KR20160105543A - Method for producing pharmaceutical preparation containing calcium antagonist/angiotensin ii receptor antagonist - Google Patents

Abstract

A calcium antagonist and an angiotensin II receptor antagonist as an active ingredient, characterized in that it comprises a granulation step of assembling the calcium antagonist and the angiotensin II receptor antagonist together or separately without using water And a method for producing the pharmaceutical preparation. The pharmaceutical preparation prepared by this method can realize a dissolution profile close to the dissolution profile of each of the commercial calcium antagonist drug and the angiotensin II receptor antagonist drug.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a pharmaceutical composition containing a calcium antagonist and an angiotensin II receptor antagonist,

The present invention relates to a method for producing a pharmaceutical preparation containing, as an active ingredient, a calcium antagonist and an angiotensin II receptor antagonist.

Hypertension refers to a state in which the blood pressure is continuously higher than the normal range. Hypertension is one of the lifestyle-related diseases, and if hypertension persists, it sometimes develops arteriosclerosis, ischemic heart disease, stroke and the like.

Currently, blood pressure control using a hypertensive drug (coercive agent) is widely practiced in the treatment of hypertensive patients. As a hypertension therapeutic drug, calcium antagonist (CCB), angiotensin converting enzyme inhibitor, and angiotensin II receptor antagonist (ARB) are generally used.

Calcium antagonists (CCB) is suppressed by the incorporation of Ca ^{2 +} into the cell through the ion channel and weaken the sense of contraction of smooth muscle, it is known to exhibit a step-down operation. Calcium antagonists are currently the most commonly used coercive drugs in Japan and are recommended as first-line drugs because they have fewer side effects and are less expensive than diuretics.

It has been known that the angiotensin II receptor antagonist (ARB) inhibits the physiological action of angiotensin II, which is produced in the renin · angiotensin system and has a strong boosting action, by antagonizing the angiotensin II receptor specifically.

As such, calcium antagonists and angiotensin II receptor antagonists cause coercive effects by different mechanisms. Therefore, it has also been attempted to use a calcium antagonist and an angiotensin II receptor antagonist together with hypertension patients whose symptoms are not improved by single-agent administration (Patent Document 1).

Japanese Patent Application Laid-Open No. 2008-44871

However, both the calcium antagonist and the angiotensin II receptor antagonist have low solubility in water, which means that it takes time until the effect is obtained even if the drug is administered. For example, one of the calcium antagonists, cilindipine, has a solubility in water of several ng / mL at 20 ° C and one of the angiotensin II receptor antagonists has solubility in water at 20 ° C 0.17 mg / mL. For this reason, currently available calcium antagonist drugs and angiotensin II receptor antagonist drugs have been studied to increase the dissolution rate.

However, since the commercial calcium antagonist drug and the angiotensin II receptor antagonist drug each improve the dissolution rate by a separate method, it is difficult to realize the dissolution profile of the two with a single pharmaceutical preparation (compounding agent).

The present invention has been made in view of the above problems, and it is an object of the present invention to provide a method for producing a medicinal preparation (compounding agent) capable of realizing a dissolution profile close to the dissolution profile of each of the commercial calcium antagonist drug and angiotensin II receptor antagonist drug .

In order to solve the above problems, the present invention employs the following configuration.

(1) A method for producing a pharmaceutical preparation containing, as an active ingredient, a calcium antagonist and an angiotensin II receptor antagonist, wherein the calcium antagonist and the angiotensin II receptor antagonist are separately or granulated without using water And a granulation step.

(2) The production process according to (1) above, wherein an organic solvent is used in the granulation step.

(3) The method according to the above (1) or (2), wherein the calcium antagonist is granulated together with the angiotensin II receptor antagonist without using water and the granules containing the calcium antagonist and the angiotensin II receptor antagonist are obtained 2).

(4) A calcium antagonist is granulated without using water to obtain calcium antagonist-containing granules. Then, an angiotensin II receptor antagonist is mixed with the granules without using water and assembled, The method according to the above (3), wherein the drug is assembled with an angiotensin II receptor antagonist, and a granulate containing a calcium antagonist and an angiotensin II receptor antagonist is obtained.

