WO2017003186A1 - Pharmaceutical complex formulation comprising amlodipine, losartan and rosuvastatin - Google Patents

Pharmaceutical complex formulation comprising amlodipine, losartan and rosuvastatin Download PDF

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WO2017003186A1
WO2017003186A1 PCT/KR2016/006977 KR2016006977W WO2017003186A1 WO 2017003186 A1 WO2017003186 A1 WO 2017003186A1 KR 2016006977 W KR2016006977 W KR 2016006977W WO 2017003186 A1 WO2017003186 A1 WO 2017003186A1
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Prior art keywords
pharmaceutically acceptable
rosuvastatin
acceptable salt
amlodipine
losartan
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PCT/KR2016/006977
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French (fr)
Inventor
Yong Il Kim
Ho Taek IM
Hyuk Jun Cho
Youngsu YOON
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 MX2017014311A priority Critical patent/MX2017014311A/en
Priority to RU2018103213A priority patent/RU2724338C2/en
Priority to CN201680031203.4A priority patent/CN108156807A/en
Publication of WO2017003186A1 publication Critical patent/WO2017003186A1/en
Priority to PH12017501986A priority patent/PH12017501986A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
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    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a pharmaceutical composition and a complex formulation for oral administration comprising amlodipine, losartan and rosuvastatin, which exhibit improved dissolution rate, stability and bioavailability.
  • hypertension cases About 90 to 95% of hypertension cases are categorized as primary hypertension, the cause of which is unknown. Risk factors that are related to hypertension include psychological and environmental factors such as drinking, smoking, aging, lack of exercise, obesity, too much salt in the diet, stress and the like. Furthermore, when both parents have hypertension, the offspring has a high chance of having hypertension; and therefore, genetic factors are also known as an important cause of hypertension.
  • a combination of drugs of different mechanisms has an advantage over individual drugs in terms of therapeutic effect. Also, a combination therapy reduces doses of individual drugs, thereby reducing side effects which may occur due to long-term administration of individual drugs.
  • medications that are often used in the treatment of hypertension are categorized into diuretics, sympatholytic agents and vasodilators; and vasodilators are further categorized as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers and calcium channel blockers.
  • ACE angiotensin-converting enzyme
  • hyperlipidemia is a disorder in which an excessively high level of lipids in the blood cause a buildup of plaque on blood vessels, followed by inflammation and, ultimately, cardiovascular disorders.
  • an abnormal amount of lipids in the blood is defined as dyslipidemia.
  • non-drug therapies such as diet, lifestyle changes and maintaining ideal body weight, may be used in conjunction with medication.
  • Statin-based drugs inhibit cholesterol synthesis and reduce plasma LDL-cholesterol level and triglyceride level.
  • Amlodipine is a generic name for 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)- 4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate. Amlodipine blocks calcium channel, and is useful in the treatment of cardiovascular disorders such as angina pectoris, hypertension and congestive heart failure.
  • Losartan is a generic name for 2-butyl-4-chloro-1-[ ⁇ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]- 4-yl ⁇ methyl]-1H-imidazole-5-methanol, as disclosed in U.S. Pat. Nos. 5,608,075, 5,138,069 and 5,153,197.
  • losartan is mainly used for treating hypertension, heart failure, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), diabetic neuropathy and glaucoma, and also for preventing the progression of post-myocardial infarction heart failure.
  • a complex formulation of amlodipine and losartan has an advantage over the individual drugs in terms of prevention and treatment of hypertension and cardiovascular diseases.
  • such formulation reduces doses of the individual drugs, thereby decreasing side effects and improving drug compliance.
  • Rosuvastatin is a generic name for (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhep-6-enoic acid. Rosuvastatin is used in the treatment of hypercholesterolemia, hyperlipoproteinemia or atherosclerosis.
  • the co-occurrence rate of hypertension and hyperlipidemia is approximately 49%, and co-administration of Amosartan ® and statin-based drugs takes up about 30% in the drug treatment of cardiovascular disorders.
  • Amosartan ® and statin-based drugs takes up about 30% in the drug treatment of cardiovascular disorders.
  • statin-based drugs takes up about 30% in the drug treatment of cardiovascular disorders.
  • amlodipine, losartan and rosuvastatin for more effective treatment of cardiovascular disorders.
  • it is difficult to commercialize such formulation due to complexity in designing and a possibility of deterioration in dissolution and stability due to interaction among the active ingredients.
  • the present inventors have conducted intensive research to redress the problems of the conventional formulations, and found that rosuvastatin having a specific particle size exhibited excellent solubility profile and bioavailability, and thus accomplished the present invention.
  • Another object of the present invention is to provide a method for preparing a complex formulation comprising amlodipine, losartan and rosuvastatin.
  • a pharmaceutical composition for preventing or treating a cardiovascular disorder comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D 90 ) of 50 ⁇ m or less.
  • a pharmaceutical complex formulation for preventing or treating a cardiovascular disorder comprising a first mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and a second mixture part comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said first and second mixture parts are physically separated from each other, and said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D 90 ) of 50 ⁇ m or less.
  • a method for preparing a pharmaceutical complex formulation for preventing or treating a cardiovascular disorder comprising the steps of a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and b) admixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D 90 ) of 50 ⁇ m or less.
  • a method for preparing a bilayer tablet for preventing or treating a cardiovascular disorder comprising the steps of a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; b) admixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive to form a mixture, and then granulating the mixture; and c) tableting a mixture part prepared in step a) and a mixture part prepared in step b) to obtain a bilayer tablet, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D 90 ) of 50 ⁇ m or less.
  • D 90 particle size
  • the pharmaceutical composition and the complex formulation comprising amlodipine, losartan and rosuvastatin according to an embodiment of the present invention can be effectively used to prevent or treat a cardiovascular disorder.
  • the pharmaceutical composition and the complex formulation exhibit excellent dissolution rate, bioavailability, stability and content uniformity.
  • Fig. 1 is a graph showing the change in dissolution rate of rosuvastatin in the tablets of Examples 1 to 3 and Comparative Examples 1 to 3.
  • Fig. 2 is a graph showing the change in dissolution rate of amlodipine in the tablets of Examples 1 to 3 and Comparative Examples 1 to 3.
  • Fig. 3 is a graph showing the change in dissolution rate of losartan in the tablets of Examples 1 to 3 and Comparative Examples 1 to 3.
  • Fig. 4 is a graph showing the change in dissolution rate of rosuvastatin in the tablets of Examples 1 and 4 to 10.
