WO2022045759A1 - Pharmaceutical composition in single dosage form for treating or preventing hypertension and hypercholesterolemia - Google Patents
Pharmaceutical composition in single dosage form for treating or preventing hypertension and hypercholesterolemia Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- pharmaceutical composition
- rosuvastatin
- ezetimibe
- amlodipine
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 242
- 239000002552 dosage form Substances 0.000 title claims description 49
- 206010020772 Hypertension Diseases 0.000 title claims description 14
- 208000035150 Hypercholesterolemia Diseases 0.000 title claims description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 488
- 229960000672 rosuvastatin Drugs 0.000 claims abstract description 264
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims abstract description 264
- 229960000815 ezetimibe Drugs 0.000 claims abstract description 219
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 claims abstract description 219
- 239000000203 mixture Substances 0.000 claims abstract description 80
- 238000004090 dissolution Methods 0.000 claims abstract description 63
- 229940043092 olmesartan medoxomil and amlodipine Drugs 0.000 claims abstract description 43
- 238000009472 formulation Methods 0.000 claims abstract description 33
- 239000002245 particle Substances 0.000 claims description 239
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims description 94
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- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 claims description 56
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- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical class [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 claims description 28
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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
Description
성분명Ingredient name |
제조예production example
1One |
제조예production example
22 |
제조예production example
33 |
제조예production example
44 |
제조예production example
55 |
제조예production example
66 |
제조예production example
77 |
|
과립부granular part | 로수바스타틴 칼슘Rosuvastatin Calcium | 20.820.8 | 18.7218.72 | 15.615.6 | 10.410.4 | 5.25.2 | 2.082.08 | -- |
에제티미브ezetimibe | 1010 | 1010 | 1010 | 1010 | 1010 | 1010 | 1010 | |
저치환도히드록시프로필셀룰로오스Low-substituted hydroxypropyl cellulose | 6666 | 6666 | 6666 | 6666 | 6666 | 6666 | 6666 | |
인산수소칼슘수화물Calcium Hydrogen Phosphate Hydrate | 1111 | 1111 | 1111 | 1111 | 1111 | 1111 | 1111 | |
유당수화물lactose hydrate | 6262 | 6262 | 6262 | 6262 | 6262 | 6262 | 6262 | |
크로스카르멜로오스나트륨Croscarmellose Sodium | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 | |
히드록시프로필셀룰로오스Hydroxypropyl Cellulose | 1414 | 1414 | 1414 | 1414 | 1414 | 1414 | 1414 | |
후혼합부post-mix | 로수바스타틴 칼슘Rosuvastatin Calcium | -- | 2.082.08 | 5.25.2 | 10.410.4 | 15.615.6 | 18.7218.72 | 20.820.8 |
유당수화물(일수화물)Lactose hydrate (monohydrate) | 19.519.5 | 19.519.5 | 19.519.5 | 19.519.5 | 19.519.5 | 19.519.5 | 19.519.5 | |
인산수소칼슘수화물Calcium Hydrogen Phosphate Hydrate | 1111 | 1111 | 1111 | 1111 | 1111 | 1111 | 1111 | |
크로스카르멜로오스나트륨Croscarmellose Sodium | 88 | 88 | 88 | 88 | 88 | 88 | 88 | |
스테아르산마그네슘magnesium stearate | 1212 | 1212 | 1212 | 1212 | 1212 | 1212 | 1212 | |
코팅부coating | 오파드라이Opadry | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 |
총량total amount | 250250 | 250250 | 250250 | 250250 | 250250 | 250250 | 250250 |
크기 (um)size (um) |
제조예production example
1One |
제조예production example
22 |
제조예production example
33 |
제조예production example
44 |
제조예production example
55 |
제조예production example
66 |
제조예production example
77 |
|
입도분포 (중량%)particle size distribution (weight%) |
0 - 750 - 75 | 4.30 4.30 | 3.10 3.10 | 3.70 3.70 | 4.00 4.00 | 2.22.2 | 2.52.5 | 1.21.2 |
75 - 15075 - 150 | 11.80 11.80 | 12.90 12.90 | 12.50 12.50 | 13.70 13.70 | 8.58.5 | 7.37.3 | 5.45.4 | |
150 - 250150 - 250 | 29.90 29.90 | 19.30 19.30 | 21.00 21.00 | 29.30 29.30 | 25.725.7 | 20.120.1 | 1010 | |
250 - 355250 - 355 | 19.00 19.00 | 26.00 26.00 | 25.40 25.40 | 9.70 9.70 | 10.410.4 | 17.917.9 | 22.222.2 | |
355 - 425355 - 425 | 1.30 1.30 | 4.00 4.00 | 2.50 2.50 | 1.80 1.80 | 1.51.5 | 1.21.2 | 1.91.9 | |
425 - 1000425 - 1000 | 31.20 31.20 | 31.50 31.50 | 31.40 31.40 | 36.00 36.00 | 48.548.5 | 47.847.8 | 56.556.5 | |
1000 - 14001000 - 1400 | 2.50 2.50 | 3.20 3.20 | 3.50 3.50 | 5.50 5.50 | 3.13.1 | 33 | 2.72.7 | |
1400 이상over 1400 | 0.00 0.00 | 0.00 0.00 | 0.00 0.00 | 0.00 0.00 | 0.10.1 | 0.20.2 | 0.10.1 | |
밀도 (g/ml)density (g/ml) |
Bulk 밀도Bulk density | 0.540.54 | 0.530.53 | 0.530.53 | 0.520.52 | 0.510.51 | 0.530.53 | 0.50.5 |
Tap 밀도Tap Density | 0.640.64 | 0.640.64 | 0.660.66 | 0.680.68 | 0.640.64 | 0.650.65 | 0.640.64 | |
Hausner's ratioHausner's ratio | 1.191.19 | 1.211.21 | 1.251.25 | 1.311.31 | 1.251.25 | 1.231.23 | 1.281.28 | |
Compressibility Index (%)Compressibility Index (%) | 15.6315.63 | 17.1917.19 | 19.7019.70 | 23.5323.53 | 20.3120.31 | 18.4618.46 | 21.8821.88 | |
안식각 (°)angle of repose (°) | 34.4834.48 | 34.2434.24 | 34.4834.48 | 39.1039.10 | 34.4834.48 | 36.5736.57 | 37.3637.36 |
