CN112933093A - Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin - Google Patents

Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin Download PDF

Info

Publication number
CN112933093A
CN112933093A CN202110171819.4A CN202110171819A CN112933093A CN 112933093 A CN112933093 A CN 112933093A CN 202110171819 A CN202110171819 A CN 202110171819A CN 112933093 A CN112933093 A CN 112933093A
Authority
CN
China
Prior art keywords
pharmaceutically acceptable
rosuvastatin
acceptable salt
particle size
pharmaceutical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110171819.4A
Other languages
Chinese (zh)
Inventor
金用镒
林昊泽
曺赫俊
尹英洙
朴宰贤
禹钟守
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanmi Pharmaceutical Co Ltd
Original Assignee
Hanmi Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hanmi Pharmaceutical Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Publication of CN112933093A publication Critical patent/CN112933093A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • 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
    • A61K9/2013—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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • 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

Abstract

The invention discloses a pharmaceutical composition containing amlodipine, rosuvastatin and losartan for preventing or treating cardiovascular diseases, and also discloses a pharmaceutical composite preparation, which comprises a first mixture part containing amlodipine and rosuvastatin and a second mixture part containing losartan. The composition and the composite preparation contain particle size (D)90) Rosuvastatin of 50 μm or less, which has excellent dissolution rate, bioavailability, stability, content uniformity, and thus is useful in the pharmaceutical industry.

