WO2022045759A1 - Composition pharmaceutique à dose unique pour le traitement ou la prévention de l'hypertension et de l'hypercholestérolémie - Google Patents

Composition pharmaceutique à dose unique pour le traitement ou la prévention de l'hypertension et de l'hypercholestérolémie Download PDF

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WO2022045759A1
WO2022045759A1 PCT/KR2021/011350 KR2021011350W WO2022045759A1 WO 2022045759 A1 WO2022045759 A1 WO 2022045759A1 KR 2021011350 W KR2021011350 W KR 2021011350W WO 2022045759 A1 WO2022045759 A1 WO 2022045759A1
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Prior art keywords
salt
pharmaceutical composition
rosuvastatin
ezetimibe
amlodipine
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PCT/KR2021/011350
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English (en)
Korean (ko)
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박정현
김지연
김보훈
김관영
이경민
이재협
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주식회사 대웅제약
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Priority to BR112023003323A priority Critical patent/BR112023003323A2/pt
Priority to MX2023002403A priority patent/MX2023002403A/es
Publication of WO2022045759A1 publication Critical patent/WO2022045759A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K9/2072—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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

Definitions

  • the present invention relates to a single dosage form pharmaceutical composition for the treatment of hypertension and hypercholesterolemia.
  • Rosuvastatin is an HMG-CoA reductase inhibitor, and dyslipidemia and dyslipidemia-related diseases such as hypercholesterolemia, hyperlipidproteinemia and atherosclerosis It is used for the treatment of atherosclerosis and is currently sold under the trade name Cresto Tablet TM .
  • HMG-CoA reductase inhibitors are often used in combination with other therapeutic agents having different mechanisms.
  • Ezetimibe is a selective cholesterol absorption inhibitor marketed under the trade names EZETROLTM or ZETIATM. It is well known that egemitive has a mechanism of inhibiting cholesterol reabsorption in the small intestine, and that its use in combination with rosuvastatin, an HMG-CoA reductase inhibitor, has a beneficial therapeutic effect.
  • rosuvastatin and ezetimibe were developed as a combination formulation, and a representative product includes Rosuzet TM for treating primary hypercholesterolemia.
  • rosuvastatin is generally known to be unstable in strong acid, so it is often designed as a pharmaceutical formulation containing a basic stabilizer.
  • a basic stabilizer On the contrary, it has been mentioned that it is difficult to secure the stability of the active ingredient in the preparation of a combination formulation of these two drugs because it is unstable in a strong basic environment and produces a number of related substances.
  • Examples of drugs used to treat hypertension include olmesartan medoxomil and amlodipine.
  • Olmesartan medoxomil is an excellent angiotensin II receptor blocker (ARB), and is known to be useful as a medicament for the treatment or prevention of hypertension and heart disease.
  • ARB angiotensin II receptor blocker
  • Olmesartan Medoxomil is currently sold under the trade name of Olmetec Tablet TM .
  • Amlodipine is known to be useful as a medicament for the treatment or prevention of hypertension and heart disease as a calcium channel blocker (CCB). Amlodipine is currently marketed under the trade name Novasque TM .
  • Olmesartan medoxomil is particularly useful for renin-dependent hypertension as an angiotensin II receptor antagonist
  • amlodipine is useful for renin-independent hypertension because it has a natriuretic action in addition to calcium channel dilatation action. Therefore, a combination drug of olmesartan medoxomil and amlodipine was developed to treat high blood pressure regardless of the etiology, and it is currently sold under the trade name Sevica Tablet TM .
  • Patent Document 2 Korean Patent Application No. 10-2013-0030734
  • Patent Document 2 a combination drug containing olmesartan medoxomil and rosuvastatin is sold under the trade name of OLOSTA TABLET TM .
  • a combination drug comprising olmesartan medoxomil, amlodipine and rosuvastatin through Korean Patent Application No. 10-2019-0022739 (Patent Document 3).
  • Patent Document 3 a combination drug containing olmesartan medoxomil, amlodipine and rosuvastatin is sold under the trade name Olomax Tablet TM .
  • An object of the present invention is to provide a composition of a combination drug that can secure the comparability with a reference drug while minimizing the drug interaction and stability degradation of the drug that occurs in the development of the combination drug.
  • the present invention provides a single dosage form pharmaceutical composition
  • a single dosage form pharmaceutical composition comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and an extraparticulate phase.
  • the pharmaceutical composition of a single dosage form comprising rosuvastatin or a salt thereof and ezetimibe and a salt thereof according to the present invention comprises rosuvastatin or a salt thereof and ezetimibe or a salt thereof as active ingredients, ,
  • the active ingredient is included in at least one of the particles and the external particle phase.
  • the term “particles” refers to granules or pellets prepared by granulating all or part of a composition including drugs and additives during the formulation process.
  • extra-particle phase means a post-mixing part that is post-mixed with the phase existing outside the particles, that is, pre-processed granules or pellets.
  • particle and particle trauma is also referred to as “granular and extragranular phase” or “pellet and pellet trauma”.
  • the particles and extragranular phase mean granules and extragranular phases, respectively, and when particles in the form of pellets are used, the particles and extra-particle phases mean pellets and extra-pellet phases, respectively.
  • rosuvastatin or a salt thereof and ezetimibe or a salt thereof are included in the particle or the outer particle phase. All of the following are included in the embodiments of the present invention.
  • ezetimibe or a salt thereof When a part of ezetimibe or a salt thereof is included in the particle, and the remainder of rosuvastatin or a salt thereof and ezetimibe or a salt thereof is included in the particle outer shell.
  • the sum of 'some' and 'remaining' represents the total amount of the drug included in the pharmaceutical composition.
  • a part of drug A included in the pharmaceutical composition is 100 parts by weight
  • a part of drug A included in the particles is If X parts by weight
  • the remainder of drug A is 100-X parts by weight.
  • a part of drug B included in the particle and the remainder of drug B is included in the particle outer phase
  • the total amount of drug B in the pharmaceutical composition is 100 parts by weight
  • a part of drug B included in the particle is Y weight parts
  • the remainder of drug B is 100-Y parts by weight.
  • rosuvastatin in a pharmaceutical composition of a single dosage form comprising particles and a particle phase, may be present only in the particle, but may also be present in the particle phase.
  • rosuvastatin or a salt thereof may be included in both the particle and the particle phase.
  • the amount of rosuvastatin or a salt thereof contained in the particles is 10 parts by weight or more, based on 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition.
  • the amount of rosuvastatin or a salt thereof contained in the particle is 10 parts by weight based on 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition
  • rosuvastatin or a salt thereof contained in the outer particle of the particle may be 90 parts by weight based on 100 parts by weight of the total of rosuvastatin or a salt thereof included in the pharmaceutical composition.
