KR101725462B1 - Pharmaceutical preparation containing calcium antagonist/angiotensin ii receptor antagonist - Google Patents

Abstract

A calcium antagonist as an active ingredient, an angiotensin II receptor antagonist and a disintegrant at 5 mass% or more, and at least a calcium antagonist is in the form of a solid dispersion. This medicinal preparation can improve the storage stability of an angiotensin II receptor antagonist. In addition, the pharmaceutical preparation can realize a dissolution profile close to the dissolution profile of each of the commercial calcium antagonist drug and the angiotensin II receptor antagonist.

Description

[0001] PHARMACEUTICAL PREPARATION CONTAINING CALCIUM ANTAGONIST / ANGIOTENSIN II RECEPTOR ANTAGONIST [0002]

The present invention relates to 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

Summary of the Invention

However, both of the drugs lack storage stability, and the calcium antagonist has a problem that degradation progresses with time with respect to light. On the other hand, when the angiotensin II receptor antagonist is stored under a high temperature condition, the dissolution rate is extremely lowered. For this reason, the calcium antagonist drug is required to be preserved under light-shielding conditions, and the angiotensin II receptor antagonist drug is required to be stored at a temperature.

If the two drugs are merely used in combination, the above-mentioned drawbacks do not become a big problem because the two drugs need to be separately stored in different ways.

However, in the case of the compounding agent, since the two drugs can not be separately stored, the problem can not be solved by the same method as the combination drug. Therefore, it is necessary to always keep the temperature and the light in mind.

In addition, since the calcium antagonist and the angiotensin II receptor antagonist are all low in solubility in water, there is a problem that it takes time until an effect is obtained even when the drug is administered. For example, cilydipine, a calcium antagonist, has a solubility of several ng / mL in water at room temperature, and valsartan, an angiotensin II receptor antagonist, has a solubility in water of about 0.17 mg / mL to be. 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).

SUMMARY OF THE INVENTION The present invention has been made in view of the above problems, and it is an object of the present invention to provide a medicinal preparation in which the storage stability of an angiotensin II receptor antagonist is enhanced and thereby the preservation condition is relaxed. It is another object of the present invention to provide a medicinal preparation (compounding agent) capable of realizing a dissolution profile close to the dissolution profile of each of the commercially available 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 calcium antagonist and an angiotensin II receptor antagonist as an active ingredient; and 5% or more of a disintegrant

And at least a calcium antagonist is in the form of a solid dispersion.

(2) The pharmaceutical preparation according to (1), wherein the calcium antagonist is in the form of granules, and the angiotensin II receptor antagonist is present so as to cover part or all of the granules containing the calcium antagonist.

(3) The pharmaceutical preparation according to (2), wherein the disintegrant is contained in the granules.

(4) The pharmaceutical preparation according to (2) or (3), wherein the disintegrant is present together with the angiotensin II receptor antagonist so as to cover part or all of the granule.

(5) The pharmaceutical composition according to (1), wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, crospovidone, To (4) above.

(6) The pharmaceutical composition according to any one of (1) to (3), wherein the calcium antagonist is at least one member selected from the group consisting of sildenafil, amlodipine, neilbodipine, nifedipine, azelidipine, nisol dipine, nicaldine, nimodipine, The medicinal preparation according to any one of (1) to (5) above.

(7) The pharmaceutical preparation according to (6) above, wherein the calcium antagonist is cinindipine.

(8) The method according to (1) above, wherein the angiotensin II receptor antagonist is at least one selected from the group consisting of valsartan, candesartan, irbesartan, rhodanthan, telmisartan, oreselectartan, irbesartan, To (7) above.

(9) The medicinal preparation according to (8), wherein the angiotensin II receptor antagonist is valsartan.

(10) The pharmaceutical preparation according to any one of (1) to (9) above, wherein the mass ratio of the calcium antagonist to the angiotensin II receptor antagonist is from 1: 1 to 1:32.

(11) The pharmaceutical preparation according to any one of (1) to (10) above, which comprises a coating film containing at least one coloring agent selected from the group consisting of yellow ferric oxide, ferric oxide and black iron oxide.