Description

Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin
The present application is a divisional application of the following original applications:
application date of the original application: 2016, 06, 29 months
- -application number of the original application: 201680031203.4
The invention of the original application is named: pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin
Technical Field
The present invention relates to an oral pharmaceutical composition and a complex formulation containing amlodipine, losartan and rosuvastatin, which exhibit improved dissolution, stability and bioavailability.
Background
Approximately 90 to 95% of cases of hypertension are classified as essential hypertension for unknown reasons. Risk factors associated with hypertension include psychological and environmental factors such as alcohol consumption, smoking, aging, lack of exercise, obesity, excessive dietary salt, stress, and the like. In addition, when parents suffer from hypertension, their offspring have a possibility of hypertension, and thus, genetic factors are also considered as an important cause of hypertension.
Since it is necessary to take the drugs for a long time in the treatment of hypertension, the combination of drugs of different mechanisms has an advantage in therapeutic effect over the individual drugs. In addition, combination therapy reduces the dosage of individual drugs, thereby reducing the side effects that can result from long-term administration of individual drugs. Generally, the drugs commonly used to treat hypertension are divided into diuretics, sympatholytic agents, and vasodilators; vasodilators are further classified as Angiotensin Converting Enzyme (ACE) inhibitors, angiotensin II receptor blockers, and calcium channel blockers.
Meanwhile, hyperlipidemia is a disorder of plaque on blood vessels due to excessive lipid levels in blood, accompanied by inflammation, and finally, cardiovascular diseases. In recent years, lipid abnormalities in the blood have been defined as dyslipidemia.
In the treatment of hyperlipidemia, non-drug therapies such as diet, change of lifestyle and maintenance of ideal body weight are used in combination with drugs. Statins inhibit cholesterol synthesis and lower plasma low density lipoprotein cholesterol and triglyceride levels.
Amlodipine is the common name for 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydro-3, 5-pyridinedicarboxylic acid (3-ethyl-5-methyl-2- (2-aminoethoxy-methyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydro-3,5-pyridine dicarboxylic acid). Amlodipine blocks calcium channels and can be used for treating cardiovascular diseases such as angina pectoris, hypertension and congestive heart failure.
Losartan is the common name for 2-butyl-4-chloro-1- [ {2'- (1H-tetrazol-5-yl) [1,1' -biphenyl ] -4-yl } methyl ] -1H-imidazole-5-methanol (2-butyl-4-chloro-1- [ {2'- (1H-tetrazol-5-yl) [1,1' -biphenyl ] -4-yl } methyl ] -1H-imidozole-5-methanol), disclosed in U.S. patent nos. 5608075, 5138069 and 5153197. Losartan is mainly used for treating hypertension, heart failure, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), diabetic neuropathy and glaucoma, and preventing the occurrence of heart failure after acute myocardial infarction, by blocking the interaction of angiotensin II which contracts blood vessels and its receptor.
The complex formulation of amlodipine and losartan is more advantageous than a single drug in preventing and treating hypertension and cardiovascular diseases. In addition, such dosage forms reduce the dosage of individual drugs, thereby reducing side effects and improving drug compliance.
Rosuvastatin is the generic name of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] - (3R,5S) -3, 5-dihydroxyhept-6-enoic acid ((E) -7- [4- (4-fluorophenyl) -6-isoproyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] - (3R,5S) -3, 5-dihydroohep-6-enoic acid). Rosuvastatin is used for the treatment of hypercholesterolemia, hyperlipidemia and atherosclerosis.
The co-incidence of hypertension and hyperlipidemia is about 49%, while the combined use of Amosartan and statins accounts for about 30% of cardiovascular disease drug treatments. In order to more effectively treat cardiovascular diseases, there is an increasing demand for complex formulations containing amlodipine, losartan, rosuvastatin, and the like. However, it is difficult to commercialize such a formulation due to the complexity of its design and the possibility of deterioration in solubility and stability caused by interaction between active ingredients.
The present inventors have conducted intensive studies to solve the problems of the conventional formulations and found that rosuvastatin having a specific particle size has a good dissolution profile and bioavailability, thereby completing the present invention.
Disclosure of Invention
Therefore, it is an object of the present invention to provide an oral pharmaceutical composition and a complex formulation containing amlodipine, losartan and rosuvastatin, which have excellent bioavailability, stability and content uniformity.
It is another object of the present invention to provide a method for preparing a complex formulation containing amlodipine, losartan and rosuvastatin.
According to an aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cardiovascular diseases, comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, wherein the particle size (D) of the rosuvastatin or a pharmaceutically acceptable salt thereof is90) Is 50 μm or less.
According to another aspect of the present invention, there is also provided a pharmaceutical composite formulation for preventing or treating cardiovascular diseases, which comprises a first mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable additives; and a second mixture part comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the first and second mixture parts are physically separated from each other, and the particle size (D) of the rosuvastatin or a pharmaceutically acceptable salt thereof is90) Is 50 μm or less.
According to another aspect of the present invention, there is provided a method for preparing a pharmaceutical composite preparation for preventing or treating cardiovascular diseases, the method comprising the steps of: a) amlodipine or pharmaceutically acceptable salt thereof, rosuvastatin or pharmaceutically acceptable salt thereof and pharmaceutically acceptable additives are mixed; and b) mixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the particle size (D) of the rosuvastatin or a pharmaceutically acceptable salt thereof90) Is 50 μm or less.
In another aspect of the present invention, there is provided a method for preparing a bilayer tablet for preventing or treating cardiovascular diseases, the method comprising the steps of: a) amlodipine or pharmaceutically acceptable salt thereof, rosuvastatin or pharmaceutically acceptable salt thereof and pharmaceutically acceptable additives are mixed; b) mixing losartan or pharmaceutically acceptable salt thereof and pharmaceutically acceptable additives to form a mixture, and then granulating the mixture; c) tabletting the mixture part prepared in the step a) and the mixture part prepared in the step b) to obtain a double-layer tablet, wherein the relcason isParticle size (D) of atorvastatin or pharmaceutically acceptable salt thereof90) Is 50 μm or less.
Compared with the prior art, the invention has the following beneficial effects:
according to the embodiments of the present invention, the pharmaceutical composition and the complex formulation containing amlodipine, losartan and rosuvastatin can be effectively used for preventing or treating cardiovascular diseases. Particularly, the pharmaceutical composition and the compound preparation have excellent dissolution rate, bioavailability, stability and content uniformity.