  • the amount of rosuvastatin or a salt thereof contained in the particle is 90 parts by weight based on 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition, rosuvastatin or a salt thereof included in the outer particle of the particle.
  • the salt may be 10 parts by weight based on 100 parts by weight of the total of rosuvastatin or a salt thereof included in the pharmaceutical composition.
  • 10 parts by weight or more for example, 15 parts by weight or more, 20 parts by weight or more, 25 parts by weight or more, of rosuvastatin or a salt thereof contained in the particles relative to 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition , 30 parts by weight or more, 35 parts by weight or more, 40 parts by weight or more, 45 parts by weight or more, 50 parts by weight or more, 55 parts by weight or more, 60 parts by weight or more, 65 parts by weight or more, 70 parts by weight or more, 75 parts by weight or more , 80 parts by weight or more, 85 parts by weight or more, 90 parts by weight or more, 95 parts by weight or more, or 100 parts by weight or more.
  • 10 to 100 parts by weight of rosuvastatin or a salt thereof contained in the particles relative to 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition may be included.
  • the amount of rosuvastatin or a salt thereof contained in the particles relative to 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition may be present within a range of 10 parts by weight or more and 100 parts by weight or less, and within various lower numerical ranges.
  • 15 parts by weight or more and 100 parts by weight or less 20 parts by weight or more and 95 parts by weight or less, 25 Part by weight or more and 90 parts by weight or more, 30 parts by weight or more and 90 parts by weight or less, 35 parts by weight or more and 90 parts by weight or less, 40 parts by weight or more and 100 parts by weight or less, 45 parts by weight or more and 100 parts by weight or less, 50 parts by weight or more and 100 parts by weight parts by weight or less, 55 parts by weight or more and 95 parts by weight or less, 60 parts by weight or more and 90 parts by weight or less, 65 parts by weight or more and 95 parts by weight or less, 70 parts by weight or more and 100 parts by weight or less, 75 parts by weight or more and 100 parts by weight or less, 80 parts by weight Parts by weight or more and 100 parts by weight or less, 85 parts by weight or more and 100 parts by weight or less, 90 parts by weight or more and 100 parts by weight or less, 95 parts by weight or more and 100 parts by weight or less, or 100 parts by weight.
  • the pharmaceutical composition of a single dosage form comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and an external particle may contain rosuvastatin or a salt thereof. there is.
  • rosuvastatin or a salt thereof included in the particle outer shell is included in an amount of not more than 90 parts by weight based on 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition.
  • rosuvastatin or a salt thereof may be included only in the particle phase.
  • the egemitic may be present only in the particle, but may also be present in the particle phase.
  • the pharmaceutical composition of a single dosage form comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and an extraparticulate composition comprises only egemitic or a salt thereof in the particles, and the particles It may not be included in the trauma.
  • the pharmaceutical composition of a single dosage form comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and an external particle may include ezetimibe or a salt thereof in the particle phase.
  • egemitic or a salt thereof may be included in both particles and extraparticulate phases.
  • 10 parts by weight or more of egemitic or a salt thereof contained in the particles relative to 100 parts by weight of the total of egemitic or a salt thereof included in the pharmaceutical composition.
  • the amount of egemitic or a salt thereof contained in the particle is 10 parts by weight based on 100 parts by weight of the total amount of egemitic or a salt thereof included in the pharmaceutical composition
  • egemitic or a salt thereof contained in the outer particle of the particle may be 90 parts by weight based on 100 parts by weight of the total of egemitive or a salt thereof included in the pharmaceutical composition.
  • the egemitic or its salt contained in the particle is 90 parts by weight based on 100 parts by weight of the total of the egemitic or its salt contained in the pharmaceutical composition
  • the egemitic or its salt contained in the outer particle of the particle may be in an amount of 10 parts by weight based on 100 parts by weight of the total amount of egemitive or a salt thereof included in the pharmaceutical composition.
  • 10 parts by weight or more for example, 15 parts by weight or more, 20 parts by weight, 25 parts by weight or more , 30 parts by weight or more, 35 parts by weight or more, 40 parts by weight or more, 45 parts by weight or more, 50 parts by weight or more, 55 parts by weight or more, 60 parts by weight or more, 65 parts by weight or more, 70 parts by weight or more, 75 parts by weight or more , 80 parts by weight or more, 85 parts by weight or more, 90 parts by weight or more, 95 parts by weight or more, or 100 parts by weight or more.
  • 10 parts by weight to 100 parts by weight of the egemitic or its salt contained in the particles relative to 100 parts by weight of the total amount of the egemitic or its salt included in the pharmaceutical composition may be included.
  • the amount of egemitic or its salt contained in the particles relative to 100 parts by weight of the total amount of egemitic or its salt included in the pharmaceutical composition is 10 parts by weight or more and 100 parts by weight or less.
  • 15 parts by weight or more and 100 parts by weight or less 20 parts by weight or more and 95 parts by weight or less, 25 Part by weight or more and 90 parts by weight or more, 30 parts by weight or more and 90 parts by weight or less, 35 parts by weight or more and 90 parts by weight or less, 40 parts by weight or more and 100 parts by weight or less, 45 parts by weight or more and 100 parts by weight or less, 50 parts by weight or more and 100 parts by weight parts by weight or less, 55 parts by weight or more and 95 parts by weight or less, 60 parts by weight or more and 90 parts by weight or less, 65 parts by weight or more and 95 parts by weight or less, 70 parts by weight or more and 100 parts by weight or less, 75 parts by weight or more and 100 parts by weight or less, 80 parts by weight Parts by weight or more and 100 parts by weight or less, 85 parts by weight or more and 100 parts by weight or less, 90 parts by weight or more and 100 parts by weight or less, 95 parts by weight or more and 100 parts by weight or less, or 100 parts by weight.
  • the pharmaceutical composition of a single dosage form comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and an external particle may include ezemitive or a salt thereof in the particle phase.
  • the egemitic or a salt thereof included in the outer particle phase is included in an amount of 90 parts by weight or less based on 100 parts by weight of the total amount of egemitic or a salt thereof included in the pharmaceutical composition.
  • ezetimibe or a salt thereof may be included only in the particle phase.
  • the pharmaceutical composition of a single dosage form comprising rosuvastatin or a salt thereof and particles comprising ezetimibe or a salt thereof and an extraparticulate agent is characterized in that it does not contain a solubilizing agent for ezetimibe or a salt thereof.
  • ezetimibe is a poorly soluble drug, in the prior art, a solubilizing agent such as sodium lauryl sulfate has been used for ezetimibe granules.
