BR112014025956B1 - composition comprising amlodipine and losartan having improved stability and use thereof - Google Patents

Abstract

Summary "composition comprising amlodipine and losartan having improved stability" disclosed herein is a composition comprising amlodipine and losartan having improved stability.

Description

COMPOSITION UNDERSTANDING ANLODIPINO AND LOSARTANA HAVING IMPROVED STABILITY AND USE OF THE SAME

TECHNICAL FIELD [001] The present invention relates to a composition stabilized with an antioxidant, comprising amlodipine and losartan.

BACKGROUND [002] Since hypertension is the biggest risk factor for life-threatening coronary artery diseases such as stroke, heart failure, myocardial infarction, etc .; and a cause of cardiovascular complications such as kidney failure, it is important to continually control blood pressure, instead of curing hypertension itself. Likewise, long-term administration of antihypertensive drugs is required, so that patients are circumspect on selective drugs. For the continued treatment of hypertension, a combination of two or more drugs differing in their therapeutic mechanism may have better therapeutic and preventive effects than a single drug. In addition, a combination therapy with different drugs reduces the dosage of single drugs, and thus the side effects that can occur after long-term administration of a drug.

[003] Drugs for use in hypertension therapy are typically classified into diuretics, sympatholytic agents and vasodilators according to the mechanism of action. Most vasodilators in current use are again divided into ACE inhibitors (angiotensin converting enzymes), angiotensin II receptor blockers (ARB) and calcium channel blockers according to the mechanism of action.

[004] Amlodipine is a dihydropyridine-type calcium channel blocker (DHP) used to lower blood pressure and to treat angina pectoris pain. Once absorbed, amlodipine lowers blood pressure by relaxing the

2/40 arterial smooth muscle, which decreases total peripheral resistance and therefore reduces blood pressure and increases blood flow to the myocardium. Amlodipine is commercially available as various salts such as besylate, maleate, cansilate, etc., with the predominance of amlodipine besylate.

[005] Losartan is one of the oldest drugs developed among anti-hypertensive agents ARB (angiotensin II receptor blocker), and acts as an angiotensin II receptor antagonist.

[006] Differing from one another in the mechanism, amlodipine calcium channel blocker and losartan ARB are expected to exert therapeutic effects on hypertension synergistically when administered together. However, a compound formulation made by making tablets directly from a simple mixture of amlodipine and losartan is very poor in stability under conditions of acceleration.

[007] An amlodipine formulation is generally comprised of a combination of amlodipine representing pharmaceutical efficacy with a salt useful for activating and formulating the active ingredient. The amlodipine can preferably be in the form of a free base considering that the salts are responsible for stabilizing the amlodipine active ingredient. However, amlodipine is preferably administered as pharmaceutically acceptable acid addition salts since the alkali salt is poor in water solubility. Currently, compound formulations are available in which amlodipine acid addition salts that act in synergy with other drugs. Examples include a combination of amlodipine besylate and atorvastatin calcium (US Patent No. 6,455,574), a combination of amlodipine and valsartan besylate (US Patent No. 6,395,728), and a combination of amlodipine and simvastatin cansilate (Korean Patent No. 742432).

[008] As a free base prone to being destabilized by light, heat or

3/40 water, amlodipine exhibits weak therapeutic effects under such conditions. In order to overcome this disadvantage, several amlodipine acid salts are currently marketed in a package. However, the formulations developed so far are still insufficient to guarantee the amlodipine stability.

[009] Particularly, when amlodipine acid salts are physically mixed with losartan, the stability of amlodipine becomes weak because losartan and excipients react chemically with the salts.

[010] In general, losartan is used in the form of potassium salts. Losartan potassium salts are stable under normal conditions, but are degraded when heated under acidic conditions. That is, when combined with losartan, amlodipine acid addition salts degrade the stability of losartan.

[011] For example, the formulation of the amlodipine / losartan compound currently commercialized comprising amlodipine cansilate and potassium salt rosaltan (Korean Unexamined Patent Publication No. 20080052852) does not guarantee sufficient stability between the two ingredients.

DISCLOSURE

TECHNICAL PROBLEM [012] Therefore, the present invention has kept in mind the above problems that occur in the prior art, and an object of the present invention is to provide a composition comprising amlodipine and losartan in which the physical interaction between amlodipine and losartan is minimized and that it is improved in stability by an antioxidant and simplified in the formulation process.

TECHNICAL SOLUTION [013] In accordance with one aspect thereof, the present invention provides a composition for preventing and treating cardiovascular disorders,

4/40 comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and propyl gallate.

ADVANTAGEOUS EFFECTS [014] Being designed to minimize the physical interaction of amlodipine with losartan and to employ propyl gallate as an antioxidant, the composition to prevent and treat cardiovascular disorders according to the present invention is greatly improved in stability and simplified in formulation process.

DESCRIPTION OF THE DRAWINGS [015] Figure 1 shows dissolved amlodipine curves from tablets of examples 8 to 17.

[016] Figure 2 shows losartan dissolution curves from tablets of examples 8 to 17.

BEST MODE [017] Below is a detailed description of the present invention.

[018] The present invention is directed to a composition for preventing and treating cardiovascular disorders, comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and propyl gallate.

[019] Propyl gallate (CwH ^ Os) is an antioxidant and works not only to increase the stability of the active ingredients losartan and amlodipine when they are formulated in admixture with other pharmaceutically acceptable additives, thus yielding highly stable products, but also to decrease the heat or moisture-induced degradation of the active ingredients, thus increasing resistance against change over time. Propyl gallate is safe compared to other antioxidants as it does not cause skin irritation.

[020] The composition can be formulated in tubular tablets, capsules,

5/40 two layer tablets, multiple layer tablets, and single tablets. In the present invention, amlodipine or the pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof are formulated in a dosage form in which the active ingredients physically separate from each other so that the surface area of contact between them is reduced to the greatest degree as possible. More preferably it is a two-layer tablet in which the amlodipine layer composed of amlodipine or a pharmaceutically acceptable salt thereof and a losartan layer composed of losartan or a pharmaceutically acceptable salt thereof are separated from each other. The two-layer tablet can be manufactured, for example, by placing an upper layer of amlodipine and additives in a lower hard layer of losartan potassium and additives and pressing the resulting two layers with a tablet press machine.

[021] In this regard, propyl gallate may preferably be contained in the amlodipine layer comprised of amlodipine or a pharmaceutically acceptable salt thereof.

[022] Preferably, propyl gallate is used in an amount of 0.001 to 1% by weight, based on the total weight of the composition, more preferably in an amount of 0.001 to 0.5% by weight, and more preferably in an amount from 0.001 to 0.1% by weight. When used in this amount, propyl gallate properly increases the stability of the active agents.