(5) The method according to the above (1), wherein the calcium antagonist and the angiotensin II receptor antagonist are separately granulated without using water, and the granules containing the calcium antagonist and the angiotensin II receptor antagonist are obtained, Or (2).

(6) The production method according to any one of (3) to (5) above, further comprising a step of compression-molding the granules obtained after the granulation process.

(7) The production method according to any one of (1) to (6) above, wherein the calcium antagonist comprises a 1,4-dihydropyridine derivative.

(8) The method according to (1), wherein the 1,4-dihydropyridine derivative is selected from the group consisting of cilindipine, amlodipine, neilbodipine, nifedipine, azelidipine, nisolodipine, nicaldin, nimodipine, nitrenedipine and manidipine (7) above, wherein the at least one is at least one species.

(9) The pharmaceutical composition according to any one of (1) to (6), wherein the angiotensin II receptor antagonist is at least one selected from the group consisting of valsartan, candesartan, irbesartan, rhodanthan, telmisartan, olmesartan, irbesartan, (8). ≪ / RTI >

(10) The process according to any one of (2) to (9), wherein the organic solvent is at least one selected from the group consisting of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone and diethyl ether ≪ / RTI >

(11) The production method according to any one of (1) to (10) above, wherein the calcium antagonist and the angiotensin II receptor antagonist contained in the medicinal preparation are in a mass ratio of 1: 1 to 1:32.

(12) The production method according to any one of (1) to (11) above, wherein a disintegrating agent is used in the assembling step.

(13) In a dissolution test based on the paddle method, 25 to 55% by weight of the calcium antagonist is dissolved in water after 7 minutes from the start of the test, and the angiotensin II receptor antagonist is not less than 75% The production method according to any one of (1) to (12) above, having an elution profile dissolved in water.

(14) In a dissolution test based on the paddle method, the calcium antagonist is dissolved in water at 75% by weight or more thereof 90 minutes after the initiation of the test, and at least 85% by weight of the angiotensin II receptor antagonist is dissolved in water (1) to (13), which has an elution profile which is dissolved in a solvent.

(15) The production method according to any one of (1) to (14) above, wherein the pharmaceutical preparation is a pressure-reducing agent.

The pharmaceutical preparation prepared by the method of the present invention can realize a dissolution profile close to the dissolution profile of each of the commercial calcium antagonist drug and the angiotensin II receptor antagonist drug preparation.

Hereinafter, embodiments for carrying out the present invention will be described.

A method for producing a pharmaceutical preparation of the present invention is a method for producing a pharmaceutical preparation containing, as an active ingredient, a calcium antagonist and an angiotensin II receptor antagonist, wherein the calcium antagonist and the angiotensin II receptor antagonist are administered together or separately And an assembling step of assembling the semiconductor device into the semiconductor device.

In the medicinal preparation obtained by the production method of the present invention, it is preferable that at least the calcium antagonist is in the form of a solid dispersion. The calcium antagonist and the angiotensin II receptor antagonist may be in the form of a solid dispersion.

In the present specification and claims, the term "solid dispersion" means a solid in which a drug is dispersed in a monomolecular form in an inert carrier. In the solid dispersion, the drug is present in the carrier in an amorphous state. As the inert carrier, any polymeric compound may be used without particular limitation, and examples thereof include polymer compounds such as a binder, a suspending agent, and a surfactant. Examples of the suspending agent include gum arabic, xanthan gum, sodium alginate, and the like. Examples of the surfactant include polyoxyethylene hydrogenated castor oil, sodium lauryl sulfate, and polyoxyethylene-polyoxypropylene glycol.

The solid dispersion can be obtained, for example, by using a solution prepared by dissolving a drug and a carrier component in an organic solvent, followed by drying.

[Assembly process]

The manufacturing method of the present invention includes a process (assembling process) of assembling a calcium antagonist and an angiotensin II receptor antagonist together or separately without using water. Thus, in the present invention, the calcium antagonist and the angiotensin II receptor antagonist are assembled without dissolving in water.