Drawings
Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:
fig. 1 is a graph showing the change in dissolution rate of rosuvastatin in 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 example 1, examples 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.
Detailed Description
According to an aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cardiovascular diseases, comprising amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, wherein the particle size (D) of the rosuvastatin or a pharmaceutically acceptable salt thereof is small90) Is 50 μm or less.
The pharmaceutical composition of the invention has higher dissolution rate, bioavailability and the like due to the specific particle size range of the rosuvastatin or the pharmaceutically acceptable salt thereof. In particular, the particle size (D) of rosuvastatin or its pharmaceutically acceptable salt90) Is 50 μm or less. In one embodiment of the invention, the particle size (D) of rosuvastatin or its pharmaceutically acceptable salt90) About 25 μm or less, more preferably about 10 μm or less. In one embodiment, the particle size (D) of rosuvastatin or pharmaceutically acceptable salt thereof90) It 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 an example of the present invention, the particle size (D) of rosuvastatin or pharmaceutically acceptable salt thereof90) And may be about 0.8 μm to about 50 μm, or about 0.8 μm to about 25 μm, or about 0.8 μm to about 10 μm. Particle size of rosuvastatin or pharmaceutically acceptable salt (D)90) At about 0.8 μm or more, the composition is easier to prepare. Here, the size of the particles depends on the longest diameter of the particles, D90Meaning the average diameter of the particles contained in the 90 th percentile, based on the cumulative percentage. The rosuvastatin may be pulverized by a wet method or a dry method, for example, using a jet mill, a fluid energy mill, a micronizer, etc., but is not limited thereto. By adopting the crushing method, the particle size of rosuvastatin can be reduced.
As an example of the present invention, when the composition is subjected to a dissolution test in water according to USP paddle method, the dissolution rate of rosuvastatin measured 30 minutes after the start of the dissolution test may be 85% or more. More preferably, the composition has a dissolution rate of rosuvastatin of 85% or more measured 15 minutes after the start of the dissolution test when the dissolution test is performed using USP paddle method in water. Specifically, the dissolution rate can be measured at a temperature of 30-40 ℃, more specifically at 35-38 ℃ according to the USP paddle method, and the paddle rotation speed is 50-100 rpm, more specifically 70-80 rpm. According to one embodiment of the invention, dissolution may be measured at a temperature of 37 ℃ and a paddle speed of 75 rpm.
In addition, the composition of the present invention comprises rosuvastatin, amlodipine and rosuvastatin as active ingredients, and can be used as an oral pharmaceutical preparation for preventing or treating cardiovascular diseases.
According to one of the present inventionIn an aspect, there is provided a pharmaceutical composite formulation for preventing or treating cardiovascular diseases, which comprises 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 the first and second mixture parts are physically separated from each other, and the particle size (D) of the rosuvastatin or a pharmaceutically acceptable salt thereof is90) Is 50 μm or less.
The complex formulation of the present invention comprises first and second mixture parts which are physically separated from each other, i.e., amlodipine and rosuvastatin are preserved separately from losartan. Thereby, interaction between the components can be prevented, thereby exhibiting improved stability.
In one embodiment of the present invention, the complex formulation is a capsule or a two-layer tablet, which comprises 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. In addition to bi-layer tablets, in other embodiments of the invention, the composite formulation may be prepared in various forms in which the first mixture portion and the second mixture portion are physically separated from each other (e.g., core-shell structure).
In one embodiment, the particle size (D) of rosuvastatin or its pharmaceutically acceptable salt90) 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. In addition, the particle size (D) of rosuvastatin or its pharmaceutically acceptable salt90) Can be about 50 μm or less, about 0.8 μm to about 50 μm, about 0.8 μm to 25 μm, or about 0.8 μm to about 10 μm.
The composition or complex formulation of the present invention includes amlodipine or a pharmaceutically acceptable salt thereof in the first mixture part (or first layer). The pharmaceutically acceptable salt of amlodipine of the present invention is prepared with an acid containing a pharmaceutically acceptable anion, which can form non-toxic acid addition salts such as hydrogen chloride, hydrogen bromide, sulfate, phosphate, acetate, malate, fumarate, lactate, tartrate, citrate, gluconate, benzenesulfonate or camphorsulfonate. Preferably, the pharmaceutically acceptable salt of amlodipine can be amlodipine besylate or amlodipine camsylate. Further, amlodipine of the present invention includes a racemic mixture and (S) -amlodipine. Amlodipine or a pharmaceutically acceptable salt thereof can be administered in a daily dose of about 5 to 10mg of amlodipine.
The composition or complex formulation of the present invention includes rosuvastatin or a pharmaceutically acceptable salt thereof in the first mixture portion (or first layer). Examples of pharmaceutically acceptable salts of rosuvastatin may include inorganic salts of polycations, preferably rosuvastatin calcium, but are not limited thereto. Rosuvastatin or a pharmaceutically acceptable salt thereof may be administered in a daily dose of about 5 to 20mg rosuvastatin.
The composition or complex formulation of the present invention includes losartan or a pharmaceutically acceptable salt thereof in the second mixture part (or second layer). Examples of the pharmaceutically acceptable salt of losartan may include losartan potassium, but are not limited thereto. Losartan or a pharmaceutically acceptable salt thereof may be administered in a daily dose of about 50 to 100mg of losartan.
In the composition or the composite preparation of the invention, amlodipine or pharmaceutically acceptable salt thereof, rosuvastatin or pharmaceutically acceptable salt thereof and losartan or pharmaceutically acceptable salt thereof can be prepared according to the weight ratio of 1: 0.3-4: 5-20, preferably, the weight ratio of the components can be 1: 1-4: 10 to 20 by weight, but not limited thereto.
In the composition or complex formulation of the present invention, the pharmaceutically acceptable additive 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 pharmaceutically acceptable carriers or excipients include lactose (lactose hydrate), microcrystalline cellulose, mannitol, sodium citrate, calcium phosphate, glycine and starch, disintegrants (e.g., crospovidone, copovidone, croscarmellose sodium, sodium carboxymethyl starch, pregelatinized starch and complex silicates), and binders (e.g., polyvinylpyrrolidone, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), sucrose, gelatin and acacia).
