WO2018093096A2 - Pharmaceutical complex preparation comprising amlodipine, losartan and rosuvastatin - Google Patents

Pharmaceutical complex preparation comprising amlodipine, losartan and rosuvastatin Download PDF

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WO2018093096A2
WO2018093096A2 PCT/KR2017/012703 KR2017012703W WO2018093096A2 WO 2018093096 A2 WO2018093096 A2 WO 2018093096A2 KR 2017012703 W KR2017012703 W KR 2017012703W WO 2018093096 A2 WO2018093096 A2 WO 2018093096A2
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Prior art keywords
pharmaceutically acceptable
losartan
complex preparation
acceptable salt
amlodipine
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PCT/KR2017/012703
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French (fr)
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WO2018093096A3 (en
Inventor
Hyuk Jun Cho
Sol Ee Lim
Ho Taek IM
Yong Il Kim
Jae Hyun Park
Jong Soo Woo
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Hanmi Pharm. Co., Ltd.
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Application filed by Hanmi Pharm. Co., Ltd. filed Critical Hanmi Pharm. Co., Ltd.
Priority to SG11201903132YA priority Critical patent/SG11201903132YA/en
Priority to MX2019005230A priority patent/MX2019005230A/en
Priority to EA201991190A priority patent/EA201991190A1/en
Priority to CR20190265A priority patent/CR20190265A/en
Publication of WO2018093096A2 publication Critical patent/WO2018093096A2/en
Publication of WO2018093096A3 publication Critical patent/WO2018093096A3/en
Priority to PH12019500779A priority patent/PH12019500779A1/en
Priority to ZA2019/02720A priority patent/ZA201902720B/en
Priority to CONC2019/0004796A priority patent/CO2019004796A2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)

Definitions

  • the present invention relates to a pharmaceutical complex preparation including amlodipine, losartan and rosuvastatin as active ingredients.
  • Hypertension refers to a condition in which a systolic blood pressure is greater than or equal to 140 mmHg or a diastolic blood pressure is greater than or equal to 90 mmHg in adults over the age of 18 years. Hypertension is a disease that has the highest incidence frequency among chronic circulatory diseases and shows relatively few symptoms, but requires more intensive cares and treatments because it may cause fetal complications such as strokes, heart failure, coronary artery diseases, and the like.
  • Amlodipine is the generic name of 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(-2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate, which is a kind of a dihydropyridine-based calcium channel blocker and is used to block calcium channels so as to treat cardiovascular diseases such as angina, hypertension, and congestive heart failure.
  • Losartan is the generic name of 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol, which is used to block binding of a vasoconstrictor substance such as angiotensin II to receptors so as to treat hypertension and heart failure, cure an ischemic peripheral circulatory disorders and myocardial ischemia (angina), prevent the progression of post-myocardial infarction heart failure, and treat diabetic neuropathy, glaucoma, and the like.
  • a vasoconstrictor substance such as angiotensin II
  • a complex preparation of amlodipine and losartan having different mechanisms of action has advantages in that the complex preparation has superior effects in preventing or treating hypertension and cardiovascular diseases when compared to conventional single preparations, reduces side effects of drugs when the drugs are used alone, and has high patients' compliance.
  • the complex preparations are disclosed in Korean Patent Nos. 1160151 and 1232296, and currently sold under the trade name of Amosartan ® .
  • hyperlipidemia refers to a condition in which, when an excessive amount of fatty substances is present in blood, the fatty substances are deposited on a blood vessel wall, thereby causing inflammation, thereby causing cardiovascular diseases.
  • hyperlipidemia results in an increased probability of causing severe complications such as hypertension, coronary arteriosclerosis (angina, myocardial infarction), cerebral arteriosclerosis (cerebral infarction), and the like.
  • Hypertension and hyperlipidemia frequently occur together, and thus an anti-hypertensive agent and an anti-hyperlipidemic agent are prescribed together with high frequency.
  • a combination therapy including a HMG-CoA reductase inhibitor and a dihydropyridine-based calcium channel blocker has been already proposed as a combination treatment for improving cardiovascular diseases and metabolic syndromes caused by the hypertension and hyperlipidemia.
  • Rosuvastatin is the generic name of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxy-hept-6-enoic acid, which acts as a HMG-CoA reductase inhibitor to interfere with synthesis of cholesterol and reduce levels of blood LDL-cholesterol and neutral fats. Rosuvastatin has an excellent effect in treating hypercholesterinemia, hyperlipoproteinemia, or arteriosclerosis.
  • Publicized Korean Patent No. 10-2015-0067777 dicloses a complex preparation which includes a first mixing portion including amlodipine and rosuvastatin and a second mixing portion including losartan, wherein the first and second mixing portions are present in a separated state.
  • the complex preparation may be realized as a bilayer tablet, and has an effect of improving a dissolution rate of drugs and stability of the active ingredients with respect to rays and heat due to a minimized interaction between the drugs.
  • the complex preparation has a drawback in that an unexpected increase in volume of a tablet is caused and a layer separation phenomenon occurs when the complex preparation is prepared into bilayer tablets. Therefore, a plan for improving stability of the complex preparation when stored for a long period of time while maintaining constant dissolution characteristics of the complex preparation is needed.
  • Patent Document 1 Registered Korean Patent No. 1160151 entitled “Solid Pharmaceutical Composition Comprising Amlodipine and Losartan”
  • Patent Document 2 Registered Korean Patent No. 1232296 entitled “Solid Pharmaceutical Composition Comprising Amlodipine and Losartan and Having an Improved Stability"
  • Patent Document 3 Publicized Korean Patent No 2015-0067777 entitled “Pharmaceutical Complex Formulation Comprising Amlodipine, Losartan and Rosuvastatin”
  • the present inventors have investigated a cause of instability of phenomenons such as the layer separation phenomenon, and conducted research on methods capable of improving preparation stability of a pharmaceutical complex preparation including amlodipine, losartan and rosuvastatin. Therefore, the present invention has been completed based on the facts.
  • a pharmaceutical complex preparation including amlodipine, losartan and rosuvastatin, which exhibits good dissolution characteristics and has improved preparation stability.
  • a pharmaceutical complex preparation which includes:
  • a first mixing portion including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof;
  • a second mixing portion including losartan or a pharmaceutically acceptable salt thereof
  • first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other, and outer surfaces of the first and second mixing portions are coated with a film coating layer, and
  • the film coating layer includes a coating base and a plasticizer.
  • the coating base includes polyvinyl alcohol.
  • the complex preparation may be a bilayer tablet including:
  • a first layer including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof;
  • a second layer including losartan or a pharmaceutically acceptable salt thereof including losartan or a pharmaceutically acceptable salt thereof.
  • the film coating layer may be included at a content of 2 to 4% by weight, based on the total weight of the complex preparation.
  • the polyvinyl alcohol may have a weight average molecular weight of 2,000 to 130,000 g/mol.
  • the polyvinyl alcohol may be included at a content of 20% by weight or more and less than 60% by weight, based on the total weight of the film coating layer.
  • the plasticizer may be polyethylene glycol, propylene glycol, diacetin, triacetin, triethyl citrate, talc, or a mixture thereof.
  • the plasticizer may be polyethylene glycol having a number average molecular weight of 2,000 to 6,000 g/mol.
  • the plasticizer may be included a content of 5 to 35% by weight, based on the total weight of the film coating layer.
  • a fixed-dose combination formulation which includes:
  • a first mixing portion including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof;
  • a second mixing portion including losartan or a pharmaceutically acceptable salt thereof
  • first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other, and outer surfaces of the first and second mixing portions are coated with a film coating layer, and
  • the film coating layer includes a coating base and a plasticizer.
  • the coating base includes polyvinyl alcohol.
  • amlodipine or pharmaceutically acceptable salt thereof may be included at an amount of 5 to 10 mg in the form of an amlodipine free acid.
  • the rosuvastatin or pharmaceutically acceptable salt thereof may be included at an amount of 3 to 20 mg in the form of a rosuvastatin free acid.
  • the losartan or pharmaceutically acceptable salt thereof may be included at an amount of 40 to 100 mg in the form of a losartan free acid.
  • the aforementioned pharmaceutical complex preparation of the present invention may be used to prevent or treat cardiovascular diseases.
  • the pharmaceutical complex preparation of the present invention including amlodipine, losartan and rosuvastatin as active ingredients exhibits excellent dissolution characteristics of all the active ingredients, and also has improved preparation stability. Therefore, the complex preparation of the present invention can be used as a prophylactic or therapeutic agent for cardiovascular diseases, which has ensured quality stability even when stored for a long period of time.
  • FIG. 1 show results of a hygroscopicity test on amlodipine camsylate used as a raw material of a preparation according to the present invention.
  • FIG. 2 show results of a hygroscopicity test on rosuvastatin calcium used as a raw material of the preparation according to the present invention.
  • FIG. 3 show results of a hygroscopicity test on losartan potassium used as a raw material of the preparation according to the present invention.
  • FIG. 4 is an image for comparing an initial appearance of a tablet of Preparative Example 1 with an appearance of the tablet after the elapse of 3 days under conditions for an accelerated exposure test described in Test Example 2.
