Pharmaceutical composition for use in cardiovascular therapy

Abstract

A pharmaceutical composition comprising a diuretic and at least one additional active ingredient selected from the group consisting of ACE inhibitors, sartans, calcium channel blockers, alpha blockers, and beta blockers, wherein the diuretic is in a first pharmaceutical form that increases its dissolving rate. The invention also relates to the above composition for use in the treatment of a condition selected from heart failure, arterial hypertension, myocardial fibrosis, and cardiac hypertrophy.

Description

[0001] PHARMACEUTICAL COMPOSITION FOR USE IN CARDIOVASCULAR THERAPY

[0002] The present invention relates to a pharmaceutical composition comprising a diuretic and at least one further active ingredient selected from the group consisting of ACE inhibitors, sartans, calcium channel blockers, alpha blockers and beta blockers, and to said composition for use in the treatment of arterial hypertension, heart failure, myocardial fibrosis or cardiac hypertrophy.

[0003] Background art

[0004] The incidence of primary heart failure or secondary heart failure due to myocardial infarction or consequent to arterial hypertension has been steadily increasing for several years and is a particularly significant health problem. In diabetic patients, this is even more important, as cardiovascular events are very frequent with respect to the non-diabetic population.

[0005] Diuretics are commonly used in the treatment of heart failure, including thiazide diuretics (such as hydrochlorothiazide and chlorthalidone), loop diuretics (such as furosemide, bumetanide, torasemide, and ethacrynic acid), potassium-sparing diuretics (such as amiloride and triamterene) and aldosterone receptor antagonists (such as spironolactone, eplerenone, canrenone, and finerenone).

[0006] Aldosterone promotes the reabsorption of Na2+in the kidney, in the lower gastrointestinal tract, and in the salivary and sweat glands, and also has a pro-fibrotic and inflammatory activity.

[0007] The role of aldosterone synthesis and metabolism is crucial in the etiopathogenesis of heart failure in both post-infarction and hypertensive patients. In fact, in a post-ischemic situation, tissue necrosis and inflammation with subsequent scarring develop. If primary or secondary hyperaldosteronism is present, the necrotic heart muscle suffers more and scarring leads to increased fibrosis (formation of non-contractile tissue) with a high risk of subsequent contractile deficit of the heart itself and associated functional failure.

[0008] Moreover, the renin-angiotensin-aldosterone system plays a decisive role in the development of arterial hypertension. The angiotensin-converting enzyme (ACE) has two catalytic sites. Angiotensin I exhibits its highest affinity for the C-terminal catalytic site of ACE. ACE can induce tissue fibrosis through the production of angiotensin II, and an ACE inhibitor may therefore be useful for attenuating fibrosis. Several ACE inhibitors are known, including ACE inhibitors with a sulfhydryl group (such as captopril and zofenopril), ACE inhibitors with a carboxyl group (such as enalapril, lisinopril, delapril, quinapril, ramipril, and perindopril), and ACE inhibitors with a phosphinic group, such as fosinopril.

[0009] Although generally well tolerated, ACE inhibitors are known to have side effects such as, for example, in the case of enalapril, hypotension, fatigue, insomnia, dizziness or syncope, and dyspnea.

[0010] Moreover, the renin-angiotensin-aldosterone system is involved in the pathogenesis of fibrosis and an angiotensin II receptor antagonist may therefore attenuate it. Several angiotensin II receptor antagonists are known, including sartans such as losartan, irbesartan, olmesartan, candesartan, valsartan, and telmisartan.

[0011] Although they are generally well tolerated drugs, angiotensin II receptor antagonists, and in particular sartans, are associated with side effects such as hypotension, fatigue, insomnia, dizziness, and syncope.

[0012] Beta-blockers are compounds that cover the cellular beta-adrenergic receptor, preventing its activation and thus modulating beta-adrenergic activity. At the level of the heart, this results in less stimulation with consequent “resting” of the heart muscle, a situation that may be favorable to the recovery of organ function. Clearly, the concentration of the drug in the bloodstream at any given time is crucial. If excessively high blood concentration peaks are reached, the “resting” effect on the myocardium becomes a serious adverse event, since cardiac function is slowed down excessively in an already compromised patient. It is therefore highly desirable to be able to obtain, following oral administration, a plasma kinetic curve without excessive peaks, which can then be maintained at useful dosage levels over a 24-hour period. In fact, at present, attempts are being made to avoid too rapid and excessive release of the beta-blocker at the time of administration by using “B.I.D.” formulations, with obvious disadvantages both in terms of plasma steady state and in terms of patient compliance. Commonly used beta-blockers include selective beta-1 blockers (such as bisoprolol, atenolol, and metoprolol), non-selective beta-blockers (such as propranolol and nadolol), and beta-blockers with ISA (intrinsic sympathomimetic activity), such as pindolol.

