JP6883401B2 - Azilsartan-containing tablets and methods for stabilizing azilsartan in tablets - Google Patents

Description

The present invention relates to an azilsartan-containing pharmaceutical composition, a method for stabilizing azilsartan in the pharmaceutical composition, and a stabilizer for azilsartan.

Azyl sartan is a compound represented by the following structural formula (chemical name: 2-Ethoxy-1-{[2'-(5-oxo-4, 5-dihydro-1, 2, 4-oxodiazol-3-3). yl) biphenyl-4-yl] methyl} -1H-benzo [d] imidazole-7-carboxylic acid). Azilsartan is an angiotensin II receptor blocker and is known as a therapeutic agent for hypertension.

So far, as a pharmaceutical composition containing azilsartan, a solid pharmaceutical composition containing azilsartan, a low melting point oil-like substance, and a low-viscosity binder has been proposed (for example, Patent Document 1). reference). In this proposal, a low-viscosity binder is added to the formulation in order to suppress the decomposition of azilsartan over time by blending a low-melting oil-like substance and improve the drug elution of the formulation with enhanced stability. Has been done.

However, even in the above proposal, the stability of azilsartan over time is not sufficient, and there is a strong demand for further improvement in stability.

International Release 2008/018569

An object of the present invention is to solve the above-mentioned problems in the past and to achieve the following object. That is, an object of the present invention is to provide an azilsartan-containing pharmaceutical composition having excellent stability over time, a method for stabilizing azilsartan in the pharmaceutical composition, and a stabilizer for azilsartan.

The means for solving the above-mentioned problems are as follows. That is,
<1> An azilsartan-containing pharmaceutical composition containing azilsartan and a substance having plasticity, wherein the substance having plasticity is triethyl citrate.
<2> A method for stabilizing azilsartan in a pharmaceutical composition.
Including the step of bringing azilsartan into contact with a plastic substance,
A method for stabilizing azilsartan in a pharmaceutical composition, wherein the plastic substance in the pharmaceutical composition is triethyl citrate.
<3> A stabilizer of azilsartan used in a pharmaceutical composition containing azilsartan and containing a substance having plasticity.
In the pharmaceutical composition, the substance having plasticity is a stabilizer of azilsartan, which is characterized by being triethyl citrate.

According to the present invention, an azilsartan-containing pharmaceutical composition capable of solving the above-mentioned problems in the past and achieving the above-mentioned object and having excellent stability over time, a method for stabilizing azilsartan in the pharmaceutical composition, and the like. And azilsartan stabilizers can be provided.

(Azilsartan-containing pharmaceutical composition)
The azilsartan-containing pharmaceutical composition of the present invention contains at least azilsartan and a substance having plasticity, and further contains other components as necessary.

<Azilsartan>
The azil sultan is a compound represented by the following structural formula (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).
As the azilsartan, one produced by a known method may be used, or a commercially available product may be used.

The content of the azilsartan in the azilsartan-containing pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include 5% by mass to 40% by mass.

<Plastic substance>
The plasticity substance is not particularly limited as long as it contains triethyl citrate, and can be appropriately selected depending on the intended purpose.
As the plastic substance, a substance produced by a known method may be used, or a commercially available product may be used.

By containing triethyl citrate as the plastic substance, the stability of azilsartan over time can be further improved.

The content of the plastic substance in the azilsartan-containing pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.3% by mass or more, preferably 0.5% by mass. ~ 1.5% by mass is more preferable, and 0.5% by mass to 1.2% by mass is particularly preferable. If the content of the plastic substance is less than 0.3% by mass, the stability of azilsartan may decrease, and if it exceeds 1.2% by mass, the azilsartan-containing pharmaceutical composition is tableted. If so, the hardness may decrease. On the other hand, when the content of the substance having plasticity is within the particularly preferable range, it is advantageous in that the hardness required for the tablet can be maintained and the stability of azilsartan is also excellent.

The amount of the plastic substance with respect to the azilsartan is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 1 part by mass to 60 parts by mass with respect to 100 parts by mass of the azilsartan. , 0.75 parts by mass to 30 parts by mass, more preferably 1.25 parts by mass to 20 parts by mass.

