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WO2012002921A1 - Formes galéniques multiples comprenant du fénofibrate ou de l'acide fénofibrique combiné à des inhibiteurs de hmg co a réductase tels que les statines - Google Patents

Formes galéniques multiples comprenant du fénofibrate ou de l'acide fénofibrique combiné à des inhibiteurs de hmg co a réductase tels que les statines Download PDF

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Publication number
WO2012002921A1
WO2012002921A1 PCT/TR2011/000164 TR2011000164W WO2012002921A1 WO 2012002921 A1 WO2012002921 A1 WO 2012002921A1 TR 2011000164 W TR2011000164 W TR 2011000164W WO 2012002921 A1 WO2012002921 A1 WO 2012002921A1
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Prior art keywords
fenofibrate
fenofibric acid
hmg
pharmaceutical formulation
formulation according
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PCT/TR2011/000164
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Mahmut Bilgic
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • 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
    • A61K31/185—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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • 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
    • A61K31/33—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
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—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

Definitions

  • the present invention relates to pharmaceutical formulations comprising a HMG-CoA reductase enzyme inhibitor and a fibric acid derivative in order to be used in the treatment of hyperlipoproteinemia, hypertriglyceridemia, hypercholesterolemia, myocardial infarction and stroke and/or related diseases.
  • Cardiovascular disease is one of the leading causes of death in the world.
  • One of the most significant factors for these diseases is total/high density lipoprotein (HDL) cholesterol level.
  • HDL high density lipoprotein
  • new developments are required in the treatment of dislipidemia.
  • researchers have found that use of various cardiovascular active agents in combination provides a more effective treatment method. Fibrate and statin combinations can be given as an example of these combinations.
  • Atorvastatin ⁇ Formula I which has the chemical name ( R, ⁇ 5i?)-2-(4-fluoro-phenyl)- ⁇ , ⁇ - dihydroxy-5 -( 1 -methylethyl)-3 -phenyl-4- [(phenylamino)carbanoyl]- 1 H-pyrrol- 1 -heptanoic acid, is a HMG CoA reductase inhibitor firstly described in the patent numbered EP409281 Bl.
  • HMG CoA reductase inhibitor rosuvastatin which has the chemical name (3i?,5S,6E)-7-[4-(4-fluorophenyl)-6-(l -methylethyl)-2[methyl(methylsulphonyl)amino]-5- pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid, is a HMG CoA enzyme inhibitor displayed in formula (II):
  • rosuvastatin that is displayed in formula (I) inhibits the activation of the enzyme named HMG-CoA reductase which is responsible for cholesterol synthesis in the body and prevents cholesterol formation and it is effective in the treatment of cardiovascular diseases such as hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
  • Fenofibrate which has the chemical name 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl - propanoic acid, 1 - methylethyl ester, is a fibric acid derivative lipid regulating agent firstly disclosed in the patent numbered US4058552 (A):
  • Fenofibrate starts its action by being hydrolyzed to fenofibric acid and when considered from this aspect, it is a prodrug. It is used in the treatment of lipid diseases such as type IV and type V hyperlipoproteinemia which are related with extremely high levels of serum triglyceride and very high density lipoprotein (VHDL). It has been seen in fenofibrate treatments that triglyceride levels decrease approximately at 30%. Its non-micronized form has been used in the treatment of type Ila, type lib and type IV dislipidemia in various countries for more than 10 years. It is produced in micronized form in order to increase absorption and provide use of a single dose per day. It is hardly dissolved in water or does not dissolve at all.
  • lipid diseases such as type IV and type V hyperlipoproteinemia which are related with extremely high levels of serum triglyceride and very high density lipoprotein (VHDL). It has been seen in fenofibrate treatments that triglycer
  • statin group active agents easily disintegrate affected by external factors such as humidity, light, and this poses serious obstacles in development of stable pharmaceutical formulations and combinations.
  • Both rosuvastatin and atorvastatin are transformed into lactone as a result of "intramolecular esterification" reaction which occurs between carboxylic acid in its structure and hydroxyl groups on ⁇ and ⁇ carbons of this carboxylic acid. These reactions take place in acidic environment and basic agents cause the reaction to be reversed.
  • Major degradation products (3R, 5S) produced as a result of disintegration of statins are lactones and oxidation products. This feature reduces the stability of atorvastatin and therefore shortens its shelf life.
  • Solutions developed aiming to disintegration of statins in acidic environment are about keeping pH of the environment neutral and even basic, if possible. For instance, use of calcium, magnesium or lithium ions in order to provide stability of pharmaceutical formulations comprising atorvastatin. However, as indicated in the patent numbered WO0035425, use of much basic agents in the formulations causes regional irritation in the digestive tract.
  • two active agents are formulated separately and prepared in layered tablet form.
  • a formulation prepared this way it is not possible to formulate the active agents such that they can provide different release characteristics.
  • the patent numbered WO 2005/034908 defines fenofibrate and statin formulations combined in a single dosage form.
  • statins tend to be oxidized and disintegrate; therefore it is rather difficult to combine them with another active agent in a single dosage form.
  • combining them in a single dosage form does not enable to provide the required characteristics as the two active agents have different release characteristics.
  • neither the pharmaceutical formulations comprising statin alone nor the combinations composed of statin and one or more active agents can be produced effectively.
