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WO2012002920A1 - Nouvelles formes pharmaceutiques pour le traitement de maladies cardiovasculaires - Google Patents

Nouvelles formes pharmaceutiques pour le traitement de maladies cardiovasculaires Download PDF

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Publication number
WO2012002920A1
WO2012002920A1 PCT/TR2011/000163 TR2011000163W WO2012002920A1 WO 2012002920 A1 WO2012002920 A1 WO 2012002920A1 TR 2011000163 W TR2011000163 W TR 2011000163W WO 2012002920 A1 WO2012002920 A1 WO 2012002920A1
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WIPO (PCT)
Prior art keywords
aspirin
tablet formulation
cellulose
tablet
coating
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/TR2011/000163
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English (en)
Inventor
Mahmut Bilgic
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Individual
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Individual
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Priority to EP11746335.6A priority Critical patent/EP2588102A1/fr
Publication of WO2012002920A1 publication Critical patent/WO2012002920A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to dosage forms comprising effective amounts of aspirin and atorvastatin or their pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorphous forms and/or combinations thereof.
  • Cardiovascular disease is one of the leading causes of death in the world and one of the most significant factors for these diseases is total/high density lipoprotein (HDL) cholesterol level.
  • HDL high density lipoprotein
  • recent developments have indicated that only taking the cholesterol level under control is not sufficient for cardiovascular treatment.
  • researchers have found that use of some active agents in combination provides a more effective treatment method.
  • thrombosis means obstruction of blood vessels in consequence of formation of a blood clot in the blood vessels. This obstruction may occur in any part of the body. Due to the obstruction, blood flow through the target organ gets slower and it may completely stop in advanced stages. Rarely, this clot obstructs brain vessels and causes brain hemorrhage or obstruction of heart veins, in other terms coronary infarction. Formation of thrombosis in brain or blood veins going to the brain generally leads to fatal results.
  • aspirin One of the drugs commonly used in the treatment and prevention of thrombosis is aspirin.
  • aspirin chemical name of which is 2-(acetyloxy)benzoic acid
  • analgesic and antipyretic drug for more than 100 years
  • use of aspirin in low doses reduces platelet formation and therefore prevents thrombosis.
  • use of 20-40 mg aspirin once a day prevents formation of thrombosis.
  • Atorvastatin is a hypolipidemic drug used as a HMG-CoA reductase enzyme inhibitor as the other statins. Distinctly from other drugs in this group, it is the only drug having the indication of lowering both the increased LDL cholesterol and triglyceride levels in patients with hypercholesterolemia. In various publications, it is suggested that atorvastatin is more effective than other HMG CoA reductase enzyme inhibitors when used in recommended doses:
  • Atorvastatin lowers LDL cholesterol levels by 60%; when administered in low doses, such as 2.5 mg/day, it displays activity at recommended routine level of other HMG CoA reductase enzyme inhibitors. While atorvastatin lowers the triglyceride levels in patients with hypercholesterolemia by 45%, it may raise HDL cholesterol level at 12%. It was disclosed in the tricentric double-blind study conducted with patients having hypercholesterolemia that atorvastatin lowers total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride levels compared with lolvastatin, pravastatin and simvastatin.
  • statin group active agents are effective in prevention and treatment of cardiovascular, cerebrovascular diseases (Ridker PM, Cushman M, Stampfer MJ et al. Inflammation, aspirin, and the risk of cardiovaskuler disease apparently healthy in men. NengJMed 1997; 336:973-9).
  • statin group active agents Use of aspirin and statin group active agents in combination is known to decrease mortality rates of cardiovascular diseases. Hennekens et. al. attested that aspirin reduces the risk of contracting cardiovascular diseases by 24% averagely in comparison with statin treatment only. In parallel with this, statin treatment alone reduces the same risk by 13% in comparison with aspirin treatment (Hennekens CH, Sacks FM, Tonkin A, Jukema JW, Byington RP, Pitt B, Berry DA, Berry SM, Ford NF, Walker AJ, Natarajan K, Sheng-Lin C, Fiedorek FT, Belder R: Additive benefits of pravastatin and aspirin to decrease risks of cardiovascular disease: randomized and observational comparisons of secondary prevention trials and their metaanalyses. Arch Intern Med 164:40-44, 2004).
  • statin is an active agent with weak acidic features while most of the statins are basic active agents used in their salt forms. Therefore, formulation of the two active agents together causes the statins to be degraded and their bioavailability to decrease.
  • EP 1581194 relates to multilayer tablet dosage form comprising pravastatin and aspirin as the active agents.
  • the layers comprising the active agents are separated by a barrier layer in order to impede their interaction.
  • the barrier layer would maintain its effect during the shelf life of the tablet dosage form.
  • the present invention relates to dosage forms comprising effective amounts of atorvastatin and aspirin or their pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline or amorphous forms and/or combinations thereof.
  • the dosage forms according to the present invention are obtained by formulating the two active agents separately and then combining them in a compact dosage form.
  • Multiple dosage forms which are prepared by combining separate dosage forms in a single, compact dosage form has reduced the interaction of the two active agents both with each other and with other pharmaceutically acceptable excipients. Hence, the problems of the active agent have been efficiently solved and the efficiency of the combined drug has been improved.
  • multiple dosage forms are more advantageous compared to single dosage forms such as pellets, micro tablets, granules, coated tablets.
  • Multiple dosage forms are dispersed in gastrointestinal tract homogeneously and transmitted from the stomach to the intestines. Both the effective dispersion of the active agents in the stomach is ensured and the bioavailability is improved this way.