(12) The pharmaceutical preparation according to (11), wherein the ratio of the coloring agent is within a range of 0.1 to 5 parts by mass with respect to 100 parts by mass of the coating film.

(13) The pharmaceutical preparation according to (11) or (12), wherein the coating film further contains titanium oxide.

(14) The pharmaceutical preparation according to any one of (1) to (13), which is in the form of tablets, capsules, fine granules or granules.

(15) The pharmaceutical preparation according to (14), which is in the form of a tablet.

(16) The pharmaceutical preparation according to any one of (1) to (15) above, which is a pressure-reducing agent.

The pharmaceutical preparation of the present invention can improve the storage stability of the angiotensin II receptor antagonist. In addition, the pharmaceutical preparation can realize a dissolution profile close to the dissolution profile of each of the commercial calcium antagonist drug and the angiotensin II receptor antagonist.

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

The medicinal preparation of the present invention is characterized by containing a calcium antagonist as an active ingredient, an angiotensin II receptor antagonist and 5 mass% or more of a disintegrant and at least a calcium antagonist in the form of a solid dispersion.

In addition, the pharmaceutical preparation of the present invention preferably contains a granule containing a calcium antagonist and an angiotensin II receptor antagonist, and may be coated with a part or all of the granules containing a calcium antagonist so that an angiotensin II receptor antagonist It is more preferable to be present. Examples of such pharmaceutical preparations include granules, fine granules, granules containing one or more calcium antagonists and angiotensin II receptor antagonists (granules) coated with an angiotensin II receptor antagonist around a calcium antagonist-containing granule And tablets obtained by tableting a mixture of these tablets.

It is also preferable that the medicinal preparation of the present invention contains an angiotensin II receptor antagonist so as to cover part or all of the granules containing the calcium antagonist and at least the calcium antagonist is in the form of a solid dispersion. An angiotensin II receptor antagonist may be in the form of a solid dispersion together with a calcium antagonist.

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.

<Calcium antagonist>

Calcium antagonists are, by inhibiting the incorporation of Ca ^{2 +} into the cell through the ion channel and weaken the sense of contraction of smooth muscle, a substance showing an action of lowering blood pressure.

The calcium antagonist to be used in the present invention is preferably a 1,4-dihydropyridine derivative, and is preferably selected from the group consisting of a cyclodipine, amlodipine, neil bodypin, nifedipine, azelidipine, nisol dipine, nicaldine, nimodipine, And at least one member selected from the group consisting of manidipine. 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 an angiotensin II receptor antagonist include valsartan, candesartan, rhodanthane, telmisartan, ormecartan, 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.

<Collapse agent>

A disintegrant means an additive that, when taken or placed in water, is wetted with water and disintegrates the formulation.

The disintegrant contained in the pharmaceutical preparation of the present invention is preferably sodium croscarmellose, croscarmellose calcium, low-substituted hydroxypropylcellulose, carboxymethylstarch sodium, crospovidone and pregelatinized starch, and croscarmellose sodium , Low-substituted hydroxypropylcellulose, sodium carboxymethylstarch and crospovidone are more preferable, and sodium croscarmellose and low-substituted hydroxypropylcellulose are 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 contained in an amount of 5 mass% or more, preferably 5 to 35 mass%, and more preferably 6 to 30 mass%, based on 100 mass% of the pharmaceutical preparation.

The disintegrant is preferably contained in the granules together with the calcium antagonist. It is also preferred that the disintegrant is present so as to coat some or all of the granules together with the angiotensin II receptor antagonist. The disintegrating agent (first disintegrating agent) contained in the granules containing the calcium antagonist and the disintegrating agent (second disintegrating agent) present together with the angiotensin II receptor antagonist around the granules may be the same disintegrating agent, May be used. Only one of the first disintegrant and the second disintegrant may be contained in the pharmaceutical preparation, but it is preferable that both the first disintegrant and the second disintegrant are contained in the pharmaceutical preparation.

