KR20130117048A - Pharmaceutical composition comprising amlodipine and losartan having an improved stability - Google Patents

Abstract

PURPOSE: A complex composition containing amlodipine and losartan is provided to minimize physical bond between amlodipine and losartan with high stability because the complex composition contains propyl gallate and to minimize formulation processes. CONSTITUTION: A complex composition for preventing and treating cardiovascular diseases contains amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and propyl gallate. The complex composition is a double-layer tablet comprising an amlodipine layer containing amlodipine or a pharmaceutically acceptable salt thereof and a losartan layer containing losartan or a pharmaceutically acceptable salt thereof. [Reference numerals] (AA) Example 8; (BB) Example 9; (CC) Example 10; (DD) Example 11; (EE) Example 12; (FF) Example 13; (GG) Example 14; (HH) Example 15; (II) Example 16; (JJ) Example 17

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING AMLODIPINE AND LOSARTAN HAVING AN IMPROVED STABILITY [0002]

The present invention relates to a combination composition containing amlodipine and losartan with improved stability by including an antioxidant.

It is important to maintain high blood pressure in the normal range of blood pressure rather than treating blood pressure itself, so it is important to prevent cardiovascular complications such as life-threatening strokes, coronary artery disease such as heart failure, myocardial infarction, and renal failure. It is important to do. As such, blood pressure medication is required to be taken for a long period of time. Therefore, rather than choosing one drug for steady-state therapy, the drugs with different mechanisms can be used in combination with each other for better prevention and treatment effects, and can be achieved by long-term use of the drug It is possible to reduce the side effects that can occur.

The most commonly used drugs for the treatment of hypertension are diuretics, sympathomimetics, and vasodilators, depending on the mechanism of action of the drug. The angiotensin converting enzyme (ACE) inhibitors, angiotensin II Angiotensin II receptor blockers (ARB) and calcium channel blockers.

Amlodipine is a dihydropyridine-based calcium channel blocker, and is a representative drug for the treatment of hypertension or angina. When the drug is absorbed, it relaxes the smooth muscle of the arterial wall, thereby lowering blood pressure and increasing blood flow to the myocardium. Amlodipine is commercially available in the form of various salts such as bezylic acid, maleic acid, and camphanic acid, and amlodipine besylate is the most widely used.

Lozartan is one of the earliest drugs developed for the treatment of hypertension in the ARB (Angiotensin II receptor blocker) line, and angiotensin II blocks the binding to the receptor.

The calcium channel blocker, amlodipine, and ARB, a losartan, have different mechanisms and may be beneficial in the treatment of hypertension when both drugs are taken at the same time. However, when the combination preparation of amlodipine and losartan is carried out by simple mixing and laminating, there is a problem that the stability of such a preparation is greatly deteriorated under accelerated conditions.

Amlodipine preparations are generally made by combining amlodipine, a drug-efficacious ingredient, with salts that aid in the activation and formulation of medicinal products. The salt is a part to help stabilize amlodipine as an active ingredient. Although amlodipine is in the form of free base, it is preferably administered in salt form with pharmaceutically acceptable acid because of its low solubility in water. A combination of amlodipine besylate with another drug capable of producing a synergistic effect is widely used, and examples thereof include a combination preparation of amlodipine besylate and atorvastatin calcium (U.S. Patent No. 6,455,574), amlodipine besylate A combination preparation of valsartan (U.S. Patent No. 6,395,728) and a combination preparation of amlodipine camsylate and simvastatin (Korean Patent Registration No. 742432).

Amlodipine is an unstable free base, which is greatly influenced by light, heat and moisture, and has a disadvantage in that its therapeutic effect is inferior. To overcome this, amlodipine is commercially available in combination with various acid addition salts described above, And its stability is maintained. However, the achievement of securing pharmaceutical stability is still insignificant.

In particular, when amlodipine acid salt was physically mixed with losartan, it was confirmed that losartan and excipient accelerated the chemical reaction and lowered the stability of amlodipine.

Lozartan is commonly used in the form of potassium salts and generally has a disadvantage in that a decomposition product polymer is formed when heat is applied under acidic conditions. In other words. When compounded, the stability of losartan is reduced by acid addition of amlodipine.

For example, existing commercial amlodipine and losartan combination preparations using a combination preparation of amlodipine camsylate and potassium salt of losartan (Korean Patent Laid-Open Publication No. 2008-0052852) have a disadvantage in that the stability between the two components can not be sufficiently secured.

US 6,455,574 US 6,395,728 KR 0742432 KR 2008-0052852 A

Accordingly, in order to solve the above-mentioned problems, the present invention relates to a pharmaceutical composition containing amlodipine and losartan, which has minimized physical binding between amlodipine and losartan, has an improved antioxidant and simplified preparation process, Or a combination thereof.

The present invention provides a combination composition for prevention and treatment of cardiovascular diseases comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof and a propyl gallate.

The combination composition for prevention and treatment of cardiovascular diseases containing amlodipine and losartan of the present invention minimizes the physical bonding between amlodipine and losartan and has excellent stability by containing galactosyl propionate and has a merit that the preparation process is simplified.

1 is a graph showing the results of a dissolution test of amlodipine against the combination agents of Examples 8 to 17,
Fig. 2 is a graph showing the results of a dissolution test of losartan against the combination agents of Examples 8 to 17. Fig.

Hereinafter, the present invention will be described in more detail.

The present invention relates to a pharmaceutical composition for the prevention and treatment of cardiovascular diseases comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof and a propyl gallate.