Further, in the assembling step, it is preferable to assemble the calcium antagonist and the angiotensin II receptor antagonist together or separately using an organic solvent without using water. It is also preferred to perform the above assembly with a disintegrant, together with a calcium antagonist and / or an angiotensin II receptor antagonist.

As a method for assembling the calcium antagonist and the angiotensin II receptor antagonist without using water, there is a method of assembling by spraying the calcium antagonist with the angiotensin II receptor antagonist without using water using a fluidized bed granulator have. Preferably, the spray is sprayed with a solution obtained by dissolving a calcium antagonist in an organic solvent, with an angiotensin II receptor antagonist. After the granulation, it may be dried by using a fluidized bed drier, for example, by a sizing machine. By this method, granules containing a calcium antagonist and an angiotensin II receptor antagonist can be obtained.

Also, as a method of assembling a calcium antagonist and an angiotensin II receptor antagonist together without using water, a calcium antagonist is granulated without using water (preferably using an organic solvent) to prepare a calcium antagonist-containing granule And then granulating and mixing the angiotensin II receptor antagonist without using the granules and water. After the granulation, it may be dried by using a fluidized bed drier, for example, by a sizing machine. By this method, granules containing a calcium antagonist and an angiotensin II receptor antagonist can be obtained.

As a method of granulating a mixture of the angiotensin II receptor antagonist and the calcium antagonist-containing granule, for example, a granulation method using a dry granulator is listed. In this method, granules containing a calcium antagonist and an angiotensin II receptor antagonist can be obtained in a form in which an angiotensin II receptor antagonist is present in such a way that it covers some or all of the granules containing the calcium antagonist . In the obtained granules, it is preferable that a disintegrant is present in both the granules containing the calcium antagonist and the outside of the granules.

As a method of separately assembling the calcium antagonist and the angiotensin II receptor antagonist without using water, the calcium antagonist is assembled without using water and the angiotensin II receptor antagonist is assembled without using water . After the granulation, it may be dried by using a fluidized bed drier, for example, by a sizing machine. By this method, a mixture containing granules containing a calcium antagonist and an angiotensin II receptor antagonist can be obtained.

<Calcium antagonist>

By the calcium antagonist is, through an ion channel inhibited the incorporation of Ca ^{2 +} into the cells, and a sense of fatigue contraction of smooth muscle, a substance showing an action of lowering blood pressure.

The calcium antagonist used in the present invention preferably contains a 1,4-dihydropyridine derivative. Examples of the 1,4-dihydropyridine derivative include at least one selected from the group consisting of a cyclodipine, amlodipine, neilbodipine, nifedipine, azelidipine, nisol dipine, nicaldine, nimodipine, . Among them, the use of a silydipine (chemical name: () -2-methoxyethyl 3-phenyl-2 (E) -propenyl 1,4-dihydro-2,6-dimethyl- 4- (3-nitrophenyl) -3,5-pyridinedicarboxylate ) Is particularly preferable.

Cynidipine is a known compound as an L / N type calcium antagonist that simultaneously inhibits L-type calcium channel and N-type calcium channel, and can be produced by a known production method. It is also possible to obtain a commercially available formulation of the agent. Cynidipine can also be obtained by extraction from the preparation.

The calcium antagonist may be a pharmaceutically acceptable salt, hydrate or solvate, if necessary. Examples of pharmacologically acceptable salts include salts with inorganic acids (hydrochloride, hydrobromide, phosphate and sulfate) and salts with organic acids (acetate, succinate, maleate, fumarate, malate, Salts, etc.). The calcium antagonist used in the present invention may be a suitable optically active substance, if necessary.

The calcium antagonist is preferably contained in an amount of 0.1 to 10 mass%, more preferably 0.5 to 5 mass%, based on 100 mass% of the pharmaceutical preparation.

