JP2018080119A - Method for maintaining and stabilizing the rapid dissolution of azilsartan in a pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an azilsartan-containing pharmaceutical composition that is capable of maintaining the quick elution of azilsartan and also improving the stability of the azilsartan over time, and a method for producing the same; and a method for maintaining the quick elution of azilsartan in a pharmaceutical composition and stabilizing the azilsartan.SOLUTION: A pharmaceutical composition contains azilsartan, the azilsartan having an average particle size of more than 1.6 μm and less than 14.3 μm.SELECTED DRAWING: None

Description

  The present invention relates to an azilsartan-containing pharmaceutical composition and a method for producing the same, and a method for maintaining the rapid dissolution of azilsartan in the pharmaceutical composition and stabilizing the azilsartan.

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.

  So far, as a pharmaceutical composition containing azilsartan, a solid pharmaceutical composition containing azilsartan, a low melting point oily 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 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, 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.

  Therefore, an azilsartan-containing pharmaceutical composition capable of improving the temporal stability of azilsartan while maintaining rapid elution of azilsartan, a method for producing the same, and rapid elution of azilsartan in the pharmaceutical composition At present, there is a strong demand to provide a method for maintaining the properties and stabilizing the azilsartan.

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, the present invention relates to an azilsartan-containing pharmaceutical composition capable of improving the temporal stability of azilsartan while maintaining rapid elution of azilsartan, a method for producing the same, and azilsartan in the pharmaceutical composition It is an object of the present invention to provide a method for maintaining the rapid elution property of and stabilizing the azilsartan.

Means for solving the problems are as follows. That is,
<1> A pharmaceutical composition containing azilsartan,
The azilsartan-containing pharmaceutical composition is characterized in that the average particle size of the azilsartan is more than 1.6 μm and less than 14.3 μm.
<2> The azilsartan-containing pharmaceutical composition according to <1>, wherein the average particle size of the azilsartan is 5.0 μm to 12.0 μm.
<3> A method for producing an azilsartan-containing pharmaceutical composition comprising using azilsartan having an average particle size of more than 1.6 μm and less than 14.3 μm.
<4> The method for producing an azilsartan-containing pharmaceutical composition according to <3>, wherein the average particle size of the azilsartan is 5.0 μm to 12.0 μm.
<5> A method for maintaining rapid dissolution of azilsartan in a pharmaceutical composition and stabilizing the azilsartan,
The method is characterized by using azilsartan having an average particle diameter of more than 1.6 μm and less than 14.3 μm.
<6> The method according to <5>, wherein an average particle size of the azilsartan is 5.0 μm to 12.0 μm.

  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 temporal stability of azilsartan can be improved, maintaining the quick dissolution property of azilsartan. It is possible to provide an azilsartan-containing pharmaceutical composition and a method for producing the same, and a method for maintaining rapid dissolution of azilsartan in the pharmaceutical composition and stabilizing the azilsartan.

FIG. 1 is a diagram showing the results of verification of the influence degree of the average particle diameter in Test Example 1.

(Azilsartan-containing pharmaceutical composition)
The azilsartan-containing pharmaceutical composition of the present invention contains at least azilsartan, 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.

-Average particle diameter (D50)-
The average particle size (D50) of the azilsartan is not particularly limited as long as it is more than 1.6 μm and less than 14.3 μm, and can be appropriately selected according to the purpose, but is 5.0 μm to 12.0 μm. Is preferable, and 7.0 μm to 10.0 μm is more preferable. It is advantageous that the average particle diameter (D50) is within the above preferable range in that the elution property of azilsartan in the pharmaceutical composition and the stability over time are more excellent.
The average particle diameter (D50) in the present invention refers to a volume-based average particle diameter measured by a laser diffraction method. In principle, this means the particle size at the time when particles having a volume of 50% are sorted by sieving the particles of a certain volume in order from the smallest one (hereinafter also referred to as “median diameter”).

  The method for adjusting the average particle size (D50) of the azilsartan is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a method using a jet mill, a method using a pin mill, or a feather mill is used. Examples thereof include a method, a method using a ball mill, a method using a hammer mill, and a method using a mortar.

