WO2018062685A1 - Composite formed into single layer, comprising candesartan and amlodipine - Google Patents

Abstract

The present invention relates to a composite formed into a single layer, comprising: (i) candesartan or candesartan cilexetil or a pharmaceutically acceptable salt thereof; (ii) amlodipine or a pharmaceutically acceptable salt thereof; (iii) triethyl citrate as a stabilizer; and (iv) mannitol as a filler. The composite of the present invention has improved stability of candesartan during preparation processing and storage, has an excellent dissolution rate, and has an effect of facilitating preparation into a formulation such as a tablet.

Description

Combination of monolayers containing candesartan and amlodipine

The present invention relates to a composite composed of a single layer containing candesartan and amlodipine, and is prepared by improving the problems that are difficult to develop into a single layer composite due to the inherent properties of the candesartan and amlodipine materials. A single layer composite of candesartan and amlodipine having properties.

It is important to keep blood pressure in a normal range rather than to treat the blood pressure itself, so it is important to prevent cardiovascular complications such as coronary artery disease such as life-threatening stroke, myocardial infarction, and heart failure. It is important.

By using drugs with different mechanisms in combination with each other, rather than selecting one drug for steady treatment, a better prophylactic and therapeutic effect can be exerted, and it can be caused by long-term use of the drug by reducing the use of a single drug in combination administration. Because there is an advantage that can reduce the side effects of the combination of the two or more drugs through the complementary action of the blood pressure control as well as the cardiovascular protective effect that can exhibit a synergistic effect is attracting 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 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 inventors of the present invention have attempted to develop a combination of candesartan, an angiotensin II receptor antagonist, and amlodipine, a calcium channel blocker.

Candesartan, on the other hand, belongs to angiotensin II receptor antagonist (Angiotensin II Receptor Blocker) and has excellent efficacy as a useful therapeutic agent for circulatory diseases such as hypertension, heart disease, seizures, stroke and nephritis. However, due to the very low absorption rate during oral administration, the prodrug candesartan cilexetil was developed, and during absorption into the gastrointestinal tract, cilexetil was liberated from the candesartan cilexetil and rapidly hydrolyzed to the active candesartan. do.

Candesartan cilexetil is a white to off-white powder and hardly soluble in water and methanol. In addition, it is known that the stability rapidly decreases due to the compression pressure and the exothermic heat generated during the molding into tablets, and thus, the technology for improving the stability and improving the bioavailability of candesartan cilexetil according to physical changes in the tablet molding process is developed. Many studies have been conducted to do this.

For example, Korean Patent No. 256633 discloses polymers of hydrocarbons, higher fatty acids, higher alcohols, fatty acid esters of polyhydric alcohols, higher ethers of polyhydric alcohols and alkylene oxides to improve the stability of candesartan cilexetil, or Disclosed is a stabilization method of preparing a mixed oily phase material selected from the group consisting of copolymers. However, in the case of manufacturing a mixture of these oily phase materials, the release property of poorly soluble candesartan cilexetil is difficult to be constantly controlled under the influence of the oily phase material, and thus, there is a disadvantage in that the variation between individuals is increased during dosing.

US Patent 2012 / 516,539 discloses a method of using triethyl citrate as a stabilizer to solve the stability problem of candesartan cilexetil. When using 1% by weight of triethyl citrate, the soft substance of candesartan cilexetil showed a very low content of 0.48% after 4 weeks at 50 ° C.

U.S. Patent No. 2012 / 305,283 also discloses a method of using triethyl citrate as a stabilizer in order to solve the stability problem of candesartan cilexetil, and when using 2.1% by weight of triethyl citrate 50 After 2 weeks, the soft substance of candesartan cilexetil showed a very low content of 0.1%.

In addition, the Republic of Korea Patent No. 256633 shows a flexible material of candesartan 0.9% after 4 weeks at 50 ℃ when 0.46% by weight of polyethylene glycol 6000 is added in Example 1.

