WO2020141825A1 - Comprimé et son procédé de préparation - Google Patents

Comprimé et son procédé de préparation Download PDF

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Publication number
WO2020141825A1
WO2020141825A1 PCT/KR2019/018684 KR2019018684W WO2020141825A1 WO 2020141825 A1 WO2020141825 A1 WO 2020141825A1 KR 2019018684 W KR2019018684 W KR 2019018684W WO 2020141825 A1 WO2020141825 A1 WO 2020141825A1
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WIPO (PCT)
Prior art keywords
tablet
granules
layer
atorvastatin
pharmaceutically acceptable
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PCT/KR2019/018684
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English (en)
Korean (ko)
Inventor
김윤삼
김명식
신동철
황용연
Original Assignee
보령제약 주식회사
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Application filed by 보령제약 주식회사 filed Critical 보령제약 주식회사
Priority to KR1020217024291A priority Critical patent/KR102465736B1/ko
Priority to SG11202106025WA priority patent/SG11202106025WA/en
Priority to MX2021007734A priority patent/MX2021007734A/es
Priority to CN201980087258.0A priority patent/CN113260355A/zh
Publication of WO2020141825A1 publication Critical patent/WO2020141825A1/fr
Priority to PH12021551334A priority patent/PH12021551334A1/en
Priority to ZA2021/04403A priority patent/ZA202104403B/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
    • A61K31/40—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
    • A61K31/41—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
    • 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
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to tablets and methods for their preparation.
  • Hypertension is important to prevent coronary artery disease and cardiovascular complications such as life-threatening stroke, heart failure, and myocardial infarction by maintaining blood pressure in the normal range rather than treating blood pressure itself, so it is steadily lowering blood pressure below a certain pressure. It is important to adjust.
  • Fimasartan represented by the following Chemical Formula 1 is known as an angiotensin II receptor antagonist developed to treat hypertension and other medical signs (Korean Patent No. 10-1058284).
  • the fimasartan is 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyri Midine-4(3H)-one, a non-peptide molecule chemically described, empirical formula is C 27 H 30 N 7 OS, and molecular weight is 501.65.
  • Fimasartan is marketed in Korea as an item license with fimasartan potassium trihydrate.
  • atorvastatin represented by the following formula (2) is a selective and competitive HMG-CoA reductase inhibitor, atorvastatin calcium salt, which is a representative salt of atorvastatin (chemical name: [R-(R*,R*)]-2- (4-Fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptate calcium salt (2:1)) is a lipid-lowering agent that lowers the concentration of low-density lipoprotein cholesterol and is useful in the treatment of hyperlipidemia.
  • atorvastatin calcium is known to reduce mortality and stroke from cardiovascular-related diseases.
  • Tablets containing fimasartan and atorvastatin with different mechanisms of action may be considered to more effectively treat cardiovascular disease, including hypertension, but tableting such as stirring of atorvastatin during this tableting process Disability occurs.
  • Non-Patent Document 1 Compatibility study of Atorvastatin Calcium and Telmisartan with selected excipients and formulation of a bilayer tablet using box behnkein design, Bajracharya et. al., Am. J. PharmTech Res. 2015; 5(3) ISSN: 2249-3387
  • the present invention relates to a tablet and a method of manufacturing the atorvastatin granules having a particle size distribution of a certain level or more so that the tableting process can be remarkably improved in a tableting process with fimasartan.
  • the present invention is a fimasartan granule part containing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a pharmaceutically acceptable additive; And an atorvastatin granule part containing atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable additive, wherein the fimasartan granule part and the atorvastatin granule part are present separately.
  • the present invention is fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a first layer comprising granules containing a pharmaceutically acceptable additive; And a second layer comprising granules containing atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable additive, wherein the granule of the second layer has a D 50 of 80 ⁇ m or more.
  • Provided are tablets that exhibit a particle size distribution.
  • the present invention fimasartan, a pharmaceutically acceptable salt, a hydrate or solvate thereof and a first layer containing a granule containing a pharmaceutically acceptable additive; (S2) preparing a second layer containing granules comprising atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable additive; And (S3) tableting the first layer and the second layer to produce a two-layer tablet.
  • the present invention provides a pharmaceutical composition comprising the tablet.
  • the present invention provides a method for preventing or treating cardiovascular disease, comprising administering to a mammal, including a human, in a therapeutically effective amount of the tablet.
  • the present invention provides the use of such tablets for use in the manufacture of cardiovascular disease agents.
  • the present invention provides the use of the tablets for the treatment of cardiovascular diseases.
  • tablets containing fimasartan active ingredient and atorvastatin active ingredient were developed by solving the tableting disorder of atorvastatin in the process of tabletting with fimasartan by applying the particle size control technology of atorvastatin granules, and the tablets are particularly useful. It was confirmed that the mass variation of atorvastatin was within a suitable range, so that it could be produced according to a target weight, so that it could have excellent content uniformity.
  • the present invention is a fimasartan granule part containing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a pharmaceutically acceptable additive; And an atorvastatin granule part containing atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable additive, wherein the fimasartan granule part and the atorvastatin granule part are present separately.
  • the present invention comprises a first layer comprising granules containing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a pharmaceutically acceptable additive; And a second layer comprising granules containing atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable additive, wherein the granule of the second layer has a D 50 of 80 ⁇ m or more.
  • a first layer comprising granules containing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a pharmaceutically acceptable additive
  • a second layer comprising granules containing atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable additive, wherein the granule of the second layer has a D 50 of 80 ⁇ m or more.
