WO2011141381A1 - Association of xanthine oxidase inhibitors and calcium antagonists and use thereof - Google Patents

Association of xanthine oxidase inhibitors and calcium antagonists and use thereof Download PDF

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Publication number
WO2011141381A1
WO2011141381A1 PCT/EP2011/057326 EP2011057326W WO2011141381A1 WO 2011141381 A1 WO2011141381 A1 WO 2011141381A1 EP 2011057326 W EP2011057326 W EP 2011057326W WO 2011141381 A1 WO2011141381 A1 WO 2011141381A1
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pharmaceutically acceptable
association
acceptable salts
composition according
therapeutic treatment
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PCT/EP2011/057326
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French (fr)
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Francesco Melani
Sandro Giuliani
Carlo Alberto Maggi
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Menarini International Operations Luxembourg S.A.
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to an association of active principles, i.e. of a xanthine oxidase inhibitor with one or more calcium antagonists, pharmaceutical compositions comprising said active principles, for use in a human or veterinary therapeutic treatment, and methods for the preparation thereof.
  • active principles i.e. of a xanthine oxidase inhibitor with one or more calcium antagonists
  • pharmaceutical compositions comprising said active principles, for use in a human or veterinary therapeutic treatment, and methods for the preparation thereof.
  • Such associations and such compositions proved particularly effective in the treatment of hypertension, alone or in association with hyperuricemia or to other disorders in the clinical context of the metabolic syndrome.
  • Gout is an invalidating chronic disease characterized by hyperuricemia and deposition of monosodium urate crystals in various tissues, mainly at the joint level and in the kidney. Hyperuricemia and gout are frequently associated to other cardiovascular risk factors such as hypertension and other elements that are part of the metabolic syndrome, like obesity, fasting hyperglycemia, low HDL levels and high triglycerid levels.
  • a xanthine oxidase inhibitor well-known in the literature is allopurinol. More recently, other xanthine oxidase inhibitors have appeared on the market; among them, febuxostat is of particular relevance.
  • Febuxostat is a powerful non-purine selective inhibitor of xanthine oxidase which in clinical studies has been shown to reduce hyperuricemia more effectively than allopurinol.
  • Febuxostat is a thiazole derivative having formula (I), belonging to the class of xanthine oxidase inhibitors, and was originally described in EP513379.
  • EP1020454 it is also described a polymorphic form of febuxostat and a process for obtaining it. I n addition to its use as anti-hyperuricemic agent and in the treatment of gout, references are also found to the potential use of febuxostat in other pathologies.
  • WO2004060489 it is described the use of xanthine oxidase inhibitors for increasing cardiac contractility in CHF (Chronic Heart Failure) patients.
  • febuxostat is used to reduce the QT interval in patients in which such interval is prolonged, and in the pathologies associated thereto.
  • WO2008064015 the use of xanthine oxidase inhibitors, among which febuxostat, is indicated to preserve renal function.
  • xanthine oxidase inhibitors among which febuxostat, preferably for the treatment of prehypertension characterized by systolic pressure between 120 and 139 mm Hg and diastolic pressure between 80 and 89 mmHg; here, xanthine oxidase inhibitors seem to be indicated also in the treatment of more marked hypertensions, though results obtained do not seem to be equal to those of already known anti-hypertensive agents.
  • Amlodipine acts by blocking calcium influx in cells, causing vasodilation and subsequent pressure reduction.
  • amlodipine salt besylate (benzene sulphonate) is claimed.
  • the present invention is based on the surprising discovery made by the Inventors that the association of a xanth i ne oxidase in hi bitor, in particular febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof, in combination with one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof exhibits a synergistic therapeutic effect in the treatment of hypertension.
  • experimental data reported in the present description demonstrate th at the therapeutic effect resulting from the association of the two active principles is greater than the sum of the therapeutic effects resulting from the same dosages of each active principle administered alone.
  • a first object of the present invention is an association of th e active principles:
  • a second object of the present invention is a pharmaceutical composition comprising, as active principle, a mixture of:
  • xanthine oxidase inhibitor febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof;
  • one or more pharmaceutically acceptable excipients and/or carriers and/or diluents for use in a human or veterinary therapeutic treatment.
  • Another object of the present invention is a method for the preparation of the composition according to the present description, wherein the active mixture comprising:
  • the present invention advantageously entails a greater anti-hypertensive activity compared to that observed using the sole calcium antagonist or the sole xanthine oxidase inhibitor. Moreover, a further advantage is given by the possibility of obtaining significant effects in the treatment of hypertension with a reduced amount of calcium antagonist with respect to the monotherapy treatment.
  • the present invention relates to an association of the active principles:
  • association in the present description it is meant an association of the active principles, both in the form of a physical mixture constituted by said active principles in a single dosage unit, and in the form of dosage units physically separated according to active principle, but for concomitant administration. In both cases, association must ensure a synergy of the therapeutic effects obtained from the individual active principles with respect to the effect obtained in monotherapy.
  • the non-purine xanthine oxidase inhibitor of said association is preferably febuxostat, a thiazole derivative having formula (I), or pharmaceutically acceptable salts thereof or polymorphic forms thereof.
  • Pharmaceutically acceptable salts of xanthine oxidase inhibitors, and in particular of febuxostat include but are not limited to cations of alkali metals and of alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium or aluminium salts, or non-toxic derivatives with quaternary ammonium and cations of a m i n es su ch as a m m on i u m , tetram ethyla m mon i u m, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, or derive from the addition of organic amines such as ethylendiamine, ethanolamine, diethanolamine, piperazine, tromethamine, lysine, arginine and the like.
