JP2019104726A - Molded tablet which contains azilsartan or salt thereof and amlodipine or salt thereof and manufacturing method thereof, as well as method for improving stability of molded tablet which contains azilsartan or salt thereof and amlodipine or salt thereof - Google Patents

Abstract

To provide molded tablets containing azilsartan or salt thereof and amlodipine or salt thereof which is excellent in stability of both drugs of azilsartan or a salt thereof and amlodipine or a salt thereof, and production methods thereof, as well as to provide a method for improving stability of a molded tablet containing azilsartan or salt thereof and amlodipine or salt thereof.SOLUTION: Provided is a molded tablet containing azilsartan or a salt thereof and amlodipine or a salt thereof, and a tablet containing amlodipine or a salt thereof, as well as a method for producing and improving stability of a molded tablet containing azilsartan or a salt thereof and amlodipine or a salt thereof, which comprises: adding an either of water or water-containing organic solvent in which a binder is dissolved to a mixture containing azilsartan or a salt thereof and amlodipine or a salt thereof to obtain wetting powders; and subjecting the wetting powders to compression molding.SELECTED DRAWING: None

Description

  The present invention relates to azilsartan or a salt thereof and amlodipine or a salt-containing wet tablet thereof, a method for producing the same, and a method for improving the stability of azilsartan or a salt thereof and amlodipine or a salt-containing tablets.

Azilsartan (chemical name: chemical name: 2-Ethoxy-1-{[2 '-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) biphenyl-4-yl] methyl } -1H-benzo [d] imidazole-7-carboxylic acid, Structural formula: Structural formula (1) below, and amlodipine besylate (chemical name: 3-Ethyl 5-methyl (4RS) -2-[(2-) aminoethoxy) methyl] -4- (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylate monostructure sulfonate, structural formula: the following structural formula (2) is useful as a therapeutic agent for hypertension Reported as Cage, also these of the mixture have been manufactured and sold.

  In addition, as a technique for appropriately controlling the elution of the calcium antagonist and the calcium antagonist from the preparation in the digestive tract, a step of preparing a granule containing the specific drug, and a granule containing the calcium antagonist There has been proposed a method for producing a solid preparation, which comprises the steps of preparing (1) and compressing the above-mentioned respective granulated products (see, for example, Patent Document 1).

  However, in the tablet containing azilsartan or a salt thereof and amlodipine or a salt thereof, further improvement of the stability of each drug is currently required.

  Therefore, there is a strong demand for the rapid provision of techniques capable of enhancing the stability of both azilsartan or a salt thereof and amlodipine or a salt thereof.

WO 2010/126168

  An object of the present invention is to solve the above-mentioned problems in the prior art and to achieve the following objects. That is, the present invention provides azilsartan or a salt thereof which is excellent in the stability of both azilsartan or a salt thereof, and amlodipine or a salt thereof, and amlodipine or a salt containing amlodipine or a salt thereof, a method for producing the same It is an object of the present invention to provide a method for improving the stability of a salt thereof and amlodipine or a tablet containing the salt thereof.

  In order to improve the stability of a pharmaceutical containing a plurality of active ingredients, there is known a method such that each active ingredient is not brought into physical contact, for example, a laminated tablet or granulation of each active ingredient separately. Although those cases are also described in the above-mentioned Patent Document 1, as a result of intensive studies to solve the above problems, the present inventors have brought two active ingredients into physical contact. It has been found that by preparing tablets using a wet tableting method, the stability of the drug of both azilsartan or its salt and amlodipine or its salt under various storage conditions can be improved.

The present invention is based on the findings of the present inventors, and means for solving the problems are as follows. That is,
<1> Azilsartan or a salt thereof, and amlodipine or a salt-containing tablet comprising the amlodipine, characterized in that the azylsartan or a salt thereof and amlodipine or a salt thereof are contained.
<2> The azilsartan or a salt thereof according to <1> and amlodipine or a salt thereof, which further contains triethyl citrate.
<3> A step of obtaining a wet powder by adding either water in which a binder is dissolved or a water-containing organic solvent to a mixture containing azirsartan or a salt thereof and amlodipine or a salt thereof to obtain a wet powder,
And a step of compacting the wet powder, thereby producing azilsartan or a salt thereof, and amlodipine or a salt-containing compressed tablet thereof.
<4> The method for producing azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof, according to the above <3>, wherein the wet powder contains triethyl citrate.
<5> A step of obtaining a wet powder by adding either water in which a binder is dissolved or a water-containing organic solvent to a mixture containing azirsartan or a salt thereof and amlodipine or a salt thereof, and obtaining a wet powder,
And a step of compressing and molding the wet powder, which is a method for improving the stability of azilsartan or a salt thereof and amlodipine or a tablet containing the salt thereof.
<6> The method for improving the stability of azilsartan or a salt thereof and amlodipine or a tablet containing the salt thereof according to <5>, wherein the wet powder contains triethyl citrate.