  • Atorvastatin is very difficult to formulate when preparing a complex with fimasartan, and because of low stability of atorvastatin, a large amount of finely precipitated calcium carbonate is added as a stabilizing agent, thereby causing tabletting failure during tableting with fimasartan and bilayer tablets. This leads to cosmetic disorders that lack part of the formulation. In the case of manufacturing on a production scale, it is envisaged that such a tableting impediment causes the machine to stop, and the production itself becomes difficult. In addition, even when the identification code is imprinted on the tablet surface, omission of imprinting occurs due to a tableting problem, which is a major problem.
  • the particle size distribution of the atorvastatin granules included in the second layer is adjusted to a value equal to or more than a predetermined value, so that it is possible to express ease of tableting in the purification process for preparing fimasartan and the complex agent. .
  • the term "fimasartan” means 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-) represented by the following formula (1) 5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one, meaning angiotensin II receptor antagonist developed to treat hypertension and other medical signs.
  • atorvastatin is a lipid-lowering agent that lowers the concentration of low-density lipoprotein cholesterol represented by the following formula (2), a selective and competitive HMG-CoA reductase inhibitor that is useful for the treatment of hyperlipidemia to be.
  • the term "pharmacologically acceptable” refers to a physiologically acceptable, when administered to humans, that usually does not cause an allergic reaction such as gastrointestinal disorders, dizziness or similar reactions, and the term “salt” Iran means an acid addition salt formed by a pharmaceutically acceptable free acid.
  • the pharmaceutically acceptable salt of the fimasartan may be selected from the group consisting of inorganic ionic salts, inorganic acid salts, organic acid salts, sulfonate salts, amino acid salts and amine salts.
  • the pharmaceutically acceptable salt of fimasartan is an inorganic ionic salt made of calcium, potassium, sodium or magnesium, an inorganic acid salt made of hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid or sulfuric acid, Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic 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, methanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, made of ascorbic acid, carbonic acid, vanic acid, mandelic acid, mumic acid
  • the pharmaceutically acceptable salt of atorvastatin is an inorganic ion salt made of calcium, strontium, sodium, potassium, magnesium, ammonium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, Inorganic acid salts made of perchloric acid or sulfuric acid, and the like, but the types of salts in the present invention are not limited by the salts listed.
  • the pharmaceutically acceptable salt of atorvastatin may be atorvastatin calcium salt.
  • the term "hydrate” means that the active ingredient and water are bound by the force between non-covalent molecules, and includes a stoichiometric or non-stoichiometric amount of water.
  • the hydrate may include water in an amount 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, about 2 mol, about 3 moles, about 5 moles, and the like.
  • the fimasartan hydrate is fimasartan potassium trihydrate, fimasartan hydrochloride trihydrate, fimasartan calcium trihydrate, fimasartan sulfate trihydrate, fimasartan adipate trihydrate, fimasartan camsylate trihydrate It may be any one selected from the group consisting of cargo and fimasartan besylate trihydrate, but is not limited thereto, and may specifically be fimasartan potassium trihydrate.
  • the hydrate of the fimasartan or a pharmaceutically acceptable salt thereof may be a monohydrate or a trihydrate, specifically a fimasartan potassium monohydrate or a trihydrate, and more specifically It may be a trihydrate of fimasartan potassium.
  • the hydrate of the atorvastatin or a pharmaceutically acceptable salt thereof may be a trihydrate, specifically, a trihydrate of atorvastatin calcium, but is not limited thereto.
  • solvate means that the active ingredient and the solvent are combined by the force between non-covalent molecules, and includes a stoichiometric or non-stoichiometric amount of a solvent.
  • Preferred solvents are volatile, non-toxic, and can be administered in very small amounts to humans.
  • solvates of the present invention are not limited by these examples, specifically, the solvate contains 1 mole of the active ingredient.
  • water may be included in a ratio of about 0.25 mol to about 10 mol, and more specifically, may include about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 3 mol, about 5 mol, and the like. .
  • the term "about” means a 10% deviation from the labeled value (eg, 1 mol, 2 mol%, 3 mol%, etc.), or in the case of a numerical range, both the lower and upper limits of the range. Means 10% deviation from.
  • “about 1 mole” refers to a range from 0.9 mole to 1.1 mole.
  • the term “granules” means smaller primary particles or solid particles composed of primary particles.
  • the term "fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a granule containing a pharmaceutically acceptable additive” refers to fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a pharmaceutical
  • a primary particle formed by mixing an acceptable additive it means a solid particle composed from the primary particle, and contains the term ⁇ atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable additive.
  • "Granule to be” means atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a primary particle formed by mixing a pharmaceutically acceptable additive, or a solid particle composed of primary particles.
  • particle size may be expressed as a particle size distribution such that D(X) is Y (where X and Y are positive numbers).
  • D(X) is Y
  • the particle size distribution of a drug obtained by measuring the particle diameter of a drug in a formulation is represented by a cumulative curve, the particle size accumulates in the order of smallest X% (% is based on number, volume or weight) Is calculated) means that the particle diameter at point Y is Y.
  • D(10) is the particle diameter of the point at which the particle size of the drug is 10% by accumulating the particle size in small order
  • D(50) is the particle at the point of 50% by accumulating the particle size of the drug in small order.
  • the diameter of, D (90) may be to represent the diameter of the particle at a point that is 90% by accumulating the particle size of the drug in small order.
  • D(X) is alternatively expressed as D(0.X), and D(X) and D(0.X) can be used interchangeably.
  • D(50) is also represented as D(0.5)
  • D(10) and D(90) are also represented as D(0.1) and D(0.9), respectively.