  • alkali metals and of alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium or aluminium salts
  • febuxostat include, but are not limited to the forms described in European Patent EP1020454.
  • Febuxostat, its salts or polymorphic forms thereof could be obtained or prepared according to methods described in the known art, like e.g. in EP513379.
  • the calcium antagonists according to the present description belong, as indicated in the foregoing, to the class of dihydropyridine calcium antagonists of general formula (II).
  • the calcium antagonists are selected from th e g rou p comprising: amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine or pharmaceutically acceptable salts thereof.
  • the dihydropyridine calcium antagonists may be chiral or non-chiral.
  • chiral molecules a single enantiomer, a mixture of enantiomers or diastereoisomers or the racemic mixture could be used.
  • those specific stereoisomers, as well as polymorphic forms, which exhibit a greater biological activity are to be preferred.
  • salts of calcium antagonists having an acid function in the molecule include but are not limited to cations of alkali metals and of alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium or aluminium salts, or non-toxic derivatives with quaternary ammonium and cations of a m i n es su ch as a m m on i u m , tetram ethyla m mon i u m, tetraethylammonium, methylammonium, dimethylammonium , trimethylammonium , or derive from the addition of organic amines such as ethylendiamine, ethanolamine, diethanolamine, piperazine, tromethamine, lysine, arginine and the like; whereas salts of calcium antagonists having a basic function in the molecule, and among them amlodipine, include anions formally derived from inorganic acids, such as hydro
  • the pharmaceutically acceptable salt is amlodipine besylate.
  • the xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof are associated with one or more of said calcium antagonists or pharmaceutically acceptable salts thereof in a weight ratio of febuxostat/Ca antagonist comprised between 0.5 and 400, e.g. a weight ratio comprised between 2.5 and 120.
  • febuxostat in an amount comprised between 10-200 mg, or better comprised between 25-120 mg, in association with an amount of calcium inhibitor comprised between 0.5-20 mg, e.g. comprised between 1 -10 mg.
  • association envisages a physical mixture of two compounds, as active principles, having the one an acid fuction and the other one a basic function, also the forming of an internal salt between the two is possible, in proportion to the respective amounts present in the mixture.
  • a further embodiment of the present invention relates to pharmaceutical compositions comprising, as active principle, a mixture of:
  • xanthine oxidase inhibitor febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof;
  • one or more usual pharmaceutically acceptable excipients and/or additives and/or diluents for use in the therapeutic or veterinary treatment.
  • the calcium antagonist or the calcium antagonists to be used according to the above-described composition are selected from the group comprising: amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine or pharmaceutically acceptable salts thereof.
  • compositions according to the present invention may be formulated in various forms depending on the selected administration route.
  • the pharmaceutical composition is suitable for oral administration of solid forms and may include formulations such as capsules, tablets, pills, powders and granules.
  • the two active principles, the xanthine oxidase inhibitor and the antihypertensive agent can be mixed with one or more pharmaceutically acceptable inert excipients.
  • excipients may be selected among those commonly known in the state of the art and include, but are not limited to: a) carriers, such as sodium citrate and calcium phosphate, b) fillers, such as starch, lactose, microcrystalline cellulose, sucrose, glucose, mannitol and colloidal silica, c) moistening agents, such as glycerol, d) disintegrating agents, such as alginates, calcium carbonate, starches, derivatives of starch, of cellulose and polyvinylpyrrolidone, silicates and sodium carbonate, e) binders, such as carboxymethyl cellulose, alginates, gelatin , polyvinylpyrrolidone, sucrose, polymeric derivatives of cellulose, starch derivatives f) retarding agents, such as paraffin , cellulose polymers, fatty acid esters, g) absorption accelerators, such as quaternary ammonium compounds, h ) wetting agents and su rfactants, such as cetyl
  • the excipients include but are not limited to compounds of the type: lactose, high molecular weight polyethylene glycol, and the like.
  • Solid-dosage forms may be coated with enteric, gastric coatings, or coatings of other type well-known in the state of the art. They may contain matting agents and may be of the type such as to allow the release of active ingredients only or preferably in a certain section of the intestine, optionally in a delayed manner. Substances capable of allowing such a delayed use include, but are not limited to, polymers and waxes.
  • Liqu id forms suitable for oral ad min istration are emulsions, solutions, prepared or extemporary suspensions, syrups and elixirs.
  • Excipients suitable for the formulations according to the present invention in liquid forms for oral use include, but are not limited to diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents selected from ethyl alcohol, polyalcohols, propylene glycol, glycerol, polyethylene glycol and sorbitan esters. These formulations can also contain sweeteners and aromas selected from those well-known in the state of the art.
  • compositions suitable for pharmaceutically acceptable parenteral injections may comprise sterile aqueous solutions, sterile dispersions, suspensions or emulsions or powders for a reconstitution in injectable solutions or dispersions; examples of excipients suitable therefor include, but are not limited to aqueous or non-aqueous carriers, diluents, solvents or vehicles selected from: water, ethanol, polyoils (propylene or polyethylene glycol, glycerol, and the like), polyalcohols, isopropyl alcohol, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 .3-butylene glycol, dimethylformamide, vegetable oils (in particular of olive, cotton, peanut, corn, wheat germ, olive, castor, sesame), organic esters such as ethyl oleate or the like.