The propyl gallate (C ₁₀ H ₁₂ O ₅ ) is an antioxidant, and when the combination preparation of losartan and amlodipine is mixed with other pharmaceutically acceptable additives, the stability of the active ingredient is increased, Not only can it be produced, but also reduces the deformation of the active ingredient due to temperature and moisture, thereby increasing the stability against changes over time. Glycans are more safe than antioxidants in that they do not show toxicity to the extent that no skin irritation occurs.

The complex composition may be prepared in the form of a tablet, a capsule, a tablet, a multilayer tablet, or a tablet, but the present invention physically separates amlodipine or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof, It is desirable to prepare a combined preparation with the greatest reduction in contact surface area and more preferably to the amlodipine layer comprising the amlodipine or a pharmaceutically acceptable salt thereof and the losartan layer comprising losartan or a pharmaceutically acceptable salt thereof, It is preferable to be a double-layered structure having a double-layer structure. The method for preparing the double layer may be prepared by forming losartan potassium and a mixture thereof as a lower layer and then granulating amlodipine and a mixture thereof to form an upper layer and then tableting using a tableting machine.

At this time, it is preferable that the glacial acetic acid profile is contained in the amlodipine layer containing amlodipine or a pharmaceutically acceptable salt thereof.

The propyl gallate is preferably included in an amount of 0.001 to 1% by weight, more preferably 0.001 to 0.5% by weight, and most preferably 0.001 to 0.1% by weight based on the total weight of the composition. When the gallate propylate is included in the above range, the stability of the active ingredient is increased and the stability is high.

It is also preferred that the amlodipine or pharmaceutically acceptable salt thereof is contained in an amount of 1 to 6% by weight and the losartan or a pharmaceutically acceptable salt thereof in an amount of 5 to 30% by weight based on the total weight of the composition of the present invention, The amlodipine or pharmaceutically acceptable salt thereof may be included in an amount of 1.2 to 3.5% by weight and the losartan or a pharmaceutically acceptable salt thereof in an amount of 10 to 20% by weight.

Amlodipine is preferably contained in an amount of 3 to 12 mg, more preferably 5 to 10 mg, and preferably 30 to 120 mg, and more preferably 50 to 100 mg of losartan in the combination preparation .

The pharmaceutically acceptable salt of amlodipine is formed from an acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, and includes, for example, hydrochloride, hydrobromide, sulfate, phosphate, acetate, Most preferably, the pharmaceutically acceptable salt of amlodipine is amlodipine besylate, and the pharmacologically acceptable salt of losartan can be used as a pharmaceutically acceptable salt of losartan, Possible salts are preferably losartan potassium.

The pharmaceutical composition of the present invention comprises an amlodipine layer comprising amlodipine besylate, microcrystalline cellulose, D-mannitol, sodium glycoconjugate, povidone, magnesium stearate and propyl gallate, and losartan potassium, microcrystalline cellulose, crospovidone and magnesium stearate But it is not limited thereto.

The pharmaceutical composition of the present invention may further include a coating base to ensure long-term stability, and may be used as long as it is commonly used in the art, but preferably the coating base is a polyvinyl alcohol derivative in a water-soluble coating base. methacrylic coating base and Kollicoat including acid derivatives, and polyacrylic acid ^derivatives? Protect, Opadry ^? , Hydroxypropyl methyl cellulose (HPMC) may be used one or two or more selected from the group consisting of, more preferably Kollicoat ^? Protect is available.

In addition, the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive. The additive may be included in an amount of 5 to 90% by weight, more preferably 50 to 90% by weight based on the total weight of the composition of the present invention. Examples of such additives include fillers, extenders, binders, disintegrators, lubricants, preservatives, antioxidants, isotonic agents, buffers, encapsulating agents, sweeteners, solubilizers, bases, dispersants, wetting agents, , A stabilizer, a coloring agent, a fragrance, a water-soluble additive, an excipient and the like can be used as long as they are pharmaceutically acceptable. More specifically, microcrystalline cellulose, lactose, mannitol, sodium citrate, calcium phosphate, glycine and starch; Disintegrants including sodium starch glycolate, crospovidone, croscarmellose sodium and certain complex silicates, and the like; Polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia gum, macrogol, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate Silicate derivatives such as aluminates, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, and mixtures thereof and metal salts of stearic acid, metal stearates such as calcium stearate or magnesium stearate, talc, colloidal silica , Sucrose fatty acid esters, hydrogenated vegetable oils, high melting point waxes, glyceryl fatty acid esters, glycerol dibehenate, talc, and mixtures thereof.

The disintegrant of the present invention refers to a material that promotes the disintegration of the solid composition in a digestive solution to help achieve a sufficient dissolution rate. The disintegrant of the appropriate type is selected to improve the solubility of the solid preparation, particularly the tablet, It is important to use release. If there is a decrease in dissolution due to the delay of disintegration, the amount of disintegrant can be increased to improve the dissolution. However, if the disintegrant is used excessively, the preparation of the solid dosage form, the packing process, As much as possible, the tablets can not exhibit strong strength. Thus, the choice of the appropriate disintegration is very important and there is also a limit to the amount of disintegrant to be used.

The disintegrant is preferably contained in an amount of 1 to 10% by weight, more preferably 3 to 7% by weight based on the total weight of the composition. When the disintegration is satisfied within the above range, the disintegration of the preparation is promoted so that the absorption of moisture and the release of the principal component can be enhanced, thereby increasing the dissolution of the main component, thereby facilitating the attainment of the pharmacologically effective concentration.