  • Korean Patent Publication No. 10-2019-0109892 describes that when 15 to 30 parts by weight is used based on 100 parts by weight of ezetimibe, the stability of the ezetimibe granules and the dissolution rate of ezetimibe can be secured.
  • solubilizing agent such as sodium lauryl sulfate is a surfactant, it is never desirable to use it in large amounts in pharmaceuticals.
  • the present invention is advantageous in terms of safety because a solubilizing agent is not used in the preparation of particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof.
  • the pharmaceutical composition of a single dosage form comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and an external particle is crospovidone, croscarmellose sodium, sodium starch glycolate And it may include one or more disintegrants selected from the group consisting of low-substituted hydroxypropyl cellulose.
  • the disintegrant in a pharmaceutical composition of a single dosage form comprising particles including rosuvastatin or a salt thereof, and ezetimibe or a salt thereof, and the disintegrant, is 10 to 100 parts by weight of the total pharmaceutical composition. 60 parts by weight, for example, 15 to 55 parts by weight, 20 to 50 parts by weight may be included. More specifically, the disintegrant is 3 to 15 parts by weight of crospovidone, 3 to 20 parts by weight of croscarmellose sodium, 3 to 20 parts by weight of sodium starch glycolate, low The substituted hydroxypropyl cellulose may be included in an amount of 10 to 40 parts by weight.
  • a single dosage form pharmaceutical composition comprising particles and extraparticulate particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof is selected from the group consisting of hydroxypropyl cellulose, povidone, copovidone and hypromellose. It may contain one or more binders.
  • the binder may be included in an amount of 3 to 15 parts by weight based on 100 parts by weight of the total pharmaceutical composition.
  • the single dosage form pharmaceutical composition comprising particles and extraparticulates comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof may also include calcium hydrogen phosphate hydrate, anhydrous calcium phosphate, calcium carbonate or a mixture thereof. . Formulation stability can be ensured when calcium hydrogen phosphate hydrate, anhydrous calcium phosphate, calcium carbonate or a mixture thereof is included in the pharmaceutical composition.
  • calcium hydrogen phosphate hydrate, anhydrous calcium phosphate, carbonate based on 100 parts by weight of a pharmaceutical composition in a single dosage form including particles and outer particles comprising the rosuvastatin or a salt thereof and ezetimibe or a salt thereof Calcium or a mixture thereof may be included in an amount of 3 to 20 parts by weight, for example, 3 to 14 parts by weight, 3 to 10 parts by weight.
  • the pharmaceutical composition according to the present invention may include an excipient, a disintegrant, an additive, etc. in addition to the drug.
  • excipients include lactose (including hydrates), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose (e.g., Celphere TM ), silicified microcrystalline cellulose (e.g., Prosolv TM ) (Prosolv TM )], calcium phosphate hydrate, anhydrous calcium phosphate, calcium carbonate, saccharides, or mixtures thereof.
  • the binder is polyvinylpyrrolidone, povidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose (eg, hydroxypropylmethylcellulose) , and mixtures thereof.
  • the lubricant is stearic acid, stearate (eg, magnesium stearate), talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white wax, titanium oxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, and mixtures thereof.
  • a single dosage form pharmaceutical composition comprising particles and extraparticulate particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof may have a dosage form in the form of a tablet.
  • the pharmaceutical composition may have a monolayer tablet formulation comprising granules and extragranular phases including rosuvastatin or a salt thereof and ezetimibe or a salt thereof.
  • rosuvastatin and/or ezetimibe-containing granules may be prepared by preparing rosuvastatin and/or ezetimibe-containing granules, mixing them with the extragranular phase, and then tableting them using a tableting machine.
  • the rosuvastatin and/or ezetimibe-containing granules may be prepared by a dry granulation or wet granulation process according to a conventional method.
  • the granules comprising rosuvastatin or a salt thereof and/or ezetimibe or a salt thereof may be prepared by a wet granulation process.
  • ezetimibe is a poorly soluble drug, it may be preferable to use ethanol instead of water as a solvent for kneading in the wet granulation process. In addition, it may be desirable to use a speed mixer during the union. This may aid in dissolution and dispersion of ezetimibe.
  • the post-mixture comprising the granules and the extragranular phase satisfies the conditions of a Hausner's ratio of 1.34 or less, a Compressibility Index of 25% or less, and an angle of repose of 40° or less. may be doing
  • the pharmaceutical composition of the present invention in the form of a dosage form comprising a mini-tablet is prepared as a mini-tablet comprising rosuvastatin or a salt thereof and/or ezetimibe or a salt thereof, which is then applied to the post-mixing part It can be prepared by filling the capsule with the powder.
  • the pharmaceutical composition of the present invention in the form of a pellet-containing capsule is prepared into pellets comprising rosuvastatin or a salt thereof and/or ezetimibe or a salt thereof, and is used in the post-mixing section. It can be prepared by filling the capsule with powder.
  • the pellets containing rosuvastatin or a salt thereof and/or ezetimibe or a salt thereof are prepared by, for example, placing beads such as non-pareil beads in a fluidized bed coater, It can be prepared by dissolving a statin or a salt thereof and/or ezetimibe or a salt thereof, an excipient (diluent), a binder, a disintegrant in a suitable solvent, for example, ethanol or a mixed solvent of water and methanol, and coating with a coating solution prepared there is.
  • the viscosity of the coating solution is preferably in the range of 5 mPa ⁇ s to 100 mPa ⁇ s.
  • a single dosage form pharmaceutical composition comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and a pharmaceutical composition in a single dosage form may be coated with a coating agent if necessary in the case of a tablet dosage form.
  • the pharmaceutical composition may be a single-layer tablet coated with a coating agent.
  • the coating agent for example, the film coating agent may include a conventional polymer such as Opadry TM (Opadry TM ).
  • the film coating agent may be polyvinyl alcohol (polyvinyl alcohol, PVA), polyvinyl alcohol copolymer, hydroxypropyl methylcellulose (HPMC), or the like.
  • the polyvinyl alcohol copolymer may be, but are not limited to, PVA/macrogol grafted polymer.
  • the pharmaceutical composition of the present invention may be a single-layer tablet coated with polyvinyl alcohol or polyvinyl alcohol copolymer.
  • the amount of the film coating agent used is preferably a minimum amount capable of providing an optimal formulation size, and is not particularly limited.
  • the salt of rosuvastatin includes conventional pharmaceutically acceptable salts, for example, calcium salt, hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, Lactate, tartrate, citrate, gluconate, besylate, camsylate, and the like can be used.
  • rosuvastatin calcium may be used.