용출시간dissolution time | 0분0 minutes | 5분5 minutes | 10분10 minutes | 15분15 minutes | 30분30 minutes | 45분45 minutes |
제조예 1Preparation Example 1 | 00 | 56.856.8 | 79.479.4 | 89.589.5 | 95.195.1 | 98.798.7 |
제조예 2Preparation 2 | 00 | 60.260.2 | 78.978.9 | 84.384.3 | 90.490.4 | 92.392.3 |
제조예 3Preparation 3 | 00 | 61.361.3 | 79.479.4 | 86.886.8 | 93.093.0 | 95.095.0 |
제조예 4Preparation 4 | 00 | 61.261.2 | 87.087.0 | 91.691.6 | 97.097.0 | 97.697.6 |
제조예 5Preparation 5 | 00 | 66.266.2 | 85.185.1 | 88.988.9 | 92.992.9 | 93.693.6 |
제조예 6Preparation 6 | 00 | 67.367.3 | 83.383.3 | 87.287.2 | 91.791.7 | 92.592.5 |
제조예 7Preparation 7 | 00 | 68.568.5 | 82.982.9 | 86.786.7 | 90.290.2 | 91.591.5 |
크레스토+이지트롤Cresto + Easy Troll | 00 | 44.544.5 | 73.973.9 | 89.689.6 | 99.799.7 | 100.6100.6 |
용출시간dissolution time | 0분0 minutes | 5분5 minutes | 10분10 minutes | 15분15 minutes | 30분30 minutes | 45분45 minutes |
제조예 1Preparation Example 1 | 00 | 44.6 44.6 | 70.8 70.8 | 83.0 83.0 | 93.1 93.1 | 94.2 94.2 |
제조예 2Preparation 2 | 00 | 46.8 46.8 | 71.8 71.8 | 81.2 81.2 | 93.1 93.1 | 94.1 94.1 |
제조예 3Preparation 3 | 00 | 43.9 43.9 | 67.9 67.9 | 79.6 79.6 | 91.6 91.6 | 94.2 94.2 |
제조예 4Preparation 4 | 00 | 51.9 51.9 | 74.0 74.0 | 82.1 82.1 | 93.1 93.1 | 97.7 97.7 |
제조예 5Preparation 5 | 00 | 48.1 48.1 | 67.9 67.9 | 77.1 77.1 | 88.5 88.5 | 94.2 94.2 |
제조예 6Preparation 6 | 00 | 55.0 55.0 | 74.0 74.0 | 86.8 86.8 | 95.6 95.6 | 97.6 97.6 |
제조예 7Preparation 7 | 00 | 51.5 51.5 | 71.8 71.8 | 81.2 81.2 | 89.7 89.7 | 94.6 94.6 |
크레스토+이지트롤Cresto + Easy Troll | 00 | 51.151.1 | 77.677.6 | 83.083.0 | 90.390.3 | 93.693.6 |
성분명Ingredient name
|
제조예 8Preparation 8 | 제조예 9Preparation 9 | 제조예 10Preparation 10 | 제조예 11Preparation 11 | 제조예 12Preparation 12 | 제조예 13Preparation 13 | 제조예 14Preparation 14 | ||
조성물1composition 1 | 올메사탄 메독소밀Olmesartan medoxomil | 4040 | 4040 | 4040 | 4040 | 4040 | 4040 | 4040 | |
암로디핀 베실산염Amlodipine Besylate | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | ||
전호화전분pregelatinized starch | 4040 | 4040 | 4040 | 4040 | 4040 | 4040 | 4040 | ||
크로스카르멜로오스나트륨Croscarmellose Sodium | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 | ||
크로스포비돈crospovidone | 2020 | 2020 | 2020 | 2020 | 2020 | 2020 | 2020 | ||
규소화미결정셀룰로오스Siliconized Microcrystalline Cellulose | 59.0559.05 | 59.0559.05 | 59.0559.05 | 59.0559.05 | 59.0559.05 | 59.0559.05 | 59.0559.05 | ||
인산수소칼슘수화물Calcium Hydrogen Phosphate Hydrate | 4040 | 4040 | 4040 | 4040 | 4040 | 4040 | 4040 | ||
암로디핀 베실산염Amlodipine Besylate | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | ||
적색산화철red iron oxide | 0.060.06 | 0.060.06 | 0.060.06 | 0.060.06 | 0.060.06 | 0.060.06 | 0.060.06 | ||
스테아르산마그네슘magnesium stearate | 1212 | 1212 | 1212 | 1212 | 1212 | 1212 | 1212 | ||
조성물2composition 2 | 과립부granular part | 로수바스타틴 칼슘Rosuvastatin Calcium | 5.25.2 | 5.25.2 | 5.25.2 | 5.25.2 | 5.25.2 | 5.25.2 | 5.25.2 |
에제티미브ezetimibe | 1010 | 1010 | 1010 | 1010 | 1010 | 1010 | 1010 | ||
저치환도히드록시프로필셀룰로오스Low-substituted hydroxypropyl cellulose | 6666 | 6666 | 6666 | 6666 | 6666 | 6666 | 6666 | ||
인산수소칼슘수화물Calcium Hydrogen Phosphate Hydrate | 1111 | 1111 | 1111 | 1111 | 1111 | 1111 | 1111 | ||
유당수화물lactose hydrate | 6262 | 6262 | 6262 | 6262 | 6262 | 7171 | 3636 | ||
크로스카르멜로오스나트륨Croscarmellose Sodium | 1515 | -- | -- | 1515 | 1515 | 1515 | 1515 | ||
전분글리콜산나트륨Sodium starch glycolate | -- | 1515 | -- | -- | -- | -- | -- | ||
크로스포비돈crospovidone | -- | -- | 1515 | -- | -- | -- | -- | ||
히드록시프로필셀룰로오스Hydroxypropyl Cellulose | 1414 | 1414 | 1414 | -- | -- | 55 | 4040 | ||
포비돈povidone | -- | -- | -- | 1414 | -- | -- | -- | ||
전호화전분pregelatinized starch | -- | -- | -- | -- | 1414 | -- | -- | ||
에탄올ethanol | 2525 | 2525 | 2525 | 2525 | 2525 | 2525 | 2525 | ||
후혼합부post-mix | 로수바스타틴 칼슘Rosuvastatin Calcium | 15.615.6 | 15.615.6 | 15.615.6 | 15.615.6 | 15.615.6 | 15.615.6 | 15.615.6 | |
유당수화물(일수화물)Lactose hydrate (monohydrate) | 28.428.4 | 28.428.4 | 28.428.4 | 28.428.4 | 28.428.4 | 28.428.4 | 28.428.4 | ||
인산수소칼슘수화물Calcium Hydrogen Phosphate Hydrate | 1111 | 1111 | 1111 | 1111 | 1111 | 1111 | 1111 | ||
크로스카르멜로오스나트륨Croscarmellose Sodium | 88 | -- | -- | 88 | 88 | 88 | 88 | ||
전분글리콜산나트륨Sodium starch glycolate | -- | 88 | -- | -- | -- | -- | -- | ||
크로스포비돈crospovidone | -- | -- | 88 | -- | -- | -- | -- | ||
스테아르산마그네슘magnesium stearate | 3.83.8 | 3.83.8 | 3.83.8 | 3.83.8 | 3.83.8 | 3.83.8 | 3.83.8 | ||
코팅coating | 오파드라이Opadry | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 | |
합계Sum | 1정 총 질량1 tablet total mass | 505505 | 505505 | 505505 | 505505 | 505505 | 505505 | 505505 |
용출시간dissolution time | 0분0 minutes | 5분5 minutes | 10분10 minutes | 15분15 minutes | 30분30 minutes | 45분45 minutes |
제조예 8Preparation 8 | 00 | 65.065.0 | 93.793.7 | 92.792.7 | 100.4100.4 | 96.396.3 |
제조예 9Preparation 9 | 00 | 61.461.4 | 83.483.4 | 85.385.3 | 95.195.1 | 98.598.5 |
제조예 10Preparation 10 | 00 | 72.172.1 | 88.388.3 | 86.586.5 | 91.091.0 | 105.8105.8 |
제조예 11Preparation 11 | 00 | 56.856.8 | 79.479.4 | 83.283.2 | 89.189.1 | 93.493.4 |