The first disintegrant is preferably contained in an amount of from 1 to 15 mass%, more preferably from 1 to 10 mass%, based on 100 mass% of the pharmaceutical preparation.

The second disintegrant is preferably contained in an amount of 1 to 30 mass%, more preferably 2 to 25 mass%, based on 100 mass% of the pharmaceutical preparation.

<Binder>

The pharmaceutical preparation of the present invention may contain a binder. As the binder, various ones can be used, and the binder is not particularly limited, and examples thereof include water-soluble polymers. 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.

<Lubricant agent>

The pharmaceutical preparation of the present invention may contain a lubricant. As the lubricant, various lubricants can be used and are not particularly limited, and examples thereof include magnesium stearate, stearic acid, calcium stearate, and magnesium carbonate. The lubricant is preferably contained in an amount of 0.5 to 2% by mass based on 100% by mass of the pharmaceutical preparation.

When a lubricant is used, it is preferable that the lubricant is present so as to coat a part or the whole of the granule together with the angiotensin II receptor antagonist.

<Excipients>

The pharmaceutical preparation of the present invention may contain an excipient. 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, And cellulose derivatives such as crystalline cellulose and microcrystalline cellulose, 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. In the case of using an excipient, an excipient (first excipient) contained in the granules containing a calcium antagonist and an excipient (first excipient), which are present together with the angiotensin II receptor antagonist to cover part or all of the granules ) May be the same or different. Only one of the first excipient and the second excipient may be contained in the pharmaceutical preparation.

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

The second excipient is contained preferably in an amount of 1 to 40 mass%, more preferably 5 to 30 mass%, based on 100 mass% of the pharmaceutical preparation.

<Fluidizing agent>

The pharmaceutical preparation of the present invention may contain a fluidizing agent. As the fluidizing agent, various agents can be used without particular limitation, and examples thereof include hydrous silicon dioxide, light anhydrous silicic acid, and talc. Of these, the hydrous silicon dioxide is more preferable.

The fluidizing agent is preferably contained in an amount of 1 to 10 mass%, more preferably 1 to 5 mass%, based on 100 mass% of the pharmaceutical preparation.

When a fluidizing agent is used, it is preferable that the fluidizing agent is present in such a manner that it coats some or all of the granules together with the angiotensin II receptor antagonist.

<Coating film>

The pharmaceutical preparation of the present invention preferably has a coating film on its surface. The mass ratio of the coating film may be adjusted depending on the purpose, but it is preferably 1 to 10% by mass, more preferably 3 to 8% by mass with respect to 100% by mass of the pharmaceutical preparation.

The coating film can be formed on the surface of the pharmaceutical preparation, for example, by applying a coating solution in which a coating agent is dissolved in water, using a pan coating device, a drum type coating device, a flow coating device or the like.

Examples of the coating agent include hyphromelose, macrogol 6000, and the like.

<Colorant>

It is preferable that the coating film contains an iron oxide based coloring agent such as yellow 32 iron oxide, 32 iron oxide, and black iron oxide. These colorants may be used singly or in combination of two or more kinds.

The colorant is contained preferably in a proportion of 0.1 to 5 parts by mass, more preferably 0.25 to 1 part by mass with respect to 100 parts by mass of the coating film.

By having the coating film containing the colorant, the light stability of the calcium antagonist contained in the pharmaceutical preparation can be improved. That is, not only the problem of the angiotensin II receptor antagonist whose dissolution rate is lowered at high temperature preservation but also the problem of the calcium antagonist which is easily photodegraded can be improved.

The coating film may further contain other coloring agents such as titanium oxide in addition to the iron oxide-based coloring agent. When titanium oxide is contained, it is preferable that titanium oxide is contained in an amount of 5 to 25 parts by mass, more preferably 10 to 20 parts by mass with respect to 100 parts by mass of the coating film.

The pharmaceutical preparation 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 shape of the tablets is not particularly limited and may be, for example, circular, elliptical (oval, oval, elliptical, small-plate, 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.

In the pharmaceutical preparation of the present invention, it is preferable that in the dissolution test based on the paddle method, 48 to 78% by mass of the calcium antagonist is dissolved in water after 15 minutes from the start of the test. 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.

