JP2017145238A - Azilsartan-containing wet tablet and method for producing the same - Google Patents

Abstract

To provide an azilsartan-containing wet tablet excellent in stability over time and a method for producing the same.
SOLUTION: A step of adding a water in which a binder is dissolved and a water-containing organic solvent to a mixture of azilsartan and a saccharide and kneading the mixture to obtain a wet powder; and compression molding the wet powder. The manufacturing method of the azilsartan containing wet tablet including a process, and the azilsartan containing wet tablet containing azilsartan, saccharides, and a binder.
[Selection figure] None

Description

  The present invention relates to an azilsartan-containing wet tablet and a method for producing the same.

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

Until now, as a pharmaceutical composition containing azilsartan, a solid pharmaceutical composition manufactured by dry tableting, in which azilsartan, a low melting point oily substance, and a low viscosity binder are essential has been proposed ( For example, see Patent Document 1). In this proposal, a low-viscosity binder is added to the formulation in order to suppress the degradation of azilsartan over time by blending a low melting point oily substance and improve the drug dissolution of the formulation with improved stability. Has been.
However, the above proposal has a problem that the moldability of the tableting powder may be lowered and the disintegration property of the tablet may be deteriorated.

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

International Publication No. 2008/018569

  An object of the present invention is to solve the above-described problems and achieve the following objects. That is, an object of the present invention is to provide an azilsartan-containing wet tablet excellent in stability over time and a method for producing the same.

Means for solving the problems are as follows. That is,
<1> A step of obtaining wet powder by adding and kneading either water or a water-containing organic solvent in which a binder is dissolved to a mixture of azilsartan and a saccharide;
A method for producing an azilsartan-containing wet tablet, comprising a step of compression-molding the wet powder.
<2> The method for producing an azilsartan-containing wet tablet according to <1>, wherein the saccharide is at least one of lactose and mannitol.
<3> The method for producing an azilsartan-containing wet tablet according to any one of <1> to <2>, wherein the binder is polyvinyl alcohol.
<4> The method for producing an azilsartan-containing wet tablet according to any one of <1> to <3>, wherein the tablet does not contain a low melting point oily substance.
<5> An azilsartan-containing wet tablet containing azilsartan, a saccharide, and a binder.
<6> The azilsartan-containing wet tablet according to <5>, wherein the saccharide is at least one of lactose and mannitol.
<7> The azilsartan-containing wet tablet according to any one of <5> to <6>, wherein the binder is polyvinyl alcohol.
<8> The azilsartan-containing wet tablet according to any one of <5> to <7>, which does not contain a low melting point oily substance.

  ADVANTAGE OF THE INVENTION According to this invention, the said various problems in the past can be solved, the said objective can be achieved, and the azilsartan containing wet tablet excellent in stability with time, and its manufacturing method can be provided.

(Azilsartan-containing wet tablet and method for producing the same)
The azilsartan-containing wet tablet of the present invention contains at least azilsartan, a saccharide, and a binder, and further contains other components as necessary.
The azilsartan-containing wet tablet of the present invention can be suitably produced by the method for producing an azilsartan-containing wet tablet of the present invention.
Hereinafter, the azilsartan-containing wet tablet of the present invention will be described together with the description of the method for producing the azilsartan-containing wet tablet of the present invention.

<Method for producing wet tablets containing azilsartan>
The azilsartan-containing wet tablet of the present invention includes at least a wet powder preparation step and a compression molding step, and further includes other steps as necessary.

<< wet powder preparation process >>
The wet powder preparation step is a step in which either wet water or a water-containing organic solvent is added to a mixture of azilsartan and saccharide and kneaded to obtain a wet powder.

-Mixture-
The mixture contains at least azilsartan and a saccharide, and further contains other components as necessary.

--Azilsartan--
The azilsartan is a compound represented by the following structural formula (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 said azilsartan may use what was manufactured by the well-known method, and may use a commercial item.

  There is no restriction | limiting in particular as content in the azilsartan containing wet tablet of the said azilsartan, According to the objective, it can select suitably, For example, 5-40 mass% etc. are mentioned.