  • the particle size distribution D(X) represents the percentage of the total cumulative particles based on number, volume, or weight depends on the method used to measure the particle size distribution. Methods for measuring the particle size distribution and the type of% in this regard are known to those skilled in the art. For example, when the particle size distribution is measured by a well-known laser diffraction method, the X value in D(X) may represent the percentage calculated by the volume average. It is known to those skilled in the art that the results of particle size distribution measurements obtained by a particular method may correlate with those obtained from other techniques based on experience with conventional experiments. For example, laser diffraction provides a volume average particle size in response to the volume of the particle, which corresponds to a weight average particle size when the density is constant.
  • the granules of the second layer may have a particle size distribution in which D 50 is 80 ⁇ m or more, but is not limited thereto, specifically, 80 ⁇ m to 260 ⁇ m, 90 ⁇ m to 240 ⁇ m, or It may be 100 ⁇ m to 235 ⁇ m.
  • the granules of the second layer may provide easy tabletting properties during the tableting process with fimasartan and a two-layer tablet. In addition, it is possible to maintain excellent content uniformity of each component included in each tablet, it is possible to economically easily mass production.
  • the granules of the second layer D 10 may be 14 to 70 ⁇ m, but is not limited thereto, specifically, the granules of the second layer may be 14 to 50 ⁇ m.
  • the granules of the second layer may provide easy tabletting properties during the tableting process with fimasartan and a two-layer tablet.
  • the granules of the second layer may be D 90 is 290 to 600 ⁇ m, but is not limited thereto, specifically, the granules of the second layer have D 90 of 300 to 550 ⁇ m or It may be 300 to 500 ⁇ m.
  • the granules of the second layer may provide easy tabletting properties during the tableting process with fimasartan and a two-layer tablet. In addition, it is possible to maintain excellent content uniformity of each component included in each tablet, it is possible to economically easily mass production.
  • the tablet may be a bilayer tablet form included in the first layer containing the fimasartan granules and the second layer containing the atorvastatin granules, but is not limited thereto.
  • the term "tablet” means to include compressed pharmaceutical dosage forms of all shapes and sizes, and the term “bilayer tablet” does not mix two or more other components, and separates the compartments. Refers to a combination of two or more different components, each component independently present.
  • the first layer of the bilayer tablet contains fimasartan granules
  • the second layer may contain atorvastatin granules
  • the fimasartan granules and atorvastatin granules independently present in the first and second layers Since they are not mixed with each other and exist independently in different compartments, treatment of cardiovascular diseases including hypertension can be more effectively performed.
  • the term “fimasartan granules” refers to granules containing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a pharmaceutically acceptable additive
  • the term “Atorvastatin granule” means a granule containing atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable additive.
  • first, second is used only to distinguish the various layers, films, steps, etc. from each other, and does not indicate order or to indicate importance, and the first and second
  • the terms such as layer, film, step, etc. are not limited by the terms. Therefore, the terms such as first and second may not all be used identically in the detailed description, examples, and claims of the invention, and it is sufficient if each can be distinguished from each other by terms such as first and second. .
  • the fimasartan, its pharmaceutically acceptable salt, its hydrate or solvate may be included in an amount of 0.5 to 240.0 mg per unit dosage form, but is not limited thereto. It may be included in an amount of 10 to 180 mg or 20 to 120 mg.
  • the atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof may be included in an amount of 1.0 to 100.0 mg per unit dosage form, but is not limited thereto. May be included in an amount of 10 to 80 mg.
  • the additives of the first layer and the second layer may be any one selected from the group consisting of excipients, dissolution aids, disintegrating agents, binders, lubricants, and mixtures thereof. no.
  • the term "excipient” means any substance that is not a therapeutic agent, and is used as a carrier or medium for delivery of the therapeutic agent or is added to a pharmaceutical composition. This will improve handling and storage properties or allow and promote the formation of unit doses of the composition.
  • the excipient may be any one or more selected from the group comprising precipitated calcium carbonate, lactose or hydrates thereof, microcrystalline cellulose, mannitol and colloidal silicon dioxide, and more specifically, precipitated calcium carbonate, microcrystalline cellulose, and lactose It may be any one or more selected from the group, but is not limited thereto.
  • dissolution aid means a substance added for the purpose of increasing the solubility of a poorly soluble drug and easily dissolving in a solvent (mainly water).
  • dissolution aids are isotonic solutions comprising physiological saline, glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol and sodium chloride; Alcohol such as ethanol; Polyols such as propylene glycol and polyethylene glycol; And nonionic surfactants such as polysorbate 80 and HCO-50, but is not limited thereto.
  • disintegrant means a substance added for the purpose of promoting disintegration of tablets, capsules, granules, etc. in the digestive fluid.
  • disintegrants include crospovidone (crosslinked polyvinylpyrrolidone), croscarmellose sodium (crosslinked carboxymethylcellulose sodium), sodium starch glycolate, corn starch, pregelatinized starch, and low substituted It may be selected from the group consisting of hydroxypropyl cellulose and microcrystalline cellulose, but is not limited thereto.
  • binder means a substance that is added to form a pill when making a pill or pill.
  • binders include polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone), hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose and pregelatinized starch. It may be selected from the group consisting, but is not limited thereto.
  • the term "lubricant” means an additive used to give fluidity to granules and make it easier for tablets to escape from the mold when making tablets.
  • the lubricant may be talc, magnesium stearate, sodium stearyl fumarate, or colloidal silicon dioxide, but is not limited thereto.
  • the granules of the second layer include a mixture of lactose hydrate and microcrystalline cellulose, and the mixture may include 40 to 50% by weight relative to the total weight of the granules of the second layer, It is not limited to this.
  • the mixture of lactose hydrate and microcrystalline cellulose may affect the tableting process of atorvastatin granules in the tableting process when preparing a complex comprising an active ingredient of atorvastatin and fimasartan.
  • the granules of the second layer may further include precipitated calcium carbonate, but are not limited thereto. Specifically, a large amount of precipitated calcium carbonate may be added for stabilization of atorvastatin in the purification process when preparing a combination of atorvastatin and fimasartan.
