WO2015102331A1 - Composite formulation comprising eprosartan and amlodipine, and method for preparation thereof - Google Patents

Abstract

The present invention relates to a composite formulation comprising eprosartan and amlodipine, and a method for the preparation thereof. The composite formulation according to the present invention has an effect of increasing a patient's compliance by reducing a tablet size by at least about 10% compared to a single tablet by improving the stability of two active ingredients.

Description

Complex preparations containing eprosatan and amlodipine and preparation method thereof

The present invention relates to a composite formulation comprising eprosatan and amlodipine and a method for preparing the same.

Because hypertension is more important than preventing blood pressure itself, it is important to keep blood pressure in a normal range and prevent cardiovascular complications such as coronary artery disease such as life-threatening stroke, myocardial infarction, and heart failure. It is important to adjust.

Therefore, by using drugs having different mechanisms together in combination with each other, rather than selecting one drug for a continuous treatment, it is possible to exert a better prophylactic and therapeutic effect, and by long-term administration of the drug by reducing the use of a single drug in combination administration Since there is an advantage that can reduce the side effects that can occur due to the complementary action of two or more drugs, combination drugs that can exhibit synergistic effects in the blood pressure control as well as cardiovascular protection has attracted attention.

In particular, angiotensin II receptor antagonists and calcium channel blockers are widely used clinically for the treatment and prevention of hypertension, such as a combination of amlodipine besylate and atorvastatin calcium (US Pat. No. 6,455,574), amlodipine besil A combination of latex and valsartan (US Pat. No. 6,395,728), a combination of amlodipine besylate and benazipril hydrochloride (US Pat. No. 6,162,802), a combination of amlodipine camsylate and simvastatin (Korean Patent Registration No. 742432), A combination of amlodipine and telmisartan (Korean Patent Publication No. 2007-7012726) and a combination of amlodipine camsylate and rozatan calcium salt (Korean Patent Publication No. 2008-0052852).

Therefore, the present invention focused on the composite composition of angiotensin II receptor antagonist eprosatan and calcium channel blocker amlodipine.

Eprosatan, on the other hand, is an angiotensin II receptor antagonist, useful for blocking angiotensin II receptors, and is known to be useful for hypertension, congestive heart failure and renal failure, and is associated with the effect of ACEIs on the concentration of active peptides such as bradykinin. It has the advantage of not showing major side effects such as cough and angioedema.

In addition, amlodipine is a calcium channel blocker that inhibits calcium ions from entering slow channels, or inhibits calcium ions from entering voltage-sensitive sites in myocardium and vascular smooth muscle during depolarization. Causes relaxation of vascular smooth muscle and expansion of coronary vessels. It also acts to increase oxygen transport to the myocardium in patients with vasospasmodic angina pectoris.

However, despite the need for a combination formulation for the convenience of taking eprosatan and amlodipine so far, it is difficult to completely and evenly mix the two drugs with the size of the tablet. In fact, when these two drugs are mixed in the solid phase, the weight ratios of the active ingredients are not the same even in the same batch of preparation units, resulting in a change in the titer. In addition, it is difficult to secure a similar dissolution rate with the conventional single tablet when the two preparations are simply mixed, and the tablet size increases as the weight of the two substances is increased, causing inconveniences when taking the preparation, and thus easy formulation of the combination. Not.

Accordingly, the present inventors have studied intensively for the development of a combination preparation for simple and easy parallel administration containing eprosatan or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof having different mechanisms of action. As a result, it was confirmed that the present invention can provide a homogeneous composition of eprosatan and amlodipine having different mechanisms of action and improve the dissolution rate which is lowered due to the mixing of two substances, thereby providing a more stable method for preparing a composite formulation. It was completed.

The present invention provides a combination preparation capable of preventing or treating cardiovascular diseases containing eprosatan or a pharmaceutically acceptable salt thereof having different mechanisms, and amlodipine or a pharmaceutically acceptable salt thereof, and a method of preparing the same. It is to provide.