  • FIG. 5 is an image for comparing an initial appearance of a tablet of Comparative Example 1 with appearances of tablets Comparative Example 1 and Example 2 after the elapse of 3 days under the conditions for an accelerated exposure test described in Test Example 2.
  • FIG. 6 is a graph illustrating results of amlodipine dissolution tests on tablets of Preparative Example 1, Examples 1 to 5, 8 and 9, and Comparative Examples 2 and 8.
  • FIG. 7 is a graph illustrating results of losartan dissolution tests on tablets of Preparative Example 1, Examples 1 to 5, 8 and 9, and Comparative Examples 2 and 8.
  • FIG. 8 is a graph illustrating results of rosuvastatin dissolution tests on tablets of Preparative Example 1, Examples 1 to 5, 8 and 9, and Comparative Examples 2 and 8.
  • FIG. 9 is a graph illustrating results of amlodipine dissolution tests on tablets of Preparative Example 2, Examples 6 and 7, and Comparative Example 5.
  • FIG. 10 is a graph illustrating results of losartan dissolution tests on tablets of Preparative Example 2, Examples 6 and 7, and Comparative Example 5.
  • FIG. 11 is a graph illustrating results of rosuvastatin dissolution tests on tablets of Preparative Example 2, Examples 6 and 7, and Comparative Example 5.
  • the present invention provides a pharmaceutical complex preparation, which includes:
  • a first mixing portion including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof;
  • a second mixing portion including losartan or a pharmaceutically acceptable salt thereof
  • first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other, and outer surfaces of the first and second mixing portions are coated with a film coating layer, and
  • the film coating layer includes a coating base and a plasticizer.
  • the coating base includes polyvinyl alcohol.
  • the complex preparation of the present invention may include a film coating layer, and thus may prevent moisture absorption of amlodipine, losartan, rosuvastatin as active ingredients. Accordingly, the complex preparation of the present invention may maintain excellent quality due to a minimal generation of related compounds and a minimal change in shapes thereof even when stored for a long period time. Also, the complex preparation of the present invention includes the film coating layer, and includes losartan, amlodipine and rosuvastatin in a state in which losartan is separated from amlodipine and rosuvastatin. Therefore, the complex preparation exhibits high stability and excellent dissolution characteristics as well because the complex preparation may prevent an interaction between the active ingredients.
  • the complex preparation of the present invention may be prepared in various forms in which first and second mixing portions may be physically separated like a core-shell structure.
  • the complex preparation may be a bilayer tablet which includes a first layer including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and a second layer including losartan or a pharmaceutically acceptable salt thereof.
  • the complex preparation of the present invention includes amlodipine or a pharmaceutically acceptable salt thereof in a first mixing portion (or a first layer) thereof.
  • the pharmaceutically acceptable salt of amlodipine is formed from acids which form a non-toxic acid addition salt containing pharmaceutically acceptable anions, and may, for example, include hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, besylate, or camsylate, but the present invention is not limited thereto. Among these, amlodipine besylate salt and amlodipine camsylate salt are preferred, and amlodipine camsylate salt is more preferred. Also, the amlodipine of the present invention includes an amlodipine racemate and (S)-amlodipine. For amlodipine, the daily dose of the amlodipine or pharmaceutically acceptable salt thereof is in the range of 5 to 10 mg.
  • the complex preparation of the present invention includes rosuvastatin or a pharmaceutically acceptable salt thereof in the first mixing portion (or first layer) thereof.
  • Examples of the pharmaceutically acceptable salt of rosuvastatin may include inorganic salts containing polyvalent cations, preferably a rosuvastatin calcium salt, but the present invention is not limited thereto.
  • the daily dose of the rosuvastatin or pharmaceutically acceptable salt thereof is in the range of 3 to 20 mg.
  • the complex preparation of the present invention includes losartan or a pharmaceutically acceptable salt thereof in a second mixing portion (or a second layer) thereof.
  • Examples of the pharmaceutically acceptable salt of losartan may include a losartan potassium salt, but the present invention is not limited thereto.
  • the daily dose of the losartan or pharmaceutically acceptable salt thereof is in a range of 40 to 100 mg.
  • the weight ratio of the amlodipine or pharmaceutically acceptable salt thereof, the rosuvastatin or pharmaceutically acceptable salt thereof and the losartan or pharmaceutically acceptable salt thereof included in the complex preparation according to the present invention may be in a weight ratio of 1:0.6 to 4:8 to 20 for amlodipine, rosuvastatin, and losartan, but the present invention is not limited thereto.
  • the amlodipine or pharmaceutically acceptable salt thereof included in the complex preparation according to the present invention may be in a range of 0.5 to 4.5% by weight, as converted in the form of an amlodipine free acid, but the present invention is not limited thereto.
  • the complex preparation according to the present invention includes film coating layer surrounding the first and second mixing portions which are present in a physically separated state.
  • the film coating layer includes polyvinyl alcohol (PVA) as a coating base.
  • PVA polyvinyl alcohol
  • the present inventors have conducted an experiment of comparing polyvinyl alcohol with a material such as hypromellose (HPMC) as the coating base, and found that PVA exhibits the most excellent characteristics in the complex preparation including amlodipine, losartan and rosuvastatin. That is, when PVA is used as the coating base, PVA has an excellent moisture-blocking effect while maintaining excellent dissolution characteristics of the active ingredients. Therefore, it is confirmed that PVA may prevent the complex preparation from absorbing moisture and prevent a change in shape such as layer separation, and the like.
  • HPMC hypromellose
  • PVA is a compound that forms a film, and thus may be used without limitation as long as PVA is generally used in the related art.
  • PVA having a weight average molecular weight of 2,000 to 130,000 g/mol is used.
  • a material having a degree of hydrolysis of 85 to 99, which is suitable for the criteria of the United States Pharmacopoeia (USP) is preferably used as the PVA.
  • the PVA is preferably included at a content of 20% by weight or more and less than 60% by weight, more preferably a content of 30 to 50% by weight, based on the total weight of the film coating layer.
  • the content of PVA is less than 20% by weight, the PVA may not exhibit a sufficient film coating effect.
  • the content of PVA is greater than 60% by weight, a coloring effect and fluidity of the film coating may be degraded.
  • the film coating layer may further include a plasticizer.
  • the plasticizer serves to enhance flexibility and adhesivity of the film coating, and thus is not particularly limited in the present invention as long as the plasticizer is generally used in the related art.
  • polyethylene glycol, propylene glycol, diacetin, triacetin, triethyl citrate, talc, or a mixture thereof may be used as the plasticizer.
  • polyethylene glycol (PEG) having a weight average molecular weight of 2,000 to 6,000 may be used.
  • the plasticizer is preferably included at a content of 5 to 35% by weight, more preferably a content of 10 to 30% by weight, based on the total weight of the film coating layer.
  • the content of the plasticizer is less than 5% by weight, fluidity of the film coating may be degraded.
  • the content of the plasticizer is greater than 35% by weight, a film coating effect expressed by the coating base may be reduced. Therefore, the content of the plasticizer is properly adjusted within this content range.
  • the film coating layer is preferably included at a content of 2 to 4% by weight, based on the total weight of the complex preparation.
  • the content of the film coating layer is less than 2% by weight, it is difficult to completely coat the outside of the preparation and ensure a moisture absorption-shielding effect due to a very small thickness of the coating layer.
  • the content of the film coating layer is greater than 4% by weight, dissolution of the active ingredients may be hindered due to a very high thickness of the coating layer, and in vivo absorption of the drug may be affected.
  • the complex preparation of the present invention may include a pharmaceutically acceptable additive, for example, a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable carrier or excipient may, for example include lactose (i.e., lactose hydrate), microcrystalline cellulose, mannitol, sodium citrate, calcium phosphate, glycine, or starch, a disintegrating agent (for example, crospovidone, copovidone, sodium starch glycolate, croscarmellose sodium, or a certain complex silicate), a binder (for example, polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, or acacia gum), a lubricant (for example, palmitic acid, talc, magnesium stearate, zinc stearate, or calcium stearate), and a coloring agent (for example, titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, or aluminum lake).
  • lactose i.e., lactose hydrate
  • the complex preparation of the present invention may further include a pH control agent, a suspending agent, a preservative, a flavoring agent, a sweetening agent, an absorbent, a solubilizing agent, and the like, when necessary.
  • the additive may be included in any of the first mixing portion (or first layer), the second mixing portion (or second layer) and the film coating layer of the complex preparation according to the present invention.
  • the content of the additive is not particularly limited in the present invention, and may be properly adjusted when necessary.
  • the present invention provides a fixed-dose combination formulation for preventing or treating cardiovascular diseases, which includes a first mixing portion including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and a second mixing portion including losartan or a pharmaceutically acceptable salt thereof, wherein the first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other.
  • the amlodipine or pharmaceutically acceptable salt thereof may be included at an amount of 5 mg to 10 mg, as converted in the form of an amlodipine free acid.
  • the rosuvastatin or pharmaceutically acceptable salt thereof may be included at an amount of 3 mg to 20 mg, as converted in the form of a rosuvastatin free acid.