<Angiotensin II receptor antagonist>

Angiotensin II receptor antagonist is a drug that antagonizes angiotensin II, a boosting substance, and inhibits the binding of angiotensin II to angiotensin II receptor, thereby lowering blood pressure. Examples of angiotensin II receptor antagonists include valsartan, candesartan, irbesartan, rhodanthan, telmisartan, olmesartan, irbesartan, and fructan. Particularly preferred is valsartan (chemical name: (-) - N- {4- [2- (1H-tetrazol-5-yl) phenyl] benzyl} -N-valeryl-L-valine.

The angiotensin II receptor antagonist may be a pharmaceutically acceptable salt, hydrate or solvate, if necessary. Examples of pharmacologically acceptable salts include salts with inorganic acids (hydrochloride, hydrobromide, phosphate and sulfate) and salts with organic acids (acetate, succinate, maleate, fumarate, malate, Salts, etc.). In addition, the angiotensin II receptor antagonist used in the present invention may be appropriately used as an optically active substance thereof.

The angiotensin II receptor antagonist may be used singly or in combination of two or more.

The angiotensin II receptor antagonist is preferably contained in an amount of 5 to 50 mass%, more preferably 10 to 40 mass%, based on 100 mass% of the pharmaceutical preparation.

In addition, the mass ratio of the calcium antagonist and the angiotensin II receptor antagonist is preferably in the range of 1: 1 to 1:32, and more preferably in the range of 1: 4 to 1:16.

<Organic solvent>

Examples of the organic solvent that can be used in the granulation process include dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone or diethyl ether. Among them, it is preferable to use at least one organic solvent selected from the group consisting of dichloromethane, methanol, ethanol, propanol and isopropanol. The organic solvent may be used singly or in combination of two or more kinds.

The amount of the organic solvent is not particularly limited as long as it can assemble the calcium antagonist or the calcium antagonist and the angiotensin II receptor antagonist, and it may be suitably adjusted according to the assembly method.

<Collapse agent>

In the production method of the present invention, it is preferable to use a disintegrant in the assembling step, and it is more preferable to perform the assembly using the mixture obtained by mixing the disintegrant and the calcium antagonist and / or the angiotensin II receptor antagonist Do. It is also preferred that the disintegrant is dissolved in an organic solvent together with a calcium antagonist and / or an angiotensin II receptor antagonist to effect assembly.

Examples of disintegrators include sodium croscarmellose, low-substituted hydroxypropylcellulose, carboxymethylstarch sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, low-substituted carboxymethylstarch sodium, More preferred are sodium croscarmellose, low-substituted hydroxypropylcellulose, carmellose, carmellose sodium, crospovidone and low-substituted carboxymethylstarch sodium, more preferably croscarmellose sodium, low-substituted hydroxypropyl Cellulose is even more preferred, and croscarmellose sodium is particularly preferred.

One type of disintegrant may be used alone, or two or more types may be used in combination.

The disintegrant is preferably contained in an amount of 5 mass% or more, more preferably in a range of 5 to 35 mass%, further preferably in a range of 6 to 30 mass%, based on 100 mass% of the pharmaceutical preparation . When the calcium antagonist is granulated, the disintegrant is preferably contained in the range of 1 to 15 mass%, more preferably in the range of 1 to 10 mass%. In the case of granulating a mixture of a calcium antagonist-containing granule and an angiotensin II receptor antagonist, it is preferable to add 1 to 30 mass% of a disintegrant to the mixture, and adding 2 to 25 mass% of a disintegrant to the mixture More preferable.

<Binder>

The pharmaceutical preparation of the present invention may contain a binder. As the binder, various ones can be used and are not particularly limited, and for example, water-soluble polymers are listed. Among these, hydroxypropyl cellulose, hydroxypropyl cellulose phthalate, methyl cellulose, hydroxypropylmethyl cellulose acetate succinate, carboxymethyl ethyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, acetic acid phthalic acid Cellulose is preferred, and hydroxypropyl cellulose and hydroxypropyl phthalate are more preferred.

The binder is preferably contained in an amount of 1 to 90 mass%, more preferably 3 to 40 mass%, and still more preferably 5 to 20 mass%, based on 100 mass% of the pharmaceutical preparation.