[023] In a preferred embodiment of the present invention, amlodipine or a pharmaceutically acceptable salt thereof is contained in an amount of 1 to 6% by weight, and losartan or a pharmaceutically acceptable salt thereof is contained in 5 to 30% by weight, more preferably, the levels of amlodipine

6/40 or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof may be in the order of 1.2 to 3.5% by weight and in the order of 10 to 20% by weight, respectively.

[024] Based, for example, on the same tablet, the compound formulation of the present invention can preferably contain amlodipine in an amount of 3 to 12 mg and losartan in an amount of 30 to 120 mg, more preferably amlodipine in an amount 5 to 10 mg, and losartan in an amount of 50 to 100 mg.

[025] For use in the present invention, the pharmaceutically acceptable salt of amlodipine can be prepared with a non-toxic addition salt containing a pharmaceutically acceptable anion, as exemplified by: chloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, besylate, and cansilate, with better performance for amlodipine besylate and losartan potassium.

[026] More preferably, the pharmaceutical composition of the present invention may contain: amlodipine besylate, microcrystalline cellulose, D-mannitol, sodium starch glycolate, povidone, magnesium stearate and propyl gallate for an amlodipine layer, and potassium losartan, microcrystalline cellulose, crospovidone and magnesium stearate for a losartan layer.

[027] To ensure long-term stability, the pharmaceutical composition of the present invention can further promote a coating agent. As long as it is typically used in the art, any coating agent can be employed. Preferably it is at least one selected from a group consisting of a water soluble coating agent comprising a polyvinyl alcohol derivative, methacrylic acid derivative, and a polyacrylic acid derivative, Kollicoat® Protect, Opadry, and hydroxypropylmethyl cellulose (HPMC ), with Kollicoat® Protect being more preferred.

[028] In addition, the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive. The additive can be used in an amount of 5 to 90% by weight, based on the total weight of the composition, and more preferably in an amount of 50 to 90% by weight. As long as it is pharmaceutically acceptable, any additive can be used. Examples of additives include: a filler, a thickener, a disintegrator, a lubricant, a preservative, an antioxidant, an isotonic agent, a buffer, a coating agent, a sweetener, a solubility enhancer, a base, a dispersant, a humectant, a suspending agent, a stabilizer, a dye, an aromatic, a water-soluble addition, and an excipient. In more detail, the disintegrator can be exemplified by: microcrystalline cellulose, lactose, mannitol, sodium citrate, calcium phosphate, glycine, starch, sodium starch glycolate, cropovidone, sodium croscamellose, and specific compound silicate; the binder can include povidone, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, acacia gum, macrogol, silicate derivatives such as light anhydride silicic acid, synthetic aluminum silicate, calcium silicate or aluminate magnesium metasilicate, phosphates such as hydrogen calcium phosphate, carbonates such as calcium carbonate, a combination thereof; and the lubricant includes stearic acid, metal stearate such as calcium stearate or magnesium stearate, talc, colloidal silica, fructose fatty acid esters, hydrogenated vegetable oil, high melting wax, glyceryl fatty acid esters, dibenate of glyceryl, talc, and a mixture thereof.

[029] For use in the present invention, the disintegrator acts to cause the solid formulation to break down quickly into smaller fragments in the digestive juice, facilitating dissolution at a sufficient rate.

[030] In perfecting the dissolution of solid formulations, namely tablets, it is important to select a compatible disintegrator

8/40 and use a compatible amount of the disintegrator. When dissolution is slowed by the disintegration delay, a disintegrator can be used in a high amount. An excessive amount of a disintegrator, however, can incapacitate the tablet from retaining its strength sufficiently to maintain its shape and properties after the preparation and packaging processes of the tablet or during transport and storage of the tablet. Therefore, the selection of a compatible disintegrator is very important, and a limitation is placed on the amount of the disintegrator.

[031] Preferably, the disintegrator can be used in an amount of 1 to 10% by weight, based on a total weight of the composition, and more preferably in an amount of 3 to 7% by weight. Given the range of quantity, the disintegrator absorbs water to cause the formulation to break down into smaller fragments, thus facilitating the release of the active ingredients and achieving a pharmacologically effective serum level of the active ingredients.

[032] Cardiovascular disorders of which the composition of the present invention can be preventive and curative can be selected from a group consisting of, but not limited to: angina pectoris, hypertension, arteriospasm, cardiac arrhythmia, cardiomegaly, congestive heart failure , thrombosis, and myocardial infarction.

[033] Using a typical method, a solid pharmaceutical composition according to the present invention can be formulated into tablets, capsules, multiparticulates, etc., which can be administered orally, sublingually or by other routes. Preferably, the composition of the present invention can be formulated into tablets for oral dosing. For example, the components of the composition of the present invention can simply be mixed, and readily formulated into tablets using a press machine.

9/40 tablets. It will be apparent to a person skilled in the art that the compatible total daily dose can be determined by a responsible physician within the scope of the medical judgment.

[034] A better understanding of the present invention can be obtained through the following examples which are set out to illustrate, but are not construed as limiting the present invention.

MODE FOR INVENTION

EXAMPLE TEST 1: Test for stability between amlodipine and losartan [035] To examine a change in stability between amlodipine and losartan with interaction between them, their contents were measured after they were physically mixed and exposed to accelerating conditions.

Test method [036] Amlodipine and losartan were physically mixed in amounts shown in Comparative Examples 1 and 2 in Table 1, below. In Comparative Example 3, the composition of Comparative Example 3 was formulated into a tablet in order to examine the effect of pressure and heat, applied to the formulation, on the stability between amlodipine and losartan. The mixture was compressed at a pressure of 20 kPa in Comparative Example 3.

Table 1

Feature Ingredient Example C. 1 Example C. 2 Example C. 3 Content (mg) Content proportion (%) Content (mg) Content proportion (%) Content (mg) Content proportion (%) Pharmaceutically active ingredient Besylate Amlodipine 6.94 12.2 6.94 1.7 6.94 1.7 Losartana 50 87.8 50 12.5 50 12.5

10/40

potassium Filler Cellulose Microcristali na (101) - - 130 32.6 130 32.6 Cellulose Microcristali na (102) - - 135.1 33.9 135.1 33.9 Excipient D-mannitol - - 40 10.0 40 10.0 Disintegrator Glycolate Starch sodium - - 17 4.3 17 4.3 Crospovidon a - - 12 3.0 12 3.0 Binder Povidona - - 5 1.3 5 1.3 Lubricant Stearate magnesium - - 3 0.8 3 0.8 Weight 56.94 100 399.04 100 399.04 100 state Powder Powder Tablet

[037] To test the stability between amlodipine and losartan, mixtures of Comparative Examples 1 and 2, and the tablets of Comparative Example 3 were exposed to an acceleration chamber. The contents of amlodipine and losartan were measured immediately after preparation of the mixtures and the tablet; and after two and five weeks of exposure to accelerating conditions.