  • the salt of ezetimibe includes conventional pharmaceutically acceptable salts, for example, calcium salt, hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, lactate. , tartrate, citrate, gluconate, besylate, camsylate, and the like can be used.
  • conventional pharmaceutically acceptable salts for example, calcium salt, hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, lactate. , tartrate, citrate, gluconate, besylate, camsylate, and the like can be used.
  • the particle size of rosuvastatin or a salt thereof, ezetimibe or a salt thereof may be appropriately adjusted.
  • a conventional mill capable of micronizing particles such as a jet mill, a hammer mill, a ball mill, and a fluid energy mill, is used can be crushed.
  • a sieve method performed using a sieve or a size classification method such as air current classification may be used to subdivide the particle size of the drug.
  • Methods for controlling the desired particle size are well known in the art. See, eg, Pharmaceutical dosage forms: volume 2, 2nd edition, Ed.: H.A.Lieberman, L.Lachman, J.B.Schwartz (Chapter 3: SIZE REDUCTION).
  • D(10) is the diameter of the particle at the point where it becomes 10% by accumulating the particle size of the drug in decreasing order
  • D(50) is the particle at the point where the particle size of the drug becomes 50% by accumulating the particle size in the smallest order.
  • the diameter of , D (90) represents the diameter of the particle at the point where the particle size of the drug is accumulated in decreasing order and becomes 90%.
  • the particle size distribution D(X) represents a percentage of the total cumulative particles by number, volume, or weight depends on the method used to measure the particle size distribution.
  • Methods for determining particle size distribution and the types of percentages associated therewith are known in the art.
  • the value of X in D(X) represents the percentage calculated by the volume average.
  • the particle size distribution measurement results obtained by a particular method may be correlated with those obtained from other techniques based on experience by routine experimentation. For example, laser diffraction gives a volume average particle size in response to the volume of the particle, which corresponds to the weight average particle size when the density is constant.
  • the particle size distribution of the drug particles can be measured using a commercially available device based on the laser diffraction/scattering method based on the Mie theory. For example, it measures using commercially available apparatuses, such as a Malvern Instruments Mastersizer laser diffraction apparatus.
  • a commercially available device based on the laser diffraction/scattering method based on the Mie theory.
  • it measures using commercially available apparatuses, such as a Malvern Instruments Mastersizer laser diffraction apparatus.
  • a helium-neon laser beam and a blue light emitting diode are irradiated to particles, scattering occurs and a light scattering pattern appears on the detector, and the particle size distribution is obtained by analyzing the light scattering pattern according to the Mie theory.
  • the measurement method may be either a dry method or a wet method.
  • D(90) may be 5 to 50 um, preferably 15 to 40 um, more preferably 20 to 35 um. In the case of ezetimibe or a salt thereof, D(90) may be 5 to 60 um, preferably 5 to 45 um.
  • the particle size of rosuvastatin or a salt thereof, ezetimibe or a salt thereof is within the above range, the dissolution rate and/or the bioequivalent level of the drug and/or the blood concentration-area under the time curve (AUC) and peak plasma concentration of the drug at the same level as that of the reference drug It may be suitable to represent (C max ).
  • a pharmaceutical composition of a single dosage form comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and a particle trauma may be for treatment or prevention of primary hypercholesterolemia.
  • a pharmaceutical composition in a single dosage form comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and a particle injury may be used in a patient who needs to be administered rosuvastatin and ezetimibe at the same time.
  • a pharmaceutical composition of a single dosage form comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and an external particle has a dissolution rate of rosuvastatin or a salt thereof at a level equivalent to that of rosuvastatin defined by Cresto TM .
  • rosuvastatin or a salt thereof in the pharmaceutical composition exhibits bioequivalent levels of blood concentration-area under the time curve (AUC) and peak blood concentration (C max ) compared to Cresto TM tablets having the same active ingredient dose.
  • the pharmaceutical composition of a single dosage form comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and an external particle has a dissolution rate of ezetimibe equal to the dissolution rate of ezetimibe defined by ezetrol TM . indicates.
  • the egemitive in the pharmaceutical composition exhibits bioequivalent levels of blood concentration-area under the time curve (AUC) and peak blood concentration (C max ) compared to Easyrol TM tablets having the same active ingredient dose.
  • the pharmaceutical composition of the present invention is particularly useful for patients in need of simultaneous administration of rosuvastatin and ezetimibe.
  • the active ingredient rosuvastatin or a salt thereof, ezetimibe, olmesartan medoxomil, amlodipine or a salt thereof may be used in a therapeutically effective amount.
  • the therapeutically effective amount may vary depending on the patient's symptoms, age, weight, severity of disease, and the like.
  • rosuvastatin or a salt thereof may contain from about 2 mg to about 40 mg, preferably from about 2.5 mg to about 20 mg. and ezetimibe or a salt thereof may be used in an amount of about 5 mg to about 20 mg, preferably 10 mg.
  • the pharmaceutical composition of the present invention may include 40 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 40 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 40 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may contain 20 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe.
  • the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe.
  • the present invention also relates to the present invention.
  • compartments comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and a particle phase; and a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof, wherein the compartments provide a pharmaceutical composition of a single dosage form formulated in a form separated from each other.
  • Particles containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and the description of each drug included in the compartment including the particle and particle trauma, as well as the description of the particle and particle trauma, refer to the above-described rosuvastatin or salt and Since the contents are the same as those described in the pharmaceutical composition of a single dosage form including particles including ezetimibe or a salt thereof and a particle injury, the description of overlapping contents will be omitted.
  • particles refer to granules or pellets prepared by granulating all or part of a composition including drugs and additives during the formulation process.
  • extra-particle phase means a post-mixing part that is post-mixed with the phase existing outside the particles, that is, pre-processed granules or pellets.
  • particle and particle trauma is also referred to as “granular and extragranular phase” or “pellet and pellet trauma”.
  • the particles and extragranular phase mean granules and extragranular phases, respectively, and when particles in the form of pellets are used, the particles and extra-particle phases mean pellets and extra-pellet phases, respectively.
  • Particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and a compartment comprising a particle phase include rosuvastatin or a salt thereof and ezetimibe or a salt thereof as active ingredients, and the active ingredient is a particle And it may be included in one or more of the particle trauma.
  • rosuvastatin may be present only in the particle, but may also be present in the particle phase.
  • the egemitic may be present only in the particle, but may also be present in the particle phase.
  • the pharmaceutical composition of the present invention may have a dosage form in separate compartments, for example, double-layer tablets, cored tablets, mini-tablets- and/or pellet-containing capsules.