  • the inventors have solved these problems by designing multiple dosage forms having different release characteristics which comprise at least one HMG CoA reductase enzyme inhibitor and fenofibrate and/or fenofibric acid.
  • multiple dosage forms having different release characteristics which comprise at least one HMG CoA reductase enzyme inhibitor and fenofibrate and/or fenofibric acid.
  • HMG CoA reductase inhibitor used throughout the text refers to rosuvastatin, atorvastatin, simvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin and/or their pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms and/or combinations thereof.
  • HMG CoA reductase inhibitor used in the formulations of the present invention are preferably rosuvastatin and/or atorvastatin.
  • atorvastatin fenofibrate and/or fenofibric acid
  • rosuvastatin used throughout the text comprise pharmaceutically acceptable salts such as choline fenofibrate, atorvastatin calcium, rosuvastatin calcium; hydrates, enantiomers, racemates, esters, polymorphs of these active agents and/or combinations thereof.
  • the present invention relates to pharmaceutical formulations designed based on the synergistic effect that use of fenofibrate and/or fenofibric acid with statins would induce.
  • Said formulations are presented as multiple dosage forms produced by formulating the two active agents separately.
  • the excipients used in the formulations are selected such that the interaction between them and the active agents is minimized and the formulations are prepared accordingly. Multiple dosage forms prepared this way can be produced such that the two active agents can have different and/or the same release characteristics.
  • both fenofibrate and/or fenofibric acid, and statin group active agents hardly dissolve in water. It is known that it is very difficult to develop a pharmaceutical form having high dissolving speed of a hardly dissolving drug. Yet, the inventors have succeeded to produce multiple dosage forms comprising fenofibrate and/or fenofibric acid with statin in which at least one of the active agents have fast dissolving characteristics in scope of the present invention.
  • multiple dosage forms refers to oral dosage forms produced by combining at least two unit dosage forms having different and/or the same physical features.
  • the unit dosage forms of the present invention can be in the form of granule, powder, pellet, tablet, mini tablet, micro tablet, capsule or combinations thereof.
  • the unit dosage forms prepared are combined preferably in a gelatin capsule in order to prepare multiple dosage forms according to the present invention.
  • 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. By this way, both effective dispersion of the active agents in the stomach is ensured and the drug- food interaction is minimized.
  • Unit dosage forms of the present invention are preferably in micro tablet, granule and/or pellet form and they have pharmaceutically similar contents as known tablet and capsule dosage forms. Tablets, granules and/or pellets can be coated with protective coating, enteric coating, film coating and/or coatings that can enable different release characteristics afterwards. At least one active agent comprised in the formulations is in fast-release form.
  • micro tablet used throughout the text refers to tablets, round ones of which have a radius smaller than 10 mm or the longest one of which is smaller than 10 mm.
  • the present invention in the form of micro tablet, granule and/or pellet contained in gelatin capsules comprises an effective amount of fenofibrate and/or fenofibric acid, at least one statin group active agent, coating materials so as to provide different release characteristics, polymers and pharmaceutically acceptable excipients.
  • Gelatin capsules used here can be hard or soft.
  • the present invention comprises statin and fenofibrate and/or fenofibric acid formulations which are prepared such that they have sufficient stability.
  • the present invention comprises statin and fenofibrate and/or fenofibric acid formulations which have different or similar release characteristics.
  • the present invention relates to multiple dosage forms comprising fenofibrate and/or fenofibnc acid and a statin group active agent having fast release characteristics.
  • the present invention comprises a production method designed in order to minimize the interaction of fenofibrate and/or fenofibric acid and statin group active agents both with each other and with other pharmaceutically acceptable excipients.
  • the present invention comprises formulations which can be formulated without causing abdominal tenderness in patients.
  • the invention further comprises formulating the active agents separately in order to minimize drug-drug interaction and preparing the two different formulations by combining them in a capsule.
  • Atorvastatin used in the formulations according to the present invention is preferably atorvastatin calcium trihydrate and it is preferably in crystalline form polymorphically.
  • Rosuvastatin used in the formulations according to the present invention is preferably in the form of a pharmaceutically acceptable salt thereof and it is preferably in amorphous form polymorphically.
  • Fenofibrate and/or fenofibric acid used in the formulations of the present invention is preferably in the form of a pharmaceutically acceptable salt of fenofibric acid; more preferably used salt is cholin fenofibrate.
  • the particle size of fenofibrate and/or fenofibric acid used in the formulations of the present invention is preferably in the range of 1-500 ⁇ , more preferably in the range of 1-300 ⁇ , even more preferably in the range of 1-200 ⁇ .
  • the present invention relates to multiple dosage forms comprising fenofibrate and/or fenofibric acid and statin, at least one of which has fast release characteristics.
  • the formulations of the present invention can comprise pharmaceutically acceptable components such as additives selected from binders, disintegrants, viscosity enhancing components, filling materials, drying agents, lubricants, diluents, binders, glidants, surfactants, wetting agents, coating agents designed so as to provide various release characteristics, anti-adhesive agents, solvents, sweeteners and excipients.
