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WO2005053687A1 - Combinaison de composes organiques - Google Patents

Combinaison de composes organiques Download PDF

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Publication number
WO2005053687A1
WO2005053687A1 PCT/EP2004/013351 EP2004013351W WO2005053687A1 WO 2005053687 A1 WO2005053687 A1 WO 2005053687A1 EP 2004013351 W EP2004013351 W EP 2004013351W WO 2005053687 A1 WO2005053687 A1 WO 2005053687A1
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WO
WIPO (PCT)
Prior art keywords
hypertension
combination
valsartan
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2004/013351
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English (en)
Inventor
Daniel Lucius Vasella
Yasser Khder
Suraj Shivappa Shetty
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH Austria
Novartis AG
Original Assignee
Novartis Pharma GmbH Austria
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2005053687A1 publication Critical patent/WO2005053687A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to a combination, especially a pharmaceutical composition, comprising at least three therapeutic ingredients selected from the group consisting of (i) the AT-i-receptor antagonist valsartan or the AT-i receptor antagonist valsartan combined with a diuretic or, in each case, a pharmaceutically acceptable salt thereof; (ii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof; and (iii) aspirin; especially for use in the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of hyperlipidemia and dyslipidemia, atherosclerosis, endothelial dysfunction, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure (e.g.
  • the invention furthermore relates to a pharmaceutical composition for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of hyperlipidemia and dyslipidemia, atherosclerosis, endothelial dysfunction, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure (e.g.
  • the invention furthermore relates to a method of prevention of, delay of progression of or treatment of hyperlipidemia and dyslipidemia, atherosclerosis, endothelial dysfunction, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure (e.g.
  • the invention furthermore relates to the use of
  • the AT-i-receptor antagonist valsartan or the ATi receptor antagonist valsartan combined with a diuretic or, in each case, a pharmaceutically acceptable salt thereof; or (ii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof; or (iii) aspirin; for the manufacture of a medicament for the prevention of, delay of progression of, or treatment of hyperlipidemia and dyslipidemia, atherosclerosis, endothelial dysfunction, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure (e.g.
  • the therapeutic ingredients consists of (i) the AT receptor antagonist valsartan or the AT-, receptor antagonist valsartan combined with a diuretic or, in each case, a pharmaceutically acceptable salt thereof; (ii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof; and (iii) aspirin.
  • AT1 -receptor antagonists also called angiotensin II receptor antagonists
  • angiotensin II receptor antagonists are understood to be those active ingredients which bind to the AT1 -receptor subtype of angiotensin II receptor but do not result in activation of the receptor.
  • these antagonists can, for example, be employed as antihypertensives or for treating congestive heart failure.
  • the class of AT1 receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones.
  • Preferred AT receptor antagonist are those agents which have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof.
  • a diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorthalidon. The most preferred is hydrochlorothiazide.
  • a preferred combination component "ATi receptor antagonist combined with a diuretic” is a combination of losartan or, most preferably, valsartan or, in each case, a pharmaceutically acceptable salt thereof and hydrochlorothiazide.
  • HMG-Co-A reductase inhibitors also called ⁇ -hydroxy- ⁇ -methylglutaryl-co-enzyme-A reductase inhibitors
  • HMG-Co-A reductase inhibitors are understood to be those active agents which may be used to lower the lipid levels including cholesterol in blood.
  • the class of HMG-Co-A reductase inhibitors comprises compounds having differing structural features.
  • HMG-Co-A reductase inhibitors are those agents which have been marketed, most preferred is fluvastatin, atorvastatin, pitavastatin, rosuvastatin or simvastatin or a pharmaceutically acceptable salt thereof. Most preferred HMG-Co-A reductase inhibitors comprise fluvastatin, pitavastatin or simvastatin.
  • a preferred composition comprises the combination of (i) the A ⁇ receptor antagonist valsartan or a pharmaceutically acceptable salt thereof; (ii) a HMG-Co-A reductase inhibitor selected from the group consisting of fluvastatin, atorvastatin, pitavastatin, rosuvastatin and simvastatin or, in each case, a pharmaceutically acceptable salt thereof; and (iii) aspirin.
  • a HMG-Co-A reductase inhibitor selected from the group consisting of fluvastatin, atorvastatin, pitavastatin, rosuvastatin and simvastatin or, in each case, a pharmaceutically acceptable salt thereof; and (iii) aspirin.
  • Most preferred is the composition comprising (i) valsartan or a pharmaceutically acceptable salt thereof;
  • a preferred composition comprises the combination of (i) the AT1 receptor antagonist valsartan or a pharmaceutically acceptable salt thereof and (ii) aspirin.