  • the pharmaceutical composition is a two-layer tablet formulation comprising a layer comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and a layer comprising olmesartan medoxomil and amlodipine or a salt thereof can have
  • the pharmaceutical composition of the present invention is an oil composed of a core containing rosuvastatin or a salt thereof and ezetimibe and an outer layer containing olmesartan medoxomil and amlodipine or a salt thereof nuclear tablet formulation; or a core containing olmesartan medoxomil and amlodipine or a salt thereof, and a shell containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof.
  • the pharmaceutical composition of the present invention is a capsule formulation comprising a mini-tablet comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and a mini-tablet comprising olmesartan medoxomil and amlodipine or a salt thereof ;
  • the pharmaceutical composition comprises: a compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and an extragranular phase; and a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof.
  • the pharmaceutical composition may be a double-layer tablet.
  • the granules comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof may be prepared by wet granulation using ethanol.
  • the post-mixture comprising the granules and the extragranular phase satisfies the conditions of a Hausner's ratio of 1.34 or less, a Compressibility Index of 25% or less, and an angle of repose of 40° or less. may be doing
  • rosuvastatin or a salt thereof in a compartment including particles and an outer particle comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, rosuvastatin or a salt thereof may be included in the outer particle.
  • the amount of rosuvastatin or a salt thereof included in the outer particle phase is 25 to 90 parts by weight, such as 30 to 90 parts by weight, 40 parts by weight based on 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition. to 90 parts by weight, 50 to 90 parts by weight may be included.
  • rosuvastatin or a salt thereof included in the outer particle phase may be included in an amount of 60 to 85 parts by weight based on 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition.
  • the egemitic may be present only in the particle, but may also be present in the particle phase.
  • egemitive or a salt thereof is included only in the particle and not in the particle phase may not be
  • egemitive or a salt thereof in a compartment comprising a particle comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and in a compartment comprising a particle phase, egemitive or a salt thereof may be included in the particle phase.
  • egemitic or a salt thereof may be included in both particles and extraparticulate phases.
  • egemitive or a salt thereof in a compartment comprising a particle comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and in a compartment comprising a particle phase, egemitive or a salt thereof may be included in the particle phase.
  • the egemitic or a salt thereof included in the outer particle phase is included in an amount of 90 parts by weight or less based on 100 parts by weight of the total of egemitic or a salt thereof included in the pharmaceutical composition.
  • the egemitic or a salt thereof contained in the outer particle phase is 25 to 90 parts by weight, such as 30 to 90 parts by weight, 40 parts by weight, based on 100 parts by weight of the total of egemitic or a salt thereof included in the pharmaceutical composition. to 90 parts by weight, 50 to 90 parts by weight may be included.
  • ezetimibe or a salt thereof may be included only in the particle phase.
  • the compartment comprising particles and extraparticulate phases comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof does not contain a solubilizing agent for ezetimibe or a salt thereof.
  • the compartment comprising the particle and the outer particle phase comprising the rosuvastatin or a salt thereof and ezetimibe or a salt thereof is crospovidone, croscarmellose sodium, sodium starch glycolate and low-substituted It may include one or more disintegrants selected from the group consisting of dohydroxypropyl cellulose.
  • the disintegrant is 3 to 15 parts by weight of crospovidone with respect to a total of 100 parts by weight of the compartment including particles and extraparticulate phases including rosuvastatin or a salt thereof and ezetimibe or a salt thereof, cross Sodium carmellose may be included in an amount of 3 to 20 parts by weight, sodium starch glycolate in an amount of 3 to 20 parts by weight, and low-substituted hydroxypropyl cellulose in an amount of 10 to 40 parts by weight.
  • the compartment comprising the particle and the outer phase of the particle comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof is hydroxypropyl cellulose, povidone, hypromellose and copovidone. It may include one or more binders selected from the group consisting of.
  • the binder may be included in an amount of 3 to 15 parts by weight based on 100 parts by weight of a total of 100 parts by weight of the partition including the particles including rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and the outer particle phase. As can be seen in the examples below, when it is outside this range, it may be undesirable in terms of the dissolution rate of the egemitic.
  • Particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and a compartment comprising an extraparticulate phase may also include calcium hydrogen phosphate hydrate, anhydrous calcium phosphate, calcium carbonate or mixtures thereof.
  • calcium hydrogen phosphate hydrate, anhydrous calcium phosphate, calcium carbonate, or a mixture thereof is included in the compartment, formulation stability can be ensured.
  • calcium hydrogen phosphate hydrate, anhydrous calcium phosphate, calcium carbonate or a mixture thereof is added to a total of 100 parts by weight of the compartment including the particles including rosuvastatin or a salt thereof and ezetimibe or a salt thereof and the outer particle phase.
  • 3 to 20 parts by weight, for example, 3 to 14 parts by weight, may be included in the range of 3 to 10 parts by weight.
  • Particles containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and the compartment including the extraparticulate phase may include excipients, disintegrants, additives, and the like, in addition to the drug.
  • excipients include lactose (including hydrates), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose (e.g., Celphere TM ), silicified microcrystalline cellulose (e.g., Prosolv TM ) (Prosolv TM )], calcium phosphate hydrate, anhydrous calcium phosphate, calcium carbonate, saccharides, or mixtures thereof.
  • the binder is polyvinylpyrrolidone, povidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose (eg, hydroxypropylmethylcellulose) , and mixtures thereof.
  • the lubricant is stearic acid, stearate (eg magnesium stearate), talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white wax, titanium oxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, and mixtures thereof.
  • the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof is pregelatinized starch, croscarmellose sodium, crospovidone, carboxymethyl cellulose calcium, sodium starch glycolate, copovidone and two kinds from the group consisting of complex silicate. It may include a disintegrant selected above.
  • the disintegrant may be included in an amount of 5 to 60 parts by weight based on 100 parts by weight of the total of the compartment including the olmesartan medoxomil and amlodipine or a salt thereof.
  • the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof may include calcium hydrogen phosphate hydrate.
  • the calcium hydrogen phosphate hydrate may be included in an amount of 1 to 30 parts by weight based on 100 parts by weight of the total of the compartment including olmesartan medoxomil and amlodipine or a salt thereof.
  • the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof may contain suitable excipients and additives in addition to the calcium hydrogen phosphate hydrate and a disintegrant.
  • excipients include lactose (including hydrates), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose (e.g., Celphere TM ), silicified microcrystalline cellulose (e.g., Prosolv TM ) (Prosolv TM )], calcium carbonate, saccharides, or mixtures thereof.
  • other additives include binders, lubricants, colorants, and the like.
  • the binder is polyvinylpyrrolidone, copovidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose (eg, hydroxypropylmethylcellulose). ), and mixtures thereof.
  • the lubricant is stearic acid, stearate (eg, magnesium stearate), talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white wax, titanium oxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, and mixtures thereof.
