WO2011060944A2 - Capsules de principes actifs pharmaceutiques et d'esters d'acides gras polyinsaturés - Google Patents

Capsules de principes actifs pharmaceutiques et d'esters d'acides gras polyinsaturés Download PDF

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WO2011060944A2
WO2011060944A2 PCT/EP2010/007024 EP2010007024W WO2011060944A2 WO 2011060944 A2 WO2011060944 A2 WO 2011060944A2 EP 2010007024 W EP2010007024 W EP 2010007024W WO 2011060944 A2 WO2011060944 A2 WO 2011060944A2
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capsule according
pharmaceutical
pharmaceutical capsule
microcapsules
group formed
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PCT/EP2010/007024
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WO2011060944A8 (fr
WO2011060944A3 (fr
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Antonio PARENTE DUEÑA
Paolo Carminati
Maria Gabriella Singrossi
Silvia Carminati
Giuseppe Paolo Carminati
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Gp Pharm, S.A.
Defiante Farmaceutica, S.A.
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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
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • 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
    • A61K31/435—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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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
    • 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
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)

Definitions

  • This invention relates to a pharmaceutical composition in the form of a capsule 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 active pharmaceutical ingredient, and its use for the treatment and/or prevention of cardiovascular diseases and/or inflammatory processes.
  • PUFA polyunsaturated fatty acids
  • the calcium channel blockers or antagonists include beta blockers or beta-adrenergic antagonists, the platelet antiaggregants and/or anticoagulants.
  • Beta blockers are competitive antagonists of the beta-adrenergic receptors and are used for the treatment of cardiovascular disorders such as hypertension, angina pectoris, cardiac dysrhythmia, myocardial infarction and heart failure.
  • Platelet antiaggregants reduce platelet aggregation and are used to prevent thromboembolic episodes in patients who have suffered a myocardial infarction, ischemic cerebral infarction or transitory ischemic attacks, unstable angina and for primary prevention of thromboembolic episodes in patients at risk. Some of them are used for the prevention of reocclusion or restenosis after an angioplasty or a coronary bypass.
  • Anticoagulant drugs are used for the treatment and profilaxis of thromboembolic disorders.
  • Non-steroidal anti-inflammatory drugs are drugs with analgesic and anti-inflammatory properties, of generalized use. They are particularly suitable for the treatment of illnesses or processes involving inflammation and/or pain, such as rheumatic disorders, among others.
  • 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 have numerous studies on anti-hypertensive, reduction of serum cholesterol, anti-hypertriglyceridemic, antiarrhythmic, antiplatelet and anti-inflammatory effects of PUFAs [Bucher H.C. ef al. Am. J. Med. 112: 298-304 (2002); Benatti P. et al. J. Am. Coll. Nutr. 23: 281-302 (2004); Lee J.H. et al. Mayo Clin. Proc. 83: 324-332 (2008); Heinz R. Adv. Ther. 26: 675-690 (2009)].
  • 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 alkyl 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.
  • Amiodipine presents formulation problems due to the fact that it is hygroscopic and can degrade in the presence of moisture by a process of oxidation which leads to, among others, an impurity with the dihydropyridine ring aromatized to pyridine [WO 2008/062435 A2].
  • Amiodipine besylate is photosensitive and degrades both in solution and in solid state forming pyridine derivatives which lack therapeutic activity.
  • the degradation studies show that amiodipine degrades slowly under heat stress, but it degrades quicker under photo-stress and even in acidic, alkaline and oxidative conditions, with the highest level of degradation in alkaline conditions [Aryal, S. et al. Acta Pharm. 58: 299-308 (2008)].
  • the amino group of carvedilol can react with aldehyde or ester functional groups [WO 2005/051383 A1], and degrades in the presence of polyvinylpyrrolidone and moisture [Galanopoulou, O. er al. J. Pharm. Biomed. Anal. 48: 70-77 (2008)].
  • Atenolol, nadolol and sotalol present, furthermore, formulation problems since they are solids with a sticky nature and difficult to compress; therefore, they require the addition of high quantities of excipients [EP 0454396 A1].
