TW201427720A - Method for producing pharmaceutical preparation containing calcium antagonist/angiotensin ii receptor antagonist - Google Patents

Abstract

Provided is a method for producing a pharmaceutical preparation containing a calcium antagonist and an angiotensin II receptor antagonist as active ingredients, said method being characterized by comprising a granulation step of granulating the calcium antagonist and the angiotensin II receptor antagonist together or separately without using water. A pharmaceutical preparation produced by the method can have an elution profile close to the elution profile of a commercially available calcium antagonist preparation and the elution profile of a commercially available angiotensin II receptor antagonist preparation.

Description

Method for producing pharmaceutical preparation containing calcium antagonist and angiotensin II receptor antagonist

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

Hypertension refers to a state in which blood pressure continues to be higher than the normal range. One of the diseases caused by high blood pressure living habits, if the state of hypertension persists, there is complicated atherosclerosis, or ischemic heart disease, stroke and the like.

At present, in order to treat patients with hypertension, blood pressure control using a therapeutic agent for hypertension (hypertensive agent) is generally carried out widely. In the treatment of hypertension, calcium antagonists (CCB), angiotensin exchange enzyme inhibitors, and angiotensin II receptor antagonists (ARB) are generally used.

Calcium antagonists (CCB) are known to exert a blood pressure lowering effect by inhibiting the absorption of Ca ²⁺ into the cells through the ion channel and attenuating the contraction of smooth muscle. Calcium antagonists, which are currently the most widely used antihypertensive agents in Japan, are generally recommended as the first choice because they have few serious side effects and are second only to diuretics and are low in price.

Angiotensin II receptor antagonist (ARB), which is known to inhibit vascular tone induced by the renin-angiotensin system by specific antagonism of the angiotensin II receptor The physiological role of the hormone II, and play a role in lowering blood pressure.

As described above, a calcium antagonist and an angiotensin II receptor antagonist mean that a blood pressure lowering effect is obtained by a different mechanism. Therefore, for hypertensive patients who are less likely to observe an improvement in symptoms in a single dose, the use of a calcium antagonist in combination with an angiotensin II receptor antagonist has also been attempted for the purpose of improving the therapeutic effect ( Patent Document 1).

[Previous Technical Literature] [Patent Document]

[Patent Document 1] Japanese Patent Laid-Open Publication No. 2008-44871

However, the drug substance of the calcium antagonist and the angiotensin II receptor antagonist has a low solubility in water, and it takes time even if the drug substance is administered until the effect is exhibited. For example, Cilnidipine, one of the calcium antagonists, has a solubility in water of several ng/mL at 20 ° C, and is one of the angiotensin II receptor antagonists, Valsartan. The solubility in water at 20 ° C is about 0.17 mg / mL. Therefore, currently available calcium antagonist preparations and angiotensin II receptor antagonist preparations are carefully designed to increase the dissolution rate.

However, commercially available calcium antagonist preparations and angiotensin II receptor antagonist preparations are difficult to achieve a dissolution profile by a single pharmaceutical preparation (admixture) because the dissolution rate is increased by an individual method.

The present invention has been made in view of the above problems, and an object thereof is to provide a method for producing a pharmaceutical preparation (admixture) which can achieve dissolution of each of a commercially available calcium antagonist preparation and an angiotensin II receptor antagonist preparation. The elution profile is close to the dissolution profile.

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

(1) A method for producing a pharmaceutical preparation comprising a calcium antagonist and an angiotensin II receptor antagonist as an active ingredient, which comprises a calcium antagonist and a blood vessel tension without using water A granulation step in which the nucleoside receptor antagonists are granulated together or separately.

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

(3) The production method according to (1) or (2) above, wherein in the granulating step, the calcium antagonist is granulated together with the angiotensin II receptor antagonist without using water. Granules containing a calcium antagonist and an angiotensin II receptor antagonist are obtained.

(4) The production method according to the above (3), wherein after the calcium antagonist is granulated without using water to obtain a calcium-containing antagonist particle, the angiotensin II receptor antagonist is not used without using water The granules are mixed and granulated, thereby using the calcium antagonist and the angiotensin II receptor without using water. The antagonists are granulated together to obtain granules containing a calcium antagonist and an angiotensin II receptor antagonist.

(5) The production method according to the above (1) or (2), wherein the calcium antagonist and the angiotensin II receptor antagonist are individually granulated without using water in the granulation step. Calcium-containing antagonist particles and angiotensin II receptor antagonist particles are obtained.