  • the pharmaceutical composition of the present invention in the form of a bilayer tablet comprises a mixture of particles and extraparticulate phases comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and olmesartan medoxomil and amlodipine or a salt thereof
  • a bilayer tablet press After preparing the mixture according to a conventional method, it can be prepared by tableting using a double-layer tablet press.
  • each drug may be manufactured by first processing into granules and then tableting using a double-layer tablet press.
  • olmesartan medoxomil/amlodipine besylate granules and rosuvastatin/ezetimibe granules may be prepared by dry granulation or wet granulation process according to a conventional method.
  • a film coating layer such as Opadry TM may be formed on the obtained bilayer tablet.
  • compartments comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and a particle phase; and a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof, wherein the compartments provide a pharmaceutical composition of a single dosage form formulated in a form separated from each other.
  • the pharmaceutical composition of the present invention in the form of a cored tablet is prepared as described above after forming particles including rosuvastatin or a salt thereof and ezetimibe or a salt thereof and a core tablet including an extraparticulate phase.
  • the core tablet may be manufactured by tableting the core tablet together with granules containing olmesartan medoxomil and amlodipine or a salt thereof using a single-shot tableting machine (EKO, Korsch) or the like.
  • the core tablet comprising particles and extraparticulate particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof comprises, for example, granules comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof. It can be manufactured by manufacturing dry granules or wet granules, mixing them with the outer particle phase, and then tableting with a continuous tablet press (Piccola D-8, RIVA). If necessary, a film coating layer such as Opadry TM may be formed on the obtained nucleated tablet.
  • a film coating layer such as Opadry TM may be formed on the obtained nucleated tablet.
  • the pharmaceutical composition of the present invention in the form of a dosage form comprising a mini-tablet is a mini-tablet containing olmesartan medoxomil/amlodipine or a salt thereof and/or rosuvastatin or a salt thereof in a method similar to the method for manufacturing the core tablet.
  • mini-tablet containing ezetimibe or a salt thereof it is prepared into a mini-tablet, pellet, or powder containing rosuvastatin or a salt thereof and ezetimibe, or olmesartan medoxomil/amlodipine or a salt thereof It can be prepared by filling the capsules with the containing mini-tablets, pellets, or powder.
  • the pharmaceutical composition of the present invention in the form of pellet-containing capsules may be prepared by preparing olmesartan medoxomil/amlodipine besylate pellets and rosuvastatin/ezetimibe granules, respectively, and then filling the capsules. there is.
  • the pharmaceutical composition of the present invention in the form of granules or pellet-containing capsules may be prepared by preparing olmesartan medoxomil/amlodipine besylate granules and rosuvastatin/ezetimibe pellets, respectively, and then filling the capsules.
  • the olmesartan medoxomil / amlodipine besylate pellets are, for example, non-pareil beads (non-pareil beads), etc., put in a fluid bed coater, olmesartan medoxomil, amlodipine, an excipient (diluent), It can be prepared by coating with a coating solution prepared by dissolving a binder and a disintegrant in an appropriate solvent, for example, a mixed solvent of water and methanol.
  • the viscosity of the coating solution is preferably in the range of 5 mPa ⁇ s to 100 mPa ⁇ s.
  • the pharmaceutical composition of the present invention may be coated with a coating agent in the case of tablets.
  • the pharmaceutical composition of the present invention may be a double-layer tablet or a core-coated tablet coated with a coating agent.
  • the coating agent for example, the film coating agent may include a conventional polymer such as Opadry TM (Opadry TM ).
  • the film coating agent may be polyvinyl alcohol (polyvinyl alcohol, PVA), polyvinyl alcohol copolymer, hydroxypropyl methylcellulose (HPMC), or the like.
  • the polyvinyl alcohol copolymer may be, but are not limited to, PVA/macrogol grafted polymer.
  • the pharmaceutical composition of the present invention may be a double-layer tablet or a core-coated tablet coated with polyvinyl alcohol or polyvinyl alcohol copolymer.
  • the amount of the film coating agent used is preferably a minimum amount capable of providing an optimal formulation size, and is not particularly limited.
  • the salt of rosuvastatin includes conventional pharmaceutically acceptable salts, for example, calcium salt, hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, Lactate, tartrate, citrate, gluconate, besylate, camsylate, and the like can be used.
  • rosuvastatin calcium may be used.
  • the salt of ezetimibe includes conventional pharmaceutically acceptable salts, for example, calcium salt, hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, and lactate. , tartrate, citrate, gluconate, besylate, camsylate, and the like can be used.
  • the salt of amlodipine includes conventional pharmaceutically acceptable salts, for example, besylate, hydrochloride, hydrobromide, fumarate, citrate, tartrate, maleate, cansylate, lactate, mesyl. lactate, camsylate, gluconate, and the like can be used.
  • amlodipine besylate can be used.
  • the particle size of rosuvastatin or a salt thereof, ezetimibe or a salt thereof, olmesartan medoxomil, amlodipine or a salt thereof may be appropriately adjusted.
  • D(90) may be 5 to 50 um, preferably 15 to 40 um, more preferably 20 to 35 um. In the case of ezetimibe or a salt thereof, D(90) may be 5 to 60 um, preferably 5 to 45 um. In the case of olmesartan medoxomil, D (90) may be 5 to 45 um, preferably 5 to 30 um. In the case of amlodipine or a salt thereof, D(90) may be 5 to 100 um, preferably 10 to 60 um, more preferably 15 to 45 um.
  • the dissolution rate and/or bioequivalent blood concentration-time of the drug compared to the reference drug It may be appropriate to represent the area under the curve (AUC) and the peak plasma concentration (C max ).
  • a compartment comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and a particle phase; and a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof, wherein the pharmaceutical composition of a single dosage form formulated in a form in which the compartments are separated from each other may be for the treatment or prevention of hypertension and hypercholesterolemia.
  • the pharmaceutical composition of the present invention can be used in patients who need to simultaneously administer rosuvastatin, ezetimibe, olmesartan medoxomil and amlodipine.
  • rosuvastatin is used for the treatment of hypercholesterolemia, hyperlipidproteinemia and/or atherosclerosis.
  • Ezetimibe is being used for the treatment of primary hypercholesterolemia.
  • Combinations of rosuvastatin and ezetimibe are also used for the treatment of primary hypercholesterolemia. Indications information for each drug is already well known.
  • the present invention provides a pharmaceutical composition in which the dissolution rate of rosuvastatin or a salt thereof is equivalent to that of Cresto TM defined rosuvastatin.
  • whether the dissolution rate represents an equivalent level can be determined according to the drug equivalence test management regulations.
