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WO2011060943A1 - Formulations pharmaceutiques contenant des capsules de substance active bêta-bloquante et des esters d'acides gras polyinsaturés - Google Patents

Formulations pharmaceutiques contenant des capsules de substance active bêta-bloquante et des esters d'acides gras polyinsaturés Download PDF

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Publication number
WO2011060943A1
WO2011060943A1 PCT/EP2010/007023 EP2010007023W WO2011060943A1 WO 2011060943 A1 WO2011060943 A1 WO 2011060943A1 EP 2010007023 W EP2010007023 W EP 2010007023W WO 2011060943 A1 WO2011060943 A1 WO 2011060943A1
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Prior art keywords
pharmaceutical composition
composition according
microcapsules
group formed
alkyl esters
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Ceased
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PCT/EP2010/007023
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English (en)
Inventor
Antonio PARENTE DUEÑA
Paolo Carminati
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GP Pharm SA
CARMINATI GIUSEPPE PAOLO
Defiante Farmaceutica SA
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GP Pharm SA
CARMINATI GIUSEPPE PAOLO
Defiante Farmaceutica SA
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Publication of WO2011060943A1 publication Critical patent/WO2011060943A1/fr
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    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A61K9/5057—Gelatin
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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

  • This invention relates to an pharmaceutical composition for oral administration which comprises a suspension of polymeric microcapsules suspended in an oil which contains alkyl esters of polyunsaturated fatty acids (PUFA), wherein the microcapsules contain at least one polymer and one beta-blocking active ingredient, and its use for the treatment and/or prevention of cardiovascular diseases.
  • PUFA polyunsaturated fatty acids
  • beta blockers are used active pharmaceutical ingredients for the treatment of cardiovascular diseases.
  • active pharmaceutical ingredients for the treatment of cardiovascular diseases there are beta blockers.
  • Beta blockers are competitive antagonists of the beta-adrenergic receptors and are used for the treatment of cardiovascular diseases such as hypertension, angina pectoris, cardiac dysrhythmia, myocardial infarction and heart failure. They are also used to control alcohol withdrawal symptoms, in anxiety disorders, in hyperthyroidism and in tremors, as well as in migraine prophylaxis and bleeding of varicose veins associated with portal hypertension.
  • Polyunsaturated fatty acids (PUFA) also possess a known beneficial effect on the prevention of cardiovascular events and are often used in combination therapy in patients who have suffered some type of cardiovascular episode.
  • PUFAs are essential fatty acids and should be obtained from a person's diet. They are divided into omega-3 and omega-6 fatty acids depending on the position of the first unsaturation (n-3 and n-6 respectively).
  • the principal omega-3 fatty acids are found in fish oils, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • PUFAs can be found in the form of triglycerides or aikyl esters. Commercial compositions of omega-3 fatty acid alkyl esters vary in purity and content of fatty acids and are normally expressed in relation to the content in EPA and DHA.
  • PUFAs in any of their forms, are easily oxidized and should be stored under an inert atmosphere and protected from light.
  • Commercial compositions contain antioxidants to minimize their degradation.
  • formulations based on lipids increase the bioavailability of certain active pharmaceutical ingredients.
  • examples of formulations which increase the bioavailability of active ingredients through the use of PUFA are described in the literature, generally by the formation of emulsions.
  • the preparation of microemulsions formed by nanoparticles of biocompatible oils such as eicosapentaenoic acid (EPA) are described in WO 2006/135415 A2, these contain active pharmaceutical ingredients such as the beta blockers, among others.
  • beta-blocking active ingredients The instability of the aforementioned beta-blocking active ingredients is known.
  • the presence of the secondary amino group in alpha position relative to the hydroxyl group affords them chemical instability, due to possible interactions with the excipients, and this represents a problem during their storage. Therefore, the amino group of the beta blockers can react with aldehyde or ester functional groups, as is described, for example, for carvedilol in WO 2005/051383 A1. It would be an advantage to have a stable formulation which contained the two active ingredients, PUFA and beta blockers, avoiding the degradation caused by the interaction of the reactive amino functional group in alpha position to the hydroxyl group of beta blockers with the ester functional groups of PUFAs.
  • WO 2007/103557 A2 the physical separation of the components in a hard or soft gelatin capsule is proposed as a solution to the problems of chemical incompatibilities in compositions with two or more active ingredients.