When a binder is used, it is preferable that the binder is contained in granules containing a calcium antagonist.

In addition to the disintegrants and binders, lubricants, excipients, fluidizers, and the like may be added to the calcium antagonists and / or angiotensin II receptor antagonists.

Examples of the excipient include, but are not limited to, lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol and the like, corn starch, potato starch, partially alpha-starch, dextrin , Pullulan and the like, derivatives thereof, crystalline cellulose, microcrystalline cellulose and the like, macrogol, and magnesium metasilicate aluminate, or a mixture of two or more thereof. Among these, lactose hydrate, mannitol, partially-alpha-starch and crystalline cellulose are preferable, and lactose hydrate and crystalline cellulose are more preferable.

One type of excipient may be used alone, or two or more types may be used in combination.

The excipient is preferably contained in an amount of 1 to 40 mass%, more preferably 1 to 30 mass%, based on 100 mass% of the pharmaceutical preparation.

[Compression molding process]

The method for producing a pharmaceutical preparation of the present invention may include a step of compression-molding the granules obtained in the granulation step.

The compression molding may be carried out by a known method. For example, magnesium stearate, talc, stearic acid, calcium stearate or magnesium carbonate may be added and mixed and compression molded by a tablet machine.

The shape of the tablets obtained by compression molding is not particularly limited and may be, for example, circular, elliptical (all rounds except for the square circle: oval, oval, elliptical, Small format), etc.), diamonds, and triangles. In the case of providing a dividing line, the shape of the dividing line may be any of a flat groove type, a U-shaped groove type, and a V-groove type, and when the tablet has an elliptical shape, it is preferably formed along the minor axis.

[Other processes]

The method for producing a pharmaceutical preparation of the present invention may include a step of performing a coating process after the compression molding process. Examples of the coating agent used in the coating treatment include hydroformose, macrogol 6000, and the like. For example, a coating solution prepared by dissolving a coating agent in a solvent such as water may be coated on the surface of a pharmaceutical preparation using a pan coating apparatus, a drum type coating apparatus, a flow coating apparatus, or the like. Coating is good. In addition to the coating agent, coloring agents such as yellow 32 iron oxide, 32 iron oxide, black iron oxide, titanium oxide, edible blue No. 1, edible yellow No. 4, edible red No. 2 may be added to the coating liquid. By adding these coloring agents, the light stability of the calcium antagonist can be improved.

The pharmaceutical preparation obtained by the method of the present invention is preferably a solid preparation, more preferably in the form of tablets, capsules, fine granules or granules, particularly preferably in the form of tablets.

The pharmaceutical preparation obtained by the method of the present invention is preferably such that 25 to 55% by mass of the calcium antagonist is dissolved in water after 7 minutes from the start of the test in the dissolution test based on the paddle method. Likewise, in the dissolution test based on the paddle method, it is preferable that the calcium antagonist dissolves in water at 75 mass% or more thereof 90 minutes after the start of the test.

In addition, in the dissolution test based on the paddle method, it is preferable that the angiotensin II receptor antagonist is dissolved in water in an amount of not less than 75% by mass after 15 minutes from the start of the test. Likewise, in the dissolution test based on the paddle method, it is preferable that the angiotensin II receptor antagonist is dissolved in water in an amount of not less than 85% by mass thereof after 30 minutes from the start of the test.

When the dissolution rate is within the above range, a dissolution profile close to the dissolution profile of each of the commercially available calcium antagonist and angiotensin II receptor antagonist can be achieved. Therefore, a pharmaceutical preparation (compounding agent) exhibiting the same effect as the case of coadministering two kinds of preparations can be obtained.

<Applications>

The pharmaceutical preparation obtained by the production method of the present invention has a depressurizing action and is thus useful as a depressant for treating hypertensive patients.

&Lt;

Mammals such as mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, and humans are enumerated as subjects to which the pharmaceutical preparations obtained by the production method of the present invention are administered. Particularly, human is preferable as an administration subject.