  • excipients suitable therefor include, but are not limited to aqueous or non-aqueous carriers
  • compositions may also contain preservatives of antibacterial or antifungal type, selected, yet not exclusively, from: paraben, chlorbutanol, phenol, sorbic acid and the like. It may also be useful to include an isotonic agent, e.g., a sugar, sodium chloride or the like. Moreover, pharmaceutical forms with a delayed absorption may be obtained with agents such as, for instance, yet not exclusively, aluminium monostearate and gelatin.
  • the suspensions may contain suspend ing agents such as, for instance, yet not exclusively, ethoxylated isostearic alcohols, polyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium hydroxide, bentonite, alginates and cellulose derivatives in general or the like.
  • suspend ing agents such as, for instance, yet not exclusively, ethoxylated isostearic alcohols, polyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium hydroxide, bentonite, alginates and cellulose derivatives in general or the like.
  • the right fluidity can be maintained with a coating material such as lecithin, with the maintaining of the right particle sizes in the dispersions or with the use of surfactants.
  • slow-release formulations can be prepared , by the techniques and products well-known in the state of the art.
  • the associations and compositions according to the present invention are extremely effective in the treatment, also meant as prophylaxis and therapy, of hypertension, in humans or animals.
  • hypotension that with diastolic values higher than 80 mm/Hg and/or systolic values higher than 120 mm/Hg.
  • Hypertension can be associated or not associated to other pathologies or syndromes and symptoms.
  • the association described herein is useful also in the therapeutic treatment of hypertension associated to hyperuricemia and/or hyperglycemia.
  • Symptoms such as hypertension, hyperuricemia or hyperglycemia can also be associated, individually or in combination, to specific syndromes like, e.g., the metabolic syndrome.
  • metabolic syndrome it is meant a clinical condition accompanied by situations such as obesity.
  • the associations and compositions described herein can therefore be used in the therapeutic treatment of hypertension associated to hyperuricemia and/or hyperglycemia and/or other disorders in the context of the metabolic syndrome.
  • Dosage may vary depending on the patient's age and general conditions, the nature and seriousness of the pathology or disorder and on the administration route and type. Dosage should therefore take into account the specific condition to be treated (e.g., hyperglycemia alone or in association with hyperuricemia and/or glycemia), the severity of the condition to be treated, the age, weight and general physical conditions of the specific patient, as well as other drugs that the patient is taking, as is well-known to those skilled in the art. Moreover, it is evident that said effective amount may, when required , be lowered or raised according to the responses of the treated patient and/or according to the assessment of the physician prescribing the compounds of the present invention.
  • the specific condition to be treated e.g., hyperglycemia alone or in association with hyperuricemia and/or glycemia
  • said effective amount may, when required , be lowered or raised according to the responses of the treated patient and/or according to the assessment of the physician prescribing the compounds of the present invention.
  • compositions for oral use in solid form can contain an amount of xanthine oxidase inhibitor, febuxostat, of between 10 and 200 mg per dosage unit, and preferably of between 25 and 120 mg, and an amount of calcium antagonist, preferably amiodipine, of between 0.5 and 20 mg per dosage unit, preferably of between 1 and 10 mg; should amiodipine be administered as besylate, the amounts would be of between 0.7 and 27.0 mg per dosage unit.
  • xanthine oxidase inhibitor febuxostat
  • calcium antagonist preferably amiodipine
  • dosage unit in the present description it is meant the unitary formulation for a single administration, e.g. a tablet, capsule, etc.
  • unit dosage it is meant the amount of active principle for a single administration.
  • compositions of the invention could be prepared according to techniques known in the field , both using the previously prepared association of active principles, and mixing the individual compounds directly during the preparation of the composition.
  • association of active principles may be obtained by a step of mixing the xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof with one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof, in a weight ratio comprised between 0.5 and 400, or between 2.5 and 120.
  • the mixture of active principles is formulated in suitable dosage units with one or more pharmaceutically acceptable excipients and additives.
  • SBP Systolic pressure
  • Hyperuricemia was induced with administration of oxonic acid (750 mg/kg per day, orally in the meal), an uricase inhibitor capable of inducing experimental hyperuricemia associated to a slight hypertensive effect in normotensive rats (Mazzali et al., Hypertension 38: 1 101 -1 106, 2001 ).
  • Febuxostat and/or amlodipine were administered orally once per day, by gavage, at the dose of 1 -2.5-5 mg/kg for febuxostat and of 0.5-1 -2 mg/kg for amlodipine, for 4 weeks beginning from the fourth week from the start of the treatment with oxonic acid.
  • SBP systolic pressure
  • plasma uric acid/urate levels as well as basal values, both 4 and 8 weeks after start of treatment with oxonic acid.
  • Blood was collected from a tail vein.
  • Basal values of plasma uric acid were comparable in all groups and comprised between 0.45 and 0.60 mg/dL. After 4 weeks from the daily treatment with oxonic acid, rats showed a significant increase of plasma uric acid, higher than over 100% with respect to the basal value. Oral administration of febuxostat from the fourth to the eighth week from the start of the treatment with oxonic acid reduced hyperuricemia values in a dose-dependent manner (Table 1 ) whereas amlodipine, non active per se, in combination with febuxostat surprisingly made febuxostat effect significant in reducing hyperuricemia even at the lower dose (1 mg/kg per os).