[0013] Aldosterone receptor antagonists generally have low solubility, which contributes to low bioavailability after oral administration of the product. This entails the need to administer relatively high doses of the compound to the patient in order to obtain a clinically useful kinetic curve and area under the absorption curve (AUC). However, since the most debilitating side effect of these drugs (gynecomastia), which can even lead to discontinuation of treatment, is closely correlated to the amount of drug in circulation and therefore to the dosage administered, it is necessary to obtain a more favorable kinetic curve and associated AUC.

[0014] In contrast, other drugs administered for the same therapeutic indications, and in particular beta-blockers, tend to have a very rapid release profile. The different kinetics make it difficult to fully benefit from a synergy of the different active ingredients.

[0015] The aim of the present invention is to provide a pharmaceutical composition that is particularly effective for the treatment of arterial hypertension, heart failure, myocardial fibrosis, and cardiac hypertrophy.

[0016] Within the scope of this aim, an object of the present invention is to provide a therapy based on a combination of active ingredients comprising a diuretic and sartans, ACE inhibitors, calcium channel blockers, alpha blockers or beta blockers which overcomes the limitations associated with the low solubility of commonly used diuretics.

[0017] A further object of the present invention is to provide a therapy based on a combination of active ingredients comprising a diuretic and betablockers which makes it possible to overcome the current need for multiple daily administrations, improving tolerability and compliance.

[0018] Summary of the invention

[0019] This aim, as well as these and other objects that will become more apparent hereinafter, are achieved by a pharmaceutical composition comprising a diuretic and at least one further active ingredient selected from the group consisting of ACE inhibitors, sartans, calcium channel blockers, alpha blockers and beta blockers, wherein said diuretic is in a first pharmaceutical form which increases its dissolving rate, said first pharmaceutical form being selected from the group consisting of a matrix that disintegrates directly in the mouth before swallowing (ODT- orally disintegrating tablet), a disintegrating tablet, a readily soluble tablet, a lyophilized matrix, an orodispersible film, and readily soluble or disintegrating granules.

[0020] The aim and objects of the invention are also achieved by said pharmaceutical composition for use in the treatment of a condition selected from heart failure, arterial hypertension, myocardial fibrosis and cardiac hypertrophy.

[0021] Further characteristics and advantages of the invention will become more apparent from the detailed description that follows.

[0022] Detailed description of the invention

[0023] Within the scope of the present invention, “active ingredient” is understood to mean a compound that produces a pharmacological effect leading to a physiological change. Within the scope of the present invention, the active ingredients are the diuretic and at least one additional active ingredient selected from the group consisting of ACE inhibitors, sartans, calcium channel blockers, alpha blockers, and beta blockers, which are used in combination.

[0024] However, the present invention also considers the possibility of combining said active ingredients with further active ingredients, in particular with further antihypertensive active ingredients, including diuretics and calcium channel blockers (for example amlodipine).

[0025] Within the scope of the present invention, the term “pharmaceutical composition” refers to a combination of two or more active ingredients for the treatment of a single pathological condition for use by means of concomitant administration. The active ingredients may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same day or on separate days.

[0026] Of course, the pharmaceutical composition may further comprise any pharmaceutically acceptable excipient normally used in the preparation of pharmaceutical compositions. Said excipients are “acceptable” in the sense that they must be compatible with the other ingredients of the composition and not be harmful to the patient.

[0027] Examples of commonly used excipients comprise pharmaceutically acceptable vehicles or diluents, a flavoring agent, a sweetening agent, a preservative, a coloring agent, a binder, a suspending agent, a dispersing agent, a disintegrant, a lubricant, a plasticizer, an edible oil, or any combination of two or more of the above cited products.

[0028] In a first aspect, the present invention relates to a pharmaceutical composition comprising a diuretic and at least one additional active ingredient selected from the group consisting of ACE inhibitors, sartans, calcium channel blockers, alpha blockers and beta blockers, wherein said diuretic is in a first pharmaceutical form selected from the group consisting of a matrix that disintegrates directly in the mouth before swallowing (ODT- orally disintegrating tablet), a disintegrating tablet, a readily soluble tablet, a lyophilized matrix, an orodispersible film, and readily soluble or disintegrating granules. Said pharmaceutical forms promote the solubilization of the active ingredient.