In order to solve the above problems, the present invention provides a combination formulation comprising:

Granules comprising eprosatan or a pharmaceutically acceptable salt thereof, and a first disintegrant,

Amlodipine or a pharmaceutically acceptable salt thereof, and

Second disintegrant.

The co-formulation of the present invention contains eprosatan and amlodipine as active ingredients, and includes a disintegrant to exhibit a similar dissolution pattern with a single preparation of the same amount of eprosatan and amlodipine, and also eprosatan and amlodipine. It is the composite preparation which improved stability by isolate | separating and containing.

In the case of co-formulation of eprosatan and amlodipine, there is a problem in that dissolution rate is lower than that of a conventional single agent due to simple mixing of them due to differences in the physical properties of each component. Therefore, in the present invention, while selecting a disintegrant to improve the dissolution rate, the size reduction of the tablet by excipient optimization was considered. In addition, in consideration of the stability between the active ingredient was prepared a composite mixture of eprosatan and amlodipine individually.

The term 'eprosatan' used in the present invention is a compound represented by the following Chemical Formula 1, and its chemical name is (E) -α- [2-n-butyl-1-[(4-carboxyphenyl) methyl] -1H- Imidazol-5-yl] methylene-2-thiophenepropionic acid. Eprosatan is disclosed in US Pat. No. 5,185,351.

Formula 1

Eprosatan used in the present invention is typically provided as a mesylate salt, the daily dosage of eprosatan being 100 to 1000 mg, preferably 300 to 1000 mg, more preferably based on the eprosatan active ingredient Is 500 to 800 mg. In addition, the eprosatan or a pharmaceutically acceptable salt thereof is preferably included in 60 to 90% by weight based on the total weight of the co-formulation.

The term 'amlodipine' used in the present invention is a compound represented by the following formula (2) is a calcium channel blocker. The chemical name is 3-ethyl-5methyl-2- (2-aminoethoxy-methyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate to be. Amlodipine is a salt form formed from an acid that forms a nontoxic acid addition salt containing a pharmaceutically acceptable anion, for example hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate lactate, tart It can be used in the form of salts such as late, citrate, gluconate and the like. Among these salts, it has been disclosed that amlodipine besylate disclosed in Korean Patent Registration No. 9920 meets physicochemical criteria such as superior solubility, excellent stability, non-hygroscopicity, and processability into tablet formulations compared to hydrochloride, acetate, mesylate, and the like. .

Formula 2

The daily dose of amlodipine is from 0.5 to 20 mg, preferably from 1 to 10 mg, more preferably from 5 to 10 mg, based on the amlodipine active ingredient, which also applies to the present invention. In addition, the amlodipine or a pharmaceutically acceptable salt thereof is preferably included in 0.2 to 2% by weight based on the total weight of the co-formulation.

The first disintegrant and the second disintegrant are each independently at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate and carboxymethyl cellulose. In particular, the first disintegrant forms granules with eprosatan or a pharmaceutically acceptable salt thereof such that eprosatan is separated from amlodipine. The total content of the first disintegrant and the second disintegrant is preferably included in 1 to 10% by weight based on the total weight of the composite preparation. Preferably, the first disintegrant is croscarmellose sodium and the second disintegrant is crospovidone.

In addition, the co-formulation according to the present invention may further include a binder, an excipient or a lubricant.

The binder is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, hard silicic anhydride, synthetic aluminum silicate and calcium hydrogen phosphate. Preferably, hydroxypropyl cellulose can be used as the binder.

In addition, the excipient is any one or more selected from the group consisting of microcrystalline cellulose, lactose, sodium citrate, glycine and starch. Preferably, an excipient may be used in the eprosatan granules and the amlodipine mixture, respectively, and microcrystalline cellulose may be used.

In addition, the lubricant is any one or more selected from the group consisting of stearic acid, calcium stearate, magnesium stearate, talc, colloidal silica, hydrogenated vegetable oil and glycerol dibehenate. Preferably, magnesium stearate may be used as the lubricant.

Since the combination preparation according to the present invention contains eprosatan and amlodipine as active ingredients, it can be usefully used for the prevention or treatment of cardiovascular diseases.