  • the mixture of the lactose hydrate and microcrystalline cellulose may exhibit a particle size distribution in which D 50 is 75 ⁇ m or more, but is not limited thereto, and specifically, 75 ⁇ m to 200 ⁇ m, 85 ⁇ m to 180 It may be ⁇ m or 95 ⁇ m to 170 ⁇ m.
  • D 50 is 75 ⁇ m or more, but is not limited thereto, and specifically, 75 ⁇ m to 200 ⁇ m, 85 ⁇ m to 180 It may be ⁇ m or 95 ⁇ m to 170 ⁇ m.
  • the mixture of lactose hydrate and microcrystalline cellulose may exhibit a particle size distribution in which D 10 is 15 to 50 ⁇ m, but is not limited thereto, and specifically, 20 to 40 ⁇ m or 23 to 35 May be ⁇ m.
  • D 10 is 15 to 50 ⁇ m, but is not limited thereto, and specifically, 20 to 40 ⁇ m or 23 to 35 May be ⁇ m.
  • the mixture of lactose hydrate and microcrystalline cellulose may exhibit a particle size distribution in which D 90 is 150 to 400 ⁇ m, but is not limited thereto, specifically, 180 to 350 ⁇ m or 200 to 300 May be ⁇ m.
  • D 90 is 150 to 400 ⁇ m
  • the particle size of the granules of the second layer can be increased, thereby facilitating easy tabletting in the purification process when preparing a composite agent with fimasartan.
  • the granules of the second layer, atorvastatin, a pharmaceutically acceptable salt thereof, hydrate or solvate thereof 1 to 10 parts by weight, excipients 50 to 99.9 parts by weight, dissolution aid 0.1 to 2 Parts by weight, 0.5 to 15 parts by weight of a disintegrant, 0.1 to 10 parts by weight of a binder, and 0.1 to 5 parts by weight of a lubricant, but is not limited thereto.
  • the unit "parts by weight” may mean a ratio of weights between components, unless otherwise specified.
  • the granules of the second layer include atorvastatin, a pharmaceutically acceptable salt thereof, 1 to 10 parts by weight of a hydrate or solvate, 50 to 99.9 parts by weight of an excipient, 0.1 to 2 parts by weight of a dissolution aid, and a disintegrant 0.5 to 15 parts by weight, 0.1 to 10 parts by weight of the binder and 0.1 to 5 parts by weight of the lubricant means that the granule of the second layer is atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, an excipient, a dissolution aid,
  • the disintegrating agent, the binder and the lubricant may be mixed in a weight ratio of 1 to 10: 50 to 99.9: 0.1 to 2: 0.5 to 15: 0.1 to 10: 0.1 to 5 to form granules of the second layer.
  • the granule of the second layer contains atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, an excipient, a solubilizer, a disintegrant, a binder, and a lubricant 3-7: 70-85: 0.1-0.5: 1 to 10: 0.5 to 2: may be mixed in a weight ratio of 0.1 to 0.5 to form the atorvastatin granule portion.
  • the granule of the second layer is 1 to 20% by weight of atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, 50 to 98.2% by weight of an excipient, 0.1 to 5% by weight of a dissolution aid, 0.5 It may mean that the granules of the second layer are formed by mixing from 15 to 15% by weight of disintegrant, 0.1 to 10% by weight of binder, and 0.1 to 5% by weight of lubricant.
  • the granule of the second layer is 5 to 15% by weight of atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, 70 to 85% by weight of an excipient, 0.1 to 1% by weight of a dissolution aid, 1 to 10% by weight of disintegrant, 0.5 to 5% by weight of the binder and 0.1 to 3% by weight of the lubricant may be mixed means that the granules of the second layer was formed.
  • the excipient may be any one of precipitated calcium carbonate, lactose hydrate, microcrystalline cellulose, or a mixture thereof, but is not limited thereto.
  • the mixture of excipients may include 30 to 50 parts by weight of precipitated calcium carbonate, 20 to 40 parts by weight of lactose hydrate, and 15 to 35 parts by weight of microcrystalline cellulose, but is not limited thereto.
  • the mixture may mean that a mixture of excipients is formed by mixing precipitated calcium carbonate, lactose hydrate, and microcrystalline cellulose in a weight ratio of 30 to 50: 20 to 40: 15 to 35.
  • the tablet may be for the treatment of cardiovascular disease.
  • cardiovascular disease means any disease that appears in the heart and/or vascular system (all blood vessels such as arteries, capillaries, and veins).
  • the cardiovascular disease is hypertension, diabetes, obesity, hyperlipidemia, coronary artery disease, chronic stability angina, vasospastic angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin resistance, Impaired glucose tolerance, pre-diabetes, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive dysfunction, dementia, and combinations thereof, but is not limited thereto.
  • the tablet may be in the form of a coated tablet further comprising a coating layer on the outside, but is not limited thereto.
  • Opadry Colorcon; 415 Moyer Blvd., P.O.Box 4, West Point, PA 19486-0024, U.S.A.
  • the coating layer may be used as the coating layer.
  • the tablet further comprising a coating layer on the outside may further include a light-emitting agent on the outside, but is not limited thereto.
  • the term "lighting agent” means a substance that is polished on the surface of the formulation to improve the properties of the formulation.
  • the brightener may be beeswax or carnauba wax, but is not limited thereto.
  • the granules of the first layer and the second layer may be dry granules or wet granules, specifically wet granules.
  • the present invention (S1) preparing a first layer containing granules containing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a pharmaceutically acceptable additive; (S2) preparing a second layer containing granules comprising atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable additive; And (S3) tableting the first layer and the second layer to produce a two-layer tablet.