  • This capsule should contain a first active ingredient such as omega-3 fatty acids, with one or more internal capsule coatings wherein at least one of them consists of a polymer combined with another active ingredient, and the coating which contains this active ingredient should be isolated from the capsule and optionally from the outside by additional coatings.
  • the combination therapy is achieved by successive internal coatings of a capsule which contains omega-3 fatty acids with coatings which comprise antiarrhythmic active ingredients, among them beta blockers.
  • the manufacturing process is complex due to the fragility and solubility in water of the gelatin coating and requires rigorous control of the temperature and speed of deposition during coating.
  • the solution proposed by this invention is an pharmaceutical composition for oral administration which incorporates the described agents, with the active ingredient isolated by means of a polymer, and which does not use excipiehts which may cause adverse secondary effects in a chronic treatment.
  • the subject-matter of this invention is pharmaceutical composition for oral administration which contains a suspension of microcapsules of beta-blocking active ingredients in an oil which contains polyunsaturated fatty acids alkyl esters.
  • This composition provides greater protection of the beta-blocking active pharmaceutical ingredients against their chemical interaction with the alkyl esters of PUFA, as well as against moisture, light and oxidizing agents.
  • this invention relates to a new pharmaceutical composition for oral administration which avoids the problems of degradation of beta-blocking active ingredients when they are formulated together with oils which contain alkyl esters of PUFA.
  • this invention relates to an pharmaceutical composition for oral administration which comprises a suspension of polymeric microcapsules which comprise at least one polymer and a beta-blocking active ingredient, these microcapsules being suspended in an oil which contains polyunsaturated fatty acid alkyl esters.
  • the polymer of the microcapsules constitutes their external part and provides a complete coating for the encapsulated active pharmaceutical ingredient.
  • the beta-blocking active ingredients are found in the inside of the polymeric microcapsules in suspension in an oil which contains alkyl esters of PUFA.
  • the beta-blocking active ingredients are isolated both from the outside medium and from the alkyl esters of PUFA by the polymer, which easily disintegrates in the gastrointestinal medium.
  • the pharmaceutical composition of this invention allows, as well as the joint administration of active pharmaceutical ingredients in a combination therapy, the beta-blocking active ingredient to be isolated from the alkyl esters of PUFA.
  • the polymeric coating provides stability to these beta blockers, avoiding the formation of degradation products caused by the interaction of the reactive amino functional group in alpha position in relation to the hydroxyl group with the ester groups of the alkyl esters of PUFA.
  • the fatty acids of the alkyl esters of PUFA belong to the omega-3 series.
  • the PUFAs are selected from the group formed by the (all-cis)-5, 8,11 ,14,17- eicosapentaenoic or eicosapentaenoic (EPA) or timnodonic acid or icosapent (C20:5 n-3), the ⁇ a//-c/ ' s -4,7,10,13,16,19-docosahexaenoic or docosahexaenoic (DHA) or cervonic acid or doconexent (C22:6 n-3), and/or mixtures thereof, such as Omacor ® , Lovaza ® or Zodin ® , among others.
  • the EPA:DHA relationship can range between 100:0 and 0:100, preferably between 4:1 and 1 :4, and more preferably between 1 :2 and 2:1.
  • the PUFAs can comprise just EPA or just DHA.
  • the alkyl radical of the alkyl esters of PUFA is selected from the group formed by short chain alkyl radicals, with from 1 to 8 carbon atoms.
  • the alkyl radical is selected from the group formed by ethyl, methyl, propyl, butyl and/or mixtures thereof. More preferably, the alkyl radical is an ethyl group.
  • the oil containing alkyi esters of PUFA is an oil enriched in alkyi esters of PUFA, preferably, the oil contains more than 50% of alkyi esters of PUFA, more preferably more than 60% of alkyi esters of PUFA and even more preferably, more than 85% of alkyi esters of PUFA.
  • the quantity of alkyi esters of PUFA contained in the pharmaceutical capsule of the invention is comprised between 0.01 and 4 g, preferably between 0.1 and 2 g.
  • the beta-blocking active ingredient is selected, without restriction, from the group formed by acebutolol, alprenolol, amosulalol, arotinolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bupranolol, carazolol, carteolol, carvedilol, celiprolol, esatenolol, esmolol, indenolol, labetalol, landiolol, levobunolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, talinol
  • the polymer of the microcapsules of the pharmaceutical capsule of this invention is selected, without restriction, from the group formed by proteins, polysaccharides, polyesters, polyacrylates, polycyanoacrylates, polyethylene glycol and/or mixtures thereof.
  • the polymer of the microcapsules is selected from the group formed by gelatin, albumin, alginates, carrageenans, pectins, gum arabic, chitosan, carboxymethylcellulose, ethylcellulose, hydroxypropyl methylcellulose (HPMC), nitrocellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate-succinate, polyvinyl acetate phthalate, poly(8-caprolactone), poly(p-dioxanone), poly(5-valerolactone), poly(p-hydroxybutyrate), poly( -hydroxybutyrate) copolymers and ⁇ -hydroxyvalerate