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

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

(8) The production method according to the above (7), wherein the 1,4-dihydropyridine derivative is Cilnidipine, Amlodipine, Nilvadipine, Nifedipine, Azelnidipine, Nisoldipine, Nicardipine, Nimodipine, Nitrindipine, and Manidipine At least one of the selected groups.

(9) The production method according to any one of the above (1) to (8) wherein the angiotensin II receptor antagonist is derived from Valsartan, Candesartan, and Ai Selected from the group consisting of ibsartan, losartan, telmisartan, olmesartan, irbesartan, and eprosartan At least one of them.

(10) The manufacturing method according to any one of (2) to (9) above, The organic solvent is at least one selected from the group consisting of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone, and diethyl ether.

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

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

(13) The production method according to any one of the above (1) to (12), which is characterized in that, in the dissolution test by the liquid-containing method, the calcium antagonist has a mass of 25 to 55 after 7 minutes from the start of the test. % will dissolve in water, and an angiotensin II receptor antagonist will dissolve in an elution profile in water after 15 minutes from the start of the test.

(14) The production method according to any one of the above (1) to (13), wherein, in the dissolution test by the liquid-containing method, the calcium antagonist has a mass ratio of 75 mass% or more after 90 minutes from the start of the test. It will be dissolved in water, and an angiotensin II receptor antagonist will dissolve in an elution profile of water at 85 mass% or more after 30 minutes from the start of the test.

(15) The production method according to any one of (1) to (14) wherein the pharmaceutical preparation is a hypotensive agent.

The pharmaceutical preparation produced by the method of the present invention can achieve antagonism with a commercially available calcium antagonist preparation and angiotensin II receptor The respective dissolution profiles of the formulation are close to the dissolution profile.

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

A method for producing a pharmaceutical preparation according to the present invention, which is a method for producing a pharmaceutical preparation comprising a calcium antagonist and an angiotensin II receptor antagonist as an active ingredient, which comprises calcium antagonist and angiotensin without using water A granulation step in which the II receptor antagonists are granulated together or separately.

The pharmaceutical preparation obtained by the production method of the present invention preferably has a form in which at least the calcium antagonist is a solid dispersion. The calcium antagonist and the angiotensin II receptor antagonist may also be in the form of a solid dispersion.

In the context of the present specification and claims, "solid dispersion" means that the drug is a monomolecularly dispersed solid in an inert carrier. In the solid dispersion, the drug is present in the carrier in an amorphous state. The inert carrier is not particularly limited as long as it is a polymer compound, and examples thereof include a polymer compound 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 hardened castor oil, sodium lauryl sulfate, polyoxyethylene-polyoxypropylene glycol, and the like.

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

[granulation step]

The production method of the present invention comprises a step of granulating a calcium antagonist and an angiotensin II receptor antagonist together or separately without using water (granulation step). Therefore, in the present invention, the calcium antagonist and the angiotensin II receptor antagonist are granulated without being dissolved in water.

Further, in the granulation step, it is preferred to use an organic solvent to granulate the calcium antagonist and the angiotensin II receptor antagonist together or separately without using water. Further, it is preferred to carry out the above-described granulation using a disintegrant together with a calcium antagonist and/or an angiotensin II receptor antagonist.

A method of granulating a calcium antagonist together with an angiotensin II receptor antagonist without using water can be exemplified by using a fluid bed granulator to spray a calcium antagonist to an angiotensin II receptor without using water. An antagonist, whereby a method of granulation is carried out. In the above spraying, it is preferred to dissolve the calcium antagonist in an organic solvent, and spray the obtained solution onto an angiotensin II receptor antagonist. After granulation, for example, it can be granulated by a granulator and dried using a fluid bed dryer. By the above method, particles containing a calcium antagonist and an angiotensin II receptor antagonist can be obtained.

Further, a method of granulating a calcium antagonist together with an angiotensin II receptor antagonist without using water may be exemplified by granulating a calcium antagonist without using water (preferably using an organic solvent). After the calcium-containing antagonist particles are obtained, a method in which an angiotensin II receptor antagonist is mixed with the particles without using water and granulated is carried out. After granulation, for example, it can be granulated by a granulator and dried using a fluid bed dryer. Calcium antagonist and angiotensin II receptor can be obtained by the above method Granules of antagonists.