  • the step of tableting the first layer and the second layer may be performed by applying a tableting pressure of 5 to 15 KN, but is not limited thereto.
  • composition comprising tablets
  • the present invention provides a pharmaceutical composition comprising the tablet.
  • the pharmaceutical composition of the present invention shows a remarkable effect on the prevention and treatment of cardiovascular diseases.
  • the pharmaceutical composition of the present invention may be for oral administration.
  • oral administration means that the active substance is administered to a substance prepared to be digested, that is, to the gastrointestinal tract for absorption.
  • Non-limiting examples of the formulation for oral administration include tablets, troches, lozenges, aqueous suspensions, oily suspensions, preparation powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, etc. Can be heard.
  • a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin, etc.
  • Excipients such as dicalcium phosphate
  • Disintegrants such as corn starch or sweet potato starch
  • Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax can be used, and sweeteners, fragrances, syrups and the like can also be used.
  • a liquid carrier such as fatty oil, etc. may be additionally used.
  • the present invention provides a method of preventing or treating cardiovascular disease, comprising administering to a mammal, including a human, in a therapeutically effective amount of the tablet.
  • prevention means a delay in the development of a disease, disorder or disease. Prevention may be considered complete if the onset of the disease, disorder or condition is delayed for a predetermined period of time.
  • treatment partially or completely alleviates, ameliorates, alleviates, inhibits or delays the onset of a specific disease, disorder and/or disease, reduces the severity, or develops one or more symptoms or characteristics It means reducing.
  • the term "therapeutically effective amount” is an effective amount of the tablet of the present invention effective for the prevention or treatment of cardiovascular disease, preventing the occurrence or recurrence of cardiovascular disease, alleviating symptoms, It may include all amounts of tablets that inhibit direct or indirect pathological consequences, prevent metastasis, reduce the rate of progression, alleviate or temporarily relieve the condition, or improve the prognosis. That is, the therapeutically effective amount may be interpreted to encompass all doses in which symptoms of cardiovascular disease are improved or cured by the tablet.
  • the cardiovascular disease includes all of hypertension and complications of those with so-called metabolic syndrome, such as hypertension, or diabetes, obesity, hyperlipidemia, coronary artery disease, etc., and chronic stable angina. , Vasospastic angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive decline and dementia.
  • the prophylactic or therapeutic methods of the present invention include not only treating the disease itself prior to the onset of symptoms by administering tablets, but also inhibiting or avoiding the symptoms thereof.
  • the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route the active ingredient is administered. The dose and frequency of dose will vary depending on the age, weight and response of the individual patient. Suitable dosage regimens can be readily selected by those of ordinary skill in the art taking these factors into account.
  • the treatment method of the present invention may further include the administration of a therapeutically effective amount of an additional active agent conducive to the treatment of a disease together with a tablet, and the additional active agent is synergistic or additive effect with the pharmaceutical composition. Can represent.
  • mammals refers to each animal belonging to the mammalian class in the bio taxonomy.
  • mammals including humans include mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats, and mice.
  • the present invention provides the use of such tablets for use in the manufacture of cardiovascular disease agents.
  • Tablets of the present invention for the manufacture of a pharmaceutical agent may mix the above-mentioned acceptable additives, etc., for example, within a range that does not impair the effects of the present invention, a pharmaceutically acceptable stabilizer, binder, disintegrant, lubricant Agents, diluents, coating agents, pH adjusting agents, dissolution aids, surfactants, and other additives may be included.
  • the cardiovascular disease includes all of hypertension and complications of those with so-called metabolic syndrome, such as hypertension, or diabetes, obesity, hyperlipidemia, coronary artery disease, etc., and chronic stable angina. , Vasospastic angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive decline and dementia.
  • the present invention provides the use of such tablets for the treatment of cardiovascular diseases.
  • the cardiovascular disease includes all of hypertension and complications of those with so-called metabolic syndrome, such as hypertension, or diabetes, obesity, hyperlipidemia, coronary artery disease, etc., and chronic stable angina. , Vasospastic angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive decline and dementia.
  • the present invention relates to a tablet and a method for manufacturing the same, and by adjusting the particle size distribution of the atorvastatin granules to a certain value or more, the tableting process is remarkably improved in the purification process with fimasartan, and thus it can exhibit excellent content uniformity, making it economically easy Mass production may be possible.
  • FIG. 1 is a flow chart schematically showing a method for manufacturing a tablet of the present invention.
  • Figure 2 shows the surface of the tablet according to Comparative Example 1.
  • Figure 3 shows the surface of the tablet according to Example 1.
  • Figure 4 shows the surface of the tablet according to Example 2.
  • Example 5 shows the surface of a tablet according to Example 3.
  • the fimasartan calcium trihydrate used in the following preparation example is Boryeong Pharmaceutical Co., Ltd.
  • atorvastatin calcium trihydrate is Dr. reddy's
  • precipitated calcium carbonate is Bihoku
  • lactose hydrate is DFE Pharma
  • microcrystalline cellulose is Asahi kasei
  • poly Sorbate 80 is Croda
  • croscarmellose sodium is DPE Pharma
  • hydroxypropyl cellulose is Nippon soda
  • magnesium stearate is FACI
  • Opadry is Colorcon
  • other reagents are purchased from sigma-aldrich.
  • the granule part containing fimasartan potassium trihydrate as an active ingredient was prepared in the following manner so as to have the components and contents shown in Table 1 per unit dosage form (350 mg).
  • fimasartan potassium trihydrate After mixing fimasartan potassium trihydrate, microcrystalline cellulose, and croscarmellose sodium for about 10 minutes, put the mixture in a high-speed stirrer and mix for about 3 minutes to prepare a mixture containing fimasartan as an active ingredient. Did.