  According to the present invention, the aforementioned problems in the prior art can be solved, and the above object can be achieved, and azilsartan or a salt thereof which is excellent in the stability of drugs of both azilsartan or a salt thereof and amlodipine or a salt thereof And amlodipine or a salt thereof containing a salt thereof, a method for producing the same, and a method for improving the stability of azilsartan or a salt thereof and amlodipine or a salt containing the salt thereof.

(Azilsartan or a salt thereof and amlodipine or a salt-containing compressed tablet thereof and a method for producing the same)
The azilsartan or a salt thereof and amlodipine or a salt-containing compressed tablet thereof according to the present invention at least contain azilsartan or a salt thereof and amlodipine or a salt thereof, and further optionally contain other components.
The method for producing the azilsartan or a salt thereof and amlodipine or a salt thereof containing amlodipine is not particularly limited and may be appropriately selected depending on the purpose. However, the azilsartan or a salt thereof and amlodipine or a portion thereof of the present invention It can manufacture suitably by the manufacturing method of a salt containing moist tablet.
Hereinafter, the azilsartan or salt thereof and amlodipine or salt-containing wet tablets thereof will be described together with the description of the method for producing the azilsartan or salt thereof and amlodipine or a salt thereof containing amlodipine of the present invention.

<A method for producing azilsartan or a salt thereof and amlodipine or a salt-containing compressed tablet>
The method for producing azilsartan or a salt thereof and amlodipine or a salt thereof, according to the present invention at least includes a wet powder preparation step and a compression molding step, and may further include other steps as necessary.

<< wet powder preparation process >>
In the wet powder preparation step, either a water in which a binder is dissolved or a water-containing organic solvent is added to a mixture containing azilsartan or a salt thereof and amlodipine or a salt thereof to obtain a wet powder. It is a process.

-Mixture-
The mixture contains at least azilsartan or a salt thereof and amlodipine or a salt thereof, and further contains other components as necessary.

--Azilsartan or its salt--
The azilsartan is a compound represented by the following structural formula (1) (chemical name: 2-Ethoxy-1-{[2 ′-(5-oxo-4, 5-dihydro-1, 2, 4-) oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzo [d] imidazole-7-carboxylic acid).

  The salt of azilsartan is not particularly limited as long as it is a pharmacologically acceptable salt, and can be appropriately selected depending on the purpose. Examples thereof include azilsartan medoxomil and the like.

  As the azilsartan or a salt thereof, those produced by known methods may be used, or commercially available products may be used.

  There is no restriction | limiting in particular as content in the said mixture of the said azilsartan or its salt, According to the desired content in a wet tablet, it can select suitably, For example, 10 mass%-40 mass% etc. are mentioned Be

--Amlodipine or a salt thereof--
The amlodipine is a compound represented by the following structural formula (3): (Chemical name: 3-Ethyl 5-methyl (4RS) -2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl)- 6-methyl-1,4-dihydropyridine-3,5-dicarboxylate).

  The amlodipine salt is not particularly limited as long as it is a pharmacologically acceptable salt, and can be appropriately selected according to the purpose. For example, amlodipine besylate (benzenesulfonate), amlodipine maleate, And amlodipine mesylate.

  The amlodipine or a salt thereof may be produced by a known method, or a commercially available product may be used.

  There is no restriction | limiting in particular as content in the said mixture of the said amlodipine or its salt, According to the desired content in a wet tablet, it can select suitably, For example, 1 mass%-10 mass% etc. are mentioned .

--Other ingredients--
The other components in the mixture are not particularly limited as long as the effects of the present invention are not impaired, and additives commonly used in the pharmaceutical field can be appropriately selected according to the purpose, for example, an excipient, A fluidizer, a binder, surfactant, a plasticizer, a disintegrant, a lubricant, a flavor, a fragrance, a pH adjuster, etc. are mentioned. These may be used alone or in combination of two or more.

  The excipient is not particularly limited and may be appropriately selected according to the purpose. For example, mannitol (hereinafter sometimes referred to as "D-mannitol"), lactose (anhydride may be used) And may be hydrate), xylitol, sorbitol, corn starch, sucrose, erythritol, talc, purified gelatin, hydroxypropyl starch, calcium silicate and the like. These may be used alone or in combination of two or more.

  The fluidizing agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include light anhydrous silicic acid, talc, hydrous silicon dioxide, magnesium aluminometasilicate, magnesium alumina hydroxide and the like. . These may be used alone or in combination of two or more.

  The binder is not particularly limited and may be appropriately selected according to the purpose. Examples thereof include polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hydroxypropyl cellulose, hypromellose, hydroxy Propyl methylcellulose sodium, sodium starch glycolate, hydroxyethyl cellulose and the like can be mentioned. These may be used alone or in combination of two or more.

  There is no restriction | limiting in particular as said surfactant, According to the objective, it can select suitably, for example, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 60, sodium lauryl sulfate, sucrose fatty acid ester, glycerol, a macro Examples include goal, lauromacrogol, polysorbate, polyethylene glycol, triethyl citrate and the like. These may be used alone or in combination of two or more.