  • the losartan or pharmaceutically acceptable salt thereof may be included at an amount of 40 mg to 100 mg, as converted in the form of a losartan free acid.
  • the first mixing portion (or first layer) and the second mixing portion (or second layer) may be simply mixed, and then pressed into tablets, or may be granulated by a conventional granulation method, for example, a compacting granulation method, and the resulting granules may be then pressed into tablets.
  • the first and second mixing portions may be in the form of granules subjected to a roller compaction process. As described above, when the compacted/granulated first and second mixing portions are pressed into bilayer tablets, the amlodipine, rosuvastatin and losartan have high dissolution rates, and the amlodipine and rosuvastatin exhibit excellent dissolution patterns.
  • the complex preparation of the present invention may be prepared by the method of preparing a pharmaceutical complex preparation, which includes a) mixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to prepare a first mixing portion (or a first layer); b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to prepare a second mixing portion (or a second layer); and c) coating surfaces of the first and second mixing portions with a film coating solution including a coating base.
  • the complex preparation of the present invention may also be prepared by the method of preparing a pharmaceutical complex preparation, which includes a) mixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive and subjecting the resulting mixture to compacting granulation to prepare a first mixing portion (or a first layer); b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive and subjecting the resulting mixture to compacting granulation to prepare a second mixing portion (or a second layer); and c) coating surfaces of the first and second mixing portions with a film coating solution including a coating base.
  • the aforementioned complex preparation of the present invention may be used to prevent or treat cardiovascular diseases such as angina, hypertension, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarction, congestive heart failure, and myocardial infarction.
  • cardiovascular diseases such as angina, hypertension, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarction, congestive heart failure, and myocardial infarction.
  • Bilayer tablets including amlodipine, losartan and rosuvastatin as active ingredients were prepared based on the compositions listed in the following Table 1.
  • Amlodipine camsylate, rosuvastatin calcium, and microcrystalline cellulose were dispersed and screened through a sieve (16 mesh), and lactose hydrate and crospovidone were added thereto. Thereafter, the resulting mixture was mixed for 15 minutes to prepare mixed granules for a first layer.
  • the mixed granules for a first layer were compressed at a hydraulic pressure of 4 MPa, a feeder speed of 5 rpm and a roller speed of 1 rpm using a roller compactor (TF-1-A60, Freund vector) to form flakes. Then, the flakes were screened through a sieve (mesh size: 1.0mm). Subsequently, magnesium stearate was screened through a 24 mesh sieve, and then added thereto. The resulting mixture was mixed for 5 minutes to obtain final mixed granules for a first layer.
  • TF-1-A60, Freund vector roller compactor
  • Losartan potassium, microcrystalline cellulose, and crospovidone were mixed for 20 minutes to obtain mixed granules for a second layer.
  • the mixed granules for a second layer were compressed at a hydraulic pressure of 6 MPa, a feeder speed of 5 rpm and a roller speed of 1 rpm using a roller compactor (TF-1-A60, Freund vector) to form flaks. Then, the flakes were screened through a sieve (mesh size: 0.8mm). Subsequently, magnesium stearate was screened through a 24 mesh sieve, and then added thereto. The resulting mixture was mixed for 5 minutes to obtain final mixed granules for a second layer.
  • a bilayer tablet (an uncoated tablet), which included a first layer including amlodipine and rosuvastatin and a second layer including losartan, was prepared using a tablet press (Autotab-200TR, Ichihashi Seiki Co., Ltd.).
  • Film-coated bilayer tablets of Examples 1 to 5 were prepared by coating the bilayer tablet of Preparative Example 1 with a film coating solution using the following methods.
  • polyvinyl alcohol having a weight average molecular weight (M w ) of 18,000 was used as a coating base
  • polyethylene glycol having a number average molecular weight (M n ) of 3,000 or 5,000 was used as a plasticizer.
  • Raw materials for a coating layer listed in the following Table 2 were slowly added to purified water, which has been stirred at 1,200 rpm using a homogenizer (RZR 2102 control, Heidolph), so that the raw materials dis not form lumps, and completely dissolved and dispersed while stirring for 30 minutes. Thereafter, the resulting mixture was screened through a 200 mesh sieve to prepare a coating solution (Concentration (w/w) of the coating solution: 5%).
  • film-coated tablets in which the mass of the film coating layer was 18.0 mg (3.17% by weight based on the total weight of the film-coated bilayer tablet) were prepared using the bilayer tablet of Preparative Example 1 under the following conditions (Equipment used: SFC-30F from Sejong Pharmatech Co., Ltd.).
  • Example 1 Example 2
  • Example 3 Example 4
  • Polyethylene glycol 3000 10.0 20.0 30.0 - - Polyethylene glycol 5000 - - - 10.0 30.0
  • Pigment (red iron oxide) 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0
  • Raw materials for a coating layer was prepared, as listed in the following Table 3, to prepare a coating solution, and the bilayer tablet of Preparative Example 2 was coated with the coating solution in the same manner as in Examples 1 to 5 to prepare film-coated tablets in which the mass of the film coating layer was 7.5 mg (3.17% by weight based on the total weight of the film-coated bilayer tablet).
  • Example 6 Polyvinyl alcohol 40.0 40.0 Titanium oxide 24.0 24.0 Polyethylene glycol 3000 20.0 - Polyethylene glycol 5000 - 20.0 Talc 15.0 15.0 Pigment (red iron oxide) 1.0 1.0 Total 100.0 100.0
  • the bilayer tablet of Preparative Example 1 was coated with a coating solution having the same compositions as in Example 2 in the same manner as in Examples 1 to 5 to prepare film-coated tablets of Examples 8 and 9 in which the masses of the film coating layers were 14 mg (2.48% by weight based on the total weight of the film-coated bilayer tablet) and 22 mg (3.85% by weight based on the total weight of the film-coated bilayer tablet), respectively.
  • Comparative Examples 1 to 3 Preparation of film-coated bilayer tablets including amlodipine , losartan and rosuvastatin as active ingredients
  • Film-coated tablets of Comparative Examples 1 to 3 were prepared using a coating solution in which hypromellose was used as the coating base instead of the polyvinyl alcohol or polyvinyl alcohol was used as the coating base without using a plasticizer.
  • hypromellose 2910 having different viscosities (i.e., a P645 viscosity of approximately 4.5 mPa*s and a P615 viscosity of approximately 15 mPa*s) was used as the hypromellose.
  • Raw materials for a coating layer were prepared as listed in the following Table 4, and the bilayer tablet of Preparative Example 1 was coated in the same manner as in Examples 1 to 5 to prepare film-coated tablets in which the mass of the film coating layer was 18.0 mg (3.17% by weight based on the total weight of the film-coated bilayer tablet).
  • Raw materials for a coating layer were prepared as listed in the following Table 5, and the bilayer tablet of Preparative Example 2 was coated in the same manner as in Examples 1 to 5 to prepare film-coated tablets in which the mass of the film coating layer was 7.5 mg (3.17% by weight based on the total weight of the film-coated bilayer tablet).
  • Hypromellose 2910 (P645) 40.0 - - Hypromellose 2910 (P615) - 40.0 - Polyvinyl alcohol - - 60.0 Titanium oxide 24.0 24.0 24.0 Polyethylene glycol 3000 20.0 20.0 - Talc 15.0 15.0 15.0 Pigment (red iron oxide) 1.0 1.0 1.0 Total 100.0 100.0 100.0
  • Comparative Examples 7 and 8 Preparation of film-coated bilayer tablets including amlodipine , losartan and rosuvastatin as active ingredients
  • the bilayer tablet of Preparative Example 1 was coated with a coating solution having the same compositions as in Example 2 in the same manner as in Examples 1 to 5 to prepare film-coated tablets of Comparative Examples 7 and 8 in which the masses of the film coating layers were 10 mg (1.78% by weight based on the total weight of the film-coated bilayer tablet) and 26 mg (4.51% by weight based on the total weight of the film-coated bilayer tablet), respectively.
  • amlodipine camsylate (FIG. 1) exhibited low hygroscopicity
  • Test Example 2 Accelerated exposure test
  • the film-coated bilayer tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 8 were stored under accelerated exposure conditions (Petri-dish, 40 °C, and 75% RH) for 3 days, and the shapes, thicknesses (mm), and moisture contents (LoD) of the film-coated bilayer tablets were determined. The results are listed in the following Tables 6 to 8.
  • Example 8 Example 9 Comparative Example 7 Comparative Example 8 Shape Good Good Poor Good Increase in thickness (%) 7.7 7.2 9.2 7.0 Increase in moisture content (%) 1.6 1.3 2.1 1.3
  • the second layer (lower layer) including losartan had a significant change in shape caused due to the moisture absorption, that is, had an uneven surface, and the tablet was deformed as the tablet was slightly bent due to an expansion of the second layer.
  • losartan potassium used as the raw material in Examples and Comparative Examples was a raw material suitable for the moisture criteria (0.5%) in the European Pharmacopoeia (EP) and the United States Pharmacopoeia (USP), it was judged that such moisture absorption occurred after preparation of the tablet.