In another aspect, the present invention provides a method for producing the composite formulation comprising the following steps:

Preparing a granule by mixing eprosatan or a pharmaceutically acceptable salt thereof, and a first disintegrant (step 1); And

Mixing amlodipine or a pharmaceutically acceptable salt thereof, and a second disintegrant into the granules (step 2).

The composite preparation according to the present invention may be formulated by the above-described preparation method and be administered orally. In order to separately prepare two drugs of eprosatan and amlodipine, the eprosatan granules may be prepared by a wet granulation process. have. Since eprosatan has an effective content of 600 mg, which is poor in compression tableting property and fluidity, it can be produced by a wet granulation process because it is difficult to manufacture by a simple mixed straight process.

In more detail, a disintegrant such as eprosatan mesylate and croscarmellose sodium as an active ingredient is mixed and then granulated with an ethanol solution in which a binder is dissolved to prepare wet granules. Separately, amlodipine besylate, disintegrant, excipients and the like are mixed as active ingredients. Each of the granules prepared above may be sufficiently mixed to produce a homogeneous composite agent.

The carbon burn in the main component in the present invention, amlodipine and F. The weight percent difference is 98-110 times, and the co-formulation of the present invention includes 60-90 wt% of eprosatan, and 0.6-0.8 wt% of amlodipine. This large difference in weight% results in a lower uniformity of the two main component contents. To overcome this, each tablet was prepared by including three or more times of dispersing.

In addition, the combination of eprosatan and amlodipine according to the present invention includes croscarmellose sodium as a disintegrating agent by the excipient optimization process, thereby ensuring a dissolution pattern similar to the existing single formulation, and the two drugs are separately mixed to improve the stability The formulation was developed.

In a specific embodiment, it was confirmed that the dissolution rate was improved in the case of using the croscarmellose sodium alone than in the case of using cellulose, such as crospovidone or sodium starch glycolate, carboxymethyl cellulose disintegrant in the optimization process of the tablet.

Thus, the combination of eprosatan and amlodipine of the present invention was found to be an optimized combination with dissolution rate and stability with a single formulation. Therefore, the combination formulation of eprosatan and amlodipine of the present invention can provide high dose compliance while reducing side effects than when each is used as a single formulation.

The present invention provides a combination formulation containing eprosatan or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof, wherein the combination formulation has improved dissolution rate and stability of the two active ingredients while showing similar dissolution rate as a single formulation. To provide.

In addition, the present invention by reducing the size of the tablet compared to a single tablet of commercially available eprosatan by at least about 10%, by providing a combination of eprosatan and amlodipine, there is an effect of increasing the patient's dose compliance.

Figure 1a shows a plasma concentration analysis graph of eprosatan after the administration of the combination preparation and the control agent according to an embodiment of the present invention.

Figure 1b shows a plasma concentration analysis graph of amlodipine after administration of the combination preparation and the control according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.

Hereinafter, eprosatan used eprosatan mesylate, and amlodipine used amlodipine besylate. Lactose hydrate is DMV-Fonterra Excipient, microcrystalline cellulose is Avicel 102 (MINGTAL), gelled starch is Starch 1500 (Colorcon), calcium dihydrogen phosphate INNOPHOS, hydroxypropyl cellulose is NIPPONSODA, and crospovidone is Kolidon CL (BASF Co., Ltd.), sodium starch glycolate was used by JRS, Croscarmellose Sodium JRS, and magnesium stearate as FACI raw materials.

Examples 1 to 5: Preparation of Eprosatan and Amlodipine Complex Formulations

One) Example 1

735.8 mg of eprosatanmesylate, 6.94 mg of amlodipine besylate, 100 mg of lactose monohydrate, 156.2 mg of microcrystalline cellulose, 55 mg of gelled starch, 55.06 mg of calcium dihydrogen phosphate and 50 mg of crospovidone were mixed for 3 minutes to 5 minutes. To the mixture prepared above, 23 mg of hydroxypropyl cellulose was dissolved in ethanol, followed by granulation. The wet mixture was passed through # 16 to # 20 mesh screens and then dried. The dried powder was passed through a # 16 to # 30 mesh screen and then mixed by lubricating with 18 mg of magnesium stearate.