  • Multiple dosage forms are also advantageous as they can be formulated such that they enable different release characteristics of the two active agents.
  • Multiple dosage forms of the present invention are composed by combining one or more unit dosage forms preferably in a capsule.
  • These unit dosage forms can be in granule, powder, pellet, tablet, mini tablet, micro tablet, capsule, micro capsule form and/or combinations thereof.
  • the multiple dosage form preferred according to the present invention is obtained by combining micro tablet, granule, powder and/or pellet formulations comprising atorvastatin calcium with tablet formulations comprising aspirin in a capsule preferably made of soft gelatin. Tablet formulations of aspirin of the present invention are preferably enterically coated.
  • the enteric coating layer reacts with the layer comprising the active agents in aspirin tablet formulations which are enterically coated as aspirin causes stomach problems.
  • acetic acid is produced.
  • acetic acid produced also reacts with the atorvastatin formulation in the multiple dosage form and hence the stability of these formulations decrease in addition that the amount of aspirin in the dosage is reduced.
  • the tablet formulations of aspirin of the present invention are composed of an active agent layer comprising an effective amount of aspirin, a pharmaceutically acceptable filling material, a binder, a disintegrant and at least one lubricant; a sub-coating layer on said active agent layer; and finally an enteric coating layer.
  • a characteristic feature of said sub-coating layer is that the coating material comprises a cellulose derivative coating agent and talc.
  • the coating material comprises at least 70%, preferably in the range of 70-90% of a cellulose derivative coating agent by weight; and at least 10%, preferably in the range of 10-30% talc by weight.
  • the ratio of the cellulose derivative coating material to talc by weight is in the range of 1 to 30; preferably in the range of 1 to 25, more preferably in the range of 1 to 20, even more preferably in the range of 1 to 15.
  • the cellulose derivative coating material comprised in the sub-coating of the present invention is selected from a group comprising hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose phthalate or combinations thereof.
  • enteric coating material plays a role in providing sufficient stability of formulations of the present invention. To this end, enteric coating material has been chosen carefully in order to hinder the potential interaction of the enteric coating material with the sub-coating material in the multiple dosage forms produced in scope of the present invention.
  • the enteric coating material of the present invention comprises at least one release rate determinant polymer, at least one plasticizer agent and at least one other pharmaceutically acceptable excipient.
  • the release rate determinant polymers used in the enteric coating material of formulations of the present invention can be selected from methacrylic copolymers, for instance methacrylic acid/methyl methacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose trimellitate, cellulose acetate phthalates, polyvinyl acetate phthalates or combinations thereof.
  • the release rate determinant polymer is comprised in the range of 1- 30%, preferably in the range of 1-20%, more preferably in the range of 1-15% of the total weight of the unit dose.
  • the plasticizer agent used in the enteric coating material of the present invention is triacetyl citrate and it is in the range of 0.1-5%, preferably in the range of 0.1-3%, more preferably in the range of 0.1-1% by weight in proportion to the total weight of the unit dose.
  • the enteric coating material of the present invention comprises at least one other pharmaceutically acceptable excipient in addition to the ones listed above.
  • Said excipients can be opacifying agents (for instance, titanium dioxide), anti-adhesive substances (for instance talc), filling materials, lubricants etc.
  • the amount of aspirin used in the formulations of the present invention is approximately in the range of 1-500 mg., preferably approximately in the range of 1-300 mg., more preferably approximately in the range of 1-150 mg. per unit dosage form.
  • Atorvastatin formulations of the present invention are in the form of micro tablet, granule, powder and/or pellet form and they comprise an effective amount of atorvastatin calcium, at least one pharmaceutically acceptable filling material, at least one binder, at least one disintegrant, at least one diluent, at least one surfactant, at least one buffer substance and at least one other excipient.
  • Atorvastatin used in the formulations of the present invention is preferably atorvastatin calcium and it is preferably in crystalline form polymorphically.
  • One feature of the multiple dosage forms of the present invention is that said forms comprise atorvastatin calcium in micro tablet, granule, powder and/or pellet form; and aspirin in tablet form.
  • aspirin tablet formulations are enterically coated and there is a sub-coating between the enteric coating and the active agent layer comprising aspirin.
  • compositions of the present invention are selected from binders, disintegrants, viscosity enhancing components, filling materials, drying agents, lubricants, buffer substances, diluents, binders, glidants, wetting agents, coating agents designed so as to provide various release characteristics, anti-adhesive agents, solvents, sweeteners or combinations thereof.
  • the buffer substances of the present invention are either water-soluble or water-insoluble and selected from a group comprising meglumine, tromethamol, sodium bicarbonate, sodium carbonate, sodium citrate, calcium gluconate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium tartrate, sodium acetate, calcium glycerophosphate, tromethamine, magnesium oxide, magnesium hydroxide, aluminum hydroxide, dihydroxy aluminum, sodium carbonate, calcium carbonate, aluminum carbonate, dihydroxy aluminum amino acetate, diethanolamine, triethanolamine, N-methyl-glucamine, glucosamine, ethylenediamine, triethyleneamine, isopropylamine, di-isopropyl amine or combinations thereof.
  • the filling agents used in the present invention comprise one or more components selected from the group comprising lactose, sugar, starch, modified starch, corn starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and lactitol and/or pharmaceutically acceptable hydrates thereof.
  • the filling material used in the atorvastatin formulations is preferably lactose and/or a pharmaceutically hydrate or anhydrate thereof.