  • the film-coated tablet of Comparative Example 1 in which hypromellose 2910 (P645) was used had higher changes in thickness and moisture content when exposed to the accelerated conditions, compared to the film-coated tablets of Examples 1 to 5. Also, the separation of the upper and lower layers and the tearing of the coatings were observed during the accelerated exposure conditions (FIG. 5), but the film-coated tablet of Comparative Example 2 in which hypromellose 2910 (P615) having a high viscosity was used exhibited no specific change in shape.
  • the film-coated tablet of Comparative Example 3 in which polyvinyl alcohol was used as the coating base without using the plasticizer had patterns similar to those of Comparative Example 1, that is, had a considerable change in thickness, an uneven shape, and the like.
  • the film-coated tablets of Examples 8 and 9 and Comparative Examples 7 and 8 were the film-coated tablets in which polyethylene glycol was used as the coating base and polyethylene glycol was used as the plasticizer, but the coating base and the plasticizer of the film coating layer were used at different contents.
  • polyvinyl alcohol was used as the coating base to secure stability of the preparation without interfering with the dissolution characteristics of the drug.
  • PVA was preferably used together with a plasticizer such as polyethylene glycol, and the content of the film coating layer was preferably in a range of 2 to 4% by weight, based on the total weight of the complex preparation.

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Abstract

The present invention relates to a pharmaceutical complex preparation including amlodipine, losartan and rosuvastatin as active ingredients. The pharmaceutical complex preparation of the present invention including amlodipine, losartan and rosuvastatin as the active ingredients exhibits excellent dissolution characteristics of all the active ingredients, and also has improved preparation stability. Therefore, the complex preparation of the present invention can be used as a prophylactic or therapeutic agent for cardiovascular diseases, which has ensured quality stability even when stored for a long period of time.

Description

PHARMACEUTICAL COMPLEX PREPARATION COMPRISING AMLODIPINE, LOSARTAN AND ROSUVASTATIN
This application claims priority to and the benefit of Korean Patent Application No. 10-2016-0152077, filed on November 15, 2016, the disclosure of which is incorporated herein by reference in its entirety.
The present invention relates to a pharmaceutical complex preparation including amlodipine, losartan and rosuvastatin as active ingredients.
Hypertension refers to a condition in which a systolic blood pressure is greater than or equal to 140 mmHg or a diastolic blood pressure is greater than or equal to 90 mmHg in adults over the age of 18 years. Hypertension is a disease that has the highest incidence frequency among chronic circulatory diseases and shows relatively few symptoms, but requires more intensive cares and treatments because it may cause fetal complications such as strokes, heart failure, coronary artery diseases, and the like.
Amlodipine is the generic name of 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(-2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate, which is a kind of a dihydropyridine-based calcium channel blocker and is used to block calcium channels so as to treat cardiovascular diseases such as angina, hypertension, and congestive heart failure.
Losartan is the generic name of 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol, which is used to block binding of a vasoconstrictor substance such as angiotensin II to receptors so as to treat hypertension and heart failure, cure an ischemic peripheral circulatory disorders and myocardial ischemia (angina), prevent the progression of post-myocardial infarction heart failure, and treat diabetic neuropathy, glaucoma, and the like.
A complex preparation of amlodipine and losartan having different mechanisms of action has advantages in that the complex preparation has superior effects in preventing or treating hypertension and cardiovascular diseases when compared to conventional single preparations, reduces side effects of drugs when the drugs are used alone, and has high patients' compliance. The complex preparations are disclosed in Korean Patent Nos. 1160151 and 1232296, and currently sold under the trade name of Amosartan®.
Meanwhile, hyperlipidemia refers to a condition in which, when an excessive amount of fatty substances is present in blood, the fatty substances are deposited on a blood vessel wall, thereby causing inflammation, thereby causing cardiovascular diseases. When such hyperlipidemia is left untreated, hyperlipidemia results in an increased probability of causing severe complications such as hypertension, coronary arteriosclerosis (angina, myocardial infarction), cerebral arteriosclerosis (cerebral infarction), and the like.
Hypertension and hyperlipidemia frequently occur together, and thus an anti-hypertensive agent and an anti-hyperlipidemic agent are prescribed together with high frequency. In this way, a combination therapy including a HMG-CoA reductase inhibitor and a dihydropyridine-based calcium channel blocker has been already proposed as a combination treatment for improving cardiovascular diseases and metabolic syndromes caused by the hypertension and hyperlipidemia.
Rosuvastatin is the generic name of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxy-hept-6-enoic acid, which acts as a HMG-CoA reductase inhibitor to interfere with synthesis of cholesterol and reduce levels of blood LDL-cholesterol and neutral fats. Rosuvastatin has an excellent effect in treating hypercholesterinemia, hyperlipoproteinemia, or arteriosclerosis.
Accordingly, research on a complex preparation of amlodipine, losartan and rosuvastatin as a therapeutic agent for cardiovascular diseases has been conducted. By way of example, Publicized Korean Patent No. 10-2015-0067777 dicloses a complex preparation which includes a first mixing portion including amlodipine and rosuvastatin and a second mixing portion including losartan, wherein the first and second mixing portions are present in a separated state. The complex preparation may be realized as a bilayer tablet, and has an effect of improving a dissolution rate of drugs and stability of the active ingredients with respect to rays and heat due to a minimized interaction between the drugs.
However, the complex preparation has a drawback in that an unexpected increase in volume of a tablet is caused and a layer separation phenomenon occurs when the complex preparation is prepared into bilayer tablets. Therefore, a plan for improving stability of the complex preparation when stored for a long period of time while maintaining constant dissolution characteristics of the complex preparation is needed.
[Prior-art Documents]
[Patent Documents]
Patent Document 1: Registered Korean Patent No. 1160151 entitled "Solid Pharmaceutical Composition Comprising Amlodipine and Losartan"
Patent Document 2: Registered Korean Patent No. 1232296 entitled "Solid Pharmaceutical Composition Comprising Amlodipine and Losartan and Having an Improved Stability"
Patent Document 3: Publicized Korean Patent No 2015-0067777 entitled "Pharmaceutical Complex Formulation Comprising Amlodipine, Losartan and Rosuvastatin"
The present inventors have investigated a cause of instability of phenomenons such as the layer separation phenomenon, and conducted research on methods capable of improving preparation stability of a pharmaceutical complex preparation including amlodipine, losartan and rosuvastatin. Therefore, the present invention has been completed based on the facts.
Accordingly, it is an aspect of the present invention to provide a pharmaceutical complex preparation including amlodipine, losartan and rosuvastatin, which exhibits good dissolution characteristics and has improved preparation stability.
To solve the above problems, according to an aspect of the present invention, there is provided a pharmaceutical complex preparation which includes:
a first mixing portion including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and
a second mixing portion including losartan or a pharmaceutically acceptable salt thereof,
wherein the first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other, and outer surfaces of the first and second mixing portions are coated with a film coating layer, and
the film coating layer includes a coating base and a plasticizer. In this case, the coating base includes polyvinyl alcohol.
In this case, the complex preparation may be a bilayer tablet including:
a first layer including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and
a second layer including losartan or a pharmaceutically acceptable salt thereof.
In this case, the film coating layer may be included at a content of 2 to 4% by weight, based on the total weight of the complex preparation.
In this case, the polyvinyl alcohol may have a weight average molecular weight of 2,000 to 130,000 g/mol.
In this case, the polyvinyl alcohol may be included at a content of 20% by weight or more and less than 60% by weight, based on the total weight of the film coating layer.
In this case, the plasticizer may be polyethylene glycol, propylene glycol, diacetin, triacetin, triethyl citrate, talc, or a mixture thereof.
In this case, the plasticizer may be polyethylene glycol having a number average molecular weight of 2,000 to 6,000 g/mol.
In this case, the plasticizer may be included a content of 5 to 35% by weight, based on the total weight of the film coating layer.
According to another aspect of the present invention, there is provided a fixed-dose combination formulation which includes:
a first mixing portion including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and
a second mixing portion including losartan or a pharmaceutically acceptable salt thereof,
wherein the first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other, and outer surfaces of the first and second mixing portions are coated with a film coating layer, and
the film coating layer includes a coating base and a plasticizer. In this case, the coating base includes polyvinyl alcohol.
In this case, the amlodipine or pharmaceutically acceptable salt thereof may be included at an amount of 5 to 10 mg in the form of an amlodipine free acid.
In this case, the rosuvastatin or pharmaceutically acceptable salt thereof may be included at an amount of 3 to 20 mg in the form of a rosuvastatin free acid.
In this case, the losartan or pharmaceutically acceptable salt thereof may be included at an amount of 40 to 100 mg in the form of a losartan free acid.
The aforementioned pharmaceutical complex preparation of the present invention may be used to prevent or treat cardiovascular diseases.
The pharmaceutical complex preparation of the present invention including amlodipine, losartan and rosuvastatin as active ingredients exhibits excellent dissolution characteristics of all the active ingredients, and also has improved preparation stability. Therefore, the complex preparation of the present invention can be used as a prophylactic or therapeutic agent for cardiovascular diseases, which has ensured quality stability even when stored for a long period of time.