  • Clopidogrel An antiplatelet drug, clopidogrel, is marketed in salt form.
  • Clopidogrel hydrogen sulfate is, furthermore, very hygroscopic and degrades on contact with the atmosphere which leads to racemization and impurities such as the hydrolysis product of the ester group.
  • Warfarin sodium salt tends to decompose in the presence of water and excessive alkalinity, particularly if the temperature rises [US 6673944 B2].
  • NSAID ibuprofen
  • ibuprofen is very soluble, it has a low melting point and is not directly compressible, since it leads to tablets which stick to the press and easily disintegrate or break.
  • ibuprofen is normally subjected to a process of wet granulation as a prior step to compression [US 20080131507 A1].
  • the compositions obtained by wet granulation often age during storage, causing a reduction in the speed of dissolution of ibuprofen. This aging is influenced by factors such as temperature and moisture, and causes the ibuprofen particles to become compressed together, reducing their solubility.
  • a way of minimizing this problem is to increase the level or percentage of excipients or diluents to isolate the individual particles as much as possible, but this leads to tablets or capsules which are too large [EP 0172014 B1].
  • ibuprofen, naproxen and flurbiprofen formulations in soft gelatin capsule form are described in the literature; in them, suspensions of these active pharmaceutical ingredients are stabilized by the addition of different excipients [US6251426 B1 ; WO 2008/070950 A1 ; EP 1365749 B1 ; WO 97/03655 A1].
  • EP 1321140 B1 the use of surfactants is considered indispensable, but this compromises the integrity of the capsule due to the interaction of the surfactant with the coating's membrane.
  • compositions of other NSAIDs also present problems of stability, such as ketoprofen and pranoprofen, which are photolabile [US 5856345; EP 1688129 A1 ; EP 1526849 A1], or pirprofen, which tends to decompose oxidatively due to exposure to heat, light or air [US 4565807 A].
  • ketoprofen and pranoprofen which are photolabile [US 5856345; EP 1688129 A1 ; EP 1526849 A1]
  • pirprofen which tends to decompose oxidatively due to exposure to heat, light or air [US 4565807 A].
  • Ketoprofen salt tablets present a great instability due to its great hygroscopicity, which forces storage in an environment with a strict control of moisture [EP 0523153 B1].
  • Compressive forces that promote degradation are inevitable in the preparation of solid oral formulations such as tablets.
  • An alternative to these types of solid oral formulations are gelatin capsules.
  • Gelatin capsules whether they are hard or soft, allow active pharmaceutical ingredients to be incorporated into their interior, but the protection of the active ingredient is not satisfactory in the event that the substance is degradable or unstable in the presence of moisture or oxidizing agents.
  • Conventional gelatin capsules possess an external layer whose basic ingredient is gelatin, and in general this capsule can be hard or soft, the latter one containing plasticizers.
  • the coating of the conventional gelatin capsules consists of an external layer, with a uniform thickness and composition, which covers the inside, which contains the active pharmaceutical ingredient mixed with suitable excipients.
  • the content of the soft gelatin capsules is normally liquid or semi-liquid: oils, polar liquids, microemulsions, suspensions, waxes or colloids. The content in water of the interior liquid cannot exceed 20% so it does not dissolve the gelatin layer.
  • the external layer of the capsule contains a certain amount of water as a component.
  • water in the coating of the conventional gelatin capsules constitutes a serious problem, in the event that the active pharmaceutical ingredients or their salts to be formulated are water soluble, degradable in the presence of moisture or unstable in contact with water.
  • the active pharmaceutical ingredients or their salts to be formulated are water soluble, degradable in the presence of moisture or unstable in contact with water.
  • the outer coating of the capsule contains, as well as water, a notable quantity of conventional additives such as plasticizers, colorants, opacifiers and preservatives, it is also very difficult to satisfactorily prevent or control any possible incompatibilities between them and the active ingredient.
  • additives can facilitate oxidation, degradation or hydrolysis processes, causing a loss of activity of the active ingredient formulated [EP 0769938 B1].