The cardiovascular diseases described in the present invention are selected from the group consisting of angina pectoris, hypertension, arterial spasm, heart arrhythmia, cerebral infarction, cardiomyopathy, congestive heart failure, thrombosis, and myocardial infarction.

The solid pharmaceutical composition of the present invention may be formulated in the form of tablets, capsules, multiparticulates or the like according to a conventional formulation method and may be administered by oral, oral, or sublingual routes. Preferably, the composition of the present invention can be formulated in the form of tablets and orally administered, and can be easily formulated into tablets by simple mixing and tableting of the components constituting the composition of the present invention. The method of administration will be measured by a physician after evaluation of symptoms and requirements of the individual.

Hereinafter, the present invention will be described in more detail with reference to examples and test examples. Since these examples and test examples are only for illustrating the present invention, the scope of the present invention is not construed as being limited by these examples and test examples.

Test Example  One. Amlodipine  And Lausanne  Stability test of liver

Amlodipine and losartan were physically mixed with each other to measure the changes in stability with the interaction between the two drugs.

(1) Test method

Amlodipine and losartan were physically mixed at the same weight as the prescription shown in Table 1 below to give Comparative Example 1 and Comparative Example 2, respectively. In order to examine the effect of the pressure and heat upon tabletting on the stability of amlodipine and losartan, Comparative Example 3 was prepared by purifying Comparative Example 2. Comparative Example 3 was processed at a pressure of 20 kPa in the step of purifying.

Classification ingredient Comparative Example 1 Comparative Example 2 Comparative Example 3 content
(mg) Content ratio
(%) content
(mg) Content ratio
(%) content
(mg) Content ratio
(%) Pharmacologically active ingredient Amlodipine
Besylate 6.94 12.2 6.94 1.7 6.94 1.7 Pharmacologically active ingredient Losartan potassium 50 87.8 50 12.5 50 12.5 Filler The microcrystalline cellulose (101) - - 130 32.6 130 32.6 Filler The microcrystalline cellulose (102) - - 135.1 33.9 135.1 33.9 Excipient D-mannitol - - 40 10.0 40 10.0 Disintegration Sodium gluconate - - 17 4.3 17 4.3 Disintegration Crospovidone - - 12 3.0 12 3.0 Binder Povidone - - 5 1.3 5 1.3 Lubricant Magnesium stearate - - 3 0.8 3 0.8 weight 56.94 100 399.04 100 399.04 100 State Powder Powder Tablet

For the stability test of amlodipine and losartan, each of the prepared mixtures of Comparative Example 1 and Comparative Example 2 and the tablet of Comparative Example 3 were exposed to the acceleration chamber under the conditions shown in Table 2, and then the contents were measured immediately after the preparation, 2 weeks, Respectively.

Temperature 40 ± 2 ° C Relative humidity 75 ± 5%

The contents of amlodipine and losartan were measured by the following methods.

① How to measure the content of amlodipine

Take 3 samples of each sample or the same amount and weigh accurately and put into powder. 5 mg of amlodipine was weighed into a 100 mL brown capacity flask and the mobile phase was added to make exactly 100 mL. 25 mL of the above solution was placed in a 50 mL brown capacity flask, adjusted to the same level as the mobile phase, filtered through a 0.45 μm membrane filter, and the content was measured using HPLC under the same conditions as in Table 3.

② How to measure the content of losartan

Take 3 samples of each sample or the same amount and weigh accurately and put into powder. 50 mg of losartan potassium was precisely weighed into a 200-mL volumetric flask, filled with about 100 mL of mobile phase A (phosphate buffer: acetonitrile (85:15, v / v%)), sonicated for about 10 minutes, The filtrate was filtered through a 0.45 μm membrane filter and the content was measured by HPLC under the same conditions as in Table 3.

Amlodipine Lausanne Detector Ultraviolet absorption spectrophotometer (measuring wavelength 350 nm) Ultraviolet absorption spectrophotometer (measurement wavelength: 250 nm) column A stainless steel tube having an internal diameter of 4.6 mm and a length of about 150 mm was charged with a column packed with octadecylsilylated silica gel for a liquid chromatograph A stainless steel tube having an internal diameter of 4.6 mm and a length of about 150 mm was charged with a column packed with octadecylsilylated silica gel for a liquid chromatograph Mobile phase Methanol: 0.03 mol / L potassium dihydrogen phosphate solution (600: 400, v / v) Mobile phase A: Phosphate buffer: acetonitrile (85:15, v / v%)
Mobile phase B: acetonitrile Flow rate 1.5 mL / min 1.2 mL / min Column temperature 35 ℃ Gradient system 0 min: mobile phase A 80%, mobile phase B 20%
2 minutes: 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%
15 minutes: mobile phase A 80%, mobile phase B 20%

(2) Test results

The results according to the above test methods are shown in Table 4 below.

At this time, the amlodipine content was expressed by the following formula 1, and the content of losartan was represented by the following formula 2.

[Formula 1]

[Formula 2]

content Comparative Example 1 Comparative Example 2 Comparative Example 3 Amlodipine

Initial content 97.9% 98.3% 89.3% 2 weeks 83.1% 94.1% 43.7% 5 weeks 19.4% 19.0% 18.8% Lausanne

Initial content 99.7% 99.4% 105.5% 2 weeks 97.1% 99.5% 103.1% 5 weeks 98.4% 100.7% 111.3%

As shown in Table 4 above, the content of amlodipine was significantly lowered by physical contact with losartan, and it decreased to about 20% in 5 weeks, indicating that losartan potassium was greatly affected. Also, in the case of Comparative Example 3 in which the physical mixture was purified, it was found that the decrease in the content over time tends to be larger, so that heat and pressure also have a great influence on the stability of amlodipine.