In one embodiment, the composition or complex formulation of the present invention contains lactose hydrate and microcrystalline cellulose as additives in the first mixture part or the first layer. Lactose hydrate may constitute 40 to 60 wt% of the total weight of the first mixture part or first layer. The microcrystalline cellulose may constitute 15 to 35 wt% of the total weight of the first mixture part or the first layer. In another embodiment lactose hydrate and microcrystalline cellulose may be used in the ratio range of 1:0.2 to 1:0.9 in the first mixture part or first layer.
When lactose hydration is used as a water-soluble additive in the stated range, lactose hydrate can form hydrophilic channels that promote dissolution of the active ingredient, thereby allowing the ingredient to be rapidly dissolved. In particular, dissolution can be improved when 40% by weight or more of lactose hydrate is contained. If the amount of lactose hydrate exceeds the range, the time required to completely dissolve lactose hydrate is extended, thereby slowing the dissolution of the active ingredient. If the microcrystalline cellulose is used within the range, the tabletting process becomes easy. However, an amount less than the range may cause some difficulties in tableting, and an excess may cause the dosage form to be oversized. Therefore, the dissolution rates of amlodipine, rosuvastatin and losartan can be remarkably improved using lactose hydrate and microcrystalline cellulose within the range.
In one embodiment, the composition or composite formulation of the present invention may comprise crospovidone, croscarmellose sodium, sodium carboxymethyl starch, pregelatinized starch, or a combination thereof as a disintegrant in the first mixture portion or first layer. In one embodiment, the composition or composite formulation of the present invention may comprise crospovidone, croscarmellose sodium, sodium carboxymethyl starch, or a combination thereof as a disintegrant in the first mixture portion or first layer. The disintegrant may account for 3 to 10 wt% of the total weight of the first mixture part or the first layer. If the disintegrant is used within the range, the dissolution rate can be improved, the production of the relevant substance can be reduced, and sufficient stability can be secured with the passage of time under heat stress conditions.
In the complex formulation of the present invention, the first mixture portion may be present in the form of wet granules or dry granule portions.
In one embodiment, the second mixture portion or second layer of the composite formulation of the present invention may be prepared by conventional granulation methods such as compaction granulation followed by tableting. In another embodiment, the second mixture portion may be prepared in the form of particles using a roller compaction process. According to the test results of the present invention, when the composite formulation is prepared as a bi-layer tablet by tabletting the simply mixed first mixture part and the compaction granulation prepared second mixture part, the composite formulation exhibits improved dissolution rates of amlodipine, rosuvastatin and losartan, and simultaneously, amlodipine, rosuvastatin exhibit good dissolution rate profiles.
Meanwhile, the present invention also provides a fixed-dose multiple dosage form for preventing or treating cardiovascular diseases, which comprises 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 the first and second mixture parts are physically separated from each other, and the particle size (D) of the rosuvastatin or a pharmaceutically acceptable salt thereof is90) Is 50 μm or less.
In one embodiment of the fixed-dose combination dosage form, the amount of amlodipine or a pharmaceutically acceptable salt thereof converted into the free radical form of amlodipine is 5-10 mg. In one embodiment of the fixed-dose composite dosage form, rosuvastatin or a pharmaceutically acceptable salt thereof, is converted to rosuvastatin in an amount of 5 to 20mg in free acid form. In addition, in one embodiment of the fixed-dose composite dosage form, losartan, or a pharmaceutically acceptable salt thereof, is converted into losartan acid form in an amount of 50-100 mg.
According to an embodiment of the present invention, when the complex formulation is subjected to a dissolution test according to USP slurry method in water at a slurry speed of about 75rpm, the dissolution rate of rosuvastatin measured after 30 minutes may be 85% or more.
In addition, the present invention provides a method for preparing a pharmaceutical composite preparation for preventing or treating cardiovascular diseases, the method comprising the steps of: a) amlodipine or pharmaceutically acceptable salt thereof, rosuvastatin or pharmaceutically acceptable salt thereof and pharmaceutically acceptable additives are mixed; and b) mixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the particle size (D) of the rosuvastatin or a pharmaceutically acceptable salt thereof90) Is 50 μm or less.
The method further comprises the step of mixing a mixture part comprising amlodipine, rosuvastatin and a 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 cardiovascular diseases, the method comprising the steps of: a) amlodipine or pharmaceutically acceptable salt thereof, rosuvastatin or pharmaceutically acceptable salt thereof and pharmaceutically acceptable additives are mixed; b) mixing losartan or pharmaceutically acceptable salt thereof and pharmaceutically acceptable additives to form a mixture, and then granulating the mixture; c) tabletting the mixture part prepared in step a) and the mixture part prepared in step b) to obtain a bilayer tablet, wherein the particle size (D) of the rosuvastatin or pharmaceutically acceptable salt thereof90) Is 50 μm or less.
In the present invention, the cardiovascular disease is a group selected from the group consisting of angina pectoris, hypertension, arterial spasm, arrhythmia, cardiac hypertrophy, cerebral infarction, congestive heart failure and myocardial infarction.
The present invention will be described more specifically by the following examples. However, these examples are for illustrative purposes only, and the present invention is not limited thereto.
Example 1: preparation of pharmaceutical composition containing micronized rosuvastatin
The rosuvastatin calcium powder is pulverized by a jet mill to prepare a powder having a particle size (D) of 22.5 μm90) Micronized rosuvastatin calcium of (a). According to the composition shown in the following table 1, amlodipine camsylate, micronized rosuvastatin calcium, lactose hydrate, microcrystalline cellulose, crospovidone were mixed, sieved through a 30-mesh sieve, added with magnesium stearate, and finally mixed with a blender to obtain a mixture part containing amlodipine and rosuvastatin.
Meanwhile, the losartan potassium, the microcrystalline cellulose and the crospovidone are mixed and sieved by a 30-mesh sieve. The sifted powder is then compacted with a roller compactor (roller compactor wp200, alexanderwerk) at a roller speed of 2 to 10rpm with a compaction force of at least 20kN to form the flaky particles. The resulting granules were pulverized with a pulverizer (Fitz Mill; BAS 06, Fitz Patrick, USA), sieved with a 20-mesh sieve, magnesium stearate was added, and finally mixed with a blender to obtain a granule fraction containing losartan.
Subsequently, a composite bilayer tablet comprising a mixture part (first layer; upper layer) containing amlodipine, rosuvastatin and a granule part (second layer; bottom layer) containing losartan was prepared by a tablet press (Kilian Synthesis 700, Germany).
TABLE 1
Figure BDA0002939167740000081
Figure BDA0002939167740000091