  • a preferred composition comprises the combination of (i) a HMG-Co-A reductase inhibitor selected from the group consisting of fluvastatin, atorvastatin, pitavastatin and simvastatin or, in each case, a pharmaceutically acceptable salt thereof and (ii) aspirin.
  • a HMG-Co-A reductase inhibitor selected from the group consisting of fluvastatin, atorvastatin, pitavastatin and simvastatin or, in each case, a pharmaceutically acceptable salt thereof and (ii) aspirin.
  • a HMG-Co-A reductase inhibitor selected from the group consisting of fluvastatin, atorvastatin, pitavastatin and simvastatin or, in each case, a pharmaceutically acceptable salt thereof and (ii) aspirin.
  • valsartan is replaced with a combination of valsartan with hydrochlorothiazide.
  • the structure of the active agents identified hereinbefore or hereinafter by generic or tradenames may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g. Life Cycle Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
  • the corresponding active ingredients or a pharmaceutically acceptable salts thereof may also be used in form of a solvate, such as a hydrate or including other solvents, used for crystallization.
  • the compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds having an acid group (for example COOH) can also form salts with bases.
  • the pharmaceutical activities as effected by administration of representatives of the class of ATi-receptor antagonists, or of the combination of active agents used according to the present invention can be demonstrated e.g. by using corresponding pharmacological models known in the pertinent art. The person skilled in the pertinent art is fully enabled to select a relevant animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.
  • Endothelial dysfunction is being acknowledged as a critical factor in vascular diseases.
  • the endothelium plays a bimodal role as the source of various hormones or by-products with opposing effects: vasodilation and vasoconstriction, inhibition or promotion of growth, fibrinolysis or thrombogenesis, production of anti-oxidants or oxidising agents.
  • Genetically predisposed hypertensive animals with endothelial dysfunction constitute a valid model for assessing the efficacy of a cardiovascular therapy.
  • Endothelial disfunction is characterized by, for example, increased oxidative stress, causing decreased nitric oxide, increased factors involved in coagulation or fibrinolysis such as plasminogen activating inhibitor-1 (PAI-1 ), tissue factor (TF), tissue plasminogen activator (tPA), increased adhesion molecules such as ICAM and VCAM, increased growth factors such as bFGF, TGFb, PDGF, VEGF, all factors causing cell growth inflammation and fibrosis.
  • PAI-1 plasminogen activating inhibitor-1
  • TF tissue factor
  • tPA tissue plasminogen activator
  • ICAM interleukinogen activator
  • VCAM increased adhesion molecules
  • growth factors such as bFGF, TGFb, PDGF, VEGF, all factors causing cell growth inflammation and fibrosis.
  • the treatment e.g. of endothelial dysfunction can be demonstrated in the following pharmacological test:
  • valsartan, simvastatin, aspirin and HCTZ singly or in combination.
  • the drugs are administered via oral gavage, mixed in food, or included in the drinking water.
  • the rats are then killed by decapitation at 20 weeks of age.
  • Normotensive Wistar-Kyoto (WKY 20-week- old) rats serve as control group.
  • Hearts and the descending thoracic aorta are dissected out and fixed in Bouin's solution. After dehydration, the left ventricle and the aorta are embedded in paraffin.
  • Serial sections are obtained and appropriately stained. Collagen deposition in the heart is evaluated as described by Pu and Schiffrin (2001). From each of the serial sections, a predetermined number of fields are recorded.
  • the extent and severity of cardiac fibrosis is evaluated after Sirius red staining with the use of an image analysis system.
  • Collagen density was defined as the ratio of the area stained by Sirius red to the area of the studied field (expressed as percentage).
  • the perivascular collagen area is normalized to vessel luminal area of intramural coronary arteries. Total collagen content per unit area of aortic section is calculated.
  • Third-order branches of the mesenteric vasculature are isolated and mounted on a pressurized myograph as described previously (Pu et al., Hypertension. 2003;42:49-55). Endothelium-dependent and -independent relaxation are assessed in norepinephrine -precontracted resistance arteries with acetylcholine and sodium nitroprusside, respectively.
  • Heart failure is induced male Sprague Dawley rats by the method of Bates et al. (Am J Physiol Heart Circ Physiol. 2002;283:H768-75). Briefly, a left thoracotomy is performed in anesthetized rats. A ligature is placed around the proximal left coronary artery and the thorax is closed. MI is ascertained 3 wk later by hemodynamics [left venticular end-diastolic pressure (LVEDP) > 16 mmHg] and the presence of a myocardial scar on the free wall of the left ventricle. Rats with hemodynamic evidence for large Ml are used in the heart failure group.
  • LVEDP left venticular end-diastolic pressure