<Other ingredients>
The other components in the azilsartan-containing pharmaceutical composition 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, binders, lubricants, disintegrants, flavoring agents, fragrances and the like. These may be used alone or in combination of two or more.
As the other components in the azilsartan-containing pharmaceutical composition, those produced by a known method may be used, or commercially available products may be used.
The content of other components in the azilsartan-containing pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose.

− Sugar −
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.

-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.

-Sliding agent-
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.

-Disintegrant-
The disintegrant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, starch (corn starch or the like), crystalline cellulose, carmellose calcium, sodium starch glycolate, crospovidone, croscarmellose sodium. , Croscarmellose calcium and the like. These may be used alone or in combination of two or more.

− 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.

-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 dosage form of the azilsartan-containing pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include uncoated tablets, chewable tablets, film-coated tablets, orally disintegrating tablets and the like. Can be mentioned.

When the azilsartan-containing pharmaceutical composition is a tablet, its hardness is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 4.0 kgF or more.

The method for producing the azilsartan-containing pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose. However, a granulation step, a tableting step, and further other steps, if necessary, are included. It is preferable to produce by the method including.

The granulation step is a step of granulating the azilsartan, the substance having plasticity, and a component selected from the other components, if necessary, to obtain an azilsartan-containing granulated product.
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.
The granulation conditions are not particularly limited and may be appropriately selected depending on the intended purpose.

In the tableting step, a mixed powder of the azilsartan-containing granulated product and, if necessary, a component selected from the other components (hereinafter, may be referred to as “tablet powder”) is tableted. This is the process of obtaining uncoated tablets.
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.

The other steps are not particularly limited and may be appropriately selected depending on the intended purpose. For example, a drying step of drying the azir sultan-containing granules and a sizing of the azil sartane-containing granules. Granulation step, a powder preparation step for tableting, in which the azil sartane-containing granulated product is mixed with a component selected from the other components as necessary to obtain a powder for tableting, and a coating solution is applied to the uncoated tablet. Examples thereof include a film coating step of applying and obtaining a film-coated tablet.
The method of the other steps is not particularly limited, and a known method can be appropriately selected.

Since the azilsartan-containing pharmaceutical composition of the present invention contains the above-mentioned plastic substance, the azilsartan-containing pharmaceutical composition is excellent in stability over time.
Therefore, the present invention also relates to a method for stabilizing an azilsartan-containing pharmaceutical composition, which comprises using the above-mentioned substance having plasticity.

(Method for stabilizing azilsartan in pharmaceutical composition)
The method for stabilizing azilsartan in the pharmaceutical composition of the present invention includes at least a contact step and, if necessary, other steps.

<Contact process>
The contact step is a step of bringing azilsartan into contact with a substance having plasticity.
In the contacting step, other components other than the azilsartan and the plastic substance may be present.

-Azilsartan-
The azilsartan is the same as that described in the item of <Azilsartan> of the above-mentioned azilsartan-containing pharmaceutical composition of the present invention.

-Plastic substance-
The substance having plasticity is the same as that described in the item of <substance having plasticity> of the above-mentioned azilsartan-containing pharmaceutical composition of the present invention, and the preferred embodiment is also the same.

-Other ingredients-
The other ingredients are not particularly limited and may be appropriately selected depending on the intended purpose. For example, those described in the item of <Other Ingredients> of the azilsartan-containing pharmaceutical composition of the present invention described above can be used. Can be mentioned.

− Contact −
The contact method is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the contact method described in the item <Production method> of the azilsartan-containing pharmaceutical composition of the present invention can be used for contact. There is a method of making it.

<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.

According to the method for stabilizing azilsartan in the pharmaceutical composition of the present invention, it is possible to improve the decrease in stability of azilsartan over time.

(Azilsartan stabilizer)
The stabilizer for azilsartan of the present invention is used in a pharmaceutical composition containing azilsartan, contains a substance having plasticity, and further contains other components as necessary.

<Plastic substance>
The substance having plasticity is the same as that described in the item of <substance having plasticity> of the above-mentioned azilsartan-containing pharmaceutical composition of the present invention, and the preferred embodiment is also the same.

<Other ingredients>
The other ingredients are not particularly limited and may be appropriately selected depending on the intended purpose. For example, those described in the item of <Other Ingredients> of the azilsartan-containing pharmaceutical composition of the present invention described above can be used. Can be mentioned.

