan.

Example 2

Film-coated tablets

ingredients Quantity per unit (mg) standards granulation Valsartan [= active substance] 160.00 Microcrystalline cellulose / Avicel PH 102 108.00 NF, Ph. Eur crospovidone 40.00 NF, Ph. Eur Colloidal anhydrous silica / colloidal silica / Aerosil 200 1.50. Ph. Eur / NF Magnesium stearate 5.00 NF, Ph. Eur mixing Colloidal anhydrous silica / colloidal silica / Aerosil 200 1.50 Ph. Eur / NF Magnesium stearate 4.00 NF, Ph. Eur coating Opadry Light Brown 00F33172 10.00 Total tablet weight 330.00

A film-coated tablet is prepared, for example, as described in Example 1.

Example 3

Film-coated tablets

ingredients Quantity per unit (mg) standards Core: Internal phase Valsartan [= active substance] 40.00 Silica, colloidal anhydrous (colloidal silica) [= glidant] 1.00 Ph. Eur. USP / NF Magnesium stearate [= lubricant] 2.00 USP / NF Crospovidone [disintegrant] 20.00 Ph. Eur Microcrystalline cellulose [= binder] 124.00 USP / NF

External phase Silica, colloidal anhydrous (colloidal silica) [= glidant 1.00 Ph. Eur. USP / NF Magnesium stearate [= lubricant] 2.00 USP / NF Film cover Opadry® brown 00F 1671i ' ¹ 9.40 Purified water ” ¹ - Total tablet weight 199.44

´ The composition of Opadry® brown OOF16711 is shown in the table below. ’’ Deleted during processing.

Opadry® composition:

substance Approximate% of the composition Iron oxide, black (C.I. No 77499, E 172) 0.50 Iron oxide, brown (C.I. No 77499, E 172 0.50 Iron oxide, red (C.I. No 77491, E 172) 0.50 Iron oxide, yellow (C.I. No. 77492, E 172) 0.50 Macrogolum (Ph. Eur) 4.00 Titanium dioxide (C.I. No. 77891, E 171) 14,00 Hypromellosis (Ph. Eur) 80.00

A film-coated tablet is prepared, for example as described in Example 1.

Example 4

capsule

ingredients Quantity per unit (mg) Valsartan [= active substance] 80.00 Microcrystalline cellulose 25,10 crospovidone 13,00 povidone 12.50 Magnesium stearate 1.30 Nátriumleurylsulfát 0, 60 Case Iron oxide, red (C.I. No 77491, EC No E 172) 0,123 Iron oxide, yellow (C.I. No 77492, EC No E 172) 0, 123

Iron Oxide, Black (C.I. No 77499, EC No E 172) 0, 245 Titanium dioxide 1, 540 gelatin 74,969 Total mass of the capsule 209.50

For example, a capsule is prepared as follows:

Granulation / Drying

Valsartan and microcrystalline cellulose are spray granulated in a fluid bed granulator with a granulating solution consisting of povidone and sodium lauryl sulfate dissolved in purified water. The granulate obtained is dried in a fluid bed dryer.

The grinding / mixing

The dry granulate is ground together with crospovidone and magnesium stearate. The mass is then mixed in a conical screw mixer for about 10 minutes.

encapsulation

Empty hard gelatin capsules are filled with mixed bulk granules at controlled temperature and humidity. The filled capsules are aspirated, visually inspected, checked for weight and guaranteed by the Quality Assurance Department.

Example 5

capsule

ingredients Quantity per unit (mg) Valsartan [= active substance] 160.00 Microcrystalline cellulose 50.20 crospovidone 26.00 povidone 25.00

Magnesium stearate 2, 60 sodium lauryl sulphate 1.20 Case Iron oxide, red (C.I. No 77491, EC No E 172) 0, 123 Iron oxide, yellow (C.I. No 77492, EC No E 172) 0, 123 Iron Oxide, Black (C.I. No 77499, EC No E 172) 0,245 Titanium dioxide 1,540 gelatin 74,969 Total mass of the capsule 342.00

A capsule is prepared, for example, as described in Example 4.

Example 6

Hard gelatin capsule

ingredients Quantity per unit (mg) Valsartan [= active substance] 80.00 sodium lauryl sulphate 0.60 Magnesium stearate 1, 30 povidone 12.50 crospovidone 13,00 Cellulose crystalline 21, 10 Total mass of the capsule 130.00

Example 7

Hard gelatin capsule containing, as an active ingredient, for example (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2'- (1H-tetrazol-5-yl) biphenyl- 4-ylmethyl] amine can be prepared, for example, as follows:

Ingredients:

(D valsartan 80.0 mg (2) microcrystalline cellulose 110.0 mg (3) polyvidon K30 45.2 mg (4) sodium lauryl sulphate 1.2 mg (5) crospovidone 26.0 mg

(6) magnesium stearate 2.6 mg

Components (1) and (2) are granulated with a solution of components (3) and (4) in water. Components (5) and (6) are added to the dry granulate and the mixture is filled into size 1 hard gelatin capsules.