2) Example 2

Eprosatan mesylate 735.8 mg, amlodipine besylate 6.94 mg, lactose monohydrate 45.2 mg, microcrystalline cellulose 85 mg, gelling starch 55 mg, calcium dihydrogen phosphate 55.06 mg, crospovidone 20 mg and the binding solution of Example 1 was added The mixture was prepared by lubricating with 18 mg of magnesium stearate.

3) Example 3

Wet granules were prepared by mixing 735.8 mg of eprosatan mesylate, 45.2 mg of lactose monohydrate, 85 mg of microcrystalline cellulose, and 55 mg of gelled starch, and then adding 23 mg of hydroxypropyl cellulose dissolved in ethanol. 6.94 mg of amlodipine besylate, 20 mg of microcrystalline cellulose, 55.06 mg of calcium dihydrogen phosphate, and 20 mg of crospovidone were added to the prepared wet granules, mixed with 18 mg of magnesium stearate, and finally mixed.

The component configurations of the composite preparations of Examples 1 to 3 are shown in Table 1 below.

Table 1

Ingredient (% by weight)	Example 1	Example 2	Example 3
Eprosatan mesylate	61.32	70.48	69.15
Amlodipine besylate	0.58	0.66	0.65
Lactose Carb	8.33	4.33	4.25
Microcrystalline cellulose	13.02	8.14	9.87
Gelling starch	4.58	5.27	5.17
Calcium dihydrogen phosphate	4.59	5.27	5.17
Hydroxypropyl cellulose	1.92	2.20	2.16
Crospovidone	4.17	1.92	1.88
Magnesium stearate	1.50	1.72	1.69
system	100	100	100

4) Example 4

Wet granules were prepared by mixing 735.8 mg of eprosatanmesylate, 45.2 mg of lactose monohydrate, 65 mg of microcrystalline cellulose, and 55 mg of gelled starch, and then adding 20 mg of hydroxypropyl cellulose dissolved in ethanol (step 1).

6.94 mg of amlodipine besylate, 20 mg of microcrystalline cellulose, 55.06 mg of calcium dihydrogen phosphate, and 20 mg of crospovidone were added to the prepared wet granules, mixed with 18 mg of magnesium stearate, and finally mixed (step 2).

5) Example 5

6.84 mg of amlodipine besylate, 20 mg of microcrystalline cellulose, 55.06 mg of calcium dihydrogen phosphate, and 20 mg of crospovidone were mixed, and 3 mg of povidone dissolved in ethanol was added to prepare wet granules. Step 1 granules of Example 4 were added and mixed with the prepared wet granules, and the final mixture was lubricated with 18 mg of magnesium stearate.

The composition of components of the composite preparations of Examples 4 and 5 is shown in Table 2 below.

TABLE 2

Ingredient (% by weight)	Example 4	Example 5
Eprosatan mesylate	70.68	70.48
Amlodipine besylate	0.67	0.66
Lactose Carb	4.34	4.33
Microcrystalline cellulose	8.17	8.14
Gelling starch	5.28	5.27
Calcium dihydrogen phosphate	5.29	5.27
Hydroxypropyl cellulose	1.92	1.92
Crospovidone	1.92	1.92
Povidone	-	0.29
Magnesium stearate	1.73	1.72
system	100	100

6) Dissolution Rate Evaluation

The pharmaceutical formulations (Examples 2 and 4) exhibiting representativeness in Examples 1 to 5 were tested in Disintegration Test Method 2 (pH 6.8), 900 mL, and 50 rpm, according to Method 2 of the Korean Pharmacopoeia Dissolution Test. Was carried out. The eprosatan control used as a control in this experiment was tebeten tablet (eprosatanmesylate), and the amlodipine control was Novasque (amlodipine besylate) tablet. After the start of elution, a certain amount of the eluate was taken at regular intervals, and the dissolution rate was measured. The results are shown in Table 3 below.