According to the stabilizer of azilsartan of the present invention, the decrease in stability of azilsartan over time can be improved.

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

(Test Example 1-1)
The powder for tableting according to the formulation shown in Table 1 below was produced as follows.
Azilsartan (manufactured by Zhejiang Tianyu Pharmaceutical Co., Ltd.), lactose (manufactured by Pharmatose 200M, manufactured by DFE Pharma), and cornstarch (manufactured by Cornstarch W, Japan Cornstarch Co., Ltd.) were weighed and mixed.
In the obtained mixture, 6 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) was dissolved in 32.4 g of water using a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.). The aqueous solution was sprayed at an air supply temperature of 75 ° C. to granulate and dry.
Hydroxypropyl cellulose having a low degree of substitution (L-HPC LH21, manufactured by Shin-Etsu Chemical Co., Ltd.) and magnesium stearate were added to and mixed with the obtained granulated product to obtain a powder for tableting.

(Test Example 1-2)
Tablets having the formulations shown in Table 1 below were produced as follows.
The tableting powder obtained in Test Example 1-1 was used at a pressure of 8,000 N using a universal material testing device (Autograph, manufactured by Shimadzu Corporation) and a punch and mortar having a diameter of 8.0 mm. The tablets were beaten to obtain 120 mg tablets per tablet.

(Test Example 2-1)
In Test Example 1-1, the point that an aqueous solution prepared by dissolving 6 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) in 32.4 g of water was used is that hydroxypropyl cellulose (HPC-SSL, Nippon Soda Co., Ltd.) was used. 6 g (manufactured by Morimura Brothers Co., Ltd.) and 1.2 g of triethyl citrate (Citroflex-2, manufactured by Morimura Brothers Co., Ltd.) were replaced with an aqueous solution dissolved in 32.4 g of water, except for the formulation shown in Table 1 below. , A powder for tableting was obtained in the same manner as in Test Example 1-1.

(Test Example 2-2)
In Test Example 1-2, the point that the tableting powder obtained in Test Example 1-1 was used is replaced with the tableting powder obtained in Test Example 2-1 in Table 1 below. 120 mg of tablets were obtained per tablet in the same manner as in Test Example 1-2 except for the formulation described.

<Evaluation 1>
After storing the tableting powder or tablet obtained in Test Examples 1-1 to 2-2 under the following storage conditions for 1 to 2 weeks, the amount of azilsartan-related substance, that is, azilsartan. The amount of degradable material was measured using HPLC as follows. The amount of azilsartan relatives (%) was expressed as% of the peak area of the relatives in the total peak area derived from the HPLC azilsartan drug substance. The results are shown in Tables 3-1 to 3-3.

− Preservation conditions −
・ 4 ℃ (sealed)
・ 50 ° C, relative humidity 90% (open)
・ 60 ℃ (open)

-Measurement of the amount of azilsartan relatives-
--Preparation of sample solution ---
90% acetonitrile was added to the obtained tableting powder or tablet to make 20 mL.
Each of the obtained solutions was filtered using a 0.45 μm filter (trade name: Millex-LH, manufactured by Millipore) to prepare a sample solution to be subjected to HPLC.

--HPLC conditions ---
Equipment: Hitachi Chromaster 5000 Series Column: Inertsil ODS-3 5 μm, 4.6 mm × 150 mm, 25 ° C
Injection volume: 10 μL
Detection: UV 250 nm
Flow rate: 1.5 mL / min Collection time: 60 minutes Buffer: 10 mM potassium dihydrogen phosphate, adjusted to pH 3.0 with phosphoric acid.
Mobile phase A: Mixed solution of buffer: acetonitrile = 65:35 (volume ratio) Mobile phase B: Mixed solution of buffer: acetonitrile = 30:70 (volume ratio) Gradient program: Listed in Table 2 below.

Table 3-1 shows the results when the storage condition is "4 ° C. (sealed)".

Table 3-2 shows the results when the storage conditions are "50 ° C. and relative humidity 90% (open)". In Table 3-2, the initial value (0 week) is the value stored at 4 ° C. (sealed) for 1 week.

Table 3-3 shows the results when the storage condition is "60 ° C. (open)". In Table 3-3, the initial value (0 week) is the value stored at 4 ° C. (sealed) for 1 week.

