WO2019212214A1 - Préparation pharmaceutique - Google Patents

Préparation pharmaceutique Download PDF

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Publication number
WO2019212214A1
WO2019212214A1 PCT/KR2019/005151 KR2019005151W WO2019212214A1 WO 2019212214 A1 WO2019212214 A1 WO 2019212214A1 KR 2019005151 W KR2019005151 W KR 2019005151W WO 2019212214 A1 WO2019212214 A1 WO 2019212214A1
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WIPO (PCT)
Prior art keywords
layer
pharmaceutically acceptable
acid
amlodipine
rosuvastatin
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PCT/KR2019/005151
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English (en)
Korean (ko)
Inventor
김상엽
Original Assignee
보령제약 주식회사
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Application filed by 보령제약 주식회사 filed Critical 보령제약 주식회사
Priority to MX2020010259A priority Critical patent/MX2020010259A/es
Priority to CN201980029029.3A priority patent/CN112040933A/zh
Priority to RU2020138708A priority patent/RU2756452C1/ru
Priority to SG11202009187YA priority patent/SG11202009187YA/en
Publication of WO2019212214A1 publication Critical patent/WO2019212214A1/fr
Priority to PH12020551547A priority patent/PH12020551547A1/en
Priority to ZA2020/06346A priority patent/ZA202006346B/en

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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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a combination formulation comprising Pimasartan, amlodipine and rosuvastatin as active ingredients. More specifically, the present invention relates to a unit dosage form comprising pimasartan, amlodipine, and rosuvastatin as active ingredients, exhibiting excellent dissolution patterns and stability, and improved convenience of medication.
  • High blood pressure is important to keep blood pressure at a normal range rather than to treat blood pressure itself, and to prevent coronary artery disease and cardiovascular complications such as life-threatening stroke, heart failure, and myocardial infarction. It is important to adjust.
  • hypertensive patients are often accompanied by other types of cardiovascular diseases, including hyperlipidemia, and therefore, high prescription rates of two or more drugs are high.
  • long-term medications are required, so care must be taken in the selection of therapeutic drugs.As a result, long-term use of drugs with different mechanisms of action and the use of a single drug can be reduced, rather than selecting one drug. There is a need to reduce the side effects that can be caused by medication.
  • Fimasartan is known as angiotensin II receptor antagonist developed to treat hypertension and other medical indications. (Patent 10-1058284)
  • Amlodipine is known as a calcium channel blocker developed to treat high blood pressure and other medical indications.
  • Rosuvastatin is an HMG-CoA reductase inhibitor that prevents HMG-CoA from being reduced to mevalonate, thereby lowering blood lipid concentrations and cholesterol. It is used for hyperlipidemia, hypercholesterolemia and atherosclerosis.
  • a combination formulation containing all of the above-described mechanisms of fimasartan, amlodipine, and rosuvastatin may be considered. This may cause problems affecting the dissolution of each active ingredient.
  • canab marketed as a single Pimasartan formulation, has low solubility at low pH (eg, pH 1.2 to pH 1.4), which is lower than the dissolution rate in a single formulation when combined with other pharmacologically active ingredients. Dissolution rate may also be indicated.
  • the present invention comprises a first layer comprising Pimasartan, 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 second layer is to provide a formulation containing a low substituted hydroxypropyl cellulose (Low Substituted Hydroxypropyl cellulose).
  • the present invention is a.
  • a first layer comprising fimasartan, 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 second layer provides a formulation comprising Low Substituted Hydroxypropylcellulose.
  • the second layer comprising low-substituted hydroxypropyl cellulose swells rapidly upon contact with water so that the first layer and the second layer are directly separated and thus the first layer and the second layer are separated from each other. In each state can be disintegrated.
  • the first layer and the second layer are not affected by each other, and each layer is disintegrated, and the active ingredient belonging to each layer may be eluted. That is, even if the disintegration patterns of the first layer and the second layer are different, pharmaceutically acceptable carriers, additives such as disintegrating agents or pharmacologically active ingredients belonging to the respective layers may affect the disintegration pattern and dissolution of the other layers. Can't reach In particular, since each layer can be directly separated even in an acidic gaseous state having a pH of 3 or less, the disintegration of the first and second layers does not affect the disintegration and dissolution of the active ingredients of the other layers, and each component is excellent. Elution pattern is shown. As a result, the three pharmacologically active ingredients included in the formulations of the present invention may exhibit nearly the same or similar dissolution patterns as the single preparations containing the respective ingredients.
