WO2019143213A1 - Préparation pharmaceutique - Google Patents

Préparation pharmaceutique Download PDF

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Publication number
WO2019143213A1
WO2019143213A1 PCT/KR2019/000850 KR2019000850W WO2019143213A1 WO 2019143213 A1 WO2019143213 A1 WO 2019143213A1 KR 2019000850 W KR2019000850 W KR 2019000850W WO 2019143213 A1 WO2019143213 A1 WO 2019143213A1
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WO
WIPO (PCT)
Prior art keywords
layer
pharmaceutically acceptable
amlodipine
acceptable salt
rosuvastatin
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PCT/KR2019/000850
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English (en)
Korean (ko)
Inventor
김상엽
Original Assignee
보령제약 주식회사
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Publication of WO2019143213A1 publication Critical patent/WO2019143213A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/495—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds

Definitions

  • the present invention relates to a combination preparation comprising as an active ingredient piasmartan, amlodipine and rosuvastatin. More particularly, the present invention relates to a unit dosage form containing as an active ingredient pimazartan, amlodipine and rosuvastatin, exhibiting excellent dissolution pattern and stability, and improving convenience of administration.
  • hypertensive patients are often accompanied by other types of cardiovascular diseases including hyperlipidemia, so the combined prescription rate of two or more drugs is high.
  • drugs with different mechanisms of action and reducing the use of single drugs rather than choosing one drug There is a need to reduce the side effects that may be caused by drug use.
  • Pimersartan is known to be an angiotensin II receptor antagonist developed to treat hypertension and other medical indications. (Registered patent 10-1058284)
  • Amlodipine is known as a calcium channel blocker developed to treat hypertension and other medical indications.
  • Rosuvastatin is an HMG-CoA reductase inhibitor, which is effective in reducing HMG-CoA to mevalonate to lower blood lipid levels and cholesterol, and is therefore used for hyperlipidemia, hypercholesterolemia and atherosclerosis.
  • a combination preparation containing both of the above-mentioned different mechanisms of action such as pimasartan, amlodipine and rosuvastatin can be considered.
  • pimasartan amlodipine and rosuvastatin
  • cannab which is commercially available as a single product of a pimarastine single agent has a low solubility at a low pH (for example, pH 1.2 to pH 1.4), and when it is combined with other pharmacologically active ingredients, it is lower than the dissolution rate Elution.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a first layer comprising a phamacartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof;
  • a second layer comprising rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof, and amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof or a hydrate or solvate thereof;
  • the present invention is a.
  • a first layer comprising a phamacartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof;
  • a second layer comprising rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof, and amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof, ;
  • the separation layer is in direct contact with the first layer containing the above-mentioned paramsartan as an active ingredient, and the second layer containing rosuvastatin and amlodipine as an active ingredient is directly contacted with the first layer And is completely physically isolated.
  • the first layer and the second layer are not affected by each other, and the respective layers are disintegrated so that the active component belonging to each layer can be eluted. That is, even if the disintegration pattern of the first layer and the second layer is different, the pharmaceutically acceptable carrier, disintegrating additive or pharmacologically active ingredient belonging to each layer may affect the disintegration pattern and elution of the other layer I can not go crazy.
  • the three pharmacologically active ingredients included in the formulations of the present invention may exhibit an elution pattern that is approximately the same or similar to a single formulation comprising each ingredient.
  • the components contained in the first layer and the second layer of the combination preparation of the present invention can sufficiently exert their pharmacological activity without interfering with each other, and there is no problem such as a decrease in stability due to drug mutual interference And the medicinal convenience can be remarkably improved, and mass production is possible easily.
  • the separation layer can be easily dissolved in water.
  • the separation layer of a preparation according to the present invention can be rapidly dissolved in vivo. Therefore, the preparation according to the present invention is characterized in that the first layer and the second layer are separated from each other immediately after dissolution of the separation layer, although they contain all three kinds of active ingredients of pimazartan, amlodipine and rosuvastatin in one unit dosage form So that their pharmacological activity is sufficiently exhibited without interfering with each other, and the stability does not deteriorate.
  • the separation layer does not contain an active ingredient exhibiting pharmacological activity against cardiovascular diseases.
  • first, second, etc. are used for distinguishing between different layers, films, steps, etc., and are not intended to represent the order or importance, and the first,
  • the terms such as layer, film, and step are not limited by the term. Therefore, the terms first, second, etc. may not be used equally in the detailed description, examples, claims, and the like of the invention, and it is sufficient if they can be distinguished from each other by the first and second terms .