--Sugars--
There is no restriction | limiting in particular as said saccharides, According to the objective, it can select suitably, For example, lactose, a mannitol, a xylitol, sorbitol etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together.
Among these, at least one of lactose and mannitol is preferable because it is widely used as a pharmaceutical excipient.
Examples of the lactose include lactose hydrate, anhydrous lactose, spray-dried lactose, fluidized bed granulated lactose, isomerized lactose, and reduced lactose. These may be used individually by 1 type and may use 2 or more types together.
Examples of the mannitol include D-form, L-form, and racemic form. These may be used individually by 1 type and may use 2 or more types together.
What was manufactured by the well-known method may be used for the said saccharides, and a commercial item may be used for it.

  There is no restriction | limiting in particular as content in the azilsartan containing wet tablet of the said saccharide | sugar, Although it can select suitably according to the objective, 60 mass%-99.6 mass% are preferable, 70 mass%-99 mass% % Is more preferable, and 75% by mass to 99% by mass is particularly preferable. When the content is less than 60% by mass, the size per tablet may be too small and difficult to handle. When the content exceeds 99.6% by mass, the mass and size per tablet are too large. Sometimes. On the other hand, when the content is in a particularly preferable range, it is advantageous in terms of tablet size.

-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 according to the purpose. For example, a lubricant, Disintegrating agents, flavoring agents, fragrances and the like can be mentioned. These may be used individually by 1 type and may use 2 or more types together.
As other components in the mixture, those produced by a known method may be used, or commercially available products may be used.
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.

  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 individually by 1 type and may use 2 or more types together.

  There is no restriction | limiting in particular as said disintegrating agent, According to the objective, it can select suitably, For example, starch (corn starch etc.), crystalline cellulose, carmellose calcium, starch glycolate sodium, crospovidone, croscarmellose sodium And croscarmellose calcium. These may be used individually by 1 type and may use 2 or more types together.

  There is no restriction | limiting in particular as said taste masking agent, According to the objective, it can select suitably, For example, sucralose, aspartame, acesulfame potassium, thaumatin etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together.

  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 individually by 1 type and may use 2 or more types together.

-Either water in which the 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 the binder, and further contains other components as necessary.

-Either water or water-containing organic solvent-
Either the water or 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, and isopropanol, are mentioned.

  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 kneading solvent, Although it can select suitably according to the objective, 0-4 are preferable, 0- 3 is more preferable, and 0.05 to 0.5 is particularly preferable. If the blending ratio exceeds 4, it is economically disadvantageous and may cause problems such as precipitation depending on the type of binder, and the risk of ignition may increase. On the other hand, when the mixing ratio is in a particularly preferable range, it is advantageous in that the tablet physical properties after molding are suitably maintained.

  The addition amount of the kneading solvent is not particularly limited and may be appropriately selected depending on the intended purpose. It is 1 mass with respect to 100 mass parts of the total amount of the azilsartan, the saccharide, and the binder. Parts to 25 parts by mass are preferable, and 3 parts to 20 parts by mass are more preferable.

--Binder--
The binder is not particularly limited and may be appropriately selected depending on the intended purpose. For example, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose , Sodium hydroxypropylmethylcellulose, sodium starch glycolate, hydroxyethylcellulose and the like. These may be used individually by 1 type and may use 2 or more types together.
Among these, polyvinyl alcohol is preferable in terms 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 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, the saponification degree is preferably 78 mol% to 96 mol% (partially saponified product), 97 mol% or more (completely saponified product), and particularly preferably 78 mol% to 96 mol% (partially saponified product). The saponification degree 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 azilsartan containing 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 within a more preferable range, it is advantageous in that sufficient tablet strength can be maintained and suitable tablet physical properties can be obtained.

-Other ingredients-
The other components in either the water in which the binder is dissolved or the water-containing organic solvent is 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 mixture The same thing as the other component in is mentioned.

-Kneading-
There is no restriction | limiting in particular as the said kneading | mixing method, 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 granulator, are mentioned.
There is no restriction | limiting in particular as said kneading | mixing conditions, According to the objective, it can select suitably.

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

  The wet granulation method is not particularly limited, and a known method can be appropriately selected. For example, extrusion granulation using a cylindrical granulator, a pelleter, etc., crushing using a speed mill, a power mill, etc. Examples thereof include a granulating method, a minimizer, a power kneader, a speed mill, a melmerizer and the like, and a rolling granulation method in which granulation is mainly performed for rolling operation, and a fluidized bed granulation method by spray drying.