Test Example 2. Antioxidant effect test

The mixture of amlodipine and losartan was found to be poor in stability over time due to the physical mixing of the two drugs and heat and pressure. As a result, two kinds of antioxidants, which can be used as pharmaceutical additives, The effects of antioxidants on the stability of amlodipine and losartan were investigated.

It has been shown that the selective chelating antioxidant citric acid which forms a chelate with the chemical synthetic antioxidant Butylated Hydroxy Anisole (BHA), which is a typical chemical antioxidant, .

(1) Test method

Amlodipine and losartan were prepared as Comparative Example 4 and Comparative Example 6, respectively, and antioxidant-containing physical mixtures as in the formulation shown in Table 5 below, respectively. Comparative Example 5 and Comparative Example 7 were purified by the same formulation. The tabletting was carried out using a rotary tablet press under the conditions of a pressure of 10 kPa and a thickness of 5.10 mm.

Each mixture and tablet was exposed to the acceleration chamber under the conditions of Table 2, and then the content was measured immediately after preparation and after 5 weeks.

The content of amlodipine and losartan was measured by the same method as described in Test Example 1. [ At this time, the amlodipine content was described according to the formula 1, and the content of losartan was given according to the formula 2.

Classification ingredient Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Content (mg) Content ratio
(%) Content (mg) Content ratio
(%) Content (mg) Content ratio
(%) Content (mg) Content ratio
(%) Pharmacologically active ingredient Amlodipine
Besylate 6.94 1.67 6.94 1.67 6.94 1.38 6.94 1.38 Pharmacologically active ingredient Losartan potassium 50 12.02 50 12.02 50 9.96 50 9.96 Filler The microcrystalline cellulose (101) 130 31.25 130 31.25 130 25.89 130 25.89 Filler The microcrystalline cellulose (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 Disintegration Sodium gluconate 17 4.09 17 4.09 17 3.39 17 3.39 Disintegration Crospovidone 12 2.88 12 2.88 12 2.39 12 2.39 Binder Povidone 5 1.20 5 1.20 5 1.00 5 1.00 Lubricant Magnesium stearate 3 0.72 3 0.72 3 0.60 3 0.60 Antioxidant BHA 17 4.09 17 4.09 - - - - Citric acid - - - - 103 20.52 103 20.52 weight 416.04 100.00 416.04 100.00 502.04 100.00 502.04 100.00 State Powder Tablet Powder Tablet

(2) Test results

The test results are shown in Table 6 below.

content Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Amlodipine
Initial content 99.7% 91.9% 97.1% 90.4% 5 weeks 93.3% 83.4% 102.7% 92.1% Lausanne
Initial content 100.7% 101.0% 103.6% 101.3% 5 weeks 105.5% 101.9% 100.0% 97.9%

As shown in Table 6, when the antioxidant was added, the content of amlodipine, which showed a great change only by physical contact, was maintained constantly. When the two kinds of antioxidants were used, the stability was improved I could. In addition, it was found that the stability of amlodipine could be improved by using antioxidants while maintaining the content over time even in the case of heat or pressure generated by the tableting. In addition, the content of losartan potassium did not significantly change with the use of the antioxidant, and the stability tended to be maintained without significant change in heat or pressure.

Test Example  3. Selection test for antioxidants

3.1 Stability test according to antioxidant

Based on the results of improving the stability of the antioxidants identified in the above test, 12 kinds of antioxidants were used to select the optimum antioxidants.

(1) Manufacturing method of complex agent

Amlodipine and losartan were prepared as Example 1 and Comparative Example 8 to Comparative Example 21, respectively, containing 12 kinds of antioxidants as shown in Table 7, Table 8, Table 9 and Table 10, A mixture prepared by mixing BHA and BHT, which exhibit an additive effect, and a mixture obtained by mixing citric acid and BHA were used as Comparative Example 14, and a mixture containing no antioxidant was used as Comparative Example 8 Respectively.

Each formulation was physically mixed and exposed to the accelerating chamber under the conditions of Table 2 in the form of tablets using a tablet machine, and the contents were measured immediately after the preparation, 2 weeks and 5 weeks after the preparation. The preparation was prepared under a constant pressure, 10 kPa pressure condition.

The content of amlodipine and losartan was measured by the same method as described in Test Example 1. [

Classification ingredient Example 1 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Amlodipine besylate 6.94 1.74 6.94 1.74 6.94 1.67 6.94 1.67 6.94 1.38 Pharmacologically active ingredient Losartan potassium 50 12.53 50 12.53 50 12.02 50 12.02 50 9.96 Filler The microcrystalline cellulose (101) 130 32.57 130 32.58 130 31.25 130 31.25 130 25.89 The 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 Disintegration Sodium gluconate 17 4.26 17 4.26 17 4.09 17 4.09 17 3.39 Crospovidone 12 3.01 12 3.01 12 2.88 12 2.88 12 2.39 Binder Povidone 5 1.25 5 1.25 5 1.20 5 1.20 5 1.00 Lubricant Magnesium stearate 3 0.75 3 0.75 3 0.72 3 0.72 3 0.60 Antioxidant BHA - - - - - - 17 4.09 - - Citric acid - - - - - - - - 103 20.52 BHT - - - - 17 4.09 - - - - Gallan profile 0.06 0.02 - - - - - - - - weight 399.1 100 399.04 100 416.04 100 416.04 100 502.04 100