Example 8

component Quantity per unit [mg] The core Fadrozole (hydrochloride), hemihydrate 1,035 ^1! Aerosil 200 (silica airgel) 0,200 Avicel PH 102 (cellulose) 37,300 Cellulose-HP-M 603 (hydroxypropylmethylcellulose) 2,000 Lactose basis 53,965 Magnesium stearate 0,500 Polyvinyl-polypyrrolidone XL 5,000 Core weight 100,000 skin Cellulose-HP-M 603 (hydroxy- methylcellulose) 1,8 37 Iron oxide, red, 172661 0.017 mg Iron oxide, yellow, 17268 0.017 mg Polyethylene glycol 8000, vo flaked 0.333 mg Talc, PH 1,330 mg Titanium dioxide 0,466 Coating weight 4,000

¹¹ 1.035 mg of CGS 16949 and the hemihydrate is equivalent to 1,000 mg of the anhydrate.

Claims (10)

Use of a pharmaceutical composition comprising (i) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, alone or in combination with (ii) an AT 1 -receptor antagonist or Τ -receptor antagonist combined with a diuretic or, in each case, a pharmaceutically acceptable salt thereof, and ( iii) a pharmaceutically acceptable carrier; for preventing, delaying the progression or treating a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, in particular chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary arterial bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, type 2 diabetes mellitus, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival after myocardial infarction, coronary heart disease, old age hypertension, congenital dyslipidemic hypertension, increased collagen production, fibrosis and remodeling after hypertension - antiproliferative effect of the combination, all of these hypertension or conditions without or associated with hypertension; and (c) endothelial dysfunction with or without hypertension. Use according to claim 1, wherein said AT 1 receptor antagonist is selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan, the compound designated E-1477 of the following formula the compound designated SC-52458 of the following of the formula and the compound designated ZD-8731 of the following formula and, in each case, a pharmaceutically acceptable salt thereof. Use according to claim 2, wherein said AT 1 receptor antagonist is valsartan or a pharmaceutically acceptable salt thereof. The use according to any one of claims 1 to 3, wherein said aldosterone synthase inhibitor is selected from the group consisting of anastrozole, fadrozole, including their (+) - enantiomer, and exemestane and, in any case where applicable, a pharmaceutically acceptable salt thereof. sol. Use according to any one of claims 1 to 4, wherein said aldosterone synthase inhibitor is the (+) - enantiomer of fadrozole hydrochloride of formula HCl Use according to any one of claims 1 to 5, wherein the diuretic is hydrochlorothiazide. Use of a pharmaceutical composition comprising an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing, delaying progression or treating a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure restenosis after percutaneous transluminal angioplasty and restenosis after surgical treatment using coronary arterial bypass; (β) atherosclerosis, insulin resistance and syndrome X, type 2 diabetes mellitus, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival after myocardial infarction, coronary heart disease, old age hypertension, congenital dyslipidemic hypertension, increased collagen production, fibrosis and remodeling after hypertension - antiproliferative effect of the combination, all of these hypertension-free conditions and conditions; and (χ) endothelial dysfunction with or without hypertension. A pharmaceutical composition comprising (i) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, either alone or in combination with (ii) an AT 1 -receptor antagonist or an AT 1 -receptor antagonist combined with a diuretic or, in any case, their a pharmaceutically acceptable salt; and (iii) a pharmaceutically acceptable carrier; for preventing, delaying progression or treating a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, in particular chronic renal failure, restenosis to percutaneous transluminal angioplasty, and restenosis after coronary bypass artery surgery; (b) atherosclerosis, insulin resistance and syndrome X, type 2 diabetes mellitus, obesity, nephropathy, renal failure, e.g. chronic kidney failure, hypothyroidism, survival after myocardial infarction, coronary heart disease, hypertension in old age, congenital dyslipidaemic hypertension, increased collagen production, fibrosis and remodeling after hypertension - antiproliferative effect of the combination, with or without any of these hypertension and conditions; and (c) endothelial dysfunction with or without hypertension. A method of preventing, delaying the progression or treating a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, in particular chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, type 2 diabetes mellitus, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival after myocardial infarction, coronary heart disease, old age hypertension, congenital dyslipidemic hypertension, increased collagen production, fibrosis and remodeling after hypertension - antiproliferative effect of the combination, all or associated with the disease or condition associated with the disease or condition. ; and (c) endothelial dysfunction with or without hypertension, comprising administering a therapeutically effective amount of an aldosterone synthase inhibitor in free form or in the form of a pharmaceutically acceptable salt to a warm-blooded animal, including a human. The method of claim 9, further comprising administering a therapeutically effective amount of an AT 1 -receptor antagonist or an AT 1 -receptor antagonist combined with a diuretic, in each case in their free form or in a pharmaceutically acceptable salt form.