Therefore, when triethyl citrate is used as a stabilizer, it can be seen that the effect is better in a small amount than polyethylene glycol. In addition, cases have been found in which polyethylene glycol causes delayed and immediate hypersensitivity (Sapna Shah MD, et al., Hypersensitivity to Polyethylene Glycols, The Journal of Clinical Pharmacology). In addition, polyethylene glycol is likely to cause changes in pharmacokinetic behavior due to ABC Phenomenon (accelerated blood clearance), and has the disadvantage of not being a biodegradable polymer (US Schuber et al., Polyethylene glycol in Drug delivery, Angewandte chemie). Therefore, the present inventors considered a method of using triethyl citrate instead of polyethylene glycol as a stabilizer to solve the stability problem of candesartan cilexetil.

However, when using liquid triethyl citrate as a stabilizer of candesartan, a filler is essential, and lactose, which is a water-soluble filler, is generally used because candesartan is poorly soluble. U.S. Patent Nos. 2012 / 516,539 and 2012 / 305,283 also show that triethyl citrate and lactose were added together.

However, there is a problem that can not be added to the lactose in the production of a single-layer composite of candesartan and amlodipine. That is, since lactose reacts with amlodipine to produce a degradation product of amlodipine, lactose cannot be added in the preparation of a single layer composite of candesartan and amlodipine. In order to solve this problem, when candesartan and amlodipine are separated and manufactured in a double layer, the volume of the tablet becomes large and a difficulty of undergoing various processes in manufacturing occurs.

Accordingly, the inventors of the present invention have shown excellent properties in terms of pharmaceutical properties such as properties, hardness, active ingredients are not decomposed during the manufacturing process and storage, and canesartantan and amlodipine which have a simple dissolution rate and have a simple manufacturing process. A composite comprising a single layer was completed.

In order to solve the above problems, the present inventors have prepared a monolayer combination containing (i) candesartan, candesartan cilexetil or a pharmaceutically acceptable salt thereof, and (ii) amlodipine or a pharmaceutically acceptable salt thereof. As a stabilizer, there is provided a single layer composite comprising triethyl citrate as a stabilizer and mannitol as a filler.

The present inventors

(i) candesartan, candesartan cilexetil, or a pharmaceutically acceptable salt thereof,

(ii) amlodipine or a pharmaceutically acceptable salt thereof,

(iii) triethyl citrate as stabilizer, and

(iv) mannitol as filler

It provides a composite consisting of a single layer comprising a.

The chemical name of the term “candesartan” used in the present invention is 2-ethoxy-1-[[2 '-(4,5-dihydro-5-oxo-1,2,4-oxadiazole-3- Yl) biphenyl-4-yl] methyl] -1 H-benzimidazole-7-carboxylic acid.

As used herein, the term “candesartan cilexetil” is a prodrug of candesartan, and its chemical name is 1- (cyclohexyloxycarbonyloxy) ethyl-2-ethoxy-1-[[2'- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

As used herein, the term “pharmaceutically acceptable salts” means salts formed with any inorganic or organic acid, or base, that do not cause serious irritation upon administration to the human body and do not impair the biological activity and properties of the compound. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbon acids such as citric acid, acetic acid, trichloroacetic acid, trichloroacetic acid, succinic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed by the same sulfonic acid, etc. In addition, pharmaceutically acceptable salts include Is a metal salt formed by lithium, sodium, potassium, calcium, magnesium or the like, an amino acid salt such as alkaline earth metal salt, lysine, arginine, guanidine, dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl Organic salts such as methylamine, diethanolamine, choline and triethylamine, and the like.

As used herein, the term "amlodipine" is a calcium channel blocker, the specific chemical name of which is 3-ethyl-5methyl-2- (2-aminoethoxy-methyl) -4- (2-chlorophenyl) -6- Methyl-1,4-dihydro-3,5-pyridine dicarboxylate.

Preferably, amlodipine is a non-toxic acid addition salt form containing a pharmaceutically acceptable anion, for example hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate lactate, tartrate, citrate , Salts such as gluconate, besylate, and the like. More preferably, amlodipine besylate may be used, and amlodipine besylate has superior solubility, stability, non-hygroscopicity, and the like compared to hydrochloride, acetate, mesylate, and the like.

The candesartan, candesartan cilexetil, or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 to 30% by weight, more preferably 0.5 to 20% by weight, based on the total weight of the combination. Preferably it may be included in 1 to 10% by weight.

In addition, the amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 to 30% by weight, more preferably 0.5 to 20% by weight, and most preferably 1 to 10% by weight, based on the total weight of the combination. May be included as a%.

