KR20240014345A - Pharmaceutical formulation comprising amlodipine, valsartan, indapamide and method for preparing the same - Google Patents

Abstract

The present invention relates to a pharmaceutical preparation containing amlodipine, valsartan and indapamide and a method for preparing the same. Specifically, the pharmaceutical formulation of the present invention includes amlodipine, valsartan, and indapamide, and the indapamide has the form of wet granules and has excellent dissolution rate and stability.

Description

Pharmaceutical preparation comprising amlodipine, valsartan and indapamide and method for preparing the same {PHARMACEUTICAL FORMULATION COMPRISING AMLODIPINE, VALSARTAN, INDAPAMIDE AND METHOD FOR PREPARING THE SAME}

The present invention relates to pharmaceutical preparations containing amlodipine, valsartan and indapamide and methods for their preparation. Specifically, the pharmaceutical formulation of the present invention includes amlodipine, valsartan, and indapamide, and the indapamide has the form of wet granules and has excellent dissolution rate and stability.

Cardiovascular disease refers to diseases that occur in the heart and major arteries. Major diseases include high blood pressure, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, atherosclerosis, cerebrovascular disease, stroke, and arrhythmia. there is. Risk factors related to cardiovascular disease, especially atherosclerosis, include age (middle-aged or older), gender (male), hyperlipidemia, diabetes, smoking, lack of exercise, and obesity. Many drugs are used to treat cardiovascular diseases such as high blood pressure, angina, arrhythmia, and hypercholesterolemia, and these drugs are sometimes used in combination with each other.

Treatments for high blood pressure include beta blockers, which reduce heart rate and the burden on the heart by reducing electrical stimulation of nerves to the heart and blood vessels, and reduce the amount of circulating fluid by promoting the excretion of water, sodium, and chlorine in the body. Diuretics that lower blood pressure, angiotensin-converting enzyme inhibitors that relax blood vessels by inhibiting the conversion of angiotensin I to angiotensin II in the body, alpha blockers that lower blood pressure by inhibiting the vasoconstrictive action of catecholamines, and calcium channels that block calcium channels. Calcium channel blockers are used to lower blood pressure by dilating blood vessels by inhibiting inflow.

Amlodipine is 3-ethyl-5-methyl-(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-l,4-dihydro-6-methylpyridine. -3,5-dicarboxylate, a calcium channel blocker used to treat high blood pressure. Amlodipine is a racemic compound with absent carbon. Among enantiomers, (S)-amlodipine is known to have better activity, and is available in various salt forms including benzenesulfonate, camphorsulfonate, nicotinate, and maleate. It is used. Amlodipine is highly hygroscopic and decomposes by absorbing water; one of the main decomposition products is 3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-), also known as impurity D. It is chlorophenyl)-6-methylpyridine-3,5-dicarboxylate.

Valsartan is (2s)-3-methyl-2-[N-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl) [Pentanamido]butyric acid is an angiotensin II receptor used to treat hypertension, heart failure, ischemic peripheral circulatory disorders, and angina pectoris.

Combination drugs with different mechanisms of action, such as s-amlodipine, a calcium channel blocker, and valsartan, an angiotensin II receptor blocker, are more effective in preventing or treating cardiovascular disease than single drugs due to the complementary actions of the drugs. , it has the advantage of increasing patient compliance compared to the drugs used respectively. However, because there are many patients with severe hypertension whose blood pressure cannot be controlled even after taking a two-drug combination drug, there is a great demand for the development of a three-drug combination drug.

Meanwhile, Indapamide is 4-chloro-N-(2-methyl-2,3-dihydro-1H-indol-1-yl)-3-sulfamoylbenzamide and is a thiazide-like diuretic. It is used for cardiovascular diseases because it has a longer duration of action and a stronger blood pressure lowering effect than hydrochlorothiazide, a diuretic in the form of zide, at a similar dosage level.

In particular, among diuretics, indapamide was confirmed to further lower maximum blood pressure compared to hydrochlorothiazide, reduce mortality due to stroke and cardiovascular disease, lower the risk of electrolyte disorders and metabolic disorders, and relieve sympathetic nerve and insulin resistance problems. was found to be low.

Accordingly, the present inventor discovered a novel pharmaceutical formulation and manufacturing method that can improve the dissolution rate of indapamide in a three-drug combination formulation containing amlodipine, valsartan, and indapamide, and completed the present invention.

Korean Patent No. 10-1454070

The purpose of the present invention is to provide a novel pharmaceutical formulation containing amlodipine, valsartan and indapamide.

The purpose of the present invention is to provide a method for producing a pharmaceutical formulation containing amlodipine, valsartan, and indapamide.

The present invention relates to amlodipine or a pharmaceutically acceptable salt thereof; Valsartan or a pharmaceutically acceptable salt thereof; and a formulation comprising indapamide or a pharmaceutically acceptable salt thereof, wherein the indapamide or a pharmaceutically acceptable salt thereof is in the form of wet granules.

The amlodipine or a pharmaceutically acceptable salt thereof may be amlodipine besylate, preferably (S)-amlodipine or (S)-amlodipine besylate.