<Manufacturing Method>

The pharmaceutical preparation of the present invention can be produced by a conventionally known method in the art. For example, it can be produced by a dry granulation method, a wet granulation method, or a direct granulation method. More specifically, it can be produced, for example, by granulating a calcium antagonist, mixing the resultant calcium antagonist-containing granule with an angiotensin II receptor antagonist, and granulating it by dry granulation, followed by tableting.

<Applications>

Since the pharmaceutical preparation of the present invention has a coercive action, it is useful as a coercive agent 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 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. In the examples, &quot;% &quot; means mass% unless otherwise stated.

[Example 1]

The granules were subjected to agitation by using an organic solvent (dichloromethane and methanol) to obtain the granules of the present invention.

A predetermined (plain) tablet of a cilindipine / valsartan blending agent was obtained by blending, dry-assembling, sizing, and tableting the components shown in Table 2 in the above-mentioned sildenafine granules (amount of disintegrant added: 22.5 mg / Party 9%).

Using the predetermined fan type coating machine obtained above, the formulation of Table 3 was coated to obtain a film coat tablet. The ratio of the first disintegrant to the second disintegrant was 3.8% (total disintegrant: 8.6%). The content of the disintegrant was 1.9%, the proportion of the balun was 15.2%, the content of the first disintegrant was 4.8%

[Example 2]

By the granulation with stirring using an organic solvent (dichloromethane and methanol), the granules of the present invention as shown in Table 1 were obtained. The components shown in Table 4 were mixed, dry-assembled, sieved, and tableted into the obtained silymarin dipeptide granules to obtain a predetermined amount of a cyclodipine / valsartan blender (amount of disintegrant added: 52.5 mg / tablet, 21% . Using the obtained pan coater, the formulation of Table 3 was coated to obtain a film coat tablet. The ratio of the first disintegrant: 4.8%, the proportion of the second disintegrant: 15.2% (total disintegrant: 20.0%),

[Example 3]

By the granulation with stirring using an organic solvent (dichloromethane and methanol), the granules of the present invention as shown in Table 1 were obtained. The components shown in Table 5 were mixed, dry-assembled, sieved, and tableted into the obtained siltydipine granules to obtain a predetermined amount of the cyclindipine / valsartan compounding agent (amount of disintegrant added: 12.5 mg / tablet, 29% . Using the obtained pan coater, the formulation of Table 3 was coated to obtain a film coat tablet. The ratio of the first disintegrant to the second disintegrant was 22.9% (the total disintegrant: 27.6%). The content of the disintegrant was 1.9%

[Comparative Example 1]

By the granulation with stirring using an organic solvent (dichloromethane and methanol), the granules of the present invention as shown in Table 1 were obtained. The obtained sindydipine granules were mixed with the components shown in Table 6, and subjected to dry granulation, sizing and tableting to obtain a predetermined amount of the cydipyrin / valsartan blending agent (disintegrant added: 12.5 mg / tablet, 5% ). Using the obtained pan coater, the formulation of Table 3 was coated to obtain a film coat tablet. The ratio of the first disintegrant: 4.8%, the proportion of the second disintegrant: 0.0% (the total disintegrant: 4.8%),

[Test Example 1]

With respect to the dissolution test for valsaltane, the test was carried out at a rate of 50 revolutions per minute and 900 mL of water as the test liquid, according to the dissolution test method (paddle method) described in the 16th Japanese Pharmacopoeia. The test liquid was collected 15 minutes and 30 minutes after the start of the test, and the test was carried out by liquid chromatography to calculate the dissolution rate of balchatane.

[Test Example 2]

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. Test liquids were taken 15 minutes and 90 minutes after the start of the test, and the test was carried out by liquid chromatography to calculate the dissolution rate of the cilindipine.

[Test solution 3]

And kept at a temperature of 60 캜 in an airtight state for one month, and a dissolution rate was calculated according to Test Example 1.

<Result>

Examples 1 to 3 and Comparative Example 1 were evaluated in terms of percent dissolution (%) according to Test Examples 1 and 2.