<< Compression molding process >>
The compression molding step is a step of compression molding the wet powder.

-Compression molding-
The compression molding method is not particularly limited, and a known apparatus can be appropriately selected. For example, it is disclosed in a universal material testing apparatus (Autograph, manufactured by Shimadzu Corporation), Japanese Patent Application Laid-Open No. 8-19589. For example, a tablet manufacturing apparatus disclosed in JP-A-8-19588, and a method using a device such as a rotary tableting machine.

As the pressure of the filling pressurization in the compression molding step is not particularly limited and may be appropriately selected depending on the purpose, is ^{usually, 0.5N / cm 2 ~1,500N / cm} 2, 0 preferably ^{.5N / cm 2 ~900N / cm 2} , more preferably ^{0.5N / cm 2 ~600N / cm 2} , 0.5N / cm 2 ~500N / cm 2 is particularly preferred. If the pressure is less than 0.5 N / cm ² , good moldability may not be obtained. If the pressure exceeds 1,500 N / cm ² , depending on the composition, the environmental stability of desired azilsartan may be reduced. It may not be obtained. On the other hand, when the pressure is in a particularly preferable range, it is advantageous in that the stability of azilsartan is further improved.

There is no restriction | limiting in particular as a shape, a structure, a magnitude | size, and a weight of the said azilsartan containing wet tablet, It can select suitably according to the objective.
The azilsartan-containing wet tablet may be film-coated.

<< 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 according to the purpose. Examples thereof include a mixture preparation step and a drying step.

-Mixture preparation process-
The said mixture preparation process is a process of mixing the said azilsartan, the said saccharides, and the said other component further as needed, and preparing a mixture.
There is no restriction | limiting in particular as said mixing method, A well-known apparatus can be selected suitably and can be used, for example, the method of using a mecanom mill (made by Okada Seiko Co., Ltd.), etc. are mentioned.
There is no restriction | limiting in particular as said mixing conditions, 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 said drying method, A well-known apparatus can be selected suitably, For example, the method of using a shelf type dryer etc. are mentioned.
The drying conditions are not particularly limited and may be appropriately selected depending on the purpose.

  There is no restriction | limiting in particular as hardness of the said azilsartan containing wet tablet, According to the objective, it can select suitably, For example, 2 kgf-20 kgf etc. are mentioned.

The azilsartan-containing wet tablet preferably does not contain a low melting point oily substance in terms of tablet hardness, disintegration, and stability.
The low melting point oily substance refers to a substance having an oily form and usually having a melting point of 20 ° C to 90 ° C.
Examples of the low melting point oily substance include hydrocarbons, higher fatty acids, higher alcohols, fatty acid esters of polyhydric alcohols, higher alcohol ethers of polyhydric alcohols, and polymers or copolymers of alkylene oxides.

  Examples of the hydrocarbon include n-heptadecane, n-octadecane, n-nonadecane, n-eicosane, n-heneicosan, n-docosan, n-tricosane, n-tetracosane, n-pentacosane, n-triacontane, n Examples thereof include n-alkanes having 17 to 50 carbon atoms such as pentatriacontane, n-tetracontane and n-pentacontane, and mixtures thereof (such as petrolatum, paraffin wax and microcrystalline wax).

  Examples of the higher fatty acids include capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, serotic acid and mixtures thereof, and higher fatty acids collected from natural fats and oils. It is done.

  Examples of the higher alcohol include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, aralkyl alcohol and mixtures thereof, and higher alcohol collected from natural oils.

Examples of the fatty acid ester of the polyhydric alcohol include alcohols having two or more hydroxyl groups in the molecule (for example, polyalkylene glycol such as alkylene glycol such as ethylene glycol and propylene glycol, polyethylene glycol, polypropylene glycol, and copolymers thereof). Sugars such as alkylene glycol, sorbitol, sucrose, intramolecular dehydration compounds of sorbitol such as 1,5-sorbitan, 1,4-sorbitan, 3,6-sorbitan, glycerin, diethanolamine, pentaerythritol, etc.) and fatty acids (for example, acetic acid) , Propionic acid, butyric acid, pelargonic acid, capric acid, undecyl acid, lauric acid, tridecyl acid, myristic acid, pentadecylic acid, palmitic acid, heptadecyl acid, stearic acid, nonadecanoic acid, undecyl Phosphate, oleic acid, elaidic acid, sorbic acid, linoleic acid, linolenic acid, arachidonic acid, esters of stearic or roll acid).
Specific examples thereof include, for example, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan monopalmitate and other sorbitan fatty acid esters having a molecular weight of 400 to 900; polyoxyethylene sorbitan tristearate, Polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tripalmitate, and other polyoxyalkylene sorbitan fatty acid esters having a molecular weight of 1000 to 1500; polyoxyethylene sorbitol hexastearate, polyoxyethylene sorbitol hexaoleate, polyoxyethylene sorbitol tristearate Polyoxyalkylene sorbitol fatty acid ester such as polyoxyethylene sorbitol tetralaurate Polyoxyalkylene sorbitol beeswax derivatives such as polyoxyethylene sorbitol beeswax derivatives; polyoxyalkylene lanolin derivatives such as polyoxyethylene lanolin derivatives; propylene glycol monopalmitate, propylene glycol monostearate, propylene glycol dilaurate, propylene glycol 200-700 molecular weight propylene glycol fatty acid esters such as dimyristate, propylene glycol dipalmitate, propylene glycol distearate; ethylene glycol monolaurate, ethylene glycol palmitate, ethylene glycol margarate, ethylene glycol stearate, ethylene glycol dilaurate , Ethylene glycol dimyristate, ethylene glycol Alkylene glycol fatty acid esters such as ethylene glycol fatty acid esters having a molecular weight of 500 to 1200 such as palmitate and ethylene glycol dimer gallate; polyoxyalkylene castor oil derivatives having a molecular weight of 3500 to 4000 such as polyoxyethylene castor oil derivatives; polyoxyethylene stearate, polyoxy Polyoxyalkylene fatty acid esters having a molecular weight of 1900 to 2200 such as ethylene oleate, polyoxyethylene palmitate, polyoxyethylene linoleate; glycerol monoacetate, glycerol monopropionate, glycerol monostearate, glycerol monooleate, glycerol monopalmi Glycerin monofatty acid ester having a molecular weight of 300-600 such as tate, glycerin monolinoleate; sucrose monolaure And sucrose monomyristate, sucrose monopalmitate, sucrose monostearate, sucrose trimyristate, sucrose tripalmitate, and sucrose tristearate.

Examples of the higher alcohol ether of the polyhydric alcohol include, for example, polyhydric alcohol (listed as the alcohol component of the fatty acid ester of the polyhydric alcohol) and higher fatty alcohol (for example, cetyl alcohol, stearyl alcohol, oleyl alcohol, octyl alcohol). , Decyl alcohol) and ether.
Specific examples thereof include, for example, polyoxyethylene lauryl alcohol ether, polyoxyethylene cetyl alcohol ether, polyoxyethylene stearyl alcohol ether, polyoxyethylene oleyl alcohol ether, polyoxyethylene octyl alcohol ether, polyoxyethylene decyl alcohol ether, and the like. Polyoxyethylene higher alcohol ether, polyoxypropylene polyoxyethylene cetyl alcohol ether, polyoxypropylene polyoxyethylene stearyl alcohol ether, polyoxypropylene polyoxyethylene oleyl alcohol ether, polyoxypropylene polyoxyethylene octyl alcohol ether, polyoxy Propylene polyoxyethylene lauryl alcohol Polyoxypropylene polyoxyethylene higher alcohol ethers such as ether.

Preferred examples of the alkylene oxide polymer include those having a molecular weight of 1,000 to 10,000 (eg, polyethylene glycol 6000 (macrogol 6000)).
Examples of the alkylene oxide include ethylene oxide, propylene oxide, trimethylene oxide, and tetrahydrofuran (preferably ethylene oxide).
Preferred examples of the alkylene oxide copolymer include copolymers of two or more of the above alkylene oxides having an average molecular weight of 1,000 to 10,000.