  • &quot pharmaceutically acceptable " means physiologically acceptable and non-toxic, non-toxic, non-toxic, non-toxic, non-may mean that it is conventionally used in manufacture.
  • hydrate refers to a pharmaceutically acceptable salt of pimersartan, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, amlodipine, a pharmaceutically acceptable salt or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, , Or an optical isomer thereof, and water in a stoichiometric or non-stoichiometric amount in which water is bonded with non-conjugated intermolecular forces.
  • the hydrate may comprise from about 0.25 mole to about 10 mole percent of water based on 1 mole of active ingredient, and more specifically about 0.5 mole, about 1 mole, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, and the like.
  • solvate refers to a pharmaceutically acceptable salt of pimersartan, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, amlodipine, a pharmaceutically acceptable salt or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A salt, or an optical isomer thereof and a non-water solvent, are bound to each other by an intermolecular force, and the solvent can be contained in a stoichiometric or non-stoichiometric amount.
  • the solvate may comprise from about 0.25 mole to about 10 mole percent of solvent molecules based on 1 mole of active ingredient, and more specifically about 0.5 mole, about 1 mole, about 1.5 moles, about 2 moles , About 2.5 moles, about 3 moles, about 5 moles, and the like.
  • the term “comprising as an active ingredient” may refer to a "pimaseartan free base, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof” .
  • the term “layer comprising as an active ingredient” refers to a layer comprising a free base of a pimarastane, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof , &Quot; a mixture comprising pimaractan as an active ingredient " refers to a mixture comprising a free base of a pimarastane, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.
  • 'comprising amlodipine as an active ingredient' can mean 'amlodipine free base, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof'.
  • 'a layer comprising amlodipine as an active ingredient' refers to a layer comprising a free base of amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof
  • As used herein refers to a mixture comprising the free base of amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.
  • the term “comprising rosuvastatin as an active ingredient” may mean “comprising rosuvastatin free base, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof” .
  • &quot layer containing rosuvastatin as an active ingredient " refers to a layer comprising a free base of rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof
  • a mixture comprising rosuvastatin as an active ingredient refers to a mixture comprising a free base of rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.
  • the preparation may be a unit dosage form containing both pimicatan, rosuvastatin and amlodipine as an active ingredient.
  • the material contained in the separating layer may be water-soluble, and specifically may be a material having a solubility of greater than 1 w / v% in purified water at 25 ° C.
  • the separation layer is formed from a sugar, a sugar alcohol, starch, crospovidone, stearic acid, magnesium stearate, calcium stearate, sucralose, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, Hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, methacrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, N-vinylpyrrolidone, a copolymer of acetate or a mixture thereof.
  • the separation layer may be formed of at least one selected from the group consisting of sugar alcohols, crospovidone, stearic acid, magnesium stearate, calcium stearate, sucralose, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose , A methacrylate copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, N-vinyl pyrrolidone, a copolymer of acetate, or a mixture thereof. More specifically, the separation layer may comprise sugar alcohols, crospovidone, magnesium stearate or mixtures thereof, and more specifically may include sugar alcohols, crospovidone, and magnesium stearate.
  • the separating layer comprises at least one selected from the group consisting of sugars, sugar alcohols, starch, crospovidone, stearic acid, magnesium stearate, calcium stearate, sucralose, gum arabic, hydroxypropylcellulose, May contain no substances other than those selected from the group consisting of hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, methacrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, N-vinylpyrrolidone and acetate have.
  • the separating layer may be formed of at least one selected from the group consisting of sugar alcohols, crospovidone, stearic acid, magnesium stearate, calcium stearate, sucralose, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose,
  • the separating layer may be a layer made of a sugar alcohol, a cross-linked polyvinyl pyrrolidone, a polyvinyl pyrrolidone, a copolymer of N-vinylpyrrolidone and acetate, or a mixture thereof, more specifically, a cellulose, a methacrylate copolymer, Povidone, magnesium stearate, or a mixture thereof, and may not contain any components other than the above components.
  • the separation layer may comprise a sugar alcohol, in which case mass production is easy and the stability of the preparation can be improved.
  • the separating layer contains sugar alcohols, even if the weight of the mixture contained in the separating layer is increased, the separating separating layer can be easily dissolved. Also, when the weight of the mixture contained in the separation layer is too small, it may not be easy to adjust the weight in mass production.
  • the separation layer is made thicker by using sugar alcohols, the weight deviation can be controlled, And commercialization of the product through this can be facilitated.
  • the separation between the layer and the layer can be reliably separated by including the sugar alcohol in the separation layer to increase the thickness of the layer, stability of the preparation hardly occurs due to interference between the layer and the layer, .