  • Febuxostat (1 -2.5-5 mg/kg per os for 4 months) reduced systolic pressure to control values at the dose of 5 mg/kg per os.
  • Amlodipine (0.5-1 -2 mg/kg per os for 4 months) reduced systolic pressure in a significant and dose-dependent manner (Table 1 ).
  • Combined administration of febuxostat and amiodipine at the lowest doses of each compound reduced the systolic pressure in hypertensive rats to the values obtained with the higher dose of amiodipine (2 mg/kg per os) showing consistent enhancement of the hypotensive effect of the calcium antagonist compound.
  • Table 1 Effect of oral administration of febuxostat, amiodipine or their combination on uricemia and pressure values in spontaneously hypertensive rats (SHR) treated with oxonic acid for 8 weeks.
  • tablet for oral administration containing:
  • silicified microcrystalline cellulose (filler) 32.656 mg
  • tablet for oral administration containing:
  • silicified microcrystalline cellulose (filler) 72.256 mg
  • tablet for oral administration containing:

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Abstract

The present invention relates to an association of active principles, i.e. of a xanthine oxidase inhibitor with one or more calcium antagonists, pharmaceutical compositions comprising said active principles, for use in a human or veterinary therapeutic treatment, and methods for the preparation thereof.

Description

ASSOCIATION OF XANTHINE OXIDASE INHIBITORS AND CALCIUM ANTAGONISTS AND USE THEREOF
DESCRIPTION TECHNICAL FIELD OF THE INVENTION
The present invention relates to an association of active principles, i.e. of a xanthine oxidase inhibitor with one or more calcium antagonists, pharmaceutical compositions comprising said active principles, for use in a human or veterinary therapeutic treatment, and methods for the preparation thereof.
Such associations and such compositions proved particularly effective in the treatment of hypertension, alone or in association with hyperuricemia or to other disorders in the clinical context of the metabolic syndrome.
STATE OF THE PRIOR ART
Gout is an invalidating chronic disease characterized by hyperuricemia and deposition of monosodium urate crystals in various tissues, mainly at the joint level and in the kidney. Hyperuricemia and gout are frequently associated to other cardiovascular risk factors such as hypertension and other elements that are part of the metabolic syndrome, like obesity, fasting hyperglycemia, low HDL levels and high triglycerid levels.
Hence, the need to always have novel means of treatment in order to better manage chronic therapy of hyperuricemia and pathologies frequently correlated thereto.
A xanthine oxidase inhibitor well-known in the literature is allopurinol. More recently, other xanthine oxidase inhibitors have appeared on the market; among them, febuxostat is of particular relevance.
Febuxostat is a powerful non-purine selective inhibitor of xanthine oxidase which in clinical studies has been shown to reduce hyperuricemia more effectively than allopurinol.
Febuxostat is a thiazole derivative having formula (I), belonging to the class of xanthine oxidase inhibitors, and was originally described in EP513379.
Figure imgf000002_0001
(I)
In EP1020454 it is also described a polymorphic form of febuxostat and a process for obtaining it. I n addition to its use as anti-hyperuricemic agent and in the treatment of gout, references are also found to the potential use of febuxostat in other pathologies.
In WO2004060489 it is described the use of xanthine oxidase inhibitors for increasing cardiac contractility in CHF (Chronic Heart Failure) patients.
In WO2007062028 febuxostat is used to reduce the QT interval in patients in which such interval is prolonged, and in the pathologies associated thereto.
In WO2008064015 the use of xanthine oxidase inhibitors, among which febuxostat, is indicated to preserve renal function.
In WO2007019153 it is claimed the use of some xanthine oxidase inhibitors, among which febuxostat, preferably for the treatment of prehypertension characterized by systolic pressure between 120 and 139 mm Hg and diastolic pressure between 80 and 89 mmHg; here, xanthine oxidase inhibitors seem to be indicated also in the treatment of more marked hypertensions, though results obtained do not seem to be equal to those of already known anti-hypertensive agents.
In WO2007019153, besides the above-mentioned use it is also mentioned the optional possibility of administering to a hypertensive subject an amount of at least one anti-hypertensive compound with at least one inhibitor of a xanthine oxidase; no example however is reported with associations of a xanthine oxidase inhibitor and an anti-hypertensive agent, nor is it indicated a way of selecting, among the various classes of anti-hypertensive agents or the very large number of compounds exhibiting evident anti-hypertensive activity, that class or those compounds which may be useful for a pharmaceutical composition suitable for a treatment of hypertension combined with an anti-hypertensive agent and a xanthine oxidase inhibitor.
Feig DL et al, JAMA 2008; 300: 924, report that allopurinol in monotherapy shows an anti-hypertensive effect in 30 hypertensive subjects, yet only on teenagers.
Arterial hypertension is successfully treated with several drugs belonging to different therapeutic classes. Among them, the class of calcium antagonists must be considered of particular relevance; in it we include, by way of example, amlodipine, representing one of the most effective anti-hypertensives, commonly used in clinical practice.
Amlodipine acts by blocking calcium influx in cells, causing vasodilation and subsequent pressure reduction.
Chanard J et al, in Nephrol. Dial Transplant., 2003, 18 (10), 2147- 2153, also report that amlodipine can reduce hyperuricemia in hypertensive kidney transplant recipients.
In EP89167 it is claimed the product amlodipine, effective in the treatment of hypertensions.