[0029] The increased solubility of the diuretic makes it possible to reduce the dosage of the active ingredient to be administered, resulting in a reduced frequency of adverse events, in particular gynecomastia, directly correlated to the dosage of the drug.

[0030] In one embodiment of the pharmaceutical composition according to the invention, the diuretic is an aldosterone receptor antagonist.

[0031] In one embodiment of the pharmaceutical composition according to the invention, the aldosterone receptor antagonist is selected from the group consisting of spironolactone, eplerenone, canrenone, and pharmaceutically acceptable salts thereof. Preferably, the aldosterone receptor antagonist is canrenone or a pharmaceutically acceptable salt thereof.

[0032] The at least one further active ingredient of the pharmaceutical composition according to the invention is preferably selected from the group consisting of irbesartan, enalapril and bisoprolol.

[0033] In a preferred embodiment, the pharmaceutical composition according to the invention comprises canrenone or a pharmaceutically acceptable salt thereof and bisoprolol.

[0034] In a preferred embodiment, said diuretic is present in the first pharmaceutical form in a form selected from the group consisting of a pharmaceutically acceptable salt, a hot solid dispersion, a solid dispersion with solvent, and a mixture or complex with one or more excipients which increase its apparent solubility, selected from the group consisting of a cyclodextrin, meglumine, and mesoporous silica.

[0035] The additional active ingredient of the composition may be in a second pharmaceutical form which slows down its release, prolonging it over time, thus helping to avoid plasma peaks that adversely affect the clinical use of the active ingredient itself. The second pharmaceutical form may, for example, be selected from a hydrophilic swelling matrix, an insoluble matrix, and a coated system with controlled permeability.

[0036] In a preferred embodiment, the second pharmaceutical form contains a release control agent consisting of one or more of (i) hydrophilic swelling polymers, and (ii) insoluble polymers.

[0037] The pharmaceutical composition according to the invention may be selected from a single-unit system and a multiple-unit system.

[0038] In a preferred embodiment, the pharmaceutical composition according to the invention is a single-unit system; said single dosage form may be, for example, a capsule or tablet comprising effective amounts of an aldosterone receptor antagonist and the at least one additional active ingredient in association with one or more pharmaceutically acceptable excipients.

[0039] In a preferred embodiment, the pharmaceutical composition according to the invention is a multilayer single-unit system comprising canrenone or a pharmaceutically acceptable salt thereof in the form of a disintegrating tablet and bisoprolol in the form of a sustained-release matrix. In one embodiment, the canrenone or its pharmaceutically acceptable salt and the bisoprolol are, within the multilayer system, in distinct layers separated by an inert layer which prevents contact between the two active ingredients.

[0040] In another preferred embodiment, the pharmaceutical composition according to the invention is a multiple-unit system, where the combination of active ingredients can be supplied as a kit comprising separate dosage forms for the aldosterone antagonist and for the at least one additional active ingredient, for example capsules or tablets comprising an effective amount of active ingredient in association with one or more pharmaceutically acceptable excipients. Said kit may further comprise instructions for separate, simultaneous or sequential use of the dosage forms of the aldosterone antagonist and the at least one additional active ingredient.

[0041] For example, in one embodiment the kit contains a first dosage form comprising the aldosterone antagonist and a second dosage form comprising the at least one additional active ingredient.

[0042] In a preferred embodiment, the pharmaceutical composition according to the invention is a multiple-unit system comprising canrenone or a pharmaceutically acceptable salt thereof in the form of readily soluble granules and bisoprolol in the form of sustained-release granules. The granules can be delivered all together in a sachet or capsule or separated by using a system of the Capsugel®DuoCap® type (Lonza Biologies Inc.).

[0043] Preferably, the pharmaceutical composition according to the invention comprises canrenone in an amount comprised between 10 and 100 mg, preferably between 25 and 50 mg, and bisoprolol is present in an amount comprised between 1 and 10 mg, preferably between 1.25 and 10 mg.

[0044] In a second aspect, the present invention relates to the pharmaceutical composition according to the invention for use in the treatment of a condition selected from heart failure, arterial hypertension, myocardial fibrosis, and cardiac hypertrophy.

[0045] The dosage of the active ingredients of the pharmaceutical composition for the use according to the present invention will depend on several factors such as the age, weight and sex of the patient, as well as the severity of the condition to be treated. The dosage may therefore vary within wide limits which can in any case be determined by the experienced clinician on the basis of his knowledge and experience.