Examples 2 and 3 and comparative examples 1 to 3: preparation of pharmaceutical composition containing rosuvastatin of different particle size
As shown in table 2 below, the procedure of example 1 was repeated using rosuvastatin of various particle sizes to obtain composite bilayer tablets.
TABLE 2
Figure BDA0002939167740000092
Examples 4 to 10: preparing pharmaceutical compositions containing different amounts of disintegrant in the upper layer
As shown in table 3 below, the procedure of example 1 was repeated using different amounts of disintegrant according to the total weight of the upper layer, to obtain a composite bilayer tablet. In the examples, the particle size (D) of rosuvastatin90)22.5 μm was used.
TABLE 3
Figure BDA0002939167740000093
Test example 1: according to different particle sizes of rosuvastatin (D)90) Change in dissolution of oral complex formulation
The tablets prepared in examples 1 to 3 and comparative examples 1 to 3 were subjected to a drug dissolution test under the following conditions, respectively, to determine the change in dissolution rates of rosuvastatin, amlodipine, and losartan according to time.
Test conditions-
Dissolution medium: 900mL of water
USP pulp method, 75rpm
The temperature is 37 DEG C
Dissolution times of 5, 10, 15 and 30 minutes
Analytical conditions-
Column: stainless steel column (inner diameter: about 4.6mm, length: 15cm) packed with 3 μm of octadecylsilylated silica gel for liquid chromatography
Mobile phase: 6mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid: acetonitrile (60:40, v/v)
(. 6mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid: 1.24g sodium hexanesulfonate hydrate was added to 1L flask, followed by careful addition of 0.5mL phosphoric acid, addition of purified water, stirring well.)
A detector: ultraviolet spectrophotometer (absorbance at 254 nm)
Flow rate: 1.3 mL/min
Injection volume: 10 μ L
Column temperature: 45 deg.C
Acceptance criteria-
At 30 minutes, the dissolution rate is 85% or more
The dissolution test results are shown in FIGS. 1 to 3. As shown in fig. 2 and 3, the particle size (D) of rosuvastatin90) The difference in size did not affect the dissolution rate of amlodipine and losartan. The dissolution rates of the two substances meet the acceptance standard.
At the same time, as shown in fig. 1, according to the particle size (D) of rosuvastatin90) Size, the dissolution rate of rosuvastatin showed significant difference. The tablets containing micronized rosuvastatin prepared in examples 1 to 3 showed rapid dissolution in the early stage and met the acceptance criteria. However, the tablets containing rosuvastatin having a larger particle size prepared in comparative examples 1 to 3 show a relatively low dissolution rate at the initial stage and do not meet the acceptance criteria.
The above results indicate that the dissolution rate can be controlled by the particle size (D) of rosuvastatin90) Adjusted to a certain range for improvement.
Test example 2: content uniformity test of oral compound preparation
In order to evaluate the variation of content uniformity of the composition according to the particle size of rosuvastatin, content uniformity test of korean pharmacopoeia was performed.
The tablets prepared in examples 1 to 3 and comparative examples 1 to 3 were subjected to a content uniformity test as described in a general test of the Korean pharmacopoeia. The content was determined according to the calculated acceptance value of High Performance Liquid Chromatography (HPLC) in test example 1. The results are shown in Table 4.
TABLE 4
Figure BDA0002939167740000101
Figure BDA0002939167740000111
As shown in Table 4, the particles prepared in examples 1 to 3 contained a particle size of (D)90) Tablets of rosuvastatin of 50 μm or less, and the tablets prepared in comparative examples 1 to 3, having a particle size of more than (D)90) The acceptance of the former was significantly improved compared to 50 μm tablets of rosuvastatin. This result indicates that a range of particle sizes of rosuvastatin can be used to prepare formulations with improved mixing uniformity and content uniformity.
Test example 3: the dissolution rate of the oral compound preparation varies according to different dosage of the upper layer disintegrant
The tablets prepared in example 1 and examples 4 to 10 were tested for their dissolution rate over time under the same conditions as in test example 1. The results are shown in FIG. 4. As shown in fig. 4, the tablets of examples 4 and 5 had relatively low initial dissolution rates and failed to meet the acceptance criteria. However, the tablets of example 1 and examples 6 to 10 showed rapid dissolution in the early stage and met the acceptance criteria.
Test example 4: stability test of oral compound preparation containing different contents of disintegrating agent in upper layer under heat stress storage condition
The tablets prepared in example 1 and examples 4 to 10 were subjected to a stability test under heat stress storage conditions, and the stability of the tablets was evaluated by analyzing the content change of rosuvastatin derived related substances. The results are shown in Table 5.
Stability laboratory conditions (thermal stress conditions) -
(1) Temperature and humidity: 50 ℃ plus or minus 2 DEG C
(2) Sample preparation: stored in high density polyethylene bottles
(3) And (3) testing time: initial and after 28 days of storage
Analytical conditions-
Column: stainless steel column filled with 5 μm octadecylsilylated silica gel for liquid chromatography (inner diameter: about 4.6mm, length: 25cm)
Mobile phase: 6mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid: acetonitrile (6:4, v/v)
A detector: ultraviolet spectrophotometer (absorbance at 239 nm)
Flow rate: 1.0 mL/min
Injection volume: 10 μ L
Column temperature: 45 deg.C
TABLE 5
Figure BDA0002939167740000112
Figure BDA0002939167740000121
As shown in Table 5, the tablets of example 1 and examples 6 to 8 exhibited high stability under heat stress conditions while producing small amounts of amlodipine, rosuvastatin and losartan related substances. On the other hand, the tablets of examples 9 and 10 produced 5 to 8 times more amlodipine and rosuvastatin-related substances than the tablet of example 1.
Meanwhile, the tablets of examples 4 and 5 having a smaller content of disintegrant produced related substances close to or lower than those of example 1, as compared with the tablets of examples 1 and 6 to 8. This result indicates that when the amount of the disintegrant in the tablet is more than 10% by weight based on the total weight of the above layers, it is difficult to secure sufficient stability with the lapse of time under heat stress conditions.
Test example 5: evaluation of bioavailability of rosuvastatin
The bioavailability of beagle dogs was evaluated using the compositions prepared in example 1 and comparative example 1. The trial was conducted by a random crossover study on six beagle dogs. The results are shown in table 6 and fig. 5. FIG. 5 depicts a linear plot of the arithmetic mean of rosuvastatin plasma concentration (ng/mL) versus time (HR).
TABLE 6
Figure BDA0002939167740000122
Figure BDA0002939167740000131
As shown in Table 6 and FIG. 5, the particles contained therein had a particle size of (D)90) Composition of rosuvastatin of 22.5 μm (prepared in example 1) and a composition containing rosuvastatin of particle size (D)90) The bioavailability of the 60 μm rosuvastatin composition (prepared in comparative example 1) was higher. The results are related to improved dissolution performance, as shown in figure 1. Thus, the results indicate that micronized rosuvastatin may improve its dissolution rate and ultimately its bioavailability.