A method of granulating a mixture of an angiotensin II receptor antagonist and a calcium-containing antagonist particle may, for example, be a granulation method using a dry granulator. In this method, an angiotensin II receptor antagonist is present in such a manner as to cover a part or all of the particles containing the calcium antagonist, thereby obtaining a calcium antagonist and an angiotensin II receptor antagonist. Particles. Among the particles obtained, it is preferred that a disintegrant is present in both the particles containing the calcium antagonist and the outside of the particles.

A method of granulating a calcium antagonist and an angiotensin II receptor antagonist individually without using water can be exemplified by granulating a calcium antagonist without using water, and subjecting angiotensin II to water without using water. A method in which a body antagonist is granulated. After granulation, for example, it can be granulated by a granulator and dried using a fluid bed dryer. By the above method, a mixture of particles containing a calcium antagonist and particles containing an angiotensin II receptor antagonist can be obtained.

<calcium antagonist>

A calcium antagonist is a drug which exhibits a blood pressure lowering effect by inhibiting the absorption of Ca ²⁺ through an ion channel and attenuating the contraction of smooth muscle.

The calcium antagonist used in the present invention is preferably a 1,4-dihydropyridine derivative. a 1,4-dihydropyridine derivative, preferably Cilinidipine, Amlodipine, Nilvadipine, Nifedipine, adipine At least one selected from the group consisting of (Azelnidipine), Nisoldipine, Nicardipine, Nimodipine, Nitrindipine, and Manidipine . Among them, Tedicillin (Cilnidipine; chemical name: (±)-2-methoxyethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3- Nitrophenyl)-3,5-pyridinedicarboxylate).

Cilnidipine is a well-known compound of an L/N type calcium antagonist which blocks an L-type calcium channel and an N-type calcium channel together, and can be produced by a known production method. In addition, commercially available preparations can also be obtained. Further, Cilnidipine can also be obtained by extraction from the preparation or the like.

Calcium antagonists can also be used as pharmacologically acceptable salts, hydrates, and solvates, as needed. Pharmacologically acceptable salts include, for example, salts with inorganic acids (hydrochloride, hydrobromide, phosphate, sulfate, etc.), and salts with organic acids (acetate, succinate, Malay). Acid salt, fumarate, malate, tartrate, etc.). Further, the calcium antagonist used in the present invention may suitably use an optically active substance thereof as needed.

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

<Angiotensin II receptor antagonist>

Angiotensin II receptor antagonist Angiotensin II antagonizes drugs that block the binding of angiotensin II to angiotensin II receptors while exhibiting a decrease in blood pressure. Examples of the angiotensin II receptor antagonist include valsartan, candesartan, Irbesartan, losartan, and telmisartan. Olmesartan, Irbesartan, and Eprosartan. Among them, valsartan (chemical name: (-)-N-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-N-valeryl-L-valine).

Angiotensin II receptor antagonists may also be pharmacologically acceptable salts, hydrates, and solvates, as needed. Pharmacologically acceptable salts include, for example, salts with inorganic acids (hydrochloride, hydrobromide, phosphate, sulfate, etc.), and salts with organic acids (acetate, succinate, Malay). Acid salt, fumarate, malate, tartrate, etc.). Further, the angiotensin II receptor antagonist used in the present invention may suitably use an optically active substance thereof as needed.

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

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

Further, the mass ratio of the calcium antagonist to 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>

The organic solvent used in the granulation step may, for example, be dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone or diethyl ether. Among them, it is preferred to use at least one organic solvent selected from the group consisting of dichloromethane, methanol, ethanol, propanol, and isopropyl alcohol. One type of the organic solvent may be used alone or two or more types may be used in combination.

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

<Disintegrant>

In the production method of the present invention, in the granulation step, it is preferred to use a disintegrating agent, and more preferably a mixture obtained by mixing a disintegrant with a calcium antagonist and/or an angiotensin II receptor antagonist. To granulate. Further, it is preferred that the disintegrating agent is dissolved in an organic solvent together with a calcium antagonist and/or an angiotensin II receptor antagonist to perform granulation.

a disintegrant, preferably croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose , crospovidone, low-substituted sodium carboxymethyl starch and alpha-starch, more preferably croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl Cellulose sodium, crospovidone and low-substituted sodium carboxymethyl starch, more preferably croscarmellose Sodium, low-substituted hydroxypropyl cellulose, particularly preferably croscarmellose sodium.