  • Another factor to take into account is the possible chemical interaction between the content and the gelatin of the capsule, which may favor cross-linking and thus reduce the solubility in aqueous medium of the capsule (delaying its speed of disintegration).
  • Certain active pharmaceutical ingredients favor cross-linking in the capsule's coating, such as nifedipine [US 5874106 A]. Therefore, although soft gelatin capsules are widely used in the pharmaceutical industry, their use is not recommended in the case of active ingredients which are unstable in the presence of moderate quantities of water.
  • gelatin capsules which contain ketoprofen salts in an oily solution of polyethoxylated vegetable oils, ricin oil, or fatty acid or polyol esters are prepared.
  • gelatin capsules do not establish proper isolation from moisture for the active ingredients contained in its interior.
  • formulations based on lipids increase the bioavailability of certain active pharmaceutical ingredients.
  • examples of formulations which increase the bioavailability of the active ingredients by using PUFA are described in the literature, generally by formation of emulsions. Therefore, in US 5447729 A a delivery system is proposed which consists of an emulsion or dispersion of particles of an active ingredient which may be nifedipine, indometacin or naproxen, among others, which alternate different hydrophobic and hydrophilic layers; the emulsion can be incorporated into capsules and tablets, and for its formation long-chain hydrophobic fatty acid agents such as linolenic, linoleic or arachidonic acids are used.
  • WO 01/021154 A2 is proposed as a delivery system based on the formation of particles of 0.01 to 10 micrometers in diameter and with a modified surface which comprise an active ingredient insoluble in water such as nifedipine or piroxicam, among others, dissolved in a non-aqueous medium such as fish oil or PUFA, with phospholipids such as surfactants and an alcohol or polyol.
  • a non-aqueous medium such as fish oil or PUFA
  • phospholipids such as surfactants and an alcohol or polyol.
  • EPA eicosapentaenioc acid
  • US 2007009559 A1 proposes an improvement of the bioavailability of different active pharmaceutical ingredients poorly water soluble, such as carvedilol, felodipine or amlodipine, among others, through their incorporation into compositions which contain unsaturated fatty acids, such as linoleic acid or ethyl linoleate, as well as water, a surfactant, a polyol and phospholipids. ⁇ In all these cases contact with water or with excipients of the formulation would not be avoided, which is a cause of degradation for many of the active ingredients.
  • WO 2007/103557 A2 proposes the physical separation of the components in a hard or soft gelatin capsule which contains a first active ingredient such as omega-3 fatty acids, with one or more internal coatings of the capsule wherein at least one of them consists of a polymer combined with another active ingredient, and the coating which contains this active ingredient is isolated from the capsule and optionally from the outside through additional coatings.
  • a first active ingredient such as omega-3 fatty acids
  • WO 2008/063323 A2 the combination therapy is achieved by consecutive internal coatings of a capsule which contains omega-3 fatty acids with coatings which comprise antiarrhythmic active ingredients.
  • the consecutive coatings comprise one or more NSAID.
  • the manufacturing process is complex due to the fragility and solubility in water of the gelatin coatings and requires a rigorous control of the temperature and speed of deposition during the coating.
  • WO 2006/081518 A2 with the aim of achieving a modified release of multiple active ingredients, among them antiarrhythmic drugs, beta blockers or anti-inflammatory drugs, complexes of the active ingredients with ion exchange resins are prepared, with or without polymeric coatings, suspended in a non-ionic and non-aqueous vehicle ("NINA" vehicle) such as alcohols, polyols, polyethers, oils, triglycerides or waxes, among them omega-3.
  • NINA non-ionic and non-aqueous vehicle
  • the active pharmaceutical ingredient must contain an acid or basic functional group in order to be able to form the complex.
  • the application of these formulations is solely by topical route.
  • the solution proposed by this invention is a pharmaceutical capsule which incorporates alkyl esters of PL) FA and microcapsules of the desired active ingredient which is isolated by means of a polymer.
  • the subject-matter of this invention is a pharmaceutical composition in the form of a capsule which provides a greater protection for the active pharmaceutical ingredients against moisture, oxidizing agents and/or the possible chemical interactions with the additives of the exterior coating.