Example

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[Example 1]

22.4 kg of magnesium metasilicate aluminate, 6.41 kg of crystalline cellulose, 4.86 kg of lactose monohydrate and 5.10 kg of sodium croscarmellose were mixed in a stirring granulator. Thereafter, a bonding liquid was prepared by dissolving cadidipine (2.04 kg), macrogol 400 (1.43 kg) and hydroxypropyl cellulose (8.16 kg) in methanol (28.3 kg) and dichloromethane (8.5 kg). After assembling, the granules were screened (screen: 1.6 mm) by a sizing machine (Comill) and dried at an exhaust temperature of 60 ° C or lower for 90 minutes using a fluidized bed dryer to obtain granules A.

Next, magnesium metasilicate aluminate (52.4 kg), crystalline cellulose (14.95 kg) and croscarmellose sodium (11.90 kg) were put into a stirring granulator and mixed. Thereafter, a bonding solution prepared by dissolving 4.96 kg of cadidipine, 3.46 kg of Macrogol 400 and 19.04 kg of hyphromellose phthalate ester was added to methanol (57.8 kg) and dichloromethane (57.8 kg) . After assembly, the granules were screened by a sizing machine (screen: 1.6 mm) and dried at an exhaust temperature of 60 ° C or lower for 90 minutes using a fluidized bed dryer to obtain granules B.

The granules A and B thus obtained were mixed together to obtain the prescribed granules of the present invention shown in Table 1.

Using a mixer, 20 g of the above-mentioned sandydipine granules (2966.4 g), balticane (969.6 kg), crystalline cellulose (936 g), croscarmellose sodium (960 g), hydrated silicon dioxide (96 g) and magnesium stearate Minute, and mixed powder was obtained. The obtained mixed powder was flashed by dry granulation (roll pressure: 6 Mpa) and sized (screen: 1.6 mm) by a sizing machine (screen: 1.6 mm) to obtain the prescription silk nipin · valsartan granulated granules shown in Table 2 .

Magnesium stearate was added and mixed to the granules of the present invention obtained as described above in Table 3, and the granules were compression-molded by a tableting machine to obtain tablets of the prescription shown in Table 3. The ratio of the second disintegrant: 16.0% (total disintegrant: 21.0%), the content of the second disintegrant: 16.0%, the content of the second disintegrant: 16.0%

[Example 2]

(400 g), crystalline cellulose (340 g) and sodium croscarmellose (400 g) were placed in a fluidized bed granulator and sprayed with a coupling solution in which hydroxypropylcellulose (100 g) was dissolved in methanol (280 g) and dichloromethane (Spray rate: 70 g / mL, exhaust temperature: 30 DEG C) to obtain prescriptional balancing granules shown in Table 4.

The volunteering granules obtained in the above, the granules obtained in Example 1, and the magnesium stearate were added and mixed so as to form the formulations shown in Table 5, and the granules were compression-molded by a tableting machine to obtain tablets of the prescription shown in Table 5. The ratio of the second disintegrant: 16.0% (total disintegrant: 21.0%), the content of the second disintegrant: 16.0%, the content of the second disintegrant: 16.0%

[Example 3]

(25 g), hydroxypropyl methyl cellulose (25 g), and hydroxypropyl cellulose (20 g) were added to a fluidized bed granulator, and methanol (1120 g) and dichloromethane (280 g) were charged in a fluidized bed granulator (200 g), crystalline cellulose (550 g), croscarmellose sodium (275 g) (100 g) was sprayed (spray rate: 70 g / mL, exhaust temperature: 30 DEG C) to obtain the prescription candelipyrin / valsartan compounded granules shown in Table 6.