In addition, a target value is set in consideration of the elution rate of Diovan (registered trademark), a commercial product of Atelec (registered trademark) tablets and valsartan, which are commercially available products of cynidipine, and the dissolution rate of cynidipine, Quot ;, and &quot; not satisfying one &quot; was rated as &quot; x &quot;.

As a result, for Examples 1 to 3, it was confirmed that the formulation having the target dissolution rate was a point that the dissolution rate of the target value was shown in both of the silydipine and the valsartan. However, in Comparative Example 1, it was confirmed that the formulation did not show the dissolution rate of the target value and was not the agent having the desired dissolution rate.

The stability was confirmed in accordance with Test Example 3 using Example 1, Example 2 and 40 mg of Diovanje (commercially available). As a result, regarding the formulations of Examples 1 and 2, a high dissolution rate was maintained even after storage.

[Example 4]

By subjecting to stirring and agitation using an organic solvent (dichloromethane and methanol), the sandy dipine granules according to Table 9 were obtained.

The components shown in Table 10 were mixed, dry-assembled, sieved, and tableted into the above-mentioned silydipine granules to obtain a syringe-dipin / valsartan blending agent.

Using the predetermined fan type coating machine obtained above, the prescription of Table 11 was coated to obtain a film coat tablet. The ratio of the first disintegrant: 4.8%, the proportion of the second disintegrant: 7.6% (total disintegrant: 12.4%). The ratio of the iron oxide-based colorant to 100 parts by mass of the coating film: 1.0 part by mass, the proportion of titanium oxide: 14.8 parts by mass.

[Comparative Example 2]

By subjecting to stirring and agitation using an organic solvent (dichloromethane and methanol), the sandy dipine granules according to Table 9 were obtained.

The components shown in Table 10 were mixed, dry-assembled, sieved, and pressed into the obtained syringe suspension to obtain a syringe-dipin / valsartan compounding agent.

Using the obtained predetermined fan-type coater, the prescription of Table 12 was coated to obtain a film coat tablet. The ratio of the first disintegrant: 4.8%, the proportion of the second disintegrant: 7.6% (total disintegrant: 12.4%). The ratio of the iron oxide-based colorant to 100 parts by mass of the coating film: 0.0 part by mass, the proportion of titanium oxide: 15.0 parts by mass.

[Example 5]

By subjecting to stirring and agitation using an organic solvent (dichloromethane and methanol), the granules of the present invention as shown in Table 13 were obtained.

The components shown in Table 14 were mixed, dry-assembled, sized and pressed into the above-mentioned silydipine granules to obtain a syringipine / valsartan compounding preparation.

Using the predetermined fan type coating machine obtained above, the formulation of Table 15 was coated to obtain a film coat tablet. The ratio of the first disintegrant was 4.8% and the ratio of the second disintegrant was 15.4% (total disintegrant: 20.2%). The ratio of the iron oxide-based colorant to 100 parts by mass of the coating film: 0.25 parts by mass, and the proportion of titanium oxide: 15.0 parts by mass.

[Example 6]

By subjecting to stirring and agitation using an organic solvent (dichloromethane and methanol), the granules of the present invention as shown in Table 13 were obtained. The components shown in Table 14 were mixed, dry-assembled, sieved, and tableted into the obtained syringe suspension to obtain a syringe-dipin / valsartan compounding agent. Using the obtained pan coater, the formulation of Table 16 was coated to obtain a film coat tablet. The ratio of the first disintegrant was 4.8% and the ratio of the second disintegrant was 15.4% (total disintegrant: 20.2%). The ratio of the iron oxide-based colorant to 100 parts by mass of the coating film: 0.25 parts by mass, and the proportion of titanium oxide: 15.0 parts by mass.