  • the pharmaceutical capsule of the invention allows the active pharmaceutical ingredients known for their instability to be conveniently formulated, such as the calcium channel blockers, beta blockers, antiplatelet drugs, anticoagulants and NSAID, avoiding its degradation through the isolation provided by the combination of a polymer coating of the active pharmaceutical ingredient and its suspension in alkyl esters of PUFA.
  • this invention relates to a new pharmaceutical composition which avoids problems of degradation of active pharmaceutical ingredients such as the calcium channel antagonists, beta blockers, antiplatelet drugs, anticoagulants and NSAID, when they are formulated in pharmaceutical capsules for oral administration.
  • active pharmaceutical ingredients such as the calcium channel antagonists, beta blockers, antiplatelet drugs, anticoagulants and NSAID, when they are formulated in pharmaceutical capsules for oral administration.
  • this invention relates to a pharmaceutical capsule which comprises a suspension of polymer microcapsules which comprise at least one polymer and at least one active pharmaceutical ingredient selected from the group formed by the calcium channel antagonists, beta blockers, antiplatelet drugs, anticoagulants and non-steroidal anti-inflammatory drugs, these microcapsules are 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 active pharmaceutical ingredient in the capsule.
  • the active pharmaceutical ingredients are found inside the polymer microcapsules in suspension in an oil which contains alkyl esters of PUFA.
  • the active pharmaceutical ingredients are isolated both from the exterior medium and the alkyl esters of PUFA by the polymer, which disintegrates easily in the gastrointestinal medium.
  • the pharmaceutical capsule of the invention allows, as well as the joint administration of active pharmaceutical ingredients in a combination therapy, the active pharmaceutical ingredient to be isolated from moisture and capsule coating additives, as well as moisture and oxygen from the outside.
  • the polymer coating provides the active pharmaceutical ingredients with stability, avoiding the formation of degradation products caused by moisture, compression and high temperatures during the preparation process of the final composition in the form of pharmaceutical capsules.
  • the fatty acids of the alkyi esters of PUFA belong to the omega-3 series.
  • the PUFAs are selected from the group formed by the fa//-c/ ' s > )-5,8,11 ,14,17- eicosapentaenoic or eicosapentaenoic (EPA) or timnodonic acid or icosapent (C20:5 n-3), the fa//-c/sj-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
  • the alkyi radical of the alkyi esters of PUFA is selected from the group formed by short chain alkyi radicals, with from 1 to 8 carbon atoms.
  • the alkyi radical is selected from the group formed by ethyl, methyl, propyl, butyl and/or mixtures thereof. More preferably, the alkyi 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 active pharmaceutical ingredient is a calcium channel blocker, selective or non-selective, and/or its pharmaceutically acceptable salts.
  • the selective calcium channel blocker is selected, without restriction, from the group formed by the dihydropyridine calcium channel blockers, such as amlodipine, aranidipine, azelnidipine, azodipine, barnidipine, benidipine, cilnidipine, clevidipine, dazodipine, efonidipine, felodipine, flordipine, iodipine, isradipine, lacidipine, lercanidipine, manidipine, mesudipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, oxodipine, pranidipine, riodipine or ryosidine, phenylalkylamine calcium channel blockers, such as verapamil, galopamil, tiapamil, emopamil, falipamil,
  • non-selective calcium channel blockers are, among others, flunarizine, cinarizine, prenilamine, fendiline, mibefradil, bepridil, caroverine, lidoflazine and perhexiline.
  • the active pharmaceutical ingredient is a beta blocker, selected, without restriction, from the group formed by acebutolol, alprenolol, amosulalol, arotinolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bupranolol, carazolol, carteolol, carvedilol, celiprolol, satenolol, esmolol, indenolol, labetalol, landiolol, levobunolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, talinol
  • the active pharmaceutical ingredient is an antiplatelet drug.