  • the present invention also provides a pharmaceutical composition in which the dissolution rate of ezetimibe or a salt thereof is equivalent to the dissolution rate of ezetimibe defined by ezetrol TM .
  • the present invention also provides a pharmaceutical composition in which the dissolution rate of rosuvastatin or a salt thereof is equivalent to that of rosuvastatin defined by Rosuzet TM .
  • the present invention also provides a pharmaceutical composition in which the dissolution rate of ezetimibe or a salt thereof is equivalent to the dissolution rate of ezetimibe defined by Rosuzet TM .
  • the present invention provides a pharmaceutical composition in which the dissolution rate of olmesartan medoxomil is equivalent to that of olmesartan medoxomil defined by Sevica TM .
  • the present invention provides a pharmaceutical composition in which the dissolution rate of amlodipine or a salt thereof is equivalent to the dissolution rate of amlodipine or a salt thereof defined by Sevica TM .
  • Ezetimibe and rosuvastatin calcium salt in the pharmaceutical composition of the present invention have bioequivalent levels of blood concentration-area under the time curve (AUC) and bioequivalent compared to the combined administration of Cresto TM tablets and Easyrol TM tablets having the same active ingredient dose. It is characterized in that it represents the highest blood concentration (C max ).
  • Ezetimibe and rosuvastatin calcium salt in the pharmaceutical composition of the present invention are bioequivalent in blood concentration-area under the time curve (AUC) and peak blood concentration (C max ) compared to Rosuget TM tablets having the same active ingredient dose characterized in that it represents
  • Olmesartan medoxomil and amlodipine or a salt thereof in the pharmaceutical composition of the present invention is a bioequivalent level of blood concentration-area under the time curve (AUC) and peak blood concentration (C max ) compared to Sevica TM tablets having the same active ingredient dose characterized in that it represents
  • the pharmaceutical composition of the present invention is particularly useful for administering to a patient in need of a combination drug of amlodipine and olmesartan medoxomil and a combination drug of rosuvastatin and ezetimibe at the same time.
  • the active ingredient rosuvastatin or a salt thereof, ezetimibe, olmesartan medoxomil, amlodipine or a salt thereof may be used in a therapeutically effective amount.
  • the therapeutically effective amount may vary depending on the patient's symptoms, age, weight, severity of disease, and the like.
  • rosuvastatin or a salt thereof may contain from about 2 mg to about 40 mg, preferably from about 2.5 mg to about 20 mg. and ezetimibe or a salt thereof may be used in an amount of about 5 mg to about 20 mg, preferably 10 mg.
  • olmesartan medoxomil may be used in an amount of about 5 mg to about 80 mg, preferably about 10 mg to about 40 mg.
  • amlodipine or an amount thereof may be used in an amount of about 2.5 mg to 10 mg.
  • the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 40 mg, amlodipine or a salt thereof 10 mg.
  • the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.
  • the pharmaceutical composition of the present invention may include rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 10 mg.
  • the pharmaceutical composition of the present invention may include rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 5 mg.
  • the pharmaceutical composition of the present invention may include rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 10 mg.
  • the pharmaceutical composition of the present invention may include rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 5 mg.
  • the pharmaceutical composition according to the present invention may be orally administered once a day, but is not limited thereto.
  • the present invention by mixing a composition containing a drug and formulating it in a single form, the problems related to dissolution and absorption of the drug due to the interaction between drugs are minimized, and the stability and uniform dissolution rate of the drug are secured, so that the conventional single A bioequivalent formulation can be obtained when compared to the formulation.
  • compositions of rosuvastatin calcium/ezetimibe were prepared according to the composition and conventional methods in Table 1 below, respectively. Each preparation example was prepared as follows by changing the rosuvastatin calcium content included in the post-mixing part. Wet granules were prepared according to the composition of the granules in Table 1 and then sieved. A post-mixture was obtained by mixing the milled granule and the post-mixing part, and after tableting, the coated tablet was prepared by film coating with Opadry.
  • the rosuvastatin ratio showed similar granular properties without significantly affecting the particle size distribution, density, and angle of repose even when the ratio of post-mixing parts increased.
  • ⁇ 1.34, Compressibility Index is 25% or less, and the range of the angle of repose is about 35 to 40 °, so in Preparation Examples 1 to 7, Hausner's ratio is 1.34 or less, Compressibility Index is 25% or less, and the angle of repose corresponds to 40 ° or less. It can be seen that the productivity is excellent.
  • a comparative dissolution test was performed under the following dissolution test conditions for the formulations prepared through the Preparation Example of the present invention.
  • the reference drugs used in the comparative dissolution test are Cresto Tablet TM (Rosuvastatin) 20 mg, Easyrol Tablet TM (Ezetimibe) 10 mg, Sevica Tablet (Amlodipine Besylate/olmesartan medoxomil) 10/40 mg and Rosuzet TM (ezetimibe/rosuvastatin calcium) 10/20 mg were used.
  • Crestor Tablets TM , Sevica Tablets TM and Rosuzette Tablets are in the form of film-coated single tablets, and Easyrol Tablets TM are in the form of uncoated tablets.
  • Cresto Tablet TM contains microcrystalline cellulose, lactose hydrate, tribasic calcium phosphate, crospovidone, and magnesium stearate as excipients, and hypromellose, triacetin, titanium dioxide, and iron oxide as film coating agents.
  • Easyrol Tablet TM contains lactose hydrate, magnesium stearate, povidone, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium as excipients.
  • Sevica Tablet TM contains silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate as excipients, and polyvinyl alcohol, Macrogol/Polyethylene glycol 3350, titanium dioxide, talc, and iron oxide as film coating agents.
  • Rosuzette TM contains lactose hydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, D-mannitol, crospovidone, and magnesium stearate as excipients, and hypromellose and polyethylene glycol as film coating agents. 6000, talc, red iron oxide, and titanium oxide.
  • Test method Korean Pharmacopoeia dissolution test method 2 (paddle method)
  • the 5-minute dissolution rate increased as the post-mixing ratio of rosuvastatin calcium increased, and it was confirmed that the dissolution rate was higher than that of the reference drug as a whole, and was at the same level.
  • the proportion of rosuvastatin calcium contained in the ezetimibe granule did not have a significant effect on the dissolution of ezetimibe, and the dissolution rate was confirmed to be equivalent to that of the reference drug.
  • 2017-28, Chapter 3, Article 21 was referred to.
  • the dissolution rate deviation is within ⁇ 15%, or if the dissolution rate deviation is 60% or more in 15 minutes or more and 85% or more within 15 minutes or more, the dissolution rate deviation is ⁇ 15% near 85%.