[0046] For example, in the composition for the use according to the present invention the aldosterone receptor antagonist canrenone may be present in an amount comprised between 10 and 100 mg, preferably between 25 and 50 mg, and bisoprolol is present in an amount comprised between 1 and 10 mg, preferably between 1.25 and 10 mg.

[0047] The present invention will be further described with reference to the following non-limiting examples.

[0048] EXAMPLE 1 : PREPARATION OF TABLETS CONTAINING CANRENONE

[0049] A batch of 30 readily soluble tablets containing 50 mg of canrenone was provided, with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Luvion 50 mg (A.I.C. 024273094 - Neopharmed Gentili S.p.A.).

[0050] 27.7% by weight of canrenone was mixed with 64.5% by weight of lactose (SorboLac®400 - MEGGLE GmbH), 5.5% by weight of Kollidon CL cross-linked polymer, 1.7% by weight of magnesium stearate, and 0.6% by weight of colloidal silica. Using the mixture, tablets weighing approximately 180 mg and with a hardness of 20 N were provided using a rotary tablet press (8 mm diameter convex punch, Fa = 4 kN).

[0051] A sample of 6 tablets was tested in a USP Apparatus II dissolver equipped with paddle agitators. Process conditions: 800 mL of 0.1 N HC1 solution + 0.5% cetyl trimethyl ammonium bromide (CTAB) maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 285), using a calibration curve (y = 14.344x + 0.0098; R2= 0.9978). The dissolution profiles (Formulation 1) are shown in Figure 1.

[0052] EXAMPLE 2: PREPARATION OF “ODT” TYPE TABLETS

[0053] A batch of 30 “ODT” type tablets containing 50 mg of Canrenone was provided, with the goal of increasing the dissolving rate with respect to the commercial reference consisting of Luvion 50 mg (A.I.C. 024273094 - Neopharmed Gentili S.p.A.).

[0054] 29.3% by weight of canrenone was mixed with 68.3% by weight of the excipient for ODT Ultraburst (SPI Pharma, USA), 1.8% by weight of magnesium stearate, 0.6% by weight of colloidal silica. Using the mixture, tablets weighing approximately 170 mg and with a hardness of 20 N were provided using a rotary tablet press (8 mm diameter convex punch, Fa = 4 kN). A sample of 6 tablets was tested in a USP Apparatus II dissolver equipped with paddle stirrers. Process conditions: 800 mL of 0.1 N HC1 solution + 0.5% cetyl trimethyl ammonium bromide (CTAB) maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 285), using a calibration curve (y = 14.344x + 0.0098; R2= 0.9978). The dissolution profiles (Formulation 2) are shown in Figure 1.

[0055] EXAMPLE 3: PREPARATION OF READILY SOLUBLE GRANULES CONTAINING CANRENONE

[0056] A batch of 5 g of readily soluble granules containing canrenone was provided, with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Luvion 50 mg (A.I.C. 024273094 - Neopharmed Gentili S.p.A.).

[0057] A mixture containing 30% by weight of canrenone and 70% by weight of lactose (SorboLac®400 - MEGGLE GmbH) was wet granulated with water, breaking up the mixture with a 1-mm mesh sieve. The granulate was dried for 24 hours in an oven at 40°C.

[0058] Granulate samples containing 50 mg of canrenone (6 replicates) were tested in a USP Apparatus II dissolver equipped with paddle stirrers. Process conditions: 800 mL of 0.1 N HC1 solution + 0.5% cetyl trimethyl ammonium bromide (CTAB) maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 285), using a calibration curve (y = 14.344x + 0.0098; R2= 0.9978).

[0059] The dissolution profiles (Formulation 3) are shown in Figure 2. EXAMPLE 4: PREPARATION OF READILY SOLUBLE GRANULES CONTAINING CANRENONE

[0060] A batch of 5 g of readily soluble granules containing canrenone in the form of a solid dispersion with solvent was provided, with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Luvion 50 mg (A.I.C. 024273094 - Neopharmed Gentili S.p.A.).

[0061] A mixture containing 29.5% by weight of canrenone and 68.7% by weight of mannitol (Mannogem XL - SPI Pharma, US-MA) and 1.8% by weight of poloxamer (Parteck® PLX 188 - Merck GmbH) was wet granulated with water, breaking up the mixture with a 1-mm mesh sieve. The granules were dried for 24 hours in an oven at 40°C.

[0062] Granulate samples containing 50 mg of canrenone (6 replicates) were tested in a USP Apparatus II dissolver provided with paddle stirrers. Process conditions: 800 mL of 0.1 N HC1 solution + 0.5% cetyl trimethyl ammonium bromide (CTAB) maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 285), using a calibration curve (y = 14.344x + 0.0098; R2= 0.9978). The dissolution profiles (Formulation 4) are shown in Figure 2.