  • each component included in the first layer and the second layer of the composite formulation of the present invention can effectively exhibit the respective pharmacological activity without mutual interference with each other, and there is no problem such as deterioration in stability due to drug interaction. It may not be possible, it is possible to significantly improve the convenience of medication and mass production is easy.
  • the formulation of the present invention exhibits excellent stability and can maintain a stable state for a long time without separation of the layers.
  • the terms such as the first and the second are only used to distinguish the various layers, the films, the steps, and the like, respectively, but are not intended to indicate the order or the importance.
  • the terminology does not limit the features of layers, films, steps, and the like. Therefore, the terms such as the first and the second may not be used the same in the detailed description, the examples, the claims, and the like, and it is sufficient that the terms such as the first and the second can be distinguished from each other. .
  • ⁇ pharmaceutically acceptable '' means that when administered to a physiologically acceptable and human, a medicament of ordinary skill in the art, without causing an allergic reaction such as gastrointestinal disorders, dizziness or the like, generally It may mean that the conventional use in the preparation of the formulation.
  • 'hydrate' refers to fimasartan, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, amlodipine, a pharmaceutically acceptable salt thereof or an optical isomer thereof, or rosuvastatin, a pharmaceutically acceptable salt thereof.
  • an optical isomer thereof, and the like are combined with a non-covalent intermolecular force, and may include a stoichiometric or non-stoichiometric amount of water.
  • the hydrate may include about 0.25 moles to about 10 moles of water based on 1 mole of the active ingredient, and more specifically about 0.5 moles, about 1 moles, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, and the like.
  • a 'solvate' refers to fimasartan, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, amlodipine, a pharmaceutically acceptable salt thereof or an optical isomer thereof, or rosuvastatin, a pharmaceutically acceptable salt thereof.
  • a salt, or an optical isomer thereof, and a solvent other than water are bound by intermolecular force, and may include a solvent in stoichiometric or non-stoichiometric amounts.
  • the solvate may include a solvent molecule in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically about 0.5 mol, about 1 mol, about 1.5 mol, and about 2 mol , About 2.5 moles, about 3 moles, about 5 moles, and the like.
  • 'including Pimasartan as an active ingredient' may mean 'comprising Pimasartan free base, pharmaceutically acceptable salt thereof, optical isomer thereof, or hydrate or solvate thereof.
  • 'layer comprising Pimasartan as an active ingredient' refers to a layer comprising free base of Pimasartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.
  • 'Mixture comprising Pimasartan as an active ingredient' refers to a mixture comprising a free base of Pimasartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.
  • 'including amlodipine as an active ingredient' may mean 'comprising amlodipine free base, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.
  • '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
  • a mixture comprising as an active ingredient ' refer to a mixture comprising a free base of amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.
  • 'comprising rosuvastatin as an active ingredient' may mean 'including rosuvastatin free base, pharmaceutically acceptable salt thereof, optical isomer thereof, or hydrate or solvate thereof.
  • 'layer comprising 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.
  • '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 formulation may be a unit dosage form containing all of Pimasartan, rosuvastatin and amlodipine as an active ingredient.
  • the second layer may comprise 3% to 50% by weight of the low-substituted hydroxypropyl cellulose based on the weight of the second layer, specifically 5% by weight to 40% by weight of low substituted hydroxypropyl cellulose may be included.
  • the low-substituted hydroxypropyl cellulose is included in the above content, swelling of the second layer may proceed rapidly, and as a result, the first layer and the second layer may be separated more quickly. Therefore, even when the second layer disintegrates faster than the first layer, the dissolution of the second layer does not affect the first layer, and each of the active ingredients included in the first layer and the second layer has an excellent dissolution pattern. Can be represented.
  • the tablet when the low-substituted hydroxypropyl cellulose is included in the stomach content, the tablet can maintain an appropriate size to improve the patient's convenience of medication, and tableting may be easy. In addition, it is possible to maintain excellent content uniformity of each component included in each tablet, it may be possible to economically mass production easily.
  • the first layer and the second layer may exhibit different disintegration rates in the dissolution medium.
  • the elution medium may be an aqueous hydrochloric acid solution of pH 1.2.
  • the second layer in the elution medium may disintegrate before the first layer, wherein the elution medium may be an aqueous hydrochloric acid solution of pH 1.2.
  • the formulation may be a tablet, specifically, may be a two-layer tablet.
  • the first layer of the bilayer tablet may include Pimasartan as an active ingredient
  • the second layer may include amlodipine and rosuvastatin as an active ingredient, and as a result, the first layer
  • the active ingredient of Pimasartan and the active ingredient of the second layer, amlodipine and rosuvastatin, are separated from each other without being mixed.
  • the formulation of the present invention may exhibit an excellent dissolution pattern even though the three components are included in one tablet in the form of a two-layered tablet, and as a result, each of the formulations containing pimasartan, amlodipine, and rosuvastatin Elution patterns and bioavailability of the same or similar to those can be markedly improved patient convenience.
  • the first layer may contain granules containing Pimasartan as an active ingredient.
  • the granules may be dry granules or wet granules, specifically wet granules.
  • the second layer includes rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof; And amlodipine, pharmaceutically acceptable salts thereof, optical isomers thereof or hydrate solvates thereof may be mixed.
  • each component is simply mixed in the two layers, but may exhibit excellent stability.
  • rosuvastatin which is an active ingredient, may maintain a stable state for a long time.
  • the active ingredient contained in the second layer does not have to be manufactured in the form of granules, the production is simple and the production efficiency is high and mass production is easy.
  • the pharmaceutically acceptable salt of pimasartan may be selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonate salts, amino acid salts and amine salts.
  • pharmaceutically acceptable salts of pimasartan are inorganic ion salts made with calcium, potassium, sodium or magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid or sulfuric acid.
  • the hydrate of fimasartan, a pharmaceutically acceptable salt thereof, or an optical isomer thereof may be monohydrate or trihydrate, specifically monohydrate or trihydrate of potassium potassium And more specifically, trihydrate of potassium masartan.
  • the daily dosage of pimasartan, its pharmaceutically acceptable salts, optical isomers thereof, or hydrates or solvates thereof is about 0.5 mg to about 240 mg as potassium pimasartan. May be, specifically about 10 mg to 180 mg, more specifically may be about 20 mg to about 120 mg, even more specifically may be about 30 mg to about 60 mg, for example, castor As potassium potassium, it may be about 30 mg or about 60 mg.
  • the amlodipine of the second layer may comprise a racemate of amlodipine, (S) -amlodipine or (R) -amlodipine, specifically, a racemate of amlodipine or (S ) -Amlodipine.
  • the pharmaceutically acceptable salt of amlodipine which may be included in the second layer may be selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonate salts, amino acid salts and amine salts.
  • the pharmaceutically acceptable salt of amlodipine may be prepared with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, gluconic acid, besylic acid, or palmy acid.
  • amlodipine besylate.
  • the daily dosage of amlodipine, its pharmaceutically acceptable salt, its optical isomer, or its hydrate or solvate may be about 0.1 mg to about 20 mg as amlodipine, specifically About 3 to about 15 mg and more specifically about 5 to about 10 mg, for example, about 5 mg or about 10 mg as amlodipine.
  • the pharmaceutically acceptable salt of rosuvastatin of the second layer may be selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonate salts, amino acid salts and amine salts.
  • the pharmaceutically acceptable salt of rosuvastatin may be an inorganic ion salt made of calcium, potassium, sodium, or magnesium, and more specifically, rosuvastatin calcium salt.
  • the daily dose of rosuvastatin, its pharmaceutically acceptable salt, optical isomer, or hydrate or solvate thereof may be about 1 mg to about 40 mg as rosuvastatin, Specifically about 3 mg to about 30 mg, more specifically about 5 mg to about 20 mg, for example, about 5 mg, about 10 mg or about 20 mg as rosuvastatin.
  • the formulation comprises from about 0.5 mg to about 240 pimasartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof as potassium pymasartan per unit dosage form.
  • mg may be included, specifically about 10 mg to about 180 mg, more specifically about 20 mg to about 120 mg, and more specifically about 30 mg to about 60 mg, for example, to about 30 mg or about 60 mg as Pimasartan potassium.
  • the formulation may comprise from about 0.1 mg to about 20 mg of amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof as amlodipine per unit dosage form. It may be included to specifically about 3 mg to about 15 mg, more specifically may include about 5 mg to about 10 mg, for example, about 5 mg or about 10 mg as amlodipine. It may be included to be.
  • the formulation comprises 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 rosuvastatin per unit dosage form. It may be included to include, specifically about 3 mg to about 30 mg, and more specifically may include about 5 mg to about 20 mg, for example, as the rosuvastatin About 5 mg, about 10 mg, or about 20 mg.
  • the preparation may be administered once to several times a day, specifically, 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 is not limited thereto, and may be appropriately adjusted according to the condition of the patient.
  • the agent may treat or prevent cardiovascular disease
  • the cardiovascular disease may be hypertension, arterial spasm, deep vein, heart failure, cardiac hypertrophy, cerebral infarction, diabetes, obesity, hyperlipidemia, coronary artery disease , Chronic stable angina, vasospasmodic angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance, prediabetes, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive decline, dementia
  • it may be hypertension, hyperlipidemia and the like.
  • the first layer and the second layer may each further include a pharmaceutically acceptable additive.
  • the pharmaceutically acceptable additives included in the first layer and the second layer may be the same as or different from each other.
  • the pharmaceutically acceptable additives include carriers, excipients, diluents, extenders, antioxidants, stabilizers, dissolution aids, buffers, fillers, anticoagulants, lubricants, disintegrants, wetting agents, fragrances, emulsifiers, suspending agents, surfactants, preservatives Or mixtures thereof.
  • the additives may be formulated to include a range of dosages, usually by choice.
  • the second layer may include a stabilizer as a pharmaceutically acceptable additive.
  • the additive is lactose, dextrose, calcium silicate, corn starch, starch glyconate sodium, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, pregelatinized starch, Gelatin, calcium phosphate anhydride, monobasic calcium phosphate, dibasic calcium phosphate, calcium silicate, cellulose, methyl cellulose, 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 Free, polyethylene glycol, coll
  • the stabilizer in the additives may be used meglumine, calcium phosphate anhydride, calcium monophosphate, dibasic calcium phosphate, tribasic magnesium phosphate, tribasic aluminum phosphate, meglumine or a mixture thereof, Specifically, it may be meglumine, calcium phosphate anhydride, calcium monophosphate, dibasic calcium phosphate or a mixture thereof.
  • the binder may be hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch, gelatin, glucose syrup, polyvinylpyrrolidone, polyethylene glycol 6000, methyl cellulose, ethyl cellulose, carboxymethyl cellulose or a mixture thereof. have.
  • the disintegrant is starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch, clay such as bentonite, montmorillonite, or veegum, microcrystalline cellulose or carboxymethyl cellulose, etc.
  • Gums such as celluloses, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, guar gum and xanthan gum; Crosslinked polymers such as crospovidone, sodium bicarbonate, citric acid, or mixtures thereof can be used.
  • the lubricant may be used magnesium stearate, calcium stearate, stearic acid, sodium fumarate, polyethylene glycol, silicon dioxide or a mixture thereof.
  • the diluent may be cellulose, lactose, starch, microcrystalline cellulose, lactose hydrate, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate, or a mixture thereof.
  • the dissolution aid may be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, sodium docusate, or a mixture thereof.
  • As the surfactant sodium lauryl sulfate, cremophore, poloxamer, docusate, pharmaceutically acceptable docusate salts or mixtures thereof and the like can be used.
  • the first layer is a pharmaceutically acceptable additive, and may include a binder, a disintegrant, a lubricant, a diluent, a lubricant, or a mixture thereof, and the second layer may be a low substitution.
  • pharmaceutically acceptable additives may include disintegrants, lubricants, diluents, lubricants or mixtures thereof.
  • the second layer in addition to low-substituted hydroxypropyl cellulose, various starch, sucrose, starch 1500, calcium dihydrogen phosphate, sorbitol, calcium phosphate, calcium carbonate, mannitol, lactose, Microcrystalline cellulose or a mixture thereof may be further included.
  • the second layer may further include mannitol, lactose, microcrystalline cellulose or a mixture thereof in addition to low-substituted hydroxypropyl cellulose, and may further include microcrystalline cellulose.
  • the first layer containing Pimasartan as an active ingredient may include croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, mannitol, lactose, lactose hydrate, or a mixture thereof.
  • the second layer containing rosuvastatin and amlodipine as an active ingredient is crospovidone, mannitol, microcrystalline cellulose, lactose, lactose hydrate, meglumine, colloidal silicon oxide, magnesium stearate or Mixtures thereof.
  • the tablet may further include an outer coating layer in addition to the first layer and the second layer.
  • the method of forming the coating layer can be appropriately selected by the choice of a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer, applying a method such as fluidized bed coating method, fan coating method, dry coating method can do.
  • the coating layer may include hydroxypropyl methyl cellulose, ethyl cellulose, polyvinylacetate, polyethylene glycol, titanium dioxide, iron oxide, or the like, under the trade name Opadry.
  • the coating layer may be included in an amount of 0.5 to 10.0 wt%, specifically 1.0 to 6.0 wt%, and more specifically 2.0 to 5.0 wt%, based on the total weight of the tablet.
  • Rosuvastatin pharmaceutically acceptable salts thereof, optical isomers thereof, or hydrates or solvates thereof; Amlodipine, pharmaceutically acceptable salts thereof, optical isomers thereof, or hydrates or solvates thereof; And a second step of mixing the pharmaceutically acceptable additive to prepare a mixture; And
  • the pharmaceutically acceptable additive in the second step includes a low substituted hydroxypropyl cellulose.
  • the mixture prepared in the second step may include about 3% to about 50% by weight of the low-substituted hydroxypropyl cellulose based on the total weight of the mixture, specifically May comprise about 5% to about 40% by weight.
  • the first step may include preparing granules comprising fimasartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.
  • the step of preparing the granules may be by wet granulation or dry granulation, and more specifically by wet granulation.
  • the present invention comprises a first layer containing Pimasartan as an active ingredient
  • a second layer comprising amlodipine and rosuvastatin as an active ingredient
  • the second layer provides a pharmaceutical composition for treating or preventing a cardiovascular disease comprising low-substituted hydroxypropyl cellulose.
  • the present invention comprises a first layer containing Pimasartan as an active ingredient
  • a second layer comprising amlodipine and rosuvastatin as an active ingredient
  • the second layer provides a method for preventing or treating cardiovascular disease by administering a pharmaceutical composition comprising a low-substituted hydroxypropyl cellulose in a therapeutically effective amount.
  • the present invention comprises a first layer containing Pimasartan as an active ingredient
  • a second layer comprising amlodipine and rosuvastatin as an active ingredient
  • the second layer provides a prophylactic or therapeutic use of a cardiovascular disease of a composition comprising low-substituted hydroxypropyl cellulose.
  • the present invention is a unit preparation containing all of Pmasartan, rosuvastatin and amlodipine as active ingredients, despite all three components contained in one unit formulation, all three components exhibit excellent dissolution rate and stability without interference. Medication convenience can be significantly improved.
  • 1 is a diagram showing the dissolution rate of Pimasartan in the tablets according to the embodiments and the tablets according to the comparative examples.
  • FIG. 2 is a view showing the dissolution rate of amlodipine in the tablets according to the embodiments and the tablets according to the comparative examples.
  • Figure 3 is a view showing the dissolution rate of rosuvastatin in the tablets according to the examples and the tablets according to the comparative examples.
  • the vertical axis represents dissolution rate (%), and the horizontal axis represents minutes.
  • Pimasartan potassium trihydrate used in the above Examples and Comparative Examples is Boryeong Pharmaceutical Co., Ltd.
  • amlodipine besylate is Dr. Reddy
  • rosuvastatin calcium, MSN, meglumine, Merck and crospovidone were purchased from ISP
  • the low-substituted hydroxypropyl cellulose was purchased from NBD-021 (ShinEtsu Co., Ltd.).
  • hydroxypropyl cellulose was dissolved in 60 ml of purified water to prepare a binding solution.
  • the prepared binder solution was put into a high speed stirrer, wet granulated with a mixture containing the Pmasartan as an active ingredient, and then sintered to a 20 mesh sieve and dried. After drying, croscarmellose sodium was added and mixed in a double cone mixer for about 5 minutes, and magnesium stearate was added thereto and further mixed for about 5 minutes to prepare granules containing pimasartan as an active ingredient.
  • a mixture containing amlodipine and rosuvastatin of Example 1 as an active ingredient was prepared so as to have the content as shown in Table 1 per unit formulation.
  • amlodipine besylate, rosuvastatin calcium, stabilizer meglumine, and colloidal silicon dioxide were added and mixed for about 5 minutes, and then placed in a 30 mesh sieve and appled.
  • the apple mixture, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and crospovidone were put 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 and rosuvastatin as an active ingredient.
  • Granules containing pimasartan as an active ingredient and a mixture containing amlodipine and rosuvastatin as active ingredients were put in a punch die, respectively, to prepare a double-layered tablet.
  • the hardness of the two-layer tablet was prepared using a multi-layer tablet press (Pikola bilayer tablet press) so that the hardness of 10 ⁇ 15 kp.
  • the degree of wear was measured using a wear rate measuring system (25 rpm, 100 free falls). The degree of wear was 0.1% or less, and the strength of the tablet was good. Hardness was measured using a VARIAN VK200.
  • Two-layered tablets were prepared in the same manner as in Example 1, except that the components and contents per unit dosage form were the components and contents described in Example 2 of Table 1.
  • Two-layered tablets were prepared in the same manner as in Example 1, except that the components and contents per unit formulation were such as those described in Example 3 of Table 1.
  • Two-layered tablets were prepared in the same manner as in Example 1, except that the components and contents per unit dosage form were the components and contents described in Example 4 of Table 1.
  • Granules containing Pimasartan of Comparative Example 1 as an active ingredient were prepared to have the components and contents as shown in Table 2 per unit formulation (400 mg).
  • hydroxypropyl cellulose was dissolved in 60 ml of purified water to prepare a binding solution.
  • the prepared binder was placed in a high speed stirrer, wet granulated with a mixture containing pimasartan, and then sieved to a 20 mesh sieve and dried. After drying, croscarmellose sodium was added and mixed in a double cone mixer for about 5 minutes, and magnesium stearate was added thereto and mixed for about 5 minutes to prepare granules containing Pimasartan as an active ingredient.
  • a mixture containing amlodipine and rosuvastatin of Comparative Example 1 was prepared to have the components and contents of Table 2 per unit formulation.
  • Amlodipine besylate, rosuvastatin calcium, stabilizer meglumine and colloidal silicon oxide were added and mixed for about 5 minutes to prepare a mixture.
  • the mixture was placed in a 30 mesh sieve and appled.
  • the apple mixture, mannitol and crospovidone were put 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 and rosuvastatin as an active ingredient.
  • Granules containing pimasartan as an active ingredient and a mixture containing amlodipine and rosuvastatin as active ingredients were put in a punch die, respectively, to prepare a double-layered tablet.
  • the hardness of the tableted double-layered tablet was prepared using a double-layered tablet press (Piccola double-layer tablet press) so that the hardness of 10 ⁇ 15 kp.
  • the degree of wear was measured using a wear rate measuring system (25 rpm, 100 free falls). The degree of wear was 0.1% or less, and the strength of the tablet was good. Hardness was measured using a VARIAN VK200.
  • a two-layered tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents included in the unit formulation were the components and contents described in Comparative Example 2 of Table 2.
  • a two-layered tablet was prepared in the same manner as in Comparative Example 1 except for using microcrystalline cellulose instead of mannitol so that the components and contents included in the unit dosage form were the components and contents described in Comparative Example 3 of Table 2. .
  • the dissolution test was carried out using Examples 1 to 4, Comparative Examples 1 to 3, and commercially available control drugs, Canave tablets, Novask tablets, and Cresto tablets. Dissolution test methods are listed in Table 3. Dissolution test results are described in Figures 1 to 3, showing the average dissolution rate.
  • dissolution test method No. 2 (paddle method) of the Korean Pharmacopoeia of the composite preparation containing the Pmasartan, amlodipine and rosuvastatin prepared in Examples and Comparative Examples under the same conditions as described in Dissolution test was performed.
  • the tablets of the present invention despite being in the form of a combination formulation, exhibited the same level of elution as the single formulation without interference with each other.
  • the tablets according to the comparative example was significantly lower than the dissolution rate of the active ingredient contained in the tablet.
  • the composite formulation of the unit dosage form according to the present invention shows that three kinds of active ingredients having different mechanisms of action exhibit excellent dissolution patterns without interfering with each other, and can significantly improve the convenience of medication.

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Abstract

La présente invention concerne une préparation contenant du fimasartan, de l'amlodipine et de la rosuvastatine en tant que principes actifs. La présente invention concerne une préparation présentant un excellent taux de dissolution pour chaque principe actif et une stabilité élevée, ce qui permet d'améliorer remarquablement la commodité d'administration.
PCT/KR2019/005151 2018-04-30 2019-04-29 Préparation pharmaceutique WO2019212214A1 (fr)

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MX2020010259A MX2020010259A (es) 2018-04-30 2019-04-29 Preparacion farmaceutica.
CN201980029029.3A CN112040933A (zh) 2018-04-30 2019-04-29 药物制剂
RU2020138708A RU2756452C1 (ru) 2018-04-30 2019-04-29 Фармацевтический препарат
SG11202009187YA SG11202009187YA (en) 2018-04-30 2019-04-29 Pharmaceutical preparation
PH12020551547A PH12020551547A1 (en) 2018-04-30 2020-09-24 Pharmaceutical preparation
ZA2020/06346A ZA202006346B (en) 2018-04-30 2020-10-13 Pharmaceutical preparation

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KR20140085411A (ko) * 2012-03-30 2014-07-07 주식회사 대웅제약 올메사탄 메독소밀 및 로수바스타틴 또는 그의 염을 포함하는 약학 조성물
KR20140113512A (ko) * 2013-03-14 2014-09-24 보령제약 주식회사 약제학적 복합제제
KR20150067777A (ko) * 2013-11-29 2015-06-19 한미약품 주식회사 암로디핀, 로자탄 및 로수바스타틴을 포함하는 약제학적 복합 제제
WO2017091041A1 (fr) * 2015-11-26 2017-06-01 보령제약 주식회사 Nouveau sel de fimasartan

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JP5775522B2 (ja) * 2009-11-13 2015-09-09 アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ 二層錠製剤
KR101058284B1 (ko) 2010-01-22 2011-08-22 보령제약 주식회사 2-(2-ｎ-부틸-4-히드록시-6-메틸-피리미딘-5-일)-Ｎ,Ｎ-디메틸아세트아미드의 신규한 제조방법
CN103156842B (zh) * 2013-03-08 2014-05-28 南开大学 牛蒡子苷元在制备抗心律失常药物中的用途
EP3320903B1 (fr) * 2015-07-08 2021-05-19 HK inno.N Corporation Composition pharmaceutique contenant l'amlodipine, le valsartan et la rosuvastatine

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KR101168136B1 (ko) * 2011-08-08 2012-07-24 보령제약 주식회사 혈압 강하용 약제학적 조성물
KR20140085411A (ko) * 2012-03-30 2014-07-07 주식회사 대웅제약 올메사탄 메독소밀 및 로수바스타틴 또는 그의 염을 포함하는 약학 조성물
KR20140113512A (ko) * 2013-03-14 2014-09-24 보령제약 주식회사 약제학적 복합제제
KR20150067777A (ko) * 2013-11-29 2015-06-19 한미약품 주식회사 암로디핀, 로자탄 및 로수바스타틴을 포함하는 약제학적 복합 제제
WO2017091041A1 (fr) * 2015-11-26 2017-06-01 보령제약 주식회사 Nouveau sel de fimasartan

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CN112040933A (zh) 2020-12-04
PH12020551547A1 (en) 2021-06-07
MX2020010259A (es) 2020-10-22
KR101992400B1 (ko) 2019-06-24
TWI697339B (zh) 2020-07-01

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