TABLE 3

Eprosatan mesylate (% dissolution rate)	10 minutes	15 minutes
Reference	45	57
Example 2	19	30
Example 4	26	37
Amlodipine besylate (% dissolution rate)	10 minutes	15 minutes
Reference	84	87
Example 2	58	67
Example 4	67	75

As shown in Table 3, the prepared eprosatan combination formulation showed a lower elution pattern than the control. In addition, in the results of the stability test according to the manufacturing process formulation in the content test results of Examples 4 and 5, in Example 5 prepared by adding the amlodipine granule preparation process in Example 4, the content of amlodipine is reduced (roughly 28 days, 86% ). However, stability test conditions refer to 40 degreeC, 75%, and the bottle open.

From the above results, the formulations of Examples 2 and 4 showed lower dissolution patterns than the reference drug, and thus improved prescriptions such as disintegrant examination for dissolution improvement. In addition, in consideration of the stability according to the formulation, the granulation process of amlodipine was excluded, and after mixing eprosatan granules, amlodipine was post-mixed to prepare a stable composite. In order to ensure homogeneity between the two formulations during production, a homogeneous tablet was secured between each formulation, including three or more times of dispersing.

Examples 6 to 9: Preparation of Eprosatan and Amlodipine Complex Formulations with Enhanced Elution

One) Example 6

After mixing 735.8 mg of eprosatan mesylate, 45.2 mg of lactose monohydrate, 44 mg of microcrystalline cellulose, 55 mg of gelled starch, and 21 mg of croscarmellose sodium, a binder solution of 20 mg of hydroxypropyl cellulose in ethanol was added and granulated. After preparation, the wet mixture was passed through # 16 to # 20 mesh screens, then dried and stipulated (step 1).

6.94 mg of amlodipine besylate, 20 mg of microcrystalline cellulose, 55.06 mg of calcium monohydrogen phosphate, and 20 mg of crospovidone were added to the prepared wet granules, mixed with 18 mg of magnesium stearate, and finally mixed (step 2).

2) Example 7

Wet granules were prepared by mixing 735.8 mg of eprosatan mesylate, 45.2 mg of lactose monohydrate, 44 mg of microcrystalline cellulose, 55 mg of gelled starch, and 21 mg of croscarmellose sodium, and then adding 20 mg of hydroxypropyl cellulose dissolved in ethanol. It was. The wet granules prepared above were finally mixed according to the step 2 process of Example 6.

3) Example 8

Wet granules were prepared by mixing 735.8 mg of eprosatan mesylate, 45.2 mg of lactose monohydrate, 14 mg of microcrystalline cellulose, 55 mg of gelled starch, and 52 mg of croscarmellose sodium, followed by the addition of 20 mg of hydroxypropylcellulose dissolved in ethanol. It was. The wet granules prepared above were finally mixed according to the step 2 process of Example 6.

4) Example 9

Wet granules were prepared by mixing 735.8 mg of eprosatan mesylate, 45.2 mg of lactose monohydrate, 35 mg of microcrystalline cellulose, 55 mg of gelled starch, and 31 mg of crospovidone, followed by the addition of 20 mg of hydroxypropyl cellulose dissolved in ethanol. The wet granules prepared above were finally mixed according to the step 2 process of Example 6.

The composition of the composite preparation of Examples 6 to 9 is shown in Table 4 below.