[0063] EXAMPLE 5: PREPARATION OF READILY SOLUBLE GRANULES CONTAINING CANRENONE

[0064] A batch of 5 g of readily soluble granules containing canrenone in the form of a solid dispersion with solvent was provided, with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Luvion 50 mg (A.I.C. 024273094 - Neopharmed Gentili S.p.A.).

[0065] A mixture containing 29.5% by weight of canrenone, 68.7% by weight of lactose (SorboLac®400 - MEGGLE GmbH) and 1.8% by weight of polyethylene glycol monooleate (Tween80 - Sigma-Alrich, GmbH) was wet granulated with water, breaking up the mixture with a 1-mm mesh sieve. The granules were dried for 24 hours in an oven at 40°C. Granulate samples containing 50 mg of canrenone (6 replicates) were tested in a USP Apparatus II dissolver equipped with paddle stirrers. Process conditions: 800 mL of 0.1 N HC1 solution + 0.5% cetyl trimethyl ammonium bromide (CTAB) maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 285), using a calibration curve (y = 14.344x + 0.0098; R2= 0.9978). The dissolution profiles (Formulation 5) are shown in Figure 2.

[0066] EXAMPLE 6: PREPARATION OF READILY SOLUBLE GRANULES CONTAINING CANRENONE

[0067] A batch of 5 g of readily soluble granules containing canrenone in the form of a hot solid dispersion was provided, with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Luvion 50 mg (A.I.C. 024273094 - Neopharmed Gentili S.p.A.).

[0068] A mixture containing 30% by weight of canrenone and 70% by weight of a methacrylic acid copolymer (Eudragit™ E - Evonik Rohm GmbH) was wet granulated with water, breaking up the mixture with a 1- mm mesh sieve. The granules were dried for 24 hours in an oven at 40°C.

[0069] Granule samples containing 50 mg of canrenone (6 replicates) were tested in a USP Apparatus II dissolver provided with paddle stirrers. Process conditions: 800 mL of 0.1 N HC1 solution + 0.5% cetyl trimethyl ammonium bromide (CTAB) maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 285), using a calibration curve (y = 14.344x + 0.0098; R2= 0.9978). The dissolution profiles (Formulation 6) are shown in Figure 2.

[0070] EXAMPLE 7: PREPARATION OF TABLETS CONTAINING POTASSIUM CANRENOATE A batch of 30 readily soluble tablets containing 100 mg of potassium canrenoate was provided with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Kanrenol 100 mg (A.I.C. 023745072 - Teofarma S.R.L).

[0071] 28% by weight of potassium canrenoate was mixed with 65.4% by weight of maltodextrin (Glucidex 9 - Roquette S.p.A.), 4.7% by weight of Kollidon CL cross-linked polymer, 1.4% by weight of magnesium stearate, and 0.5% by weight of colloidal silica. Using the mixture, tablets weighing approximately 350 mg and with a hardness of 48 N were provided using a rotary tablet press (10-mm diameter convex punch, Fa = 7 kN).

[0072] A sample of 6 tablets was tested in a USP Apparatus II dissolver equipped with paddle stirrers. Process conditions: 800 mL of distilled water maintained at 37.0 ± 0.5 °C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 295), using a calibration curve (y = 12.995x + 0.002; R2= 0.999). The dissolution profiles (Formulation 7) are shown in Figure 3.

[0073] EXAMPLE 8: PREPARATION OF TABLETS CONTAINING POTASSIUM CANRENOATE

[0074] A batch of 30 readily soluble tablets containing 100 mg of potassium canrenoate was provided with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Kanrenol 100 mg (A.I.C. 023745072 - Teofarma S.R.L).

[0075] 28.3% by weight of potassium canrenoate was mixed with 65.4% by weight of lactose (SorboLac®400 - MEGGLE GmbH), 4.7% by weight of Kollidon CL cross-linked polymer, 1.4% by weight of magnesium stearate, and 0.5% by weight of colloidal silica. Using the mixture, tablets weighing approximately 350 mg and with a hardness of 48 N were provided using a rotary tablet press (10-mm diameter convex punch, Fa = 7 kN).

[0076] A sample of 6 tablets was tested in a USP Apparatus II dissolver provided with paddle agitators. Process conditions: 800 mL of distilled water maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 295), using a calibration curve (y = 12.995x + 0.002; R2= 0.999). The dissolution profiles (Formulation 8) are shown in Figure 3.