  • hydroxypropyl cellulose was dissolved in 41.7 mL of purified water to prepare a binding solution.
  • the prepared binding solution was placed in a high-speed stirrer, wet granulated with a mixture containing the fimasartan as an active ingredient, and then dried by sizing with 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 thereto and further mixed for about 5 minutes to prepare granules of fimasartan.
  • Atorvastatin granules were prepared to have the content shown in Table 2 per unit dosage form (350 mg).
  • Atorvastatin calcium trihydrate (D 50 : 3 ⁇ m), precipitated calcium carbonate (D 50 : less than 45 ⁇ m), lactose hydrate (D 50 : 40 ⁇ m) microcrystalline cellulose (D 50 : 50 ⁇ m), polysorbate 80 about 10
  • the mixture was put in a high-speed stirrer and mixed for about 3 minutes to prepare a mixture containing atorvastatin calcium trihydrate as an active ingredient.
  • the particle size distribution of the mixture of lactose hydrate and microcrystalline cellulose was 12.33 ⁇ m for D 10 , 53.56 ⁇ m for D 50 , and 128.86 ⁇ m for D 90 .
  • hydroxypropyl cellulose was dissolved in 60 mL of purified water to prepare a binding solution.
  • magnesium stearate was added thereto and further mixed for about 5 minutes to prepare an atorvastatin granule part.
  • Atorvastatin granules were prepared to have the content shown in Table 3 per unit dosage form (350 mg).
  • Atorvastatin calcium trihydrate (D 50 : 3 ⁇ m), precipitated calcium carbonate (D 50 : less than 45 ⁇ m), lactose hydrate (D 50 : 150 ⁇ m) microcrystalline cellulose (D 50 : 50 ⁇ m), polysorbate 80 about 10
  • the mixture was put in a high-speed stirrer and mixed for about 3 minutes to prepare a mixture containing atorvastatin calcium trihydrate as an active ingredient.
  • the particle size distribution of the mixture of lactose hydrate and microcrystalline cellulose that affects tableting of atorvastatin granules was 28.00 ⁇ m for D 10 , 97.70 ⁇ m for D 50 , and 229.38 ⁇ m for D 90 .
  • hydroxypropyl cellulose was dissolved in 60 mL of purified water to prepare a binding solution.
  • magnesium stearate was added thereto and further mixed for about 5 minutes to prepare an atorvastatin granule part.
  • Atorvastatin granules were prepared to have the content shown in Table 4 per unit dosage form (350 mg).
  • Atorvastatin calcium trihydrate (D 50 : 3 ⁇ m), precipitated calcium carbonate (D 50 : less than 45 ⁇ m), lactose hydrate (D 50 : 150 ⁇ m) microcrystalline cellulose (D 50 : 90 ⁇ m), polysorbate 80 about 10
  • the mixture was put in a high-speed stirrer and mixed for about 3 minutes to prepare a mixture containing atorvastatin calcium trihydrate as an active ingredient.
  • the particle size distribution of the mixture of lactose hydrate and microcrystalline cellulose that affects tableting of atorvastatin granules was 25.88 ⁇ m for D 10 , 115.11 ⁇ m for D 50 , and 234.22 ⁇ m for D 90 .
  • hydroxypropyl cellulose was dissolved in 60 mL of purified water to prepare a binding solution.
  • the particle size distribution of the granules containing atorvastatin calcium trihydrate as an active ingredient was 24.59 ⁇ m in D 10 , 160.02 ⁇ m in D 50 , and 494.80 ⁇ m in D 90 .
  • magnesium stearate was added thereto and further mixed for about 5 minutes to prepare an atorvastatin granule part.
  • Atorvastatin granules were prepared to have the content shown in Table 5 per unit dosage form (350 mg).
  • Atorvastatin calcium trihydrate (D 50 : 3 ⁇ m), precipitated calcium carbonate (D 50 : less than 45 ⁇ m), lactose hydrate (D 50 : 150 ⁇ m) microcrystalline cellulose (D 50 : 170 ⁇ m), polysorbate 80 about 10
  • the mixture was put in a high-speed stirrer and mixed for about 3 minutes to prepare a mixture containing atorvastatin calcium trihydrate as an active ingredient.
  • the particle size distribution of the mixture of lactose hydrate and microcrystalline cellulose that affects tableting of atorvastatin granules was 52.99 ⁇ m for D 10 , 115.11 ⁇ m for D 50 , and 282.48 ⁇ m for D 90 .
  • hydroxypropyl cellulose was dissolved in 60 mL of purified water to prepare a binding solution.
  • magnesium stearate was added thereto and further mixed for about 5 minutes to prepare an atorvastatin granule part.
  • Atorvastatin granules were prepared to have the content shown in Table 2 per unit dosage form (350 mg).
  • Atorvastatin calcium trihydrate (D 50 : 3 ⁇ m), precipitated calcium carbonate (D 50 : less than 45 ⁇ m), lactose hydrate (D 50 : 40 ⁇ m) microcrystalline cellulose (D 50 : 50 ⁇ m), polysorbate 80 about 10
  • the mixture was put in a high-speed stirrer and mixed for about 3 minutes to prepare a mixture containing atorvastatin calcium trihydrate as an active ingredient.
  • the particle size distribution of the mixture of lactose hydrate and microcrystalline cellulose was 12.33 ⁇ m for D 10 , 53.56 ⁇ m for D 50 , and 128.86 ⁇ m for D 90 .
  • hydroxypropyl cellulose was dissolved in 70 mL of purified water to prepare a binding solution.
  • croscarmellose sodium was added and mixed in a double cone mixer for about 5 minutes, magnesium stearate was added thereto, and further mixed for about 5 minutes to prepare atorvastatin granules.