In EP244944 the amlodipine salt, besylate (benzene sulphonate) is claimed.
Finally, in EP1491 193, EP1003503 and in EP1096932 associations between amlodipine and atorvastatin or valsartan are claimed.
SUMMARY OF THE INVENTION
The present invention is based on the surprising discovery made by the Inventors that the association of a xanth i ne oxidase in hi bitor, in particular febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof, in combination with one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof exhibits a synergistic therapeutic effect in the treatment of hypertension. In fact, experimental data reported in the present description demonstrate th at the therapeutic effect resulting from the association of the two active principles is greater than the sum of the therapeutic effects resulting from the same dosages of each active principle administered alone.
A first object of the present invention is an association of th e active principles:
a) the xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof; and
b) one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof
for use in a human or veterinary therapeutic treatment.
A second object of the present invention is a pharmaceutical composition comprising, as active principle, a mixture of:
a) xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof;
b) one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof, and
one or more pharmaceutically acceptable excipients and/or carriers and/or diluents, for use in a human or veterinary therapeutic treatment.
Another object of the present invention is a method for the preparation of the composition according to the present description, wherein the active mixture comprising:
a) the xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof;
b) one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof
is formulated in suitable dosage units with one or more pharmaceutically acceptable excipients.
As an advantage with respect to the state of the prior art, the present invention advantageously entails a greater anti-hypertensive activity compared to that observed using the sole calcium antagonist or the sole xanthine oxidase inhibitor. Moreover, a further advantage is given by the possibility of obtaining significant effects in the treatment of hypertension with a reduced amount of calcium antagonist with respect to the monotherapy treatment.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an association of the active principles:
a) xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof; and
b) one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof
for use in a human or veterinary therapeutic treatment.
By "association" in the present description it is meant an association of the active principles, both in the form of a physical mixture constituted by said active principles in a single dosage unit, and in the form of dosage units physically separated according to active principle, but for concomitant administration. In both cases, association must ensure a synergy of the therapeutic effects obtained from the individual active principles with respect to the effect obtained in monotherapy.
According to the present invention the non-purine xanthine oxidase inhibitor of said association is preferably febuxostat, a thiazole derivative having formula (I), or pharmaceutically acceptable salts thereof or polymorphic forms thereof.
Pharmaceutically acceptable salts of xanthine oxidase inhibitors, and in particular of febuxostat, include but are not limited to cations of alkali metals and of alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium or aluminium salts, or non-toxic derivatives with quaternary ammonium and cations of a m i n es su ch as a m m on i u m , tetram ethyla m mon i u m, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, or derive from the addition of organic amines such as ethylendiamine, ethanolamine, diethanolamine, piperazine, tromethamine, lysine, arginine and the like.
Polymorphic forms of febuxostat include, but are not limited to the forms described in European Patent EP1020454. Febuxostat, its salts or polymorphic forms thereof could be obtained or prepared according to methods described in the known art, like e.g. in EP513379.
In case of some polymorphic forms, reference could be made to what is disclosed in European Patent EP1020454.
The calcium antagonists according to the present description belong, as indicated in the foregoing, to the class of dihydropyridine calcium antagonists of general formula (II).
Figure imgf000006_0001
(II)
Accord ing to an embodiment of the present description, the calcium antagonists are selected from th e g rou p comprising: amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine or pharmaceutically acceptable salts thereof.
To the ends of the present invention, the dihydropyridine calcium antagonists may be chiral or non-chiral. In case of chiral molecules a single enantiomer, a mixture of enantiomers or diastereoisomers or the racemic mixture could be used. According to the present description those specific stereoisomers, as well as polymorphic forms, which exhibit a greater biological activity are to be preferred.
Pharmaceutically acceptable salts of calcium antagonists having an acid function in the molecule include but are not limited to cations of alkali metals and of alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium or aluminium salts, or non-toxic derivatives with quaternary ammonium and cations of a m i n es su ch as a m m on i u m , tetram ethyla m mon i u m, tetraethylammonium, methylammonium, dimethylammonium , trimethylammonium , or derive from the addition of organic amines such as ethylendiamine, ethanolamine, diethanolamine, piperazine, tromethamine, lysine, arginine and the like; whereas salts of calcium antagonists having a basic function in the molecule, and among them amlodipine, include anions formally derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, fosforic, carbonic acids, or organic acids, such as acetic, benzenesulfonic (besylate) metansulfonic, maleic, malonic, succinic, aspartic, glutamic acid.
In a preferred embod iment the pharmaceutically acceptable salt is amlodipine besylate.
In the association of the invention, the xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof are associated with one or more of said calcium antagonists or pharmaceutically acceptable salts thereof in a weight ratio of febuxostat/Ca antagonist comprised between 0.5 and 400, e.g. a weight ratio comprised between 2.5 and 120.
E.g., the following amounts, expressed in grams per single dose, could be associated: febuxostat in an amount comprised between 10-200 mg, or better comprised between 25-120 mg, in association with an amount of calcium inhibitor comprised between 0.5-20 mg, e.g. comprised between 1 -10 mg.
Where the association envisages a physical mixture of two compounds, as active principles, having the one an acid fuction and the other one a basic function, also the forming of an internal salt between the two is possible, in proportion to the respective amounts present in the mixture.
A further embodiment of the present invention relates to pharmaceutical compositions comprising, as active principle, a mixture of:
a) xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof;
b) one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof, and
one or more usual pharmaceutically acceptable excipients and/or additives and/or diluents, for use in the therapeutic or veterinary treatment.