Triethyl citrate used as a stabilizer in the present invention may be included in 0.1 to 20% by weight, more preferably 0.1 to 10% by weight, most preferably 0.1 to 5% by weight based on the total weight of the composite May be included.

Mannitol used as a filler in the present invention may be included in more than 30% by weight, more preferably 40 to 80% by weight, most preferably 50 to 70% by weight based on the total weight of the composite agent Can be.

The weight ratio of triethyl citrate and mannitol is 1: 30 to 90, preferably 1: 40 to 80, most preferably 1: 50 to 70.

The present invention

(i) 0.1-30% by weight of candesartan cilexetil,

(ii) 0.1 to 30 weight percent of amlodipine besylate,

(iii) 0.1 to 20 weight percent of triethyl citrate, and

(iv) at least 30% by weight of mannitol

It comprises a composite consisting of a single layer containing.

In addition, the combination according to the invention may further comprise a binder, excipient or glidant.

The binder is an additive to maintain the form of the formulation, polyvinyl alcohol- polyethylene glycol graft copolymer, polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose , Methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate and mixtures thereof, but may be any one or more selected from, but is not limited thereto.

In addition, the excipient is an additive used for dilution or increase, preferably at least one selected from the group consisting of sugars, lactose, cellulose and starch. More preferably, lactose monohydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose salt (e.g., carboxy cellulose calcium, carboxy cellulose) Sodium), other substituted and unsubstituted cellulose, corn starch, gelatinized starch, lactose, anhydrous sugars, sugar alcohols (e.g. mannitol, sorbitol), sucrose, xylitol, acrylate polymers and copolymers, dextrates, dextrins, dextrose, maltose Dextrins, pectins, gelatin, inorganic diluents (eg, calcium carbonate dibasic calcium phosphate dihydrate, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium chloride) and other excipients known in the art, including but not limited to It is not.

In addition, the lubricant is an additive for smoothing the compression operation of the granules, may be any one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate and glyceryl behenate, but is not limited thereto. .

In addition, other additives that may be incorporated into the formulation may include lubricants, preservatives, surfactants, antioxidants, colorants (eg, red iron oxide), flavors, flavor enhancers, or any other additives commonly used in the art. have.

Since the complex according to the present invention includes candesartan and amlodipine as active ingredients, it may be usefully used for the prevention or treatment of cardiovascular diseases. In addition, the combination of the present invention in order to more effectively treat hypertension or related cardiovascular diseases, therapeutically effective amounts of diuretics, beta receptors, alpha blockers, alpha-beta blockers, sympathetic inhibitors, angiotensin converting enzyme inhibitors, calcium channel blockers , Angiotensin receptor blockers, mineralocorticoid receptor antagonists, and the like.

When the formulations of the invention are tablets, they may be prepared by wet or dry granulation, or by direct compression, preferably in the form of tablets prepared by wet or dry granulation, more preferably by wet granulation.

The combination of the present invention can be used in the pharmaceutical use to treat circulatory diseases such as hypertension, heart disease, seizures, stroke and nephritis, the method of administration is not particularly limited and appropriate administration methods and administration according to the age, sex and symptoms of the patient It can be administered by route, with oral administration being preferred.

The present invention relates to (i) candesartan, candesartan cilexetil or a pharmaceutically acceptable salt thereof, (ii) amlodipine or a pharmaceutically acceptable salt thereof, (iii) triethyl citrate as stabilizer, and (iv) The present invention relates to a composite comprising a single layer containing mannitol as a filler, which improves the stability of the active ingredient during the manufacturing process and storage, has excellent dissolution rate, and is easy to prepare into a formulation such as tablets.

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.

Example 1

Complex preparations of candesartan and amlodipine

1) Preparation of binding solution

Triethyl citrate and hydroxypropyl cellulose are added to water, and the solution which is completely dissolved by stirring is used as a binding solution.

2) mixed

The active ingredient candesartan cilexetil, amlodipine besylate, mannitol, and microcrystalline cellulose are put into a mixer and mixed.

3) Union and Granulation

Put the binding solution of 1) into the mixture of 2) and then combine, then proceed with the granulation process using comil.

4) drying and formulation

The granules of 3) are put in a fluidized-bed drier and dried, and then granulated with a comil granulator.