Table 2

Temperature 40 ± 2 ° C

11/40

Relative humidity 75 ± 5%

[038] The contents of amlodipine and losartan were measured as follows.

(1) Protocol for measuring anlopidine content [039] Three tablets from Comparative Example 3 were weighed precisely, and ground. Separately, the corresponding amounts of the powders of Comparative Example 1 and 2 were taken.

[040] An amount of each sample corresponding to 5 mg of amlodipine was weighed, and placed in a 100 ml brown volumetric fraction to which a mobile phase was then added to give a volume of 100 ml. Of the solution, 25 ml was taken, and placed in a 50 ml brown volumetric flask. The mobile phase was poured into this flask to exactly align the surface of the mobile phase with the marked line, followed by filtration through a 0.45 pm membrane filter. The contents were determined by HPLC under the conditions shown in table 3 below.

(2) Protocol for measuring losartan content [041] Three tablets of Comparative Example 3 were weighed precisely, and ground. Separately, the corresponding amounts of the powders of Comparative Example 1 and 2 were taken.

[042] An amount of each sample corresponding to 50 mg of losartan potassium was weighed, and placed in a 200 ml volumetric fraction for which a mobile phase A (phosphate salt buffer: acetonitrile (85:15, v / v %) was then added to give a volume of 100 ml. Following an ultrasonic extraction for 10 min, mobile phase A was added to give an exact volume of 200 ml. Filtration was conducted through a 0.45 pm membrane filter. The contents were determined by HPLC under conditions shown in Table 3 below.

Table 3

12/40

Detector Amlodipine Losartana UV absorption spectrometer (350nm wave length) UV absorption spectrometer (wavelength 250nm) Column Stainless tube, 4.6 mm in internal diameter and 150 mm in length, filled with 5-pm silica gel octadecylsilylate sized for liquid chromatography Stainless tube, 4.6 mm in internal diameter and 150 mm in length, filled with 5-pm silica gel octadecylsilylate sized for liquid chromatography Mobile phase MeOH: 0.03 mol / L potassium dihydrogen phosphate (600: 400, v / v) Mobile phase A: phosphate buffer: acetonitrile (85:15, v / v%) Mobile phase B: acetonitrile Rate of flow 1.5 mL / min 1.2 mL / min Column temperatures 35 ° C Radiant G System 2 min: mobile phase A 80%, mobile phase B 20% 2 min: mobile phase A 80%, mobile phase B 20% 8 min: mobile phase A 40%, mobile phase B 60% 10 min: mobile phase A 80%, mobile phase B 20%

13/40

15 min: mobile phase A 80%, mobile phase B 20%

Test result [043] The results obtained from conducting the protocols are summarized in Table 4 below.

[044] In this regard, the contents of amlodipine and losartan were determined by calculation according to the following mathematical formulas 1 and 2, respectively.

[Mathematical Formula 1]

(%) Amlodipine content (C20H25N2O5CI: 408.88)

A _T Wç T 408.88 _π ⁼ VW? ^X C ^X 64W ^XDXP

A _s : peak area of amlodipine in the standard solution

A _T : peak area of amlodipine in the test solution

W _s : weight of the standard specimen taken from amlodipine cansilate (mg)

W _T : Weight of the test specimen taken

T: mean mass of the test specimen (mg)

C: Indicated weight of amlodipine per tablet (mg)

D: dilution loop

P: Purity of the amlodipine canopy standard specimen (%) [Mathematical Formula 2]

Losartan potassium content (%)

A _T W. ΊΓ ⁼ V ^ ^x c ^xF

A _T : peak area of losartan potassium in the test solution

A _s : peak area of losartan potassium in the standard solution

W _s : weight of standard specimen taken from losartan potassium (mg)

W _T : Weight of the test specimen taken

T: mean mass of the test specimen (mg)

14/40

C: Indicated weight of losartan potassium per tablet (mg)

P: Purity of the standard losartan potassium specimen (%)

Table 4

Content Ex. C. 1 Ex. C. 2 Ex. C. 3 amlodipine Previous content 97.9% 98.3% 89.3% After 2 weeks 83.1% 94.1% 43.7% After 5 weeks 19.4% 19.0% 18.8% losartana Previous content 99.7% 99.4% 105.5% After 2 weeks 97.1% 99.5% 103.1% After 5 weeks 98.4% 100.7% 111.3%

[045] As can be seen in table 4, amlodipine has been largely decreased in context even when it is only brought into physical contact with losartan. Losartan potassium greatly affected amlodipine, as understood from the observation that amlodipine content was reduced by up to 20% within just 5 weeks. For tablets that were formulated from the physical mixture in Comparative Example 3, the amlodipine content was reduced to higher rates over time, indicating that heat and pressure also have a major influence on amlodipine stability.

EXAMPLE TEST: antioxidant test for effectiveness [046] When mixed together, amlodipine and losartan were found to decrease in stability over a period due to physical contact between them, heat and pressure. As a strategy to increase stability, an antioxidant was used. In this regard, two different antioxidants available as pharmaceutical additives were selected, and examined for the effect on amlodipine and losartan stability.

[047] BHA (butylated hydroxy anisole), which is a representative synthetic antioxidant working to bind oxygen to form radicals, and citric acid,

15/40 which is a representative chelating antioxidant characterized by chelation, where selected.

Test method (1) [048] Amlodipine and losartan were physically mixed together with the antioxidants, as shown in Comparative Examples 4 and 6 in Table 5 below. The mixtures of Comparative Examples 4 and 6 were formulated into tablets in Comparative Examples 5 and 7, respectively. The formulation was carried out using a rotary tablet press machine at a pressure of 10 kPa and a thickness of 5.10 mm.

[049] The mixtures and tablets were exposed to an acceleration chamber under the conditions shown in table 2. The contents of amlodipine and losartan were measured immediately after preparation of the mixtures and tablets, and after two and five weeks of exposure to acceleration conditions.

[050] To measure the contents of amlodipine and losartan, the same protocols as in Test example 1 were used. In this regard, the contents of amlodipine and losartan were calculated according to mathematical formulas 1 and 2, respectively.