One type of the disintegrator may be used alone or two or more types may be used in combination.

The disintegrating agent is preferably contained in an amount of 5 mass% or more, more preferably 5 to 35 mass%, still more preferably 6 to 30 mass%, based on 100% by mass of the pharmaceutical preparation. Further, when the calcium antagonist is granulated, the disintegrant is preferably contained in the range of 1 to 15% by mass, more preferably in the range of 1 to 10% by mass. When the mixture containing the calcium antagonist and the angiotensin II receptor antagonist is granulated, it is preferred to add 1 to 30% by mass of a disintegrant to the mixture, preferably 2 to 25% by mass. It is more preferable to add a disintegrant to the mixture.

<Bonding agent>

The pharmaceutical preparation of the present invention may also contain a binding agent. The binder can be used in various types, and is not particularly limited, and examples thereof include a water-soluble polymer. Among them, preferred are hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl Cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, cellulose acetate phthalate, more preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose ortho-benzene Dicarboxylate.

The binder is preferably from 1 to 90% by mass, more preferably from 3 to 40% by mass, even more preferably from 5 to 20% by mass, based on 100% by mass of the pharmaceutical preparation.

When a binding agent is used, the binding agent is preferably contained in a particle containing a calcium antagonist.

Further, in addition to the disintegrating agent and the binding agent, a lubricant, an excipient, a fluidizing agent or the like may be added to the calcium antagonist and/or the angiotensin II receptor antagonist.

Here, the excipients can be used in various forms, and are not particularly limited, and examples thereof include lactose hydrate, sugar, glucose, reduced maltose, mannitol, sorbitol, sugar, corn starch, potato starch, and partial α. Starch and its derivatives of starch, dextrin, amylopectin, cellulose, cellulose, microcrystalline cellulose, etc., one or more of polyethylene glycol, magnesium metasilicate aluminate a mixture. Among them, lactose hydrate, mannitol, partially gelatinized starch, and crystalline cellulose are preferred, and lactose hydrate and crystalline cellulose are more preferred.

One type of the excipients may be used alone or two or more types may be used in combination.

The excipient is preferably from 1 to 40% by mass, more preferably from 1 to 30% by mass, based on 100% by mass of the pharmaceutical preparation.

[Compression forming step]

The method for producing a pharmaceutical preparation of the present invention may further comprise the 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 or mixed, and compression molding may be carried out by a tablet machine.

The shape of the tablet obtained by compression molding is not particularly limited, and examples thereof include a circular shape and an elliptical shape (all ovals other than a perfect circular shape: an elliptical shape, an egg shape, an ellipsoid shape, an oval shape, etc.) , diamonds, triangles, etc. When the secant line is provided, the shape of the secant line may be any one of a flat groove type, a U-groove type, and a V-shaped groove type, and when the tablet is an elliptical shape, it is preferably formed along the short axis.

[other steps]

The method for producing a pharmaceutical preparation of the present invention may further include a step of performing a coating treatment after the compression molding step. The coating agent used in the coating treatment may, for example, be hydroxypropylmethylcellulose or MACROGOL 6000. The coating treatment system may be a conventionally known method, and for example, a coating agent may be dissolved in water by using a pan coating device, a drum coating device, a flow coating device, or the like. The coating liquid in the solvent may be applied to the surface of the pharmaceutical preparation. In the coating liquid, in addition to the coating agent, yellow ferric oxide, ferric oxide, black iron oxide, titanium oxide, edible blue No. 1, edible yellow No. 4, edible red No. 2, etc. may be added. Colorant. By adding such a coloring agent, 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 a tablet, a capsule, a fine granule or a granule, and particularly preferably in the form of a tablet.

Preferably, in the dissolution test based on the liquid-containing method, the calcium antagonist obtained by the method of the present invention will be 7 minutes after the start of the test. 25 to 55 mass% thereof is dissolved in water. Similarly, it is preferred that in the dissolution test based on the liquid-containing method, the calcium antagonist is dissolved in water at 90% by mass or more after 90 minutes from the start of the test.

Further, it is preferred that the angiotensin II receptor antagonist is dissolved in water 15 minutes after the start of the test in the dissolution test by the liquid-containing method. Similarly, it is preferred that the angiotensin II receptor antagonist is dissolved in water 30 minutes after the start of the test in the dissolution test by the liquid-containing method.