  • Atorvastatin granules were prepared to have the content shown in Table 2 per unit dosage form (350 mg).
  • Atorvastatin calcium trihydrate (D 50 : 3 ⁇ m), precipitated calcium carbonate (D 50 : less than 45 ⁇ m), lactose hydrate (D 50 : 40 ⁇ m) microcrystalline cellulose (D 50 : 50 ⁇ m), polysorbate 80 about 10
  • the mixture was put in a high-speed stirrer and mixed for about 3 minutes to prepare a mixture containing atorvastatin calcium trihydrate as an active ingredient.
  • the particle size distribution of the mixture of lactose hydrate and microcrystalline cellulose was 12.33 ⁇ m for D 10 , 53.56 ⁇ m for D 50 , and 128.86 ⁇ m for D 90 .
  • hydroxypropyl cellulose was dissolved in 60 mL of purified water to prepare a binding solution.
  • magnesium stearate was added thereto and further mixed for about 5 minutes to prepare an atorvastatin granule part.
  • the granules containing fimasartan potassium trihydrate according to ⁇ Preparation Example 1> as an active ingredient and the granules containing atorvastatin calcium trihydrate according to ⁇ Preparation 2-2> as an active ingredient are respectively placed in a punch die and 5-15 KN.
  • the tablet was compressed into tablets to prepare a two-layer tablet.
  • the hardness of the double-layered tablet was prepared using a multi-layer tableting tablet (Pichola two-layered tableting tablet) so that the hardness was 5 to 20 kp.
  • a coating tablet was prepared using 10.5 mg of Opadry (Colorcon; 415 Moyer Blvd., PO Box 4, West Point, PA 19486-0024, USA,), and 0.5 mg of carnauba wax was used on the surface of the coating tablet. It was polished to prepare a bilayer tablet comprising fimasartan and atorvastatin.
  • the granules containing fimasartan potassium trihydrate according to ⁇ Preparation Example 1> as an active ingredient and the granules containing atorvastatin calcium trihydrate according to ⁇ Preparation 2-3> as an active ingredient are respectively placed in a punch die and 5-15 KN.
  • the tablet was compressed into tablets to prepare a two-layer tablet.
  • the hardness of the double-layered tablet was prepared using a multi-layer tableting tablet (Pichola two-layered tableting tablet) so that the hardness was 5 to 20 kp.
  • a coating tablet was prepared using 10.5 mg of Opadry (Colorcon; 415 Moyer Blvd., PO Box 4, West Point, PA 19486-0024, USA,), and 0.5 mg of carnauba wax was used on the surface of the coating tablet. It was polished to prepare a bilayer tablet comprising fimasartan and atorvastatin.
  • Granules containing fimasartan potassium trihydrate according to ⁇ Production Example 1> as an active ingredient and granules containing atorvastatin calcium trihydrate according to ⁇ Production Example 2-4> as an active ingredient were respectively placed in a punch die and 5-15 KN. The tablet was compressed into tablets to prepare a two-layer tablet.
  • the hardness of the double-layered tablet was prepared using a multi-layer tableting tablet (Pichola two-layered tableting tablet) so that the hardness was 5 to 20 kp.
  • a coating tablet was prepared using 10.5 mg of Opadry (Colorcon; 415 Moyer Blvd., PO Box 4, West Point, PA 19486-0024, USA,), and 0.5 mg of carnauba wax was used on the surface of the coating tablet. It was polished to prepare a bilayer tablet comprising fimasartan and atorvastatin.
  • Bilayer tablet comprising fimasartan and atorvastatin
  • the granules containing fimasartan potassium trihydrate according to ⁇ Production Example 1> as an active ingredient and the granules containing atorvastatin calcium trihydrate according to ⁇ Production Example 2-5> as an active ingredient are respectively placed in a punch die and 5-15 KN.
  • the tablet was compressed into tablets to prepare a two-layer tablet.
  • the hardness of the double-layered tablet was prepared using a multi-layer tableting tablet (Pichola two-layered tableting tablet) so that the hardness was 5 to 20 kp.
  • a coating tablet was prepared using 10.5 mg of Opadry (Colorcon; 415 Moyer Blvd., PO Box 4, West Point, PA 19486-0024, USA,), and 0.5 mg of carnauba wax was used on the surface of the coating tablet. It was polished to prepare a bilayer tablet comprising fimasartan and atorvastatin.
  • Bilayer tablet comprising fimasartan and atorvastatin
  • the granules containing fimasartan potassium trihydrate according to ⁇ Production Example 1> as an active ingredient and the granules containing atorvastatin calcium trihydrate according to ⁇ Production Example 2-6> as an active ingredient were respectively placed in a punch die and 5-15 KN.
  • the tablet was compressed into tablets to prepare a two-layer tablet.
  • the hardness of the double-layered tablet was prepared using a multi-layer tableting tablet (Pichola two-layered tableting tablet) so that the hardness was 5 to 20 kp.
  • a coating tablet was prepared using 10.5 mg of Opadry (Colorcon; 415 Moyer Blvd., PO Box 4, West Point, PA 19486-0024, USA,), and 0.5 mg of carnauba wax was used on the surface of the coating tablet. It was polished to prepare a bilayer tablet comprising fimasartan and atorvastatin.
  • Granules containing fimasartan potassium trihydrate according to ⁇ Production Example 1> as an active ingredient and granules containing atorvastatin calcium trihydrate according to ⁇ Production Example 2-1> as an active ingredient were respectively placed in a punch die and 5-15 KN. The tablet was compressed into tablets to prepare a two-layer tablet.
  • the hardness of the double-layered tablet was prepared using a multi-layer tableting tablet (Pichola two-layered tableting tablet) so that the hardness was 5 to 20 kp.