Claims (15)

1. A pharmaceutical composition for preventing or treating cardiovascular diseases, which comprises amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition according to claim 1, wherein the particle size D of rosuvastatin or pharmaceutically acceptable salt thereof is90Is 50 μm or less.
3. The pharmaceutical composition according to claim 1, wherein the particle size D of rosuvastatin or pharmaceutically acceptable salt thereof is900.8 to 50 μm.
4. The pharmaceutical composition according to claim 3, wherein the particle size D of rosuvastatin or pharmaceutically acceptable salt thereof is900.8 to 25 μm.
5. The pharmaceutical composition according to claim 4, wherein the particle size D of rosuvastatin or pharmaceutically acceptable salt thereof is900.8 to 10 μm.
6. Pharmaceutical combination according to claim 1The compound, wherein the particle size D of the rosuvastatin or pharmaceutically acceptable salt thereof is90Is 3 to 50 μm.
7. The pharmaceutical composition according to claim 1, wherein the dissolution rate of rosuvastatin measured 30 minutes after the start of the dissolution test is 85% or more when the composition is subjected to the dissolution test in water according to USP paddle method.
8. The pharmaceutical composition according to claim 7, wherein the dissolution rate of rosuvastatin measured within 15 minutes after the start of the dissolution test is 85% or more when the composition is subjected to the dissolution test in water according to USP Paddle method.
9. A pharmaceutical composite formulation for preventing or treating cardiovascular diseases, 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 of
Comprises losartan or pharmaceutically acceptable salt thereof and pharmaceutically acceptable additives,
wherein the first and second mixture portions are physically separated from each other,
the particle size D of the rosuvastatin or pharmaceutically acceptable salt thereof90Is 50 μm or less.
10. The pharmaceutical composite formulation according to claim 9, wherein the rosuvastatin or pharmaceutically acceptable salt thereof has a particle size D90Is 3 to 50 μm.
11. The pharmaceutical composite formulation according to claim 9, wherein the pharmaceutical composite formulation is a bi-layer 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;
a second layer comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.
12. The pharmaceutical composite formulation according to claim 9, wherein the first mixture portion comprises a disintegrant as an additive, the disintegrant being 3 to 10% by weight of the total weight of the first mixture portion.
13. The pharmaceutical composite formulation according to claim 12, wherein the disintegrant is crospovidone, croscarmellose sodium, sodium carboxymethyl starch, pregelatinized starch, or a combination thereof.
14. The pharmaceutical composite formulation according to claim 9, wherein the first mixture portion contains lactose hydrate and microcrystalline cellulose as additives.
15. The pharmaceutical composite formulation according to claim 9, wherein the second mixture portion is prepared in the form of granules using a roll-compaction process.
CN202110171819.4A 2015-06-30 2016-06-29 Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin Pending CN112933093A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR10-2015-0093714 2015-06-30
KR20150093714 2015-06-30
CN201680031203.4A CN108156807A (en) 2015-06-30 2016-06-29 Medicine compound preparation containing Amlodipine, Losartan and Rosuvastatin