  • the polymer is formed by copolymers of methacrylic acid (Eudragit ® L and S), polymers and copolymers of lactic, and glycolic acids, polymers and copolymers of lactic and glycolic acids and polyethylene glycol, and/or mixtures thereof.
  • methacrylic acid Eudragit ® L and S
  • polymers and copolymers of lactic, and glycolic acids polymers and copolymers of lactic and glycolic acids and polyethylene glycol, and/or mixtures thereof.
  • the polymer of the microcapsules of the pharmaceutical capsule of this invention can comprise a plasticizer additive.
  • the plasticizer additive is selected, without restriction, from the group formed by alkyl esters of the citric acid such as triethyl citrate, tributyl citrate, acetyl tributyl citrate and acetyl triethyl citrate, phthalates such as butyl phthalate and diethyl phthalate, glycerin, sorbitol, maltitol, propylene glycol, polyethylene glycol, glucose, sucrose, lanolin, palmitic acid, oleic acid, stearic acid, metal salts of fatty acids such as stearic acid or palmitic acid, sodium stearate, potassium stearate, propylene glycol monostearate, acetylated monoglycerides such as monoacetylated glycerin and glyceryl triacetate or triacetin, gly
  • fluidifying agents such as talc, colloidal silicon dioxide, glycerin, polyethylene glycol, glycerin monostearate and/or metal stearate salts.
  • the pharmaceutical capsule of this invention comprises at least one antioxidant, such as and not restricted to, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), gallic acid esters such as propyl gallate, tocopherols such as vitamin E acetate, ascorbic acid esters such as ascorbyl palmitate and ascorbyl acetate, carnitine and/or mixtures thereof.
  • BHT butylhydroxytoluene
  • BHA butylhydroxyanisole
  • TBHQ tert-butylhydroquinone
  • gallic acid esters such as propyl gallate
  • tocopherols such as vitamin E acetate
  • ascorbic acid esters such as ascorbyl palmitate and ascorbyl acetate
  • carnitine and/or mixtures thereof preferably, the antioxidant is vitamin E acetate.
  • the microcapsules represent between 0.001% and 80% of the total weight of the pharmaceutical composition of this invention, preferably between 0.01 % and 60%, and more preferably between 0.1 % and 50% of the total weight of the pharmaceutical composition of this invention.
  • the amount of beta-blocking active pharmaceutical ingredient incorporated in these microcapsules is comprised between 1% and 80% in weight, preferably between 1% and 60% in weight with respect to the total weight of the microcapsules.
  • the total amount of active pharmaceutical ingredient included in the pharmaceutical composition of this invention depends on the recommended daily doses.
  • the pharmaceutical composition for oral administration of this invention is presented in capsule form, preferably in soft capsule form.
  • This capsule can be a gelatin capsule or any usual polymer in the preparation of capsules in the pharmaceutical industry, such as and not restricted to, hydroxypropyl methylcellulose (HPMC), pullulan, modified starches, carrageenans and/or mixtures thereof.
  • the capsule has an .enteric coating.
  • the capsule's coating can contain other additives such as plasticizers, colorants, pigments, opacifiers, preservatives, moisturizers, surfactants, sweeteners and/or flavorings.
  • the preparation of the capsule is carried out through the usual procedures in the pharmaceutical industry, and can be any form and size known by the person skilled in the art.
  • the preparation of the microcapsules can be carried out by following any of the procedures described in the literature. As a description and not restricted to them, the different procedures for obtaining microcapsules can be grouped in the following sections: A) Simple coacervation procedure
  • a solution of the polymer together with its possible additives is prepared in an appropriate solvent.
  • this solution of the polymer the active pharmaceutical ingredient to be encapsulated is suspended and a solvent in which the polymer is not soluble is added to force the polymer deposition on the crystals of the active ingredient. Examples of these procedures can be found in documents such as ES
  • the active pharmaceutical ingredient to be encapsulated is dissolved in water or in a solution of another coadjuvant and is emulsified in a solution of the polymer and additives in an appropriate solvent such as dichloromethane.
  • the resulting emulsion is in turn emulsified in water or in an aqueous solution of an emulsifier such as polyvinyl alcohol.
  • an emulsifier such as polyvinyl alcohol.
  • the active pharmaceutical ingredient to be encapsulated, the polymer and the additives are jointly dissolved in an appropriate organic solvent.
  • This solution is emulsified in water or in a solution of an emulsifier such as polyvinyl alcohol and the organic solvent is eliminated by evaporation or extraction.
  • the resulting microcapsules are recovered by filtration or drying. Examples of these procedures can be found in documents such as US 5445832 A.
  • the active pharmaceutical ingredient to be encapsulated, the polymer and the additives are jointly dissolved in an appropriate solvent. This solution is evaporated and the resulting residue is micronized to obtain the suitable size, or it is dried by spray-drying. Examples of this procedure can be found in documents such as GB 2209937 A.