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

<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 according to the purpose. , Saccharides, binders, stabilizers, lubricants, disintegrants, flavoring agents, fragrances and the like. 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 other component in the said azilsartan containing pharmaceutical composition, and a commercial item may be used for it.
There is no restriction | limiting in particular as content of the other component in the said azilsartan containing pharmaceutical composition, According to the objective, it can select suitably.

-Sugar-
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.
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.

-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.

-Stabilizer-
There is no restriction | limiting in particular as said stabilizer, According to the objective, it can select suitably, For example, a triethyl citrate, macrogol, glycerol, polysorbate, sucrose fatty acid ester etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together. Among these, triethyl citrate is preferable in that the stability with time of azilsartan can be further improved.

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

-Disintegrant-
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.

-Flavoring agent-
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.

-Fragrance-
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.

  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.

  There is no restriction | limiting in particular as a manufacturing method of the said azilsartan containing pharmaceutical composition, Although it can select suitably according to the objective, It is preferable to manufacture with the manufacturing method of the azilsartan containing pharmaceutical composition of this invention mentioned later. .

The azilsartan-containing pharmaceutical composition of the present invention improves the stability of azilsartan over time while maintaining rapid dissolution of azilsartan by using azilsartan of more than 1.6 μm and less than 14.3 μm. can do.
In the present invention, rapid dissolution means that the second dissolution solution (pH 6.8) of the Japanese Pharmacopoeia is used as the dissolution test solution, and the second dissolution method (paddle method) of the Japanese Pharmacopoeia General Test Method is used. When the test is performed, it means that the dissolution rate at 15 minutes is 85% or more.

(Method for producing azilsartan-containing pharmaceutical composition)
The method for producing the azilsartan-containing pharmaceutical composition of the present invention is not particularly limited as long as an azilsartan having an average particle size of more than 1.6 μm and less than 14.3 μm is used, and a known method can be appropriately selected. However, a method comprising a tableting powder preparation step, a tableting step, and other steps as necessary is preferred.

<Powder preparation process for tableting>
The tableting powder preparation step is a step of obtaining a tableting powder containing azilsartan by mixing azilsartan and components selected from other components as necessary.
There is no restriction | limiting in particular as an aspect of the said mixing, It can select suitably according to the objective, For example, the aspect which mixes the powder of the said azilsartan and another component as needed, The said azilsartan is included. The aspect etc. which mix a granulated material and another component as needed are mentioned. The mixing method and conditions are not particularly limited and may be appropriately selected depending on the purpose.
The granulated product containing azilsartan may be composed only of azilsartan or may contain the other components.
There is no restriction | limiting in particular as an aspect of the said other component, According to the objective, it can select suitably, For example, a powder, a granulated material, etc. are mentioned.
There is no restriction | limiting in particular as the said granulation method, According to the objective, it can select suitably, For example, a wet granulation method etc. are mentioned.
The wet granulation method is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a fluidized bed granulation method, an agitation granulation method, an extrusion granulation method, and a spray granulation method. Can be mentioned. Among these, the stirring granulation method and the fluidized bed granulation method are preferable.
There is no restriction | limiting in particular as conditions for the said granulation, According to the objective, it can select suitably.

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

-Other ingredients-
There is no restriction | limiting in particular as said other component, According to the objective, it can select suitably, For example, what was described in the item of <the other component> of the azilsartan containing pharmaceutical composition of this invention mentioned above etc. Can be mentioned.

<Tabletting process>
The tableting step is a step of tableting the tableting powder to obtain an uncoated tablet.
There is no restriction | limiting in particular as the method of the said tableting method, According to the objective, it can select suitably, For example, the method of using a rotary type tableting machine etc. are mentioned.
There is no restriction | limiting in particular as conditions for the said tableting, According to the objective, it can select suitably.

<Other processes>
There is no restriction | limiting in particular as said other process, According to the objective, it can select suitably, For example, the film coating process etc. which apply | coat a coating solution to the said uncoated tablet and obtain a film-coated tablet etc. are mentioned.
There is no restriction | limiting in particular as a method of the said other process, A well-known method can be selected suitably.