Table 5

Features tica Ingredi ente C. Ex. 4 C. Ex. 5 Ç. Ex. 6 C. Ex. 7 Contents do (mg) Proportion of content (%) Content of (mg) Proportion of content (%) Content of (mg) Proportion of content (%) Content of (mg) Proportion of content (%) Pharmaceutical ingredient and active Besilat o de anlodipi 6.94 1.67 6.94 1.67 6.94 1.38 6.94 1.38

16/40

strictly at the losarta in potash ca 50 12.02 50 12.02 50 9.96 50 9.96 Fill in ache Cells and microcrystalline (101) 130 31.25 130 31.25 130 25.89 130 25.89 Cells and microcrystalline (102) 135.1 32.47 135.1 32.47 135.1 26.91 135.1 26.91 Excipient D- mannitol 40 9.61 40 9.61 40 7.97 40 7.97 Disintegrate ador Sodium starch glycolate 17 4.09 17 4.09 17 3.39 17 3.39 Crospo vidona 12 2.88 12 2.88 12 2.39 12 2.39 Binder povidon a 5 1.20 5 1.20 5 1.00 5 1.00

17/40

Lubrificant and Magnesium stearate 3 0.72 3 0.72 3 0.60 3 0.60 Antioxidan BHA 17 4.09 17 4.09 - - - - you Citric acid - - - - 103 20.52 103 20.52 Total 416.04 100.00 416.04 100.00 502.04 100.00 502.04 100.00 state powder tablet Powder tablet

(2) TEST RESULT [051] The results obtained from the test are summarized in table 6, below.

Table 6

Content C. Ex. 4 C. Ex. 5 C. Ex. 6 C. Ex. 7 Amlodipine Previous 99.7% 91.9% 97.1% 90.4% After 5 weeks 93.3% 83.4% 102.7% 92.1% Losartana Previous 100.7% 101.0% 103.6% 101.3% After 5 weeks 105.5% 101.9% 100.0% 97.9%

[052] Previously, the amlodipine was observed to exhibit a major change in content even after simple physical contact with rosaltan. In the presence of the antioxidant, as shown in table 6, the amlodipine content was maintained consistently for a long period of time. Either of the two antioxidants improved amlodipine stability in the presence of losartan, and vice versa. In addition, antioxidants ensured the stability of amlodipine for a period even after tablets under conditions of heat and pressure, so that amlodipine can retain its original content. Furthermore, the losartan content was kept stable even under pressure or

18/40 heat when the antioxidant was used together.

EXAMPLE TEST 3: test for antioxidant selection

3.1 Test for antioxidant-dependent stability [053] Based on the contribution of antioxidants to stability as shown above, 12 different antioxidants were tested to select an ideal.

(1) Preparation of the compound formulation [054] Physical mixtures comprising 12 different antioxidants were prepared, as shown for example 1 and Comparative Examples 8 to 21 of tables 7 to 10. A combination of two antioxidants was employed to exhibit effects synergistic. A combination of BHA and BHT was used in Comparative Example 13 while citric acid and p BHA were used in combination in Comparative Example 14. A compound formulation avoiding an antioxidant was configured in Comparative Example 8.

[055] Each composition was physically mixed, and formulated into a tablet using a tablet press machine. The mixtures and tablets were exposed to an acceleration chamber under the conditions shown in table 2. The contents of amlodipine and losartan were measured immediately after preparation of the mixtures and tablets, and after two to five weeks of exposure to the acceleration conditions . The mixtures were formulated into single tablets at a pressure of 10 kPa. The contents of amlodipine and losartan were measured in the same way in Test Example 1.

Table 7

Character Ingredient Ex. 1 Ç. Ex. 8 Ç. Ex. 9 C. Ex. 10 C. Ex. 11 eristic and Cont Propose Cont Propose Cont Propose Cont Propose Cont Propose The ee tion of ee tion of ee tion of ee tion of ee tion of (ms) content ^(m g) content (m) content (m) content (m) content

19/40

of (%) of (%) of (%) of (%) of (%) Pharmaceutically active ingredient amlodipine besylate 6.94 1.74 6.94 1.74 6.94 1.67 6.94 1.67 6.94 1.38 losartan potassium 50 12.53 50 12.53 50 12.02 50 12.02 50 9.96 Preenc stench Microcrystalline cellulose (101) 130 32.57 130 32.58 130 31.25 130 31.25 130 25.89 Microcrystalline cellulose (102) 135, 1 33.85 135.1 33.86 135.1 32.47 135, 1 32.47 135, 1 26.91 Excipient D-mannitol 40 10.02 40 10.02 40 9.61 40 9.61 40 7.97 Disintegrated r Sodium starch glycolate 17 4.26 17 4.26 17 4.09 17 4.09 17 3.39 Crospovid ona 12 3.01 12 3.01 12 2.88 12 2.88 12 2.39 Ligant and povidone 5 1.25 5 1.25 5 1.20 5 1.20 5 1.00 Lubrifi cant Magnesium stearate 3 0.75 3 0.75 3 0.72 3 0.72 3 0.60 Antioxi before BHA - - - - - - 17 4.09 - - Acid - - - - - - - - 103 20.52

20/40

citric B HT - - - - 17 4.09 - - - - Propyl gallate 0.06 0.02 - - - - - - - - Total 399, 1 100 399.0 4 100 416.0 4 100 416, 04 100 502, 04 100

abela 8

Character istic Ingredient C. Ex. 12 C. Ex. 13 C. Ex. 14 C. Ex. 15 Contents do (mg) Proportion of content (%) Content of (mg) Proportion of content (%) Content of (mg) Proportion of content (%) Content of (mg) Proportion of content (%) Active pharmaceutically active ingredient besylate amlodipine 6.94 1.73 6.94 1.34 6.94 1.47 6.94 1.66 losartan potassium 50 12.50 50 9.63 50 10.58 50 11.93 Fill edor Microcrystalline cellulose na (101) 130 32.50 130 25.05 130 27.51 130 31.02 Microcrystalline cellulose na (102) 135.1 33.77 135.1 26.03 135.1 28.59 135.1 32.24 Excipien you D-mannitol 40 10.00 40 7.71 40 8.46 40 9.55 Desinte grazer Glycolate starch from 17 4.25 17 3.28 17 3.60 17 4.06

21/40

sodium Crospovido at 12 3.00 12 2.31 12 2.54 12 2.86 Binder povidone 5 1.25 5 0.96 5 1.06 5 1.19 Lubricates Magnesium stearate 3 0.75 3 0.58 3 0.63 3 0.72 Antioxidant before BHA - - 8.5 1.64 8.5 1.80 - - Citric acid - - - 65 13.76 - - B HT - - 8.5 1.64 - - - - Sodium ascorbate 1 0.25 103 19.84 - - - - Zinc oxide - - - - - - 20 4.77 Total 400.04 100 519.04 100 472.54 100 419.04 100