  • the antiplatelet drug is selected from the group formed by the glycoprotein llb/llla inhibitors, such as abciximab, eptifibatide, tirofiban, orbofiban, lamifiban, sibrafiban or xemilofiban; thienopyridines such as clopidogrel, ticlopidine or prasugrel; and others such as cilostazol, cloricromen, dipyridamole, ditazole, indobufen, picotamide, sarpogrelate, trapidil, triflusal, and/or their pharmaceutically acceptable salts.
  • the glycoprotein llb/llla inhibitors such as abciximab, eptifibatide, tirofiban, orbofiban, lamifiban, sibrafiban or xemilofiban
  • thienopyridines such as clo
  • the active pharmaceutical ingredient is an anticoagulant.
  • the anticoagulant is selected, without restriction, from the group formed by direct anticoagulants such as heparins, direct inhibitors of factor Xa, direct inhibitors of thrombin (II) and indirect coagulants such as vitamin K antagonists, and/or their pharmaceutically acceptable salts.
  • Heparins include unfractioned heparins, low molecular weight heparins such as ardeparin, bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin or tinzaparin, oligosaccharides such as fondaparinux or idraparinux, and heparinoids such as danaparoid, sulodexide or dermatan sulfate.
  • Direct inhibitors of factor Xa include xabans such as apixaban, otamixaban or rivaroxaban.
  • Direct inhibitors of thrombin II include bivalents such as hirudin, bivalirudin, lepirudin or desirudin, and univalents such as argatroban, dabigatran, melagatran or ximelagatran.
  • Vitamin K antagonists include coumarins such as acenocoumarol, dicoumarol, ethyl biscoumacetate, phenprocoumon or warfarin, 1 ,3- indanodiones such as clorindione, anisindione, fluindione or phenindione, and tioclomarol, among others. Another compound with anticoagulant activity is defibrotide.
  • the active pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug (NSAID).
  • NSAID is selected from the group formed by arylalkanoic acids, 2-arylpropionic acids or profens, N- aryl-anthranilic acids, derivatives of pyrazolidin, oxicams, cyclooxygenase-2 inhibitors (COX-2), sulfonanilides, CINOD ("COX-inhibiting nitric oxide donors”) and fluproquazone, and/or their pharmaceutically acceptable salts.
  • arylalkanoic acids examples include diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac and tolmetin, among others.
  • 2- arylpropionic acids or profens include ibuprofen, dexibuprofen, alminoprofen, carprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, tarenflurbil, ibuproxam, ketoprofen, dexketoprofen, ketorolac, loxoprofen, miroprofen, naproxen, oxaprozin, pranoprofen, tiaprofenic acid and suprofen, among others.
  • Examples of /V-arylantranilic acids are mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid, among others.
  • Examples of derivatives of pyrazolidin include phenylbutazone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone and sulfinpyrazone, among others.
  • Examples of oxicams include piroxicam, lornoxicam, meloxicam and tenoxicam, among others.
  • COX-2 inhibitors examples include celecoxib, etoricoxib, firocoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib, among others.
  • An example of sulfonamide is nimesulide, and an example of CINOD is naproxcinod.
  • 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(E-caprolactone), poly(p-dioxanone), poly(6-valerolactone), poly(p-hydroxybutyrate), poly(p-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 capsule of this invention, preferably between 0.01% and 60%, and more preferably between 0.1% and 50% of the total weight of the pharmaceutical capsule of this invention.
  • the amount of active pharmaceutical ingredient incorporated into these microcapsules is comprised between 1 % and 80% in weight, preferably between 1% and 60% in weight with regards to the total weight of the microcapsules.
  • the total amount of active pharmaceutical ingredient included in the pharmaceutical capsule of this invention depends on the recommended daily doses.
  • the pharmaceutical capsule of this invention can be a hard or soft capsule, made from gelatin 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.
  • HPMC hydroxypropyl methylcellulose
  • the capsule is a gelatin capsule. More preferably, this capsule is made of soft gelatin.
  • the capsule has an enteric coating.
  • the capsule 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.
  • 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 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 2009346 A6, EP 0052510 A2 and EP 0346879 A1.
  • 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.