  The azilsartan-containing wet tablet of the present invention is excellent in stability over time, as shown in Test Examples described later.

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

Example 1
Weigh azilsartan (AZL (1827) 67, manufactured by AUROBINDO) and lactose hydrate (Pharmacatose 200M, manufactured by DFE Pharma), and use a 1 L mecanomil (manufactured by Okada Seiko Co., Ltd.) for 3 at 600 rpm. Mixed for minutes.
A water-ethanol mixed solvent (mass ratio: water: ethanol = 7: 3) in which polyvinyl alcohol (EG-03P, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved was added to the mixture, and kneaded for 1 minute. A wet powder was obtained. The weight loss on drying of the wet powder was 8.98% by mass.
The wet powder was compression molded at a pressure of 100 N / cm ² using a universal material testing apparatus (Autograph, manufactured by Shimadzu Corporation) and a punch and mortar having a diameter of 8.0 mm to obtain tablets.
The tablets were placed in a 70 ° C. shelf dryer and dried for 1 hour to obtain 100 mg tablets per tablet.
Table 1 shows the prescription.

(Comparative Example 1)
A wet powder was obtained in the same manner as in Example 1.
The wet powder was put into a shelf dryer at 70 ° C. and dried for 12 hours to obtain a dry powder. The drying loss of the dry powder was 0.38% by mass.
Using a universal material testing device (Autograph, manufactured by Shimadzu Corporation) and a pestle and mortar with a diameter of 8.0 mm, the dry powder is compression molded at a pressure of 2,500 N / cm ² , per tablet 100 mg tablets were obtained.

(Test Example 1: Severe test)
After the tablets obtained in Example 1 and Comparative Example 1 were stored at 4 ° C. (sealed) or 60 ° C. (open) for 1 week, the amount of related substances of azilsartan, ie, decomposed substances of azilsartan The amount of was measured using HPLC as follows. The amount (%) of the related substance of azilsartan was expressed as% of the peak area of the related substance in the total peak area derived from the azilsartan drug substance of HPLC.

-Measurement of the amount of related substances of azilsartan-
-Preparation of sample solution-
90% acetonitrile was added to the tablet after storage to make a 20 mL solution. Two solutions were prepared for each of the storage conditions.
The solution obtained by filtering each solution using a 0.45 μm filter (trade name: Millex-LH, manufactured by Millipore) was used as a sample solution to be subjected to HPLC.

--HPLC conditions--
HPLC was performed twice for each of the sample solutions. The results are shown in Table 3. The values in Table 3 are average values of 4 samples.
Apparatus: Hitachi Chromamaster 5000 series Column: Inertsil ODS-3 5 μm, 4.6 mm × 150 mm, 25 ° C.
Injection volume: 10 μL
Detection: UV 250nm
Flow rate: 1.5 mL / min Collection time: 60 minutes Buffer: pH adjusted to 3.0 with 10 mM potassium dihydrogen phosphate and phosphoric acid.
Mobile phase A: Buffer: acetonitrile = 65: 35 (volume ratio) mixture Mobile phase B: Buffer: acetonitrile = 30: 70 (volume ratio) mixture Gradient program: listed in Table 2 below

  From the results in Table 3, the amount of the azilsartan related substance was significantly increased in the tablet of Comparative Example 1 compared to the tablet stored at 4 ° C. (initial) in the tablet stored at 60 ° C. On the other hand, in the tablet of Example 1 of the present invention, the increased amount of the azilsartan-related substance in the tablet stored at 60 ° C. was small. Therefore, it was shown that a stable formulation can be obtained by the present invention.

(Example 2)
Weigh azilsartan (AZI / V1 6P01-TP1, manufactured by Tokuyama Co., Ltd.) and D-mannitol (Mannit P, manufactured by Mitsubishi Corporation Foodtech Co., Ltd.), and use a 1 L mechanomill (made by Okada Seiko Co., Ltd.). And mixing at 800 rpm for 3 minutes.
Next, a water-ethanol mixed solvent (mass ratio: water: ethanol = 7: 3) in which polyvinyl alcohol (EG-03P, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved at a rotation speed of the mechanomyl at 600 rpm was used. Added.
Thereafter, the mixture was kneaded for 2 minutes to obtain a wet powder.
Tableting was carried out using a tableting machine for wet tablets (device names: EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.) to obtain tablets having a diameter of 8.0 mm and 170 mg per tablet.
The molding and drying conditions were as follows: tablet molding pressure: 15 kgf, molding bowl: diameter 8.0 mm, flat bowl, drying temperature: 85 ° C.
Table 4 shows the prescription.