  • the separation layer may comprise, in addition to the sugar alcohol, crospovidone, stearic acid, magnesium stearate, calcium stearate, sucralose, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethyl Cellulose, methylcellulose, carboxymethylcellulose, methacrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, N-vinylpyrrolidone, a copolymer of acetate or a mixture thereof.
  • the sugar may be lactose, sucrose, fructose, maltose, or a mixture thereof.
  • the sugar alcohol is at least one selected from the group consisting of mannitol, sorbitol, xylitol, maltitol, traitol, adonitol, isomalt, erythritol, arabitol, pisilitol, dulcitol, inositol, trehalose, ribitol, Galactitol, lactitol, or a mixture thereof, and specifically may be mannitol.
  • the separation layer may comprise mannitol, which is a sugar alcohol.
  • the separation layer may include mannitol, crospovidone, and magnesium stearate, and more specifically, a layer made of only mannitol, crospovidone, and magnesium stearate.
  • the separation layer may be from about 3% to about 35% by weight, and more specifically from about 5% to about 32% by weight, based on the total weight of the formulation.
  • the administration of the preparation according to the present invention may be carried out in such a way that the layer containing the active ingredient of pimarastine and the layer containing amlodipine and rosuvastatin as the active ingredient Interference can be effectively inhibited, each effective ingredient can exhibit an excellent dissolution pattern, and a preparation having excellent stability can be obtained.
  • the preparation can have a size suitable for oral administration, the patient's convenience of medication can be significantly improved.
  • the pharmaceutically acceptable salts of the pimarastine may be selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonic acid salts, amino acid salts and amine salts.
  • pharmacologically acceptable salts of phimarsartan include inorganic acid salts prepared from calcium, potassium, sodium or magnesium, inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, , Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid , Organic acid salts such as ascorbic acid, carbonic acid, vanillic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid or succinic acid and the like, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, benzenesulfonic
  • the pharmaceutically acceptable salt of the above-mentioned pimasartan may be potassium pimarsatan, pimasartan toluenesulfonate or pimasartan ammonium salt, and more specifically, it may be a potassium salt of pimasartan.
  • a daily dose of a polymercaptan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof is about 0.5 mg to about 240 mg as potassium pimarate And may specifically be from about 10 mg to about 180 mg, more specifically from about 20 mg to about 120 mg, and still more specifically from about 30 mg to about 60 mg, About 30 mg or about 60 mg as potassium sartan.
  • the amlodipine in the second layer may comprise a racemate of amlodipine, (S) -amlodipine or (R) -amlodipine, specifically a racemate of amlodipine or (S ) -Amlodipine. ≪ / RTI >
  • the pharmaceutically acceptable salt of amlodipine which may be included in the second layer is selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonic acid salts, amino acid salts and amine salts .
  • the pharmaceutically acceptable salt of amlodipine may be one prepared from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, gluconic acid, More specifically, it may be amlodipine besylate.
  • the daily dosage of amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof may be from about 0.1 mg to about 20 mg as amlodipine, From about 3 to about 15 mg, and more specifically from about 5 to about 10 mg, for example, about 5 mg or about 10 mg as amlodipine.
  • the pharmaceutically acceptable salt of rosuvastatin in the second layer may be selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonic acid salts, amino acid salts and amine salts have.
  • the pharmaceutically acceptable salt of rosuvastatin may be an inorganic ionic salt such as calcium, potassium, sodium or magnesium, and more specifically rosuvastatin calcium salt.
  • a daily dosage of rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof may be about 1 mg to about 40 mg as rosuvastatin, Specifically about 3 mg to about 30 mg, and more specifically about 5 mg to about 20 mg, such as about 5 mg, about 10 mg, or about 20 mg as rosuvastatin.
  • the formulation may comprise from about 0.1 mg to about 20 mg of amlodipine per unit dosage form, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof as an amlodipine , Specifically from about 3 mg to about 15 mg, and more specifically from about 5 mg to about 10 mg, including, for example, about 5 mg or about 10 mg as amlodipine . ≪ / RTI >
  • the formulation comprises from about 1 mg to about 40 mg of rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof as a rosuvastatin per unit dosage form , Specifically from about 3 mg to about 30 mg, and more specifically from about 5 mg to about 20 mg, for example, as rosuvastatin About 5 mg, about 10 mg, or about 20 mg.
  • the preparation may be administered once to several times a day, and specifically, it may be administered once a day to three times a day, more specifically once a day or twice a day, More specifically, it may be administered once a day, but it is not limited thereto and can be appropriately adjusted according to the condition of the patient.