Table 9

Character Ingredi C. Ex. 16 C. Ex. 17 C. Ex. 18 C. Ex. 19 C. Ex. 20 C. Ex. 21 ristic ente Cont Prop Cont Prop Cont Prop Cont Prop Cont Prop Cont Prop ee prayer ee prayer ee oration ee prayer ee prayer ee prayer (mg) the of (mg) the of (mg) in (mg) the of (mg) the of (mg) the of cont count count count cont cont ee humble humble humble ee ee (%) (%) (%) (%) (%) (%) Ingredi besilat 6.94 1.66 6.94 1.66 6.94 1.69 6.94 1.66 6.94 1.66 6.94 1.74 ente the of active anlodip pharmac ino

22/40

euticam ente losarta in potash ca 50 11.9 3 50 11.9 3 50 12.21 50 11.9 3 50 11.9 3 50 12.5 1 Preenc stench Cell Phones and Microcrystalline (101) 130 31.0 2 130 31.0 2 130 31.74 130 31.0 2 130 31.0 2 130 32.5 4 Cell Phones and Microcrystalline (102) 135, 1 32.2 4 135, 1 32.2 4 135.1 32.99 135.1 32.2 4 135.1 32.2 4 135, 1 33.8 1 Excipie nte D- mannitol 40 9.55 40 9.55 40 9.77 40 9.55 40 9.55 40 10.0 1 Desinte grazer Sodium starch glycolate 17 4.06 17 4.06 17 4.15 17 4.06 17 4.06 17 4.25 Crospo vidona 12 2.86 12 2.86 12 2.93 12 2.86 12 2.86 12 3.00 Binder populated at 5 1.19 5 1.19 5 1.22 5 1.19 5 1.19 5 1.25 Lubricate before Extend act of 3 0.72 3 0.72 3 0.73 3 0.72 3 0.72 3 0.75

23/40

magné sio Antioxi dante Zinc oxide - - - - 8.5 2.08 - - - - - - Ascorbic acid 20 4.77 - - - - - - - - - - In hydrogen sulfite in - - 20 4.77 - - - - - - - - At edentat o - - - - 2 0.49 - - - - - - Acetate Tocofer ol - - - - - - 20 4.77 - - - - Tocofer ol - - - - - - - - 20 4.77 - - At pirosulf ito - - - - - - - - - - 0.5 0.13 Total 419, 04 100 419, 04 100 409.5 4 100 419.0 4 100 419.0 4 100 399, 54 100

(2) TEST RESULT

24/40 [056] The results obtained from the test are summarized in tables 10 and 11 below.

Table 10

Content Ex. 1 C. Ex. C. Ex. C. Ex. C. Ex. C. Ex. C. Ex. C. Ex. 8 9 10 11 12 13 14 anlodi Previous 93.1% 96.6% 92.8% 90.8% 91.1% 91.6% 94.1% 94.2% pin 2 weeks 93.9% 93.4% 90.9% 92.3% 98.2% 90.9% 90.6% 99.0% 5 weeks 95.8% 90.8% 94.6% 92.7% - 88.2% 93.5% - losart Previous 99.2% 96.9% 102.5% 96.4% 99.0% 94.5% 99.8% 59.4% a-N-A 2 weeks 98.3% 94.8% 99.0% 86.8% 53.2% 99.0% 95.3% 56.8% 5 weeks 100.9% 92.3% 101.2% 96.2% - 99.9% 102.4% -

Table 11

Content C. Ex. 15 C. Ex. 16 C. Ex. 17 C. Ex. 18 C.Ex.1 9 C. Ex. 20 C. Ex. 21 amlodipine Previous 97.3% 95.5% 91.5% 94.8% 96.2% 97.3% 98.2% 2 weeks 90.1% 89.5% 88.5% 90.3% 95.4% 94.2% 93.1% 5 weeks 81.5% 80.6% 75.7% 76.5% 80.8% 83.2% 77.5% losartana Previous 95.9% 102.5% 100.4% 95.7% 94.5% 93.1% 97.2% 2 weeks 92.8% 95.1% 80.8% 79.2% 98.3% 91.0% 95.3% 5 weeks 90.3% 80.2% 65.2% 70.5% 95.3% 87.5% 90.4%

[057] As understood from the data in tables 10 and 11, the 12 different antioxidants and combinations of them showed influences on the stability of amlodipine and losartan. However, citric acid, sodium hydrogen sulfite, and sodium edentate tended to decrease the losartan content while zinc oxide, ascorbic acid, tocophenol acetate, tocophenol, and sodium pyrosulfite decreased the amlodipine content. . It was observed that the other antioxidants BHA, BHT, and propyl gallate maintained the contents of

25/40 both amlodipine and losartan stable. Therefore, BHT, propyl gallate and a combination of BHT and BHA were selected to give amlodipine and losartan stability.

3.2 Test for oxidant selection [058] Of the three species of antioxidants (BHT, propyl gallate, BHT + BHA) that proved to guarantee the stability of amlodipine and losartan in Test Example 3.1, the best that showed an ideal stabilizing effect was determined as follows.

(1) TEST METHOD [059] Amlodipine and losartan were physically mixed together with three species of antioxidants as shown in Example 2 and Comparative Example 22 and 23 of table 12 below.

[060] The mixtures were formulated into tablets with two layers composed of an amlodipine layer and a losartan layer, each containing an antioxidant. The two-layer tablets were manufactured to a thickness of 5.30 mm using a two-layer tablet press machine at a pressure of 12.5 kPa. Each tablet was exposed to an acceleration chamber under the conditions in Table 2. The contents of amlodipine and losartan were measured immediately after the preparation of the tablets, and after two, four and eight weeks of exposure to the acceleration conditions.

(1) Protocol for measuring amlodipine content [061] Three tablets from each sample were weighed precisely, and crushed. An amount of each sample corresponding to 5 mg of amlodipine was weighed, and placed in a brown volumetric flask of 100 ml to which a mobile phase was then added to give a volume of 100 ml. Of the solution, 25 ml was taken, and placed in a 50 ml brown volumetric flask. The mobile phase was poured into this flask to exactly align the surface of the phase

26/40 mobile with the marked line, followed by filtration through a 0.45 μπι membrane filter. The contents were determined by HPLC under the conditions shown in table 3.