(Example 3)
Azilsartan (AZI / V1 6P01-TP1, manufactured by Tokuyama Corporation), D-mannitol (Mannit P, manufactured by Mitsubishi Corporation Foodtech Co., Ltd.), and Macrogol 6000 (polyethylene glycol 6000, which is a low melting point oily substance) Sanyo Kasei Kogyo Co., Ltd.) was weighed and mixed for 1 minute at 800 rpm using a 1 L mechanom mill (Okada Seiko Co., Ltd.).
Next, a water-ethanol mixed solvent (mass ratio: water: ethanol = 7: 3) in which polyvinyl alcohol (EG-03P, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved at a rotation speed of the mechanomyl at 600 rpm was used. Added.
Thereafter, the mixture was kneaded for 2 minutes to obtain a wet powder.
Tableting was carried out using a tableting machine for wet tablets (device names: EMT-18 and ETD-18, manufactured by Sankyo Seisakusho Co., Ltd.) to obtain tablets having a diameter of 8.0 mm and 170 mg per tablet.
The molding and drying conditions were as follows: tablet molding pressure: 15 kg, molding bowl: diameter 8.0 mm, flat bowl, drying temperature: 85 ° C.
Table 4 shows the prescription.

(Test Example 2)
<Hardness>
When the hardness of the tablets obtained in Examples 2 and 3 was measured using a load cell type tablet hardness tester portable checker PC-30 type (manufactured by Okada Seiko Co., Ltd.), the hardness of the tablet of Example 2 was 5 The hardness of the tablet of Example 3 was 3.57 kgF.
From this result, it was confirmed that the hardness of the tablet decreases when the low melting point oily substance is contained.

<Disintegration test>
About the disintegration property of the tablets obtained in Examples 2 and 3, in a disintegration tester (manufactured by Toyama Sangyo Co., Ltd., no disk, water 37 ° C.), an automatic end point measuring device destopper (manufactured by Toyama Sangyo Co., Ltd., residue thickness) When the disintegration time was evaluated using Res.0.5 mm), the disintegration time of the tablet of Example 2 was 9 seconds, and the disintegration time of the tablet of Example 3 was 13.6 seconds.
From this result, it was confirmed that the disintegration time of the tablet was prolonged when the low melting point oily substance was contained.

<Severe test>
After the tablets obtained in Examples 2 and 3 were stored at 4 ° C. (sealed) or 60 ° C. (open) for 1 week or 2 weeks, the amount of azilsartan related substances was the same as in Test Example 1 above. And measured. The results are shown in Table 5.

  From the results of Table 5, in the tablet of Example 2 that does not contain a low melting point oily substance, the increase in the amount of the azilsartan related substance was suppressed even when stored at 60 ° C. for 2 weeks. In the tablet of Example 3 containing a melting point oily substance, an increase in the amount of an azilsartan-related substance was confirmed when stored at 60 ° C. for 2 weeks.

  Therefore, it was confirmed that the tablet of the present invention preferably contains no low melting point oily substance.

Claims (6)

Adding a mixture of azilsartan and saccharide to either water in which a binder is dissolved or a water-containing organic solvent and kneading to obtain a wet powder;
A method for producing an azilsartan-containing wet tablet comprising compressing and molding the wet powder.   The method for producing an azilsartan-containing wet tablet according to claim 1, wherein the saccharide is at least one of lactose and mannitol.   The method for producing an azilsartan-containing wet tablet according to any one of claims 1 to 2, wherein the binder is polyvinyl alcohol.   An azilsartan-containing wet tablet comprising azilsartan, a saccharide, and a binder.   The azilsartan-containing wet tablet according to claim 4, wherein the saccharide is at least one of lactose and mannitol.   The azilsartan-containing wet tablet according to any one of claims 4 to 5, wherein the binder is polyvinyl alcohol.