FIG. 1 show results of a hygroscopicity test on amlodipine camsylate used as a raw material of a preparation according to the present invention.
FIG. 2 show results of a hygroscopicity test on rosuvastatin calcium used as a raw material of the preparation according to the present invention.
FIG. 3 show results of a hygroscopicity test on losartan potassium used as a raw material of the preparation according to the present invention.
FIG. 4 is an image for comparing an initial appearance of a tablet of Preparative Example 1 with an appearance of the tablet after the elapse of 3 days under conditions for an accelerated exposure test described in Test Example 2.
FIG. 5 is an image for comparing an initial appearance of a tablet of Comparative Example 1 with appearances of tablets Comparative Example 1 and Example 2 after the elapse of 3 days under the conditions for an accelerated exposure test described in Test Example 2.
FIG. 6 is a graph illustrating results of amlodipine dissolution tests on tablets of Preparative Example 1, Examples 1 to 5, 8 and 9, and Comparative Examples 2 and 8.
FIG. 7 is a graph illustrating results of losartan dissolution tests on tablets of Preparative Example 1, Examples 1 to 5, 8 and 9, and Comparative Examples 2 and 8.
FIG. 8 is a graph illustrating results of rosuvastatin dissolution tests on tablets of Preparative Example 1, Examples 1 to 5, 8 and 9, and Comparative Examples 2 and 8.
FIG. 9 is a graph illustrating results of amlodipine dissolution tests on tablets of Preparative Example 2, Examples 6 and 7, and Comparative Example 5.
FIG. 10 is a graph illustrating results of losartan dissolution tests on tablets of Preparative Example 2, Examples 6 and 7, and Comparative Example 5.
FIG. 11 is a graph illustrating results of rosuvastatin dissolution tests on tablets of Preparative Example 2, Examples 6 and 7, and Comparative Example 5.
Hereinafter, the present invention will be described in detail so that a person having ordinary skill in the art to which the present invention belongs can easily put the present invention into practice. However, the present invention can be implemented in various different forms, and is not limited to the embodiments disclosed below.
The present invention provides a pharmaceutical complex preparation, which includes:
a first mixing portion including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and
a second mixing portion including losartan or a pharmaceutically acceptable salt thereof,
wherein the first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other, and outer surfaces of the first and second mixing portions are coated with a film coating layer, and
the film coating layer includes a coating base and a plasticizer. In this case, the coating base includes polyvinyl alcohol.
The complex preparation of the present invention may include a film coating layer, and thus may prevent moisture absorption of amlodipine, losartan, rosuvastatin as active ingredients. Accordingly, the complex preparation of the present invention may maintain excellent quality due to a minimal generation of related compounds and a minimal change in shapes thereof even when stored for a long period time. Also, the complex preparation of the present invention includes the film coating layer, and includes losartan, amlodipine and rosuvastatin in a state in which losartan is separated from amlodipine and rosuvastatin. Therefore, the complex preparation exhibits high stability and excellent dissolution characteristics as well because the complex preparation may prevent an interaction between the active ingredients.
The complex preparation of the present invention may be prepared in various forms in which first and second mixing portions may be physically separated like a core-shell structure. According to one preferred embodiment of the present invention, the complex preparation may be a bilayer tablet which includes a first layer including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and a second layer including losartan or a pharmaceutically acceptable salt thereof.
The complex preparation of the present invention includes amlodipine or a pharmaceutically acceptable salt thereof in a first mixing portion (or a first layer) thereof.
The pharmaceutically acceptable salt of amlodipine is formed from acids which form a non-toxic acid addition salt containing pharmaceutically acceptable anions, and may, for example, include hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, besylate, or camsylate, but the present invention is not limited thereto. Among these, amlodipine besylate salt and amlodipine camsylate salt are preferred, and amlodipine camsylate salt is more preferred. Also, the amlodipine of the present invention includes an amlodipine racemate and (S)-amlodipine. For amlodipine, the daily dose of the amlodipine or pharmaceutically acceptable salt thereof is in the range of 5 to 10 mg.
The complex preparation of the present invention includes rosuvastatin or a pharmaceutically acceptable salt thereof in the first mixing portion (or first layer) thereof.
Examples of the pharmaceutically acceptable salt of rosuvastatin may include inorganic salts containing polyvalent cations, preferably a rosuvastatin calcium salt, but the present invention is not limited thereto. For rosuvastatin, the daily dose of the rosuvastatin or pharmaceutically acceptable salt thereof is in the range of 3 to 20 mg.
The complex preparation of the present invention includes losartan or a pharmaceutically acceptable salt thereof in a second mixing portion (or a second layer) thereof.
Examples of the pharmaceutically acceptable salt of losartan may include a losartan potassium salt, but the present invention is not limited thereto. For losartan, the daily dose of the losartan or pharmaceutically acceptable salt thereof is in a range of 40 to 100 mg.
The weight ratio of the amlodipine or pharmaceutically acceptable salt thereof, the rosuvastatin or pharmaceutically acceptable salt thereof and the losartan or pharmaceutically acceptable salt thereof included in the complex preparation according to the present invention may be in a weight ratio of 1:0.6 to 4:8 to 20 for amlodipine, rosuvastatin, and losartan, but the present invention is not limited thereto. Also, the amlodipine or pharmaceutically acceptable salt thereof included in the complex preparation according to the present invention may be in a range of 0.5 to 4.5% by weight, as converted in the form of an amlodipine free acid, but the present invention is not limited thereto.
To secure the stability, the complex preparation according to the present invention includes film coating layer surrounding the first and second mixing portions which are present in a physically separated state.
In this case, the film coating layer includes polyvinyl alcohol (PVA) as a coating base.
The present inventors have conducted an experiment of comparing polyvinyl alcohol with a material such as hypromellose (HPMC) as the coating base, and found that PVA exhibits the most excellent characteristics in the complex preparation including amlodipine, losartan and rosuvastatin. That is, when PVA is used as the coating base, PVA has an excellent moisture-blocking effect while maintaining excellent dissolution characteristics of the active ingredients. Therefore, it is confirmed that PVA may prevent the complex preparation from absorbing moisture and prevent a change in shape such as layer separation, and the like.
In the present invention, PVA is a compound that forms a film, and thus may be used without limitation as long as PVA is generally used in the related art. Preferably, PVA having a weight average molecular weight of 2,000 to 130,000 g/mol is used. Also, a material having a degree of hydrolysis of 85 to 99, which is suitable for the criteria of the United States Pharmacopoeia (USP), is preferably used as the PVA.
The PVA is preferably included at a content of 20% by weight or more and less than 60% by weight, more preferably a content of 30 to 50% by weight, based on the total weight of the film coating layer. When the content of PVA is less than 20% by weight, the PVA may not exhibit a sufficient film coating effect. On the other hand, when the content of PVA is greater than 60% by weight, a coloring effect and fluidity of the film coating may be degraded.
In the present invention, the film coating layer may further include a plasticizer.
The plasticizer serves to enhance flexibility and adhesivity of the film coating, and thus is not particularly limited in the present invention as long as the plasticizer is generally used in the related art. For example, polyethylene glycol, propylene glycol, diacetin, triacetin, triethyl citrate, talc, or a mixture thereof may be used as the plasticizer. Preferably, polyethylene glycol (PEG) having a weight average molecular weight of 2,000 to 6,000 may be used.
In this case, the plasticizer is preferably included at a content of 5 to 35% by weight, more preferably a content of 10 to 30% by weight, based on the total weight of the film coating layer. When the content of the plasticizer is less than 5% by weight, fluidity of the film coating may be degraded. On the other hand, when the content of the plasticizer is greater than 35% by weight, a film coating effect expressed by the coating base may be reduced. Therefore, the content of the plasticizer is properly adjusted within this content range.
In the present invention, the film coating layer is preferably included at a content of 2 to 4% by weight, based on the total weight of the complex preparation. When the content of the film coating layer is less than 2% by weight, it is difficult to completely coat the outside of the preparation and ensure a moisture absorption-shielding effect due to a very small thickness of the coating layer. On the other hand, when the content of the film coating layer is greater than 4% by weight, dissolution of the active ingredients may be hindered due to a very high thickness of the coating layer, and in vivo absorption of the drug may be affected.
Meanwhile, the complex preparation of the present invention may include a pharmaceutically acceptable additive, for example, a pharmaceutically acceptable carrier or excipient.
The pharmaceutically acceptable carrier or excipient may, for example include lactose (i.e., lactose hydrate), microcrystalline cellulose, mannitol, sodium citrate, calcium phosphate, glycine, or starch, a disintegrating agent (for example, crospovidone, copovidone, sodium starch glycolate, croscarmellose sodium, or a certain complex silicate), a binder (for example, polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, or acacia gum), a lubricant (for example, palmitic acid, talc, magnesium stearate, zinc stearate, or calcium stearate), and a coloring agent (for example, titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, or aluminum lake).
In addition, the complex preparation of the present invention may further include a pH control agent, a suspending agent, a preservative, a flavoring agent, a sweetening agent, an absorbent, a solubilizing agent, and the like, when necessary.
The additive may be included in any of the first mixing portion (or first layer), the second mixing portion (or second layer) and the film coating layer of the complex preparation according to the present invention. In this case, the content of the additive is not particularly limited in the present invention, and may be properly adjusted when necessary.
Meanwhile, the present invention provides a fixed-dose combination formulation for preventing or treating cardiovascular diseases, which includes a first mixing portion including amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and a second mixing portion including losartan or a pharmaceutically acceptable salt thereof, wherein the first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other.
In the fixed-dose combination formulation, the amlodipine or pharmaceutically acceptable salt thereof may be included at an amount of 5 mg to 10 mg, as converted in the form of an amlodipine free acid.
In the fixed-dose combination formulation, the rosuvastatin or pharmaceutically acceptable salt thereof may be included at an amount of 3 mg to 20 mg, as converted in the form of a rosuvastatin free acid.
Also, in the fixed-dose combination formulation, the losartan or pharmaceutically acceptable salt thereof may be included at an amount of 40 mg to 100 mg, as converted in the form of a losartan free acid.
In the complex preparation of the present invention, the first mixing portion (or first layer) and the second mixing portion (or second layer) may be simply mixed, and then pressed into tablets, or may be granulated by a conventional granulation method, for example, a compacting granulation method, and the resulting granules may be then pressed into tablets. In another exemplary embodiment, the first and second mixing portions may be in the form of granules subjected to a roller compaction process. As described above, when the compacted/granulated first and second mixing portions are pressed into bilayer tablets, the amlodipine, rosuvastatin and losartan have high dissolution rates, and the amlodipine and rosuvastatin exhibit excellent dissolution patterns.
When the complex preparation is prepared by simply mixing amlodipine, rosuvastatin and losartan, gelation of losartan may be problematic. Losartan shows a very good dissolution pattern when losartan is dissolved in purified water at a relatively high pH value such as pH 4.0, pH 6.8, and the like. However, losartan is very slowly dissolved because losartan is gelled at a low pH value (for example, pH 1.2, pH 2.0, etc.). Such a phenomenon may have a huge effect on the dissolution rate of the preparation in consideration that an organ in which oral formulations first disintegrate and dissolve when taking the oral preparation is in stomach having a low pH value. In addition, the gelation of losartan may have an influence on in vivo absorption of the drug. Further, as losartan is gelled as described above, amlodipine and rosuvastatin mixed with losartan may also be buried inside the gel, resulting in a decreased dissolution rate.
On the other hand, in the complex preparation of the present invention, a phenomenon in which dissolution of amlodipine and rosuvastatin is delayed due to the gelation of losartan may be prevented even under the low pH condition when the first mixing portion including amlodipine and rosuvastatin and the second mixing portion including losartan are present in a separated state. Therefore, excellent dissolution rates and stability of amlodipine, rosuvastatin and losartan may be achieved.
The complex preparation of the present invention may be prepared by the method of preparing a pharmaceutical complex preparation, which includes a) mixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to prepare a first mixing portion (or a first layer); b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to prepare a second mixing portion (or a second layer); and c) coating surfaces of the first and second mixing portions with a film coating solution including a coating base.
According to one exemplary embodiment of the present invention, the complex preparation of the present invention may also be prepared by the method of preparing a pharmaceutical complex preparation, which includes a) mixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive and subjecting the resulting mixture to compacting granulation to prepare a first mixing portion (or a first layer); b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive and subjecting the resulting mixture to compacting granulation to prepare a second mixing portion (or a second layer); and c) coating surfaces of the first and second mixing portions with a film coating solution including a coating base.
The aforementioned complex preparation of the present invention may be used to prevent or treat cardiovascular diseases such as angina, hypertension, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarction, congestive heart failure, and myocardial infarction.
Hereinafter, preferred exemplary embodiments of the present invention will be described in order to aid in understanding the present invention. However, it will be apparent to those skilled in the art that the following examples are given herein for the purpose of illustrations only, and various changes and modifications can be made to the embodiments of the present invention without departing from the scope of the present invention. Thus, it should be understood that the present invention covers all such changes and modifications provided they are within the scope of the appended claims and their equivalents.
[EXAMPLES]
Preparative Examples 1 and 2: Preparation of bilayer tablets (uncoated tablets) including amlodipine , losartan and rosuvastatin as active ingredients
Bilayer tablets including amlodipine, losartan and rosuvastatin as active ingredients were prepared based on the compositions listed in the following Table 1.
Amlodipine camsylate, rosuvastatin calcium, and microcrystalline cellulose were dispersed and screened through a sieve (16 mesh), and lactose hydrate and crospovidone were added thereto. Thereafter, the resulting mixture was mixed for 15 minutes to prepare mixed granules for a first layer.
The mixed granules for a first layer were compressed at a hydraulic pressure of 4 MPa, a feeder speed of 5 rpm and a roller speed of 1 rpm using a roller compactor (TF-1-A60, Freund vector) to form flakes. Then, the flakes were screened through a sieve (mesh size: 1.0mm). Subsequently, magnesium stearate was screened through a 24 mesh sieve, and then added thereto. The resulting mixture was mixed for 5 minutes to obtain final mixed granules for a first layer.
Losartan potassium, microcrystalline cellulose, and crospovidone were mixed for 20 minutes to obtain mixed granules for a second layer. The mixed granules for a second layer were compressed at a hydraulic pressure of 6 MPa, a feeder speed of 5 rpm and a roller speed of 1 rpm using a roller compactor (TF-1-A60, Freund vector) to form flaks. Then, the flakes were screened through a sieve (mesh size: 0.8mm). Subsequently, magnesium stearate was screened through a 24 mesh sieve, and then added thereto. The resulting mixture was mixed for 5 minutes to obtain final mixed granules for a second layer.
Then, a bilayer tablet (an uncoated tablet), which included a first layer including amlodipine and rosuvastatin and a second layer including losartan, was prepared using a tablet press (Autotab-200TR, Ichihashi Seiki Co., Ltd.).
Component (mg) Preparative Example 1 Preparative Example 2
First layer Amlodipine camsylate 7.84(5 mg for amlodipine) 7.84(5 mg for amlodipine)
Rosuvastatin calcium 20.8(20 mg for rosuvastatin) 5.2(5 mg for rosuvastatin)
Lactose hydrate 55.0 22.5
Microcrystalline cellulose 114.36 45.16
Crospovidone 10.0 4.5
Magnesium stearate 2.0 0.8
Total mass of upper layer 210.0 86.0
Second layer Losartan potassium 100.0(91.6 mg for losartan) 50(45.8 mg for losartan)
Microcrystalline cellulose 226.0 85.0
Crospovidone 12.0 6.0
Magnesium stearate 2.0 1.0
Total mass of lower layer 340.0 142.0
Total mass of uncoated tablet 550.0 228.0
Examples 1 to 5: Preparation of film-coated bilayer tablets including amlodipine, losartan and rosuvastatin as active ingredients
Film-coated bilayer tablets of Examples 1 to 5 were prepared by coating the bilayer tablet of Preparative Example 1 with a film coating solution using the following methods. In this case, polyvinyl alcohol having a weight average molecular weight (Mw) of 18,000 was used as a coating base, and polyethylene glycol having a number average molecular weight (Mn) of 3,000 or 5,000 was used as a plasticizer.
Raw materials for a coating layer listed in the following Table 2 were slowly added to purified water, which has been stirred at 1,200 rpm using a homogenizer (RZR 2102 control, Heidolph), so that the raw materials dis not form lumps, and completely dissolved and dispersed while stirring for 30 minutes. Thereafter, the resulting mixture was screened through a 200 mesh sieve to prepare a coating solution (Concentration (w/w) of the coating solution: 5%).
Next, film-coated tablets in which the mass of the film coating layer was 18.0 mg (3.17% by weight based on the total weight of the film-coated bilayer tablet) were prepared using the bilayer tablet of Preparative Example 1 under the following conditions (Equipment used: SFC-30F from Sejong Pharmatech Co., Ltd.).
- Supply temperature: 60 ℃
- Supply fan: 1,200 rpm
- Exhaust temperature: 55 ℃
- Exhaust fan: 1,800 rpm
- Spray rpm: 3 mL/min at the start, 4.5 mL/min after 30 minutes, and 6 mL/min after 60 minutes
- Fan rpm: 5 rpm at the start, and 7 rpm after 30 minutes
- Atomizing air: 100 L/min
Component ratio (%) Example 1 Example 2 Example 3 Example 4 Example 5
Polyvinyl alcohol 50.0 40.0 30.0 50.0 30.0
Titanium oxide 24.0 24.0 24.0 24.0 24.0
Polyethylene glycol 3000 10.0 20.0 30.0 - -
Polyethylene glycol 5000 - - - 10.0 30.0
Talc 15.0 15.0 15.0 15.0 15.0
Pigment (red iron oxide) 1.0 1.0 1.0 1.0 1.0
Total 100.0 100.0 100.0 100.0 100.0
Examples 6 and 7: Preparation of film-coated bilayer tablets including amlodipine, losartan and rosuvastatin as active ingredients
Raw materials for a coating layer was prepared, as listed in the following Table 3, to prepare a coating solution, and the bilayer tablet of Preparative Example 2 was coated with the coating solution in the same manner as in Examples 1 to 5 to prepare film-coated tablets in which the mass of the film coating layer was 7.5 mg (3.17% by weight based on the total weight of the film-coated bilayer tablet).