  • cardiovascular diseases are selected from the group formed by cardiac dysrhythmia, hypertension, angina pectoris, myocardial infarction, heart failure and/or thromboembolic disorders, among others.
  • Another aspect of this invention relates to the pharmaceutical capsule of this invention for the treatment of diseases and/or processes involving inflammation and/or pain, preferably rheumatic diseases, among others.
  • cardiovascular diseases which comprises the administration of the pharmaceutical capsule of the invention.
  • the cardiovascular diseases are selected from the group formed by cardiac dysrhythmia, hypertension, angina pectoris, myocardial infarction, heart failure and/or thromboembolic disorders.
  • Another aspect of this invention relates to a method of treatment of diseases and/or processes involving inflammation and/or pain, preferably rheumatic diseases, which comprises the administration of the pharmaceutical capsule of this invention.
  • the resulting suspension was dried by spray-drying, to give a microcapsule powder which contained 20% of amiodipine besylate.
  • 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. (3.57 g of the suspension of microcapsules obtained per 100 g of oil). Next, 1.00 g of the microcapsule dispersion in oil was incorporated to a soft gelatin capsule, to obtain a dose of 5 mg of amiodipine base (equivalent to 6.9 mg of besylate) per capsule.
  • Example 2 Preparation of pharmaceutical capsules which contain diltiazem microcapsules with poly(lactic-co-glycolic acid) and vitamin E. Preparation of the microcapsules by the simple emulsion method (oil in water).
  • Solution A A 10% solution in dichloromethane of PLGA with an intrinsic viscosity (I.V.) of 0.17 and a lactic/glycolic ratio of 1 :1 was prepared.
  • Solution B 5 g of diltiazem hydrochloride and 1 g of vitamin E acetate were dissolved in 100 mL of solution A.
  • Solution C A 1 % solution of polyvinyl alcohol (PVA) in water was prepared.
  • the microcapsule powder obtained contained 21 % of diltiazem, and was directly dispersed in oil containing a minimum of 65% of ethyl esters of PUFAi with a minimum EPA/DHA content of 45% in a ratio of 1.2:1 (2.35 g of the microcapsule suspension obtained per 10 g of oil).
  • 1 ,50 g of the microcapsule dispersion in oil was incorporated to a soft gelatin capsule, obtaining a dose of 60 mg of diltiazem per capsule.
  • Example 3 Preparation of pharmaceutical capsules which contain microcapsules of carvedilol with gelatin through a simple coacervation procedure.
  • a 1% solution of gelatin in water was prepared. 100 mL of this solution were taken and 1 g of carvedilol powder was dispersed in it. Next, 30 mL of saturated sodium sulfate solution in water were added. The mixture was stirred for 1 hour and 0.5 mL of 50% glutaraldehyde in water solution were added.
  • microcapsules formed by filtration were collected, washed with water and dried in a vacuum drying oven.
  • the carvedilol content of these microcapsules was 39%.
  • the resulting 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 suspension of microcapsules 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 4 Preparation of pharmaceutical capsules which contain atenolol microcapsules with polyethylene glycol.
  • a 10% solution of polyethylene glycol with a molecular weight of 35000 (PEG-35000) in water was prepared. 5 g of atenolol were dispersed in 100 mL of this solution through intense stirring. Once a fine dispersion without lumps was obtained the solution was dried by spray-drying.
  • the microcapsule powder obtained showed a concentration of atenolol of 33%, and was dispersed directly 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). Next, 1.00 g of the dispersion of microcapsules in oil was incorporated to a soft gelatin capsule, to obtain a dose of 50 mg of atenolol per capsule.
  • Example 5 Preparation of pharmaceutical capsules' which contain dipyridamole microcapsules with cellulose acetate phthalate.
  • a 2% solution in water of cellulose acetate sodium phthalate was prepared. 2 g of dipyridamole powder was suspended in 100 ml. of this solution. The resulting suspension was dried by spray-drying.
  • the resulting microcapsule powder contained 50% of dipyridamole, and 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 (2.5 g of the microcapsule suspension obtained per 10 g of oil). Next, 1.00 g of the microcapsule dispersion in oil was incorporated to a soft gelatin capsule, to obtain a dose of 100 mg of dipyridamole per capsule.