When the dissolution rate is within the above range, a dissolution profile close to the elution profile of each of the commercially available calcium antagonist preparation and the angiotensin II receptor antagonist preparation can be achieved. Therefore, a pharmaceutical preparation (admixture) which exhibits the same effects as those in the case where two kinds of preparations are administered in combination can be obtained.

<Use>

The pharmaceutical preparation obtained by the production method of the present invention is useful as a blood pressure lowering agent for the treatment of hypertensive patients because of its hypotensive action.

<subject to target>

The pharmaceutical preparation to be obtained by the production method of the present invention may be a mammal such as a mouse, a rat, a hamster, a rabbit, a cat, a dog, a cow, a sheep, a monkey or a human. In particular, humans are preferred for the subject of administration.

[Examples]

Hereinafter, the present invention will be described in more detail by way of examples, but the invention is not limited by these examples.

[Example 1]

Magnesium metasilicate magnesium aluminate (22.4 kg), crystalline cellulose (6.41 kg), lactose hydrate (4.86 kg), and croscarmellose sodium (5.10 kg) were placed in a stirring granulator and mixed. Thereafter, Cilnidipine (2.04 kg), polyethylene glycol 400 (1.43 kg) and hydroxypropylcellulose (8.16 kg) were dissolved in methanol (28.3 kg) and dichloromethane (8.5 kg). The combined solution is granulated. After granulation, granules (screen: 1.6 mm) were granulated by a granulator (COMIL), and dried at a discharge temperature of 60 ° C or lower for 90 minutes using a fluid bed dryer to obtain A pellets.

Next, magnesium metasilicate aluminate (52.4 kg), crystalline cellulose (14.95 kg), and croscarmellose sodium (11.90 kg) were placed in a stirring granulator and mixed. Thereafter, Cilnidipine (4.76 kg), polyethylene glycol 400 (3.33 kg) and hydroxypropylmethylcellulose phthalate (19.04 kg) were dissolved in methanol (57.8 kg). And a binding solution of dichloromethane (57.8 kg) and granulation. After granulation, the granules were sieved by a granulator (COMIL) (screen: 1.6 mm), and dried using a fluid bed dryer at a temperature of 60 ° C or lower for 90 minutes to obtain B particles.

Mixing the A particles and the B particles obtained above to obtain Table 1 Cilnidipine granules are shown.

The above-mentioned cilnidipine granules (2966.4 g), valsartan (969.6 kg), crystalline cellulose (936 g), croscarmellose sodium (960 g), and water-containing two were used using a mixer. Yttrium oxide (96 g) and magnesium stearate (24 g) were mixed for 20 minutes to obtain a mixed powder. The obtained mixed powder was diced by dry granulation (roll pressure: 6 MPa), and granulated by a granulator (COMIL) (screen: 1.6 mm) to obtain sinipine at the position shown in Table 2. (Cilnidipine) ‧ Valsartan blended particles.

In the above-mentioned Cilnidipine ‧ Valsartan blended granules, magnesium stearate was added and mixed in such a manner as shown in Table 3, and compression molding was carried out by an ingot making machine. Thus, the tablet of the square shown in Table 3 was obtained. The ratio of cilnidipine contained in the tablet: 2.0%, the ratio of valsartan: 16.0%, the ratio of the first disintegrant: 5.0%, and the ratio of the second disintegrant: 16.0% (total disintegrator: 21.0%)

[Example 2]

Valsartan (400 g), crystalline cellulose (340 g) and croscarmellose sodium (400 g) were charged to a fluid bed granulator, and hydroxypropylcellulose (100 g) was dissolved in methanol (100 g). The combined solution of 280 g) and dichloromethane (1120 g) was sprayed (spray speed: 70 g/mL, exhaust gas temperature: 30 ° C) to obtain Valsartan particles as shown in Table 4.

The Valsartan particles obtained above, the Valsartan particles obtained in Example 1, and magnesium stearate were added and mixed as shown in Table 5, and compressed by a tablet machine. Forming, thereby obtaining a tablet as shown in Table 5. The ratio of cilnidipine contained in the tablet: 2.0%, the ratio of valsartan: 16.0%, the ratio of the first disintegrant: 5.0%, and the ratio of the second disintegrant: 16.0% (total disintegrator: 21.0%)

[Example 3]

Valsartan (200 g), crystalline cellulose (550 g), croscarmellose sodium (275 g), lactose hydrate (90 g) were charged to a fluid bed granulator, and cilnidipine (Cilnidipine) (25 g) and hydroxypropylcellulose (100 g) dissolved in a combined solution of methanol (1120 g) and dichloromethane (280 g), sprayed (spray speed: 70 g/mL, exhaust gas temperature: 30 ° C), and the results are shown in Table 6. The prescription of cilnidipine ‧ Valsartan blends the granules.