제조예 12Preparation 12 | 00 | 59.959.9 | 81.581.5 | 84.584.5 | 89.989.9 | 94.894.8 |
제조예 13Preparation 13 | 00 | 60.560.5 | 88.288.2 | 89.889.8 | 90.990.9 | 93.793.7 |
제조예 14Preparation 14 | 00 | 51.751.7 | 64.564.5 | 74.374.3 | 85.785.7 | 94.294.2 |
세비카+로수젯Cevica + Rosuzette | 00 | 80.8 80.8 | 93.7 93.7 | 97.2 97.2 | 99.8 99.8 | 100.0 100.0 |
용출시간dissolution time | 0분0 minutes | 5분5 minutes | 10분10 minutes | 15분15 minutes | 30분30 minutes | 45분45 minutes |
제조예 8Preparation 8 | 00 | 52.352.3 | 78.078.0 | 81.681.6 | 87.787.7 | 91.191.1 |
제조예 9Preparation 9 | 00 | 50.150.1 | 74.274.2 | 78.678.6 | 85.085.0 | 93.793.7 |
제조예 10Preparation 10 | 00 | 51.851.8 | 71.371.3 | 76.176.1 | 84.884.8 | 89.189.1 |
제조예 11Preparation 11 | 00 | 50.350.3 | 68.168.1 | 73.273.2 | 81.381.3 | 88.488.4 |
제조예 12Preparation 12 | 00 | 49.449.4 | 70.670.6 | 72.472.4 | 82.982.9 | 87.087.0 |
제조예 13Preparation 13 | 00 | 37.837.8 | 56.156.1 | 65.065.0 | 75.775.7 | 81.281.2 |
제조예 14Preparation 14 | 00 | 41.741.7 | 58.958.9 | 66.466.4 | 80.280.2 | 88.988.9 |
세비카+로수젯Cevica + Rosuzette | 00 | 59.8 59.8 | 78.5 78.5 | 84.3 84.3 | 90.6 90.6 | 94.1 94.1 |
용출시간dissolution time | 0분0 minutes | 5분5 minutes | 10분10 minutes | 15분15 minutes | 30분30 minutes | 45분45 minutes |
제조예 8Preparation 8 | 00 | 45.345.3 | 64.064.0 | 71.971.9 | 84.884.8 | 90.090.0 |
제조예 9Preparation 9 | 00 | 53.453.4 | 68.268.2 | 76.576.5 | 89.889.8 | 92.492.4 |
제조예 10Preparation 10 | 00 | 51.751.7 | 70.070.0 | 79.479.4 | 88.388.3 | 94.494.4 |
제조예 11Preparation 11 | 00 | 49.449.4 | 68.768.7 | 75.675.6 | 88.888.8 | 92.692.6 |
제조예 12Preparation 12 | 00 | 52.752.7 | 65.265.2 | 72.172.1 | 82.582.5 | 88.588.5 |
제조예 13Preparation 13 | 00 | 50.750.7 | 69.169.1 | 74.874.8 | 86.186.1 | 89.589.5 |
제조예 14Preparation 14 | 00 | 48.448.4 | 67.867.8 | 76.976.9 | 86.986.9 | 88.488.4 |
세비카+로수젯Cevica + Rosuzette | 00 | 19.819.8 | 25.225.2 | 28.728.7 | 34.734.7 | 37.137.1 |
용출시간dissolution time | 0분0 minutes | 5분5 minutes | 10분10 minutes | 15분15 minutes | 30분30 minutes | 45분45 minutes |
제조예 8Preparation 8 | 00 | 88.988.9 | 91.291.2 | 89.689.6 | 92.392.3 | 91.491.4 |
제조예 9Preparation 9 | 00 | 88.8 88.8 | 95.2 95.2 | 92.0 92.0 | 92.2 92.2 | 89.4 89.4 |
제조예 10Preparation 10 | 00 | 86.8 86.8 | 88.8 88.8 | 88.0 88.0 | 86.4 86.4 | 88.4 88.4 |
제조예 11Preparation 11 | 00 | 84.7 84.7 | 89.6 89.6 | 89.8 89.8 | 91.4 91.4 | 88.9 88.9 |
제조예 12Preparation 12 | 00 | 86.0 86.0 | 89.0 89.0 | 89.6 89.6 | 89.7 89.7 | 88.1 88.1 |
제조예 13Preparation 13 | 00 | 85.285.2 | 89.289.2 | 90.190.1 | 90.790.7 | 89.789.7 |
제조예 14Preparation 14 | 00 | 86.786.7 | 88.188.1 | 89.889.8 | 90.190.1 | 90.590.5 |
세비카+로수젯Cevica + Rosuzette | 00 | 80.280.2 | 87.287.2 | 87.887.8 | 91.491.4 | 93.593.5 |
성분명Ingredient name
|
제조예production example
8 8 |
제조예 15Preparation 15 |
제조예 production example
1616 |
제조예 production example
1717 |
제조예 production example
1818 |
||
조성물1composition 1 | 과립부granular part | 올메사탄 메독소밀Olmesartan medoxomil | 4040 | 4040 | 4040 | 4040 | 4040 |
전호화전분pregelatinized starch | 4040 | 4040 | 4040 | 4040 | 4040 | ||
크로스카르멜로오스나트륨Croscarmellose Sodium | 1010 | 1010 | 1010 | 1010 | 1010 | ||
크로스포비돈crospovidone | 1010 | 1010 | 1010 | 1010 | 1010 | ||
규소화미결정셀룰로오스Siliconized Microcrystalline Cellulose | 4040 | 4040 | 4040 | 4040 | 4040 | ||
인산수소칼슘수화물Calcium Hydrogen Phosphate Hydrate | 4040 | 4040 | 4040 | 4040 | 4040 | ||
후혼합부post-mix | 암로디핀 베실산염Amlodipine Besylate | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | 13.8913.89 | |
크로스카르멜로오스나트륨Croscarmellose Sodium | 55 | 55 | 55 | 55 | 55 | ||
크로스포비돈crospovidone | 1010 | 1010 | 1010 | 1010 | 1010 | ||
규소화미결정셀룰로오스Siliconized Microcrystalline Cellulose | 19.0519.05 | 19.0519.05 | 19.0519.05 | 19.0519.05 | 19.0519.05 | ||
적색산화철red iron oxide | 0.060.06 | 0.060.06 | 0.060.06 | 0.060.06 | 0.060.06 | ||
스테아르산마그네슘magnesium stearate | 1212 | 1212 | 1212 | 1212 | 1212 | ||
조성물2composition 2 | 과립부granular part | 로수바스타틴 칼슘Rosuvastatin Calcium | 5.25.2 | 5.25.2 | 5.25.2 | 5.25.2 | 5.25.2 |
에제티미브ezetimibe | 1010 | 1010 | 1010 | -- | 55 | ||
저치환도히드록시프로필셀룰로오스Low-substituted hydroxypropyl cellulose | 6666 | 6666 | 6666 | 6666 | 6666 | ||
인산수소칼슘수화물Calcium Hydrogen Phosphate Hydrate | 1111 | 1111 | 1111 | 1111 | 1111 | ||
유당수화물lactose hydrate | 6262 | 6262 | 6262 | 6262 | 6262 | ||
크로스카르멜로오스나트륨Croscarmellose Sodium | 1515 | -- | -- | 1515 | 1515 | ||
전분글리콜산나트륨Sodium starch glycolate | -- | 1515 | -- | -- | -- | ||
크로스포비돈crospovidone | -- | -- | 1515 | -- | -- | ||
히드록시프로필셀룰로오스Hydroxypropyl Cellulose | 1414 | 1414 | -- | 1414 | 1414 | ||
포비돈povidone | -- | -- | 1414 | -- | -- | ||
전호화전분pregelatinized starch | -- | -- | -- | -- | -- | ||
에탄올ethanol | 2525 | -- | 2525 | 2525 | 2525 | ||
정제수Purified water | -- | 2525 | -- | -- | -- | ||
후혼합부post-mix | 로수바스타틴 칼슘Rosuvastatin Calcium | 15.615.6 | 15.615.6 | 15.615.6 | 15.615.6 | 15.615.6 | |
에제티미브ezetimibe | -- | -- | -- | 1010 | 55 | ||
유당수화물(일수화물)Lactose hydrate (monohydrate) | 28.428.4 | 28.428.4 | 39.439.4 | 39.439.4 | 28.428.4 | ||
인산수소칼슘수화물Calcium Hydrogen Phosphate Hydrate | 1111 | 1111 | -- | -- | 1111 | ||
크로스카르멜로오스나트륨Croscarmellose Sodium | 88 | -- | -- | 88 | 88 | ||