Table 4

Ingredient (% by weight)	Example 6	Example 7	Example 8	Example 9
Eprosatan mesylate	70.68	70.68	70.61	70.61
Amlodipine besylate	0.67	0.67	0.67	0.67
Lactose Carb	4.34	4.34	4.34	4.34
Microcrystalline cellulose	6.15	6.15	3.26	5.28
Gelling starch	5.28	5.28	5.28	5.28
Calcium dihydrogen phosphate	5.29	5.29	5.28	5.28
Hydroxypropyl cellulose	1.92	1.92	1.92	1.92
Crospovidone	1.92	1.92	1.92	4.89
Croscarmellose Sodium	2.02	2.02	4.99	-
Magnesium stearate	1.73	1.73	1.73	1.73
system	100	100	100	100

5) Dissolution Rate Evaluation

Examples 6 to 9 are the preparations to improve the dissolution rate by increasing the type and amount of disintegrant (crosamelose sodium or crospovidone), according to the second method of dissolution test method, disintegration test method (pH) 6.8), 900 mL, 50 rpm. After the start of elution, a certain amount of eluate was taken at regular time intervals, and the dissolution rate was measured. The results are shown in Table 5 below.

Table 5

Eprosatan mesylate (% dissolution rate)	10 minutes	15 minutes
Example 6	51	59
Example 7	55	63
Example 8	55	67
Example 9	39	47
Amlodipine besylate (% dissolution rate)	10 minutes	15 minutes
Example 6	69	73
Example 7	74	80
Example 8	87	93
Example 9	66	74

As shown in Table 5, the prepared eprosatan combination showed a dissolution pattern similar or higher than that of the reference drug. In particular, high dissolution rate was confirmed in the formulation containing sodium croscarmellose (Examples 6 to 8).

In addition, to reduce the tablet size of the eprosatan composites of Examples 6 to 9 in the tablet size of Tebeten tablets, excipient optimization was performed to secure a stable composite formulation.

Examples 10-13 Preparation of Eprosatan and Amlodipine Complex Formulations with Reduced Tablet Size

One) Example 10

Wet granules were prepared by mixing 735.8 mg of eprosatanmesylate and 45.2 mg of lactose monohydrate, and then adding 20 mg of hydroxypropyl cellulose dissolved in ethanol. The wet granules prepared above were finally mixed according to the step 2 process of Example 6.

2) Example 11

Wet granules were prepared by mixing 735.8 mg of eprosatanmesylate, 45.3 mg of lactose monohydrate, and 36 mg of croscarmellose sodium, followed by the addition of 20 mg of hydroxypropylcellulose dissolved in ethanol (step 1).

6.94 mg of amlodipine besylate, 20 mg of microcrystalline cellulose and 18 mg of croscarmellose sodium were added to the prepared wet granules, mixed with 18 mg of magnesium stearate, and finally mixed (step 2).

3) Example 12

Wet granules were prepared by mixing 735.8 mg of eprosatan mesylate and 18 mg of croscarmellose sodium, and then adding 23 mg of hydroxypropyl cellulose dissolved in ethanol. The wet granules were finally mixed according to the step 2 process of Example 11 above.

4) Example 13

Wet granules were prepared by adding 235.8 hydroxypropylcellulose dissolved in ethanol to 735.8 mg eprosatanmesylate. The wet granules were finally mixed according to the step 2 process of Example 11 above.

The composition of the composite preparation of Examples 10 to 13 is shown in Table 6.

Table 6

Ingredient (% by weight)	Example 10	Example 11	Example 12	Example 13
Eprosatan mesylate	79.89	81.75	87.62	89.54
Amlodipine besylate	0.75	0.77	0.83	0.84
Lactose Carb	4.91	5.03	-	-
Microcrystalline cellulose	2.17	2.22	2.38	2.43
Calcium dihydrogen phosphate	5.98	-	-	-
Hydroxypropyl cellulose	2.17	2.22	2.74	2.80
Crospovidone	2.17	-	-	-
Croscarmellose Sodium	-	6.00	4.29	2.19
Magnesium stearate	1.95	2.00	2.14	2.19
system	100	100	100	100

Examples 10 to 13 is a combination formulation that maximizes the convenience of the medication by improving the size of the tablet by optimizing the excipient, the formulation was improved compared to the single tablet (Tebecene) tablets despite the combination formulation. While the size of the tebene was 19.8 × 8.5 × 6.9 mm ³ , the formulation was 17.7 × 9.2 × 6.6 mm ^3, which reduced the size by about 10% to improve patient convenience.