[Example 7]

By subjecting to stirring and agitation using an organic solvent (dichloromethane and methanol), the granules of the present invention as shown in Table 13 were obtained. The components shown in Table 14 were mixed, dry-assembled, sized and pressed into the obtained syringe suspension to obtain a syringe-dipin / valsartan compounding agent. Using the obtained pan coater, the formulation of Table 17 was coated to obtain a film coat tablet. The ratio of the first disintegrant was 4.8% and the ratio of the second disintegrant was 15.4% (total disintegrant: 20.2%). The ratio of the iron oxide-based colorant to 100 parts by mass of the coating film: 0.25 parts by mass, and the proportion of titanium oxide: 15.0 parts by mass.

[Comparative Example 3]

By subjecting to stirring and agitation using an organic solvent (dichloromethane and methanol), the granules of the present invention as shown in Table 13 were obtained. The components shown in Table 14 were mixed, dry-assembled, sized and pressed into the obtained syringe suspension to obtain a syringe-dipin / valsartan compounding agent. Using the obtained predetermined fan-type coater, the prescription of Table 18 was coated to obtain a film coat tablet. The ratio of the first disintegrant was 4.8% and the ratio of the second disintegrant was 15.4% (total disintegrant: 20.2%). The ratio of the iron oxide-based colorant to 100 parts by mass of the coating film: 0.0 part by mass, the proportion of titanium oxide: 15.0 parts by mass.

[Test Example 4]

A light stability test was conducted in 1.2 million lux irradiation to calculate the total amount of the silydipine-like substance.

<Result>

With respect to Examples 4 to 7 and Comparative Examples 2 and 3, the total amount of the cilindipine-like substances was calculated in accordance with Test Example 4. As a result, as compared with Comparative Examples 2 and 3 in which only titanium oxide was added, in all of Examples 4 to 7, the total amount of the silydipine-like substance was low, confirming that it was stable to light.

The pharmaceutical preparation of the present invention can improve the storage stability of the angiotensin II receptor antagonist. In addition, the pharmaceutical preparation can realize a dissolution profile close to the dissolution profile of each of the commercial calcium antagonist drug and the angiotensin II receptor antagonist. Therefore, it is very useful in industry.

Claims (16)

A medicinal compounding agent containing from 0.1 to 10 mass% of a calcium antagonist as an active ingredient and from 5 to 50 mass% of an angiotensin II receptor antagonist and a disintegrant of 5 mass% or more in total of the first disintegrant and the second disintegrant ,
Wherein the calcium antagonist is in the form of a solid dispersion,
Wherein the calcium antagonist is a &lt; RTI ID = 0.0 &gt;
Wherein said angiotensin II receptor antagonist is valsartan,
Wherein the first and second disintegrants are each independently selected from the group consisting of croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropylcellulose, carboxymethylstarch sodium, crospovidone, and pregelatinized starch At least one species,
The first disintegrant is contained in an amount of 1 to 15% by mass based on 100% by mass of the pharmaceutical compounding agent,
The second disintegrant is contained in an amount of 1 to 30% by mass based on 100% by mass of the pharmaceutical compounding agent,
A medicinal preparation obtained by granulating and granulating a granule containing a first disintegrant and a calcium antagonist, an angiotensin II receptor antagonist and a second disintegrant. The pharmaceutical compounding agent according to claim 1, which is obtained by granulating and granulating a granule containing a first disintegrant and a calcium antagonist, an angiotensin II receptor antagonist and a second disintegrant by dry granulation. The pharmaceutical compounding agent according to claim 1, wherein the disintegrant is contained in a total amount of 6 to 30 mass% of the first disintegrant and the second disintegrant. The pharmaceutical formulation according to claim 1, wherein the mass ratio of the calcium antagonist to the angiotensin II receptor antagonist is from 1: 1 to 1:32. The pharmaceutical compounding agent according to claim 1, comprising a coating film containing at least one coloring agent selected from the group consisting of yellow ferric oxide, ferric oxide and black iron oxide. The pharmaceutical compounding agent according to claim 5, wherein the proportion of the coloring agent is within a range of 0.1 to 5 parts by mass with respect to 100 parts by mass of the coating film. The pharmaceutical compounding agent according to claim 5 or 6, wherein the coating further contains titanium oxide. The pharmaceutical compounding agent according to claim 1, which is a depressant. delete delete delete delete delete delete delete delete