  • Another aspect of this invention relates to the use of the pharmaceutical composition for oral administration of the invention in the preparation of a medicament for the treatment and/or prevention of cardiovascular diseases.
  • these cardiovascular diseases are selected from among cardiac dysrhythmia, hypertension, angina pectoris, myocardial infarction and heart failure.
  • Another aspect of this invention relates to the use of the pharmaceutical composition for oral administration of the invention in the preparation of a medicament for the treatment and/or prevention of disorders and/or pathologies selected from the group formed by alcohol withdrawal symptoms, anxiety disorders, hyperthyroidism, tremors, migraines, pheochromocytoma and/or bleeding of varicose veins associated with portal hypertension.
  • Another aspect of the invention is a method of treatment and/or prevention of cardiovascular diseases, which comprises administering a pharmaceutically efficient dose of the pharmaceutical composition of this invention.
  • these cardiovascular diseases are selected from among cardiac dysrhythmia, hypertension, angina pectoris, myocardial infarction and heart failure.
  • Another aspect of the invention is a method of treatment and/or prevention of disorders and/or pathologies selected from the group formed by alcohol withdrawal symptoms, anxiety disorders, in hyperthyroidism, tremors, migraines, pheochromocytoma and/or bleeding of varicose veins associated with portal hypertension, which comprises administering a pharmaceutically efficient dose of the pharmaceutical composition of this invention.
  • Example 1 Preparation of pharmaceutical capsules which contain carvedilol microcapsules with gelatin through a simple coacervation procedure. A 1 % solution of gelatin in water was prepared.
  • microcapsules formed by filtration were collected, they were washed with water and dried in a vacuum drying oven.
  • the content in carvedilol of these microcapsules was 39%.
  • microcapsule powder was dispersed directly in oil containing a minimum of 90% of ethyl esters of PUFA, with a minimum EPA/DHA content of 85% in a ratio of 1.2:1 (1.63 g of the microcapsules suspension obtained per 100 g of oil).
  • 1.00 g of the dispersion of microcapsules in oil was incorporated to a soft gelatin capsule, to obtain a dose of 6.25 mg of carvedilol per capsule.
  • Example 2 Preparation of pharmaceutical capsules which contain atenolol microcapsules with polyethylene glycol. A 10% solution of polyethylene glycol in water with a molecular weight of 35000 (PEG- 35000) was prepared.
  • the microcapsule powder obtained showed a concentration of atenolol of 33%, and was directly dispersed in oil containing a minimum of 65% of ethyl esters of PUFA, with a minimum EPA/DHA content of 45% in a ratio of 1.2:1 (17.9 g of the suspension of microcapsules obtained per 100 g of oil).
  • 1.00 g of the microcapsule dispersion in oil was incorporated to a soft gelatin capsule, to obtain a dose of 50 mg of atenolol per capsule.
  • Example 3 Preparation of pharmaceutical capsules which contain propranolol microcapsules with poly(lactic-co-glycolic acid) (PLGA) and vitamin E.
  • PLGA poly(lactic-co-glycolic acid)
  • Solution A 100 ml_ of 10% solution in PLGA dichloromethane with an intrinsic viscosity (I.V.) of 0.17 and lactic/glycolic ratio of 1 :1 were prepared.
  • Solution B 4 g of propranolol hydrochloride and 1 g of vitamin E acetate were dissolved in 200 ml_ of ethanol.
  • Solutions A and B were mixed under continuous stirring. During this stirring, a nitrogen current was passed through the previous solution for two hours to eliminate most of the dichloromethane and ethanol. Subsequently the resulting suspension was frozen and lyophilized. A powder was obtained which was washed with a great amount of water to eliminate the excess of ethanol and was dried at reduced pressure.
  • the microcapsule powder obtained contained 26% of propranolol, and was directly dispersed in oil containing a minimum of 90% de ethyl esters of PUFA, with a minimum EPA/DHA content of 85% in a ratio of 1.2:1. Next, the dispersion of microcapsules in oil obtained was incorporated to a soft gelatin capsule. The quantities used to prepare capsules of different sizes and doses of propranolol are shown in Table 1.
  • the percentages of the active pharmaceutical ingredient were determined through HPLC after storage of the microcapsule suspensions in amber glass containers for 1 month, 2 months, 3 months and 4 months. The percentages of the active pharmaceutical ingredient are shown in Table 2.
  • the stability of PUFAs was also studied (concentration of alkyl esters of EPA and DHA, as well as the EPA/DHA ratio) through gas chromatography, although no variations were observed in the composition.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour administration orale qui contient des esters d'alkyle d'acides gras polyinsaturés (PUFA) et des substances pharmaceutiques actives pour le traitement et/ou la prévention de maladies cardiovasculaires.
PCT/EP2010/007023 2009-11-20 2010-11-19 Formulations pharmaceutiques contenant des capsules de substance active bêta-bloquante et des esters d'acides gras polyinsaturés Ceased WO2011060943A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200931027A ES2363965B1 (es) 2009-11-20 2009-11-20 Cápsulas de principios activos betabloqueantes y ésteres de ácidos grasos poliinsaturados.
ESP200931027 2009-11-20