From the results of Tables 3-1 to 3-3, it was confirmed that the amount of azilsartan-related substances increased during the storage period in the tablets as compared with the powder for tableting. Therefore, it was found that the composition containing azilsartan was destabilized by tableting.
Further, from the results of Test Example 1-2 and Test Example 2-2, by containing triethyl citrate in the tablet, it is possible to suppress an increase in azilsartan-related substances over time, and azilsartan can be used. It was confirmed that it can be stabilized.

(Test Example 3-1)
Tablets having the formulations shown in Table 4 below were produced as follows.
Azilsartan (manufactured by Zhejiang Tianyu Pharmaceutical Co., Ltd.), lactose (manufactured by Pharmatose 200M, manufactured by DFE Pharma), and cornstarch (manufactured by Cornstarch W, Japan Cornstarch Co., Ltd.) were weighed and mixed.
An aqueous solution prepared by dissolving 6 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) in 54 g of water was added to the obtained mixture using a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.). It was sprayed at an air supply temperature of 75 ° C. to granulate and dried.
The obtained granulated product was sieved with a sieve having a mesh size of 710 μm to obtain low-substituted hydroxypropyl cellulose (L-HPC LH21, manufactured by Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (manufactured by Ohira Chemical Industry Co., Ltd.). Was added and mixed to obtain a powder for tableting.
The tableting powder is tableted at a pressure of 6,000 N using a rotary tableting machine (model name: VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) and a punch and mortar having a diameter of 7.0 mm, and one tablet. 118.8 mg tablets were obtained per.

(Test Example 3-2)
The point that the aqueous solution in which 6 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) was dissolved in 54 g of water was used in Test Example 3-1 is that hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) was used. (Manufactured) 6 g and 1.2 g of triethyl citrate (Citroflex-2, manufactured by Morimura Brothers Co., Ltd.) were replaced with an aqueous solution dissolved in 54 g of water, except for the formulation shown in Table 4 below. A powder for tableting was obtained in the same manner as in 3-1.
The tableting powder is tableted at a pressure of 6,000 N using a rotary tableting machine (model name: VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) and a punch and mortar having a diameter of 7.0 mm, and one tablet. 120 mg tablets were obtained per.

(Test Example 3-3)
In Test Example 3-2, 1.2 g of triethyl citrate (Citroflex-2, manufactured by Morimura Brothers Co., Ltd.) was replaced with 1.2 g of Macrogol 6000 (polyethylene glycol 6000, manufactured by Sanyo Chemical Industries, Ltd.) as follows. Tablets were obtained in the same manner as in Test Example 3-2, except that the formulations shown in Table 4 were used.

(Test Example 3-4)
In Test Example 3-2, 1.2 g of triethyl citrate (Citroflex-2, manufactured by Morimura Brothers, Ltd.) was replaced with 1.2 g of glycerin (manufactured by Wako Pure Chemical Industries, Ltd.) and is shown in Table 4 below. Tablets were obtained in the same manner as in Test Example 3-2, except that they were formulated.

(Test Example 3-5)
In Test Example 3-2, 1.2 g of triethyl citrate (Citroflex-2, manufactured by Morimura Brothers, Ltd.) was replaced with 1.2 g of sodium lauryl sulfate (manufactured by Wako Pure Chemical Industries, Ltd.), as shown in Table 4 below. Tablets were obtained in the same manner as in Test Example 3-2, except that the formulation was described.

<Evaluation 2>
After storing the tablets obtained in Test Examples 3-1 to 3-5 at 60 ° C. (open) for 1 to 2 weeks, the amount of azilsartan-related substance, that is, the amount of azilsartan-degrading substance. Was measured by the same method as in <Evaluation 1> above. The results are shown in Table 5. In Table 5, the initial value (0 week) is the value stored at 4 ° C. (sealed) for 1 week.

From the results in Table 5, among the plastic substances, especially when triethyl citrate is contained in the tablet, the increase of azilsartan-related substances over time can be suppressed, and azilsartan can be stabilized. Was confirmed.

<Evaluation 3>
After storing the tablets obtained in Test Examples 3-1 to 3-5 under the following storage conditions for 2 weeks, the disintegration time of the tablets was measured by the disintegration test method of the Japanese Pharmacopoeia (Japanese Pharmacopoeia). The results are shown in Table 6.