Classification ingredient Comparative Example 12 Comparative Example 13 Comparative Example 14 Comparative Example 15 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Amlodipine besylate 6.94 1.73 6.94 1.34 6.94 1.47 6.94 1.66 Pharmacologically active ingredient Losartan potassium 50 12.50 50 9.63 50 10.58 50 11.93 Filler The microcrystalline cellulose (101) 130 32.50 130 25.05 130 27.51 130 31.02 Filler The microcrystalline cellulose (102) 135.1 33.77 135.1 26.03 135.1 28.59 135.1 32.24 Excipient D-mannitol 40 10.00 40 7.71 40 8.46 40 9.55 Disintegration Sodium gluconate 17 4.25 17 3.28 17 3.60 17 4.06 Disintegration Crospovidone 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 Lubricant Magnesium stearate 3 0.75 3 0.58 3 0.63 3 0.72 Antioxidant BHA - - 8.5 1.64 8.5 1.80 - - Antioxidant Citric acid - - - 65 13.76 - - Antioxidant BHT - - 8.5 1.64 - - - - Antioxidant Sodium Ascorbate One 0.25 103 19.84 - - - - Antioxidant Zinc oxide - - - - - - 20 4.77 weight 400.04 100 519.04 100 472.54 100 419.04 100

Classification ingredient Comparative Example 16 Comparative Example 17 Comparative Example 18 Comparative Example 19 Comparative Example 20 Comparative Example 21 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Amlodipine besylate 6.94 1.66 6.94 1.66 6.94 1.69 6.94 1.66 6.94 1.66 6.94 1.74 Pharmacologically active ingredient Losartan potassium 50 11.93 50 11.93 50 12.21 50 11.93 50 11.93 50 12.51 Filler The microcrystalline cellulose (101) 130 31.02 130 31.02 130 31.74 130 31.02 130 31.02 130 32.54 Filler The microcrystalline cellulose (102) 135.1 32.24 135.1 32.24 135.1 32.99 135.1 32.24 135.1 32.24 135.1 33.81 Excipient D-mannitol 40 9.55 40 9.55 40 9.77 40 9.55 40 9.55 40 10.01 Disintegration Sodium gluconate 17 4.06 17 4.06 17 4.15 17 4.06 17 4.06 17 4.25 Disintegration Crospovidone 12 2.86 12 2.86 12 2.93 12 2.86 12 2.86 12 3.00 Binder Povidone 5 1.19 5 1.19 5 1.22 5 1.19 5 1.19 5 1.25 Lubricant Magnesium stearate 3 0.72 3 0.72 3 0.73 3 0.72 3 0.72 3 0.75 Antioxidant Zinc oxide - - - - 8.5 2.08 - - - - - - Antioxidant Ascorbic acid 20 4.77 - - - - - - - - - - Antioxidant Sodium bisulfite - - 20 4.77 - - - - - - - - Antioxidant Sodium Edetate - - - - 2 0.49 - - - - - - Antioxidant Tocopherol Acetate - - - - - - 20 4.77 - - - - Antioxidant Tocopherol - - - - - - - - 20 4.77 - - Antioxidant Sodium pyrosulfite - - - - - - - - - - 0.5 0.13 weight 419.04 100 419.04 100 409.54 100 419.04 100 419.04 100 399.54 100

(2) Test results

The test results are shown in Tables 10 and 11 below.

content Example 1 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Comparative Example 13 Comparative Example 14 Amlodipine

Initial content 93.1% 96.6% 92.8% 90.8% 91.1% 91.6% 94.1% 94.2% 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% - Lausanne

Initial content 99.2% 96.9% 102.5% 96.4% 99.0% 94.5% 99.8% 59.4% 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% -

content Comparative Example 15 Comparative Example 16 Comparative Example 17 Comparative Example 18 Comparative Example 19 Comparative Example 20 Comparative Example 21 Amlodipine

Initial content 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% Lausanne

Initial content 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%

As shown in Table 10 and Table 11 above, twelve antioxidants and mixed antioxidants affected the stability of amlodipine and losartan. However, citric acid, sodium hydrogen sulfite and sodium edetate tended to lower the content of losartan, while zinc oxide, ascorbic acid, tocopherol acetate, tocopherol and sodium pyrosulfate decreased the content of amlodipine. Other antioxidants BHA, BHT and proyl gallate maintained the stability of amlodipine and losartan. Therefore, antioxidant activity of antioxidants was relatively high when BHT, galantic acid, BHT and BHA were mixed.

3.2 Selection test for antioxidants

A test was conducted to select an antioxidant exhibiting an optimal stabilizing effect among the three antioxidants using the top three antioxidants (BHT, gallate propylate, BHT + BHA) which were confirmed to have high stability in Test Example 3.1 Respectively.

(1) manufacturing method

Amlodipine and losartan were prepared as Example 2 and Comparative Example 22 and Comparative Example 23, respectively, containing three antioxidants as shown in Table 12 below.

Each formulation was formulated into two-layer tablets divided into amlodipine layer and losartan layer, each containing antioxidant. Each tablet was tableted using a two-layer tableting machine and adjusted to a pressure of 12.5 kpa and a thickness of 5.30 mm. The contents of each tablet were measured immediately after the preparation, after 2 weeks, 4 weeks, and 8 weeks after exposure to the acceleration chamber under the conditions of Table 2.