The calcium antagonist or the calcium antagonists to be used according to the above-described composition are selected from the group comprising: amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine or pharmaceutically acceptable salts thereof.
The pharmaceutical compositions according to the present invention may be formulated in various forms depending on the selected administration route. Accord i n g to a specific em bod i ment of the i nvention, the pharmaceutical composition is suitable for oral administration of solid forms and may include formulations such as capsules, tablets, pills, powders and granules. In these solid forms the two active principles, the xanthine oxidase inhibitor and the antihypertensive agent, can be mixed with one or more pharmaceutically acceptable inert excipients. Such excipients may be selected among those commonly known in the state of the art and include, but are not limited to: a) carriers, such as sodium citrate and calcium phosphate, b) fillers, such as starch, lactose, microcrystalline cellulose, sucrose, glucose, mannitol and colloidal silica, c) moistening agents, such as glycerol, d) disintegrating agents, such as alginates, calcium carbonate, starches, derivatives of starch, of cellulose and polyvinylpyrrolidone, silicates and sodium carbonate, e) binders, such as carboxymethyl cellulose, alginates, gelatin , polyvinylpyrrolidone, sucrose, polymeric derivatives of cellulose, starch derivatives f) retarding agents, such as paraffin , cellulose polymers, fatty acid esters, g) absorption accelerators, such as quaternary ammonium compounds, h ) wetting agents and su rfactants, such as cetyl alcohol and glycerol monostearate, i) adsobents, such as bentonite clays and kaolin, k) lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, j) glidants, such as talc, colloidal silica.
In case the selected compositions constitute the filling of gelatin capsules, the excipients include but are not limited to compounds of the type: lactose, high molecular weight polyethylene glycol, and the like.
Solid-dosage forms may be coated with enteric, gastric coatings, or coatings of other type well-known in the state of the art. They may contain matting agents and may be of the type such as to allow the release of active ingredients only or preferably in a certain section of the intestine, optionally in a delayed manner. Substances capable of allowing such a delayed use include, but are not limited to, polymers and waxes.
Liqu id forms suitable for oral ad min istration are emulsions, solutions, prepared or extemporary suspensions, syrups and elixirs. Excipients suitable for the formulations according to the present invention in liquid forms for oral use include, but are not limited to diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents selected from ethyl alcohol, polyalcohols, propylene glycol, glycerol, polyethylene glycol and sorbitan esters. These formulations can also contain sweeteners and aromas selected from those well-known in the state of the art.
Compositions suitable for pharmaceutically acceptable parenteral injections may comprise sterile aqueous solutions, sterile dispersions, suspensions or emulsions or powders for a reconstitution in injectable solutions or dispersions; examples of excipients suitable therefor include, but are not limited to aqueous or non-aqueous carriers, diluents, solvents or vehicles selected from: water, ethanol, polyoils (propylene or polyethylene glycol, glycerol, and the like), polyalcohols, isopropyl alcohol, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 .3-butylene glycol, dimethylformamide, vegetable oils (in particular of olive, cotton, peanut, corn, wheat germ, olive, castor, sesame), organic esters such as ethyl oleate or the like.
These compositions may also contain preservatives of antibacterial or antifungal type, selected, yet not exclusively, from: paraben, chlorbutanol, phenol, sorbic acid and the like. It may also be useful to include an isotonic agent, e.g., a sugar, sodium chloride or the like. Moreover, pharmaceutical forms with a delayed absorption may be obtained with agents such as, for instance, yet not exclusively, aluminium monostearate and gelatin.
The suspensions, beside the active principles (xanthine oxidase inhibitors and anti-hypertensive agents), may contain suspend ing agents such as, for instance, yet not exclusively, ethoxylated isostearic alcohols, polyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium hydroxide, bentonite, alginates and cellulose derivatives in general or the like.
The right fluidity can be maintained with a coating material such as lecithin, with the maintaining of the right particle sizes in the dispersions or with the use of surfactants.
Also slow-release formulations can be prepared , by the techniques and products well-known in the state of the art.
The associations and compositions according to the present invention are extremely effective in the treatment, also meant as prophylaxis and therapy, of hypertension, in humans or animals.
To the ends of the present invention it is defined "hypertension" that with diastolic values higher than 80 mm/Hg and/or systolic values higher than 120 mm/Hg.
Hypertension can be associated or not associated to other pathologies or syndromes and symptoms. In particular, the association described herein is useful also in the therapeutic treatment of hypertension associated to hyperuricemia and/or hyperglycemia.
Symptoms such as hypertension, hyperuricemia or hyperglycemia can also be associated, individually or in combination, to specific syndromes like, e.g., the metabolic syndrome.
By "metabolic syndrome" it is meant a clinical condition accompanied by situations such as obesity.
The associations and compositions described herein can therefore be used in the therapeutic treatment of hypertension associated to hyperuricemia and/or hyperglycemia and/or other disorders in the context of the metabolic syndrome.
Dosage may vary depending on the patient's age and general conditions, the nature and seriousness of the pathology or disorder and on the administration route and type. Dosage should therefore take into account the specific condition to be treated (e.g., hyperglycemia alone or in association with hyperuricemia and/or glycemia), the severity of the condition to be treated, the age, weight and general physical conditions of the specific patient, as well as other drugs that the patient is taking, as is well-known to those skilled in the art. Moreover, it is evident that said effective amount may, when required , be lowered or raised according to the responses of the treated patient and/or according to the assessment of the physician prescribing the compounds of the present invention.