5) Dissolution Rate Evaluation

The composite formulations of Examples 11 to 13 were tested in Dissolution Test Method 2 (pH 6.8), 900 mL, and 50 rpm, according to the 2nd method of the pharmacopeia dissolution test method. After the start of elution, a certain amount of eluate was taken at regular time intervals and analyzed to measure the elution rate. The results are shown in Table 7 below.

TABLE 7

Eprosatan mesylate (% dissolution rate)	10 minutes	15 minutes
Example 11	50.5	61.5
Example 12	45.9	56.2
Example 13	39.9	40.2
Amlodipine besylate (% dissolution rate)	10 minutes	15 minutes
Example 11	76.4	82.4
Example 12	69.0	75.1
Example 13	66.0	72.0

In Example 11, although the ratio of excipient in the total weight of the tablet was 17.4% for the optimization of the tablet size, it was confirmed that the dissolution rate was similar to that of the reference drug (see Table 3). In addition, by separating and granulating the two main components, it can be seen that the two main components do not significantly affect the respective dissolutions.

6) Pharmacokinetic Evaluation

The co-formulations prepared in Example 11 were administered to Beagle dogs to measure the time-dependent drug concentrations of amlodipine and eprosatan. Four beagle dogs were used in each group, and the results were measured by fasting. Blood drug concentrations are shown in FIGS. 1A and 1B.

As shown in Figure 1a and 1b, the time-dependent blood drug concentration of amlodipine showed a similar drug concentration between the reference drug and the test drug, the time-dependent blood drug concentration of eprosatan showed a slightly higher drug concentration than the reference drug.

The present invention relates to a composite formulation comprising eprosatan and amlodipine and a preparation method thereof. The composite formulation according to the present invention improves stability of two components by homogeneously forming two active ingredients having different mechanisms of action. Cardiovascular disease, which not only yielded or improved dissolution rate in a single tablet, but also reduced the size of the tablet by about 10% or more than a single tablet, thereby improving dose compliance of cardiovascular patients. Effective as a prophylactic or therapeutic agent, it can be said that the industrial applicability in the art is extremely high.

Claims (11)

1. Granules comprising eprosatan or a pharmaceutically acceptable salt thereof, and a first disintegrant,

   Amlodipine or a pharmaceutically acceptable salt thereof, and

   Secondary disintegrant

   Containing a combination.
2. The combination preparation according to claim 1, wherein the eprosatan or a pharmaceutically acceptable salt thereof is included in an amount of 60 to 90% by weight based on the total weight of the combination preparation.
3. The combination formulation of claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 0.2 to 2 wt% based on the total weight of the combination formulation.
4. The method of claim 1, wherein the first disintegrant and the second disintegrant are each independently one or more selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate and carboxymethyl cellulose , Combinations.
5. The combination preparation according to claim 1, wherein the first disintegrant is croscarmellose sodium and the second disintegrant is crospovidone.
6. According to claim 1, The total content of the first disintegrant and the second disintegrant is a composite formulation, characterized in that contained in 1 to 10% by weight based on the total weight of the composite formulation.
7. The combination preparation according to claim 1, wherein the combination preparation further comprises a binder, excipient or glidant.
8. The method of claim 7, wherein the binder is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, hard silicic anhydride, synthetic aluminum silicate and calcium hydrogen phosphate. A composite formulation, characterized in that.
9. The combination preparation according to claim 7, wherein the excipient is any one or more selected from the group consisting of microcrystalline cellulose, lactose, sodium citrate, glycine and starch.
10. The method of claim 7, wherein the lubricant is any one or more selected from the group consisting of stearic acid, calcium stearate, magnesium stearate, talc, colloidal silica, hydrogenated vegetable oil and glycerol dibehenate ,

    Combinations.
11. A method for preparing a complex preparation according to any one of claims 1 to 10, comprising the following steps:

    Preparing a granule by mixing eprosatan or a pharmaceutically acceptable salt thereof, and a first disintegrant; And

    Admixing amlodipine or a pharmaceutically acceptable salt thereof, and a second disintegrant to the granules.

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