  • the agent may treat or prevent a cardiovascular disease, wherein the cardiovascular disease is selected from the group consisting of hypertension, arterial spasm, heart arrhythmia, heart failure, cardiomyopathy, cerebral infarction, diabetes, obesity, hyperlipidemia, coronary artery disease , Chronic stable angina pectoris, vasospastic angina pectoris, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance, pre-diabetes type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, And may be, for example, hypertension, arterial spasm, heart arrhythmia, cardiomyopathy, stroke, dyslipidemia, coronary artery disease, chronic stable angina pectoris, vasospastic angina pectoris, stroke, myocardial infarction, transient ischemic attack, congestive heart failure Specifically, it may be hypertension, hyperlipidemia, and the like.
  • the preparation may be a tablet, and may be a multi-layered tablet or a multi-tablet (core-shell structure), more specifically a multi-layered tablet.
  • the preparation of the present invention is a multilayer tablet, it can be suitable for mass production since the production method is easier and more economical.
  • the first layer may contain granules containing the pimarastane as an active ingredient.
  • the granules may be dry granules or wet granules, and in particular may be wet granules.
  • the first layer and the second layer may each further comprise a pharmaceutically acceptable additive.
  • the pharmaceutically acceptable additives contained in the first layer and the second layer may be the same or different from each other.
  • the pharmaceutically acceptable excipient may be selected from the group consisting of carriers, excipients, diluents, extenders, antioxidants, stabilizers, solubilizers, buffers, fillers, anticoagulants, lubricants, disintegrants, wetting agents, fragrances, emulsifiers, suspending agents, Or a mixture thereof.
  • the additive may be formulated to include a range of capacities by choice.
  • the layer containing rosuvastatin as an active ingredient may contain a stabilizer as a pharmaceutically acceptable additive.
  • the additive is selected from the group consisting of lactose, dextrose, calcium silicate, corn starch, sodium starch glycolate, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, pregelatinized starch, Gelatin, calcium phosphate anhydride, calcium primary phosphate, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, croscarmellose sodium, crospovidone, colloidal silicon dioxide, povidone, copovidone, polyvinylpyrrolidone, Hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, light silicic anhydride, talc, talc, stearic acid, magnesium stearate, calcium stearate, hydrogenated castor oil Free, polyethylene glycol,
  • the stabilizer may be calcium phosphate anhydride, calcium phosphate monobasic, calcium phosphate dibasic, tribasic magnesium phosphate, tribasic aluminum phosphate, meglumine or mixtures thereof.
  • the binder may be selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, gelatin, glucose syrup, polyvinylpyrrolidone, polyethylene glycol 6000, methylcellulose, ethylcellulose, carboxymethylcellulose, have.
  • the disintegrant of the additive may be selected from starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch, clay such as bentonite, montmorillonite or veegum, microcrystalline cellulose or carboxymethylcellulose Alginates such as sodium alginate or alginic acid, cross-linked cellulose such as croscarmellose sodium, gums such as guar gum and xanthan gum; A cross-linked polymer such as crospovidone, sodium bicarbonate, citric acid, or a mixture thereof.
  • the lubricant may be magnesium stearate, calcium stearate, stearic acid, sodium stearate fumarate, polyethylene glycol, silicon dioxide, or a mixture thereof.
  • the diluent may be cellulose, lactose, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate or a mixture thereof.
  • the dissolution aid may be a polyoxyethylene sorbitan fatty acid ester such as sodium lauryl sulfate or polysorbate, sodium docusate, or a mixture thereof.
  • the surfactant include sodium lauryl sulfate, cremopore, poloxamer, docusate, and pharmaceutically acceptable docusate salts or mixtures thereof.
  • the first layer comprising the pimasartan as an active ingredient may comprise croscarmellose sodium as a disintegrant
  • the layer comprising rosuvastatin and amlodipine as an active ingredient may comprise crospovidone as a disintegrant can do.
  • the layer containing amlodipine as an active ingredient may contain starch, microcrystalline cellulose, glucose, mannitol, alginate, an alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate, or a mixture thereof as a diluent.
  • the separating layer may have a thickness of about 0.5 mm to 3 mm.
  • each component contained in the tablet exhibits excellent dissolution pattern and stability without interference, and the convenience of medication can be remarkably improved.
  • the tablet may further comprise an outer coating layer in addition to the first layer, the second layer and the separation layer.
  • the method of forming the coating layer may be appropriately selected by a person skilled in the art from a method capable of forming a film-like coating layer on the surface of the tablet layer, and a fluid bed coating method, a pan coating method, a dry coating method, can do.