[0077] EXAMPLE 9: PREPARATION OF TABLETS CONTAINING POTASSIUM CANRENOATE

[0078] A batch of 30 readily soluble tablets containing 100 mg of potassium canrenoate was provided with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Kanrenol 100 mg (A.I.C. 023745072 - Teofarma S.R.L).

[0079] 29.3% by weight of potassium canrenoate was mixed with 68.3% by weight of a coprocessed starch and cellulose-based product (F-Melt, Fuji Chemical Industries Co, Ltd), 1.8% by weight of magnesium stearate, and 0.6% by weight of colloidal silica. Using the mixture, tablets weighing approximately 350 mg and with a hardness of 48 N were provided, using a rotary tablet press (10-mm diameter convex punch, Fa = 7 kN).

[0080] A sample of 6 tablets was tested in a USP Apparatus II dissolver equipped with paddle stirrers. Process conditions: 800 mL of distilled water maintained at 37.0 ± 0.5 °C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 295), using a calibration curve (y = 12.995x + 0.002; R2= 0.999). The dissolution profiles (Formulation 9) are shown in Figure 3.

[0081] EXAMPLE 10: PREPARATION OF READILY SOLUBLE GRANULES CONTAINING POTASSIUM CANRENOATE

[0082] A batch of 10 g of readily soluble granules containing potassium canrenoate was provided, with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Kanrenol 100 mg (A.I.C. 023745072 - Teofarma S.R.L).

[0083] A mixture containing 30% by weight of potassium canrenoate and 70% by weight of maltodextrin (Glucidex 9 - Roquette S.p.A.) was wet granulated with ethanol, breaking up the mixture with a 1-mm mesh sieve. The granules were dried for 24 hours in an oven at 40°C.

[0084] Samples of granules containing 100 mg of potassium canrenoate (6 replicates) were tested in a USP Apparatus II dissolver equipped with paddle stirrers. Process conditions: 800 mL of distilled water maintained at 37.0 ± 0.5 °C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 295), using a calibration curve (y = 12.995x + 0.002; R2= 0.999).

[0085] The dissolution profiles (Formulation 10) are shown in Figure 4. EXAMPLE 11 : PREPARATION OF READILY SOLUBLE GRANULES CONTAINING POTASSIUM CANRENOATE

[0086] A batch of 10 g of readily soluble granules containing potassium canrenoate was provided, with the goal of increasing its dissolving rate with respect to the commercial reference consisting of Kanrenol 100 mg (A.I.C. 023745072 - Teofarma S.R.L).

[0087] A mixture containing 30% by weight of potassium canrenoate and 70% by weight of lactose (SorboLac®400 - MEGGLE GmbH) was wet- granulated with ethanol, breaking up the mixture with a 1-mm mesh sieve. The granulate was dried for 24 hours in an oven at 40°C.

[0088] Granulate samples containing 100 mg of potassium canrenoate (6 replicates) were tested in a USP Apparatus II dissolver equipped with paddle stirrers. Process conditions: 800 mL of distilled water maintained at 37.0 ± 0.5 °C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 295), using a calibration curve (y = 12.995x + 0.002; R2= 0.999). The dissolution profiles (Formulation 11) are shown in Figure 4.

[0089] EXAMPLE 12: PREPARATION OF TABLETS CONTAINING BISOPROLOL

[0090] A batch of 30 tablets in the form of hydrophilic swelling polymer- based matrices containing 10 mg of bisoprolol was provided, with the goal of prolonging its release with respect to the commercial reference consisting of Bisoprololo Teva 10 mg (A.I.C. 40147340 - Teva Italia S.R.L).

[0091] 9.8% by weight of bisoprolol was mixed with 88.2% by weight of polyethylene oxide (PEG; POLYOX WSR 303 LEO NF - Colorcon, UK), 1.5% by weight of magnesium stearate, and 0.5% by weight of colloidal silica. Using the mixture, tablets weighing approximately 102 mg and with a hardness of 129 N were provided using a rotary tablet press (5-mm diameter convex punch, Fa = 10 kN).

[0092] A sample of 6 tablets was tested in a USP Apparatus II dissolver equipped with paddle stirrers. Process conditions: 600 mL of distilled water maintained at 37.0 ± 0.5 °C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 222), using a calibration curve (y = 34.219x + 0.0028; R2= 0.996). The dissolution profiles (Formulation 12) are shown in Figure 5.