Component ratio (%) Example 6 Example 7
Polyvinyl alcohol 40.0 40.0
Titanium oxide 24.0 24.0
Polyethylene glycol 3000 20.0 -
Polyethylene glycol 5000 - 20.0
Talc 15.0 15.0
Pigment (red iron oxide) 1.0 1.0
Total 100.0 100.0
Examples 8 and 9: Preparation of film-coated bilayer tablets including amlodipine, losartan and rosuvastatin as active ingredients
The bilayer tablet of Preparative Example 1 was coated with a coating solution having the same compositions as in Example 2 in the same manner as in Examples 1 to 5 to prepare film-coated tablets of Examples 8 and 9 in which the masses of the film coating layers were 14 mg (2.48% by weight based on the total weight of the film-coated bilayer tablet) and 22 mg (3.85% by weight based on the total weight of the film-coated bilayer tablet), respectively.
Comparative Examples 1 to 3: Preparation of film-coated bilayer tablets including amlodipine , losartan and rosuvastatin as active ingredients
Film-coated tablets of Comparative Examples 1 to 3 were prepared using a coating solution in which hypromellose was used as the coating base instead of the polyvinyl alcohol or polyvinyl alcohol was used as the coating base without using a plasticizer. In this case, hypromellose 2910 having different viscosities (i.e., a P645 viscosity of approximately 4.5 mPa*s and a P615 viscosity of approximately 15 mPa*s) was used as the hypromellose.
Raw materials for a coating layer were prepared as listed in the following Table 4, and the bilayer tablet of Preparative Example 1 was coated in the same manner as in Examples 1 to 5 to prepare film-coated tablets in which the mass of the film coating layer was 18.0 mg (3.17% by weight based on the total weight of the film-coated bilayer tablet).
Component ratio (%) Comparative Example 1 Comparative Example 2 Comparative Example 3
Hypromellose 2910 (P645) 40.0 - -
Hypromellose 2910 (P615) - 40.0 -
Polyvinyl alcohol - - 60.0
Titanium oxide 24.0 24.0 24.0
Polyethylene glycol 3000 20.0 20.0 -
Talc 15.0 15.0 15.0
Pigment (red iron oxide) 1.0 1.0 1.0
Total 100.0 100.0 100.0
Comparative Examples 4 to 6: Preparation of film-coated bilayer tablets including amlodipine , losartan and rosuvastatin as active ingredients
Raw materials for a coating layer were prepared as listed in the following Table 5, and the bilayer tablet of Preparative Example 2 was coated in the same manner as in Examples 1 to 5 to prepare film-coated tablets in which the mass of the film coating layer was 7.5 mg (3.17% by weight based on the total weight of the film-coated bilayer tablet).
Component ratio (%) Comparative Example 4 Comparative Example 5 Comparative Example 6
Hypromellose 2910 (P645) 40.0 - -
Hypromellose 2910 (P615) - 40.0 -
Polyvinyl alcohol - - 60.0
Titanium oxide 24.0 24.0 24.0
Polyethylene glycol 3000 20.0 20.0 -
Talc 15.0 15.0 15.0
Pigment (red iron oxide) 1.0 1.0 1.0
Total 100.0 100.0 100.0
Comparative Examples 7 and 8: Preparation of film-coated bilayer tablets including amlodipine , losartan and rosuvastatin as active ingredients
The bilayer tablet of Preparative Example 1 was coated with a coating solution having the same compositions as in Example 2 in the same manner as in Examples 1 to 5 to prepare film-coated tablets of Comparative Examples 7 and 8 in which the masses of the film coating layers were 10 mg (1.78% by weight based on the total weight of the film-coated bilayer tablet) and 26 mg (4.51% by weight based on the total weight of the film-coated bilayer tablet), respectively.
Test Example 1: Hygroscopicity test on main components
The hygroscopicities of amlodipine camsylate, rosuvastatin calcium, and losartan potassium used as the raw materials in Examples and Comparative Examples were determined under the following conditions. The results are shown in FIGS. 1 to 3, respectively (Measuring system: SGA-100 sorption analyzer from VTI Corp.).
- Analytical Conditions: 25 ± 2 ℃
- Analysis Range: 5 to 90 % RH
From the results of analysis, it was confirmed that amlodipine camsylate (FIG. 1) exhibited low hygroscopicity, and losartan potassium (FIG. 2) and rosuvastatin calcium (FIG. 3) exhibited significantly high hygroscopicity because each of losartan potassium and rosuvastatin calcium absorbed moisture up to approximately 8 to 10% (w/w) due to the hygroscopicity thereof.
Test Example 2: Accelerated exposure test
The film-coated bilayer tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 8 were stored under accelerated exposure conditions (Petri-dish, 40 ℃, and 75% RH) for 3 days, and the shapes, thicknesses (mm), and moisture contents (LoD) of the film-coated bilayer tablets were determined. The results are listed in the following Tables 6 to 8.
Preparative Example 1 Examples Comparative Examples
1 2 3 4 5 1 2 3
Shape Poor Good Good Good Good Good Poor Good Poor
Increase in thickness (%) 9.8 7.3 7.5 7.6 7.4 7.5 9.4 6.7 9.1
Increase in moisture content (%) 2.4 1.3 1.4 1.4 1.3 1.4 1.9 1.1 1.7
Preparative Example 2 Examples Comparative Examples
6 7 4 5 6
Shape Poor Good Good Poor Good Poor
Increase in thickness (%) 11.3 9.5 9.5 10.6 8.7 10.4
Increase in moisture content (%) 4.1 3.2 3.3 3.8 2.9 3.8
Example 8 Example 9 Comparative Example 7 Comparative Example 8
Shape Good Good Poor Good
Increase in thickness (%) 7.7 7.2 9.2 7.0
Increase in moisture content (%) 1.6 1.3 2.1 1.3
It was confirmed that the increases in moisture contents and thicknesses of the uncoated tablets of Preparative Examples 1 and 2 were significant because the uncoated tablets had very high hygroscopicity when stored under the accelerated exposure conditions. Specifically, the moisture content of the uncoated tablet of Preparative Example 1 prior to exposure to the accelerated conditions was 3.4%, but the moisture content after the exposure to the accelerated conditions increased by 2.4%, so that the uncoated tablet had a moisture content of 5.8%, and separation of the upper and lower layers was observed when the shape of the uncoated tablet was checked (FIG. 4). In particular, it can be seen that the second layer (lower layer) including losartan had a significant change in shape caused due to the moisture absorption, that is, had an uneven surface, and the tablet was deformed as the tablet was slightly bent due to an expansion of the second layer. Considering that losartan potassium used as the raw material in Examples and Comparative Examples was a raw material suitable for the moisture criteria (0.5%) in the European Pharmacopoeia (EP) and the United States Pharmacopoeia (USP), it was judged that such moisture absorption occurred after preparation of the tablet.
Meanwhile, tearing of the coatings and separation of the upper and lower layers were not observed during the accelerated exposure in the case of all the film-coated tablets of Examples 1 to 5 in which the uncoated tablet of Preparative Example 1 was coated with the coating solution including polyvinyl alcohol as the coating base and polyethylene glycol as the plasticizer (see FIG. 5).
In the case of the film-coated tablets of Comparative Examples 1 and 2 in which hypromellose was used as the coating base and polyethylene glycol was used as the plasticizer, the film-coated tablet of Comparative Example 1 in which hypromellose 2910 (P645) was used had higher changes in thickness and moisture content when exposed to the accelerated conditions, compared to the film-coated tablets of Examples 1 to 5. Also, the separation of the upper and lower layers and the tearing of the coatings were observed during the accelerated exposure conditions (FIG. 5), but the film-coated tablet of Comparative Example 2 in which hypromellose 2910 (P615) having a high viscosity was used exhibited no specific change in shape.
The film-coated tablet of Comparative Example 3 in which polyvinyl alcohol was used as the coating base without using the plasticizer had patterns similar to those of Comparative Example 1, that is, had a considerable change in thickness, an uneven shape, and the like.
In Examples 6 and 7 and Comparative Examples 4 to 6, it was confirmed that the film-coated bilayer tablets prepared using the bilayer tablet of Preparative Example 2 as the uncoated tablet had patterns similar to those of Examples 1 to 5 and Comparative Examples 1 to 3 as described above. That is, the results of the accelerated tests showed that the film-coated bilayer tablets of Examples 6 and 7 in which polyvinyl alcohol was used as the coating base and polyethylene glycol was used as the plasticizer and Comparative Example 5 in which hypromellose 2910 (P615) was used as the coating base and polyethylene glycol was used as the plasticizer had excellent stability, but the film-coated bilayer tablets of Comparative Example 5 in which hypromellose 2910 (P645) was used as the coating base and Comparative Example 6 in which polyvinyl alcohol was used as the coating base without using the plasticizer had inferior stability.