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WO2011060943A1 true WO2011060943A1 (fr) 2011-05-26

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AR (1) AR079430A1 (fr)
ES (1) ES2363965B1 (fr)
TW (1) TW201138862A (fr)
WO (1) WO2011060943A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012013331A3 (fr) * 2010-07-26 2012-06-28 Gp-Pharm, S.A. Capsules d'ingrédients pharmaceutiques actifs et d'acides gras polyinsaturés pour le traitement de maladies de la prostate
US10744087B2 (en) 2018-03-22 2020-08-18 Incarda Therapeutics, Inc. Method to slow ventricular rate

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EP0052510A2 (fr) 1980-11-18 1982-05-26 Syntex (U.S.A.) Inc. Microencapsulation de polypeptides hydrosolubles
US4652441A (en) 1983-11-04 1987-03-24 Takeda Chemical Industries, Ltd. Prolonged release microcapsule and its production
GB2209937A (en) 1987-09-21 1989-06-01 Depiopharm S A Water insoluble polypeptides
ES2009346A6 (es) 1987-09-21 1989-09-16 Debiopharm Sa Procedimiento de preparacion de composiciones farmaceuticas que contienen polipeptidos hidroinsolubles.
EP0346879A1 (fr) 1988-06-15 1989-12-20 Warner-Lambert Company Médicaments insolubles dans l'eau et enrobés par coacervation avec de la gélatine de poisson
US5391377A (en) * 1990-10-19 1995-02-21 Cortecs Limited Biphasic release formations for lipophilic acids
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US20070009559A1 (en) 2002-12-12 2007-01-11 Wenji Li Free-flowing solid formulations with improved bio-availability of poorly water soluble drugs and process for making the same
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US20050175695A1 (en) * 2003-11-25 2005-08-11 Catherine Castan Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods
WO2006135415A2 (fr) 2004-09-08 2006-12-21 University Of Florida Research Foundation, Inc. Micelles et nanoemulsions pour le traitement prophylactique et reactif de l'atherosclerose
EP1803440A1 (fr) * 2004-10-19 2007-07-04 GP Pharm S.A. Formulation pharmaceutique comprenant des microcapsules de statines en suspension dans des esters alkyliques d'acides gras polyinsatures (pufa)
WO2006081518A2 (fr) 2005-01-28 2006-08-03 Collegium Pharmaceutical, Inc. Excipients non aqueux non ioniques pour administration topique et par voie orale d'agents actifs lies a un support
US20090215852A1 (en) * 2005-03-21 2009-08-27 Chroma Group, Inc. Compositions and methods for ameliorating cachexia
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012013331A3 (fr) * 2010-07-26 2012-06-28 Gp-Pharm, S.A. Capsules d'ingrédients pharmaceutiques actifs et d'acides gras polyinsaturés pour le traitement de maladies de la prostate
US10744087B2 (en) 2018-03-22 2020-08-18 Incarda Therapeutics, Inc. Method to slow ventricular rate

Also Published As

Publication number Publication date
AR079430A1 (es) 2012-01-25
ES2363965B1 (es) 2013-01-24
TW201138862A (en) 2011-11-16
ES2363965A1 (es) 2011-08-22

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