(2) Protocol for measuring losartan content [062] Three tablets from each sample were precisely weighed and crushed. An amount of each sample corresponding to 50 mg of losartan potassium was weighed, and placed in a 200 ml volumetric fraction to which a mobile phase A was then added to give a volume of 100 ml. Following an ultrasonic extraction for 10 min, mobile phase A was added to give an exact volume of 200 ml. The filtration was conducted through a 0.45 μm membrane filter. The contents were determined by HPLC under conditions shown in Table 3.

Table 12

Characteristic Ingredient Ex. 2 C. Ex. 22 C. Ex. 23 Contents do (mg) Proportion of content (%) Contents do (mg) Proportion of content (%) Contents do (mg) Proportion of content (%) Pharmaceutical active ingredient Amlodipine besylate Amlodipine layer 6.94 1.74 6.94 1.66 6.94 1.66 Filler Microcrystalline cellulose ina (101) 130 32.57 130 31.02 130 31.02 Excipient D-mannitol 40 10.02 40 9.55 40 9.55 Disintegrated Glycolate 17 4.26 17 4.06 17 4.06

27/40

or of starch sodium Binder povidone 5 1.25 5 1.19 5 1.19 Lubricant Stearate magnesium 1.5 0.38 3 0.72 3 0.72 Antioxidant B HT 17 4.06 8.5 2.03 BHA 8.5 2.03 Propyl gallate 0.06 0.02 Pharmaceutical active ingredient losartan potassium Losartan Layer 50 12.53 50 11.93 50 11.93 Filler Microcrystalline cellulose ina (102) 135.1 33.85 135.1 32.24 135.1 32.24 Disintegrated or Crospovido at 12 3.01 12 2.86 12 2.86 Lubricant Stearate magnesium 1.5 0.38 3 0.72 3 0.72 Total weight 399.1 100.00 419.04 100.00 419.04 100.00

(2) Test result [063] The results obtained from the test are summarized in table 13 below.

Table 13

28/40

Content Ex. 2 C. Ex. 22 C. Ex. 23 Amlodipine Previous 93.6% 96.0% 99.6% 4 weeks 90.4% 87.0% 91.1% 8 Weeks 84.6% 81.2% Losartana Previous 99.3% 96.8% 101.6% 4 weeks 102.5% 103.5% 96.5% 8 Weeks 100% 97%

[064] As can be seen in Table 13, the contents of amlodipine and losartan at an early stage and 4 to 8 weeks after the acceleration test were similar for the compositions. However, the tablets of Comparative Examples 22 and 23 employing BHT alone and in combination with BHA appeared brown 4 and 8 weeks after the acceleration test, respectively. Therefore, the antioxidant propyl gallate that was used in example 2 was determined to have a strong antioxidant potential with minimal physiochemical influence on the tablets.

EXAMPLE TEST 4: test to ensure the stability of the compound [065] In order to minimize the interaction between amlodipine and losartan, formulations coated with a potentially water-protective coating agent were manufactured. They were measured for stability depending on the coating.

4.1 Comparison of formulations [066] When in contact with each other, amlodipine and losartan become weak in stability due to interaction between them or with excipients, as demonstrated in the tests mentioned above. The stability comparison was made between the two-layer tablet composed of an amlodipine layer and a losartan layer that was designed to minimize contact with the area between amlodipine and losartan, and a single tablet in which the

29/40 amlodipine and losartan were physically mixed.

[067] Amlodipine and losartan were mixed as shown in Examples 3 and 4 of table 14 and formulated in two-layer tablets composed of an amlodipine layer and a losartan layer, and in one-layer tablets, respectively. Each tablet was exposed to an acceleration chamber under table 2 conditions, and the contents of amlodipine and losartan were measured immediately after preparation of the tablets, and after 2, 4 and 8 weeks of exposure to the acceleration chamber.

[068] The measurement of amlodipine and losartan contents was conducted in the same way as in Test Example 1.

Table 14

Feature Ingredient Example 3 (tablets with two layers) Example 4 (single layer tablets) Feature Ingredient Content (mg) Proportion of content (%) Content of (mg) Proportion of content (%) Pharmaceutically active ingredient besylate amlodipine Amlodipine layer 6.94 1.74 6.94 1.74 Filler Cellulose microcrystalline (101) 130.00 32.57 130.00 32.57 Excipient D-mannitol 40.00 10.02 40.00 10.02 Disintegrator Sodium starch glycolate 17.00 4.26 17.00 4.26

30/40

Binder povidone 5.00 1.25 5.00 1.25 Lubricant Stearate magnesium 1.50 0.38 Antioxidant Propyl gallate 0.06 0.02 0.06 0.02 Pharmaceutically active ingredient losartan potassium Losartan Layer 50.00 12.53 50.00 12.53 Filler Cellulose microcrystalline (102) 135.10 33.85 135.10 33.85 Disintegrator Crospovidone 12.00 3.01 12.00 3.01 Lubricant Stearate magnesium 1.50 0.38 3.00 0.75 Total 399.10 100.00 399.10 100.00

(2) Test result [069] The results obtained in the test were given in table 15.

Table 15

Content Ex. 3 Ex. 4 Amlodipine Previous 99.6% 96.7% 2 weeks 98.4% 95.0% 4 weeks 95.6% 91.2% 8 Weeks 94.4% 88.5% losartana Previous 100.3% 96.8% 2 weeks 99.6% 96.9% 4 weeks 99.5% 96.6% 8 Weeks 98.4% 96%

[070] As understood from the data in Table 15, it was observed that the tablets of Examples 3 and 4 maintained the content of amlodipine and

31/40 losartan stable even after 8 weeks. However, the tablet in Example 3 was less likely to decrease in content over the period. Thus, two-layer tablets are superior to single-layer tablets in terms of stability, which is considered to contribute to the minimum contact between the two pharmaceutically active ingredients in a way that blocks the interaction between them.

4.2 Coating test [071] To examine long-term stability, the compound drug of the present invention was coated with three different coating agents and monitored for the change in stability over the period.

(1) Preparation [072] The amlodipine and losartan were formulated into a two-layer tablet consisting of a layer of amlodipine and a layer of losartan, as shown in table 16 below. The tablet was coated with one of the three coating agents (Kollicoat ^® Protect (BASF), Opadry, hydroxypropylmethyl cellulose (HPMC)). The tablet was exposed to an acceleration chamber under the conditions in Table 2. The tablet was measured for the contents of amlodipine and losartan immediately after preparation, and after 2, 4 and 8 weeks of exposure to accelerated conditions.