  • pharmaceutically acceptable components such as additives selected from binders, disintegrants, viscosity enhancing components, filling materials, drying agents, lubricants, diluents, binders, glidants, surfactants, wetting agents, coating agents designed so as to provide various release characteristics, anti-adhesive agents, solvents, sweeteners and excipients.
  • antioxidants chelating agents, alkalinizing agents and photoprotective agents can be used as the stabilizer.
  • the stabilizer/stabilizers used in the formulations of the present invention are preferably alkalinizing agents and they can be selected from a group comprising alkaline metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines, N,N'dibenzylethylendiamine, dietanolamine, ethy
  • the filling materials used in the invention comprise one or more components selected from a group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and lactitol.
  • 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 for instance 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.
  • 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 sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate, 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 sodium stearyl fum
  • 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.
  • the pharmaceutically acceptable emulsifying agents according to the present invention can be selected from the group comprising carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, dietanolamine, ethylene glycol, polmito stearate, glyceryl mono stearate, hydroxy propyl cellulose, lanoline, lecithine, methyl cellulose, monoethanol amine, oleic acid, polyoxy ethylene alkyl ester, prophylene glycol alginate, sodium citrate dihydrate, sodium lauryl sulfate, sorbitan esters, polysorbate.
  • the 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 release rate determinant polymers that can be used in the formulations of the present invention 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, polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, e
  • the release rate determinant polymers used in fast release dosage forms are generally carboxy alkyl cellulose derivatives (for instance carboxy methyl cellulose sodium) and they sufficiently comprise unbound hydroxyl group. These hydroxyl groups help provide water solubility by binding to microcrystalline structures in the formulations during drying.
  • the film coating material of the present invention can be the following components and/or combinations thereof: lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, triacetine, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetate phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives, waxes, fats and gelatins, triethyl citrate, glyceride, titanium oxide, talc, sodium alginate, stearic acid, lecithin.
  • the solvents used in the present invention comprise one or more components selected from a group comprising toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol and/or alcohol mixtures.
  • the production method proposed for the formulations of the present invention basically comprises the following steps: 1. Preparation of the first phase comprising statin
  • the phases comprising active agents can be produced by any methods in the prior art.
  • fast release fenofibrate micro tablets are preferably prepared by the method below:
  • the release rate determinant polymer is added into the mixture and mixed
  • the mixture obtained is granulated by being sprayed on an inert carrier
  • the dry granules are compressed in tablet form, the diameter of which is in the range of 3-10 mm, and the micro tablets prepared this way are preferably coated with film.
  • statin at least one pharmaceutically acceptable binder, diluent and filling material are mixed
  • At least one pharmaceutically acceptable binder and emulsifying agent are dissolved with deionized water and the granulation solution is prepared
  • the active agent mixture prepared in the first step is granulated wet and the granules are then dried
  • the granules obtained are compressed in pellet form and the pellets are optionally coated
  • Formulations comprising statin are preferably formulated according to the method described above.
  • the pellets obtained can optionally be coated with film coating material or a coating material such that it can have certain release characteristics.
  • the active agent formulations prepared (pellet and micro tablet) are filled into gelatin capsules. Gelatin capsules are dissolved in the stomach in a few minutes and release the micro tablets and pellets into the stomach. Multiple dosage forms are completely mixed with chyme; therefore distribution and efficiency of the active agents are improved.
  • the formulations produced according to the present invention are used in the treatment of hyperlipoproteinemia, hypertriglyceridemia, hypercholesterolemia, myocardial infarction and stroke and/or related diseases.
  • Example 1 Formulation comprising fenofibrate and atorvastatin calcium
  • micro tablets comprising fenofibrate and pellets comprising atorvastatin are preferably filled into a capsule made of soft gelatin in the last step.

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Abstract

L'invention concerne des formulations pharmaceutiques comprenant un inhibiteur de l'enzyme HMG-CoA réductase et un dérivé de l'acide fibrique, à utiliser dans le traitement de l'hyperlipoprotéinémie, l'hypertriglycéridémie, l'hypercholestérolémie, l'infarctus du myocarde, l'attaque et/ou des maladies associées.
PCT/TR2011/000164 2010-06-30 2011-06-29 Formes galéniques multiples comprenant du fénofibrate ou de l'acide fénofibrique combiné à des inhibiteurs de hmg co a réductase tels que les statines Ceased WO2012002921A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2010/05326A TR201005326A2 (tr) 2010-06-30 2010-06-30 Çoklu dozaj formları.
TR2010/05326 2010-06-30

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WO2012002921A1 true WO2012002921A1 (fr) 2012-01-05

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CN109369425A (zh) * 2018-11-05 2019-02-22 陕西威信制药有限公司 非诺贝特酸胆碱盐的制备方法

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CN109369425A (zh) * 2018-11-05 2019-02-22 陕西威信制药有限公司 非诺贝特酸胆碱盐的制备方法

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