① Measurement of amlodipine content

Take 3 samples of each sample or the same amount and weigh accurately and put into powder. Approximately 5 mg of amlodipine is weighed into a 100 mL brown capacity flask and the mobile phase is added to make exactly 100 mL. Take 25 mL of this solution and place it in a 50 mL brown capacity flask, align with the mobile phase to the marking, and filter through a 0.45 μm membrane filter to determine the content using HPLC under the same conditions as in Table 3.

② Measurement of content of losartan

Take 3 samples of each sample or the same amount and weigh accurately and put into powder. Approximately 50 mg of losartan potassium was precisely weighed into a 200-mL volumetric flask, filled with about 100 mL of mobile phase A, sonicated for about 10 minutes, and then mobile phase A was added to make exactly 200 mL. The resulting mixture was filtered through a 0.45 μm membrane filter The content is determined using HPLC under the conditions.

Classification ingredient Example 2 Comparative Example 22 Comparative Example 23 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Amlodipine besylate Amlodipine layer 6.94 1.74 6.94 1.66 6.94 1.66 Filler The microcrystalline cellulose (101) 130 32.57 130 31.02 130 31.02 Excipient D-mannitol 40 10.02 40 9.55 40 9.55 Disintegration Sodium gluconate 17 4.26 17 4.06 17 4.06 Binder Povidone 5 1.25 5 1.19 5 1.19 Lubricant Magnesium stearate 1.5 0.38 3 0.72 3 0.72 Antioxidant BHT 17 4.06 8.5 2.03 Antioxidant BHA 8.5 2.03 Antioxidant Propyl gallate 0.06 0.02 Pharmacologically active ingredient Losartan potassium Lausanne Floor 50 12.53 50 11.93 50 11.93 Filler The microcrystalline cellulose (102) 135.1 33.85 135.1 32.24 135.1 32.24 Disintegration Crospovidone 12 3.01 12 2.86 12 2.86 Lubricant Magnesium stearate 1.5 0.38 3 0.72 3 0.72 Gross weight 399.1 100.00 419.04 100.00 419.04 100.00

(2) Test results

The test results are shown in Table 13.

content Example 2 Comparative Example 22 Comparative Example 23 Amlodipine Initial content 93.6% 96.0% 99.6% 4 weeks 90.4% 87.0% 91.1% 8 weeks 84.6% 81.2% ㅡ Lausanne Initial content 99.3% 96.8% 101.6% 4 weeks 102.5% 103.5% 96.5% 8 weeks 100% 97% ㅡ

As shown in Table 13 above, the contents of the initial contents and the contents of 8 weeks were measured by each of the prescriptions, and each prescription showed similar antioxidant power. However, in Comparative Example 22 and Comparative Example 23 containing the BHT, BHA and BHT, browning of the tablets by the antioxidant was observed after 4 weeks and 8 weeks, respectively. Thus, propyl gallate, an antioxidant contained in Example 2, has a strong antioxidant ability while minimizing the physico-chemical effects on the purification.

Test Example  4. Test for ensuring stability of compound

In order to minimize the interaction between amlodipine and losartan, a formulation using a coating agent having a strong protective effect on water was applied, and the change in stability with the coating was measured.

4.1 Formulation Identification Test

As confirmed in the above test, when amlodipine and losartan are physically and chemically contacted, the stability of the drug is deteriorated by the interaction between the drug and the excipient. In order to minimize the contact area between amlodipine and losartan, we compared the stability of single - phase with physico - chemical mixing of two layers of amlodipine and losartan.

(1) manufacturing method

Amlodipine and losartan were tableted in the same manner as in the formulation shown in Table 14, except that amlodipine and losartan were fixed in Example 4, and amlodipine and losartan in Example 3, respectively. The contents were measured immediately after preparation, after 2 weeks, 4 weeks, and 8 weeks after exposure to the chamber.

The content of amlodipine and losartan was measured by the same method as described in Test Example 1. [

Classification ingredient Example 3 (Double column) Example 4 (single schedule) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Amlodipine besylate Amlodipine layer 6.94 1.74 6.94 1.74 Filler The microcrystalline cellulose (101) 130.00 32.57 130.00 32.57 Excipient D-mannitol 40.00 10.02 40.00 10.02 Disintegration Sodium gluconate 17.00 4.26 17.00 4.26 Binder Povidone 5.00 1.25 5.00 1.25 Lubricant Magnesium stearate 1.50 0.38 Antioxidant Gallan profile 0.06 0.02 0.06 0.02 Pharmacologically active ingredient Losartan potassium Lausanne Floor 50.00 12.53 50.00 12.53 Filler The microcrystalline cellulose (102) 135.10 33.85 135.10 33.85 Disintegration Crospovidone 12.00 3.01 12.00 3.01 Lubricant Magnesium stearate 1.50 0.38 3.00 0.75 Gross weight 399.10 100.00 399.10 100.00

(2) Test results

The results according to the above test are shown in Table 15.

content Example 3 Example 4 Amlodipine


Initial content 99.6% 96.7% 2 weeks 98.4% 95.0% 4 weeks 95.6% 91.2% 8 weeks 94.4% 88.5% Lausanne


Initial content 100.3% 96.8% 2 weeks 99.6% 96.9% 4 weeks 99.5% 96.6% 8 weeks 98.4% 96%

As shown in Table 15, it was shown that both Example 3 and Example 4 formed a composite having relatively stable properties even after 8 weeks. However, the content of Example 3 formulated with a double-layer gradually decreased over time lost. Thus, it has been found that the single-information, dual-formulation provides improved stability, which is believed to be due to the prevention of drug interactions by minimizing the interface between the two drugs.