5) final blend

The mixture of 4) and mannitol were added to the mixer, followed by primary mixing. Then, magnesium stearate and sodium stearyl fumarate were passed through the mixture to perform secondary mixing.

6) Tableting

The final mixture of 5) was compressed into tablets using an automatic tablet press (XP1, Korsch, Germany) to give a tablet of 130 mg in total weight.

Purpose of Mixing	Ingredient Name	Quantity (mg)	weight(%)
chief ingredient	Candesartan cilexetil	8.00	6.15
chief ingredient	Amlodipine Besylate	6.94	5.34
Excipient	Mannitol	84.16	64.74
Excipient	Microcrystalline cellulose	15.00	11.54
Excipient	Copovidone	6.00	4.62
Binder	Hydroxypropyl cellulose	6.00	4.62
Stabilizer	Triethyl citrate	1.30	1.00
Lubricant	Magnesium stearate	1.30	1.00
Lubricant	Sodium stearyl fumarate	1.30	1.00
Gross weight		130.00	100

<Comparative Example 1>

To the components and contents of the following Table 2, was prepared in the same manner as in Example 1 to prepare a composite formulation of candesartan and amlodipine. At this time, sorbitol was used instead of mannitol as an excipient.

Purpose of Mixing	Ingredient Name	Quantity (mg)
chief ingredient	Candesartan cilexetil	8.00
chief ingredient	Amlodipine Besylate	6.94
Excipient	Sorbitol	84.16
Excipient	Microcrystalline cellulose	15.00
Excipient	Copovidone	6.00
Binder	Hydroxypropyl cellulose	6.00
Stabilizer	Triethyl citrate	1.30
Lubricant	Magnesium stearate	1.30
Lubricant	Sodium stearyl fumarate	1.30
Gross weight		130.00

<Comparative Example 2>

To the components and contents of the following Table 3, was prepared in the same manner as in Example 1 to prepare a composite formulation of candesartan and amlodipine. At this time, Isomalt was used instead of mannitol as an excipient.

Purpose of Mixing	Ingredient Name	Quantity (mg)
chief ingredient	Candesartan cilexetil	8.00
chief ingredient	Amlodipine Besylate	6.94
Excipient	Isomalt	84.16
Excipient	Microcrystalline cellulose	15.00
Excipient	Copovidone	6.00
Binder	Hydroxypropyl cellulose	6.00
Stabilizer	Triethyl citrate	1.30
Lubricant	Magnesium stearate	1.30
Lubricant	Sodium stearyl fumarate	1.30
Gross weight		130.00

<Comparative Example 3>

To the ingredients and contents of the following Table 4, was prepared in the same manner as in Example 1 to prepare a complex formulation of candesartan and amlodipine. At this time, sugar was used instead of mannitol as an excipient.

Purpose of Mixing	Ingredient Name	Quantity (mg)
chief ingredient	Candesartan cilexetil	8.00
chief ingredient	Amlodipine Besylate	6.94
Excipient	White sugar	84.16
Excipient	Microcrystalline cellulose	15.00
Excipient	Copovidone	6.00
Binder	Hydroxypropyl cellulose	6.00
Stabilizer	Triethyl citrate	1.30
Lubricant	Magnesium stearate	1.30
Lubricant	Sodium stearyl fumarate	1.30
Gross weight		130.00

<Test Example 1>

The results obtained by measuring the hardness, thickness, candesartan and amlodipine content, dissolution rate, and amount of analogue of the tablets prepared according to Example 1 and Comparative Examples 1-3 are shown in Table 7 below.

 Content Test Method: HPLC

 -Detector: ultraviolet absorption photometer (wavelength: 237 nm)

 Column: C18 (4.6 mm × 250 mm, 10 μm)

 Mobile phase: A solution adjusted to pH 7.1 with glacial acetic acid in a mixture (300: 420: 280) of acetonitrile, methanol, and 0.1 mol / L ammonium acetate.

 -Flow rate: 1.0 mL / min

 Column temperature: 35 ℃

 Sample temperature: 10 ℃

The tablets obtained in Example 1 and Comparative Examples 1 to 3 according to the present invention were subjected to a dissolution test according to the Dissolution Test Method 2 (paddle method) of the General Test Method of the eleventh revised Korean Pharmacopoeia.