Typically, compositions for oral use in solid form can contain an amount of xanthine oxidase inhibitor, febuxostat, of between 10 and 200 mg per dosage unit, and preferably of between 25 and 120 mg, and an amount of calcium antagonist, preferably amiodipine, of between 0.5 and 20 mg per dosage unit, preferably of between 1 and 10 mg; should amiodipine be administered as besylate, the amounts would be of between 0.7 and 27.0 mg per dosage unit.
By the term "dosage unit" in the present description it is meant the unitary formulation for a single administration, e.g. a tablet, capsule, etc.
By "unit dosage" it is meant the amount of active principle for a single administration.
The pharmaceutical mixtures and compositions of the invention could be prepared according to techniques known in the field , both using the previously prepared association of active principles, and mixing the individual compounds directly during the preparation of the composition.
In particular, the association of active principles may be obtained by a step of mixing the xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof with one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof, in a weight ratio comprised between 0.5 and 400, or between 2.5 and 120.
For the preparation of the pharmaceutical compositions described herein the mixture of active principles is formulated in suitable dosage units with one or more pharmaceutically acceptable excipients and additives.
Testing
Testing demonstrating activity of the associations according to the invention is reported hereinafter. 1 . Biological activity measurement
Pharmacological activity of febuxostat and amlodipine, alone or in association, was measured in an experimental model of hyperuricemia in spontaneously hypertensive rat (SHR, Harlan Laboratories, Udine, Italy).
Systolic pressure (SBP) was measured in non-anesthesized animals by means of a tail cuff sphygmomanometer, using an automatic system for data acquisition (ADInstruments, Australia).
All animals were preconditioned daily for 1 week to accustom them to instrumental measuring of the pressure before starting the test. Hyperuricemia was induced with administration of oxonic acid (750 mg/kg per day, orally in the meal), an uricase inhibitor capable of inducing experimental hyperuricemia associated to a slight hypertensive effect in normotensive rats (Mazzali et al., Hypertension 38: 1 101 -1 106, 2001 ). Febuxostat and/or amlodipine were administered orally once per day, by gavage, at the dose of 1 -2.5-5 mg/kg for febuxostat and of 0.5-1 -2 mg/kg for amlodipine, for 4 weeks beginning from the fourth week from the start of the treatment with oxonic acid.
Parameters measured in conscious rats were systolic pressure (SBP) and plasma uric acid/urate levels, as well as basal values, both 4 and 8 weeks after start of treatment with oxonic acid. Blood was collected from a tail vein.
2. Plasma uric acid
Basal values of plasma uric acid were comparable in all groups and comprised between 0.45 and 0.60 mg/dL. After 4 weeks from the daily treatment with oxonic acid, rats showed a significant increase of plasma uric acid, higher than over 100% with respect to the basal value. Oral administration of febuxostat from the fourth to the eighth week from the start of the treatment with oxonic acid reduced hyperuricemia values in a dose-dependent manner (Table 1 ) whereas amlodipine, non active per se, in combination with febuxostat surprisingly made febuxostat effect significant in reducing hyperuricemia even at the lower dose (1 mg/kg per os).
3. Systolic pressure
Basal values of systolic pressure, measured with tail cuff sphygmomanometer in spontaneously hypertensive rats, were found homogeneous in the various groups and comprised between 239±18 and 264±21 mmHg. Oxonic acid administration increased systolic pressure, yet in a non-significant manner (Table 1 ).
Febuxostat (1 -2.5-5 mg/kg per os for 4 months) reduced systolic pressure to control values at the dose of 5 mg/kg per os. Amlodipine (0.5-1 -2 mg/kg per os for 4 months) reduced systolic pressure in a significant and dose-dependent manner (Table 1 ). Combined administration of febuxostat and amiodipine at the lowest doses of each compound reduced the systolic pressure in hypertensive rats to the values obtained with the higher dose of amiodipine (2 mg/kg per os) showing consistent enhancement of the hypotensive effect of the calcium antagonist compound.
Table 1 - Effect of oral administration of febuxostat, amiodipine or their combination on uricemia and pressure values in spontaneously hypertensive rats (SHR) treated with oxonic acid for 8 weeks.
Treatment Uricemia □ Uricemia SBP □ SBP mg/kg day mg/dL mg/dL mmHg mmHg per os
Control - 0.52±0.04 - 252±16 -
Control+oxonic acid - 1 .15±0.09 - 275±20 -
Febuxostat 1 0.98±0.06 - 0.17 265±15 10
2.5 0.64±0.05 - 0.51 258±21 17
5 0.48±0.04 - 0.67 249±17 26
Amiodipine 0.5 1 .19±0.09 0.04 212±1 1 63
1 1 .12±0.1 1 - 0.03 190±18 85
2 1 .08±0.08 - 0.07 168±15 107
Febuxostat+ Amiodipine 1 +0.5 0.64±0.07 - 0.51 174±16 - 10
Values at 8 weeks from the start of the oral treatment with oxonic acid (750 mg/kg day) and after 4 weeks of daily oral treatment with febuxostat and/or amiodipine. Each value is the average of 4-6 tests.
Examples of pharmaceutical formulations according to the present invention are reported hereinafter. Such examples of formulations are merely illustrative of the invention and have no limitative effect whatsoever.