  The plasticizer is not particularly limited and may be appropriately selected according to the purpose. For example, triethyl citrate, glycerin fatty acid ester, sucrose fatty acid ester, talc, triacetin, castor oil, propylene glycol, macrogol 400 , Macro Goal 600, Macro Goal 1500, Macro Goal 1540, Macro Goal 4000, Macro Goal 6000, Macro Goal 20000, Macro Goal 35000, and other macro goals. These may be used alone or in combination of two or more.

  There is no restriction | limiting in particular as said disintegrant, According to the objective, it can select suitably, For example, starch (corn starch etc.), crystalline cellulose, carmellose calcium, sodium starch glycolate, crospovidone, croscarmellose sodium And croscarmellose calcium. These may be used alone or in combination of two or more.

  The lubricant is not particularly limited and may be appropriately selected depending on the purpose. For example, magnesium stearate, calcium stearate, talc, hydrogenated oil, white beeswax, carnauba wax, polyethylene glycol 6000, stearyl sodium fumarate And stearic acid. These may be used alone or in combination of two or more.

  There is no restriction | limiting in particular as said flavoring agent, According to the objective, it can select suitably, For example, sucralose, an aspartame, acesulfame potassium, thaumatin etc. are mentioned. These may be used alone or in combination of two or more.

  There is no restriction | limiting in particular as said fragrance | flavor, According to the objective, it can select suitably, For example, 1-menthol, vanillin, orange oil etc. are mentioned. These may be used alone or in combination of two or more.

  There is no restriction | limiting in particular as said pH adjuster, According to the objective, it can select suitably, For example, an inorganic acid, an inorganic base, an acidic amino acid, a basic amino acid, an amino sugar etc. are mentioned. These may be used alone or in combination of two or more.

  The other components in the mixture may be those produced by known methods, or commercially available products.

  There is no restriction | limiting in particular as content of the other component in the said mixture, According to the objective, it can select suitably.

-Either water in which a binder is dissolved or a water-containing organic solvent-
Either the water in which the binder is dissolved or the water-containing organic solvent contains at least a binder, and may further contain other components as necessary.

-Any of water and water-containing organic solvent-
One of the water and the water-containing organic solvent is a kneading solvent.
There is no restriction | limiting in particular as an organic solvent in the said water-containing organic solvent, According to the objective, it can select suitably, For example, pharmaceutically acceptable water-soluble organic solvents, such as ethanol, propanol, isopropanol, etc. are mentioned. These may be used alone or in combination of two or more.
Among these, ethanol is preferred in view of its low toxicity to humans.

  There is no restriction | limiting in particular as a compounding ratio (mass ratio of organic solvent / water) of the organic solvent and water in the said mixing solvent, Although it can select suitably according to the objective, 0-4 are preferable, and 0 3 is more preferable. If the compounding ratio exceeds 4, it is economically disadvantageous, and depending on the type of binder, problems such as precipitation may occur, and the risk of ignition may increase. On the other hand, it is advantageous at the point by which the tablet physical property after shaping | molding is suitably maintained as the said compounding ratio is an especially preferable range.

  There is no restriction | limiting in particular as usage-amount of the said mixing solvent, According to the objective, it can select suitably.

--Binder--
The binder is not particularly limited and may be appropriately selected according to the purpose. Examples thereof include polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hydroxypropyl cellulose, hypromellose, hydroxy Propyl methylcellulose sodium, sodium starch glycolate, hydroxyethyl cellulose and the like can be mentioned. These may be used alone or in combination of two or more.
Among these, polyvinyl alcohol is preferable in view of low hygroscopicity.

The polyvinyl alcohol is a polymer obtained by saponifying polyvinyl acetate.
As the average degree of polymerization and the degree of saponification of the polyvinyl alcohol, the average degree of polymerization and the degree of saponification can be appropriately adjusted by appropriately adjusting vinyl acetate as a raw material.

  There is no restriction | limiting in particular as an average polymerization degree of the said polyvinyl alcohol, According to the objective, it can select suitably, 200-3,500 are preferable and 300-2,200 are more preferable. The average degree of polymerization can be measured according to JIS K 6726.

  There is no restriction | limiting in particular as a saponification degree of the said polyvinyl alcohol, According to the objective, it can select suitably, 65 mol% or more is preferable, and 78 mol% or more is more preferable. Among these, 78 mol% to 96 mol% (partial saponification), 97 mol% or more (complete saponification) are more preferable, and 78 mol% to 96 mol% (partial saponification) are particularly preferable. The degree of saponification can be measured according to JIS K 6726.

  As the binder, one produced by a known method may be used, or a commercially available product may be used.

  There is no restriction | limiting in particular as content in the wet tablet of the said binder, Although it can select suitably according to the objective, 0.01 mass%-5 mass% are preferable, 0.05 mass%-3 mass % Is more preferable. When the content is in the more preferable range, it is advantageous in that sufficient tablet strength can be maintained and suitable tablet physical properties can be obtained.

--Other ingredients--
There is no particular limitation on the other components in water and the water-containing organic solvent in which the binder is dissolved, as long as the effects of the present invention are not impaired, and can be appropriately selected according to the purpose. And the like as other components in the above. These may be used alone or in combination of two or more.
As the other components in any of the water and the water-containing organic solvent in which the binder is dissolved, one produced by a known method may be used, or a commercially available product may be used.
There is no restriction | limiting in particular as content of the other component in either of the water and the water-containing organic solvent which melt | dissolved the said binder, According to the objective, it can select suitably.