  • the coating layer may include hydroxypropylmethylcellulose, ethylcellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, or the trade name Opadry®fx.
  • the coating layer may contain, for example, 0.5 to 10.0% by weight, specifically 1.0 to 6.0% by weight, more specifically 2.0 to 5.0% by weight, based on the total weight of the tablet.
  • the second layer may be a single layer.
  • the second layer comprises amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof; And rosuvastatin, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, may be mixed in the second layer.
  • the formulation when the second layer is a single layer, the formulation may be three-layered.
  • a first layer comprising a pyramidal salt as an active ingredient
  • a second layer comprising amlodipine and rosuvastatin as active ingredients
  • the separation layer physically isolates the first layer and the second layer physically completely, dissolves readily upon contact with water, and rapidly dissolves in vivo to facilitate the first and second layers of the formulation .
  • the pharmacologically active ingredient contained in each layer may exhibit an excellent dissolution pattern without interfering with each other by the separation layer And can exhibit an elution pattern and stability almost equal to those of each of the above-mentioned effective ingredients, thereby remarkably improving the convenience of medicines.
  • the weight percentage and the thickness of the material included in the separation layer, the separation layer in the whole preparation, and the like are as described above.
  • the first and second layers comprise a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive is as previously described.
  • the pharmaceutically acceptable additives contained in the first layer and the second layer may be the same or different.
  • the additive may be a substance that does not react with the pharmacologically active ingredient contained in the first or second layer of the formulation and does not lower the stability of the formulation.
  • the second layer may comprise a stabilizer of a pharmaceutically acceptable additive.
  • the second layer may include two or more layers.
  • rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof and amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof physically react with each other May exist separately.
  • a layer containing rosuvastatin as an active ingredient and a layer containing amlodipine as an active ingredient may be separately present.
  • the second layer may consist of only two layers.
  • the second layer may consist of a layer containing amlodipine as an active ingredient and a layer containing rosuvastatin as an active ingredient, wherein the tablet may be a four-layered tablet.
  • a first layer comprising a pyramidal salt as an active ingredient
  • a second layer comprising amlodipine and rosuvastatin as active ingredients
  • the second layer comprises only two layers, one of the two layers containing amlodipine as an active ingredient and the other layer containing rosuvastatin as an active ingredient.
  • the separation layer physically isolates the first layer and the second layer from each other and is readily soluble in contact with water and is rapidly dissolved in vivo so that the first and second layers of the formulation It can be easily separated.
  • the active ingredient contained in each layer can exhibit an excellent dissolution pattern without interference with each other by the separation layer, It is possible to exhibit a dissolution pattern and stability which are almost the same as those in which a single agent of the active ingredient is administered, and the convenience of medication can be remarkably improved.
  • the weight percentage and the thickness of the material included in the separation layer, the separation layer in the whole preparation, and the like are as described above.
  • the first and second layers in the four-layer system include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive is as previously described.
  • the pharmaceutically acceptable additives contained in the first layer and the second layer may be the same or different.
  • the pharmaceutically acceptable additives contained in each layer may be the same or different from each other.
  • the additive may be a substance that does not react with the pharmacologically active ingredient contained in the first or second layer of the formulation and does not lower the stability of the formulation.
  • the layer containing rosuvastatin as an active ingredient may contain a stabilizer as a pharmaceutically acceptable additive.
  • the second layer there may be a separate layer between the layer containing rosuvastatin as an active ingredient and the layer containing amlodipine as an active ingredient, and the separate layer may be a pharmaceutical , It may not contain a substance exhibiting pharmacological activity in cardiovascular diseases.
  • the method for producing a preparation according to the present invention comprises:
  • Rosuvastatin a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof
  • Amlodipine a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof
  • a pharmaceutically acceptable additive to prepare a mixture
  • a third step of preparing a mixture for the production of the separation layer A third step of preparing a mixture for the production of the separation layer.
  • the preparation is provided with a separation layer between the layer containing the pyramidal salt as an active ingredient and the layer containing rosuvastatin and amlodipine as an active ingredient, Can be physically completely isolated from each other.
  • a fourth step of preparing a mixture for the production of the separation layer
  • the preparation is characterized in that the layer containing the pyramidal salt as an active ingredient is in contact with a layer containing rosuvastatin as an active ingredient and a layer containing amlodipine as an active ingredient Can be completely physically isolated.
  • said first step may comprise the step of preparing a granulate comprising a pimaserartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.