[0093] EXAMPLE 13: PREPARATION OF TABLETS CONTAINING BISOPROLOL

[0094] A batch of 30 tablets in the form of hydrophilic swelling polymer- based matrices containing 10 mg of bisoprolol was provided, with the goal of prolonging its release with respect to the commercial reference consisting of Bisoprololo Teva 10 mg (A.I.C. 40147340 - Teva Italia S.R.L).

[0095] 9.8% by weight of bisoprolol was mixed with 88.2% by weight of hydroxypropyl methylcellulose (HPMC; Methocel K4M premium - Colorcon, UK), 1.5% by weight of magnesium stearate, and 0.5% by weight of colloidal silica. Using the mixture, tablets weighing approximately 102 mg and with a hardness of 129 N were provided using a rotary tablet press (5 -mm diameter convex punch, Fa = 10 kN).

[0096] A sample of 6 tablets was tested in a USP Apparatus II dissolver provided with paddle agitators. Process conditions: 600 mL of distilled water maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 222), using a calibration curve (y = 34.219x + 0.0028; R2= 0.996). The dissolution profiles (Formulation 13) are shown in Figure 5.

[0097] EXAMPLE 14: PREPARATION OF TABLETS CONTAINING BISOPROLOL

[0098] A batch of 30 tablets in the form of hydrophilic swelling polymer- based matrices containing 10 mg of bisoprolol was provided, with the goal of prolonging its release with respect to the commercial reference consisting of Bisoprololo Teva 10 mg (A.I.C. 40147340 - Teva Italia S.R.L).

[0099] 9.8% by weight of bisoprolol was mixed with 88.2% by weight of ethylcellulose (EC; Ethocel standard 10 premium - Colorcon, UK), 1.5% by weight of magnesium stearate, and 0.5% by weight of colloidal silica. Using the mixture, tablets weighing approximately 102 mg and with a hardness of 129 N were provided using a rotary tablet press (5-mm diameter convex punch, Fa = 10 kN).

[0100] A sample of 6 tablets was tested in a USP Apparatus II dissolver provided with paddle stirrers. Process conditions: 600 mL of distilled water maintained at 37.0 ± 0.5 °C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 222), using a calibration curve (y = 34.219x + 0.0028; R2= 0.996). The dissolution profiles (Formulation 14) are shown in Figure 5.

[0101] EXAMPLE 15: PREPARATION OF GRANULES IN THE FORM OF HYDROPHILIC SWELLING POLYMER-BASED MATRICES CONTAINING BISOPROLOL

[0102] A batch of 3 g of granules in the form of hydrophilic swelling polymer-based matrices containing bisoprolol in the form of a hot solid dispersion was provided, with the goal of prolonging its release with respect to the commercial reference consisting of Bisoprololo Teva 10 mg (A.I.C. 40147340 - Teva Italia S.R.L).

[0103] A mixture containing 10% by weight of bisoprolol and 90% by weight of polyethylene oxide (PEG; POLYOX WSR 303 LEO NF - Colorcon, UK) was hot extruded (55°C) with a twin-screw extruder (20 rpm, maximum recorded stress approximately 50 N). The product extruded through a 1.8-mm diameter die was then broken up by cutting to a height of approximately 3 mm, cooled and stored in an oven for 24 hours at 40°C.

[0104] Samples of granules containing 10 mg of bisoprolol (6 replicates) were tested in a USP Apparatus II dissolver equipped with paddle stirrers. Process conditions: 600 mL of distilled water maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 222), using a calibration curve (y = 34.219x - 0.0028; R2= 0.996). The dissolution profiles (Formulation 15) are shown in Figure 6.

[0105] EXAMPLE 16: PREPARATION OF GRANULES IN THE FORM OF HYDROPHILIC SWELLING POLYMER-BASED MATRICES CONTAINING BISOPROLOL

[0106] A batch of 3 g of granules in the form of hydrophilic swelling polymer-based matrices containing bisoprolol in the form of a hot solid dispersion was provided, with the goal of prolonging its release with respect to the commercial reference consisting of Bisoprololo Teva 10 mg (A.I.C. 40147340 - Teva Italia S.R.L).

[0107] A mixture containing 10% by weight of bisoprolol and 90% by weight of a mixture of Eudragit™ RL PO and Eudragit™ RS PO, 1 :2 (Evonik Rohm GmbH) was hot extruded (55°C) with a twin-screw extruder (20 rpm, maximum recorded effort of approximately 50 N). The product extruded through a 1.8-mm diameter die was then broken up by cutting to a height of approximately 3 mm, cooled and stored in an oven for 24 hours at 40°C.