  • sham-operated controls Animals that underwent thoracotomy but did not have the coronary artery ligated are designated as sham-operated controls. Heart rate, aortic pressure, LVEDP, and the rate of LV pressure change (LV dP/dt) are measured by using a two-sensor pressure transducer. Randomization to treatment is assigned 3 wk post infarction. The animals are studied up to 6 wk after surgery. These studies are repeated after treatment with the agents (singly or in combination) for 3 - 6 wk.
  • Atherosclerosis studies in apoE-/- mice are conducted as described by Sparrow et al. (Arterioscler Thromb Vasc Biol. 2001 ;21:115-21). Briefly, male apoE-/- mice are weaned at 4 weeks of age onto a high-fat, Western-type diet that contained 21.22% (g/100 g) fat, 17.01% protein, 48.48% carbohydrate, and 0.15% cholesterol. The animals are dosed with the test agents for 6 weeks (singly or in combination) starting at 20 weeks of age. Blood samples are obtained (weekly) for evaluations of plasma lipids. The mice are sacrificed at the end of the study and the vascular tissues are excised for further processing. Vascular cholesterol content and lesion morphology are then ascertained.
  • results indicate that the combination treatment with valsartan and simvastatin leads to a synergistic improvement in survival rate in SHRsp.
  • Synergistic reductions in interstitial and perivascular fibrosis in the heart, on aortic collagen deposition, and progression of atherosclerosis are also observed following the combination treatment.
  • Chronic treatment of coronary-ligated rats with valsartan and simvastatin restores endothelial NO-dependent dysfunction and favorably modulates in a synergistic manner cardiac hypertrophy and function after myocardial infarction.
  • the combination treatment also ameliorates cerebrovascular and renal glomerular damage in SHRsp and improves survival rates.
  • composition of the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
  • the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
  • composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
  • the present invention likewise relates to a "kit-of-parts", for example, in the sense that the components to be combined according to the present invention can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. simultaneously or at different time points.
  • the parts of the kit of parts can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components.
  • Statin/aspirin/valsartan fixed dose combination (with or without hydrochlorothiazide) is a real opportunity to fight against coronary heart disease and stroke either in primary prevention or in secondary prevention.
  • the combination of the present invention is based on the efficacy of the different components of the combination on the major risk factors such as hypertension, dyslipidemia and metabolic syndrome.
  • the different components of the combination have synergistic effects.
  • statin by decreasing LDL cholesterol, by diminishing the progression of the atherosclerotic process and by stabilizing the vulnerable plaque and reducing the inflammation in the active vascular lesions, as well as, aspirin by decreasing the aggregation of the platelets and by reducing the secretion of several detrimental vasoactive agents secreted by activated platelets play complementary beneficial roles.
  • valsartan an extremely selective and highly potent angiotensin II antagonist, prevents against the deleterious effect of angiotensin II on the arterial wall, enhances the release of nitric oxide, decrease the vascular inflammation and decreases oxidative stress.
  • valsartan has strong anti-platelet property which enhances the biological effect of aspirin and induces powerful antiaggregation that can not be obtained by aspirin alone.
  • Statins and valsartan both comprise strong anti-inflammatory properties and both showed that they can reduce post PCI restenosis.
  • Clinical trials can demonstrate that the combination according to the present invention allows correcting different biological abnormalities in high risk patients:
  • 2- valsartan plus statin produce better improvement of inflammation (usCRP, adhesion molecules) pro-thrombosis (PAI-1), endothelial dysfunction markers (ADMA, von Willibrand factor) and oxidative stress (isoprostans in the urine, MDA) more than valsartan or statin alone.
  • a suitable fixed dose combination can reduce the atheroma burden to higher extent than the reference compounds by using intra coronary ultrasonography and carotid IMT.
  • the invention furthermore relates to a commercial package comprising the combination according to the present invention together with instructions for simultaneous, separate or sequential use.
  • These pharmaceutical preparations are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances.
  • the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compound.
  • Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner which is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing processes.
  • compositions for oral use can be obtained by combining the active compound with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.
  • the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commerically available.
  • an approximate daily dose of from about 1 mg to about 360 mg is to be estimated e.g. for a patient of approximately 75 kg in weight.