Among the other components, it is preferable to contain triethyl citrate in that the stability of the drug can be further improved.
There is no restriction | limiting in particular as content in the wet tablet of said triethyl citrate, Although it can select suitably according to the objective, 0.01 mass%-5 mass% are preferable, 0.05 mass%-3 % By mass is more preferred. It is advantageous at the point which can further improve the stability of a drug as the said content is a preferable range.

-Baking-
There is no restriction | limiting in particular as a method of the said kneading, A well-known method can be selected suitably.
There is no restriction | limiting in particular as an apparatus used for the said kneading | mixing, A well-known apparatus can be selected suitably, For example, apparatuses, such as a ribbon mixer and a high speed stirring mixer, are mentioned.
There is no restriction | limiting in particular as conditions for the said mixing, According to the objective, it can select suitably.

-Wet powder-
The wet powder is produced by the kneading.
The wet powder may be used as it is in a compression molding process described later, or may be used in a compression molding process after being wet granulated to form a granulated product.

  The method of wet granulation is not particularly limited, and any known method can be appropriately selected. For example, crushing by extrusion granulation using a cylindrical granulator, pelleter, etc., speed mill, power mill, etc. A granulation method, a minimizer, a power kneader, a speed mill, a malmizer, etc. are used, and a rolling granulation method of granulating mainly by rolling action, a fluidized bed granulation method by spray drying, etc. may be mentioned.

<< Compression molding process >>
The compression molding step is a step of compression molding the wet powder.
In the molding step, the wet powder may be filled in a die, and may be scraped into a fixed amount, or may be subjected to a treatment of drying the tablet after compression molding.

-Compression molding-
There is no restriction | limiting in particular as a method of the said compression molding, A well-known apparatus can be selected suitably, For example, a universal material test apparatus (Autograph, Shimadzu Corp. make) and an indication are disclosed in Unexamined-Japanese-Patent No. 8-19589. Tablet manufacturing apparatus, a tablet manufacturing apparatus disclosed in JP-A-8-19588, a method using an apparatus such as a rotary tableting machine, a wet powder tableting machine, and the like.

  There is no restriction | limiting in particular as a pressure at the time of the filling pressurization in the said compression molding process, According to the objective, it can select suitably.

<< Other process >>
There is no restriction | limiting in particular as said other process, unless the effect of this invention is impaired, According to the objective, it can select suitably, For example, a mixture preparation process, a drying process, etc. are mentioned.

-Mixture preparation process-
The mixture preparation step is a step of mixing azilsartan or a salt thereof, amlodipine or a salt thereof and, if necessary, the other components, to prepare a mixture used in the wet powder preparation step.
There is no restriction | limiting in particular as the method of the said mixing, A well-known apparatus can be selected suitably and can be used, For example, the method of using apparatuses, such as a high-speed stirring mixer and Mechano mill (made by Okada Seiko Co., Ltd.), etc. are mentioned .
There is no restriction | limiting in particular as conditions of the said mixing, According to the objective, it can select suitably.

-Drying process-
The drying step is a step of drying the tablet obtained in the compression molding step.
There is no restriction | limiting in particular as a method of the said drying, A well-known apparatus can be selected suitably, For example, the method of using a belt conveyor type dryer, a shelf type dryer, etc. are mentioned.
There is no restriction | limiting in particular as conditions for the said drying, According to the objective, it can select suitably.

The shape, structure, size, weight, and hardness of the azilsartan or a salt thereof and amlodipine or a tablet containing the salt thereof are not particularly limited, and may be appropriately selected depending on the purpose.
The azilsartan or a salt thereof and amlodipine or a salt-containing compressed tablet thereof may be film-coated.
There is no restriction | limiting in particular as a method to form a film coat layer, A method well-known in a formulation field | area can be selected suitably, For example, drip type coating, pan coating, etc. are mentioned. The coating liquid used to form the film coat layer is also not particularly limited, and any coating liquid commonly used in the field of preparations can be used. For example, water-soluble polymers, plasticizers, brighteners, colorants And the like. There is no restriction | limiting in particular as thickness of the said film coat layer, According to the objective, it can select suitably.

The azilsartan or a salt thereof and amlodipine or a salt-containing wet tablet according to the present invention have excellent drug stability under various storage conditions, as shown in the test examples described later.
According to the method for producing azilsartan or a salt thereof and amlodipine or a salt thereof, or amlodipine or a salt thereof according to the present invention, azilsartan or a salt thereof excellent in the stability of the drug by a simple process Can be manufactured.

(Method for improving the stability of azilsartan or a salt thereof and amlodipine or a salt-containing compressed tablet thereof)
The method for improving the stability of azilsartan or a salt thereof and amlodipine or a salt thereof containing amlodipine according to the present invention at least includes a wet powder preparation step and a compression molding step, and further includes other steps as necessary.

Wet powder preparation process
In the wet powder preparation step, either a water in which a binder is dissolved or a water-containing organic solvent is added to a mixture containing azilsartan or a salt thereof and amlodipine or a salt thereof to obtain a wet powder. It is a process, It is the same as that of what was described above in the item of << wet powder preparation step >> of <Azilsartan or a salt thereof and amlodipine or a tablet containing amlodipine of the present invention>.

<Compression molding process>
The compression molding step is a step of compression molding the wet powder, and << compression molding step >> of <Method of manufacturing azilsartan or a salt thereof and amlodipine or a tablet containing amlodipine or a salt thereof of the present invention described above> It is the same as that described in the item.

<Other process>
The other steps are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected according to the purpose. For example, the above-mentioned <azil-sartan or a salt thereof and amlodipine or a salt thereof of the present invention The same steps as those described in the item of << Other steps >> of <Production method of contained wet tablet> and the like can be mentioned.

  According to the method for improving the stability of azilsartan or a salt thereof and amlodipine or a salt thereof containing amlodipine of the present invention, stability of both azilsartan or a salt thereof and amlodipine or a salt thereof under various storage conditions It is possible to improve the quality.

  Hereinafter, the present invention will be more specifically described based on examples, comparative examples and test examples, but the present invention is not limited to these.

Example 1
Put 264.54 g of D-mannitol (Mannitol P, manufactured by Mitsubishi Foodtech Co., Ltd.) into a high-speed stirring mixer (NMG-5 type, manufactured by Nara Machinery Co., Ltd.), and rotate the main shaft 600 rotation, granulation shaft 3,000 rotation The mixture was mixed for 3 minutes under the following conditions. Thereafter, 40 g of azilsartan (manufactured by Tokuyama Co., Ltd.) and 13.86 g of amlodipine besilate (manufactured by Kyongbo) are added, and mixed for 1 minute under the conditions of 300 rotations of the main shaft and 1,500 rotations of the granulation shaft. And amlodipine besylate was obtained.
To the mixture is added 16 g of a water-ethanol mixed solvent (mass ratio is water: ethanol = 7: 3) in which 1.6 g of polyvinyl alcohol (EG-03P, manufactured by Japan Synthetic Chemical Industry Co., Ltd.) is dissolved. The mixture was kneaded to obtain a wet powder.
The wet powder is compression molded at a pressure of 150 N using a wet powder tableting machine (EMT-18, manufactured by Eisai Co., Ltd.) and a punch and a mill with a diameter of 8.0 mm, and a belt conveyor type dryer (ETD) -18, manufactured by Eisai Co., Ltd.) at a temperature of 85 ° C. to obtain tablets.
The tablets were placed in a tray dryer at 70 ° C. and dried for 1 hour to obtain 160 mg of wet tablets per tablet.
Table 1 shows the composition of one tablet.

(Example 2)
In Example 1, the preparation amount of D-mannitol is changed from 264.54 g to 262.94 g, triethyl citrate (TEC, manufactured by Morimura Shoji Co., Ltd.) in 16 g of water-ethanol mixed solvent in which 1.6 g of polyvinyl alcohol is dissolved A wet tablet was produced in the same manner as in Example 1 except that 1.6 g of A) was added.
Table 1 shows the composition of one tablet.

(Comparative example 1)
20 g of azirsartan (manufactured by Tokuyama Co., Ltd.), 6.93 g of amlodipine besilate (manufactured by Kyongbo), 125.07 g of D-mannitol (Mannit P, manufactured by Mitsubishi Foodtech Co., Ltd.), corn starch (corn starch W, The mixture was mixed with 40 g of Nippon Corn Starch Co., Ltd.) to obtain a mixture containing azilsartan and amlodipine besylate.
A combined solution was prepared by dissolving 6 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) and 2 g of triethyl citrate (manufactured by Morimura Shoji Co., Ltd.) in 54 g of water.
Using a fluid bed granulator (MP-01, manufactured by Powrex Corp.), the mixture containing the azilsartan and amlodipine besylate was granulated while spraying the binding solution. The resulting granulated product is sized with a sieve of 850 μm mesh to obtain azilsartan and amlodipine besylate containing granules (hereinafter sometimes referred to as "azilsartan and amlodipine besylate granules"). The

200 g of the azilsartan and amlodipine besilate granules, 10.5 g of low-substituted hydroxypropyl cellulose (LH21, manufactured by Shin-Etsu Chemical Co., Ltd.), and 0.4 g of soft anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation) The mixture was mixed with 1.05 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) to obtain granules for tableting.
The granules for tableting described above were each 211.95 mg (20 mg of azilsartan, amlodipine besilate) per tablet using a rotary tableting machine (manufactured by Kikusui Mfg. Co., Ltd.) and using a scissors having a diameter of 8.0 mm. A tablet of 6.93 mg is obtained.
Table 2 shows the composition of one tablet.

(Comparative example 2)
Azirsartan was prepared by mixing 100 g of azirsartan (manufactured by Tokuyama Co., Ltd.), 280 g of D-mannitol (Mannit P, manufactured by Mitsubishi Foodtech Co., Ltd.), and 100 g of corn starch (corn starch W, manufactured by Japan corn starch Co., Ltd.). The resulting mixture was obtained.
A combined solution of 15 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) and 5 g of triethyl citrate (manufactured by Morimura Shoji Co., Ltd.) dissolved in 135 g of water was prepared.
Using a fluid bed granulator (MP-01, manufactured by Powrex Corp.), the mixture containing the azilsartan was granulated while spraying the binding solution. The obtained granulated product was sized with a sieve having an opening of 850 μm to obtain an azilsartan-containing granulated product (hereinafter sometimes referred to as “azirsartan granules”).

Amlodipine was mixed with 34.65 g of amlodipine besilate (manufactured by Kyongbo), 350.35 g of mannitol (Mannit P, manufactured by Mitsubishi Foodtech Co., Ltd.) and 100 g of corn starch (corn starch W, manufactured by Japan Corn Starch Co., Ltd.) A mixture containing besylate was obtained.
A binding solution was prepared by dissolving 15 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in 135 g of water.
Using a fluid bed granulator (MP-01, manufactured by Powrex Co., Ltd.), the mixture containing the amlodipine besylate was granulated while spraying the binding solution. The obtained granulated product was sized with a sieve of 850 μm mesh to obtain amlodipine besylate containing granules (hereinafter sometimes referred to as "amlodipine besylate granules").

100 g of the azilsartan granules and 100 g of the amlodipine besilate granules are mixed, and further, 10.5 g of low substituted hydroxypropyl cellulose (LH21, manufactured by Shin-Etsu Chemical Co., Ltd.) and soft anhydrous silicic acid (Adsolider 101, 0.4 g of Freund Sangyo Co., Ltd. and 2.1 g of magnesium stearate (Taipei Kagaku Sangyo Co., Ltd.) were mixed to obtain granules for tableting.
The granules for tableting using a rotary tableting machine (Kikusui Mfg. Co., Ltd.) and using a pestle of diameter 8.0 mm, 213 mg per tablet (20 mg of azilsartan, 6.93 mg of amlodipine besilate) ) Tablets were obtained.
Table 3 shows the composition of one tablet.

(Comparative example 3)
In addition to azilsartan granules, amlodipine besilate granules, low substituted hydroxypropyl cellulose, light anhydrous silicic acid, magnesium stearate, crystalline cellulose (Seoras UF-711, in the preparation of tablets for tableting of Comparative Example 2). 235 mg per tablet (20 mg of azilsartan, amlodipine besilate) in the same manner as in Comparative Example 2 except that 20 g of Asahi Kasei Chemical Co., Ltd.) and 2 g of a ferric oxide / D-mannitol mixture dispersed 100 times were added. The tablet contained 6.93 mg.
Table 3 shows the composition of one tablet.

(Test Example 1: Stability Test)
After storing the tablets obtained in Examples 1 and 2 and Comparative Examples 1 to 3 for 2 weeks under the following storage conditions, the total amount of relatives of amlodipine and the total amount of relatives of azilsartan are subjected to ultra high performance liquid chromatography. Or it measured using high performance liquid chromatography.
In addition, as a reference, commercially available ZA-CLASS combination tablet HD (manufactured by Takeda Pharmaceutical Co., Ltd.) was also tested in the same manner.

<Storage condition>
4 ° C (sealed) (hereinafter sometimes referred to as "4 ° Csealed")
-40 ° C, relative humidity 75% (sealed) (hereinafter sometimes referred to as "40 ° C. 75% sealed")
-40 ° C, relative humidity 75% (open) (hereinafter, may be referred to as "40 ° C. 75% open")
50 ° C., relative humidity 90% (open) (hereinafter sometimes referred to as “50 ° C. 90% open”)
60 ° C. (open) (hereinafter sometimes referred to as “60 ° C. open”)
※ Although the humidity conditions were not stated, the humidity was assumed to be negative.

<Measurement of total mass of amlodipine>
The amount of total analogues of amlodipine in each tablet was determined using ultra-performance liquid chromatography for Examples 1-2 and the commercially available tablets and using high-performance liquid chromatography for the tablets of Comparative Examples 1-3. The measurement principle of ultra high performance liquid chromatography and high performance liquid chromatography is the same although the speed of analysis time is different, the same result is obtained for both, and the results can be compared.

-Preparation of sample solution-
One tablet was placed in a 20 mL volumetric flask, and 4 mL of water was added to disintegrate the tablet. An appropriate amount of methanol was added and shaken with a shaker for 20 minutes. Further methanol was added to make 20 mL.
The resulting solution was filtered with a 0.2 μm membrane filter to obtain a sample solution.

--High performance liquid chromatography conditions--
Ultra High Performance Liquid Chromatography System: Chromaster UP (ChromasterUltra Rs2)
Detection wavelength: UV 241 nm
Column: ACQUITY UPLC BEH C18 1.7μm 2.1mm × 50mm (2012-27)
Column temperature: Constant temperature around 40 ° C Flow rate: Adjust the amlodipine retention time to be about 4.4 minutes Mobile phase A: Acetonitrile: water: 70% HClO ₄ = 100: 900: 1 (volume ratio) mixture Mobile phase B: A mixture of acetonitrile: water: 70% HClO ₄ = 900: 100: 1 (volume ratio) Injection volume: 1.0 μL
Analysis time: 14 minutes Gradient program: described in Table 4-1 below

--High performance liquid chromatography conditions--
High-performance liquid chromatography system: Chromaster (made by Hitachi High-Technologies Corporation)
Detection wavelength: UV 241 nm
Column: Inertsil ODS-2 5μm 4.6mm × 150mm
Column temperature: Constant temperature around 40 ° C Flow rate: Adjust so that the retention time of amlodipine is 12 minutes Mobile phase A: Acetonitrile: Water: Mixed solution of 100% HClO ₄ = 100: 900: 1 (volume ratio) Mobile phase B Acetonitrile: water: 100% HClO ₄ = 900: 100: 1 (volume ratio) mixture Injection volume: 10 μL
Analysis time: 45 minutes Gradient program: described in Table 4-2 below

The amount of total related substances of amlodipine (%) was a ratio of the total of the peak areas other than azilsartan and amlodipine to the peak area derived from the amlodipine besylate base material.
The difference between the amount (%) of the total relatives of amlodipine in each sample and the amount (%) of the total relatives of amlodipine in the sample stored at 4 ° C (sealed) conditions (hereinafter referred to as "increased amount") Is shown in Table 6.

<Measurement of total amount of related substances of azilsartan>
Using ultra-performance liquid chromatography, measurement of the total relative amount of azilsartan in Examples 1-2, commercial tablets, and tablets of Comparative Examples 1-3 was performed.

-Preparation of sample solution-
One tablet was placed in a 20 mL volumetric flask, and 4 mL of water was added to disintegrate the tablet. An appropriate amount of methanol was added and shaken with a shaker for 20 minutes. Further methanol was added to make 20 mL.
The resulting solution was filtered with a 0.2 μm membrane filter to obtain a sample solution.

-Ultra high performance liquid chromatography conditions-
Ultra High Performance Liquid Chromatography System: ChromasterUltra Rs (made by Hitachi High-Technologies Corporation)
Detection wavelength: UV 250 nm
Column: ACQUITY UPLC BEH C18 1.7 μm, 2.1 × 100 mm
Column temperature: Constant temperature around 25 ° C Flow rate: Adjust the retention time of azirsartan to be about 4.7 minutes Mobile phase A: Mixed solution of phosphate buffer: acetonitrile = 65: 35 (volume ratio) Mobile phase B: Mixture of phosphate buffer: acetonitrile = 30: 70 (volume ratio) The above-mentioned phosphate buffer was prepared by adjusting a 10 mM potassium dihydrogen phosphate solution to pH 3.0 with phosphoric acid.
Injection volume: 0.8 μL
Analysis time: 25 minutes Gradient program: described in Table 5 below

The amount (%) of the total related substance of azilsartan was a ratio of the total of the peak areas other than azilsartan and amlodipine besylate to the peak area derived from azilsartan drug substance.
The difference between the amount (%) of the total related substance of azilsartan in each sample and the amount (%) of the total related substance of azilsartan in the sample stored at 4 ° C (sealed) condition (hereinafter referred to as "increased amount" Is shown in Table 6.

  From the results of Table 6, the wet tablets produced in Examples 1 and 2 are smaller in the amount of the similar substance of both drugs and are more stable than the tablets of Comparative Examples 1 to 3 which are not wet tablets and commercially available tablets. Was confirmed to be high. Therefore, it was shown that the tablet of the present invention can improve the stability of both drugs under various storage conditions.

(Example 3)
Put D-mannitol (Pearitol 50C, manufactured by Rocket Japan Co., Ltd.) 803.67 g into a high-speed stirring mixer (NMG-5 type, manufactured by Nara Machinery Co., Ltd.), and make the condition of main shaft 600 rotation, granulation shaft 3,000 rotation And mixed for 3 minutes. Thereafter, 120 g of azilsartan (manufactured by Tokuyama Co., Ltd.), 41.58 g of amlodipine besilate (manufactured by MOEHS) and 19.8 g of aspartame (Ajinomoto Healthy Supply Co., Ltd.) are added, and the spindle 300 rotation, granulation axis 1, It mixed for 2 minutes on conditions of 500 rotation, and obtained the mixture containing azilsartan and amlodipine besylate.
To the mixture is added 49.5 g of a water-ethanol mixed solvent (mass ratio is water: ethanol = 9: 1) in which 4.95 g of polyvinyl alcohol (EG-03P, manufactured by Japan Synthetic Chemical Industry Co., Ltd.) is dissolved. The mixture was kneaded for 2 minutes to obtain a wet powder. The wet powder was mixed in two batches to obtain a wet powder for tableting.
The wet powder is compression molded at a pressure of 150 N using a wet powder tableting machine (EMT-18, manufactured by Eisai Co., Ltd.) and a punch and a mill with a diameter of 8.0 mm, and a belt conveyor type dryer (ETD) -18, manufactured by Eisai Co., Ltd.) at a temperature of 85 ° C. to obtain 165 mg wet tablets per tablet.
Table 7 shows the composition of one tablet.