− Preservation conditions −
・ 4 ℃ (sealed)
・ 50 ° C, relative humidity 90% (open)
・ 60 ℃ (open)

From the results in Table 6, it was confirmed that under the condition of 60 ° C. (open), among the plastic substances, particularly when triethyl citrate was contained in the tablet, it exhibited rapid disintegration.

(Test Example 4-1)
Tablets having the formulations shown in Table 7 below were produced as follows.
Azilsartan (AZL-HM100-TP2, manufactured by Tokuyama Corporation), lactose (Phamatose 200M, manufactured by DFE Pharma), and cornstarch (Cornstarch W, manufactured by Japan Cornstarch Corporation) were weighed and mixed.
An aqueous solution prepared by dissolving 12 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) in 108 g of water was added to the obtained mixture using a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.). It was sprayed at an air supply temperature of 75 ° C. to granulate and dried.
The obtained granulated product was sieved with a sieve having a mesh size of 710 μm to obtain low-substituted hydroxypropyl cellulose (L-HPC LH21, manufactured by Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (manufactured by Ohira Chemical Industry Co., Ltd.). Was added and mixed to obtain a powder for tableting.
The tableting powder is tableted at a pressure of 6,000 N using a rotary tableting machine (model name: VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) and a punch and mortar having a diameter of 7.0 mm, and one tablet. 120 mg tablets were obtained per.

(Test Example 4-2)
The point that the aqueous solution in which 12 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) was dissolved in 108 g of water was used in Test Example 4-1 is that hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) was used. (Manufactured) 12 g and triethyl citrate (Citroflex-2, manufactured by Morimura Shoji Co., Ltd.) 0.24 g were replaced with an aqueous solution dissolved in 108 g of water, and the above test examples were used except for the formulation shown in Table 7 below. Tablets were obtained in the same manner as in 4-1.

(Test Example 4-3)
In Test Example 4-2, 0.24 g of triethyl citrate (Citroflex-2, manufactured by Morimura Brothers Co., Ltd.) was changed to 0.72 g, except for the formulation shown in Table 7 below. , Tablets were obtained in the same manner as in Test Example 4-2.

(Test Example 4-4)
In Test Example 4-2, 0.24 g of triethyl citrate (Citroflex-2, manufactured by Morimura Brothers Co., Ltd.) was changed to 1.2 g, except for the formulation shown in Table 7 below. , Tablets were obtained in the same manner as in Test Example 4-2.

(Test Example 4-5)
In Test Example 4-2, 0.24 g of triethyl citrate (Citroflex-2, manufactured by Morimura Brothers Co., Ltd.) was changed to 1.68 g, except for the formulation shown in Table 6 below. , Tablets were obtained in the same manner as in Test Example 4-2.

(Test Example 4-6)
In Test Example 4-2, 0.24 g of triethyl citrate (Citroflex-2, manufactured by Morimura Brothers Co., Ltd.) was changed to 3.6 g, except that the formulation shown in Table 7 below was used. , Tablets were obtained in the same manner as in Test Example 4-2.

<Evaluation 4>
After storing the tablets obtained in Test Examples 4-1 to 4-6 at 60 ° C. (open) for 1 to 2 weeks, the amount of azilsartan-related substance, that is, the amount of azilsartan-degrading substance. Was measured by the same method as in <Evaluation 1> above. The results are shown in Table 8. In Table 8, the initial value (0 week) is the value stored at 4 ° C. (sealed) for 1 week.

From the results in Table 8, it was confirmed that as the content of triethyl citrate in the tablet increased, the increase of azilsartan related substances over time could be suppressed and the azilsartan could be stabilized.

<Evaluation 5>
After storing the tablets obtained in Test Examples 4-1 to 4-6 at 60 ° C. (open) for 2 weeks, the hardness of the tablets was measured with a load cell type tablet hardness tester (portable checker PC-30 type, Okada Seiko Co., Ltd.). It was measured by (manufactured by the company) and evaluated based on the following evaluation criteria. The results are shown in Table 9.

-Evaluation criteria-
"○": Hardness is 4 kgF or more "△": Hardness is less than 4 kgF

From the results in Table 9, it was confirmed that the hardness of the tablet was lowered when the content of triethyl citrate in the tablet was 1.5% by mass or more.