From the results, it can be seen that the storage stability of the film-coated tablets was superior to that of the uncoated tablet. In this case, it can be seen that the film-coated tablets in which polyvinyl alcohol was used as the coating base and polyethylene glycol was used as the plasticizer had the most excellent effects.
The film-coated tablets of Examples 8 and 9 and Comparative Examples 7 and 8 were the film-coated tablets in which polyethylene glycol was used as the coating base and polyethylene glycol was used as the plasticizer, but the coating base and the plasticizer of the film coating layer were used at different contents.
In the case of the film-coated tablet of Comparative Example 7 in which the film coating layer was included at a content of 1.78% by weight based on the total weight of the film-coated tablet, a color deviation occurred and separation of the upper and lower layers was observed form the beginning, as observed with the naked eye. This was judged to be caused by an insufficient amount of the coating layer to uniformly coat the uncoated tablet. On the other hand, in the case of the film-coated tablets of Examples 8 and 9 and Comparative Example 8 in which the film coating layer was included at a content of 2% by weight based on the total weight of the film-coated tablet, the coating layer was uniformly formed. Also, the results of the accelerated exposure tests showed that the film-coated tablets exhibited a good increase in thickness and moisture content, but had no specific change in shape.
Test Example 3: Dissolution test
The uncoated tablets of Preparative Examples 1 and 2 and the film-coated bilayer tablets of Examples 1 to 9 and Comparative Examples 2, 5 and 8 which were verified to have good stability in the accelerated exposure test were tested under the following conditions to measure dissolution rates of rosuvastatin, amlodipine and losartan potassium with time.
- Dissolution conditions -
Dissolution solution: pH 1.2, 900 mL
Equipment: USP paddle method, 50 rpm
Temperature: 37 ± 0.5 ℃
- Analytical Conditions -
Column: Column in which a stainless steel pipe having an inside diameter of approximately 4.6 mm and a lengh of 15 cm is filled with octadecylsilylated silica gel for liquid chromatography of 3 μm.
Mobile phase: *6 mM sodium 1-hexanesulfonate/0.05% (v/v) phosphoric acid:acetonitrile (60:40,v/v)
(*Method of preparing 6 mM sodium 1-hexanesulfonate/0.05% (v/v) phosphoric acid: 1.24 g of sodium 1-hexanesulfonate monohydrate is put into a 1 L flask, and 0.5 mL of phosphoric acid is carefully added thereto. Thereafter, the resulting mixture is dissolved in purified water, diluted, and then thoroughly mixed.)
Detector: Ultraviolet Absorptiometer (Wavelength for measurement: 254 nm)
Flow Rate: 1.3 mL/min
Injection Volume: 10 μL
Column temperature: 45 ℃
The results of measurement of the dissolution rates are shown in FIGS. 6 to 11.
As shown in FIGS. 6 to 8, it was confirmed that there was no significant difference in dissolution characteristics in the case of losartan, but there was a significant difference in dissolution characteristics depending on the coating base in the case of amlodipine and rosuvastatin.
Specifically, it was confirmed that the initial dissolution was delayed in the case of the film-coated tablet of Comparative Example 2 in which hypromellose was used as the coating base. On the other hand, it was confirmed that no clear delay in the initial dissolution was observed in the case of the film-coated tablets of Examples 1 to 5 in which polyvinyl alcohol was used as the coating base, compared to the uncoated tablet of Preparative Example 1.
Also, it was confirmed that the film-coated tablets of Examples 6 and 7 and Comparative Example 5 prepared using the bilayer tablet of Preparative Example 2 had substantially the same patterns (FIGS. 9 to 11). That is, it was revealed that the initial dissolution of amlodipine and rosuvastatin was delayed only in the case of the film-coated tablet of Comparative Example 5 in which hypromellose was used as the coating base.
Meanwhile, in the case of the film-coated tablets of Examples 8 and 9 and Comparative Example 8 in which the mass of the film coating layer was used in varying mass (FIG. 6 to 8), it was confirmed that the initial dissolution was delayed in the film-coated tablet of Comparative Example 8 in which the film coating layer was included at a content of 4.51% by weight based on the total weight of the film-coated tablet. This was judged to be caused because the dissolution of the active ingredients was hindered due to a very large thickness of the coating layer.
From the results of Test Examples 2 and 3, it can be seen that the stability of the complex preparation including amlodipine, losartan and rosuvastatin was remarkably improved when the complex preparation included the coating layer.
In this case, polyvinyl alcohol was used as the coating base to secure stability of the preparation without interfering with the dissolution characteristics of the drug. In this case, it can be seen that PVA was preferably used together with a plasticizer such as polyethylene glycol, and the content of the film coating layer was preferably in a range of 2 to 4% by weight, based on the total weight of the complex preparation.

Claims (13)

  1. A pharmaceutical complex preparation comprising:
    a first mixing portion comprising amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and
    a second mixing portion comprising losartan or a pharmaceutically acceptable salt thereof,
    wherein the first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other, and outer surfaces of the first and second mixing portions are coated with a film coating layer, and
    the film coating layer comprises a coating base and a plasticizer, wherein the coating base comprises polyvinyl alcohol.
  2. The pharmaceutical complex preparation of claim 1, wherein the complex preparation is a bilayer tablet comprising:
    a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and
    a second layer comprising losartan or a pharmaceutically acceptable salt thereof.
  3. The pharmaceutical complex preparation of claim 1, wherein the film coating layer is included at a content of 2 to 4% by weight, based on the total weight of the complex preparation.
  4. The pharmaceutical complex preparation of claim 1, wherein the polyvinyl alcohol has a weight average molecular weight of 2,000 to 130,000 g/mol.
  5. The pharmaceutical complex preparation of claim 1, wherein the polyvinyl alcohol is included at a content of 20% by weight or more and less than 60% by weight, based on the total weight of the film coating layer.
  6. The pharmaceutical complex preparation of claim 1, wherein the plasticizer comprises one selected from the group consisting of polyethylene glycol, propylene glycol, diacetin, triacetin, triethyl citrate, talc and a mixture thereof.
  7. The pharmaceutical complex preparation of claim 1, wherein the plasticizer is polyethylene glycol having a number average molecular weight of 2,000 to 6,000 g/mol.
  8. The pharmaceutical complex preparation of claim 1, wherein the plasticizer is included at a content of 5 to 35% by weight, based on the total weight of the film coating layer.
  9. A fixed-dose combination formulation comprising:
    a first mixing portion comprising amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and
    a second mixing portion comprising losartan or a pharmaceutically acceptable salt thereof,
    wherein the first and second mixing portions are present in a state in which the first and second mixing portions are physically separated from each other, and outer surfaces of the first and second mixing portions are coated with a film coating layer, and
    the film coating layer comprises a coating base and a plasticizer, wherein the coating base comprises polyvinyl alcohol.
  10. The fixed-dose combination formulation of claim 9, wherein the amlodipine or pharmaceutically acceptable salt thereof is included at an amount of 5 to 10 mg in the form of an amlodipine free acid.
  11. The fixed-dose combination formulation of claim 9, wherein the rosuvastatin or pharmaceutically acceptable salt thereof is included at an amount of 3 to 20 mg in the form of a rosuvastatin free acid.
  12. The fixed-dose combination formulation of claim 9, wherein the losartan or pharmaceutically acceptable salt thereof is included at an amount of 40 to 100 mg in the form of a losartan free acid.
  13. The pharmaceutical complex preparation of claim 1, wherein the pharmaceutical complex preparation is used to prevent or treat cardiovascular diseases.
PCT/KR2017/012703 2016-11-15 2017-11-10 Pharmaceutical complex preparation comprising amlodipine, losartan and rosuvastatin WO2018093096A2 (en)

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SG11201903132YA SG11201903132YA (en) 2016-11-15 2017-11-10 Pharmaceutical complex preparation comprising amlodipine, losartan and rosuvastatin
MX2019005230A MX2019005230A (en) 2016-11-15 2017-11-10 Pharmaceutical complex preparation comprising amlodipine, losartan and rosuvastatin.
EA201991190A EA201991190A1 (en) 2016-11-15 2017-11-10 PHARMACEUTICAL COMPLEX PRODUCT CONTAINING AMLODIPINE, LOZARTAN AND ROSUVASTATIN
CR20190265A CR20190265A (en) 2016-11-15 2017-11-10 Pharmaceutical complex preparation comprising amlodipine, losartan and rosuvastatin
PH12019500779A PH12019500779A1 (en) 2016-11-15 2019-04-11 Pharmaceutical complex preparation comprising amlodipine, losartan and rosuvastatin
ZA2019/02720A ZA201902720B (en) 2016-11-15 2019-04-30 Pharmaceutical complex preparation comprising amlodipine, losartan and rosuvastatin
CONC2019/0004796A CO2019004796A2 (en) 2016-11-15 2019-05-10 Preparation of pharmaceutical complex comprising amlodipine, losartan and rosuvastatin

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