  • Fig. 5 is a graph showing the change in bioavailability of rosuvastatin in the tablets of Example 1 and Comparative Example 1.
  • a pharmaceutical composition for preventing or treating a cardiovascular disorder comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D 90 ) of 50 ⁇ m or less.
  • the pharmaceutical composition according to the present invention exhibits improved dissolution rate, bioavailability, and so on, due to the rosuvastatin or a pharmaceutical acceptable salt thereof having a specific particle size range.
  • the particle size (D 90 ) of rosuvastatin or a pharmaceutical acceptable salt thereof is about 50 ⁇ m or less.
  • the particle size (D 90 ) of rosuvastatin or a pharmaceutical acceptable salt thereof is about 25 ⁇ m or less, more preferably, about 10 ⁇ m or less.
  • the particle size (D 90 ) of rosuvastatin or a pharmaceutical acceptable salt thereof may be 50 ⁇ m, 47.2 ⁇ m, 45 ⁇ m, 40 ⁇ m, 35 ⁇ m, 30 ⁇ m, 25 ⁇ m, 22.5 ⁇ m, 20 ⁇ m, 15 ⁇ m, 10 ⁇ m, 8.7 ⁇ m, 5 ⁇ m, 4 ⁇ m, 3 ⁇ m, 2 ⁇ m, 1 ⁇ m, 0.8 ⁇ m, 0.5 ⁇ m or 0.1 ⁇ m.
  • the particle size (D 90 ) of rosuvastatin or a pharmaceutical acceptable salt thereof may be about 0.8 ⁇ m to about 50 ⁇ m, about 0.8 ⁇ m to about 25 ⁇ m, or about 0.8 ⁇ m to about 10 ⁇ m.
  • the particle size of rosuvastatin or a pharmaceutical acceptable salt thereof of about 0.8 ⁇ m or larger make it easier to prepare the composition.
  • the particle size is based on the longest size of the particle, and D 90 means a mean diameter of particles included in 90 th percentile based on cumulative percentage.
  • Rosuvastatin may be pulverized by wet process or dry process, such as, but not limited thereto, by using air jet mill, fluid energy mill, micron mill, and the like. The particle size of rosuvastatin may be reduced by using the above pulverizing methods.
  • a dissolution rate of rosuvastatin determined at 30 minutes after the start of dissolution test may be 85% or greater. More preferably, the dissolution rate of rosuvastatin determined at 15 minutes after the start of dissolution test is 85% or greater when the composition is subjected to a dissolution test according to USP paddle method in water.
  • the dissolution rate may be determined according to USP paddle method at the temperature of 30 to 40°C, more specifically 35 to 38°C with a paddle speed of 50 to 100 rpm, more specifically 70 to 80 rpm.
  • the dissolution rate may be determined at the temperature of 37°C with a paddle speed of 75 rpm.
  • composition of the present invention may be used as a pharmaceutical formulation for oral administration for preventing or treating a cardiovascular disorder, comprising rosuvastatin, amlodipine and rosuvastatin as active ingredients.
  • a pharmaceutical complex formulation for preventing or treating a cardiovascular disorder comprising a first mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and a second mixture part comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said first and second mixture parts are physically separated from each other, and said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D 90 ) of 50 ⁇ m or less.
  • the complex formulation according to the present invention comprises the first and the second mixture parts which are physically separated from each other, i.e., amlodipine and rosuvastatin are separately contained from losartan.
  • amlodipine and rosuvastatin are separately contained from losartan.
  • the complex formulation is in the form of a capsule or a bilayer tablet comprising a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.
  • the complex formulation may be prepared in various forms where the first mixture part and the second mixture part are physically separated from each other (for example, core-shell structure).
  • the particle size (D 90 ) of rosuvastatin or a pharmaceutical acceptable salt thereof may be 50 ⁇ m, 47.2 ⁇ m, 45 ⁇ m, 40 ⁇ m, 35 ⁇ m, 30 ⁇ m, 25 ⁇ m, 22.5 ⁇ m, 20 ⁇ m, 15 ⁇ m, 10 ⁇ m, 8.7 ⁇ m, 5 ⁇ m, 4 ⁇ m, 3 ⁇ m, 2 ⁇ m, 1 ⁇ m, 0.8 ⁇ m, 0.5 ⁇ m or 0.1 ⁇ m.
  • the particle size (D 90 ) of rosuvastatin or a pharmaceutical acceptable salt thereof may be about 50 ⁇ m or less, about 0.8 ⁇ m to about 50 ⁇ m, about 0.8 ⁇ m to about 25 ⁇ m, or about 0.8 ⁇ m to about 10 ⁇ m.
  • the composition or complex formulation of the present invention comprises amlodipine or a pharmaceutically acceptable salt thereof in the first mixture part (or the first layer).
  • the pharmaceutically acceptable salt of amlodipine employed in the present invention may be prepared by using an acid containing a pharmaceutically acceptable anion which can form a non-toxic acid addition salt, e.g. , hydrogen chloride, hydrogen bromide, sulfate, phosphate, acetate, malate, furmarate, lactate, tartrate, citrate, gluconate, besylate or camsylate.
  • the pharmaceutically acceptable salt of amlodipine is amlodipine besylate or camsylate.
  • amlodipine of the present invention includes a racemic mixture and (S)-amlodipine.
  • Amlodipine or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from about 5 to about 10 mg as amlodipine.
  • composition or complex formulation of the present invention comprises rosuvastatin or a pharmaceutically acceptable salt thereof in the first mixture part (or the first layer).
  • pharmaceutically acceptable salt of rosuvastatin include inorganic salts having polycation, preferably rosuvastatin calcium, but are not limited thereto. Rosuvastatin or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from about 5 to about 20 mg as rosuvastatin.
  • composition or complex formulation of the present invention comprises losartan or a pharmaceutically acceptable salt thereof in the second mixture part (or the second layer).
  • examples of the pharmaceutically acceptable salt of losartan include losartan potassium, but are not limited thereto.
  • Losartan or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from about 50 to about 100 mg as losartan.
  • amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof may be admixed in a weight ratio of 1 : 0.3 ⁇ 4 : 5 ⁇ 20, more preferably, 1 : 1 ⁇ 4 : 10 ⁇ 20, but not limited thereto.
  • the pharmaceutically acceptable additive which may be used in the first mixture part or the first layer and the second mixture part or the second layer may be a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable carrier or excipient include lactose (lactose hydrate), micro-crystalline cellulose, mannitol, sodium citrate, calcium phosphate, glycine and starch, a disintegrating agent (e.g. , crospovidone, copovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch and composite silicates) and a binder (e.g. , polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and acacia gum).
  • lactose lactose hydrate
  • micro-crystalline cellulose mannitol
  • mannitol sodium citrate
  • calcium phosphate calcium phosphate
  • the composition or complex formulation of the present invention comprises lactose hydrate and micro-crystalline cellulose in the first mixture part or the first layer as additives.
  • the lactose hydrate may be comprised in an amount of from 40 to 60 wt% based on the total weight of the first mixture part or the first layer.
  • the micro-crystalline cellulose may be comprised in an amount of from 15 to 35 wt% based on the total weight of the first mixture part or the first layer.
  • the lactose hydrate and micro-crystalline cellulose may be employed in a ratio of 1:0.2 to 1:0.9 within the above range of amount in the first mixture part or the first layer.
  • the lactose hydrate When the lactose hydrate is employed in the above range as water-soluble additive, the lactose hydrate may form hydrophilic channels which promote dissolution of active ingredients, thereby allowing a fast dissolution. Especially, the lactose hydrate contained in an amount of 40 wt% or more may result in improved dissolution rate. If the amount of lactose hydrate exceeds the range, time required for complete dissolution of lactose hydrate is extended and thereby slowing down the dissolution of active ingredients. If the micro-crystalline cellulose is employed in the above range, the tableting process becomes easy. However, an amount smaller than the range may cause some difficulties during the tableting process, whereas an excessive amount may lead to an excessively large size of formulation. Accordingly, dissolution rates of amlodipine, rosuvastatin and losartan may be improved significantly by employing the lactose hydrate and micro-crystalline cellulose in the above range.
  • the composition or complex formulation of the present invention may comprise crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch or combinations thereof in the first mixture part or the first layer as a disintegrating agent.
  • the composition or complex formulation of the present invention may comprise crospovidone, croscarmellose sodium, sodium starch glycolate or combinations thereof in the first mixture part or the first layer as a disintegrating agent.
  • the disintegrating agent may be comprised in an amount of from 3 to 10 wt% based on the total weight of the first mixture part or the first layer. If the disintegrating agent is employed in the above range, the dissolution rate is improved, production of related substances decreases, and sufficient stability may be secured under heat-stressed condition with elapsed time.
  • the first mixture part may be contained in the form of wet or dry granule part.
  • the second mixture part or the second layer of the inventive complex formulation may be prepared in a conventional granulation method, e.g., compaction granulation followed by tableting.
  • the second mixture part may be in the form of granules prepared by roller compaction process.
  • the present invention also provides a fixed-dose complex dosage form for preventing or treating a cardiovascular disorder, comprising a first mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and a second mixture part comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said first and second mixture parts are physically separated from each other, and said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D 90 ) of 50 ⁇ m or less.
  • D 90 particle size
  • the amount of amlodipine or a pharmaceutically acceptable salt thereof, as converted to amlodipine free base form is 5 to 10 mg. In one embodiment of the fixed-dose complex dosage form, the amount of rosuvastatin or a pharmaceutically acceptable salt thereof, as converted to rosuvastatin free acid form, is 5 to 20 mg. Also, in one embodiment of the fixed-dose complex dosage form, the amount of losartan or a pharmaceutically acceptable salt thereof, as converted to losartan free acid form, is 50 to 100 mg.
  • a dissolution rate of rosuvastatin determined at 30 minutes may be 85% or greater.
  • the present invention provides a method for preparing a pharmaceutical complex formulation for preventing or treating a cardiovascular disorder, the method comprising the steps of a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and b) admixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said rosuvastatin or a pharmaceutically acceptable salt thereof has a particle size (D 90 ) of 50 ⁇ m or less.
  • the above method may further comprise the step of admixing the mixture part comprising amlodipine and rosuvastatin and the mixture part comprising losartan, wherein the two parts are physically separated from each other.
  • the present invention provides a method for preparing a bilayer tablet for preventing or treating a cardiovascular disorder, the method comprising the steps of a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; b) admixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive to form a mixture, and granulating the mixture; and c) tableting a mixture part prepared in step a) and a mixture part prepared in step b) to obtain a bilayer tablet, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D 90 ) of 50 ⁇ m or less.
  • D 90 particle size
  • the cardiovascular disorder is selected from the group consisting of angina pectoris, hypertension, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarction, congestive heart failure and myocardial infarction.
  • Example 1 Preparation of pharmaceutical composition comprising micronized rosuvastatin
  • Powder of rosuvastatin calcium was pulverized by air jet mill to prepare micronized rosuvastatin calcium having a particle size (D 90 ) of 22.5 ⁇ m.
  • D 90 particle size of 22.5 ⁇ m.
  • amlodipine camsylate, micronized rosuvastatin calcium, lactose hydrate, micro-crystalline cellulose and crospovidone were admixed, sieved through a 30 mesh screen, added with magnesium stearate and finally admixed in a mixer to obtain a mixture part comprising amlodipine and rosuvastatin.
  • losartan potassium, micro-crystalline cellulose and crospovidone were admixed, and sieved through a 30 mesh screen. Then, the sieved powder was pressed using a roller compactor (Roller Compactor WP200, Alexanderwerk) at a minimum compaction force of 20 kN with a roller speed of from 2 to 10 rpm to form granules in the form of flakes. Granules thus obtained were crushed by using a mill (Fitz Mill; BAS 06, Fitzpatrick, USA), sieved through a 20 mesh screen, added with magnesium stearate and finally admixed in a mixer to obtain a granule part comprising losartan.
  • a roller compactor Roller Compactor WP200, Alexanderwerk
  • a complex bilayer tablet comprising the mixture part comprising amlodipine and rosuvastatin (first layer; upper layer) and the granule part comprising losartan (second layer; lower layer) was prepared by using a tablet press (Kilian Synthesis 700, Germany).
  • Example 1 The procedure of Example 1 was repeated by using rosuvastatin of different particle size as described in Table 2 below to obtain complex bilayer tablets.
  • Example 1 The procedure of Example 1 was repeated by using different amounts of disintegrating agent based on the total weight of upper layer, as described in Table 3 below, to obtain complex bilayer tablets. Rosuvastatin having a particle size (D 90 ) of 22.5 ⁇ m was used in these Examples.
  • Tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 3 were each subjected to a drug dissolution test under the following conditions to determine dissolution rates of rosuvastatin, amlodipine and losartan with elapsed time.
  • Dissolution media water 900 mL
  • Dissolution time 5, 10, 15 and 30 minutes
  • the dissolution rate of rosuvastatin showed a marked difference depending on the particle size (D 90 ) of rosuvastatin.
  • the tablets comprising micronized rosuvastatin prepared in Examples 1 to 3 showed rapid dissolution from early stage and met the criterion for acceptance.
  • the tablets comprising rosuvastatin of relatively large particle size prepared in Comparative Examples 1 to 3 showed relatively low dissolution rate in early stage and did not meet the criterion for acceptance.
  • a content uniformity test of the Korean Pharmacopoeia was performed to evaluate the content uniformity of composition depending on the particle size of rosuvastatin.
  • a dissolution test of rosuvastatin was performed with elapsed time by using the same conditions as described in Experimental Example 1 for the tablets of Examples 1 and 4 to 10. The results are shown in Fig. 4. As shown in Fig. 4, the tablets of Examples 4 and 5 showed relatively low dissolution rate in early stage and did not meet the criterion for acceptance. However, the tablets of Examples 1 and 6 to 10 showed rapid dissolution in early stage and met the criterion for acceptance.
  • the tablets of Examples 1 and 6 to 8 exhibited high stability under heat-stressed conditions, while producing a very small amount of amlodipine-, rosuvastatin- and losartan-related substances.
  • the tablets of Examples 9 and 10 produced amlodipine- and rosuvastatin-related substances 5 to 8 times greater than the tablet of Example 1.
  • the tablets of Examples 4 and 5 having the disintegrating agent less than those of Examples 1 and 6 to 8 produced related substances similarly to or lower than that of Example 1.
  • the results show that it is difficult for the tablets having the disintegrating agent in an amount of more than 10 wt% based on the total weight of upper layer to secure sufficient stability under heat-stressed condition with elapsed time.
  • Fig. 5 depicts arithmetic mean of plasma concentrations of rosuvastatin (ng/mL) versus time (hr) on a linear scale.
  • the bioavailability of the composition comprising rosuvastatin having a particle size (D 90 ) of about 22.5 ⁇ m (prepared in Example 1) increased compared with that comprising rosuvastatin having a particle size (D 90 ) of about 60 ⁇ m (prepared in Comparative Example 1).
  • the results could be associated with improved dissolution as shown in Fig. 1. Accordingly, the results demonstrate that micronized rosuvastatin may enhance its dissolution rate, and ultimately increase its bioavailability.

Abstract

Disclosed are a pharmaceutical composition for preventing or treating a cardiovascular disorder comprising amlodipine, rosuvastatin and losartan, and a pharmaceutical complex formulation comprising a first mixture part containing amlodipine and rosuvastatin and a second mixture part containing losartan. The composition and complex formulation comprise rosuvastatin having a particle size (D90) of 50 μm or less, and exhibit excellent dissolution rate, bioavailability, stability and content uniformity, and thus can be useful in pharmaceutical industries.

Description

PHARMACEUTICAL COMPLEX FORMULATION COMPRISING AMLODIPINE, LOSARTAN AND ROSUVASTATIN
The present invention relates to a pharmaceutical composition and a complex formulation for oral administration comprising amlodipine, losartan and rosuvastatin, which exhibit improved dissolution rate, stability and bioavailability.
About 90 to 95% of hypertension cases are categorized as primary hypertension, the cause of which is unknown. Risk factors that are related to hypertension include psychological and environmental factors such as drinking, smoking, aging, lack of exercise, obesity, too much salt in the diet, stress and the like. Furthermore, when both parents have hypertension, the offspring has a high chance of having hypertension; and therefore, genetic factors are also known as an important cause of hypertension.
Since it is required to take medications for a long period of time in the treatment of hypertension, a combination of drugs of different mechanisms has an advantage over individual drugs in terms of therapeutic effect. Also, a combination therapy reduces doses of individual drugs, thereby reducing side effects which may occur due to long-term administration of individual drugs. In general, medications that are often used in the treatment of hypertension are categorized into diuretics, sympatholytic agents and vasodilators; and vasodilators are further categorized as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers and calcium channel blockers.
Meanwhile, hyperlipidemia is a disorder in which an excessively high level of lipids in the blood cause a buildup of plaque on blood vessels, followed by inflammation and, ultimately, cardiovascular disorders. In recent years, an abnormal amount of lipids in the blood is defined as dyslipidemia.
In the treatment of hyperlipidemia, non-drug therapies such as diet, lifestyle changes and maintaining ideal body weight, may be used in conjunction with medication. Statin-based drugs inhibit cholesterol synthesis and reduce plasma LDL-cholesterol level and triglyceride level.
Amlodipine is a generic name for 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)- 4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate. Amlodipine blocks calcium channel, and is useful in the treatment of cardiovascular disorders such as angina pectoris, hypertension and congestive heart failure.
Losartan is a generic name for 2-butyl-4-chloro-1-[{2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]- 4-yl}methyl]-1H-imidazole-5-methanol, as disclosed in U.S. Pat. Nos. 5,608,075, 5,138,069 and 5,153,197. By blocking the interaction of vasoconstrictive angiotensin II and its receptor, losartan is mainly used for treating hypertension, heart failure, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), diabetic neuropathy and glaucoma, and also for preventing the progression of post-myocardial infarction heart failure.
A complex formulation of amlodipine and losartan has an advantage over the individual drugs in terms of prevention and treatment of hypertension and cardiovascular diseases. In addition, such formulation reduces doses of the individual drugs, thereby decreasing side effects and improving drug compliance.
Rosuvastatin is a generic name for (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhep-6-enoic acid. Rosuvastatin is used in the treatment of hypercholesterolemia, hyperlipoproteinemia or atherosclerosis.
The co-occurrence rate of hypertension and hyperlipidemia is approximately 49%, and co-administration of Amosartan® and statin-based drugs takes up about 30% in the drug treatment of cardiovascular disorders. There is a growing need for a complex formulation including amlodipine, losartan and rosuvastatin for more effective treatment of cardiovascular disorders. However, it is difficult to commercialize such formulation due to complexity in designing and a possibility of deterioration in dissolution and stability due to interaction among the active ingredients.
The present inventors have conducted intensive research to redress the problems of the conventional formulations, and found that rosuvastatin having a specific particle size exhibited excellent solubility profile and bioavailability, and thus accomplished the present invention.
Therefore, it is an object of the present invention to provide a pharmaceutical composition and a complex formulation for oral administration comprising amlodipine, losartan and rosuvastatin, which exhibit excellent bioavailability, stability and content uniformity.
Another object of the present invention is to provide a method for preparing a complex formulation comprising amlodipine, losartan and rosuvastatin.
In accordance with one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a cardiovascular disorder, comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
In accordance with another aspect of the present invention, there is provided a pharmaceutical complex formulation for preventing or treating a cardiovascular disorder, comprising a first mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and a second mixture part comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said first and second mixture parts are physically separated from each other, and said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
In accordance with still other aspect of the present invention, there is provided a method for preparing a pharmaceutical complex formulation for preventing or treating a cardiovascular disorder, the method comprising the steps of a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and b) admixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
In accordance with still further aspect of the present invention, there is provided a method for preparing a bilayer tablet for preventing or treating a cardiovascular disorder, the method comprising the steps of a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; b) admixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive to form a mixture, and then granulating the mixture; and c) tableting a mixture part prepared in step a) and a mixture part prepared in step b) to obtain a bilayer tablet, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
The pharmaceutical composition and the complex formulation comprising amlodipine, losartan and rosuvastatin according to an embodiment of the present invention can be effectively used to prevent or treat a cardiovascular disorder. Especially, the pharmaceutical composition and the complex formulation exhibit excellent dissolution rate, bioavailability, stability and content uniformity.
The above and other objects and features of the present invention will be more clearly understood from the following detailed description in conjunction with the accompanying drawings, in which:
Fig. 1 is a graph showing the change in dissolution rate of rosuvastatin in the tablets of Examples 1 to 3 and Comparative Examples 1 to 3.
Fig. 2 is a graph showing the change in dissolution rate of amlodipine in the tablets of Examples 1 to 3 and Comparative Examples 1 to 3.
Fig. 3 is a graph showing the change in dissolution rate of losartan in the tablets of Examples 1 to 3 and Comparative Examples 1 to 3.
Fig. 4 is a graph showing the change in dissolution rate of rosuvastatin in the tablets of Examples 1 and 4 to 10.
Fig. 5 is a graph showing the change in bioavailability of rosuvastatin in the tablets of Example 1 and Comparative Example 1.
As one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a cardiovascular disorder, comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
The pharmaceutical composition according to the present invention exhibits improved dissolution rate, bioavailability, and so on, due to the rosuvastatin or a pharmaceutical acceptable salt thereof having a specific particle size range. Specifically, the particle size (D90) of rosuvastatin or a pharmaceutical acceptable salt thereof is about 50 μm or less. In an embodiment of the present invention, the particle size (D90) of rosuvastatin or a pharmaceutical acceptable salt thereof is about 25 μm or less, more preferably, about 10 μm or less. As one embodiment, the particle size (D90) of rosuvastatin or a pharmaceutical acceptable salt thereof may be 50 μm, 47.2 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 22.5 μm, 20 μm, 15 μm, 10 μm, 8.7 μm, 5 μm, 4 μm, 3 μm, 2 μm, 1 μm, 0.8 μm, 0.5 μm or 0.1 μm. As one embodiment of the present invention, the particle size (D90) of rosuvastatin or a pharmaceutical acceptable salt thereof may be about 0.8 μm to about 50 μm, about 0.8 μm to about 25 μm, or about 0.8 μm to about 10 μm. The particle size of rosuvastatin or a pharmaceutical acceptable salt thereof of about 0.8 μm or larger make it easier to prepare the composition. Herein, the particle size is based on the longest size of the particle, and D90 means a mean diameter of particles included in 90th percentile based on cumulative percentage. Rosuvastatin may be pulverized by wet process or dry process, such as, but not limited thereto, by using air jet mill, fluid energy mill, micron mill, and the like. The particle size of rosuvastatin may be reduced by using the above pulverizing methods.
As one embodiment of the present invention, when the composition is subjected to a dissolution test according to USP paddle method in water, a dissolution rate of rosuvastatin determined at 30 minutes after the start of dissolution test may be 85% or greater. More preferably, the dissolution rate of rosuvastatin determined at 15 minutes after the start of dissolution test is 85% or greater when the composition is subjected to a dissolution test according to USP paddle method in water. Specifically, the dissolution rate may be determined according to USP paddle method at the temperature of 30 to 40℃, more specifically 35 to 38℃ with a paddle speed of 50 to 100 rpm, more specifically 70 to 80 rpm. According to an embodiment of the present invention, the dissolution rate may be determined at the temperature of 37℃ with a paddle speed of 75 rpm.
Furthermore, the composition of the present invention may be used as a pharmaceutical formulation for oral administration for preventing or treating a cardiovascular disorder, comprising rosuvastatin, amlodipine and rosuvastatin as active ingredients.
As one aspect of the present invention, there is provided a pharmaceutical complex formulation for preventing or treating a cardiovascular disorder, comprising a first mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and a second mixture part comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said first and second mixture parts are physically separated from each other, and said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
The complex formulation according to the present invention comprises the first and the second mixture parts which are physically separated from each other, i.e., amlodipine and rosuvastatin are separately contained from losartan. Thus, an interaction of the components is prevented, thereby exhibiting improved stability.
In one embodiment of the present invention, the complex formulation is in the form of a capsule or a bilayer tablet comprising a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive. Besides a bilayer tablet, in another embodiment of the present invention, the complex formulation may be prepared in various forms where the first mixture part and the second mixture part are physically separated from each other (for example, core-shell structure).
As one embodiment, the particle size (D90) of rosuvastatin or a pharmaceutical acceptable salt thereof may be 50 μm, 47.2 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 22.5 μm, 20 μm, 15 μm, 10 μm, 8.7 μm, 5 μm, 4 μm, 3 μm, 2 μm, 1 μm, 0.8 μm, 0.5 μm or 0.1 μm. Furthermore, the particle size (D90) of rosuvastatin or a pharmaceutical acceptable salt thereof may be about 50 μm or less, about 0.8 μm to about 50 μm, about 0.8 μm to about 25 μm, or about 0.8 μm to about 10 μm.
The composition or complex formulation of the present invention comprises amlodipine or a pharmaceutically acceptable salt thereof in the first mixture part (or the first layer). The pharmaceutically acceptable salt of amlodipine employed in the present invention may be prepared by using an acid containing a pharmaceutically acceptable anion which can form a non-toxic acid addition salt, e.g., hydrogen chloride, hydrogen bromide, sulfate, phosphate, acetate, malate, furmarate, lactate, tartrate, citrate, gluconate, besylate or camsylate. Preferably, the pharmaceutically acceptable salt of amlodipine is amlodipine besylate or camsylate. Also, amlodipine of the present invention includes a racemic mixture and (S)-amlodipine. Amlodipine or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from about 5 to about 10 mg as amlodipine.
The composition or complex formulation of the present invention comprises rosuvastatin or a pharmaceutically acceptable salt thereof in the first mixture part (or the first layer). Examples of the pharmaceutically acceptable salt of rosuvastatin include inorganic salts having polycation, preferably rosuvastatin calcium, but are not limited thereto. Rosuvastatin or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from about 5 to about 20 mg as rosuvastatin.
The composition or complex formulation of the present invention comprises losartan or a pharmaceutically acceptable salt thereof in the second mixture part (or the second layer). Examples of the pharmaceutically acceptable salt of losartan include losartan potassium, but are not limited thereto. Losartan or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from about 50 to about 100 mg as losartan.
In the composition or complex formulation of the present invention, amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof may be admixed in a weight ratio of 1 : 0.3~4 : 5~20, more preferably, 1 : 1~4 : 10~20, but not limited thereto.
In the composition or complex formulation of the present invention, the pharmaceutically acceptable additive which may be used in the first mixture part or the first layer and the second mixture part or the second layer may be a pharmaceutically acceptable carrier or excipient. Examples of the pharmaceutically acceptable carrier or excipient include lactose (lactose hydrate), micro-crystalline cellulose, mannitol, sodium citrate, calcium phosphate, glycine and starch, a disintegrating agent (e.g., crospovidone, copovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch and composite silicates) and a binder (e.g., polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and acacia gum).
In one embodiment, the composition or complex formulation of the present invention comprises lactose hydrate and micro-crystalline cellulose in the first mixture part or the first layer as additives. The lactose hydrate may be comprised in an amount of from 40 to 60 wt% based on the total weight of the first mixture part or the first layer. The micro-crystalline cellulose may be comprised in an amount of from 15 to 35 wt% based on the total weight of the first mixture part or the first layer. In another embodiment, the lactose hydrate and micro-crystalline cellulose may be employed in a ratio of 1:0.2 to 1:0.9 within the above range of amount in the first mixture part or the first layer.
When the lactose hydrate is employed in the above range as water-soluble additive, the lactose hydrate may form hydrophilic channels which promote dissolution of active ingredients, thereby allowing a fast dissolution. Especially, the lactose hydrate contained in an amount of 40 wt% or more may result in improved dissolution rate. If the amount of lactose hydrate exceeds the range, time required for complete dissolution of lactose hydrate is extended and thereby slowing down the dissolution of active ingredients. If the micro-crystalline cellulose is employed in the above range, the tableting process becomes easy. However, an amount smaller than the range may cause some difficulties during the tableting process, whereas an excessive amount may lead to an excessively large size of formulation. Accordingly, dissolution rates of amlodipine, rosuvastatin and losartan may be improved significantly by employing the lactose hydrate and micro-crystalline cellulose in the above range.
In one embodiment, the composition or complex formulation of the present invention may comprise crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch or combinations thereof in the first mixture part or the first layer as a disintegrating agent. As an embodiment, the composition or complex formulation of the present invention may comprise crospovidone, croscarmellose sodium, sodium starch glycolate or combinations thereof in the first mixture part or the first layer as a disintegrating agent. The disintegrating agent may be comprised in an amount of from 3 to 10 wt% based on the total weight of the first mixture part or the first layer. If the disintegrating agent is employed in the above range, the dissolution rate is improved, production of related substances decreases, and sufficient stability may be secured under heat-stressed condition with elapsed time.
In the complex formulation of the present invention, the first mixture part may be contained in the form of wet or dry granule part.
In one embodiment, the second mixture part or the second layer of the inventive complex formulation may be prepared in a conventional granulation method, e.g., compaction granulation followed by tableting. In another embodiment, the second mixture part may be in the form of granules prepared by roller compaction process. According to the experimental results of the present invention, a complex formulation exhibited improved dissolution rate of amlodipine, rosuvastatin and losartan, as well as excellent dissolution profiles of amlodipine and rosuvastatin when the complex formulation was prepared by tableting a simply mixed first mixture part and a second mixture part prepared by compaction granulation to a bilayer tablet.
Meanwhile, the present invention also provides a fixed-dose complex dosage form for preventing or treating a cardiovascular disorder, comprising a first mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and a second mixture part comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said first and second mixture parts are physically separated from each other, and said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
In one embodiment of the fixed-dose complex dosage form, the amount of amlodipine or a pharmaceutically acceptable salt thereof, as converted to amlodipine free base form, is 5 to 10 mg. In one embodiment of the fixed-dose complex dosage form, the amount of rosuvastatin or a pharmaceutically acceptable salt thereof, as converted to rosuvastatin free acid form, is 5 to 20 mg. Also, in one embodiment of the fixed-dose complex dosage form, the amount of losartan or a pharmaceutically acceptable salt thereof, as converted to losartan free acid form, is 50 to 100 mg.
According to an embodiment of the present invention, when the complex formulation is subjected to a dissolution test according to USP paddle method by using water with a paddle speed of about 75 rpm, a dissolution rate of rosuvastatin determined at 30 minutes may be 85% or greater.
Furthermore, the present invention provides a method for preparing a pharmaceutical complex formulation for preventing or treating a cardiovascular disorder, the method comprising the steps of a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and b) admixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein said rosuvastatin or a pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
The above method may further comprise the step of admixing the mixture part comprising amlodipine and rosuvastatin and the mixture part comprising losartan, wherein the two parts are physically separated from each other.
In one embodiment, the present invention provides a method for preparing a bilayer tablet for preventing or treating a cardiovascular disorder, the method comprising the steps of a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; b) admixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive to form a mixture, and granulating the mixture; and c) tableting a mixture part prepared in step a) and a mixture part prepared in step b) to obtain a bilayer tablet, wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
In the present invention, the cardiovascular disorder is selected from the group consisting of angina pectoris, hypertension, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarction, congestive heart failure and myocardial infarction.
Hereinafter, the present invention is described more specifically by following examples. However, these examples are provided only for illustration purposes, and the present invention is not limited thereto.
Example 1: Preparation of pharmaceutical composition comprising micronized rosuvastatin
Powder of rosuvastatin calcium was pulverized by air jet mill to prepare micronized rosuvastatin calcium having a particle size (D90) of 22.5 μm. In accordance with the ingredients as described in Table 1 below, amlodipine camsylate, micronized rosuvastatin calcium, lactose hydrate, micro-crystalline cellulose and crospovidone were admixed, sieved through a 30 mesh screen, added with magnesium stearate and finally admixed in a mixer to obtain a mixture part comprising amlodipine and rosuvastatin.
Meanwhile, losartan potassium, micro-crystalline cellulose and crospovidone were admixed, and sieved through a 30 mesh screen. Then, the sieved powder was pressed using a roller compactor (Roller Compactor WP200, Alexanderwerk) at a minimum compaction force of 20 kN with a roller speed of from 2 to 10 rpm to form granules in the form of flakes. Granules thus obtained were crushed by using a mill (Fitz Mill; BAS 06, Fitzpatrick, USA), sieved through a 20 mesh screen, added with magnesium stearate and finally admixed in a mixer to obtain a granule part comprising losartan.
Subsequently, a complex bilayer tablet comprising the mixture part comprising amlodipine and rosuvastatin (first layer; upper layer) and the granule part comprising losartan (second layer; lower layer) was prepared by using a tablet press (Kilian Synthesis 700, Germany).
Component Ingredient Content (mg)
Upper layer comprising amlodipine and rosuvastatin Amlodipine camsylate 7.84 (Amlodipine, 5 mg)
Rosuvastatin calcium 20.80 (Rosuvastatin, 20 mg)
Lactose hydrate 109.36
Micro-crystalline cellulose 50
Crospovidone 10 (5.0%)
Magnesium stearate 2
Total Weigh of upper layer 200
Lower layer comprising losartan Losartan potassium 100.0 (Losartan, 91.6 mg)
Micro-crystalline cellulose 200
Crospovidone 13
Magnesium stearate 2
Total weight of lower layer 315
Examples 2 and 3 and Comparative Examples 1 to 3: Preparation of pharmaceutical composition comprising rosuvastatin of different particle size
The procedure of Example 1 was repeated by using rosuvastatin of different particle size as described in Table 2 below to obtain complex bilayer tablets.
Composition Particle size of rosuvastatin(D90 μm)
Example 2 8.7
Example 3 47.2
Comparative Example 1 58.6
Comparative Example 2 72.3
Comparative Example 3 106.7
Examples 4 to 10: Preparation of pharmaceutical composition having different amounts of disintegrating agent in upper layer
The procedure of Example 1 was repeated by using different amounts of disintegrating agent based on the total weight of upper layer, as described in Table 3 below, to obtain complex bilayer tablets. Rosuvastatin having a particle size (D90) of 22.5 μm was used in these Examples.
Component Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10
Crospovidone (mg) 0(0.0%) 3(1.6%) 6(3.1%) 14(6.9%) 20(9.5%) 24(11.2%) 30(13.6%)
Experimental Example 1: Changes in dissolution rate of complex formulation for oral administration depending on particle size (D90) of rosuvastatin
Tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 3 were each subjected to a drug dissolution test under the following conditions to determine dissolution rates of rosuvastatin, amlodipine and losartan with elapsed time.
- Test conditions -
Dissolution media: water 900 mL
Apparatus: USP paddle method, 75 rpm
Temperature: 37℃
Dissolution time: 5, 10, 15 and 30 minutes
- Analytical conditions -
Column: stainless steel column (inner diameter: about 4.6 mm, length: 15 cm) packed with 3 μm octadecylsilylated silica gel for liquid chromatography
Mobile phase: *6 mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid : acetonitrile (60:40, v/v)
(*6 mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid : 1.24 g of sodium 1-hexanesulfonate monohydrate was added to an 1 L flask, and 0.5 mL of phosphoric acid was carefully added thereto. Purified water was added thereto and the mixture was thoroughly stirred.)
Detector: ultraviolet spectrophotometer (absorbance at 254 nm)
Flow rate: 1.3 mL/min
Injection volume: 10 μL
Column temperature: 45℃
- Criterion for acceptance -
Dissolution rate of 85% or greater at the time of 30 minutes
The results of the dissolution test are shown in Figs. 1 to 3. As shown in Figs. 2 and 3, the difference in particle size (D90) of rosuvastatin did not affect the dissolution rates of amlodipine and losartan. Both dissolution rates met the criterion for acceptance.
Meanwhile, as shown in Fig. 1, the dissolution rate of rosuvastatin showed a marked difference depending on the particle size (D90) of rosuvastatin. The tablets comprising micronized rosuvastatin prepared in Examples 1 to 3 showed rapid dissolution from early stage and met the criterion for acceptance. However, the tablets comprising rosuvastatin of relatively large particle size prepared in Comparative Examples 1 to 3 showed relatively low dissolution rate in early stage and did not meet the criterion for acceptance.
The above results show that dissolution rate may be improved by adjusting the particle size (D90) of rosuvastatin to a certain range.
Experimental Example 2: Content uniformity test of complex formulation for oral administration
A content uniformity test of the Korean Pharmacopoeia was performed to evaluate the content uniformity of composition depending on the particle size of rosuvastatin.
A uniformity of dosage units test described in general tests of the Korean Pharmacopoeia was performed for the tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 3. Contents were determined by HPLC according to the analytical method described in Experimental Example 1, which were used to calculate the acceptance values. The results are shown in Table 4.
Aceptance value (%) Ex. 1 Ex. 2 Ex. 3 Comp. Ex. 1 Comp. Ex. 2 Comp.Ex. 3
Rosuvastatin 3.76 1.75 4.89 9.71 12.60 17.98
Amlodipine 3.28 3.44 3.12 3.51 3.67 3.46
Losartan 1.22 1.53 1.41 1.35 1.28 1.62
As shown in Table 4 above, the acceptance values were markedly improved in the tablets comprising rosuvastatin having a particle size (D90) of about 50 μm or less prepared in Examples 1 to 3 compared with those comprising rosuvastatin having a particle size (D90) of more than about 50 μm prepared in Comparative Examples 1 to 3. The results demonstrate that rosuvastatin of a certain particle size range may be used to produce a formulation with improved mixing uniformity and content uniformity.
Experimental Example 3: Changes in dissolution rate of complex formulation for oral administration depending on amount of disintegrating agent in upper layer
A dissolution test of rosuvastatin was performed with elapsed time by using the same conditions as described in Experimental Example 1 for the tablets of Examples 1 and 4 to 10. The results are shown in Fig. 4. As shown in Fig. 4, the tablets of Examples 4 and 5 showed relatively low dissolution rate in early stage and did not meet the criterion for acceptance. However, the tablets of Examples 1 and 6 to 10 showed rapid dissolution in early stage and met the criterion for acceptance.
Experimental Example 4: Stability test under heat-stressed storage conditions of complex formulation for oral administration having different amounts of disintegrating agent in upper layer
A stability test was performed for the tablets of Examples 1 and 4 to 10 under heat-stressed storage conditions to evaluate the stability of the tablets by analyzing the content change in related substances derived from rosuvastatin. The results are shown in Table 5.
-Stability testing chamber conditions (heat-stressed conditions)-
(1) Temperature and humidity: 50℃±2℃
(2) Sample: stored in an HDPE bottle
(3) Test time: initial and 28 days after storage
- Analytical conditions -
Column: stainless steel column (inner diameter: about 4.6 mm, length: 25 cm) packed with 5 μm octadecylsilylated silica gel for liquid chromatography
Mobile phase: 6 mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid : acetonitrile (6:4, v/v)
Detector: ultraviolet spectrophotometer (absorbance at 239 nm)
Flow rate: 1.0 mL/min
Injection volume: 10 μL
Column temperature: 45℃
Sample Initial 50℃, stored in HDPE bottle for 28 days
Amlodipine-related substances (%) Rosuvastatin-related substances (%) Losartan-related substances (%) Amlodipine-related substances (%) Rosuvastatin-related substances (%) Losartan-related substances (%)
Ex. 1 0.02 0.01 0.01 0.08 0.10 0.04
Ex. 4 0.02 0.02 0.01 0.04 0.12 0.04
Ex. 5 0.01 0.02 0.01 0.09 0.12 0.05
Ex. 6 0.01 0.02 0.02 0.06 0.11 0.04
Ex. 7 0.03 0.01 0.01 0.13 0.11 0.05
Ex. 8 0.01 0.02 0.03 0.16 0.13 0.05
Ex. 9 0.01 0.02 0.04 0.41 0.75 0.06
Ex. 10 0.02 0.03 0.04 0.47 0.72 0.04
As shown in Table 5 above, the tablets of Examples 1 and 6 to 8 exhibited high stability under heat-stressed conditions, while producing a very small amount of amlodipine-, rosuvastatin- and losartan-related substances. On the other hand, the tablets of Examples 9 and 10 produced amlodipine- and rosuvastatin-related substances 5 to 8 times greater than the tablet of Example 1.
Meanwhile, the tablets of Examples 4 and 5 having the disintegrating agent less than those of Examples 1 and 6 to 8 produced related substances similarly to or lower than that of Example 1. The results show that it is difficult for the tablets having the disintegrating agent in an amount of more than 10 wt% based on the total weight of upper layer to secure sufficient stability under heat-stressed condition with elapsed time.
Experimental Example 5: Evaluation of bioavailability of rosuvastatin
A bioavailability was evaluated on beagle dogs for the compositions of Example 1 and Comparative Example 1. The test was performed on six beagle dogs with randomized and crossover study. The results are shown in Table 6 and Fig. 5. Fig. 5 depicts arithmetic mean of plasma concentrations of rosuvastatin (ng/mL) versus time (hr) on a linear scale.
Evaluation of bioavailability of rosuvastatin
Parameter Example 1 Comparative Example 1
AUCO-48 (ng·hr/mL) 233.86±77.40 194.97±90.03
Cmax (ng/mL) 44.38±20.73 35.90±20.51
Tmax (hr) 1.82±0.51 2.00±0.84
As shown in Table 6 and Fig. 5, the bioavailability of the composition comprising rosuvastatin having a particle size (D90) of about 22.5 μm (prepared in Example 1) increased compared with that comprising rosuvastatin having a particle size (D90) of about 60 μm (prepared in Comparative Example 1). The results could be associated with improved dissolution as shown in Fig. 1. Accordingly, the results demonstrate that micronized rosuvastatin may enhance its dissolution rate, and ultimately increase its bioavailability.

Claims (16)

  1. A pharmaceutical composition for preventing or treating a cardiovascular disorder, comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof,
    wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
  2. The pharmaceutical composition of claim 1, wherein the rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 0.8 to 50 μm.
  3. The pharmaceutical composition of claim 2, wherein the rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 0.8 to 25 μm.
  4. The pharmaceutical composition of claim 3, wherein the rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 0.8 to 10 μm.
  5. The pharmaceutical composition of claim 1, wherein a dissolution rate of rosuvastatin is 85% or greater within 30 minutes when the composition is subjected to a dissolution test according to USP paddle method in water.
  6. The pharmaceutical composition of claim 5, wherein a dissolution rate of rosuvastatin is 85% or greater within 15 minutes when the composition is subjected to a dissolution test according to USP paddle method in water.
  7. A pharmaceutical complex formulation for preventing or treating a cardiovascular disorder, comprising:
    a first mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and
    a second mixture part comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive,
    wherein said first and second mixture parts are physically separated from each other, and
    said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
  8. The pharmaceutical complex formulation of claim 7, wherein the pharmaceutical complex formulation is in the form of a bilayer tablet comprising:
    a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and
    a second layer comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
  9. The pharmaceutical complex formulation of claim 7, wherein the first mixture part comprises a disintegrating agent as additives.
  10. The pharmaceutical complex formulation of claim 9, wherein the disintegrating agent is comprised in an amount of 3 to 10 wt% based on the total weight of the first mixture part.
  11. The pharmaceutical complex formulation of claim 9, wherein the disintegrating agent is crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch or combinations thereof.
  12. The pharmaceutical complex formulation of claim 7, wherein the first mixture part comprises lactose hydrate and micro-crystalline cellulose as additives.
  13. The pharmaceutical complex formulation of claim 7, wherein the second mixture part is in the form of granules prepared by a roller compaction process.
  14. A method for preparing a pharmaceutical complex formulation for preventing or treating a cardiovascular disorder, the method comprising the steps of:
    a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and
    b) admixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive,
    wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
  15. The method of claim 14, wherein the complex formulation is a tablet or a capsule.
  16. A method for preparing a bilayer tablet for preventing or treating a cardiovascular disorder, the method comprising the steps of:
    a) admixing amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive;
    b) admixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to form a mixture, and then granulating the mixture; and
    c) tableting a mixture part prepared in step a) and a mixture part prepared in step b) to obtain a bilayer tablet,
    wherein said rosuvastatin or pharmaceutically acceptable salt thereof has a particle size (D90) of 50 μm or less.
PCT/KR2016/006977 2015-06-30 2016-06-29 Pharmaceutical complex formulation comprising amlodipine, losartan and rosuvastatin WO2017003186A1 (en)

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RU2018103213A RU2724338C2 (en) 2015-06-30 2016-06-29 Pharmaceutical complex composition containing amlodipine, losartan and rosuvastatin
CN201680031203.4A CN108156807A (en) 2015-06-30 2016-06-29 Medicine compound preparation containing Amlodipine, Losartan and Rosuvastatin
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KR20180044873A (en) 2018-05-03
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