(1) Protocol for measuring amlodipine content [073] Three tablets from each sample were weighed precisely, and crushed. An amount of each sample corresponding to 5 mg of amlodipine was weighed and placed in a 100 ml brown volumetric fraction to which a mobile phase was then added to give a 100 ml volume. Of the solution, 25 ml was taken, and placed in a 50 ml brown volumetric flask. The mobile phase was poured into this flask to exactly align the surface of the mobile phase with the marked line, followed by filtration through a 0.45 pm membrane filter. The

32/40 contents were determined by HPLC under the conditions shown in table 3.

(2) Protocol for measuring the content of losartan [074] Three tablets of Comparative Example 3 were precisely weighed, and crushed. An amount of each sample corresponding to 50 mg of losartan potassium was weighed, and placed in a 200 ml volumetric fraction to which a mobile phase A was then added to give a volume of 100 ml. Following an ultrasonic extraction for 10 min, mobile phase A was added to give an exact volume of 200 ml. Filtration was conducted through a 0.45 pm membrane filter. The contents were determined by HPLC under conditions shown in Table 3.

Table 16

Feature Ingredient Ex. 5 Ex. 6 Ex. 7 Content of (mg) Proportion of content (%) Content of (mg) Proportion of content (%) Content of (mg) Proportion of content (%) Layer of Anlodipin o Pharmaceutically active ingredient besylate amlodipine 6.94 1.70 6.94 1.70 6.94 1.70 Filler Microcrystalline cellulose ina (101) 130.00 31.78 130.00 31.78 130.00 31.78 Excipient D-mannitol 40.00 9.78 40.00 9.78 40.00 9.78 Disintegrator Sodium starch glycolate 17.00 4.16 17.00 4.16 17.00 4.16

33/40

Binder povidone 5.00 1.22 5.00 1.22 5.00 1.22 Lubricant Stearate magnesium 3.00 0.73 3.00 0.73 3.00 0.73 Antioxidant Propyl gallate 0.06 0.01 0.06 0.01 0.06 0.01 Losartana Layer Pharmaceutically active ingredient losartan potassium 50.00 12.22 50.00 12.22 50.00 12.22 Filler Microcrystalline cellulose ina (102) 135.10 33.02 135.10 33.02 135.10 33.02 Disintegrator Crospovido at 12.00 2.93 12.00 2.93 12.00 2.93 Lubricant Stearate magnesium 3.00 0.73 3.00 0.73 3.00 0.73 Coating agent kollicoat protect 7.00 1.71 - - - - Opadry - - 7.00 1.71 - - HPMC - - - - 7.00 1.71 Total weight 409.10 100.00 409.10 100.00 409.10 100.00

(2) Test result [075] The results obtained from the test are summarized in table 17 below.

Table 17

34/40

Content Ex. 5 Ex. 6 Ex. 7 Amlodipine Previous 100.2% 97.7% 101.6% 2 weeks 100.4% 95.6% 99.4% 4 weeks 99.6% 94.1% 98.8% 8 Weeks 98.9% 93.5% 95.2% Losartana Previous 99.5% 99.5% 100.3% 2 weeks 99.3% 97.6% 98.4% 4 weeks 99.9% 96.9% 96.5% 8 Weeks 99.5% 96.0% 95.3%

[076] As shown in Table 17, contents were measured immediately after preparation and after 2, 4 and 8 weeks of exposure to accelerated conditions indicated that the coated kollicoat® coated tablet of example 5 has the greatest stability. Designed to block a drug's contact with water, kollicoat ^® protect can effectively prevent the drug from being hydrolyzed. HPMC and Opadry ^® , respectively used in Examples 6 and 7, have also been observed to improve the stability of the drug, but with less effectiveness than Kollicoat® protect.

EXAMPLE TEST 5: dissolution test

5.1 Dissolution test [077] To achieve an ideal dissolution curve, the compound tablets of guaranteed stability comprising amlodipine and losartan were formulated with various excipients.

(1) Preparation [078] Amlodipine and losartan were formulated with excipients shown in tables 18 and 19 in two-layer coated tablets composed of an amlodipine layer and a losartan layer.

Table 18

35/40

Features tica Ingredi ente Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 Contents ( ^m g) Prop ortion (%) Contents ( ^m g) Proposition (%) Contents ( ^m g) Prop ortion (%) Contents ( ^m g) Proposition (%) Contents ( ^m g) Proposition (%) Cam ada in Anlod ipine Pharmaceutical Ingredient and Active Anlodipi besylate no 6.94 1.72 6.94 1.70 6.94 1.72 6.94 1.72 6.94 1.72 Fill in ache Cellulose Stalin microcrystals (101) 130, 00 32.17 130, 00 31.78 130, 00 32.17 130, 00 32.17 130. 00 32.17 Excipient Dmanitol 40.0 0 9.90 40.0 0 9.78 40.0 0 9.90 40.0 0 9.90 40.0 0 9.90 Disintegrate ador In starch glycolate 12.0 0 2.97 17.0 0 4.16 20.0 0 4.95 12.0 0 2.97 17.0 0 4.21 Binder Povido na 5.00 1.24 5.00 1.22 5.00 1.24 5.00 1.24 5.00 1.24 Lubrificant and Mg esteara to 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74 Antioxidant Propyl gallate 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01 Cam Ingredient Losarta 50.0 12.37 50.0 12.22 50.0 12.37 50.0 12.37 50.0 12.37

36/40

ada de Losar and pharmaceutically active in potash ca 0 0 0 0 0 tana Fill in Cell Phones 135, 33.43 135, 33.02 135, 33.43 135, 33.43 135. 33.43 ache and 10 10 10 10 10 Microcri stalina (102) Disintegrate Crospo 12.0 2.97 12.0 2.93 12.0 2.97 10.0 2.47 10.0 2.47 ador vidona 0 0 0 0 0 Lubrificant esteara 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74 and to of magnes io Agent Kolcoat 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 coating ® nto protect Total 404, 100.0 409, 100.0 412, 101.9 402, 99.51 407, 100.7 10 0 10 2 10 8 10 10 4

Table 19

Features tica Ingredie nte Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ex. 17 Contents ( ^m g) proportion (%) Contents (mg) proportion (%) Contents ( ^m g) proportion (%) Contents ( ^m g) proportion (%) Contents ( ^m g) proportion (%) Layer of Pharmaceutical ingredient and active besylate anlodipi 6.94 1.72 6.94 1.70 6.94 1.72 6.94 1.72 6.94 1.72