  • the step of preparing the granules may be performed by a wet granulation method or a dry granulation method, more specifically, by a wet granulation method.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first layer comprising as an active ingredient
  • a second layer comprising amlodipine and rosuvastatin as active ingredients
  • the present invention also provides a pharmaceutical composition for treating or preventing a cardiovascular disease.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first layer comprising as an active ingredient
  • a second layer comprising amlodipine and rosuvastatin as active ingredients
  • a separation layer positioned between the first layer and the second layer in a therapeutically effective amount to prevent or treat cardiovascular diseases.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first layer comprising as an active ingredient
  • a second layer comprising amlodipine and rosuvastatin as active ingredients
  • the present invention relates to a unit dosage form containing all of pisartan, rosuvastatin and amlodipine as active ingredients, and although all three components are contained in one unit dosage form, all three components exhibit excellent dissolution rate and stability without interference The convenience of medicines can be remarkably improved.
  • 1 and 2 are cross-sectional views of a tablet according to an embodiment of the present invention.
  • FIG 3 is a cross-sectional view of a tablet according to a comparative example.
  • the pimasartan layer is a layer containing pimasartan as an active ingredient
  • the amorphidin layer is a layer containing amlodipine as an active ingredient
  • the rosuvastatin layer is rosuvastatin as an effective ingredient
  • the amlodipine + rosuvastatin layer is a layer containing both amlodipine and rosuvastatin as active ingredients.
  • FIG. 4 is a graph showing dissolution rates of pimarastine in tablets according to Examples and tablets according to Comparative Examples.
  • FIG. 4 is a graph showing dissolution rates of pimarastine in tablets according to Examples and tablets according to Comparative Examples.
  • FIG. 5 is a graph showing dissolution rates of amlodipine in tablets according to Examples and tablets according to Comparative Examples.
  • Figure 6 shows dissolution rates of rosuvastatin in tablets according to the Figure 6 Examples and tablets according to Comparative Examples.
  • Granules containing permsal tea as an active ingredient were weighed to the same weight as in Table 1 per unit formulation by the following method.
  • hydroxypropylcellulose was dissolved in 60 ml of purified water to prepare a binding solution.
  • the prepared binding solution was put into a high-speed stirrer and was combined with a mixture containing the above-mentioned pimaserart as an active ingredient, wet-granulated, and dried by a 20-mesh sieve. After drying, croscarmellose sodium was added and mixed in a double cone mixer for about 5 minutes. Magnesium stearate was added to the mixture and the mixture was further mixed for about 5 minutes to prepare granules containing the pimaserartan as an active ingredient.
  • Example 1 A mixture containing amlodipine and rosuvastatin as an active ingredient of Example 1 was prepared so as to have the same contents as in Table 1 per unit dosage form.
  • amlodipine besylate, rosuvastatin calcium, and stabilizer calcium phosphate were added, mixed for about 5 minutes, and then placed in a 30 mesh sieve.
  • the apple mixture, microcrystalline cellulose and crospovidone were placed in a double cone mixer and mixed for about 15 minutes.
  • Magnesium stearate was added as a lubricant and further mixed for about 5 minutes to prepare a mixture containing amlodipine and rosuvastatin as an active ingredient.
  • D-mannitol, crospovidone and magnesium stearate were placed in a double cone mixer and mixed for about 5 minutes to prepare a mixture for the separation layer preparation.
  • FIG. 1 is a schematic cross-sectional view of the three-layer structure.
  • the hardness of the three-layered tablets 1 was made to be 10 to 15 kp using a single-action tablet press (KORSCH-Single Press). The thus obtained tablets were measured for the degree of scratching using a scratch meter (25 rpm, free fall of 100 times). The degree of fatigue was 0.1% or less and the strength of the tablets was good. Hardness was measured using VARIAN VK200.
  • the three-layered tablets were prepared in the same manner as in Example 1, except that the components and the contents per unit dosage form were the same as those described in Example 2 of Table 1.
  • the three-layered tablets were prepared in the same manner as in Example 1, except that the components and the contents per unit formulation were the same as those described in Example 3 of Table 1.
  • Example 2 Example 3 Granules containing as an active ingredient pimasartan Pimasartan potassium trihydrate 66.0 66.0 66.0 Microcrystalline cellulose 72.75 72.75 72.75 Croscarmellose sodium 7.5 7.5 7.5 Hydroxypropylcellulose 1.5 1.5 1.5 Magnesium stearate 2.25 2.25 2.25 Separation layer D-mannitol 50 100 150 Crospovidone 5 5 5 Magnesium stearate 0.5 0.5 0.5 A layer containing amlodipine and rosuvastatin as active ingredients Amlodipine besylate 13.9 13.9 13.9 Rosuvastatin calcium 20.8 20.8 20.8 Microcrystalline cellulose 132.0 132.0 132.0 Calcium phosphate 15.0 15.0 15.0 Crospovidone 15.0 15.0 Magnesium stearate 3.3 3.3 3.3 3.3 3.3 3.3
  • Permsartan granules of Example 4 were prepared so as to have the same weight as shown in Table 2 per unit dosage form.
  • Potassium palmitate trihydrate, microcrystalline cellulose and croscarmellose sodium were mixed and mixed for about 10 minutes.
  • the mixture was put into a high speed mixer for about 3 minutes to mix the mixture, A mixture was prepared.
  • hydroxypropylcellulose was dissolved in 60 ml of purified water to prepare a binding solution.
  • the prepared binding solution was put into a high-speed stirrer and wet-granulated together with a mixture containing pimasartan as an active ingredient, followed by sizing with a 20-mesh sieve and drying. After drying, croscarmellose sodium was added and mixed in a double cone mixer for about 5 minutes. Magnesium stearate was added to the mixture and the mixture was further mixed for about 5 minutes to prepare granules containing an effective ingredient of pimasartan.
  • a mixture containing the amlodipine of Example 4 as an active ingredient was prepared so as to have the same weight as in Table 2 per unit dosage form.
  • Amlodipine besylate, microcrystalline cellulose and crospovidone were mixed together in a double cone mixer and mixed for about 15 minutes. Magnesium stearate was added as a lubricant and further mixed for about 5 minutes to prepare a mixture containing amlodipine as an active ingredient.
  • a mixture containing rosuvastatin as an active ingredient of Example 4 was prepared so as to have a weight as shown in Table 2 per unit dosage form.
  • the apple mixture, microcrystalline cellulose and crospovidone were placed in a double cone mixer and mixed for about 15 minutes. Magnesium stearate was added as a lubricant and further mixed for about 5 minutes to prepare a mixture containing rosuvastatin as an active ingredient.
  • D-mannitol, crospovidone and magnesium stearate were placed in a double cone mixer and mixed for about 5 minutes to prepare a mixture for the separation layer preparation.
  • FIG. 2 is a schematic cross-sectional view of the four-layer structure.
  • the refinement was measured for the degree of fretting using a fretting meter (25 rpm, free fall of 100 times). The degree of fatigue was 0.1% or less and the strength of the tablets was good. Hardness was measured using VARIAN VK200.
  • the four-layered sheet was prepared in the same manner as in Example 4, except that the components and the contents per unit formulation were the same as those in Example 6 shown in Table 2 below.
  • Example 6 Granules containing as an active ingredient pimasartan Pimasartan potassium trihydrate 66.0 66.0 66.0 Microcrystalline cellulose 72.75 72.75 72.75 Croscarmellose sodium 7.5 7.5 7.5 Hydroxypropylcellulose 1.5 1.5 1.5 Magnesium stearate 2.25 2.25 2.25 Separation layer D-mannitol 50 100 150 Crospovidone 5 5 5 Magnesium stearate 0.5 0.5 0.5 A layer containing rosuvastatin as an active ingredient Rosuvastatin calcium 20.8 20.8 20.8 Microcrystalline cellulose 123.7 123.7 123.7 Calcium phosphate 15.0 15.0 15.0 Crospovidone 7.5 7.5 7.5 Magnesium stearate 3.0 3.0 3.0 A layer containing amlodipine as an active ingredient Amlodipine besylate 13.9 13.9 13.9 Microcrystalline cellulose 79.1 79.1 79.1 Crospovidone 5.0 5.0 Magnesium stearate 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
  • Granules containing as an active ingredient the pimasartan of Comparative Example 1 were prepared so as to have the same weight as in Table 3 per unit dosage form.
  • hydroxypropylcellulose was dissolved in 60 ml of purified water to prepare a binding solution.
  • the prepared binding solution was put into a high-speed stirrer and wet-granulated together with the mixture containing the pimasartan, followed by sizing with a 20-mesh sieve and drying. After drying, croscarmellose sodium was added and mixed in a double cone mixer for about 5 minutes. Magnesium stearate was added to the mixture and the mixture was further mixed for about 5 minutes to prepare granules containing an effective ingredient of pimasartan.
  • a mixture containing amlodipine and rosuvastatin of Comparative Example 3 was prepared so as to have the weight of Table 3 per unit dosage form.
  • Amlodipine besylate, rosuvastatin calcium, and calcium iodophosphate as a stabilizer were added and mixed for about 5 minutes to prepare a mixture.
  • the mixture was placed in a 30 mesh sieve and was then applicated.
  • the apple mixture, microcrystalline cellulose and crospovidone were placed in a double cone mixer and mixed for about 15 minutes.
  • Magnesium stearate was added as a lubricant and further mixed for about 5 minutes to prepare a mixture containing amphodipine and rosuvastatin as an active ingredient.
  • the granules containing the above-mentioned pimasartan as an active ingredient were placed in a punch die and tableted to prepare a first layer.
  • the mixture containing amlodipine and rosuvastatin as an active ingredient was placed in a punch die and tableted to prepare a two-layer tablet.
  • the two-layer defined cross-section is shown in FIG.
  • the hardness of the pressed two-layer tablet 1 was made to be 10 to 15 kp using a single-action tablet press (KORSCH-Single Press). The thus obtained tablets were measured for the degree of scratching using a scratch meter (25 rpm, free fall of 100 times). The degree of fatigue was 0.1% or less and the strength of the tablets was good. Hardness was measured using VARIAN VK200.
  • a two-layer tablet was prepared in the same manner as in Comparative Example 1, except that the components and the contents contained in the unit dosage form were the same as those in Comparative Example 2 shown in Table 3 below.
  • a two-layer tablet was prepared in the same manner as in Comparative Example 1, except that the components and the contents contained in the unit dosage form were the same as those in Comparative Example 3 shown in Table 3 below.
  • Example 3 Granules containing as an active ingredient pimasartan Pimasartan potassium trihydrate 66.0 66.0 66.0 Microcrystalline cellulose 72.75 72.75 72.75 Croscarmellose sodium 7.5 7.5 7.5 Hydroxypropylcellulose 1.5 1.5 1.5 Magnesium stearate 2.25 2.25 2.25 A layer containing rosuvastatin and amlodipine as active ingredients Amlodipine besylate 13.9 13.9 13.9 Rosuvastatin calcium 20.8 20.8 20.8 Microcrystalline cellulose 132.0 132.0 132.0 Calcium phosphate 15.0 15.0 15.0 Crospovidone 15.0 - - Croscarmellose sodium - 15.0 - Sodium starch glycolate - - 15.0 Magnesium stearate 3.3 3.3 3.3 3.3 3.3
  • the dissolution test was carried out using each of Examples 1 to 6, Comparative Examples 1 to 3, and a commercially available reference drug.
  • the dissolution test method is shown in Table 4.
  • the results of the dissolution test are shown in Figs. 4 to 6 and show an average dissolution rate.
  • the combination preparation comprising the pimazartan, amlodipine and rosuvastatin prepared in Examples and Comparative Examples as the active ingredient under the same conditions as those shown in Table 4 A dissolution test was performed.
  • Item Condition Dissolution test apparatus Hanson Vision Elite 8 Dissolution test liquid pH 1.2 solution Dissolution test liquid temperature 37 ⁇ 0.5 ° C Amount of eluate 900 mL Rotation speed 50 rpm Sample collection time 5, 10, 15, 30, 45, 60 minutes Sample weight 10 mL filter 0.45 ⁇ m syringe filter
  • the tablets of the present invention exhibit excellent dissolution of about the same degree as the single agent without interference between the components, despite the form of the combined preparation.
  • the tablets according to the comparative examples had a significantly lower dissolution rate of the active ingredient contained in the tablets than the single tablets, and showed a large variation in the dissolution rate for each tablets.
  • the combined preparation of the unit dosage form of the present invention shows excellent dissolution patterns without interference between three kinds of active ingredients having different action mechanisms, and the convenience of medication can be remarkably improved.

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Abstract

L'invention concerne une préparation comprenant du fimasartan, de l'amlodipine et de la rosuvastatine en tant qu'ingrédients actifs. La présente invention concerne une préparation qui présente d'excellentes vitesses de dissolution d'ingrédients actifs individuels et qui est très sûre, ce qui permet d'améliorer considérablement la commodité des médicaments. La présente invention concerne une préparation unitaire comprenant la totalité de la fimasartan, de la rosuvastatine et de l'amlodipine en tant qu'ingrédients efficaces. Bien qu'ils soient contenus dans une forme posologique unitaire, les trois ingrédients présentent d'excellentes vitesses de dissolution et de sécurité sans interférence les uns avec les autres et peuvent ainsi améliorer de façon remarquable commodité des médicaments.
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KR101502031B1 (ko) * 2013-03-14 2015-03-12 보령제약 주식회사 약제학적 복합제제
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