4.2 Coating test

In order to confirm the long-term stability of the composite agent of the present invention, the change of the stability according to the coating was measured using three coating agents.

(1) manufacturing method

Amlodipine and losartan were tableted in the same manner as in the formulation shown in Table 16, except that the tablets were divided into amlodipine layer and losartan layer, and each tablet was coated with three coating agents (Kollicoat Protect (BASF), Opadry, hydroxypropylmethylcellulose Hydroxypropyl methylcellulose), and exposed to the accelerating chamber under the conditions shown in Table 2, respectively. The contents were measured immediately after the preparation, 2 weeks, 4 weeks, and 8 weeks after the preparation

① Measurement of amlodipine content

Take 3 samples of each sample or the same amount and weigh accurately and put into powder. Approximately 5 mg of amlodipine is weighed into a 100 mL brown capacity flask and the mobile phase is added to make exactly 100 mL. Take 25 mL of this solution and place it in a 50 mL brown capacity flask, align with the mobile phase to the marking, and filter through a 0.45 μm membrane filter to determine the content using HPLC under the same conditions as in Table 3.

② Measurement of content of losartan

Take 3 samples of each sample or the same amount and weigh accurately and put into powder. Approximately 50 mg of potassium rosinate was precisely weighed into a 200-mL volumetric flask, filled with about 100 mL of mobile phase A, sonicated for about 10 minutes, and then mobile phase A was added to make exactly 200 mL. The mixture was filtered through a 0.45 μm membrane filter, The content is measured using HPLC under the same conditions.

Classification ingredient Example 5 Example 6 Example 7 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Amlodipine layer Pharmacologically active ingredient Amlodipine besylate 6.94 1.70 6.94 1.70 6.94 1.70 Filler The microcrystalline cellulose (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 Disintegration Sodium gluconate 17.00 4.16 17.00 4.16 17.00 4.16 Binder Povidone 5.00 1.22 5.00 1.22 5.00 1.22 Lubricant Magnesium stearate 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 Lausanne Floor Pharmacologically active ingredient Losartan potassium 50.00 12.22 50.00 12.22 50.00 12.22 Filler The microcrystalline cellulose (102) 135.10 33.02 135.10 33.02 135.10 33.02 Disintegration Crospovidone 12.00 2.93 12.00 2.93 12.00 2.93 Lubricant Magnesium stearate 3.00 0.73 3.00 0.73 3.00 0.73 Coating base kollicoat ^? protect 7.00 1.71 - - - - Opadry ^? - - 7.00 1.71 - - HPMC - - - - 7.00 1.71 Gross weight 409.10 100.00 409.10 100.00 409.10 100.00

(2) Test results

The test results are shown in Table 17 below.

content Example 5 Example 6 Example 7 Amlodipine Initial content 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% Lausanne Initial content 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%

As shown in Table 17, klipcoat ^? Kollicoat ^? It was found that Example 5, the formulation coated with protect, showed the best stability. kollicoat ^? Protect is thought to be because it can effectively block the hydrolysis of the drug by blocking the drug's contact with moisture. Other HPMC and Opadry ^? Examples 6 and 7 coated in the present invention serve to improve the stability of the drug ^. It has been observed that protect is most effectively blocked.

Test Example 5. Dissolution Test

5.1 Dissolution test

In order to find the ideal elution curve of the combination of amlodipine and losartan with stability, experiments were carried out by adjusting the amount of excipient as follows.

(1) manufacturing method

Amlodipine and losartan were prepared by tableting and coating the two layers of amlodipine and losartan layers as shown in Table 18 and Table 19, respectively.

Classification ingredient Example 8 Example 9 Example 10 Example 11 Example 12 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Amlodipine layer Pharmacologically active ingredient Amlodipine besylate 6.94 1.72 6.94 1.70 6.94 1.72 6.94 1.72 6.94 1.72 Filler The microcrystalline cellulose (101) 130.00 32.17 130.00 31.78 130.00 32.17 130.00 32.17 130.00 32.17 Excipient D-mannitol 40.00 9.90 40.00 9.78 40.00 9.90 40.00 9.90 40.00 9.90 Disintegration Sodium gluconate 12.00 2.97 17.00 4.16 20.00 4.95 12.00 2.97 17.00 4.21 Binder Povidone 5.00 1.24 5.00 1.22 5.00 1.24 5.00 1.24 5.00 1.24 Lubricant Magnesium stearate 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 Lausanne Floor Pharmacologically active ingredient Losartan potassium 50.00 12.37 50.00 12.22 50.00 12.37 50.00 12.37 50.00 12.37 Filler The microcrystalline cellulose (102) 135.10 33.43 135.10 33.02 135.10 33.43 135.10 33.43 135.10 33.43 Disintegration Crospovidone 12.00 2.97 12.00 2.93 12.00 2.97 10.00 2.47 10.00 2.47 Lubricant Magnesium stearate 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74 Coating base kolcoat protect 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 Gross weight 404.10 100.00 409.10 100.02 412.10 101.98 402.10 99.51 407.10 100.74