(Test Example 5-1)
Tablets having the formulations shown in Table 10 below were produced as follows.
Losartan potassium (chemical name: Monopotassium 5-{[4'-(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl) methyl] biphenyl-2-yl} -1H-tetrazol-1- Ide, manufactured by Dite Co., Ltd.), lactose (Phamatose 200M, manufactured by DFE Pharma), and cornstarch (Cornstarch W, manufactured by Nippon Cornstarch Co., Ltd.) were weighed and mixed.
An aqueous solution prepared by dissolving 6 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) in 54 g of water was added to the obtained mixture using a fluidized bed granulator (MP-01, manufactured by Paulec Co., Ltd.). It was sprayed at an air supply temperature of 75 ° C. to granulate and dried.
The obtained granulated product was sieved with a sieve having a mesh size of 710 μm to obtain low-substituted hydroxypropyl cellulose (L-HPC LH21, manufactured by Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (manufactured by Ohira Chemical Industry Co., Ltd.). Was added and mixed to obtain a powder for tableting.
The tableting powder is tableted at a pressure of 6,000 N using a rotary tableting machine (model name: VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) and a punch and mortar having a diameter of 7.0 mm, and one tablet. 120 mg tablets were obtained per.

(Test Example 5-2)
In Test Example 5-1, an aqueous solution prepared by dissolving 6 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) in 54 g of water was used. (Manufactured) 6 g and 1.2 g of triethyl citrate (Citroflex-2, manufactured by Morimura Shoji Co., Ltd.) were replaced with an aqueous solution dissolved in 54 g of water, and the above test examples were used except for the formulations shown in Table 10 below. Tablets were obtained in the same manner as in 5-1.

<Evaluation 6>
After storing the tablets obtained in Test Example 5-1 and Test Example 5-2 at 4 ° C. (sealed) or 60 ° C. (open) for 7 weeks, the amount of a substance related to losartan potassium, that is, decomposition of losartan potassium. The amount of substance was measured using HPLC as follows. The amount (%) of the related substance of losartan potassium was expressed as% of the peak area of the related substance in the total peak area derived from the losartan potassium drug substance of HPLC. The results are shown in Table 12.

-Measurement of the amount of related substances of losartan potassium-
--Preparation of sample solution ---
Each of the obtained tablets was placed in a 50 mL volumetric flask, about 40 mL of methanol was added, and sonication was performed for 5 minutes with occasional shaking. After shaking well, methanol was added to make exactly 50 mL.
Each of the obtained solutions was filtered using a 0.45 μm filter (Millex-LH) to prepare a sample solution to be subjected to HPLC.

--HPLC conditions ---
Equipment: Hitachi Chromaster 5000 Series Column: Inertsil ODS-3 5 μm, 4.6 mm × 250 mm, 25 ° C
Injection volume: 15 μL
Detection: UV 220 nm
Flow rate: 1.0 mL / min Sample temperature: 4 ° C
Collection time: 45 minutes Mobile phase A: Diluted phosphoric acid (1 → 1000) (phosphoric acid diluted 1,000 times to 0.1% by volume)
Mobile phase B: Acetonitrile gradient program: Table 11 below

From the results in Table 12, triethyl citrate, which was found to have a stabilizing effect on azilsartan, was contained in losartan potassium, an angiotensin II receptor blocker known as a therapeutic agent for hypertension, similar to azilsartan. In this case, the increase of the related substance of losartan potassium could not be suppressed and the loss of losartan potassium could not be stabilized under the storage condition of 60 ° C.
Therefore, the stabilizing effect of azilsartan by using triethyl citrate is considered to be an effect peculiar to the combination of the two.

Claims (4)

An azilsartan- containing tablet containing azilsartan and a substance having plasticity in an uncoated tablet, wherein the substance having plasticity is triethyl citrate. The azilsartan-containing tablet according to claim 1, which contains 1.2 parts by mass to 18 parts by mass of a substance having plasticity with respect to 100 parts by mass of azilsartan. A method for stabilizing azilsartan in tablets,
Including the step of bringing azilsartan into contact with a plastic substance,
A method for stabilizing azilsartan in a tablet, wherein the plastic substance in the tablet is triethyl citrate. The method for stabilizing azilsartan according to claim 3, wherein the contacting step is a step of bringing a plastic substance into contact with 100 parts by mass of azilsartan in an amount of 1.2 parts by mass to 18 parts by mass.