37/40

anlod strictly at the ipine Preenched Cell Phones 130, 32.17 130, 31.78 130, 32.17 130, 32.17 130. 32.17 or and 00 00 00 00 00 microcri stalina (101) Excipient D- 40.0 9.90 40.0 9.78 40.0 9.90 50.0 12.37 50.0 12.37 mannitol 0 0 0 0 0 Disintegrates Glicolat 12.0 2.97 17.0 4.16 20.0 4.95 12.0 2.97 17.0 4.21 ache the of 0 0 0 0 0 starch At Binder Povidon 7.00 1.73 7.00 1.71 7.00 1.73 7.00 1.73 5.00 1.24 The Lubrificant Esteara 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74 and to of magnes io Antioxidan Propyl 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01 you gallate Cam Ingredient losartan 50.0 12.37 50.0 12.22 50.0 12.37 50.0 12.37 50.0 12.37 ada is active The 0 0 0 0 0 in pharmaceut potash losart strictly here a-N-A Preenched Cell Phones 135, 33.43 135, 33.02 135, 33.43 135, 33.43 135. 33.43 or and 10 10 10 10 10 Microcri

38/40

stalina (102) Disintegrates ache Crospo vidona 10.0 0 2.47 10.0 0 2.44 10.0 0 2.47 10.0 0 2.47 10.0 0 2.47 Lubrificant and Esteara to Mg 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74 Agent coating nto kolcoat protect 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 Total weight 404, 10 100.0 0 409, 10 100.0 2 412, 10 101.9 8 414, 10 102.4 7 417, 10 103.2 2

[079] The formulations of Examples 8 to 17 were subjected to dissolution tests under the following conditions.

(1) Amlodipine

34.7 mg of a standard amlodipine besylate was precisely weighed, and placed in a brown 250 ml volumetric flask into which 0.001 mol / L hydrochloric acid solution was then poured to give a 250 ml volume. 10 ml of the solution was taken and placed in a brown 100 ml volumetric flask. A 0.01 mol / L solution of HCl was poured into this flask to exactly align the surface of the mobile phase with the marked line, followed by filtration through a 0.45 pm membrane filter to give a filtered solution as a standard .

[080] Separately, three tablets from each sample were weighed precisely, and subjected to a dissolution test under the conditions of table 20. 10 ml of the dissolved solution were taken 5, 10, 15, 30 and 45 min after dissolution, and filtered through a 0.45 pm membrane filter.

[081] The test solution and the standard were analyzed by HPLC under the

39/40 conditions in table 3.

Table 20

Device Stipulated in the 2nd dissolution test of the general test method, the Korean pharmacopeia Test liquid 0.01 mol / L, 500mL HCl Dissolving temperature 37 ± 0.5 ° C Rotation No. 100 ± 5 rpm

Losartan mg of a standard potassium losartan was weighed precisely, and placed in a 100 ml volumetric flask into which the mobile phase A then poured into the marked line. 10 ml of the solution was taken and placed in a 100 ml volumetric flask. Pure water was added to the marked line, followed by filtration through a 0.45 pm membrane filter to give a filtered solution as a standard.

[082] Separately, three tablets from each sample were weighed precisely, and subjected to a dissolution test under the conditions of table 21. 10 ml of the dissolved solution were taken 5, 10, 15, 30 and 45 min after dissolution, and filtered through a 0.45 pm membrane filter. The filtered solution was used as a test solution.

[083] The test and standard solutions were analyzed by HPLC under the conditions in Table 3.

Table 21

Device Stipulated in the 2nd dissolution test of the general test method, the Korean pharmacopeia Test liquid Purified water, 900 mL Dissolving temperature 37 ± 0.5 ° C

40/40

Rotation No. 75 ± 5 rpm

(2) Results of the dissolution test [084] The results of the dissolution tests are depicted in figures 1 and 2.

[085] Figure 1 shows the dissolution curves of amlodipine from the tablets of Examples 8 to 17 while figure 2 shows the dissolution curves of losartan from the tablets of Examples 8 to 17.

[086] As can be seen in figure 1, all formulations exhibited high dissolution rates at an early stage, but a dissolution rate of 85% or greater within 5 minutes was achieved only by the formulations of Examples 9 and

10. For losartan, only the formulations of Examples 9 and 10 exhibited a dissolution rate of 85% or more within 5 minutes. Therefore, the formulation comprising amlodipine and losartan according to Example 9 was determined to be ideal for the tablet having an improved stability of amlodipine and losartan.

Claims (10)

1. Composition to prevent and treat cardiovascular diseases, CHARACTERIZED by the fact that it comprises amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and propyl gallate, in which the propyl gallate is contained in an amount of 0.001 to 1% by weight, based on the total weight of the composition. 2. Composition according to claim 1, CHARACTERIZED by the fact that it is in the form of a two-layer tablet having two separate layers composed of an amlodipine layer containing amlodipine or a pharmaceutically acceptable salt thereof, and a layer of losartan containing losartan or a pharmaceutically acceptable salt thereof. 3. Composition according to claim 2, CHARACTERIZED by the fact that propyl gallate is contained in the amlodipine layer containing amlodipine or a pharmaceutically acceptable salt thereof. 4. Composition according to claim 1, CHARACTERIZED by the fact that amlodipine or a pharmaceutically acceptable salt thereof is contained in an amount of 1 to 6% by weight, and losartan or a pharmaceutically acceptable salt thereof is contained in an amount of 5 to 30% by weight, based on the total weight of the composition. 5. Composition according to claim 1, CHARACTERIZED by the fact that it still comprises a coating agent. 6. Composition according to claim 5, CHARACTERIZED by the fact that the coating agent is selected from the group consisting of a water-soluble coating agent comprising a derivative of polyvinyl alcohol, a derivative of methacrylic acid, and a derived from polyacrylic acid, Kollicoat Protect, Opadry, and hydroxypropylmethyl cellulose (HPMC). Petition 870190046834, of 20/05/2019, p. 9/10 2/2 7. Composition according to claim 1, CHARACTERIZED by the fact that the pharmaceutically acceptable salt of amlodipine is amlodipine besylate, and the pharmaceutically acceptable salt of losartan is losartan potassium. 8. Composition according to claim 1, CHARACTERIZED by the fact that it still comprises a pharmaceutically acceptable additive. 9. Composition, according to claim 8, CHARACTERIZED by the fact that the additive is contained in an amount of 5 to 90% by weight, based on the total weight of the composition. 10. Use of a composition, as defined in claim 1, CHARACTERIZED by the fact that it is in the manufacture of a drug to prevent and treat cardiovascular disorders, in which cardiovascular disorders are selected from the group consisting of angina pectoris, hypertension, arteriospasm, cardiac arrhythmia, cerebral infarction, cardiomegaly, congestive heart failure, thrombosis and myocardial infarction.