Classification ingredient Example 13 Example 14 Example 15 Example 16 Example 17 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Amlodipine layer Pharmacologically active ingredient Amlodipine besylate 6.94 1.72 6.94 1.70 6.94 1.72 6.94 1.72 6.94 1.72 Filler The microcrystalline cellulose (101) 130.00 32.17 130.00 31.78 130.00 32.17 130.00 32.17 130.00 32.17 Excipient D-mannitol 40.00 9.90 40.00 9.78 40.00 9.90 50.00 12.37 50.00 12.37 Disintegration Sodium gluconate 12.00 2.97 17.00 4.16 20.00 4.95 12.00 2.97 17.00 4.21 Binder Povidone 7.00 1.73 7.00 1.71 7.00 1.73 7.00 1.73 5.00 1.24 Lubricant Magnesium stearate 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 Lausanne Floor Pharmacologically active ingredient Losartan potassium 50.00 12.37 50.00 12.22 50.00 12.37 50.00 12.37 50.00 12.37 Filler The microcrystalline cellulose (102) 135.10 33.43 135.10 33.02 135.10 33.43 135.10 33.43 135.10 33.43 Disintegration Crospovidone 10.00 2.47 10.00 2.44 10.00 2.47 10.00 2.47 10.00 2.47 Lubricant Magnesium stearate 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74 Coating base kolcoat protect 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 Gross weight 404.10 100.00 409.10 100.02 412.10 101.98 414.10 102.47 417.10 103.22

The preparations of Examples 8 to 17 thus prepared were each subjected to a dissolution test under the following conditions.

① Amlodipine

Approximately 34.7 mg amlodipine besylate standard is precisely weighed into a 250 mL brown volumetric flask and accurately titrated with 0.001 mol / L hydrochloric acid solution to 250 mL. 10 mL of this solution is precisely taken, placed in a 100 mL brown capacity flask, mixed with 0.01 mol / L hydrochloric acid solution to the indicated line, and filtered through a 0.45 μm membrane filter.

In addition, weigh accurately and take the sample. Take 10 mL of the eluate after 5, 10, 15, 30, and 45 minutes elapsed from the elution test under the conditions shown in Table 20 and filter it through a 0.45 μm membrane filter.

The sample solution and standard solution are analyzed by HPLC under the same conditions as in Table 3 above.

Device In the dissolution test method of Method 2 of the Korean Pharmacopoeia general test method Test solution 0.01 mol / L, 500 mL of hydrochloric acid solution Elution temperature 37 ± 0.5 ° C Revolutions 100 ± 5 rpm

② Lausanne

50 mg of Lozartan potassium standard is precisely weighed, placed in a 100-mL volumetric flask, and dissolved by adding mobile phase A. The solution is mixed with 10 mL of the mixed solution into a 100-mL volumetric flask. Purified water is added to the flask and filtered through a 0.45-μm membrane filter One solution is the standard solution.

Take 3 tablets of sample and weigh accurately. Separate 10 mL of the eluate after 5, 10, 15, 30, and 45 minutes after elution test under the conditions shown in Table 21 and filter it with 0.45 um membrane filter.

The sample solution and standard solution are analyzed by HPLC under the same conditions as in Table 3 above.

Device In the dissolution test method of Method 2 of the Korean Pharmacopoeia general test method Test solution Purified water, 900 mL Elution temperature 37 ± 0.5 ° C Revolutions 75 ± 5 rpm

(2) Results of dissolution test

The results of the dissolution test are shown in Fig. 1 and Fig.

Fig. 1 is a graph showing the results of dissolution test of amlodipine for Examples 8 to 17, and Fig. 2 is a graph showing the results of dissolution test of losartan for Examples 8 to 17. Fig.

As shown in the results of the dissolution test for amlodipine shown in Fig. 1, the prescriptions for all the prescriptions initially exhibiting a high dissolution rate, but satisfying the standard of 85% or more at 5 minutes were Examples 9 and 10. In the case of the Lozartan shown in Fig. 2, Example 8 and Example 9 satisfied the criteria of 85% or more for 5 minutes. Therefore, the optimal prescription of the combination containing amlodipine and losartan with improved stability was found to be Example 9.

Claims (11)

A combination composition for preventing and treating cardiovascular diseases, including amlodipine or a pharmaceutically acceptable salt thereof, rozatan or a pharmaceutically acceptable salt thereof, and propyl gallate. The combination according to claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof is an amlodipine layer and a losartan layer comprising losartan or a pharmaceutically acceptable salt thereof. Composition. 3. The combination composition of claim 2, wherein the galantalyst profile is contained in an amlodipine layer comprising amlodipine or a pharmaceutically acceptable salt thereof. The composite composition of claim 1, wherein the propyl gallate is included in an amount of 0.001 to 1% by weight based on the total weight of the composition. The combination composition of claim 1, wherein the amlodipine or pharmaceutically acceptable salt thereof is present in an amount of 1 to 6% by weight and the losartan or a pharmaceutically acceptable salt thereof in an amount of 5 to 30% by weight based on the total weight of the composition. The combination composition of claim 1, wherein the composition further comprises a coating agent. The method of claim 6, wherein the coating base is a coating base including a polyvinyl alcohol derivative, methacrylic acid derivatives and polyacrylic acid derivatives of the water-soluble coating base and Kollicoat ^? Protect, Opadry ^? And at least one kind selected from the group consisting of hydroxypropylmethylcellulose (HPMC). 2. The combination composition of claim 1, wherein the pharmaceutically acceptable salt of amlodipine is amlodipine besylate and the pharmaceutically acceptable salt of losartan is losartan potassium. The combination composition of claim 1, further comprising a pharmaceutically acceptable additive in the composition. The combination composition according to claim 9, wherein the additive is included in an amount of 5 to 90% by weight based on the total weight of the composition. The combination composition of claim 1, wherein the cardiovascular disease is selected from the group consisting of angina pectoris, hypertension, arterial spasm, cardiac arrhythmia, cerebral infarction, cardiomyopathy, congestive heart failure and myocardial infarction.

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