  • a coating tablet was prepared using 10.5 mg of Opadry (Colorcon; 415 Moyer Blvd., PO Box 4, West Point, PA 19486-0024, USA,), and 0.5 mg of carnauba wax was used on the surface of the coating tablet. It was polished to prepare a bilayer tablet comprising fimasartan and atorvastatin.
  • the particle size of the granules containing the obtained atorvastatin calcium trihydrate as an active ingredient and the mixture of lactose hydrate and microcrystalline cellulose that affects tableting of the atorvastatin granules was measured using a HELOS particle size analyzer (Laser particle size analyzer) of Sumpatec by a dry method.
  • Examples 1 to 3 are tablets each containing granules containing atorvastatin calcium trihydrate as an active ingredient according to ⁇ Production Examples 2-2> to ⁇ Production Examples 2-4> to prepare bilayer tablets, wherein the granules are D 50 will have a particle size distribution of 80.00 ⁇ m or more.
  • the particle size distribution of the granules is below a certain level, it was confirmed that the tableting process causes sticking disorders such as sticking, and it was confirmed that the tablet properties (engraving, etc.) do not meet the drug standards.
  • the particle size distribution of lactose hydrate and microcrystalline cellulose mixture (D 50 ) To adjust the particle size distribution (D 50 ) of granules containing atorvastatin calcium trihydrate as an active ingredient to a certain level or more, resulting in a tableting disorder when performing the tableting process in the process of tabletting fimasartan and atorvastatin into two-layer tablets It was confirmed not to be.
  • the amount of the binding liquid is increased during wet granulation according to ⁇ Production Example 2-5>, or the size of the formulation is adjusted according to ⁇ Production Example 2-6>. If increased, it is possible to obtain the ⁇ Preparation example 2-1> atorvastatin calcium distribution (D 50) particle size of the granules than the increased distribution (D 50) particle size of the granules containing the trihydrate as the active ingredient in accordance with, and as a result Pima It was confirmed that the tableting process, such as sticking, did not occur when the tableting process was performed in the process of tableting with salt.
  • granules containing atorvastatin calcium trihydrate according to ⁇ Preparation Example 2-1> as an active ingredient have tableting disorders such as sticking during tableting, resulting in target weight (200 mg). Even if the equipment conditions were set properly, the target weight was not reached, and the mass deviation of the tablets was largely found to be judged to be unsuitable for the content uniformity (judgment value: 15.4, judgment factor: 2.4, reference value: 98.5).
  • a large amount of precipitated calcium carbonate should be added as a stabilizer, which is fine, so tableting disorders such as sticking during tableting of atorvastatin granules It will cause it to happen.
  • the particle size distribution (D 50 ) of granules containing atorvastatin calcium trihydrate as an active ingredient is adjusted to a particle size (D 50 ) for a mixture of lactose hydrate and microcrystalline cellulose, thereby providing tabletting stability. It was confirmed that this can be markedly improved and exhibit excellent content uniformity.

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Abstract

La présente invention concerne un comprimé et son procédé de préparation, selon lequel des granules d'atorvastatine sont ajustés pour avoir une distribution de taille de particule d'au moins une valeur prédéterminée, ce qui permet d'améliorer considérablement les caractéristiques de compression dans le processus de fabrication de comprimés avec du fimasartan, conduisant à une excellente uniformité de teneur, de telle sorte que des comprimés peuvent être fabriqués en masse de manière économique et facile.
PCT/KR2019/018684 2018-12-31 2019-12-30 Comprimé et son procédé de préparation WO2020141825A1 (fr)

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SG11202106025WA SG11202106025WA (en) 2018-12-31 2019-12-30 Tablet and method of preparing same
MX2021007734A MX2021007734A (es) 2018-12-31 2019-12-30 Comprimido y metodo de preparacion del mismo.
CN201980087258.0A CN113260355A (zh) 2018-12-31 2019-12-30 片剂及其制备方法
PH12021551334A PH12021551334A1 (en) 2018-12-31 2021-06-07 Tablet and method of preparing same
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WO2022260439A1 (fr) * 2021-06-09 2022-12-15 주식회사 보령 Formulation composite pharmaceutique et procédé de préparation d'une formulation composite pharmaceutique

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KR20110126020A (ko) * 2010-05-14 2011-11-22 한미홀딩스 주식회사 ＨＭＧ-ＣｏＡ 환원효소 억제제 및 이베살탄을 포함하는 이층정 약제학적 복합제제
KR20170061615A (ko) * 2015-11-26 2017-06-05 보령제약 주식회사 피마살탄의 신규 염
EP3184103A1 (fr) * 2015-12-21 2017-06-28 Hexal AG Composition pharmaceutique comprenant de l'atorvastatine ou un sel de celui-ci

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KR20110126020A (ko) * 2010-05-14 2011-11-22 한미홀딩스 주식회사 ＨＭＧ-ＣｏＡ 환원효소 억제제 및 이베살탄을 포함하는 이층정 약제학적 복합제제
KR20170061615A (ko) * 2015-11-26 2017-06-05 보령제약 주식회사 피마살탄의 신규 염
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CHOI, Y. ET AL.: "Pharmacokinetic interaction between fimasartan and atorvastatin in healthy male volunteers", DRUG DESIGN, DEVELOPMENT AND THERAPY, vol. 12, 24 July 2018 (2018-07-24), pages 2301 - 2309, XP055722880 *

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Publication number Priority date Publication date Assignee Title
WO2022260439A1 (fr) * 2021-06-09 2022-12-15 주식회사 보령 Formulation composite pharmaceutique et procédé de préparation d'une formulation composite pharmaceutique

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