Magnesium stearate was added to and mixed with the cilindipine · valsartan blended granules obtained above to form a formulation as shown in Table 7, followed by compression molding by a tableting machine to obtain tablets of the prescription shown in Table 7. 2.0% by mass of cadidipine contained in the tablet, 16.0% by mass of parthanthan, 22.0% by total decomposition agent,

[Comparative Example 1]

(40 g), cinindipine (5 g), crystalline cellulose (123 g), croscarmellose sodium (80 g) and magnesium stearate (2 g) were added and mixed and compression molded by a tablet machine to prepare tablets &Lt; / RTI &gt; 2.0% of the content of the cinnamipine contained in the tablet, 16.0% of the parchmenting agent, and 32.0% of the total amount of the disintegrant)

With respect to balancing, an original powder having a particle diameter (D90) of 20 m or less was used.

[Comparative Example 2]

100 g of hydroxypropylcellulose (100 g) was added to water (1400 g), and the solution was added to the fluidized bed granulator. The solubilized binding liquid was sprayed (spray rate: 70 g / mL, exhaust temperature: 30 DEG C) to obtain the cilindipine · valsartan blended granules of Table 6.

Thereafter, tablets of the prescription shown in Table 7 were obtained by the method of Example 3. 2.0% by mass of cadidipine contained in the tablet, 16.0% by mass of parthanthan, 22.0% by total decomposition agent,

[Comparative Example 3]

(484.8 g), crystalline cellulose (378 g), croscarmellose sodium (480 g) and hydroxypropyl cellulose (150 g) were placed in a stirring granulator and water (2100 g) was added thereto. After the granulation, the granules were screened (screen: 1.6 mm) by a sizing machine (Comill) and dried at an exhaust temperature of 60 ° C or lower for 45 minutes using a fluidized bed dryer to obtain prescription baluntan granules shown in Table 9.

The volunteering granules obtained in the above, the granules obtained in Example 1, and the magnesium stearate were added and mixed so as to form the formulations shown in Table 9, and the granules were compression-molded by a tableting machine to obtain formulated tablets shown in Table 10. The ratio of the second disintegrant: 16.0% (total disintegrant: 21.0%), the content of the second disintegrant: 16.0%, the content of the second disintegrant: 16.0%

[Test Example 1]

The particle sizes of baltartan in the tablets of Examples 1 to 3 and Comparative Examples 1 to 3 were measured. For the measurement of the particle size distribution of balticane, 50 mg of balticane was dispersed in a dispersion solution (silicone oil: n-heptane / 0.2: 5% span 85 containing n-heptane / 60: 40 v / v) and the particle size was measured using a Malvern Particle Size Analyzer And D90 was calculated.

[Test Example 2]

The grain size distribution of the granules was measured with an automatic dry sonic sorbent type measuring instrument robot shifter RPS-95C using a sieve having an eye size of 850 탆, 500 탆, 355 탆, 250 탆, 180 탆, 150 탆, 106 탆 and 75 탆 , The particle size distribution was measured, and D10, D50 and D90 were calculated.

[Test Example 3]

With respect to the dissolution test for valsaltane, the test was carried out using 50 rpm and 900 mL of water as the test solution according to the dissolution test method (paddle method) described in the 16th revised Japanese Pharmacopoeia. Test liquids were taken 15 minutes and 30 minutes after the start of the test, and the test liquid was subjected to liquid chromatography to calculate the dissolution rate of the cilindipine.

On the other hand, for Examples 1 and 2 and Comparative Example 1, one tablet was used, and for Example 3 and Comparative Example 2, two tablets were used.

[Test Example 4]

The dissolution test of the sindydipine was carried out according to the dissolution test method (paddle method) described in the Japanese Pharmacopoeia of the 16th Ed., A dissolution test with 50 rpm and 0.1 w / v% Polysorbate 80 as a test solution The test was carried out using 900 mL of the second solution. The test liquid after 7 minutes and 90 minutes from the start of the test was taken and tested by liquid chromatography to calculate the dissolution rate of the cilindipine.

On the other hand, for Examples 1 and 2 and Comparative Example 1, one tablet was used, and for Example 3 and Comparative Example 2, two tablets were used.

<Result>

As a result of measuring the particle size of the parchmenting, the particle size of the parchmental used in Examples 1 to 3 and Comparative Examples 1 to 3 was 20 μm or less for all D90.