The wet granules can be manufactured using water, C1-C6 lower alcohol, or a mixed solvent thereof, preferably water, ethanol, or an aqueous ethanol solution, more preferably water, or 50% aqueous ethanol solution. The following ethanol aqueous solutions can be used, and most preferably, they can be prepared using water.

The formulation may include a coating layer, and the coating layer may include polyvinyl alcohol.

The preparation may be a tablet.

The agent may treat or prevent cardiovascular disease, and the cardiovascular disease may be hypertension, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, arteriosclerosis, cerebrovascular disease, stroke, arrhythmia, or cholesterolemia. .

In addition, the present invention includes the steps of mixing indapamide or a pharmaceutically acceptable salt thereof with a solvent to prepare wet granules; Amlodipine or a pharmaceutically acceptable salt thereof, comprising the step of mixing and compressing the wet granules with amlodipine or a pharmaceutically acceptable salt thereof, and valsartan or a pharmaceutically acceptable salt thereof to prepare uncoated tablets; Valsartan or a pharmaceutically acceptable salt thereof; and a method for producing a formulation containing indapamide or a pharmaceutically acceptable salt thereof.

The amlodipine or a pharmaceutically acceptable salt thereof may be amlodipine besylate, preferably (S)-amlodipine or (S)-amlodipine besylate.

The solvent may be water, a C1-C6 lower alcohol, or a mixed solvent thereof, preferably water, ethanol, or an aqueous ethanol solution, and more preferably, water or an aqueous ethanol solution of 50% or less. and, most preferably, it may be water.

The manufacturing method may further include the step of coating the uncoated tablet preparation.

The pharmaceutical formulation containing amlodipine, valsartan, and indapamide according to the present invention has excellent dissolution rate and stability, so it can be used as a combination formulation for the prevention or treatment of cardiovascular diseases, simplifies the formulation process, and improves the patient's convenience in taking the drug. can be provided. In addition, it can be very useful for patients with severe hypertension who are difficult to treat with a single drug or a combination of two drugs.

Figures 1 to 3 show the dissolution rates of s-amlodipine, valsartan and indapamide in Examples 1 to 4 and Comparative Examples 1 to 5 according to dissolution tests.
Figure 4 shows changes in properties of Examples 5 and 6 according to stress testing.
Figures 5 to 7 show the dissolution rates of s-amlodipine, valsartan, and indapamide in Examples 5 and 6 according to the dissolution test.
Figure 8 shows the properties of the granules of Examples 1, 7, 8, and 12 according to stress testing.
Figure 9 shows the pharmacokinetic test results of Example 5.
Figures 10 and 11 show the dissolution rates of indapamide of Examples 13 to 24 according to the dissolution test.
Figure 12 shows the dissolution rate of indapamide of Examples 25 to 27 according to the dissolution test.
Figure 13 shows the dissolution rate of indapamide of Examples 28 to 30 according to the dissolution test.

Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present application may be implemented in various forms and is not limited to the embodiments and examples described herein.

Throughout the specification of the present application, when a part "includes" a certain component, this means that it may further include other components rather than excluding other components unless specifically stated to the contrary.

The present invention provides a pharmaceutical formulation containing amlodipine, valsartan and indapamide and a method for preparing the same.

Amlodipine is 3-ethyl-5-methyl-(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-l,4-dihydro-6-methylpyridine. It is a -3,5-dicarboxylate and a calcium channel blocker. In the present invention, the amlodipine is 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine Includes (S)-amlodipine, a dicarboxylate.

The amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 2.5 to 10 mg, and is preferably amlodipine besylate, (S)-amlodipine or (S)-amlodipine besylate, but is not limited thereto.

Valsartan is (2s)-3-methyl-2-[N-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl) Pentanamido]butyric acid, an angiotensin II receptor.

The valsartan or a pharmaceutically acceptable salt thereof may be included in an amount of 40 to 160 mg.

Indapamide is 4-chloro-N-(2-methyl-2,3-dihydro-1H-indol-1-yl)-3-sulfamoylbenzamide, a thiazide-like diuretic.

The indapamide or a pharmaceutically acceptable salt thereof may be included in an amount of 1.25 to 2.5 mg.

The formulation of the present invention may include, but is not limited to, microcrystalline cellulose, light anhydrous silicic acid, mannitol, crospovidone, sodium starch glycolate, magnesium stearate, and polyvinyl alcohol (PVA).

The formulation of the present invention may use water, C1-C6 lower alcohol, or a mixed solvent thereof as a solvent, preferably water, ethanol, or an aqueous ethanol solution, more preferably water, or 50% or less. It may be an aqueous solution of ethanol, and most preferably it may be water, but is not limited thereto.

The formulation of the present invention may additionally include a coating layer to ensure long-term stability, and the coating base may be one commonly used in the industry, preferably polyvinyl alcohol (PVA).

In the present invention, “cardiovascular disease” may include, but is not limited to, high blood pressure, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, atherosclerosis (arteriosclerosis), cerebrovascular disease, stroke, arrhythmia, and cholesterolemia. No.

As used in the present invention, the term “prevention” refers to any act of suppressing or delaying the onset of a disease by administering a composition, and “treatment” refers to improving or beneficially improving the symptoms of an individual suspected or developing a disease by administering a composition. It means any action that changes.

The present invention will be described in more detail through examples below. However, the examples below are for illustrative purposes only and are not intended to limit the scope of the present invention.

[Manufacturing example]

Manufacturing of amlodipine, valsartan and indapamide combination preparation

As shown in Table 1 below, composite preparations of Examples 1 to 30 and Comparative Examples 1 to 5 were prepared.

division Granulation method Granular solvent characteristic Example 1 wet granulation Purified water Disintegrant for post-mixing: Crospovidone Example 2 wet granulation Purified water Disintegrant for post-mixing: Croscarmellose sodium Example 3 wet granulation Purified water Disintegrant for post-mixing: Sodium starch glycolate Example 4 wet granulation Purified water Main ingredient: amlodipine besylate Example 5 wet granulation Purified water Coating agent: polyvinyl alcohol (PVA) Example 6 wet granulation Purified water Coating agent: Hypromellose (HPMC) Example 7 wet granulation Anhydrous Ethanol Granulating solvent: Anhydrous ethanol Example 8 wet granulation 95.0% Ethanol Granulation solvent: 95.0% ethanol Example 9 wet granulation 87.5% Ethanol Granulation solvent: 87.5% ethanol Example 10 wet granulation 75.0% Ethanol Granulation solvent: 75.0% ethanol Example 11 wet granulation 62.5% Ethanol Granulation solvent: 62.5% ethanol Example 12 wet granulation 50.0% Ethanol Granulation solvent: 50.0% ethanol Example 13 wet granulation Purified water Intragranule disintegrant: sodium starch glycolate 6 mg/T Example 14 wet granulation Purified water Intragranule disintegrant: sodium starch glycolate 12 mg/T Example 15 wet granulation Purified water Intragranule disintegrant: sodium starch glycolate 18 mg/T Example 16 wet granulation Purified water Intragranule disintegrant: low-substituted hydroxypropylcellulose 6 mg/T Example 17 wet granulation Purified water Intragranule disintegrant: low-substituted hydroxypropylcellulose 12 mg/T Example 18 wet granulation Purified water Intragranule disintegrant: low-substituted hydroxypropylcellulose 18 mg/T Example 19 wet granulation Purified water Intragranule disintegrant: croscarmellose sodium 6 mg/T Example 20 wet granulation Purified water Intragranule disintegrant: Croscarmellose sodium 12 mg/T Example 21 wet granulation Purified water Intragranule disintegrant: Croscarmellose sodium 18 mg/T Example 22 wet granulation Purified water Intragranular disintegrant: Crospovidone 6 mg/T Example 23 wet granulation Purified water Intragranular disintegrant: Crospovidone 12 mg/T Example 24 wet granulation Purified water Intragranular disintegrant: Crospovidone 18 mg/T Example 25 wet granulation Purified water Sizing screen after granule drying: 0.7 mm Example 26 wet granulation Purified water Sizing screen after granule drying: 1.0 mm Example 27 wet granulation Purified water Sizing screen after granule drying: 1.2 mm Example 28 wet granulation Purified water Coating agent (PVA): 6 mg/T loading (1.6% compared to bare tablet) Example 29 wet granulation Purified water Coating agent (PVA): 12 mg/T loading (3.2% compared to bare tablet) Example 30 wet granulation Purified water Coating agent (PVA): 18 mg/T loading (4.8% compared to bare tablets) Comparative Example 1 Direct hit granule not used simple mixing Comparative Example 2 Direct hit granule not used Indapamide particle size control (Jet-mill) Comparative Example 3 Direct hit granule not used Addition of surfactant sodium lauryl sulfate (SLS) Comparative Example 4 wet granulation Purified water 3 main ingredients, all wet granules Comparative Example 5 dry granule not used Dry granulation using high pressure

[Example 1]

Preparation of Example 1

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 1 was prepared by compressing the final mixture using a tablet press.

[Example 2]

Preparation of Example 2

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and croscarmellose sodium was added, mixed, and magnesium stearate was added to lubricate to prepare the final mixture.

3. Tablet press

Example 2 was prepared by compressing the final mixture using a tablet press.

[Example 3]

Preparation of Example 3

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granule was placed in a mixer, a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and sodium starch glycolate was added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 3 was prepared by compressing the final mixture using a tablet press.

[Example 4]

Preparation of Example 4

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, a mixture of amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 4 was prepared by compressing the final mixture using a tablet press.

[Example 5]

Preparation of Example 5

Uncoated tablets were prepared in the same manner as in Example 1, and then coated with polyvinyl alcohol (PVA, brand name: Opadry II 85F18422 White) to prepare Example 5.

<Coating process conditions>

- Supply air temperature: 50~60 ℃

- Exhaust temperature: 30~40 ℃

- Air supply fan: 1,400 rpm

- Exhaust fan: 2,400 rpm

- Spray speed (Spray rpm): 0.5 mL/min ~ 0.8 mL/min

- Pan speed (Pan rpm): 5.0~9.5 rpm

- Atomizing air: 0.4 MPa

- Coating solvent: Purified water

- Coating liquid concentration: 20%

[Example 6]

Preparation of Example 6

Uncoated tablets were prepared in the same manner as in Example 1, and then coated with hypromellose (HPMC 2910 6mPa.s, brand name Opadry 03B28796 White) to prepare Example 6.

<Coating process conditions>

- Supply air temperature: 50~60 ℃

- Exhaust temperature: 30~40 ℃

- Air supply fan: 1,400 rpm

- Exhaust fan: 2,400 rpm

- Spray speed (Spray rpm): 0.5 mL/min ~ 0.8 mL/min

- Pan speed (Pan rpm): 5.0~9.5 rpm

- Atomizing air: 0.4 MPa

- Coating solvent: Purified water

- Coating liquid concentration: 10%

[Example 7]

Preparation of Example 7

1. Wet granule production

Anhydrous ethanol solvent was added to a mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate, kneaded, and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 7 was prepared by compressing the final mixture using a tablet press.

[Example 8]

Preparation of Example 8

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with 95% ethanol solvent and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 8 was prepared by compressing the final mixture using a tablet press.

[Example 9]

Preparation of Example 9

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with 87.5% ethanol solvent and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 9 was prepared by compressing the final mixture using a tablet press.

[Example 10]

Preparation of Example 10

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with 75% ethanol solvent and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and lubricated with magnesium stearate to prepare the final mixture.

3. Tablet press

Example 10 was prepared by compressing the final mixture using a tablet press.

[Example 11]

Preparation of Example 11

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with 62.5% ethanol solvent and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 11 was prepared by compressing the final mixture using a tablet press.

[Example 12]

Preparation of Example 12

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with 50% ethanol solvent and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 12 was prepared by compressing the final mixture using a tablet press.

[Example 13]

Preparation of Example 13

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate (6 mg/T) was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 13 was prepared by compressing the final mixture using a tablet press.

[Example 14]

Preparation of Example 14

1. Wet granule production

Purified water was added to a mixture of 12 mg/T of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate, kneaded, and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 14 was prepared by compressing the final mixture using a tablet press.

[Example 15]

Preparation of Example 15

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate (18 mg/T) was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 15 was prepared by compressing the final mixture using a tablet press.

[Example 16]

Preparation of Example 16

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose (6 mg/T) was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 16 was prepared by compressing the final mixture using a tablet press.

[Example 17]

Preparation of Example 17

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose (12 mg/T) was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 17 was prepared by compressing the final mixture using a tablet press.

[Example 18]

Preparation of Example 18

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose (18 mg/T) was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 18 was prepared by compressing the final mixture using a tablet press.

[Example 19]

Preparation of Example 19

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and 6 mg/T croscarmellose sodium was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 19 was prepared by compressing the final mixture using a tablet press.

[Example 20]

Preparation of Example 20

1. Wet granule production

Purified water was added to a mixture of indapamide, mannitol, light anhydrous silicic acid, and 12 mg/T croscarmellose sodium, kneaded, and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 20 was prepared by compressing the final mixture using a tablet press.

[Example 21]

Preparation of Example 21

1. Wet granule production

Purified water was added to a mixture of indapamide, mannitol, light anhydrous silicic acid, and 18 mg/T of croscarmellose sodium, kneaded, and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 21 was prepared by compressing the final mixture using a tablet press.

[Example 22]

Preparation of Example 22

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and crospovidone 6 mg/T was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 22 was prepared by compressing the final mixture using a tablet press.

[Example 23]

Preparation of Example 23

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and 12 mg/T crospovidone was mixed with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 23 was prepared by compressing the final mixture using a tablet press.

[Example 24]

Preparation of Example 24

1. Wet granule production

Purified water was added to a mixture of indapamide, mannitol, light anhydrous silicic acid, and 18 mg/T of crospovidone, kneaded, and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Example 24 was prepared by compressing the final mixture using a tablet press.

[Example 25]

Preparation of Example 25

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Establishment

The dried granules were sized using a Power-mill (Low speed (3,450 rpm)), and the granules were sized using a screen of 0.7 mm.

3. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

4. Tablet press

Example 25 was prepared by compressing the final mixture using a tablet press.

[Example 26]

Preparation of Example 26

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Establishment

The dried granules were sized using a Power-mill (Low speed (3,450 rpm)), and the granules were sized using a 1.0 mm screen.

3. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

4. Tablet press

Example 26 was prepared by compressing the final mixture using a tablet press.

[Example 27]

Preparation of Example 27

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Establishment

The dried granules were sized using a Power-mill (Low speed (3,450 rpm)), and the granules were sized using a 1.2 mm screen.

3. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

4. Tablet press

Example 27 was prepared by compressing the final mixture using a tablet press.

[Example 28]

Preparation of Example 28

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare a mixture.

3. Tablet press

The mixture was compressed into a tablet using a tablet press to prepare a tablet.

4. Coating

Example 28 was prepared by coating the tablet with a coating agent (polyvinyl alcohol) in an amount equivalent to 6 mg/T compared to the bare tablet.

[Example 29]

Preparation of Example 29

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare a mixture.

3. Tablet press

The mixture was compressed into a tablet using a tablet press to prepare a tablet.

4. Coating

Example 29 was prepared by coating the tablet with a coating agent (polyvinyl alcohol) in an amount equivalent to 12 mg/T compared to the bare tablet.

[Example 30]

Preparation of Example 30

1. Wet granule production

A mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate was kneaded with purified water and dried to prepare granules.

2. Final mixing and lubrication

The granules were placed in a mixer, and a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone were added, mixed, and magnesium stearate was added and lubricated to prepare a mixture.

3. Tablet press

The mixture was compressed into a tablet using a tablet press to prepare a tablet.

4. Coating

Example 30 was prepared by coating the tablet with a coating agent (polyvinyl alcohol) in an amount equivalent to 18 mg/T compared to the bare tablet.

[Comparative Example 1]

Preparation of Comparative Example 1

1. Manufacturing of direct hit granules

Indapamide, mannitol, light anhydrous silicic acid, sodium starch glycolate, s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone are sieved through a 30 mesh (USP standard, 595um) and mixed to produce direct beating granules. did.

2. Gliding

Magnesium stearate was added to the direct compression granule and lubricated to prepare the final mixture.

3. Tablet press

Comparative Example 1 was prepared by compressing the final mixture using a tablet press.

[Comparative Example 2]

Preparation of Comparative Example 2

1. Indapamide particle size control

Indapamide was put into a Micronizer Jet mill machine (Feed pressure 5psi, Grind pressure 30psi) and pulverized to the particle size shown in Table 2 below, and then granules were prepared.

D ₁₀ D ₅₀ D ₉₀ Before grinding (μm) 3.85 14.31 41.07 After grinding (μm) 0.88 4.61 13.11

2. Manufacturing of direct hit granules

Indapamide, mannitol, light anhydrous silicic acid, sodium starch glycolate, s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone ground with a jet mill are sieved through 30 mesh (USP standard, 595um) and mixed. Directly pressed granules were prepared.

3. Gliding

Magnesium stearate was added to the direct compression granule and lubricated to prepare the final mixture.

4. Tablet press

Comparative Example 2 was prepared by compressing the final mixture using a tablet press.

[Comparative Example 3]

Preparation of Comparative Example 3

1. Manufacturing of direct hit granules

Indapamide, mannitol, light anhydrous silicic acid, sodium starch glycolate, s-amlodipine besylate, valsartan, microcrystalline cellulose, sodium lauryl sulfate (SLS), light anhydrous silicic acid, and crospovidone are sieved through 30 mesh (USP standard, 595um). By mixing, direct beating granules were prepared.

2. Gliding

Magnesium stearate was added to the direct compression granule and lubricated to prepare the final mixture.

3. Tablet press

Comparative Example 3 was prepared by compressing the final mixture using a tablet press.

[Comparative Example 4]

Preparation of Comparative Example 4

1. Wet granule production

A mixture of indapamide, mannitol, sodium starch glycolate, light anhydrous silicic acid, S-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone was mixed with purified water, kneaded, and dried to prepare granules.

2. Gliding

Magnesium stearate was added to the granule and lubricated to prepare the final mixture.

3. Tablet press

Comparative Example 4 was prepared by compressing the final mixture using a tablet press.

[Comparative Example 5]

Preparation of Comparative Example 5

1. Dry granule production

Dry granules were prepared from a mixture of indapamide, mannitol, light anhydrous silicic acid, and sodium starch glycolate under strong pressure using a roller compacter.

2. Final mixing and lubrication

The dry granule was placed in a mixer, a mixture of s-amlodipine besylate, valsartan, microcrystalline cellulose, light anhydrous silicic acid, and crospovidone was added, mixed, and magnesium stearate was added and lubricated to prepare the final mixture.

3. Tablet press

Comparative Example 5 was prepared by compressing the final mixture using a tablet press.

[Test Example 1]

Stability test of combination preparation according to raw drug quantity and manufacturing method

A stability test was conducted on the tablets of Examples 1 to 6 and Comparative Examples 1 to 5 by measuring the amount of related substances generated for 2 weeks under the following conditions.

<Harsh test conditions>

The amount of related substances generated over time was observed under conditions of 50°C and 80% RH. At this time, the packaging material was bottle packaging, and the bottle was made of HDPE and the lid was made of PP. The lid was kept closed.

<HPLC analysis conditions>

Detector: Ultraviolet visible absorption spectrophotometer (measurement wavelength 237nm)

Column: Capcell Pak MG C18 (4.6 * 250mm, 5um) or equivalent column

Injection volume: 30 uL

Flow rate: 1.0 mL/min

Column temperature: 50℃

Sample temperature: 5℃

Mobile phase A: Add 10 mL of triethylamine to 1 L of water and adjust the pH to 3.0 ± 0.02 with phosphoric acid.

Mobile phase B: methanol : acetonitrile = 70:30 (v/v)

Time (min) Mobile phase A (%) Mobile phase B (%) 0 70 30 70 52 48 125 52 48 130 70 30 140 70 30

The experimental results are shown in Table 4 below.

standard Early(%) Severe 2 weeks (%) Example 1 2.0% or less 0.02 0.02 Example 2 0.02 0.02 Example 3 0.02 0.02 Example 4 0.02 0.03 Example 5 0.02 0.03 Example 6 0.02 0.03 Comparative Example 1 0.04 0.04 Comparative Example 2 0.02 0.02 Comparative Example 3 0.02 0.02 Comparative Example 4 0.33 0.64 Comparative Example 5 0.02 0.03

As shown in Table 4, Examples 1 to 6 showed low generation of related substances and did not significantly increase over time, but Comparative Example 4, manufactured with all wet granules, produced related substances. It was confirmed that the amount of occurrence increased significantly.

Therefore, it was confirmed that the composition of the present invention prepared according to the wet granule production method of Examples 1 to 6 had excellent stability.

[Test Example 2]

Dissolution test of complex preparation according to raw drug quantity and manufacturing method

A dissolution test was performed on the tablets of Examples 1 to 4 and Comparative Examples 1 to 5 under the following conditions. The dissolution characteristics of S-amlodipine, valsartan, and indapamide were evaluated. As a control group, S-amlodipine and valsartan were Ahn-Gook Pharmaceutical's Levosartan Tablets 2.5/160 mg, and indapamide was Jinyang Pharmaceutical's Dapid Tablets 2.5 mg. was used.

<Dissolution test conditions>

Dissolution test method: Korean Pharmacopoeia Method 2 (Paddle method)

Eluate: 900 mL

Eluent: pH 1.2

Elution temperature: 37 ± 0.5 ℃

Exam time: 120 minutes

<HPLC analysis conditions>

Detector: Ultraviolet-visible absorption spectrophotometer (measurement wavelength 230 nm)

Column: Phenomenex Synergi polar-RP (4.6 * 150mm, 4um) or equivalent column

Injection volume: 80 uL

Flow rate: 1.2 mL/min

Column temperature: 40℃

Sample temperature: 5℃

Mobile phase: Acetonitrile : Water : Trifluoroacetic acid = 500 : 500 : 2 (v/v/v)

The experimental results are shown in Figures 1 to 3.

As shown in Figures 1 to 3, as a result of evaluating the dissolution characteristics of each of S-amlodipine, valsartan, and indapamide, Examples 1 to 4, in which only indapamide was manufactured using wet granules, were S-amlodipine, valsartan, and indapamide. While the dissolution rates of mead were all similar to the control group, Comparative Example 4, in which all of S-amlodipine, valsartan, and indapamide were manufactured using wet granules, showed that the dissolution rates of S-amlodipine, valsartan, and indapamide were all lower than the control group. Therefore, it was confirmed that the best dissolution rate was obtained when only indapamide was manufactured using wet granules.

In addition, Comparative Examples 1 to 3 and Comparative Example 5 prepared with direct hit granules and dry granules showed that the dissolution rate of indapamide was significantly lower than the control group, and the granulation method of wet granules was more effective than the direct hit granulation or dry granulation method. It was confirmed that when manufactured through this method, a better dissolution rate was achieved.

In addition, it was confirmed that Examples 1 to 3 using different disintegrants showed similar dissolution characteristics, showing that there was no difference in dissolution characteristics depending on the type of disintegrant. S-amlodipine besylate and amlodipine besylate were used, respectively. It can be seen that Examples 1 and 4, including Examples 1 and 4, exhibit similar dissolution characteristics, showing that there is no difference in dissolution characteristics between S-amlodipine and amlodipine.

[Test Example 3]

Stability test of composite preparation according to coating agent

A stability test was conducted on the tablets of Examples 5 and 6, each coated with different coating agents, by observing the amount of related substances and their properties for 4 weeks under the following conditions.

<Harsh test conditions>

The amount of related substances generated over time was observed under conditions of 50°C and 80% RH. At this time, the packaging material was bottle packaging, and the bottle was made of HDPE and the lid was made of PP. The lid was kept open.

<HPLC analysis conditions>

Detector: Ultraviolet visible absorption spectrophotometer (measurement wavelength 237nm)

Column: Capcell Pak MG C18 (4.6 * 250mm, 5um) or equivalent column

Injection volume: 30 uL

Flow rate: 1.0 mL/min

Column temperature: 50℃

Sample temperature: 5℃

Mobile phase A: Add 10 mL of triethylamine to 1 L of water and adjust the pH to 3.0 ± 0.02 with phosphoric acid.

Mobile phase B: methanol : acetonitrile = 70:30 (v/v)

The experimental results are shown in Table 5 and Figure 4 below.

(%) Example 5 Example 6 standard 2.0% or less Early 0.02 0.02 Harsh 1 week 1.11 1.25 harsh 2 weeks 1.88 2.42 harsh 4 weeks 3.18 3.50

As shown in Table 5, it was confirmed that Example 5 produced a lower amount of related substances compared to Example 6. In addition, as shown in Figure 4, as a result of comparing the properties during two weeks of harsh treatment, it was confirmed that Example 5 showed no change compared to the initial state, while Example 6 showed cracks and peeling of the coating layer.

Therefore, it can be seen that Example 5 using polyvinyl alcohol (PVA) as a coating agent has better stability than Example 6 using hypromellose (HPMC) as a coating agent.

[Test Example 4]

Dissolution test of composite preparation according to coating agent

A dissolution test was performed in the same manner as Test Example 2 on the tablets of Examples 5 and 6, each manufactured by coating with different coating agents. The results are shown in Figures 5 to 7.

As shown in Figures 5 to 7, as a result of evaluating the dissolution characteristics of S-amlodipine, valsartan, and indapamide, the dissolution rates of S-amlodipine, valsartan, and indapamide in Example 5 were all similar to the control group. , Example 6 confirmed that the dissolution rates of s-amlodipine and valsartan were similar to the control group, while the dissolution rate of indapamide was lower.

Therefore, it can be seen that Example 5 using polyvinyl alcohol (PVA) as a coating agent shows a better dissolution rate compared to Example 6 using hypromellose (HPMC) as a coating agent.

[Test Example 5]

Stability test of composite preparation according to granule solvent

A stability test was conducted on the tablets of Example 1 and Examples 7 to 12, each manufactured using different granulation solvents, by observing the amount of related substances generated and the properties of the granules over 4 weeks in the same manner as Test Example 3. did. The results are shown in Table 6 and Figure 8 below.

Manufacturing method (granulation solvent) period Total related substances Example 1 Wet granules (purified water) Early 0.29 Harsh 1 week 0.92 harsh 2 weeks 1.34 harsh 4 weeks 1.98 Example 7 Wet granulation (anhydrous ethanol) Early 0.29 Harsh 1 week 1.33 harsh 2 weeks 2.13 harsh 4 weeks 3.80 Example 8 Wet granulation (95% ethanol) Early 0.25 Harsh 1 week 1.12 harsh 2 weeks 1.63 harsh 4 weeks 3.07 Example 9 Wet granulation (87.5% ethanol) Early 0.02 Harsh 1 week 0.74 harsh 2 weeks 1.50 harsh 4 weeks - Example 10 Wet granulation (75.0% ethanol) Early 0.02 1 week harsh 0.83 harsh 2 weeks 1.64 harsh 4 weeks - Example 11 Wet granulation (62.5% ethanol) Early 0.02 Harsh 1 week 1.10 harsh 2 weeks 1.90 harsh 4 weeks - Example 12 Wet granulation (50% ethanol) Early 0.24 Harsh 1 week 0.79 harsh 2 weeks 1.16 harsh 4 weeks 1.97

As shown in Table 6, the amount of related substances generated was lowest in Example 1 using purified water as the granulating solvent, and highest in Example 7 using anhydrous ethanol as the granulating solvent. In addition, as shown in Figure 8, the agglomeration of the granules was the least in Example 1, and the agglomeration of the granules was found to be greater in that order of Example 12, Example 8, and Example 7. As the ethanol content increases, the agglomeration of the granules increases. It was confirmed that the agglomeration phenomenon increased.

Therefore, it can be seen that the lower the content of purified water or organic solvent as a granule solvent, the better the stability, and the better the properties of the granules, resulting in more excellent effects in terms of mixing uniformity and process efficiency.

[Test Example 6]

Pharmacokinetic testing of combination preparations

A pharmacokinetic test was conducted on the tablets of Example 5, which showed optimal stability and dissolution rate through Test Examples 1 to 5. A test group was formed for beagle dogs as shown in Table 7 below. The tablets of Example 5 using polyvinyl alcohol (PVA) as a coating base were used as test substances, and Dapid tablets were used as control substances. Approximately 2 mL of whole blood was collected through the jugular vein at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after test substance administration and centrifuged at 3,000 rpm for 5 minutes. After separating the plasma, the separated plasma was placed in tubes of 500 μL The results are shown in Table 8 and Figure 9 below.

army gender Number of animals (animals) animal number dosage administered substance 1st period G1 M 6 1-6 1 tablet test substance G2 M 6 7-12 1 tablet control material 2nd period G1 M 6 1-6 1 tablet control material G2 M 6 7-12 1 tablet test substance

<Blood collection information>

Blood collection agency: Notus

Phase 1 test substance administration and blood collection start date: 2018.06.25

1st blood collection end date: 2018.06.26

Phase 2 test substance administration and blood collection start date: 2018.07.02

Stage 2 blood collection end date: 2018.07.03

<Test material information>

Designation: AG-1705

Manufacturing number: R18001

Active ingredient: Indapamide

Appearance and appearance: Dark yellow oblong film-coated tablet

Manufacturer: Anguk Pharmaceutical Co., Ltd.

<Control material information>

Name: Dapid Tablet 2.5mg

Manufacturing number: 17001

Active ingredient: Indapamide

Appearance and appearance: Yellow round tablet

Manufacturer: Jinyang Pharmaceutical Co., Ltd.

Area under the blood concentration curve (AUC _t ) Highest blood concentration (C _max ) control group 778.27 ± 230.86 112.09 ± 19.72 test group 789.36 ± 240.17 123.67 ± 21.94 90% CI (T/R Ratio) 0.9251 - 1.0098 (1.01) 1.0004 - 1.1076 (1.05) CV(%) 5.2 6.0

As shown in Table 8 and Figure 9, as a result of observing pharmacokinetics (PK), the test group administered Example 5 had area under the blood concentration curve (AUC) and peak blood concentration (C _max) at levels similar to those of the control group. ) is shown.

[Test Example 7]

Dissolution test according to type and dose of disintegrant in granules

A dissolution test was performed in the same manner as Test Example 2 on the tablets of Examples 13 to 24, each manufactured using different intragranular disintegrants and doses. In order to evaluate the type and capacity of the disintegrant contained in the granules, a dissolution evaluation was conducted on indapamide, the main ingredient contained in the granules, and the results are shown in Figures 10 and 11.

As shown in Figures 10 and 11, as a result of evaluating the dissolution characteristics of indapamide, the dissolution rates of Examples 13 to 15 using sodium starch glycolate and Examples 19 to 21 using croscarmellose sodium were compared to the control group. It was confirmed that it was within the range of Example 1, and it was confirmed that the dissolution rate increased as the capacity of the disintegrant increased. On the other hand, it was confirmed that Examples 16 to 18 using low-substituted hydroxypropyl cellulose and Examples 22 to 24 using crospovidone showed a lower dissolution rate than that of Example 1.

Therefore, it can be seen that Examples 13 to 15 using sodium starch glycolate and Examples 19 to 21 using croscarmellose sodium exhibit better dissolution rates.

In addition, equivalence between Example 1 and the control group was secured through comparative clinical trials, and being within the range between Example 1 and the control group means that the possibility of clinical success is very high. Therefore, it is believed that Examples 13 to 15 using sodium starch glycolate and Examples 19 to 21 using croscarmellose sodium have a very high possibility of clinical success regardless of the dose of the disintegrant.

[Test Example 8]

Dissolution test according to tablet size

A dissolution test was performed in the same manner as Test Example 2 on the tablets of Examples 25 to 27, each manufactured using different sizing screens. After drying the granules, a dissolution evaluation was conducted on indapamide, the main ingredient contained in the granules, to evaluate the size of the granules, and the results are shown in Figure 12.

As shown in Figure 12, as a result of evaluating the dissolution characteristics of indapamide, it was confirmed that the dissolution rates of Examples 25 to 27 were within the range between the control group and Example 1, and there was no significant difference in dissolution rate depending on the size of the tablet. It was confirmed that it was not.

Therefore, it can be seen that there is no difference in dissolution characteristics depending on the size of the tablets, and it is believed that Examples 25 to 27 have a very high possibility of clinical success regardless of the size of the tablets.

[Test Example 9]

Dissolution test according to coating agent volume

A dissolution test was performed in the same manner as Test Example 2 on the tablets of Examples 28 to 30, each manufactured using different doses of coating agent. A dissolution evaluation was performed on indapamide, and the results are shown in Figure 13.

As shown in Figure 13, as a result of evaluating the dissolution characteristics of indapamide, it was confirmed that the dissolution rates of Examples 28 to 30 were within the range between the control group and Example 1, and there was a significant difference in dissolution rate depending on the dosage of the coating agent. I confirmed that it did not appear.

Therefore, it can be seen that there is no difference in dissolution characteristics depending on the dosage of the coating agent, and it is judged that Examples 28 to 30 have a very high possibility of clinical success regardless of the dosage of the coating agent.

Claims (20)

Amlodipine or a pharmaceutically acceptable salt thereof; Valsartan or a pharmaceutically acceptable salt thereof; and a formulation comprising indapamide or a pharmaceutically acceptable salt thereof, wherein the indapamide or a pharmaceutically acceptable salt thereof is in the form of wet granules.
The preparation according to claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof is amlodipine besylate.
The preparation according to claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof is (S)-amlodipine or (S)-amlodipine besylate.
The formulation according to claim 1, wherein the wet granules are manufactured using water, C1-C6 lower alcohol, or a mixed solvent thereof.
The formulation according to claim 1, wherein the wet granules are manufactured using water, ethanol, or an aqueous ethanol solution.
The formulation according to claim 1, wherein the wet granules are manufactured using water or an aqueous solution of 50% or less ethanol.
The formulation according to claim 1, wherein the wet granules are manufactured using water.
The formulation according to claim 1, wherein the formulation comprises a coating layer.
The formulation according to claim 8, wherein the coating layer contains polyvinyl alcohol.
The preparation according to claim 1, wherein the preparation is a tablet.
Preparing wet granules by mixing indapamide or a pharmaceutically acceptable salt thereof with a solvent;
Amlodipine or a pharmaceutically acceptable salt thereof, comprising the step of mixing and compressing the wet granules with amlodipine or a pharmaceutically acceptable salt thereof, and valsartan or a pharmaceutically acceptable salt thereof to prepare uncoated tablets; Valsartan or a pharmaceutically acceptable salt thereof; and a method for producing a formulation containing indapamide or a pharmaceutically acceptable salt thereof.
The method of claim 11, wherein the amlodipine or a pharmaceutically acceptable salt thereof is amlodipine besylate.
The method of claim 11, wherein the amlodipine or a pharmaceutically acceptable salt thereof is (S)-amlodipine or (S)-amlodipine besylate.
The method of claim 11, wherein the solvent is water, a C1-C6 lower alcohol, or a mixed solvent thereof.
The method of claim 11, wherein the solvent is water, ethanol, or an aqueous ethanol solution.
The method of claim 11, wherein the solvent is water or an aqueous solution of 50% or less ethanol.
The method of claim 11, wherein the solvent is water.
The method of claim 11, further comprising the step of coating the uncoated tablet.
The agent according to claim 1, wherein the agent is used to treat or prevent cardiovascular diseases.
The agent according to claim 19, wherein the cardiovascular disease is hypertension, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, arteriosclerosis, cerebrovascular disease, stroke, arrhythmia, or cholesterolemia.