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201680031203.4A Division CN108156807A (en) 2015-06-30 2016-06-29 Medicine compound preparation containing Amlodipine, Losartan and Rosuvastatin

Publications (1)

Publication Number Publication Date
CN112933093A true CN112933093A (en) 2021-06-11

Family

ID=57608904

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201680031203.4A Pending CN108156807A (en) 2015-06-30 2016-06-29 Medicine compound preparation containing Amlodipine, Losartan and Rosuvastatin
CN202110171819.4A Pending CN112933093A (en) 2015-06-30 2016-06-29 Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201680031203.4A Pending CN108156807A (en) 2015-06-30 2016-06-29 Medicine compound preparation containing Amlodipine, Losartan and Rosuvastatin

Country Status (6)

Country Link
KR (2) KR20170003459A (en)
CN (2) CN108156807A (en)
MX (2) MX2017014311A (en)
PH (1) PH12017501986A1 (en)
RU (1) RU2724338C2 (en)
WO (1) WO2017003186A1 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019022436A2 (en) * 2017-07-27 2019-01-31 에리슨제약(주) Pharmaceutical composition comprising nep inhibitor and beta-blocker
KR20190043076A (en) * 2017-10-17 2019-04-25 한미약품 주식회사 Pharmaceutical composition comprising amlodipine, losartan and rosuvastatin for prevention and treatment of cardiovascular diseases accompanied by diabetes and formulated combination including the same
CN108245516B (en) * 2017-11-09 2019-04-12 浙江京新药业股份有限公司 A kind of pharmaceutical composition and preparation method thereof containing rosuvastain calcium
CN109464407A (en) * 2018-12-27 2019-03-15 成都恒瑞制药有限公司 Rosuvastain calcium quick-release formulation and preparation method thereof
KR102500643B1 (en) * 2019-04-18 2023-02-16 한미약품 주식회사 Pharmaceutical combination preparation comprising ezetimibe and losartan
KR20220026641A (en) * 2020-08-25 2022-03-07 주식회사 대웅제약 A single dosage form of a pharmaceutical composition for the treatment or prevention of hypertension and hyperlipidemia