The granular distribution of the granules of the granules of Example 1 and the granular form of the granules of the granules of the granules was measured according to Test Example 2. The results are shown in Table 11.

The dissolution rates of the tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 3 were tested according to Test Examples 3 and 4. The results are shown in Table 12.

In addition, a reference value was set in consideration of the elution rate of Diovan (registered trademark), a commercial product of Atelec (registered trademark) tablets and commercial products of cilindipine, and the dissolution rate of each of the cilydipine and valsartan meets the reference value Was evaluated as &quot; &amp; cir &amp; &quot;

As a result, in all of Examples 1 to 3, the dissolution rate in the reference value was all but in Comparative Examples 1 to 3, the dissolution rate in the reference value was not obtained.

The pharmaceutical preparations prepared by the method of the present invention can increase the dissolution rate of the calcium antagonist and realize a dissolution profile close to the dissolution profile of each of the commercial calcium antagonist and the angiotensin II receptor antagonist. Therefore, it is very useful in industry.

Claims (15)

A calcium antagonist and an angiotensin II receptor antagonist as an active ingredient, comprising the steps of: assembling a calcium antagonist and an angiotensin II receptor antagonist together or individually without using water &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. The manufacturing method according to claim 1, wherein an organic solvent is used in the assembling step. 3. The method according to claim 1 or 2, wherein in the granulation process, calcium antagonist is granulated with an angiotensin II receptor antagonist without using water, and a granulation containing a calcium antagonist and an angiotensin II receptor antagonist is obtained , Manufacturing method. 4. The method according to claim 3, wherein the calcium antagonist is granulated without using water to obtain a calcium antagonist-containing granule, and then the angiotensin II receptor antagonist is mixed and assembled without using the granule and water, Wherein the calcium antagonist is combined with an angiotensin II receptor antagonist and a granulation containing a calcium antagonist and an angiotensin II receptor antagonist is obtained. The method according to claim 1 or 2, wherein the calcium antagonist and the angiotensin II receptor antagonist are separately agglomerated without using water, and the calcium antagonist-containing granule and the angiotensin II receptor antagonist-containing granule &Lt; / RTI &gt; The production method according to any one of claims 3 to 5, further comprising a step of compression-molding the granules obtained after the granulation process. 7. The method according to any one of claims 1 to 6, wherein the calcium antagonist contains a 1,4-dihydropyridine derivative. 8. The composition of claim 7, wherein the 1,4-dihydropyridine derivative is selected from the group consisting of: cyclindipine, amlodipine, neilbodipine, nifedipine, azelidipine, nisolodipine, nicaldin, nimodipine, nitrenedipine and manidipine , And the like. 9. The method according to any one of claims 1 to 8, wherein the angiotensin II receptor antagonist is selected from the group consisting of valsartan, candesartan, irbesartan, rhodanthan, telmisartan, olmesartan, irbesartan, Wherein at least one selected is selected from the group consisting of: 10. The method according to any one of claims 2 to 9, wherein the organic solvent is at least one selected from the group consisting of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone, Gt; 11. The method according to any one of claims 1 to 10, wherein the calcium antagonist and the angiotensin II receptor antagonist contained in the pharmaceutical preparation are in a mass ratio of 1: 1 to 1:32. The production method according to any one of claims 1 to 11, wherein a collapsing agent is used in the assembling step. The method according to any one of claims 1 to 12, wherein in the dissolution test based on the paddle method, the calcium antagonist is dissolved in water in an amount of from 25 to 55% by weight after 7 minutes from the start of the test and the angiotensin II receptor antagonist Wherein after 15 minutes from the start of the test, at least 75% by mass thereof is dissolved in water. 14. A method according to any one of claims 1 to 13, wherein in the dissolution test based on the paddle method, the calcium antagonist is dissolved in water at least 75% by weight thereof 90 minutes after the start of the test and the angiotensin II receptor antagonist is tested Wherein after at least 30 minutes of initiation, at least 85% by mass thereof is dissolved in water. 15. The production method according to any one of claims 1 to 14, wherein the pharmaceutical preparation is a pressure-reducing agent.