  • Example 6 Preparation of pharmaceutical capsules which contain sodium warfarin microcapsules with poly(lactic-co-glycolic acid) (PLGA) prepared by the triple emulsion method.
  • PLGA poly(lactic-co-glycolic acid)
  • Solution A 2.5 g of PLGA with an intrinsic viscosity (I.V.) of 0.4 dl_/g and a lactic/glycolic ratio of 1 :1 were dissolved in 10 mL of dichloromethane (DCM).
  • I.V. intrinsic viscosity
  • DCM dichloromethane
  • Solution B 1 g of sodium warfarin was dissolved in 20 mL of water.
  • Solution C A 0.5% p/v concentration solution of polyvinyl alcohol (PVA) in water was prepared.
  • aqueous phase (solution B) was emulsified in the solution of PLGA (solution A) with the help of an Ultra Turrax homogenizer (W/O emulsion).
  • the previously prepared W/O emulsion was added to 250 mL of the PVA solution (solution C) under intense stirring.
  • the new emulsion formed was stirred whilst a nitrogen current was passed through the reactor at a flow no less than 50L/minute to evaporate the DCM.
  • the microcapsules were recovered by filtration through a membrane with a pore diameter of 5 pm, they were washed with abundant water to eliminate the excess of PVA and were dried by lyophilization.
  • the microcapsule powder obtained contained 28% of sodium warfarin, and was directly dispersed 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.
  • the microcapsule dispersion in oil obtained was incorporated into a soft gelatin capsule.
  • Table 1 The quantities used to prepare capsules of different doses of sodium warfarin are shown in Table 1.
  • Ejemplo 7 Preparation of pharmaceutical capsules which contain acenocoumarol microcapsules with alginate prepared by a simple coacervation procedure.
  • microcapsules formed by filtration were collected, washed with water and dried in a vacuum drying oven.
  • the acenocoumarol content of these microcapsules was 40%.
  • microcapsule powder was directly dispersed 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.
  • the microcapsule dispersion in oil obtained was incorporated to a soft gelatin capsule.
  • the quantities used to prepare capsules of different doses of acenoucumarol are shown in Table 2.
  • Dispersion Dose of acenoucumarol g microcapsules/100 g oil Weight of dispersion/capsule / capsule
  • Example 8 Preparation of pharmaceutical capsules which contain dabigatran etexilate microcapsules with gelatin, gum arabic and pectin prepared by a complex coacervation procedure.
  • Solution A A 1% solution of gelatin in water was prepared and the pH was adjusted so it was the same or higher than 7.
  • Solution B Another 2% solution of gum arabic and pectin in water (ratio 1.2:1) and the pH was adjusted so it was the same or higher than 7. 100 mL of solution A and 100 mL of solution B were mixed and heated to 40 °C. 2 g of dabigatran etexilate powder were dispersed in the mixture. When all the powder was dispersed and there were no lumps the pH was adjusted to 4-4.5 by adding acetic acid. The mixture was stirred for 1 hour at 40°C and afterwards the solution was cooled to 10 °C, maintaining this temperature for another hour. 1 mL of 50% glutaraldehyde solution in water was added.
  • the resulting suspension was dried by spray-drying, obtaining a microcapsule powder which contained 20% of dabigatran etexilate.
  • This microcapsule powder was directly dispersed in oil containing a minimum of 60% of ethyl esters of PUFA, with a minimum DHA content of 40% (4.58 g of the microcapsule suspension obtained per 10 g of oil). Next, 1.00 g of the microcapsule dispersion in oil was incorporated to a soft gelatin capsule, obtaining a dose of 110 mg of dabigatran etexilate per capsule.
  • Example 9 Preparation of pharmaceutical capsules that contain ibuprofen microcapsules with gelatin and carboxymethyl cellulose prepared by a complex coacervation procedure.
  • Solution A A 1 % solution of gelatin in water was prepared and the pH was adjusted so it was the same or higher than 7.