  • the disintegrant used in the present invention enables the dosage form to disperse in water easily and rapidly, and it is significant from this aspect.
  • the disintegrants can be selected from a group comprising polymers having high dispersing characteristics such as cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, povidone; the products known under the trademarks Crospovidone®, Polyplasdone® or colloidal silicon dioxide, alginic acid, sodium alginate, corn starch.
  • the surfactants used in the present invention are selected from a group comprising hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin, dextran, sorbitan esters, polyoxy ethylene alkyl ethers, polyethylene glycols, polyethylene stearates, collodial silicon dioxide, phosphates, carboxymethyl cellulose calcium, carboxy methyl cellulose sodium, triethanolamine, polyvinyl alcohol, hydroxy propyl methyl cellulose phthalate.
  • the anti-adhesive agents of the present invention are used in order to prevent the mixture comprising active agents to adhere onto device and machine surfaces and create rough surfaces.
  • the substances used for this purpose comprise one or more components selected from a group comprising talc, colloidal silicone dioxide (Aerosil, Syloid, Cab-OSil), magnesium stearate and corn starch.
  • the binders used in the present invention comprise one or more components selected from a group comprising potato, wheat or corn starch; microcrystalline cellulose, for instance Avicel®, Filtrak®, Heweten® or Pharmacel®; hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropylmethyl cellulose, for instance hydroxypropylmethyl cellulose-type 2910 USP; hypromellose and polyvinylpyrrolidone, for instance Povidone® K30(BASF), lactose, guar gum, pectin, gelatin, sodium alginate.
  • microcrystalline cellulose for instance Avicel®, Filtrak®, Heweten® or Pharmacel®
  • hydroxypropyl cellulose hydroxyethyl cellulose
  • hydroxypropylmethyl cellulose for instance hydroxypropylmethyl cellulose-type 2910 USP
  • hypromellose and polyvinylpyrrolidone for instance Povidone® K30(BASF)
  • the lubricants used in the present invention comprise one or more components selected from a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohol, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulfate (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate, talc, siliconized talc and/or hydrates thereof.
  • metallic stearates such as magnesium stearate, calcium stearate, aluminum stearate
  • fatty acid esters such as sodium stearyl fumarate
  • fatty acids such as stearic acid
  • fatty alcohol glyceryl behenate
  • mineral oil such as
  • the diluents used in the present invention comprise one or more components selected from a group comprising alkali metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate, etc.), dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, direct compression lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates thereof and/or derivatives thereof.
  • Pharmaceutically acceptable carriers of the present invention can be selected from a group comprising polyether glycols, polypropylenes, xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate, glucose, lactitol, behenic acid, hydroquinone, monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citryl acid, saturated hydrocarbons, paraffins, sorbitan esters, fats, waxes, polyvinylpyrrolidone polymers, acrylic polymers and/or mixtures thereof.
  • the formulations according to the present invention can optionally be formulated so as to provide different release characteristics.
  • the release rate determinant polymers that can be used in the formulations in order to provide the required release characteristics can be pH- dependant polymers, non pH-dependant polymers, swellable polymers, non-swellable polymers, hydrophilic polymers, hydrophobic polymers and/or one or more hydrophobic substances; ionic polymers such as sodium alginate, carbomer, calcium carboxy methyl cellulose or carboxy methyl cellulose; non-ionic polymers such as hydroxy propyl methyl cellulose; natural or/synthetic polysaccharides such as alkyl celluloses, hydroxyl alkyl celluloses, cellulose ethers, nitrocellulose, dextrin, agar, carrageenan, pectin, starch and starch derivatives or mixtures thereof; cellulosic polymers; methacrylate polymers, methacrylate copolymers, polyvinylpyrroli
  • the solvents used in preparation of the formulations of the present invention comprise one or more components selected from a group comprising water, toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile; alcohol, for instance ethanol, methanole, isopropyl alcohol, butanol; and/or alcohol mixtures.
  • Atorvastatin and aspirin formulations of the present invention can be prepared by any one of the methods existing in the prior art such as wet granulation, dry granulation, dry blending.
  • the tablet formulations of aspirin of the present invention are preferably prepared by the following preparation method:
  • An effective amount of aspirin, at least one pharmaceutically acceptable binder, at least one disintegrant, at least one other excipient are blended dryly.
  • the dry mixture is treated with a pharmaceutically acceptable lubricant and tablets are compressed,
  • a cellulose derivative coating agent and talc are dissolved in deionized water for preparation of sub-coating solution.
  • the aspirin tablets obtained in the first step are coated with this sub-coating solution,
  • the tablets obtained in the second step are coated with enteric coating and the dosage form is finalized.
  • Enterically coated tablet formulations prepared this way are combined with atorvastatin calcium formulations produced according to one of the unit dosage forms given in scope of the present invention in a capsule preferably made of soft gelatin.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
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  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes pharmaceutiques comprenant des quantités efficaces d'aspirine et d'atorvastatine ou leurs sels pharmaceutiquement acceptables, hydrates, énantiomères, racémates, sels organiques, sels inorganiques, esters, formes polymorphiques, formes cristallines et formes amorphes et/ou combinaisons de celles-ci ; et des formes pharmaceutiques comprenant des combinaisons de celles-ci.
PCT/TR2011/000163 2010-06-30 2011-06-29 Nouvelles formes pharmaceutiques pour le traitement de maladies cardiovasculaires Ceased WO2012002920A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11746335.6A EP2588102A1 (fr) 2010-06-30 2011-06-29 Nouvelles formes pharmaceutiques pour le traitement de maladies cardiovasculaires