In the above-mentioned Cilnidipine ‧ Valsartan blended granules, magnesium stearate was added and mixed in such a manner as shown in Table 7, and compression molding was carried out by an ingot making machine. Thus, the tablet of the formula shown in Table 7 was obtained. The ratio of cilnidipine contained in the tablet: 2.0%, the ratio of valsartan: 16.0%, and the total amount of disintegrant: 22.0%

[Comparative Example 1]

Adding and mixing Valsartan (40g), Cilnidipine (5g), crystalline cellulose (123g), croscarmellose sodium (80g) and magnesium stearate (2g), The tablet was molded by a tablet machine to obtain a tablet as shown in Table 8. The ratio of cilnidipine contained in the tablet: 2.0%, the ratio of valsartan: 16.0%, and the total disintegrating agent: 32.0%

Further, for valsartan, a drug substance having a particle diameter D90 of 20 μm or less is used.

[Comparative Example 2]

Valsartan (200 g), cilnidipine (25 g), crystalline cellulose (550 g), croscarmellose sodium (275 g) and lactose hydrate (90 g) were placed in a fluid bed. In a granulator, a conjugated solution of hydroxypropylcellulose (100 g) dissolved in water (1400 g) was sprayed (spray speed: 70 g/mL, exhaust gas temperature: 30 ° C) to obtain Cilididipine ‧ of Table 6 Valsartan blends the granules.

Then, the tablet shown in Table 7 was obtained by the method of Example 3. The ratio of cilnidipine contained in the tablet: 2.0%, the ratio of valsartan: 16.0%, and the total amount of disintegrant: 22.0%

[Comparative Example 3]

Valsartan (484.8 g), crystalline cellulose (378 g), croscarmellose sodium (480 g) and hydroxypropyl cellulose (150 g) was placed in a stirring granulator, and water (2100 g) was poured to carry out granulation. After granulation, the granules were sieved by a granulator (COMIL) (screen: 1.6 mm), and dried using a fluid bed dryer at a temperature of 60 ° C or lower for 45 minutes to obtain a laksa as shown in Table 9. Valsartan granules.

The Valsartan granules obtained above, the Valsartan granules obtained in Example 1, and magnesium stearate were added and mixed as shown in Table 9, and compressed by a tablet machine. Forming, thereby obtaining a tablet as shown in Table 10. The ratio of cilnidipine contained in the tablet: 2.0%, the ratio of valsartan: 16.0%, the ratio of the first disintegrant: 5.0%, and the ratio of the second disintegrant: 16.0% (total disintegrator: 21.0%)

[Test Example 1]

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

[Test Example 2]

For the particle size distribution measurement of the particles, the automatic dry-type sound wave screening machine measuring device Robot Shifter RPS-95C was used, and the particle size distribution was measured using a sieve having pore diameters of 850 μm, 500 μm, 355 μm, 250 μm, 180 μm, 150 μm, 106 μm and 75 μm, and D10 was calculated. , D50, D90.

[Test Example 3]

The dissolution test for Valsartan is based on the dissolution test method (liquid method) described in the Sixteenth Correction of the Japanese Pharmacopoeia. The test was carried out by rotating 50 times per minute and using 900 mL of water as a test liquid. The test solution after 15 minutes and 30 minutes from the start of the test was tested by liquid chromatography to calculate the dissolution rate of cilnidipine.

Further, in Examples 1 and 2 and Comparative Example 1, one ingot was used, and in Example 3 and Comparative Example 2, two ingots were used.

[Test Example 4]

The dissolution test for cilnidipine is carried out according to the dissolution test method (drinking method) described in the sixteenth revision of the Japanese Pharmacopoeia, with 50 rotations per minute, and 0.1w/v% polysorbate added. In the dissolution test of the alcohol ester 80, 900 mL of the second liquid was used as a test liquid, and the test was carried out. The test solution of 7 minutes and 90 minutes from the start of the test was tested by liquid chromatography to calculate the dissolution rate of cilnidipine.

Further, in Examples 1 and 2 and Comparative Example 1, one ingot was used, and in Example 3 and Comparative Example 2, two ingots were used.