 Dissolution Test Method

 Dissolution test equipment: Hanson SR 8 (Hanson Research, USA)

 Eluent: 1% polysorbate 20 solution, 900 mL

 Eluent temperature: 37 ± 0.5 ℃

 -Speed: 75 rpm

 -Test time: 45 minutes

 [Elution Assay: HPLC]

 -Detector: ultraviolet absorbance photometer (wavelength: 237 nm)

 Column: C18 (4.6 mm × 250 mm, 10 μm)

 Mobile phase:

  A: A liquid adjusted to pH 7.1 with glacial acetic acid in a mixture (300: 420: 280) of acetonitrile, methanol, and 0.1 mol / L ammonium acetate

  B: acetonitrile

 Concentration gradient:

Minutes	Mobile phase A	Mobile phase B
0.0	100	0
9.0	100	0
9.1	10	90
13.0	10	90
13.1	100	0
24.0	100	0

 -Flow rate: 1.0 mL / min

 Column temperature: 40 ℃

 Sample temperature: 20 ℃

 [Flexible material analysis method: HPLC]

 Detector: ultraviolet absorption photometer (wavelength: 254 nm)

 Column: C18 (4.6 mm × 250 mm, 10 μm)

 Mobile phase:

 A: A mixture of acetonitrile and pH 3.0 phosphate buffer solution (340: 660)

 B: a mixture of acetonitrile and pH 3.0 phosphate buffer solution (900: 100)

 Concentration gradient:

Minutes	Mobile phase A	Mobile phase B
0	100	0
15	100	0
25	80	20
90	0	100
130	0	100
135	100	0
150	100	0

 -Flow rate: 0.8 mL / min

 Column temperature: 30 ℃

 Sample temperature: 10 ℃

Item		Example 1	Comparative Example 1	Comparative Example 2	Comparative Example 3
Constellation		Good	Surface roughness	Good	Good
Hardness (kp)		8.56	8.14	8.20	8.05
Thickness (mm)		3.23	3.13	3.10	3.13
content(%)	Candesartan	99.32	98.56	100.52	100.05
	Amlodipine	99.96	98.80	101.20	101.00
Dissolution (%)	Candesartan	88.1-89.3	46.2-50.7	2.9-3.3	15.2-16.9
	Amlodipine	94.6-96.0	94.8-101.5	34.8-36.0	44.1-47.2
Total Flexible Material (%)		0.19	0.19	0.67	0.18

As shown in the experimental results of Table 7 confirming the effect of the sugar and sugar alcohol filler, when the tableting was carried out by tableting with a hardness of about 8kp, Example 1 using mannitol showed the best dissolution rate, using sorbitol Comparative Example 1 confirmed that the dissolution rate of candesartan is low, and Comparative Example 2 using isomalt and Comparative Example 3 using white sugar showed low dissolution rates of both candesartan and amlodipine. In addition, Comparative Example 1 exhibited an unsuitable property due to the rough surface, Comparative Example 2 produced the most flexible material.

<Test Example 2>

Tablets prepared according to Example 1 and Comparative Examples 1-3 were stored for 1 week in harsh conditions (packaged Duma ^® bottle at 60 ° C), and then the hardness, thickness, candesartan and amlodipine content, dissolution rate and softening material of the tablets. The results of measuring the amount of are shown in Table 8 below.

Item		Example 1	Comparative Example 1	Comparative Example 2	Comparative Example 3
Constellation		Good	Swelling	Good	Good
Hardness (kp)		11	5.6	9.1	7.8
Thickness (mm)		3.25	3.64	3.13	3.17
content(%)	Candesartan	100.02	98.24	99.63	10.35
	Amlodipine	99.53	99.67	101.01	101.17
Total Flexible Material (%)		0.42	0.29	0.89	0.40

As shown in the experimental results of Table 8 confirming the effect of the sugar and sugar alcohol filler, Comparative Example 1 using sorbitol produced the least amount of the flexible material, but the hardness was lowered and the tablets swelled to show an inappropriate property. Comparative Example 2 using isomalt produced the most flexible material from the first time, showing the highest amount of flexible material. Example 1 using mannitol and comparative example 3 using sucrose showed similar results.