Example 1
tablet for oral administration, containing:
febuxostat 120 mg amlodipine besylate 13.888 mg
(corresponding to amlodipine free base 10 mg )
pregelatinized starch (disintegrating binder) 70 mg
silicified microcrystalline cellulose (filler) 32.656 mg
croscarmellose sodium (disintegrant) 10 mg
magnesium stearate (lubricant) 0.8 mg
Example 2
tablet for oral administration, containing:
febuxostat 80 mg
amlodipine besylate 6.944 mg
(corresponding to amlodipine free base 5 mg )
pregelatinized starch (disintegrating binder) 35 mg
silicified microcrystalline cellulose (filler) 72.256 mg
croscarmellose sodium (disintegrant) 5 mg
magnesium stearate (lubricant) 0.4 mg
(^Example 3
tablet for oral administration, containing:
febuxostat 40 mg
amlodipine besylate 3.472 mg
(corresponding to amlodipine free base 2.5 mg )
pregelatinized starch (disintegrating binder) 35 mg
silicified microcrystalline cellulose (filler) 85.312 mg
croscarmellose sodium (disintegrant) 5 mg
magnesium stearate (lubricant) 0.4 mg
The above experimental results and the specific embodiments of the invention made for the testing have the purpose of illustrating the invention, of course without limiting its embodiment to what is reported below

Claims

1 . An association of the active principles:
a) xanthine oxidase inhibitor, febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof; and
b) one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof
for use in a human or veterinary therapeutic treatment.
2. The association according to claim 1 , wherein said active principle (a) is associated to the active principle (b) in a weight ratio of (a)/(b) comprised between 0.5 and 400.
3. The association according to claim 2, wherein said weight ratio is comprised between 2.5 and 120.
4. The association according to any one of claims 1 to 3, wherein said calcium antagonist is selected from the group comprising: amiodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine or pharmaceutically acceptable salts thereof.
5. The association according to any one of claims 1 to 4, wherein said calcium antagonist is amiodipine besylate.
6. The association according to any one of claims 1 to 5, for use in the therapeutic treatment of hypertension.
7. The association according to any one of claims 1 to 6, for use in the therapeutic treatment of hypertension associated to hyperuricemia and/or hyperglycemia.
8. The association according to any one of claims 1 to 7, for use in the therapeutic treatment of hypertension associated to hyperuricemia and/or hyperglycemia in the context of the metabolic syndrome.
9. The association according to any one of claims 1 to 6, for use in the therapeutic treatment of hypertension associated to disorders of the metabolic syndrome.
10. A p h armaceutical composition for use in a human or veterinary therapeutic treatment comprising, as active principle, a mixture of:
a) xanthine oxidase inhibitor febuxostat, or pharmaceutically acceptable salts thereof or polymorphic forms thereof;
b) one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof, and
one or more pharmaceutically acceptable excipients and/or additives.
1 1 . The pharmaceutical composition according to claim 10, wherein said calcium antagonist is selected from the group comprising: amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine or pharmaceutically acceptable salts thereof.
12. The pharmaceutical composition according to any one of claims 10 or 1 1 , wherein said calcium antagonist is amlodipine besylate.
13. The pharmaceutical composition according to any one of claims 10 to 12, for use in the therapeutic treatment of hypertension.
14. The pharmaceutical composition according to any one of claims 10 to 13, for use in the therapeutic treatment of hypertension associated to hyperuricemia and/or hyperglycemia.
15. The pharmaceutical composition according to any one of claims 10 to 14, for use in the therapeutic treatment of hypertension associated to hyperuricemia and/or hyperglycemia in the context of the metabolic syndrome.
16. The pharmaceutical composition according to any one of claims 10 to 15, for use in the therapeutic treatment of hypertension associated to other disorders of the metabolic syndrome.
17. The pharmaceutical composition according to any one of claims 10 to 16, wherein said xanthine oxidase inhibitor febuxostat is in an amount comprised between 10-200 mg per dosage unit.
18. The pharmaceutical composition according to any one of claims 10 to 17, wherein said xanthine oxidase inhibitor febuxostat is in an amount comprised between 25-120 mg per dosage unit.
19. The pharmaceutical composition according to any one of claims 10 to 18, wherein the calcium antagonist is in an amount comprised between 0.5-20 mg per dosage unit.
20. The pharmaceutical composition according to any one of claims 10 to 19, wherein the calcium antagonist is in an amount comprised between 1 -10 mg per dosage unit.
21 . A method for the preparation of the composition according to any one of claims 10 to 20, wherein the active mixture comprising:
a) xanthine oxidase inhibitor febuxostat or pharmaceutically acceptable salts thereof or polymorphic forms thereof;
b) one or more calcium antagonists belonging to the class of dihydropyridine calcium antagonists or pharmaceutically acceptable salts thereof,
is formulated in suitable dosage units with one or more pharmaceutically acceptable excipients.
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WO2016155815A1 (en) * 2015-04-01 2016-10-06 Ceva Sante Animale Oral solid dosage form of amlodipine and veterinary uses thereof
AU2016239689B2 (en) * 2015-04-01 2021-06-24 Ceva Sante Animale Oral solid dosage form of amlodipine and veterinary uses thereof
US11147804B2 (en) 2015-04-01 2021-10-19 Ceva Sante Animale Oral solid dosage form of amlodipine and veterinary uses thereof

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