  • Solution B Another 1 % solution of sodium carboxymethyl cellulose in water was prepared and the pH was adjusted so it was the same or higher than 7. 250 mL of solution A and 250 mL of solution B were mixed and heated to 40 °C. 4 g of powdered ibuprofen were dispersed in the mixture. When all the powder was dispersed and there were no lumps the pH was adjusted to 4-4.5 by adding acetic acid. The mixture was stirred for 1 hour at 40°C and afterwards the solution was cooled to 10 °C, maintaining this temperature for another hour. 2 mL of 50% glutaraldehyde solution in water were added.
  • the resulting suspension was dried by spray-drying, obtaining a microcapsule powder which contained 38% of ibuprofen.
  • This microcapsule powder was directly dispersed 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 (5.40 g of the microcapsule suspension obtained per 10 g of oil). Next, 1.50 g of the dispersion of microcapsules in oil was incorporated to a soft gelatin capsule, obtaining a dose of 200 mg of ibuprofen per capsule.
  • Example 10 Preparation of pharmaceutical capsules which contain ketoprofen microcapsules and a methacrylic acid copolymer.
  • ketoprofen 10 g were suspended in 100 mL of a suspension of Eudragit FS 30D ® (suspension in water of 30% methacrylic acid, methyl methacrylate and methyl acrylate copolymers) until a fine suspension was achieved. Triethyl citrate was added to this suspension (polymer plasticizer) until a concentration of 5%. The resulting suspension was dried by spray-drying, to give a microcapsule powder which contained 22% of ketoprofen.
  • microcapsule powder was directly dispersed in oil containing a minimum of 60% of ethyl esters of PUFA, with a minimum DHA content of 40% (12.8 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 25 mg of ketoprofen per capsule.
  • Example 11
  • the percentages of the active pharmaceutical ingredient in the capsules were determined through HPLC after storage 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 3.
  • 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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Abstract

L'invention concerne une composition pharmaceutique se présentant sous la forme d'une capsule qui contient des esters d'alkyle d'acides gras polyinsaturés (PUFA) et des principes actifs pour le traitement et/ou la prévention de maladies cardiovasculaires et/ou de processus inflammatoires.
PCT/EP2010/007024 2009-11-20 2010-11-19 Capsules de principes actifs pharmaceutiques et d'esters d'acides gras polyinsaturés WO2011060944A2 (fr)

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ES200931026A ES2363964B1 (es) 2009-11-20 2009-11-20 Cápsulas de principios activos farmacéuticos y ésteres de ácidos grasos poliinsaturados.
ES200931026 2009-11-20

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Cited By (10)

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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
ITMI20112221A1 (it) * 2011-12-05 2013-06-06 Altergon Sa Formulazioni stabili in capsule di gelatina molle di antiaggreganti piastrinici, acidi grassi omega-3 e amilosio
EP2682105A1 (fr) * 2012-07-06 2014-01-08 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations à désagrégation orale de dexketoprofene
EP2682104A1 (fr) * 2012-07-06 2014-01-08 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations à désagrégation orale de dexketoprofen
CN103626689A (zh) * 2012-08-24 2014-03-12 上海医药工业研究院 一种阿哌沙班的中间体的制备方法
EP2836206A4 (fr) * 2012-04-10 2015-11-04 Rubicon Res Private Ltd Formulations pharmaceutiques à libération contrôlée d'inhibiteurs directs de la thrombine
WO2015195990A1 (fr) * 2014-06-20 2015-12-23 Banner Life Sciences Llc Capsules de gélatine molle à libération immédiate remplies de liquide
CN106620707A (zh) * 2017-03-14 2017-05-10 牡丹江医学院 一种预防和治疗心肌缺血的药物组合物及其制备方法和用途
CN114869857A (zh) * 2022-05-12 2022-08-09 郑州大学第一附属医院 一种阿加曲班微粒、制剂及其制备方法
US11980691B2 (en) 2018-03-15 2024-05-14 R.P. Scherer Technologies, Llc Enteric softgel capsules

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