  • a pharmaceutical composition of olmesartan medoxomil/amlodipine besylate and a pharmaceutical composition of rosuvastatin calcium/ezetimibe were respectively prepared, and a double-layer tablet was prepared using a double-layer tableting machine. did Thereafter, film-coated tablets were prepared using a coating machine.
  • Preparation Examples 15 to 18 Preparation of a film-coated two-layer tablet in which the binding solvent and additives were changed based on the composition of Preparation Example 8
  • a pharmaceutical composition of olmesartan medoxomil/amlodipine besylate and a pharmaceutical composition of rosuvastatin calcium/ezetimibe were respectively prepared, and a double-layer tablet was prepared using a double-layer tableting machine. did Thereafter, film-coated tablets were prepared using a coating machine.
  • PK test pharmacokinetic test
  • test subjects were divided into 2 groups, and the first group was administered with the tablet of Preparation Example 5, and the second group orally administered Cresto tablet (Rosuvastatin) 20 mg, and Easyrol tablet 10 mg together.
  • Blood was collected at 0, 0.33, 0.67, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 48, 72 hours after administration, and rosuvastatin and The plasma concentrations of ezetimibe were quantified, respectively. After quantification, the AUC and Cmax of rosuvastatin and ezetimibe at the time of administration of the control drug (combination administration) and the test drug were statistically processed to evaluate the bioequivalence between the preparations.
  • T/R ratio the geometric mean of the evaluation items (test formulation) / evaluation) geometric mean of items (control)].
  • T/R ratio the geometric mean of the evaluation items (test formulation) / evaluation) geometric mean of items (control)].
  • PK of Preparation Example 5 ingredient PK parameters T/R ratio Rosuvastatin AUC 0.9198 Cmax 0.9623 ezetimibe AUC 0.9237 Cmax 1.0963
  • PK test pharmacokinetic test
  • test subjects were divided into 2 groups, the first group was the tablet of Preparation Example 8, the second group was Sevica tablet (amlodipine besylate/olmesartan medoxomil) 10/40 mg, and rosuset tablet 10/20 mg Concomitant oral administration.
  • Blood was collected at 0, 0.33, 0.67, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 48, 72 hours after administration, and olmesartan, amlodipine , and the blood concentrations of rosuvastatin and ezetimibe were quantified, respectively.
  • the AUC and Cmax of olmesartan, amlodipine, rosuvastatin, and ezetimibe at the time of administration of the control drug (combination administration) and the test drug were statistically processed to evaluate the bioequivalence between the preparations.
  • T/R ratio the geometric mean of the evaluation items (test formulation) / evaluation) geometric mean of items (control)].
  • T/R ratio the geometric mean of the evaluation items (test formulation) / evaluation) geometric mean of items (control)].
  • PK of Preparation Example 8 ingredient PK parameters T/R ratio Olmesartan AUC 1.0268 Cmax 1.0475 amlodipine AUC 0.9714 Cmax 0.9793 Rosuvastatin AUC 0.9928 Cmax 0.9993 ezetimibe AUC 0.9279 Cmax 1.0217

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Abstract

La présente invention concerne une formulation composite pharmaceutique contenant une composition comprenant de la rosuvastatine ou un sel de celle-ci et de l'ézétimibe ou un sel de celui-ci, la composition pharmaceutique pouvant en outre comprendre de l'olmésartan médoxomil et de l'amlodipine ou un sel de ceux-ci. Selon la présente invention, la composition contenant des médicaments est mélangée et formulée sous une forme unique pour minimiser les problèmes liés à la dissolution et à l'absorption du médicament en raison de l'interaction entre les médicaments et pour garantir la stabilité et des vitesses de dissolution uniformes des médicaments, moyennant quoi une formulation biologiquement équivalente peut être obtenue en comparaison avec des formulations uniques classiques.
PCT/KR2021/011350 2020-08-25 2021-08-25 Composition pharmaceutique à dose unique pour le traitement ou la prévention de l'hypertension et de l'hypercholestérolémie WO2022045759A1 (fr)

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BR112023003323A BR112023003323A2 (pt) 2020-08-25 2021-08-25 Composição farmacêutica em forma de dosagem única
MX2023002403A MX2023002403A (es) 2020-08-25 2021-08-25 Composicion farmaceutica en forma de dosificacion individual para tratar o prevenir hipertension e hipercolesterolemia.

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Citations (6)

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KR20090065510A (ko) * 2009-03-13 2009-06-22 다이이찌 산쿄 가부시키가이샤 올메사탄 메독소밀 및 암로디핀의 고형 투여 제형
KR20150079373A (ko) * 2013-12-30 2015-07-08 한미약품 주식회사 에제티미브 및 로수바스타틴을 포함하는 경구용 복합제제
KR20160000762A (ko) * 2014-06-25 2016-01-05 한미약품 주식회사 에제티미브 및 로수바스타틴을 포함하는 경구용 복합제제 및 그 제조방법
KR20160105044A (ko) * 2015-02-27 2016-09-06 한미약품 주식회사 에제티미브 및 로수바스타틴을 포함하는 경구용 고형 복합제제
KR20170007695A (ko) * 2015-07-08 2017-01-19 씨제이헬스케어 주식회사 암로디핀, 발사르탄 및 로수바스타틴을 포함하는 약학적 조성물

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TWI425026B (zh) 2011-09-19 2014-02-01 Everlight Chem Ind Corp 聚氨酯衍生物及其組成物及包括該衍生物的染料添加劑
KR20190022739A (ko) 2016-10-07 2019-03-06 유링화 테크놀로지 컴퍼니 리미티드 오수 처리 방법 및 시스템

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009024889A2 (fr) * 2007-08-21 2009-02-26 Ranbaxy Laboratories Limited Composition pharmaceutique comprenant un inhibiteur de réductase hmg-coa et un ézétimibe
KR20090065510A (ko) * 2009-03-13 2009-06-22 다이이찌 산쿄 가부시키가이샤 올메사탄 메독소밀 및 암로디핀의 고형 투여 제형
KR20150079373A (ko) * 2013-12-30 2015-07-08 한미약품 주식회사 에제티미브 및 로수바스타틴을 포함하는 경구용 복합제제
KR20160000762A (ko) * 2014-06-25 2016-01-05 한미약품 주식회사 에제티미브 및 로수바스타틴을 포함하는 경구용 복합제제 및 그 제조방법
KR20160105044A (ko) * 2015-02-27 2016-09-06 한미약품 주식회사 에제티미브 및 로수바스타틴을 포함하는 경구용 고형 복합제제
KR20170007695A (ko) * 2015-07-08 2017-01-19 씨제이헬스케어 주식회사 암로디핀, 발사르탄 및 로수바스타틴을 포함하는 약학적 조성물

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