<Result>

As a result of measuring the particle size of valsartan, the particle size of Valsartan of Examples 1 to 3 and Comparative Examples 1 to 3 was used, and D90 was 20 μm or less.

For the granules of Cilnidipine and Cilnidipine ‧ Valsartan of Example 1, The particle size distribution was measured in accordance with 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 confirmed in accordance with Test Examples 3 and 4. The results are shown in Table 12.

In addition, a reference value is set in consideration of the dissolution rate of the Atelec (registered trademark) ingot which is a commercially available preparation of cilnidipine and the Diovan (registered trademark) ingot which is a commercially available preparation of valsartan. The dissolution rate of both Cilnidipine and Valsartan was evaluated as ○, and the unsatisfied was evaluated as ×.

As a result, in Examples 1 to 3, the dissolution rates in the reference values were all obtained. However, in Comparative Examples 1 to 3, the dissolution rate in the reference value could not be obtained.

[Industrial Applicability]

The pharmaceutical preparation produced by the method of the present invention has a high dissolution rate of the calcium antagonist, and can achieve an elution profile of each of the commercially available calcium antagonist preparation and the angiotensin II receptor antagonist preparation. Close to the outline of the dissolution. Therefore, the industry is extremely useful.

Claims (15)

A method for producing a pharmaceutical preparation comprising a calcium antagonist and an angiotensin II receptor antagonist as an active ingredient, wherein the calcium antagonist and the angiotensin II are contained without using water A granulation step in which the body antagonists are granulated together or separately. The production method according to claim 1, wherein the organic solvent is used in the granulation step. The production method according to claim 1 or 2, wherein in the granulating step, the calcium antagonist is granulated together with the angiotensin II receptor antagonist without using water, thereby obtaining a calcium antagonist and A particle of an angiotensin II receptor antagonist. The production method according to claim 3, wherein after the calcium antagonist is granulated without using water to obtain a calcium-containing antagonist particle, the angiotensin II receptor antagonist is mixed with the granule without using water. Granulation is carried out to thereby granulate the calcium antagonist together with the angiotensin II receptor antagonist without using water, thereby obtaining a granule containing a calcium antagonist and an angiotensin II receptor antagonist. The production method according to claim 1 or 2, wherein in the granulating step, the calcium antagonist and the angiotensin II receptor antagonist are individually granulated without using water to obtain a calcium-containing antagonist granule. With particles containing angiotensin II receptor antagonist. The production method according to any one of claims 3 to 5, further comprising the step of compression-molding the particles obtained after the granulation step. The production method according to any one of claims 1 to 6, wherein the calcium antagonist contains a 1,4-dihydropyridine derivative. The production method according to claim 7, wherein the aforementioned 1,4-dihydropyridine derivative is composed of cilnidipine, Amlodipine, Nilvadipine, and Nifedi. (Nifedipine), Azelnidipine, Nisoldipine, Nicardipine, Nimodipine, Nitrindipine, and Manidipine At least one selected from the group. The method according to any one of claims 1 to 8, wherein the angiotensin II receptor antagonist is derived from Valsartan, Candesartan, Irbesartan, At least one selected from the group consisting of losartan, telmisartan, olmesartan, irbisartan, and eprosartan. The production method according to any one of claims 2 to 9, wherein the organic solvent is dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone, and diethyl At least one selected from the group consisting of ethers. The production method according to any one of claims 1 to 10, wherein a mass ratio of the calcium antagonist to the angiotensin II receptor antagonist contained in the pharmaceutical preparation is 1:1 to 1:32. The production method according to any one of claims 1 to 11, wherein a disintegrating agent is used in the granulation step. The production method according to any one of claims 1 to 12, wherein in the dissolution test by the liquid-containing method, the calcium antagonist has a solubility of 25 to 55 mass% in water after 7 minutes from the start of the test. Further, after 15 minutes from the start of the test, the angiotensin II receptor antagonist was dissolved in an elution profile of water at 75 mass% or more. The production method according to any one of claims 1 to 13, wherein in the dissolution test by the liquid-containing method, the calcium antagonist is dissolved in water at 90% by mass or more after 90 minutes from the start of the test, and After 30 minutes from the start of the test, the angiotensin II receptor antagonist was dissolved in an elution profile of water at 85 mass% or more. The production method according to any one of claims 1 to 14, wherein the pharmaceutical preparation is a hypotensive agent.