  • the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • Valsartan as a representative of the class of ATi-receptor antagonists, will be supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising a therapeutically effective amount, e.g. from about 20 to about 320 mg, of valsartan which may be applied to patients.
  • a suitable dosage unit form may comprise 40 mg, 80 mg, 160 mg or 320 mg per dosaqe unit form.
  • the application of the active ingredient may occur once up to three times a day, starting e.g. with a daily dose of 20 mg or 40 mg of valsartan, increasing via 80 mg daily and further to 160 mg daily up to 320 mg daily.
  • valsartan is applied twice a day with a dose of 80 mg or 160 mg, respectively, each. Corresponding doses may be taken, for example, in the morning, at mid-day or in the evening.
  • preferred dosage unit forms of HMG-Co-A reductase inhibitors are, for example, tablets or capsules comprising e.g. from about 1 to 180 mg, especially, 5 mg to about 120 mg, preferably, when using fluvastatin, for example, 20 mg, 40 mg or 80 mg (equivalent to the free acid) of fluvastatin, for example, administered once a day or per dosage unit form, respectively.
  • fluvastatin for example, 20 mg, 40 mg or 80 mg (equivalent to the free acid) of fluvastatin, for example, administered once a day or per dosage unit form, respectively.
  • simvastatin for example, 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin is used per dosage unit form.
  • pitavastatin for example, 1 mg, 3 mg, 6 mg, 8 mg or 16 mg of pitavastatin is used per dosage unit form, especially 3 mg or 6 mg, per dosage unit form.
  • preferred dosage form comprise of tablets containing from about 10 to 1000mg, especially, 81 mg to 325 mg or a dose selected from 200 mg, 325 mg, 389 mg, 500 mg, 650 mg and 770 mg, especially 325 mg, of the drug substance, for example administered once a day or per dosage unit form, respectively.
  • compositions comprising (i) a dose of valsartan selected from 40 mg, 80 mg, 160 mg and 320 mg of valsartan, (ii) a dose of simvastatin selected from 5 mg, 10 mg, 20 mg, 40 mg and 80 mg of simvastatin or a dose of pitavastatin selected from 1 mg, 3 mg, 6 mg, 12 mg or 16 mg of pitavastatin or a dose of fluvastatin selected from 20 mg, 40 mg and 80 mg (equivalent to the free acid) of fluvastatin and a dose selected from 200 mg, 325 mg, 389 mg, 500 mg, 650 mg and 770 mg, especially 325 mg of aspirin.
  • Preferred are dosage unit forms or a single dosage unit form comprising (i) a dose of valsartan selected from 40 mg, 80 mg, 160 mg and 320 mg, especially 80 mg, of valsartan, (ii) a dose of simvastatin selected from 5 mg, 10 mg, 20 mg, 40 mg and 80 mg of simvastatin or a dose of pitavastatin selected from 1 mg, 3 mg, 6 mg, 12 mg or 16 mg, especially 3 mg or 6 mg, of pitavastatin or a dose of fluvastatin selected from 20 mg, 40 mg and 80 mg (equivalent to the free acid) of fluvastatin and a dose of aspirin selected from 200 mg, 325 mg, 389 mg, 500 mg, 650 mg and 770 mg, especially 325 mg mg, of aspirin.
  • aspirin selected from 200 mg, 325 mg, 389 mg, 500 mg, 650 mg and 770 mg, especially 325 mg mg, of aspirin.
  • dosage unit forms or a single dosage unit form comprising (i) a dose of valsartan selected from 40 mg, 80 mg, 160 mg and 320 mg, especially 80 mg, of valsartan, (ii) a dose of simvastatin selected from 5 mg, 10 mg, 20 mg, 40 mg and 80 mg of simvastatin or a dose of pitavastatin selected from 1 mg, 3 mg, 6 mg, 12 mg or 16 mg, especially 3 mg or 6 mg, of pitavastatin and a dose of aspirin selected from 200 mg, 325 mg, 389 mg, 500 mg, 650 mg and 770 mg, especially 325 mg mg, of aspirin.
  • the film-coated tablet is manufactured e.g. as follows:
  • a mixture of valsartan, microcrystalline cellulose, crospovidone, part of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200, silicon dioxide and magnesium stearate is premixed in a diffusion mixer and then sieve through a screnning mill.
  • the resulting mixture is again pre-mixed in a diffusion mixer, compacted in a roller compacter and then sieve through a screening mill.
  • the rest of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200 are added and the final blend is made in a diffusion mixer.
  • the whole mixture is compressed in a rotary tabletting machine and the tabletts are coated with a film by using Diolack pale red in a perforated pan.
  • Formulation Example 2 Film-coated tablets:
  • the film-coated tablet is manufactured e.g. as described in Formulation Example 1.
  • the film-coated tablet is manufactured e.g. as described in Formulation Example 1.
  • the tablet is manufactured e.g. as follows:
  • Valsartan and microcrystallin cellulose are spray-granulated in a fluidised bed granulator with a granulating solution consisting of povidone and sodium lauryl sulphate dissolved in purified water.
  • the granulate obtained is dried in a fluidiesd (Check spelling) bed dryer.
  • the dried granulate is milled together with crospovidone and magnesium stearate.
  • the mass is then blended in a conical srew (Check spelling) type mixer for approximately 10 minutes.
  • the empty hard gelatin capsules are filled with the blended bulk granules under controlled temperature and humidity conditions.
  • the filed capsules are dedustee (check spelling), visually inspected, weightchecked and guarantied until by Quality assurance department.
  • the formulation is manufactured e.g. as described in Formulation Example 4.
  • Example 14 Round, slightly bi-convex, film-coated tablets with beleved edges:

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Abstract

L'invention concerne une combinaison d'au moins trois ingrédients thérapeutiques choisis dans le groupe constitué par (i) un antagoniste du récepteur AT1 ou un antagoniste du récepteur AT1 combiné avec un diurétique ou, dans chaque cas, un sel pharmaceutiquement acceptable correspondant, (ii) un inhibiteur de HMG-Co-A réductase ou un sel pharmaceutiquement acceptable correspondant, et (iii) de l'aspirine. Cette combinaison peut être utilisée pour prévenir ou traiter des maladies et des affections sélectionnées ou pour en freiner l'évolution.
PCT/EP2004/013351 2003-11-25 2004-11-24 Combinaison de composes organiques Ceased WO2005053687A1 (fr)

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US52506203P 2003-11-25 2003-11-25
US60/525,062 2003-11-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007051007A3 (fr) * 2005-10-28 2007-09-13 Novartis Ag Combinaison de composes organiques
EP1888102A4 (fr) * 2005-06-10 2008-10-15 Univ Louisiana State Modulation des horloges peripheriques dans le tissu adipeux
WO2013159166A1 (fr) * 2012-04-26 2013-10-31 Hypermarcas S.A. Forme pharmaceutique orale pour la prévention de maladies vasculaires, comprimé utilisé comme forme pharmaceutique et capsule gélatineuse utilisée comme forme pharmaceutique

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Publication number Priority date Publication date Assignee Title
WO2000002543A2 (fr) * 1998-07-10 2000-01-20 Novartis Ag Methode de traitement et composition pharmaceutique
WO2000044378A1 (fr) * 1999-01-26 2000-08-03 Novartis Ag Utilisation des antagonistes du recepteur d'angiotensine ii dans le traitement de l'infarctus aigu du myocarde
US6204281B1 (en) * 1998-07-10 2001-03-20 Novartis Ag Method of treatment and pharmaceutical composition
GB2361185A (en) * 2000-04-10 2001-10-17 Nicholas J Wald Pharmaceutical formulation for the prevention of cardiovascular disease
US20030068366A1 (en) * 2001-08-28 2003-04-10 Shubha Chungi Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin
WO2004080488A2 (fr) * 2003-03-10 2004-09-23 Bayer Healthcare Ag Preparations combinees d'acide acetylsalycilique pour la prevention primaire de maladies cardiovasculaires

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000002543A2 (fr) * 1998-07-10 2000-01-20 Novartis Ag Methode de traitement et composition pharmaceutique
US6204281B1 (en) * 1998-07-10 2001-03-20 Novartis Ag Method of treatment and pharmaceutical composition
WO2000044378A1 (fr) * 1999-01-26 2000-08-03 Novartis Ag Utilisation des antagonistes du recepteur d'angiotensine ii dans le traitement de l'infarctus aigu du myocarde
GB2361185A (en) * 2000-04-10 2001-10-17 Nicholas J Wald Pharmaceutical formulation for the prevention of cardiovascular disease
US20030068366A1 (en) * 2001-08-28 2003-04-10 Shubha Chungi Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin
WO2004080488A2 (fr) * 2003-03-10 2004-09-23 Bayer Healthcare Ag Preparations combinees d'acide acetylsalycilique pour la prevention primaire de maladies cardiovasculaires

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1888102A4 (fr) * 2005-06-10 2008-10-15 Univ Louisiana State Modulation des horloges peripheriques dans le tissu adipeux
WO2007051007A3 (fr) * 2005-10-28 2007-09-13 Novartis Ag Combinaison de composes organiques
WO2013159166A1 (fr) * 2012-04-26 2013-10-31 Hypermarcas S.A. Forme pharmaceutique orale pour la prévention de maladies vasculaires, comprimé utilisé comme forme pharmaceutique et capsule gélatineuse utilisée comme forme pharmaceutique

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