CN112933093A

CN112933093A - Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin

Info

Publication number: CN112933093A
Application number: CN202110171819.4A
Authority: CN
Inventors: 金用镒; 林昊泽; 曺赫俊; 尹英洙; 朴宰贤; 禹钟守
Original assignee: Hanmi Pharmaceutical Co Ltd
Current assignee: Hanmi Pharmaceutical Co Ltd
Priority date: 2015-06-30
Filing date: 2016-06-29
Publication date: 2021-06-11
Also published as: CN108156807A; RU2724338C2; RU2018103213A; MX2021005210A; WO2017003186A1; KR20170003459A; KR20180044873A; MX2017014311A; RU2018103213A3; PH12017501986A1

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

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

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

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

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

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

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

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.