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030124191A1 (en) * 2001-12-27 2003-07-03 Jerome Besse Use of an immediate-release powder in pharmaceutical and nutraceutical compositions
WO2015080433A1 (en) * 2013-11-29 2015-06-04 Hanmi Pharm. Co., Ltd. Pharmaceutical combination formulation comprising amlodipine, losartan and rosuvastatin

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GT199800126A (en) * 1997-08-29 2000-01-29 COMBINATION THERAPY.
US20050096391A1 (en) * 2003-10-10 2005-05-05 Per Holm Compositions comprising fenofibrate and rosuvastatin
KR100582347B1 (en) * 2004-12-30 2006-05-22 한미약품 주식회사 Complex composition of 3-hydroxy-3-methyl glutaryl coa reductase inhibitor and antihypertensive agent, and process for preparing same
US8642083B2 (en) * 2006-10-30 2014-02-04 Hanall Biopharma Co., Ltd. Controlled release complex composition comprising angiotensin-II-receptor blockers and HMG-CoA reductase inhibitors
WO2009154810A2 (en) * 2008-02-25 2009-12-23 Dr. Reddy's Laboratories Ltd. Delivery systems for multiple active agents
UA102721C2 (en) * 2009-01-23 2013-08-12 Ханми Сайенс Ко., Лтд. Solid pharmaceutical composition comprising amlodipine and losartan and a process for the preparation thereof
CN101690816A (en) * 2009-08-16 2010-04-07 王丽燕 Medicinal composition of calcium-containing antagonist, A II receptor antagonist and statins
KR101378973B1 (en) * 2012-04-13 2014-03-28 한미약품 주식회사 Composite formulation comprising multi-unit spheroidal tablet(must) encapsulated in a hard capsule and method for preparing the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030124191A1 (en) * 2001-12-27 2003-07-03 Jerome Besse Use of an immediate-release powder in pharmaceutical and nutraceutical compositions
WO2015080433A1 (en) * 2013-11-29 2015-06-04 Hanmi Pharm. Co., Ltd. Pharmaceutical combination formulation comprising amlodipine, losartan and rosuvastatin
CN105792813A (en) * 2013-11-29 2016-07-20 韩美药品株式会社 Pharmaceutical combination formulation comprising amlodipine, losartan and rosuvastatin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KARTHICK PALANI ET AL: "Enhancement of Rosuvastatin Calcium Bioavailability Applying Nanocrystal Technology and in-vitro, in-vivo evaluations" *
李全林, 中国医药科技出版社 *

Also Published As

Publication number Publication date
MX2017014311A (en) 2018-03-07
WO2017003186A1 (en) 2017-01-05
RU2018103213A (en) 2019-07-31
RU2018103213A3 (en) 2019-12-09
PH12017501986A1 (en) 2018-03-19
RU2724338C2 (en) 2020-06-23
KR20170003459A (en) 2017-01-09
KR20180044873A (en) 2018-05-03
CN108156807A (en) 2018-06-12
MX2021005210A (en) 2021-06-18

Similar Documents

Publication Publication Date Title
TWI649099B (en) Formulation of a pharmaceutical composition comprising amlodipine, ALSARTAN and ROSUVASTATIN
EP2413931B1 (en) Solid pharmaceutical composition comprising amlodipine and losartan and process for producing same
CN112933093A (en) Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin
JP6068765B2 (en) Pharmaceutical combination preparation
CN108289850B (en) Pharmaceutical composite preparation containing amlodipine, losartan and chlorthalidone
CN111886003A (en) Pharmaceutical combination preparation containing ezetimibe and rosuvastatin
CN101653440B (en) Treatment composition containing amlodipine series salt and pril medicament
AU2011339150B2 (en) Complex formulation comprising lercanidipine hydrochloride and valsartan and method for the preparation thereof
US20160045497A1 (en) Complex preparation including valsartan and rosuvastatin calcium and manufacturing method therefor
KR20150034120A (en) Direct-compressible pharmaceutical composition comprising amlodipine and losartan, and tablet using the same
TWI827828B (en) Pharmaceutical combination preparation comprising ezetimibe and losartan
KR101506148B1 (en) Direct-compressible pharmaceutical composition comprising amlodipine and losartan, and tablet using the same
TWI503119B (en) Solid pharmaceutical composition comprising amlodipine and losartan and process for producing same
KR20210074428A (en) Pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination