JP7101464B2 - A method for improving the quality of azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof, and azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof and a method for producing the same. - Google Patents

Description

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

Azil sartane (chemical name: chemical name: 2-Ethoxy-1-{[2'-(5-oxo-4, 5-dihydro-1, 2, 4-oxodiazol-3-yl) biphenyl-4-yl] methyl } -1H-benzo [d] imidazole-7-carboxylic acid, structural formula: the following structural formula (1)) and amlogipin besilate (chemical name: 3-Ethyl 5-methyl (4RS) -2-[(2-). aminoethoxy) methyl] -4- (2-chromopheneyl) -6-methyl-1,4-dihydropylidine-3,5-dicarboxylate monobenenesulfonate, structural formula: the following structural formula (2)) is useful as a therapeutic agent for hypertension. It is reported that these mixtures are also manufactured and sold.

In addition, as a technique for appropriately controlling the elution of a specific drug and a calcium antagonist from a pharmaceutical product in the gastrointestinal tract, a step of preparing a granule containing the specific drug and a granule containing the calcium antagonist. A method for producing a solid pharmaceutical product including a step of preparing the above-mentioned granulated product and a step of compression-molding each of the granulated products has been proposed (see, for example, Patent Document 1).

However, tablets containing azilsartan or a salt thereof and amlodipine or a salt thereof are required to further improve the stability of the drug and improve the quality such as suppressing the decrease in the hardness of the tablet over time. The current situation.

Therefore, there is a strong demand for the prompt provision of a technique capable of both improving the stability of a drug and suppressing the decrease in hardness of a tablet.

International Publication No. 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 improves the quality of azyl sartane or a salt thereof and amlogipine or a salt-containing tablet thereof, which can both improve the stability of the drug and suppress the decrease in hardness of the tablet, and the stability of the drug. Moreover, it is an object of the present invention to provide azil sartane or a salt thereof and amlogipin or a salt-containing tablet thereof and a method for producing the same, in which the decrease in hardness is suppressed.

As a result of diligent studies to solve the above problems, the present inventors prepared azilsartan or a salt thereof and amlogipine or a salt thereof as different granulations, and replaced these granulations with low substitution. It was found that by compression molding together with hydroxypropyl cellulose, it is possible to improve the stability of the drug over time and suppress the decrease in the hardness of the tablet at the same time.

The present invention is based on the above-mentioned findings of the present inventors, and the means for solving the above-mentioned problems are as follows. That is,
<1> A method for improving the quality of azilsartan or a salt thereof and amlodipine or a tablet containing a salt thereof.
A step of granulating a composition containing azilsartan or a salt thereof to prepare an azilsartan or a salt-containing granulated product thereof.
A step of granulating a composition containing amlodipine or a salt thereof to prepare an amlodipine or a salt-containing granulated product thereof.
A step of compression molding a mixture containing the azilsartan or a salt-containing granulation thereof, the amlodipine or a salt-containing granulation thereof, and a low-degree-of-substitution hydroxypropyl cellulose.
The quality improvement is a method characterized by improving the stability of the drug and suppressing the decrease in hardness of the tablet.
<2> The method according to <1>, wherein the improvement in quality further comprises suppressing discoloration of the tablet.
<3> Azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof, which comprises azilsartan or a salt-containing granulation product thereof, amlodipine or a salt-containing granulation product thereof, and a low-substituted hydroxypropylcellulose. Is.
<4> A step of granulating a composition containing azilsartan or a salt thereof to prepare an azilsartan or a salt-containing granulated product thereof.
A step of granulating a composition containing amlodipine or a salt thereof to prepare an amlodipine or a salt-containing granulated product thereof.
Azilsartan or azilsartan thereof, which comprises a step of compression molding a mixture containing the azilsartan or a salt-containing granule thereof, the amlodipine or a salt-containing granule thereof, and a low-substituted hydroxypropylcellulose. A method for producing salt and amlodipine or a salt-containing tablet thereof.

According to the present invention, azilsartan or a salt thereof and amlodipine, which can solve the above-mentioned problems in the past, can achieve the above-mentioned object, and can achieve both improvement of drug stability and suppression of tablet hardness decrease. Alternatively, it is possible to provide a method for improving the quality of the salt-containing tablet thereof, and azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof and a method for producing the azilsartan or a salt thereof, in which the stability of the drug is improved and the decrease in hardness is suppressed.

(Quality improvement method)
The quality improving method of the present invention is a method for improving the quality of azil sartane or a salt thereof and amlogipin or a salt-containing tablet thereof, and is a step of preparing azil sartane or a salt-containing granule thereof and preparation of amlodipine or a salt-containing granule thereof. It includes at least a step and a compression molding step, and further includes other steps as needed.
The improvement in quality includes at least improvement in drug stability and suppression of tablet hardness reduction, and preferably includes suppression of tablet discoloration.

<Azilsartan or its salt-containing granulated product preparation process>
The step of preparing azilsartan or a salt-containing granulated product thereof is a step of granulating a composition containing azilsartan or a salt thereof to prepare azilsartan or a salt-containing granulated product thereof.

-Composition containing azilsartan or a salt thereof-
The composition containing azilsartan or a salt thereof contains at least azilsartan 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-). oxadiazole-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 intended purpose. Examples thereof include azilsartan medoxomil.

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

The content of the azilsartan or a salt thereof in the composition containing the azilsartan or a salt thereof is not particularly limited and may be appropriately selected depending on the desired content in the tablet, for example, from 10% by mass to 40% by mass and the like can be mentioned.

－－Other ingredients －－
The other components in the composition containing azilsartan or a salt thereof are not particularly limited as long as the effects of the present invention are not impaired. The same as those described in the item of. These may be used alone or in combination of two or more.
As the other components in the composition containing the azilsartan or a salt thereof, those produced by a known method may be used, or commercially available products may be used.
The content of other components in the composition containing the azilsartan or a salt thereof is not particularly limited and may be appropriately selected depending on the intended purpose.

The composition containing the azilsartan or a salt thereof can contain, for example, mannitol and corn starch as the other components.

The method for preparing the composition containing the azilsartan or a salt thereof is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the azilsartan or a salt thereof and the other components as needed. Can be prepared by mixing with.
The mixing method and conditions are not particularly limited and may be appropriately selected depending on the intended purpose.

-Granulation-
The granulation method is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a wet granulation method.
The method of the wet granulation method is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method, a spray granulation method and the like can be used. Can be mentioned. Among these, the stirring granulation method and the fluidized bed granulation method are preferable, and the fluidized bed granulation method is more preferable.
The granulation conditions are not particularly limited and may be appropriately selected depending on the intended purpose.

For example, in the case of the fluidized bed granulation method, the stability of azilsartan or a salt thereof can be improved by using a binder in which hydroxypropyl cellulose and triethyl citrate are dissolved in water. In that respect, it is preferable. The amount of hydroxypropyl cellulose and the amount of triethyl citrate in the binding liquid are not particularly limited and may be appropriately selected depending on the intended purpose.

<Amlodipine or its salt-containing granulated product preparation process>
The step of preparing amlodipine or a salt-containing granulated product thereof is a step of granulating a composition containing amlodipine or a salt thereof to prepare amlodipine or a salt-containing granulated product thereof.

-Composition containing amlodipine or a salt thereof-
The composition containing amlodipine or a salt thereof contains at least amlodipine or a salt thereof, and further contains other components as necessary.

--Amlodipine or its salt ---
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-chloropheneyl)-. 6-methyl-1,4-dihydropyridine-3,5-dicarboxylate).

The salt of amlodipine is not particularly limited as long as it is a pharmacologically acceptable salt, and can be appropriately selected depending on the intended purpose. For example, amlodipine besylate (benzenesulfonate), amlodipine maleate, and the like. Examples include amlodipine mesylate.

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

The content of the amlodipine or a salt thereof in the composition containing the amlodipine or a salt thereof is not particularly limited and may be appropriately selected depending on the desired content in the tablet, for example, 1% by mass to 10% by mass. % And so on.

－－Other ingredients －－
The other components in the composition containing amlodipine or a salt thereof are not particularly limited as long as the effects of the present invention are not impaired. The same as those described in the item can be mentioned.
As the other components in the composition containing amlodipine or a salt thereof, those produced by a known method may be used, or commercially available products may be used.
The content of other components in the composition containing amlodipine or a salt thereof is not particularly limited and may be appropriately selected depending on the intended purpose.

The composition containing amlodipine besilate can contain, for example, mannitol and corn starch as the other components.

The method for preparing the composition containing the amlodipine or a salt thereof is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the amlodipine or a salt thereof and the other components thereof may be used. It can be prepared by mixing.
The mixing method and conditions are not particularly limited and may be appropriately selected depending on the intended purpose.

-Granulation-
The granulation method and conditions are not particularly limited and may be appropriately selected depending on the intended purpose. For example, the above-mentioned <Azilsartan or salt-containing granulated product preparation step> -granulation- item. The same as those described in.

For example, in the case of the fluidized bed granulation method, a solution in which hypromellose is dissolved in water can be used as the binding liquid.

<Compression molding process>
The compression molding step is a step of compression molding a mixture containing the azilsartan or a salt-containing granule thereof, the amlodipine or a salt-containing granule thereof, and a low-substituted hydroxypropyl cellulose.

-blend-
The mixture contains at least the azilsartan or a salt-containing granulation thereof, the amlodipine or a salt-containing granulation thereof, and the low-degree-of-substitution hydroxypropyl cellulose, and further contains other components as necessary.

--Azilsartan or its salt-containing granules ---
The content of the azilsartan or a salt-containing granulated product thereof in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include 30% by mass to 70% by mass.

--Amlodipine or its salt-containing granules ---
The content of the amlodipine or a salt-containing granulated product thereof in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include 30% by mass to 70% by mass.

--Low degree of substitution hydroxypropyl cellulose ---
As the low-degree-of-substitution hydroxypropyl cellulose, those produced by a known method may be used, or commercially available products may be used.

The content of the low-substitution hydroxypropyl cellulose in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 1% by mass to 15% by mass. If the content of the low-degree-of-substitution hydroxypropyl cellulose is less than 1% by mass, it may not be possible to sufficiently suppress the decrease in the hardness of the tablet. On the other hand, when the content of the low-degree-of-substitution hydroxypropyl cellulose is within the above-mentioned preferable range, it is advantageous in terms of suppressing a decrease in the hardness of the tablet and suppressing discoloration of the tablet.

－－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 usually used in the pharmaceutical field can be appropriately selected depending on the intended purpose, for example, sugars and binders. , Stabilizers, lubricants, disintegrants, fluidizers, flavoring agents, fragrances and the like. These may be used alone or in combination of two or more.
As the other components in the mixture, those produced by a known method may be used, or commercially available products may be used.
The content of the other components in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.

－－－ Sugars －－－
The saccharide is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include lactose, mannitol, xylitol and sorbitol. These may be used alone or in combination of two or more.
The content of saccharides in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.

--- Binder ---
The binder is not particularly limited and may be appropriately selected depending on the intended purpose. For example, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose , Hydroxypropylmethylcellulose, sodium starchglycolate, hydroxyethylcellulose and the like. These may be used alone or in combination of two or more.
The content of the binder in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.

--- Stabilizer ---
The stabilizer is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include triethyl citrate, glycerin, polysorbate and sucrose fatty acid ester. These may be used alone or in combination of two or more. Among these, triethyl citrate is preferable because it can further improve the stability of azilsartan or a salt thereof over time.
The content of the stabilizer in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.

---lubricant---
The lubricant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include magnesium stearate, calcium stearate, and sodium stearyl fumarate. These may be used alone or in combination of two or more.
The content of the lubricant in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.

--- Disintegrant ---
The disintegrant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, low-substituted hydroxypropyl cellulose, starch (corn starch, etc.), crystalline cellulose, carmellose calcium, sodium starch glycolate, etc. , Crospovidone, croscarmellose calcium and the like. These may be used alone or in combination of two or more, but low-degree-of-substitution hydroxypropyl cellulose is preferable in terms of suppressing a decrease in tablet hardness and suppressing discoloration of tablets.
The content of the disintegrant in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.

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

－－－ Flavoring agent －－－
The flavoring agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sucralose, aspartame, acesulfame potassium and thaumatin. These may be used alone or in combination of two or more.
The content of the flavoring agent in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.

－－－ Fragrance －－－
The fragrance is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include l-menthol, vanillin and orange oil. These may be used alone or in combination of two or more.
The content of the fragrance in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.

The mixture may contain, for example, a suitable fluidizing agent, lubricant and the like as the other components.

The method for preparing the mixture is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the azilsartan or a salt-containing granule thereof is mixed with the amlodipine or a salt-containing granule thereof. Then, if necessary, it can be prepared by mixing with the other components.
The mixing method and conditions are not particularly limited and may be appropriately selected depending on the intended purpose.

-Compression molding-
The compression molding method is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a method of locking the mixture.
The method of locking is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a method using a rotary locking machine.
The conditions for locking are not particularly limited and may be appropriately selected depending on the intended purpose.

<Other processes>
The other steps are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. For example, a step of sizing the azilsartan or a salt-containing granulated product thereof. Examples thereof include a step of sizing the amlodipine or a salt-containing granulated product thereof.
The sizing method is not particularly limited and may be appropriately selected depending on the intended purpose.

(Azilsartan or its salt and amlodipine or its salt-containing tablet and its manufacturing method)
The azilsartan or a salt thereof and amlogipine or a salt-containing tablet thereof of the present invention contain at least azilsartan or a salt-containing granule thereof, azilsartan or a salt-containing granule thereof, and a low-substituted hydroxypropylcellulose, and are required. It also contains other ingredients depending on the condition.
The method for producing the azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof is not particularly limited and may be appropriately selected depending on the intended purpose, but contains azilsartan or a salt thereof and amlodipine or a salt thereof of the present invention. It can be suitably produced by the method for producing tablets.
Hereinafter, along with the description of the method for producing azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof of the present invention, azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof of the present invention will also be described.

<Method for producing azilsartan or its salt and amlodipine or its salt-containing tablets>
The method for producing azilsartan or a salt thereof and amlogipin or a salt-containing tablet thereof according to the present invention comprises a step of preparing azilsartan or a salt-containing granule thereof, a step of preparing azilsartan or a salt-containing granule thereof, and a compression molding step. At least includes, and if necessary, further includes other steps.

<< Azilsartan or its salt-containing granulated product preparation step >>
The step of preparing azilsartan or a salt-containing granule thereof is a step of granulating a composition containing azilsartan or a salt thereof to prepare azilsartan or a salt-containing granule thereof, and is described above (method for improving quality). ), The same as that described in the item of <Azilsartan or its salt-containing granulated product preparation step>.

<< Amlodipine or its salt-containing granulated product preparation process >>
The step of preparing an amlogipin or a salt-containing granulated product thereof is a step of granulating a composition containing amlogipin or a salt thereof to prepare an amlogipin or a salt-containing granulated product thereof, and is a step of preparing the above-mentioned (quality improvement method). It is the same as that described in the item of "Step of preparing granulated product containing amlogipin or its salt".

<< Compression molding process >>
The compression molding step is a step of compression molding a mixture containing the azilsartan or a salt-containing granule thereof, the amlogipine or a salt-containing granule thereof, and a low-substituted hydroxypropylcellulose. It is the same as that described in the item of <Compression molding process> of (Quality improvement method).

<< Other processes >>
The other steps are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. Examples thereof include the same steps as described.

According to the method for producing azilsartan or a salt thereof and amlogipine or a salt-containing tablet thereof of the present invention, it is possible to efficiently produce a tablet in which both improvement in drug stability and suppression of tablet hardness decrease are achieved.

<Azilsartan or its salt and amlodipine or its salt-containing tablets>
Since the azil sartane or a salt thereof and the amlogipin or a salt-containing tablet thereof of the present invention contain azil sartane or a salt-containing granule thereof, an amlogipine or a salt-containing granule thereof, and a low-substituted hydroxypropyl cellulose, a drug. It is possible to improve the stability of the tablet and suppress the decrease in the hardness of the tablet at the same time, and further, it is possible to suppress the discoloration of the tablet.

The embodiment of the azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof is not particularly limited and may be appropriately selected depending on the intended purpose. For example, uncoated tablets, chewable tablets, film-coated tablets, orally disintegrating tablets. And so on.

The shape, structure, size, weight, and hardness of the azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof are not particularly limited and may be appropriately selected depending on the intended purpose.

Hereinafter, the present invention will be described in more detail based on Test Examples and Reference Examples, but the present invention is not limited to these Test Examples and Reference Examples.

(Test Example 1)
<Manufacturing of Tablet 1-1>
<< Azilsartan-containing granulated product preparation process >>
Azilsartan (manufactured by Tokuyama Co., Ltd.) 40 g, mannitol (mannit P, manufactured by Mitsubishi Food Tech Co., Ltd.) 112 g, and corn starch (cornstarch W, manufactured by Japan Corn Starch Co., Ltd.) 40 g are mixed, and a mixture containing azilsartan. Got
A binding 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 Brothers Co., Ltd.) in 54 g of water.
Using a fluidized bed granulator (MP-01, manufactured by Paulek Co., Ltd.), the mixture containing azilsartan was granulated while spraying the binding liquid. The obtained granulated product was sized with a sieve having an opening of 850 μm to obtain an azilsartan-containing granule (hereinafter, may be referred to as “azilsartan granule”).

<< Amlodipine besilate-containing granule preparation process >>
Amlogipin besilate (manufactured by Kyongbo) 13.86 g, mannitol (mannit P, manufactured by Mitsubishi Food Tech Co., Ltd.) 140.14 g, and corn starch (cornstarch W, manufactured by Japan Corn Starch Co., Ltd.) 40 g are mixed and amlogipin. A mixture containing besilate was obtained.
A binding solution was prepared by dissolving 6 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in 54 g of water.
Using a fluidized bed granulator (MP-01, manufactured by Paulek Co., Ltd.), the mixture containing the amlodipine besylate was granulated while spraying the binding liquid. The obtained granulated product was sized with a sieve having an opening of 850 μm to obtain an amlodipine besylate-containing granule (hereinafter, may be referred to as “amlodipine besilate granule”).

<< Compression molding process >>
200 g of the azil sultan granules and 200 g of the amlogipine besilate granules are mixed, and 21 g of low-substituted hydroxypropyl cellulose (LH21, manufactured by Shin-Etsu Chemical Industry Co., Ltd.) and soft anhydrous silicic acid (Adsolider 101, Freund Sangyo Co., Ltd.) are further mixed. 0.8 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) and 2.1 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) were mixed to obtain granules for tableting.
The granules for tableting were prepared using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) using a pestle with a diameter of 8.0 mm, and 211.95 mg (20 mg of azilsartan, 6 amlodipine besylate) per tablet. A tablet containing .93 mg was obtained. Table 1-1 shows the composition in one tablet.

<Manufacturing of tablets 1-2>
<< Granulation preparation process >>
Azilsartan (manufactured by Tokuyama Co., Ltd.) 20 g, amlodipine besilate (manufactured by Kyongbo) 6.93 g, mannitol (mannit P, manufactured by Mitsubishi Food Tech Co., Ltd.) 81.55 g, and corn starch (corn starch W, Japan Corn Starch) (Manufactured by Co., Ltd.) 32 g was mixed to obtain a mixture containing azilsartan and amlodipine besilate.
A binding solution was prepared by dissolving 8 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) and 1.6 g of triethyl citrate (manufactured by Morimura Brothers Co., Ltd.) in 72 g of water.
Using a fluidized bed granulator (MP-01, manufactured by Paulek Co., Ltd.), the mixture containing azilsartan and amlodipine besilate was granulated while spraying the binding liquid. The obtained granulated product is sized with a sieve having an opening of 850 μm to obtain azilsartan and amlodipine besilate-containing granules (hereinafter, may be referred to as “azilsartan and amlodipine besilate granules”). rice field.

<< Compression molding process >>
Azil sartane and amlogipin besilate granules 150.08 g, low-substituted hydroxypropyl cellulose (LH21, manufactured by Shin-Etsu Chemical Industry Co., Ltd.) 8 g, and soft anhydrous silicic acid (Adslider 101, manufactured by Freund Sangyo Co., Ltd.) 0.32 g. And 1.6 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) were mixed to prepare granules for tableting.
Using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.), the granules for tableting are 160 mg per tablet (20 mg of azilsartan, 6.93 mg of amlodipine besilate) using a pestle with a diameter of 8.0 mm. Included.) Was obtained. Table 1-2 shows the composition in one tablet.

<Manufacturing of tablets 1-3>
<< Azilsartan-containing granulated product preparation process >>
Azilsartan (manufactured by Tokuyama Co., Ltd.) 20 g, mannitol (mannit P, manufactured by Mitsubishi Food Tech Co., Ltd.) 81.55 g, and corn starch (cornstarch W, manufactured by Japan Corn Starch Co., Ltd.) 32 g are mixed to obtain azilsartan. A mixture containing was obtained.
A binding solution was prepared by dissolving 8 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) and 1.6 g of triethyl citrate (manufactured by Morimura Brothers Co., Ltd.) in 72 g of water.
Using a fluidized bed granulator (MP-01, manufactured by Paulek Co., Ltd.), the mixture containing azilsartan was granulated while spraying the binding liquid. The obtained granulated product was sized with a sieve having an opening of 850 μm to obtain an azilsartan-containing granule (hereinafter, may be referred to as “azilsartan granule”).

<< Compression molding process >>
The azil sultan granules 143.15 g, low-substituted hydroxypropyl cellulose (LH21, manufactured by Shin-Etsu Chemical Industry Co., Ltd.) 8 g, amlogipine besilate (Kyongbo) 6.93 g, and soft anhydrous silicic acid (addorider 101, Freund). 0.32 g (manufactured by Sangyo Co., Ltd.) and 1.6 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) were mixed to obtain granules for tableting.
Using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.), the granules for tableting are 160 mg per tablet (20 mg of azilsartan, 6.93 mg of amlodipine besilate) using a pestle with a diameter of 8.0 mm. Included.) Was obtained. Table 1-3 shows the composition in one tablet.

<Stability test>
After storing the tablets 1-1 to 1-3 under the following storage conditions for 2 weeks, the total amount of related substances of azil sartane and the total amount of related substances of amlogipin besilate were measured by ultra-high performance liquid chromatography (HPLC). Was measured.

-Preservation conditions-
・ 4 ℃ (sealed)
・ 40 ° C, relative humidity 75% (sealed)
・ 40 ° C, relative humidity 75% (open)
・ 50 ° C, relative humidity 90% (open)
・ 60 ° C (open)
* Humidity conditions are not stated, but the humidity is assumed to be Nariyuki.

-Measurement of total amount of substances related to azilsartan-
--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 the mixture was shaken with a shaker for 20 minutes. Further methanol was added to make 20 mL.
The obtained solution was filtered through a 0.2 μm membrane filter to obtain a sample solution.

--HPLC conditions ---
HPLC system: Chromaster Ultra Rs (manufactured 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: Adjusted so that the retention time of azyl sartane is about 4.7 minutes Mobile phase A: Phosphate buffer: acetonitrile = 65:35 (volume ratio) mixed solution Mobile phase B: Phosphoric acid buffer: acetonitrile = 30:70 (volume ratio) mixed solution The above phosphoric acid buffer is a 10 mM potassium dihydrogen phosphate solution adjusted to pH 3.0 with phosphoric acid.
Injection volume: 0.8 μL
Analysis time: 25 minutes Radiant program: Listed in Table 1-4 below

The amount (%) of the total related substances of azilsartan was the ratio of the peak area other than azilsartan and amlodipine besilate to the peak area derived from the azilsartan drug substance. The difference between the total amount of azilsartan related substances (%) in each sample and the total amount of azilsartan related substances (%) in the samples stored under 4 ° C (sealed) conditions (hereinafter referred to as "increased amount"). (May be) is shown in Table 1-6.

-Measurement of total amount of related substances of amlodipine besilate-
--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 the mixture was shaken with a shaker for 20 minutes. Further methanol was added to make 20 mL.
The obtained solution was filtered through a 0.2 μm membrane filter to obtain a sample solution.

--HPLC conditions ---
HPLC system: Chromaster (manufactured by Hitachi High-Technologies Corporation)
Detection wavelength: UV 241 nm
Column: Inertsil ODS-2 5 μm 4.6 mm × 150 mm
Column temperature: Constant temperature around 40 ° C Flow rate: Adjusted so that the peak of amlogipin is 12 minutes Mobile phase A: Acetonitrile: Water: 100% HClO ₄ = 100: 900: 1 (volume ratio) mixed solution Mobile phase B: Acetonitrile: water: 100% HClO ₄ = 900: 100: 1 (volume ratio) mixed solution Injection amount: 10 μL
Analysis time: 45 minutes Radiant program: Listed in Table 1-5 below

The amount (%) of the total relatives of amlodipine besilate was taken as the ratio of the peak area other than azilsartan and amlodipine besilate to the peak area derived from the amlodipine besylate drug substance. Difference between the amount (%) of the total relatives of amlogipin besilate in each sample and the amount (%) of the total relatives of amlogipin besilate in the samples stored under 4 ° C (sealed) conditions (hereinafter, "increase"). (Sometimes referred to as "quantity") is shown in Table 1-6.

From the results in Table 1-6, the tablets 1-1 containing the azil sartane-containing granules, the amlodipine besilate-containing granules, and the low-substituted hydroxypropyl cellulose were prepared with azyl sartane and amlodipine besilate. Compared with tablets 1-2 contained in the same granulated product and tablets 1-3 using non-granulated amlogipine besilate, the amount of related substances of each drug is equal to or less than that under all storage conditions. Also, the increase in related substances was low. Therefore, according to the present invention, it has been shown that the stability of the drug can be improved under various storage conditions.

(Test Example 2)
<Manufacturing of Tablet 2-1>
<< Azilsartan-containing granulated product preparation process >>
100 g of azilsartan (manufactured by Tokuyama Co., Ltd.), 280 g of mannitol (mannitol P, manufactured by Mitsubishi Food Tech Co., Ltd.) and 100 g of corn starch (cornstarch W, manufactured by Japan Corn Starch Co., Ltd.) are mixed to contain azilsartan. Got
A binding solution was prepared by dissolving 15 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) and 5 g of triethyl citrate (manufactured by Morimura Brothers Co., Ltd.) in 135 g of water.
Using a fluidized bed granulator (MP-01, manufactured by Paulek Co., Ltd.), the mixture containing azilsartan was granulated while spraying the binding liquid. The obtained granulated product was sized with a sieve having an opening of 850 μm to obtain an azilsartan-containing granule (hereinafter, may be referred to as “azilsartan granule”).

<< Amlodipine besilate-containing granule preparation process >>
Amlogipin besilate (manufactured by Kyongbo) 34.65 g, mannitol (mannit P, manufactured by Mitsubishi Food Tech Co., Ltd.) 350.35 g, and corn starch (cornstarch W, manufactured by Japan Corn Starch Co., Ltd.) 100 g are mixed and amlogipin. A mixture containing besilate 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 fluidized bed granulator (MP-01, manufactured by Paulek Co., Ltd.), the mixture containing the amlodipine besylate was granulated while spraying the binding liquid. The obtained granulated product was sized with a sieve having an opening of 850 μm to obtain an amlodipine besylate-containing granule (hereinafter, may be referred to as “amlodipine besilate granule”).

<< Compression molding process >>
100 g of the azil sultan granules and 100 g of the amlogipine besilate granules are mixed, and further, 10.5 g of low-substituted hydroxypropyl cellulose (LH21, manufactured by Shin-Etsu Chemical Industry Co., Ltd.) and soft anhydrous silicic acid (addorider 101, 0.4 g of Freund Sangyo Co., Ltd.) and 2.1 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) were mixed to obtain granules for tableting.
Using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.), the granules for tableting were 213 mg per tablet (20 mg of azilsartan, 6.93 mg of amlodipine besylate) using a pestle with a diameter of 8.0 mm. Included.) Was obtained. Table 2-1 shows the composition in one tablet.

<Manufacturing of tablets 2-2>
Same as the production of the tablet 2-1 except that the low-substituted hydroxypropyl cellulose used in the compression molding step in the production of the tablet 2-1 was replaced with croscarmellose sodium (Primellose, manufactured by DFE Pharma). Then, 160 mg of tablets (containing 20 mg of azilsartan and 6.93 mg of amlodipine besilate) were obtained per tablet. Table 2-1 shows the composition in one tablet.

<Hygroscopic equilibrium test>
The tablets 2-1 and 2-2 are stored for 2 weeks under the conditions of relative humidity of 0%, 33%, 43%, 58%, 75%, 84%, 93%, or 97%, and then each tablet is stored. The hardness was measured using a load cell type tablet hardness tester PC-30 (manufactured by Okada Seiko Co., Ltd.). Table 2-2 shows the hardness (kg) of each tablet, and Table 2-3 shows the hardness maintenance rate (%) based on the sample stored at 0% relative humidity.

表２－２及び２－３中、「－」は、錠剤が崩れるため、硬度測定ができなかったことを表す。

In Tables 2-2 and 2-3, "-" indicates that the hardness could not be measured because the tablet collapsed.

From the results shown in Tables 2-2 and 2-3, the tablets 2-1 containing the azil sultan-containing granules, the amlogipin besilate-containing granules, and the low-substituted hydroxypropyl cellulose were found in the azil sartane-containing granules. Compared to tablets 2-2 containing the product, amlogipin besilate-containing granules, and croscarmellose sodium, the tablet has a higher maintenance rate of hardness and higher stability against humidity under all storage conditions. It was confirmed that. Therefore, according to the present invention, it has been shown that the decrease in hardness of tablets when stored under various humidity conditions can be suppressed.

<Change in tablet appearance>
The tablets 2-1 and 2-2 were stored at 50 ° C. and a relative humidity of 90% (open) for 1 month. When the appearance of each tablet was visually confirmed, the azilsartan-containing granulation, the azilsartan-containing granulation, and the tablet 2-1 containing the azilsartan-containing granules and the low-substituted hydroxypropylcellulose were found. It was confirmed that the degree of yellowing was smaller than that of the tablet 2-2 containing the product, the granulated product containing azilsartan besilate, and croscarmellose sodium. Therefore, according to the present invention, it has been shown that discoloration of tablets during storage, particularly during storage under high temperature and high humidity conditions, can be suppressed.

(Reference example 1)
<Manufacturing of Tablet 3-1>
<< Granulation preparation process >>
Azilsartan (manufactured by Tokuyama Co., Ltd.) 20 g, amlodipine besilate (manufactured by Kyongbo) 6.93 g, mannitol (mannit P, manufactured by Mitsubishi Food Tech Co., Ltd.) 125.07 g, and corn starch (corn starch W, Japan Corn Starch) (Manufactured by Co., Ltd.) 40 g was mixed to obtain a mixture containing azilsartan and amlodipine besilate.
A binding solution was prepared by dissolving 6 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Shin-Etsu Chemical Co., Ltd.) and 2 g of triethyl citrate (manufactured by Morimura Brothers Co., Ltd.) in 54 g of water.
Using a fluidized bed granulator (MP-01, manufactured by Paulek Co., Ltd.), the mixture containing azilsartan and amlodipine besilate was granulated while spraying the binding liquid. The obtained granulated product is sized with a sieve having an opening of 850 μm to obtain azilsartan and amlodipine besilate-containing granules (hereinafter, may be referred to as “azilsartan and amlodipine besilate granules”). rice field.

<< Compression molding process >>
200 g of the azil sultan and amlodipine besilate granules, 10.5 g of low-substituted hydroxypropyl cellulose (LH21, manufactured by Shin-Etsu Chemical Industry Co., Ltd.), and 0.4 g of soft anhydrous silicic acid (Adslider 101, manufactured by Freund Sangyo Co., Ltd.). And 1.05 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) were mixed to obtain granules for tableting.
The granules for tableting were prepared using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) using a pestle with a diameter of 8.0 mm, and 211.95 mg (20 mg of azilsartan, 6 amlodipine besylate) per tablet. A tablet containing .93 mg was obtained. Table 3-1 shows the composition in one tablet.

<Manufacturing of tablets 3-2>
Similar to the production of Tablet 3-1 except that azilsartan in the production of Tablet 3-1 was replaced with candesartan cilexetil (manufactured by Yungjin), 211.95 mg per tablet (Candesartan cileki). Tablets containing 20 mg of cetyl and 6.93 mg of amlodipine besilate were obtained. Table 3-2 shows the composition in one tablet.

<Stability test>
After storing the tablets 3-1 and 3-2 under the following storage conditions for 2 weeks, the total amount of related substances of azil sartane or the total amount of related substances of candesartane cilexetil and the total amount of related substances of amlogipin besilate Was measured using ultra-high performance liquid chromatography (HPLC).

-Preservation conditions-
・ 4 ℃ (sealed)
・ 50 ° C, relative humidity 90% (open)
・ 60 ° C (open)
* Humidity conditions are not stated, but the humidity is assumed to be Nariyuki.

-Measurement of total amount of substances related to azilsartan-
In the same manner as in the stability test of Test Example 1, the amount (%) of the total related substances of azilsartan was determined. The results are shown in Table 3-4 together with the difference from the total amount of substance (%) of azilsartan in the sample stored under the condition of 4 ° C. (sealed) (hereinafter, may be referred to as “increased amount”).

-Measurement of total amount of related substances of candesartan cilexetil-
--Preparation of sample solution ---
Two tablets were pulverized, a powder amount (211.95 mg) corresponding to 20 mg of candesartan cilexetil was weighed in a 20 mL volumetric flask, and 4 mL of water was added to disperse the mixture. An appropriate amount of methanol was added, and the mixture was shaken with a shaker for 20 minutes. Further methanol was added to make 20 mL.
The obtained solution was filtered through a 0.2 μm membrane filter to obtain a sample solution.

--HPLC conditions ---
HPLC system: Chromaster (manufactured by Hitachi High-Technologies Corporation)
Detection wavelength: UV 242 nm
Column: Inertsil ODS-4 3 μm, 4.6 mm × 150 mm
Column temperature: Constant temperature around 25 ° C Flow rate: Adjusted so that the retention time of candesartan cilexetil is about 17 minutes Mobile phase A: acetonitrile: water: acetic acid = 57: 43: 1 (volume ratio) mixed liquid mobile phase B: Acetonitrile: Water: Acetic acid = 90: 10: 1 (volume ratio) mixed solution Injection amount: 10 μL
Analysis time: 45 minutes Radiant program: Listed in Table 3-3 below

The amount (%) of the total related substances of candesartan cilexetil was the ratio of the peak area other than candesartan cilexetil and amlodipine besilate to the peak area derived from the candesartan cilexetil drug substance. Difference between the amount of candesartan cilexetil total relatives (%) in each sample and the amount of candesartan cilexetil total relatives (%) in the samples stored under 4 ° C (sealed) conditions (hereinafter, "increase") (Sometimes referred to as "quantity") is shown in Table 3-4.

-Measurement of total amount of related substances of amlodipine besilate-
In the same manner as in the stability test of Test Example 1, the amount (%) of the total related substances of amlodipine besilate was determined. Table 3-4 shows the difference from the total amount of substance (%) of amlodipine besilate in the sample stored under the condition of 4 ° C. (sealed) (hereinafter, referred to as “increased amount”). show.

From the results in Table 3-4, the stability of amlodipine besilate was worse in tablets 3-1 formulated with azilsartan than in tablets 3-2 formulated with candesartan cilexetil. Therefore, it was confirmed that the stability of amlodipine besylate behaves differently depending on the drug to be combined.

Claims (8)

A method for improving the quality of azilsartan or a salt thereof and amlodipine or a tablet containing a salt thereof.
A step of granulating a composition containing azilsartan or a salt thereof to prepare an azilsartan or a salt-containing granulated product thereof.
A step of granulating a composition containing amlodipine or a salt thereof to prepare an amlodipine or a salt-containing granulated product thereof.
A step of compression molding a mixture containing the azilsartan or a salt-containing granulation thereof, the amlodipine or a salt-containing granulation thereof, and a low-degree-of-substitution hydroxypropyl cellulose.
The improvement in quality includes improvement in drug stability and suppression of tablet hardness reduction.
A method comprising two kinds of drugs contained in the tablet, azilsartan or a salt thereof and amlodipine or a salt thereof. The method of claim 1, wherein the improvement in quality further comprises suppressing discoloration of the tablet. The method according to any one of claims 1 to 2, wherein the tablet contains only mannitol as a saccharide . Contains azilsartan or its salt-containing granulation, amlodipine or its salt-containing granulation, and low-degree-of-substitution hydroxypropyl cellulose.It ’s a pill,
The tablet is a single layer tablet.
Said Azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof, wherein the drug contained in the tablet is azilsartan or a salt thereof and amlodipine or a salt thereof. The tablet according to claim 4, wherein the azilsartan or a salt-containing granulation thereof and the amlodipine or a salt-containing granulation thereof do not contain the low-degree-of-substitution hydroxypropyl cellulose. The tablet according to any one of claims 4 to 5, wherein the tablet contains only mannitol as a saccharide. A step of granulating a composition containing azilsartan or a salt thereof to prepare an azilsartan or a salt-containing granulated product thereof.
A step of granulating a composition containing amlodipine or a salt thereof to prepare an amlodipine or a salt-containing granulated product thereof.
A step of compression molding a mixture containing the azilsartan or a salt-containing granulation thereof, the amlodipine or a salt-containing granulation thereof, and a low-degree-of-substitution hydroxypropyl cellulose.
A method for producing azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof, wherein the drug contained in the tablet is azilsartan or a salt thereof and amlodipine or a salt thereof. The production method according to claim 7, wherein the tablet contains only mannitol as a saccharide.