[0108] Samples of granules containing 10 mg of bisoprolol (6 replicates) were tested in a USP Apparatus II dissolver provided with paddle stirrers. Process conditions: 600 mL of distilled water maintained at 37.0 ± 0.5°C, 75 rpm. At predefined times, samples of the dissolution medium were automatically taken by a peristaltic pump connected to the dissolver and analyzed spectrophotometrically (X max = 222), using a calibration curve (y = 34.219x - 0.0028; R2 = 0.996). The dissolution profiles (Formulation 16) are shown in Figure 6.

[0109] The examples have demonstrated the following:

[0110] I. the possibility of increasing the dissolving rate of canrenone with respect to currently commercially available reference medicines (with the same contained active ingredient and dose) through its formulation in soluble tablets or ODT-type (orally disintegrating tablet) tablets and readily soluble granules, containing the drug as such, in the form of a solid dispersion with solvent or a hot dispersion, or in the form of potassium salt. Multiparticulate formulations are particularly efficient, benefiting from an increased surface area initially exposed to contact with the dissolving fluids;

[0111] IE the possibility of controlling the release rate of bisoprolol with respect to the currently commercially available reference drug, obtaining a prolongation of its release between 2 and 8 hours, depending on the type of formulation provided (matrices or granules based on inert or hydrophilic swelling polymers);

[0112] III. the possibility of providing a pharmaceutical composition containing formulations of canrenone (with high dissolving rate) and bisoprolol (with prolonged release) in the form of granules to be delivered in separate capsules contained one inside the other, taking advantage of greater patient compliance, safety of administration and dosage, and increased adherence to therapy.

[0113] The disclosures in Italian Patent Application No. 102024000020077 from which this application claims priority are incorporated herein by reference.

Claims

CLAIMS1. A pharmaceutical composition comprising a diuretic and at least one additional active ingredient selected from the group consisting of ACE inhibitors, sartans, calcium channel blockers, alpha blockers, and beta blockers, wherein said diuretic is in a first pharmaceutical form that increases its dissolving rate, said first pharmaceutical form being selected from the group consisting of a matrix that disintegrates directly in the mouth before swallowing (ODT - orally disintegrating tablet), a disintegrating tablet, a readily soluble tablet, a lyophilized matrix, an orodispersible film, and readily soluble or disintegrating granules.

2. The composition according to claim 1, wherein said diuretic is an aldosterone receptor antagonist.

3. The composition according to claim 2, wherein said aldosterone receptor antagonist is selected from the group consisting of spironolactone, eplerenone, canrenone, and their pharmaceutically acceptable salts.

4. The composition according to claim 3, wherein said aldosterone receptor antagonist is selected from the group consisting of canrenone and a pharmaceutically acceptable salt thereof.

5. The composition according to any one of the preceding claims, wherein said at least one additional active ingredient is selected from the group consisting of irbesartan, enalapril, and bisoprolol.

6. The composition according to claim 5, wherein said aldosterone receptor antagonist is selected from the group consisting of canrenone and a pharmaceutically acceptable salt thereof, and said at least one additional active ingredient is bisoprolol.

7. The composition according to claim 6, wherein canrenone is in an amount comprised between 10 and 100 mg, preferably between 25 and 50 mg, and bisoprolol is present in an amount comprised between 1 and 10 mg, preferably between 1.25 and 10 mg.

8. The pharmaceutical composition according to any one of thepreceding claims, wherein said diuretic is present in the first pharmaceutical form in a form selected from the group consisting of a pharmaceutically acceptable salt, a hot solid dispersion, a solid dispersion with solvent, and a mixture or complex with one or more excipients selected from the group consisting of a cyclodextrin, meglumine, and mesoporous silica.

9. The composition according to any one of the preceding claims, wherein said at least one additional active ingredient is in a second pharmaceutical form consisting of a sustained-release system selected from a hydrophilic swelling matrix, an insoluble matrix, and a coated system with controlled permeability.

10. The pharmaceutical composition according to claim 9, wherein said composition is a multilayer single-unit system comprising canrenone or a pharmaceutically acceptable salt thereof in disintegrating tablet form and bisoprolol in sustained-release matrix form.

11. The pharmaceutical composition according to claim 9, wherein said composition is a multiple-unit system comprising canrenone or a pharmaceutically acceptable salt thereof in the form of readily soluble granules and bisoprolol in the form of sustained-release granules.

12. The pharmaceutical composition according to any one of the preceding claims for use in the treatment of a condition selected from heart failure, arterial hypertension, myocardial fibrosis, and cardiac hypertrophy.

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