전분글리콜산나트륨Sodium starch glycolate | -- | 88 | -- | -- | -- | ||
크로스포비돈crospovidone | -- | -- | 88 | -- | -- | ||
스테아르산마그네슘magnesium stearate | 3.83.8 | 3.83.8 | 3.83.8 | 3.83.8 | 3.83.8 | ||
코팅coating | 오파드라이Opadry | 1515 | 1515 | 1515 | 1515 | 1515 | |
합계Sum | 1정 총 질량1 tablet total mass | 505505 | 505505 | 505505 | 505505 | 505505 |
용출시간dissolution time | 0분0 minutes | 5분5 minutes | 10분10 minutes | 15분15 minutes | 30분30 minutes | 45분45 minutes |
제조예 8Preparation 8 | 00 | 65.065.0 | 93.793.7 | 92.792.7 | 100.4100.4 | 96.396.3 |
제조예 15Preparation 15 | 00 | 61.261.2 | 88.888.8 | 91.191.1 | 94.694.6 | 95.495.4 |
제조예 16Preparation 16 | 00 | 57.457.4 | 84.284.2 | 89.489.4 | 98.498.4 | 99.599.5 |
제조예 17Preparation 17 | 00 | 76.376.3 | 91.491.4 | 94.994.9 | 98.398.3 | 99.499.4 |
제조예 18Preparation 18 | 00 | 56.756.7 | 77.477.4 | 90.390.3 | 99.699.6 | 99.899.8 |
세비카+로수젯Cevica + Rosuzette | 00 | 80.8 80.8 | 93.7 93.7 | 97.2 97.2 | 99.8 99.8 | 100.0 100.0 |
용출시간dissolution time | 0분0 minutes | 5분5 minutes | 10분10 minutes | 15분15 minutes | 30분30 minutes | 45분45 minutes |
제조예 8Preparation 8 | 00 | 52.352.3 | 78.078.0 | 81.681.6 | 87.787.7 | 91.191.1 |
제조예 15Preparation 15 | 00 | 43.943.9 | 60.460.4 | 67.367.3 | 78.378.3 | 82.5.82.5. |
제조예 16Preparation 16 | 00 | 53.753.7 | 80.480.4 | 85.185.1 | 89.889.8 | 93.093.0 |
제조예 17Preparation 17 | 00 | 49.449.4 | 85.885.8 | 96.096.0 | 100.0100.0 | 100.2100.2 |
제조예 18Preparation 18 | 00 | 54.554.5 | 87.687.6 | 93.193.1 | 95.595.5 | 95.695.6 |
세비카+로수젯Cevica + Rosuzette | 00 | 59.8 59.8 | 78.5 78.5 | 84.3 84.3 | 90.6 90.6 | 94.1 94.1 |
유연물질 항목Related Substances | 기준standard | 제조예 8Preparation 8 | 제조예 15Preparation 15 | 제조예 16Preparation 16 | 제조예 17Preparation 17 | 제조예 18Preparation 18 |
에제티미브 총 유연물질Ezetimibe Total Related Substances | 1.0 % 이하1.0% or less | 0.840.84 | 0.960.96 | 0.810.81 | 0.780.78 | 0.750.75 |
로수바스타틴칼슘 총 유연물질Rosuvastatin Calcium Total Related Substances | 3.0 % 이하3.0% or less | 1.621.62 | 3.133.13 | 1.641.64 | 1.511.51 | 1.571.57 |
성분ingredient | PK parameterPK parameters | T/R ratioT/R ratio |
로수바스타틴Rosuvastatin | AUCAUC | 0.91980.9198 |
CmaxCmax | 0.96230.9623 | |
에제티미브ezetimibe | AUCAUC | 0.92370.9237 |
CmaxCmax | 1.09631.0963 |
성분ingredient | PK parameterPK parameters | T/R ratioT/R ratio |
올메사탄Olmesartan | AUCAUC | 1.02681.0268 |
CmaxCmax | 1.04751.0475 | |
암로디핀amlodipine | AUCAUC | 0.97140.9714 |
CmaxCmax | 0.97930.9793 | |
로수바스타틴Rosuvastatin | AUCAUC | 0.99280.9928 |
CmaxCmax | 0.99930.9993 | |
에제티미브ezetimibe | AUCAUC | 0.92790.9279 |
CmaxCmax | 1.02171.0217 |
Claims (66)
- 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 입자 및 입자외상을 포함하는 단일 제형의 약학 조성물.A pharmaceutical composition in a single dosage form, comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and an external particle.
- 제1항에 있어서, 상기 약학 조성물 중 포함되는 로수바스타틴 또는 그의 염의 전체 100 중량부 대비 상기 입자 내 포함되는 로수바스타틴 또는 그의 염은 10 중량부 이상으로 포함되는 것인 약학 조성물.The pharmaceutical composition according to claim 1, wherein 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.
- 제1항에 있어서, 상기 약학 조성물 중 포함되는 로수바스타틴 또는 그의 염의 전체 100 중량부 대비 상기 입자 내 포함되는 로수바스타틴 또는 그의 염은 10 중량부 내지 100 중량부로 포함되는 것인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the amount of rosuvastatin or a salt thereof contained in the particles is 10 to 100 parts by weight relative to 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition.
- 제1항에 있어서, 상기 입자외상에 로수바스타틴 또는 그의 염을 포함하는 약학 조성물.The pharmaceutical composition according to claim 1, comprising rosuvastatin or a salt thereof in the outer particle phase.
- 제4항에 있어서, 상기 입자외상에 포함되는 로수바스타틴 또는 그의 염은 상기 약학 조성물 중 포함되는 로수바스타틴 또는 그의 염의 전체 100 중량부 대비 90 중랑부 이하로 포함되는 것인 약학 조성물.The pharmaceutical composition according to claim 4, wherein the amount of rosuvastatin or a salt thereof included in the outer particle phase is 90 parts by weight or less based on 100 parts by weight of the total amount of rosuvastatin or a salt thereof included in the pharmaceutical composition.
- 제1항에 있어서, 상기 입자외상에 에제티미브 또는 그의 염을 포함하는 약학 조성물.The pharmaceutical composition according to claim 1, comprising ezetimibe or a salt thereof in the outer particle phase.
- 제1항에 있어서, 상기 약학 조성물은 에제티미브 또는 그의 염에 대한 가용화제를 포함하지 않는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition does not contain a solubilizing agent for ezetimibe or a salt thereof.
- 제1항에 있어서, 상기 약학 조성물은 크로스포비돈, 크로스카르멜로오스나트륨, 전분글리콜산나트륨 및 저치환도히드록시프로필셀룰로오스로 이루어진 군으로부터 선택되는 하나 이상의 붕해제를 포함하는 것인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises one or more disintegrants selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate and low-substituted hydroxypropyl cellulose.
- 제8항에 있어서, 상기 붕해제는 상기 약학 조성물 총 100 중량부에 대하여 크로스포비돈은 3 내지 15 중량부, 크로스카르멜로오스나트륨은 3 내지 20 중량부, 전분글리콜산나트륨은 3 내지 20 중량부, 저치환도히드록시프로필셀룰로오스는 10 내지 40 중량부로 포함되는 것인 약학 조성물.The method of claim 8, wherein 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, based on 100 parts by weight of the total pharmaceutical composition. , The low-substituted hydroxypropyl cellulose is a pharmaceutical composition that is included in 10 to 40 parts by weight.
- 제1항에 있어서, 상기 약학 조성물은 히드록시프로필셀룰로오스, 포비돈, 코포비돈 및 히프로멜로오스로 이루어진 군으로부터 선택되는 하나 이상의 결합제를 포함하는 것인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises one or more binders selected from the group consisting of hydroxypropylcellulose, povidone, copovidone and hypromellose.
- 제10항에 있어서, 상기 결합제는 상기 약학 조성물 총 100 중량부에 대하여 히드록시프로필셀룰로오스, 포비돈, 코포비돈 및 히프로멜로오스는 3 내지 15 중량부로 포함되는 것인 약학 조성물.The pharmaceutical composition according to claim 10, wherein the binder is included in an amount of 3 to 15 parts by weight of hydroxypropyl cellulose, povidone, copovidone and hypromellose based on 100 parts by weight of the total pharmaceutical composition.
- 제1항에 있어서, 상기 약학 조성물은 정제의 제형을 갖는 것인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of a tablet.
- 제1항에 있어서, 상기 약학 조성물은 코팅제로 코팅된 단층정인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a single-layer tablet coated with a coating agent.
- 제13항에 있어서, 상기 약학 조성물은 폴리비닐알코올, 폴리비닐알코올 공중합체 또는 하이드록시프로필 메틸셀룰로스(hydroxypropyl methylcellulose, HPMC)로 코팅된 단층정인 약학 조성물.The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is a single-layer tablet coated with polyvinyl alcohol, polyvinyl alcohol copolymer, or hydroxypropyl methylcellulose (HPMC).
- 제1항에 있어서, 상기 약학 조성물은 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 과립 및 과립외상을 포함하는 단층정의 제형을 갖는 것인 약학 조성물. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a monolayer tablet formulation comprising granules and extragranular phases comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof.
- 제15항에 있어서, 상기 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 과립은 에탄올을 이용한 습식과립화에 의해 제조된 것인 약학 조성물.The pharmaceutical composition according to claim 15, wherein the granules comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof are prepared by wet granulation using ethanol.
- 제15항에 있어서, 과립 및 과립외상을 포함하는 후혼합물은 하우스너 비율(Hausner's ratio)이 1.34 이하이고, 압축지수(Compressibility Index)가 25% 이하이며, 안식각이 40° 이하의 조건을 만족하는 것인 약학 조성물.The method according to claim 15, wherein the post-mixture comprising granules and extragranular phase has 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. a pharmaceutical composition.
- 제1항에 있어서, 로수바스타틴의 염은 로수바스타틴 칼슘염인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the salt of rosuvastatin is rosuvastatin calcium salt.
- 제1항에 있어서, 로수바스타틴 또는 그의 염의 D(90)이 5 내지 50 ㎛인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the D(90) of rosuvastatin or a salt thereof is 5 to 50 μm.
- 제1항에 있어서, 에제티미브 또는 그의 염의 D(90)이 5 내지 60 ㎛ 이하인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the D(90) of ezetimibe or a salt thereof is 5 to 60 μm or less.
- 제1항에 있어서, 상기 입자는 과립 또는 펠렛인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the particles are granules or pellets.
- 제1항에 있어서, 상기 약학 조성물은 단층정, 과립-, 펠렛- 및/또는 미니 타블렛-함유 캡슐제의 제형을 갖는 것인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a dosage form of a monolayer tablet, granule-, pellet- and/or mini-tablet-containing capsule.
- 제1항에 있어서, 상기 약학 조성물은 원발성 고콜레스테롤혈증의 치료 또는 예방을 위한 것인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for the treatment or prevention of primary hypercholesterolemia.
- 제1항에 있어서, 상기 약학 조성물은 로수바스타틴 또는 그의 염의 용출률이 크레스토TM정의 로수바스타틴의 용출률과 동등한 수준을 나타내는 것인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition exhibits a dissolution rate of rosuvastatin or a salt thereof equal to the dissolution rate of rosuvastatin defined by Cresto ™ .
- 제1항에 있어서, 상기 약학 조성물 내 로수바스타틴 또는 그의 염은 동일한 활성성분 용량을 갖는 크레스토TM정과 비교하여 생물학적 동등 수준의 혈중농도-시간곡선하면적(AUC)과 최고혈중농도(Cmax)를 나타내는 것을 특징으로 하는 약학 조성물.According to claim 1, wherein rosuvastatin or a salt thereof in the pharmaceutical composition is a bioequivalent level 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 Pharmaceutical composition characterized in that it represents.
- 제1항에 있어서, 상기 약학 조성물은 에제미티브의 용출률이 이지트롤TM정의 에제미티브의 용출률과 동등한 수준을 나타내는 것인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition exhibits a dissolution rate of egemitive equivalent to that of ezetrol TM defined egemitic.
- 제1항에 있어서, 상기 약학 조성물 내 에제미티브는 동일한 활성성분 용량을 갖는 이지트롤TM정과 비교하여 생물학적 동등 수준의 혈중농도-시간곡선하면적(AUC)과 최고혈중농도(Cmax)를 나타내는 것을 특징으로 하는 약학 조성물.The method according to claim 1, wherein the egemitive in the pharmaceutical composition exhibits bioequivalent blood concentration-area under the time curve (AUC) and peak blood concentration (C max ) compared to easytrol TM tablets having the same active ingredient dose. Pharmaceutical composition, characterized in that.
- 제1항에 있어서, 상기 약학 조성물은 단위 제제를 기준으로 로수바스타틴 및 에제티미브를 하기 용량으로 포함하는 것인 약학 조성물:The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises rosuvastatin and ezetimibe in the following doses based on a unit dosage form:로수바스타틴 또는 그의 염 40 mg, 에제티미브 20 mg; rosuvastatin or a salt thereof 40 mg, ezetimibe 20 mg;로수바스타틴 또는 그의 염 40 mg, 에제티미브 10 mg;rosuvastatin or a salt thereof 40 mg, ezetimibe 10 mg;로수바스타틴 또는 그의 염 40 mg, 에제티미브 5 mg;rosuvastatin or a salt thereof 40 mg, ezetimibe 5 mg;로수바스타틴 또는 그의 염 20 mg, 에제티미브 20 mg; 20 mg of rosuvastatin or a salt thereof, 20 mg of ezetimibe;로수바스타틴 또는 그의 염 20 mg, 에제티미브 10 mg;20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe;로수바스타틴 또는 그의 염 20 mg, 에제티미브 5 mg;20 mg of rosuvastatin or a salt thereof, 5 mg of ezetimibe;로수바스타틴 또는 그의 염 10 mg, 에제티미브 20 mg;10 mg of rosuvastatin or a salt thereof, 20 mg of ezetimibe;로수바스타틴 또는 그의 염 10 mg, 에제티미브 10 mg;10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe;로수바스타틴 또는 그의 염 10 mg, 에제티미브 5 mg;10 mg of rosuvastatin or a salt thereof, 5 mg of ezetimibe;로수바스타틴 또는 그의 염 5 mg, 에제티미브 20 mg;5 mg of rosuvastatin or a salt thereof, 20 mg of ezetimibe;로수바스타틴 또는 그의 염 5 mg, 에제티미브 10 mg;5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe;로수바스타틴 또는 그의 염 5 mg, 에제티미브 5 mg;5 mg of rosuvastatin or a salt thereof, 5 mg of ezetimibe;로수바스타틴 또는 그의 염 2.5 mg, 에제티미브 20 mg;rosuvastatin or a salt thereof 2.5 mg, ezetimibe 20 mg;로수바스타틴 또는 그의 염 2.5 mg, 에제티미브 10 mg;rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg;로수바스타틴 또는 그의 염 2.5 mg, 에제티미브 5 mg.rosuvastatin or a salt thereof 2.5 mg, ezetimibe 5 mg.
- 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 입자 및 입자외상을 포함하는 구획; 및 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 구획을 포함하고, 상기 구획들이 서로 분리된 형태로 제제화된 단일 제형의 약학 조성물.a compartment comprising particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and a particle phase; And a pharmaceutical composition of a single dosage form comprising a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof, wherein the compartments are separated from each other.
- 제29항에 있어서, 상기 약학 조성물은 이층 정제, 유핵정, 미니 타블렛- 및/또는 펠렛-함유 캡슐제의 제형을 갖는 것인 약학 조성물.30. The pharmaceutical composition according to claim 29, wherein the pharmaceutical composition has a dosage form of a double-layer tablet, a core-coated tablet, a mini-tablet- and/or a pellet-containing capsule.
- 제29항에 있어서, 상기 약학 조성물은 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 층, 및 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 층으로 구성된 이층 정제의 제형을 갖는 것인 약학 조성물. 30. The method of claim 29, wherein the pharmaceutical composition has a dosage form of a bilayer tablet 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 a pharmaceutical composition.
- 제29항에 있어서, 상기 약학 조성물은 로수바스타틴 또는 그의 염 및 에제티미브을 포함하는 핵(core) 및 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 외층(shell)로 구성된 유핵정의 제형; 또는 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 핵(core) 및 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 외층(shell)로 구성된 유핵정의 제형을 갖는 것인 약학 조성물.30. The method according to claim 29, wherein the pharmaceutical composition comprises: a core containing rosuvastatin or a salt thereof and ezetimibe, and a shell containing olmesartan medoxomil and amlodipine or a salt thereof; Or a pharmaceutical composition having a core containing olmesartan medoxomil and amlodipine or a salt thereof, and a core containing rosuvastatin or a salt thereof and an outer layer containing ezetimibe or a salt thereof, having a core-coated tablet dosage form. .
- 제29항에 있어서, 상기 약학 조성물은 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 미니 타블렛 및 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 미니 타블렛을 포함하는 캡슐제 제형; 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 미니 타블렛 및 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 펠렛 또는 파우더를 포함하는 캡슐제의 제형; 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 미니 타블렛 및 로스바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 펠렛 또는 파우더를 포함하는 캡슐제의 제형; 또는 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 펠렛 및 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 펠렛을 포함하는 캡슐제의 제형을 갖는 것인 약학 조성물.30. The method of claim 29, wherein the pharmaceutical composition comprises: 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; Formulation of capsules containing mini-tablets containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and pellets or powder containing olmesartan medoxomil and amlodipine or a salt thereof; Formulation of capsules including mini-tablets containing olmesartan medoxomil and amlodipine or a salt thereof, and pellets or powder containing rosvastatin or a salt thereof and ezetimibe or a salt thereof; Or a pharmaceutical composition having the dosage form of a capsule comprising pellets comprising olmesartan medoxomil and amlodipine or a salt thereof, and pellets comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof.
- 제29항에 있어서, 상기 약학 조성물은 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 과립 및 과립외상을 포함하는 구획; 및 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 구획을 포함하는 것인 약학 조성물.30. The method of claim 29, wherein the pharmaceutical composition comprises: a compartment comprising an extragranular phase and granules comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof; and a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof.
- 제34항에 있어서, 상기 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 과립은 에탄올을 이용한 습식과립화에 의해 제조된 것인 약학 조성물. The pharmaceutical composition according to claim 34, wherein the granules comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof are prepared by wet granulation using ethanol.
- 제34항에 있어서, 상기 과립 및 과립외상을 포함하는 후혼합물은 하우스너 비율(Hausner's ratio)이 1.34 이하이고, 압축지수(Compressibility Index)가 25% 이하이며, 안식각이 40° 이하의 조건을 만족하는 것인 약학 조성물.35. The method of claim 34, wherein 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. A pharmaceutical composition that does.
- 제29항에 있어서, 상기 입자외상에 로수바스타틴 또는 그의 염을 포함하는 약학 조성물.The pharmaceutical composition according to claim 29, comprising rosuvastatin or a salt thereof in the outer particle phase.
- 제37항에 있어서, 상기 입자외상에 포함되는 로수바스타틴 또는 그의 염은 상기 약학 조성물 중 포함되는 로수바스타틴 또는 그의 염의 전체 100 중량부 대비 25 내지 90 중량부로 포함되는 것인 약학 조성물.The pharmaceutical composition according to claim 37, wherein the amount of rosuvastatin or a salt thereof included in the outer particle phase is 25 to 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.
- 제37항에 있어서, 상기 입자외상에 포함되는 로수바스타틴 또는 그의 염은상기 약학 조성물 중 포함되는 로수바스타틴 또는 그의 염의 전체 100 중량부 대비 60 내지 85 중량부로 포함되는 것인 약학 조성물.The pharmaceutical composition according to claim 37, wherein the amount of rosuvastatin or a salt thereof included in the outer particle phase is 60 to 85 parts by weight based on 100 parts by weight of the total of rosuvastatin or a salt thereof included in the pharmaceutical composition.
- 제29항에 있어서, 상기 입자외상에 에제티미브 또는 그의 염을 포함하는 약학 조성물.30. The pharmaceutical composition according to claim 29, comprising ezetimibe or a salt thereof in the outer particle phase.
- 제29항에 있어서, 상기 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 입자 및 입자외상을 포함하는 구획은 에제티미브 또는 그의 염에 대한 가용화제를 포함하지 않는 것을 특징으로 하는 약학 조성물.30. The method of claim 29, wherein the compartment comprising the particle and extraparticulate phase comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof does not contain a solubilizing agent for ezetimibe or a salt thereof. pharmaceutical composition.
- 제29항에 있어서, 상기 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 입자 및 입자외상을 포함하는 구획은 크로스포비돈, 크로스카르멜로오스나트륨, 전분글리콜산나트륨 및 저치환도히드록시프로필셀룰로오스로 이루어진 군으로부터 선택되는 하나 이상의 붕해제를 포함하는 것인 약학 조성물.30. The method of claim 29, wherein the compartment comprising the particle and the extraparticulate phase comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof is crospovidone, croscarmellose sodium, sodium starch glycolate and low-substituted hydro A pharmaceutical composition comprising one or more disintegrants selected from the group consisting of hydroxypropyl cellulose.
- 제42항에 있어서, 상기 붕해제는 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 입자 및 입자외상을 포함하는 구획의 총 100 중량부에 대하여 크로스포비돈은 3 내지 15 중량부, 크로스카르멜로오스나트륨은 3 내지 20 중량부, 전분글리콜산나트륨은 3 내지 20 중량부, 저치환도히드록시프로필셀룰로오스는 10 내지 40 중량부로 포함되는 것인 약학 조성물.43. The method of claim 42, wherein the disintegrant is 3 to 15 parts by weight of crospovidone based on 100 parts by weight of the total of the compartment including the particles and the extraparticulate phase comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof; Croscarmellose sodium is 3 to 20 parts by weight, sodium starch glycolate is 3 to 20 parts by weight, and low-substituted hydroxypropyl cellulose is a pharmaceutical composition comprising 10 to 40 parts by weight.
- 제29항에 있어서, 상기 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 입자 및 입자외상을 포함하는 구획은 히드록시프로필셀룰로오스, 포비돈, 히프로멜로오스 및 코포비돈으로 이루어진 군으로부터 선택되는 하나 이상의 결합제를 포함하는 것인 약학 조성물.30. The method of claim 29, wherein the particle comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof and the compartment comprising the extraparticulate phase are selected from the group consisting of hydroxypropylcellulose, povidone, hypromellose and copovidone. A pharmaceutical composition comprising one or more selected binders.
- 제44항에 있어서, 상기 결합제는 로수바스타틴 또는 그의 염 및 에제티미브 또는 그의 염을 포함하는 입자 및 입자외상을 포함하는 구획의 총 100 중량부에 대하여 히드록시프로필셀룰로오스, 포비돈, 코포비돈 및 히프로멜로오스는 3 내지 15 중량부로 포함되는 것인 약학 조성물.45. The method according to claim 44, wherein the binder is hydroxypropylcellulose, povidone, copovidone and Hypromellose is a pharmaceutical composition comprising 3 to 15 parts by weight.
- 제29항에 있어서, 상기 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 구획은 인산수소칼슘수화물을 포함하는 것인 약학 조성물.The pharmaceutical composition according to claim 29, wherein the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof comprises calcium hydrogen phosphate hydrate.
- 제46항에 있어서, 상기 인산수소칼슘수화물은 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 구획의 총 100 중량부에 대하여 1 내지 30 중량부로 포함되는 것인 약학 조성물.The pharmaceutical composition according to claim 46, wherein the calcium hydrogen phosphate hydrate is included in an amount of 1 to 30 parts by weight based on 100 parts by weight of the total of the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof.
- 제29항에 있어서, 상기 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 구획은 전호화전분, 크로스카르멜로스나트륨, 크로스포비돈, 카르복시메틸셀룰로오스칼슘, 전분글리콜산나트륨, 코포비돈 및 복합실리케이트로 이루어진 군으로부터 2종 이상 선택된 붕해제를 포함하는 것인 약학 조성물.30. The method of claim 29, wherein the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof consists of pregelatinized starch, croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, sodium starch glycolate, copovidone and complex silicate. A pharmaceutical composition comprising two or more disintegrants selected from the group.
- 제48항에 있어서, 상기 붕해제는 상기 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 구획의 총 100 중량부에 대하여 5 내지 60 중량부의 양으로 포함되는 것인 약학 조성물. The pharmaceutical composition according to claim 48, wherein the disintegrant is included in an amount of 5 to 60 parts by weight based on 100 parts by weight of the total of the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof.
- 제48항에 있어서, 상기 올메사탄 메독소밀 및 암로디핀 또는 그의 염을 포함하는 구획의 총 100 중량부에 대하여 전호화전분은 4 내지 40 중량부, 크로스카르멜로스나트륨은 1 내지 10 중량부, 크로스포비돈은 1 내지 20 중량부로 포함되는 것인 약학 조성물.49. The method according to claim 48, wherein the pregelatinized starch is 4 to 40 parts by weight, croscarmellose sodium is 1 to 10 parts by weight, crospovidone based on 100 parts by weight of the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof. A pharmaceutical composition comprising 1 to 20 parts by weight of silver.
- 제29항에 있어서, 상기 약학 조성물은 코팅제로 코팅된 이층 정제 또는 유핵정인 약학 조성물.30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is a double-layer tablet or a core-coated tablet coated with a coating agent.
- 제51항에 있어서, 상기 약학 조성물은 폴리비닐알코올, 폴리비닐알코올 공중합체 또는 하이드록시프로필 메틸셀룰로스(hydroxypropyl methylcellulose, HPMC)로 코팅된 이층정제 또는 유핵정인 약학 조성물.52. The pharmaceutical composition of claim 51, wherein the pharmaceutical composition is a double-layer tablet or a core-coated tablet coated with polyvinyl alcohol, polyvinyl alcohol copolymer, or hydroxypropyl methylcellulose (HPMC).
- 제29항에 있어서, 암로디핀의 염은 암로디핀 베실산염인 약학 조성물.30. The pharmaceutical composition of claim 29, wherein the salt of amlodipine is amlodipine besylate.
- 제29항에 있어서, 로수바스타틴의 염은 로수바스타틴 칼슘염인 약학 조성물.30. The pharmaceutical composition according to claim 29, wherein the salt of rosuvastatin is rosuvastatin calcium salt.
- 제29항에 있어서, 로수바스타틴 또는 그의 염의 D(90)이 5 내지 50 ㎛인 약학 조성물.30. The pharmaceutical composition according to claim 29, wherein the D(90) of rosuvastatin or a salt thereof is 5 to 50 μm.
- 제29항에 있어서, 에제티미브 또는 그의 염의 D(90)이 5 내지 60 ㎛ 이하인 약학 조성물.30. The pharmaceutical composition according to claim 29, wherein the D(90) of ezetimibe or a salt thereof is 5 to 60 μm or less.
- 제29항에 있어서, 올메사탄 메독소밀의 D(90)이 5 내지 45 ㎛인 약학 조성물.30. The pharmaceutical composition according to claim 29, wherein the D(90) of olmesartan medoxomil is 5 to 45 μm.
- 제29항에 있어서, 암로디핀 또는 그의 염의 D(90)이 5 내지 100 ㎛인 약학 조성물. 30. The pharmaceutical composition according to claim 29, wherein the D(90) of amlodipine or a salt thereof is 5 to 100 μm.
- 제29항에 있어서, 상기 약학 조성물은 고혈압 및 고콜레스테롤혈증의 치료 또는 예방을 위한 것인 약학 조성물.The pharmaceutical composition according to claim 29, wherein the pharmaceutical composition is for the treatment or prevention of hypertension and hypercholesterolemia.
- 제29항에 있어서, 상기 약학 조성물은 암로디핀 또는 그의 염의 용출율이 세비카TM정의 암로디핀 또는 그의 염의 용출율과 동등한 수준을 나타내는 것인 약학 조성물.30. The pharmaceutical composition according to claim 29, wherein the pharmaceutical composition exhibits a dissolution rate of amlodipine or a salt thereof equal to the dissolution rate of amlodipine or a salt thereof defined by Sevica TM .
- 제29항에 있어서, 상기 약학 조성물은 로수바스타틴 또는 그의 염의 용출률이 로수젯TM정의 로수바스타틴의 용출률과 동등한 수준을 나타내는 것인 약학 조성물.The pharmaceutical composition according to claim 29, wherein the pharmaceutical composition exhibits a dissolution rate of rosuvastatin or a salt thereof equal to the dissolution rate of rosuvastatin defined by Rosuzet ™ .
- 제29항에 있어서, 상기 약학 조성물은 에제티미브 또는 그의 염의 용출률이 로수젯TM정의 에제티미브의 용출률과 동등한 수준을 나타내는 것인 약학 조성물.30. The pharmaceutical composition according to claim 29, wherein the pharmaceutical composition exhibits a dissolution rate of ezetimibe or a salt thereof equal to the dissolution rate of ezetimibe defined by Rosuzet ™ .
- 제29항에 있어서, 상기 약학 조성물 내 올메사탄 메독소밀 및 암로디핀 또는 그의 염은 동일한 활성성분 용량을 갖는 세비카TM정과 비교하여 생물학적 동등 수준의 혈중농도-시간곡선하면적(AUC)과 최고혈중농도(Cmax)를 나타내는 것을 특징으로 하는 약학 조성물.30. The method according to claim 29, wherein olmesartan medoxomil and amlodipine or a salt thereof in the pharmaceutical composition is bioequivalent compared to Sevica TM tablets having the same active ingredient dose - area under the time curve (AUC) and peak plasma concentration (C max ) A pharmaceutical composition, characterized in that it represents.
- 제29항에 있어서, 상기 약학 조성물 내 로수바스타틴 칼슘염은 동일한 활성성분 용량을 갖는 로수젯TM정과 비교하여 생물학적 동등 수준의 혈중농도-시간곡선하면적(AUC)과 최고혈중농도(Cmax)를 나타내는 것을 특징으로 하는 약학 조성물.30. The method according to claim 29, wherein the rosuvastatin calcium salt in the pharmaceutical composition has a bioequivalent level of blood concentration-area under the time curve (AUC) and peak blood concentration (C max ) compared to Rosuzet TM tablets having the same active ingredient dose. Pharmaceutical composition characterized in that it represents.
- 제29항에 있어서, 상기 약학 조성물은 암로디핀과 올메사탄 메독소밀의 복합제와 로수바스타틴과 에제티미브의 복합제를 동시에 투여하여야 하는 환자에 투여하기 위한 것인 약학 조성물.30. The pharmaceutical composition according to claim 29, wherein the pharmaceutical composition is for administration to a patient who must simultaneously administer a combination of amlodipine and olmesartan medoxomil and a combination of rosuvastatin and ezetimibe.
- 제29항에 있어서, 상기 약학 조성물은 단위 제제를 기준으로 로수바스타틴, 에제티미브, 올메사탄 메독소밀 및 암로디핀을 하기 용량으로 포함하는 것인 약학 조성물:30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises rosuvastatin, ezetimibe, olmesartan medoxomil and amlodipine in the following dosages on a unit basis:로수바스타틴 또는 그의 염 20 mg, 에제티미브 10 mg, 올메사탄 메독소밀 40 mg, 암로디핀 또는 그의 염 10 mg; rosuvastatin or a salt thereof 20 mg, ezetimibe 10 mg, olmesartan medoxomil 40 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 20 mg, 에제티미브 10 mg, 올메사탄 메독소밀 40 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 20 mg, ezetimibe 10 mg, olmesartan medoxomil 40 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 20 mg, 에제티미브 10 mg, 올메사탄 메독소밀 20 mg, 암로디핀 또는 그의 염 10 mg;rosuvastatin or a salt thereof 20 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 20 mg, 에제티미브 10 mg, 올메사탄 메독소밀 20 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 20 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 20 mg, 에제티미브 10 mg, 올메사탄 메독소밀 10 mg, 암로디핀 또는 그의 염 10 mg; rosuvastatin or a salt thereof 20 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 20 mg, 에제티미브 10 mg, 올메사탄 메독소밀 10 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 20 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 10 mg, 에제티미브 10 mg, 올메사탄 메독소밀 40 mg, 암로디핀 또는 그의 염 10 mg;rosuvastatin or a salt thereof 10 mg, ezetimibe 10 mg, olmesartan medoxomil 40 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 10 mg, 에제티미브 10 mg, 올메사탄 메독소밀 40 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 10 mg, ezetimibe 10 mg, olmesartan medoxomil 40 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 10 mg, 에제티미브 10 mg, 올메사탄 메독소밀 20 mg, 암로디핀 또는 그의 염 10 mg;rosuvastatin or a salt thereof 10 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 10 mg, 에제티미브 10 mg, 올메사탄 메독소밀 20 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 10 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 10 mg, 에제티미브 10 mg, 올메사탄 메독소밀 10 mg, 암로디핀 또는 그의 염 10 mg;rosuvastatin or a salt thereof 10 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 10 mg, 에제티미브 10 mg, 올메사탄 메독소밀 10 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 10 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 40 mg, 암로디핀 또는 그의 염 10 mg;rosuvastatin or a salt thereof 5 mg, ezetimibe 10 mg, olmesartan medoxomil 40 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 40 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 5 mg, ezetimibe 10 mg, olmesartan medoxomil 40 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 20 mg, 암로디핀 또는 그의 염 10 mg;. rosuvastatin or a salt thereof 5 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 20 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 5 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 10 mg, 암로디핀 또는 그의 염 10 mg;rosuvastatin or a salt thereof 5 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 10 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 5 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 2.5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 40 mg, 암로디핀 또는 그의 염 10 mg;rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 40 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 2.5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 40 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 40 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 2.5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 20 mg, 암로디핀 또는 그의 염 10 mg;rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 10 mg;로수바스타틴 또는 그의 염 2.5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 20 mg, 암로디핀 또는 그의 염 5 mg;rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 20 mg, amlodipine or a salt thereof 5 mg;로수바스타틴 또는 그의 염 2.5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 10 mg, 암로디핀 또는 그의 염 10 mg; 또는rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 10 mg; or로수바스타틴 또는 그의 염 2.5 mg, 에제티미브 10 mg, 올메사탄 메독소밀 10 mg, 암로디핀 또는 그의 염 5 mg. rosuvastatin or a salt thereof 2.5 mg, ezetimibe 10 mg, olmesartan medoxomil 10 mg, amlodipine or a salt thereof 5 mg.
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MX2023002403A MX2023002403A (en) | 2020-08-25 | 2021-08-25 | Pharmaceutical composition in single dosage form for treating or preventing hypertension and hypercholesterolemia. |
BR112023003323A BR112023003323A2 (en) | 2020-08-25 | 2021-08-25 | PHARMACEUTICAL COMPOSITION IN SINGLE DOSAGE FORM |
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Citations (6)
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WO2009024889A2 (en) * | 2007-08-21 | 2009-02-26 | Ranbaxy Laboratories Limited | Pharmaceutical composition comprising a hmg-coa reductase inhibitor and ezetimibe |
KR20090065510A (en) * | 2009-03-13 | 2009-06-22 | 다이이찌 산쿄 가부시키가이샤 | Solid dosage form of olmesartan medoxomil and amlodipine |
KR20150079373A (en) * | 2013-12-30 | 2015-07-08 | 한미약품 주식회사 | Composite formulation for oral administration comprising ezetimibe and rosuvastatin |
KR20160000762A (en) * | 2014-06-25 | 2016-01-05 | 한미약품 주식회사 | Composite formulation for oral administration comprising ezetimibe and rosuvastatin and a process for the preparation thereof |
KR20160105044A (en) * | 2015-02-27 | 2016-09-06 | 한미약품 주식회사 | Solid composite formulation for oral administration comprising ezetimibe and rosuvastatin |
KR20170007695A (en) * | 2015-07-08 | 2017-01-19 | 씨제이헬스케어 주식회사 | Pharmaceutical Composition Comprising Amlodipine, Valsartan and Rosuvastatin |
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TWI425026B (en) | 2011-09-19 | 2014-02-01 | Everlight Chem Ind Corp | Polyurethane derivatives, composition thereof and dye additives comprising the derivatives |
EP3524578A4 (en) | 2016-10-07 | 2020-10-07 | Yulinghua Technology Co. Ltd | Sewage treatment method and system |
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- 2021-08-25 TW TW110131530A patent/TW202224681A/en unknown
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009024889A2 (en) * | 2007-08-21 | 2009-02-26 | Ranbaxy Laboratories Limited | Pharmaceutical composition comprising a hmg-coa reductase inhibitor and ezetimibe |
KR20090065510A (en) * | 2009-03-13 | 2009-06-22 | 다이이찌 산쿄 가부시키가이샤 | Solid dosage form of olmesartan medoxomil and amlodipine |
KR20150079373A (en) * | 2013-12-30 | 2015-07-08 | 한미약품 주식회사 | Composite formulation for oral administration comprising ezetimibe and rosuvastatin |
KR20160000762A (en) * | 2014-06-25 | 2016-01-05 | 한미약품 주식회사 | Composite formulation for oral administration comprising ezetimibe and rosuvastatin and a process for the preparation thereof |
KR20160105044A (en) * | 2015-02-27 | 2016-09-06 | 한미약품 주식회사 | Solid composite formulation for oral administration comprising ezetimibe and rosuvastatin |
KR20170007695A (en) * | 2015-07-08 | 2017-01-19 | 씨제이헬스케어 주식회사 | Pharmaceutical Composition Comprising Amlodipine, Valsartan and Rosuvastatin |
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MX2023002403A (en) | 2023-03-22 |
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BR112023003323A2 (en) | 2023-03-21 |
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