<Test Example 3>

The tablets prepared according to Example 1 and Comparative Examples 1-3 were stored for 1 week under accelerated conditions (40 ° C., ^Duma® bottle packaging at RH 75%), and then the hardness, thickness, candesartan and amlodipine content of the tablets, The results of measuring the dissolution rate and the amount of lead substance are shown in Table 9 below.

Item		Example 1	Comparative Example 1	Comparative Example 2	Comparative Example 3
Constellation		Good	Color change	Good	Good
Hardness (kp)		8.8	7.2	8.4	8.4
Thickness (mm)		3.28	3.2	3.12	3.12
content(%)	Candesartan	100.44	100.64	100.48	101.47
	Amlodipine	99.20	101.63	100.63	102.51
Total Flexible Material (%)		0.21	0.23	0.67	0.20

As shown in the experimental results of Table 9 confirming the effect of the sugar and sugar alcohol filler, Example 1, Comparative Example 2, Comparative Example 3 showed a test result similar to the initial test results. However, Comparative Example 1 using the isomalt showed a decrease in hardness, and the color was changed to pale gray, indicating an inadequate property.

<Test Example 4>

Tablets prepared according to Example 1 and Comparative Examples 1-3 were stored for 1 week under accelerated conditions (opened at 40 ° C., RH 75%) for one week, then the hardness, thickness, candesartan and amlodipine content, dissolution rate and softness of the tablets. The results of measuring the amount of the substance are shown in Table 10 below.

Item		Example 1	Comparative Example 1	Comparative Example 2	Comparative Example 3
Constellation		Good	Swelling badly	Good	Good
Hardness (kp)		10.2	Not measurable	7.8	8.6
Thickness (mm)		3.25	3.7	3.13	3.15
content(%)	Candesartan	101.63	98.88	99.98	99.85
	Amlodipine	101.65	97.98	100.92	101.86
Total Flexible Material (%)		0.22	0.22	0.68	0.19

As shown in the experimental results of Table 10 confirming the effect of the sugar and sugar alcohol filler, Example 1, Comparative Example 2, Comparative Example 3 showed the test results similar to the initial test results. However, Comparative Example 1 using isomalt showed a severe hardness decrease that is impossible to measure, and the tablet swelled severely and showed inadequate properties.

As a result, it was confirmed that mannitol has a very good pharmaceutical formulation in all aspects of properties, hardness, thickness, dissolution rate and stability under all conditions. On the other hand, when sorbitol is used, it has a disadvantage in that the surface property is very rough after tableting and the dissolution rate of candesartan is low, and it cannot be manufactured as a tablet due to severe swelling under severe and open acceleration conditions. In addition, when the isomalt is used, the dissolution rate of candesartan and amlodipine is very low, and in all conditions, the total amount of the flexible compound is relatively high, which is not suitable for use in the manufacture of tablets. Finally, even in the case of white sugar, the dissolution rate was so low that it could not be used to prepare tablets.

Claims (9)

1. (i) candesartan, candesartan cilexetil, or a pharmaceutically acceptable salt thereof;

   (ii) amlodipine or a pharmaceutically acceptable salt thereof;

   (iii) triethyl citrate as stabilizer; And

   (iv) mannitol as filler

   A composite consisting of a single layer comprising a.
2. The combination according to claim 1, wherein the candesartan, candesartan cilexetil, or a pharmaceutically acceptable salt thereof is candesartan cilexetil.
3. The combination according to claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof is amlodipine besylate.
4. The combination according to claim 1, wherein the candesartan, candesartan cilexetil, or a pharmaceutically acceptable salt thereof is 0.1 to 30% by weight based on the total weight of the combination.
5. The combination according to claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof is 0.1 to 30% by weight based on the total weight of the combination.
6. The composite agent according to claim 1, wherein the triethyl citrate is 0.1 to 20% by weight based on the total weight of the composite agent.
7. The composite agent according to claim 1, wherein the mannitol is 30% by weight or more based on the total weight of the composite agent.
8. The composite agent according to claim 1, wherein the weight ratio of triethyl citrate and mannitol is 1:50 to 70.
9. The method of claim 1,

   (i) 0.1-30% by weight of candesartan cilexetil,

   (ii) 0.1 to 30 weight percent of amlodipine besylate,

   (iii) 0.1 to 20 weight percent of triethyl citrate, and

   (iv) at least 30% by weight of mannitol

   Composite agent comprising a.