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2010/05325 2010-06-30
TR2010/05325A TR201005325A2 (tr) 2010-06-30 2010-06-30 Atorvastatin ve aspirin içeren farmasötik formülasyonlar

Publications (1)

Publication Number Publication Date
WO2012002920A1 true WO2012002920A1 (fr) 2012-01-05

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Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/TR2011/000161 Ceased WO2012002919A1 (fr) 2010-06-30 2011-06-29 Formulations pharmaceutiques comprenant de l'atorvastatine et de l'aspirine
PCT/TR2011/000162 Ceased WO2012011882A1 (fr) 2010-06-30 2011-06-29 Combinaison d'atorvastatine et d'aspirine destinée à être utilisée dans le traitement de maladies cardiovasculaires
PCT/TR2011/000163 Ceased WO2012002920A1 (fr) 2010-06-30 2011-06-29 Nouvelles formes pharmaceutiques pour le traitement de maladies cardiovasculaires

Family Applications Before (2)

Application Number Title Priority Date Filing Date
PCT/TR2011/000161 Ceased WO2012002919A1 (fr) 2010-06-30 2011-06-29 Formulations pharmaceutiques comprenant de l'atorvastatine et de l'aspirine
PCT/TR2011/000162 Ceased WO2012011882A1 (fr) 2010-06-30 2011-06-29 Combinaison d'atorvastatine et d'aspirine destinée à être utilisée dans le traitement de maladies cardiovasculaires

Country Status (3)

Country Link
EP (2) EP2588103A1 (fr)
TR (1) TR201005325A2 (fr)
WO (3) WO2012002919A1 (fr)

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ES2524645B1 (es) * 2013-06-06 2015-12-02 Ferrer Internacional, S.A. Formulación oral para el tratamiento de enfermedades cardiovasculares
RU2536275C1 (ru) * 2013-08-06 2014-12-20 Строяковский Валентин Меерович Антигипоксическое и гиполидемическое фармацевтическое средство, улучшающее коронарный и мозговой кровоток
KR20180073665A (ko) * 2015-11-06 2018-07-02 젬파이어 세러퓨틱스 인코포레이티드 심혈관 질환의 치료를 위한 젬카빈 조합
AR111786A1 (es) * 2017-05-11 2019-08-21 Gemphire Therapeutics Inc Composiciones de gemcabeno y su uso

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