(Example 4)
After dissolving 5.25 g of polyvinyl alcohol (EG-03P, manufactured by Japan Synthetic Chemical Industry Co., Ltd.) and 3.57 g of dextrin (manufactured by Japan Pharmacopoeia dextrin, manufactured by Nichire Kagaku Co., Ltd.) in 189 g of water, corn starch (day Food Bureau Corn starch, manufactured by Nippon Foods Co., Ltd. 3.57 g, titanium oxide (titanium oxide A-HR, manufactured by Freund Industrial Co., Ltd.) 6.09 g, talc (Talkan Hayashi manufactured by Hayashi Kasei Co., Ltd.) 2.1 g And 0.42 g of yellow ferric oxide were dispersed to prepare a coating solution.
About 100 g of the tablet of Example 3 is put into a pan coating machine (HC-LABO, manufactured by Freund Corporation), and the mass per tablet increases by 5 mg at an air supply temperature of 70 ° C. and a pan rotation of 30 rpm. The coating solution was coated to obtain coated tablets.
Table 7 shows the composition of one tablet.

(Test Example 2: Stability Test)
About the tablet obtained in the said Examples 3-4, stability test was done like the said Experiment 1 except having changed storage conditions into the following storage conditions. The results are shown in Table 8.
<Storage condition>
4 ° C (sealed) (hereinafter sometimes referred to as "4 ° Csealed")
-40 ° C, relative humidity 75% (sealed) (hereinafter sometimes referred to as "40 ° C. 75% sealed")
-40 ° C, relative humidity 75% (open) (hereinafter, may be referred to as "40 ° C. 75% open")
60 ° C., relative humidity 75% (open) (hereinafter sometimes referred to as “60 ° C. 75% open”)
60 ° C. (open) (hereinafter sometimes referred to as “60 ° C. open”)
※ Although the humidity conditions were not stated, the humidity was assumed to be negative.

  From the results shown in Table 8, it was confirmed that the tablets produced in Examples 3 to 4 also had small amounts of the related substances of both drugs and high stability.

(Example 5)
Put 402.825 g of D-mannitol (Pearitol 50C, Rocket Japan Co., Ltd.) into a high-speed stirring mixer (NMG-5 type, manufactured by Nara Machinery Co., Ltd.), and make the spindle 600 rotation and granulation shaft 3,000 rotation Mix for 3 minutes. Thereafter, 60 g of azilsartan (manufactured by Tokuyama Co., Ltd.), 20.79 g of amlodipine besilate (manufactured by Kyongbo) and 9.9 g of aspartame (Ajinomoto Healthy Supply Co., Ltd.) are added, and the main shaft 300 rotation, granulation axis 1, It mixed for 2 minutes on conditions of 500 rotation, and obtained the mixture containing azilsartan and amlodipine besylate.
To the mixture was added 34.65 g of water in which 1.485 g of polyvinyl alcohol (EG-03P, manufactured by Japan Synthetic Chemical Industry Co., Ltd.) was dissolved, and the mixture was kneaded for 2 minutes to obtain a wet powder.
The wet powder is compression molded at a pressure of 150 N using a wet powder tableting machine (EMT-18, manufactured by Eisai Co., Ltd.) and a punch and a mill with a diameter of 8.0 mm, and a belt conveyor type dryer (ETD) -18, manufactured by Eisai Co., Ltd.) at a temperature of 85 ° C. to obtain 165 mg wet tablets per tablet.
Table 9 shows the composition of one tablet.

(Test Example 3: Stability Test)
The stability test was conducted on the tablet obtained in Example 5 in the same manner as in Test Example 2 above. The results are shown in Table 10.

From the results of Table 10, it was confirmed that the moist tablets produced in Example 5 also had small amounts of the related substances of both drugs and high stability.

Claims (6)

  Azilsartan or a salt thereof, and amlodipine or a salt-containing tablet comprising the amlodipine or salt thereof, comprising azirsartan or a salt thereof, and amlodipine or a salt thereof.   The tablet containing azilsartan or a salt thereof and amlodipine or a salt thereof according to claim 1, further comprising triethyl citrate. Adding a binder-dissolved water or a water-containing organic solvent to a mixture containing azirsartan or a salt thereof and amlodipine or a salt thereof and kneading to obtain a wet powder;
And a step of compacting the wet powder, thereby producing azilsartan or a salt thereof and amlodipine or a salt-containing tablet comprising the salt.   The method for producing azilsartan or a salt thereof and amlodipine or a salt-containing tablet according to claim 3, wherein the wet powder contains triethyl citrate. Adding a binder-dissolved water or a water-containing organic solvent to a mixture containing azirsartan or a salt thereof and amlodipine or a salt thereof and kneading to obtain a wet powder;
And a step of compacting the wet powder, wherein the method for improving the stability of azilsartan or a salt thereof and amlodipine or a tablet containing the salt thereof.   The method for improving the stability of azilsartan or a salt thereof and amlodipine or a salt-containing wet tablet according to claim 5, wherein the wet powder contains triethyl citrate.