  According to the method for producing an azilsartan-containing pharmaceutical composition of the present invention, the azilsartan-containing pharmaceutical composition of the present invention having both rapid dissolution properties and stability over time can be efficiently produced.

(Method for maintaining rapid dissolution of azilsartan in pharmaceutical composition and stabilizing said azilsartan)
As a method for maintaining the rapid dissolution of azilsartan in the pharmaceutical composition of the present invention and stabilizing the azilsartan, as long as an azilsartan having an average particle size of more than 1.6 μm and less than 14.3 μm is used, There is no particular limitation, and a known method can be appropriately selected. However, a method including a tableting powder preparation step, a tableting step, and other steps as necessary is preferable.

<Powder preparation process for tableting>
The tableting powder preparation step is the same as that described in the item <Tablet powder preparation step> of the above-described method for producing the azilsartan-containing pharmaceutical composition of the present invention.

<Tabletting process>
The tableting step is the same as that described in the item <tablet step> of the method for producing the azilsartan-containing pharmaceutical composition of the present invention described above.

<Other processes>
There is no restriction | limiting in particular as said other process, According to the objective, it can select suitably, For example, it described in the item of <the other process> of the manufacturing method of the azilsartan containing pharmaceutical composition of the above-mentioned this invention. Things.

  According to the method for stabilizing azilsartan in the pharmaceutical composition of the present invention, it is possible to suppress a decrease in the stability of azilsartan over time while maintaining rapid elution of azilsartan.

  Hereinafter, although this invention is demonstrated more concretely based on a test example, this invention is not limited to these test examples.

(Test Example 1)
<Production of tablets-1 to 6>
-Azilsartan-
The following 6 types of azilsartans having different average particle diameters (D50) were prepared. In addition, the particle size distribution of each azilsartan was measured by a dry method using a laser diffraction particle size distribution measuring device Mastersizer 3000 (manufactured by Malvern).
(1) Azilsartan (raw material for tablet-1) having an average particle size of 27.4 μm
(2) Azilsartan having an average particle diameter of 14.3 μm (raw material for tablet-2)
(3) Azilsartan (raw material for tablet-3) having an average particle size of 8.3 μm
(4) Azilsartan (raw material for tablet-4) having an average particle size of 7.9 μm
(5) Azilsartan (raw material for tablet-5) having an average particle size of 5.3 μm
(6) Azilsartan (raw material for tablet-6) having an average particle size of 1.6 μm

-Preparation of powder for tableting-
Lactose (Phamatose 200M, manufactured by DFE pharma) 66.8 g, and corn starch (Corn Starch W, manufactured by Nippon Corn Starch Co., Ltd.) 20 g, Hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) 6 g, low-substituted hydroxypropyl cellulose (L-HPC LH21, manufactured by Shin-Etsu Chemical Co., Ltd.) 6 g was weighed and mixed with a high-speed stirring mixer (Mechanomill 1L, Okada Seiko Co., Ltd.) to obtain an excipient mixed powder.
9.88 g of this excipient mixed powder was taken, 2 g of azilsartan of any of the above (1) to (6) and 0.12 g of magnesium stearate were added and mixed to obtain a powder for tableting.

-Tableting-
The tableting powder was tableted at a pressure of 8,000 N using a universal material testing apparatus (Autograph, manufactured by Shimadzu Corporation) and a punch and mortar with a diameter of 8.0 mm, and 240 mg per tablet ( Tablets 1 to 6 containing 40 mg as azilsartan were obtained.
Table 1 below shows the composition of one tablet.

<Evaluation>
-Dissolution test-
For each of tablets-1 to 6, a dissolution test was conducted by the Japanese Pharmacopoeia General Test Method Dissolution Test Method 2 (Paddle Method) using the Japanese Pharmacopoeia Dissolution Test Solution 2 (pH 6.8) as the dissolution test solution. . The results are shown in Table 2.
The amount of azilsartan eluted in the dissolution test was measured and calculated as follows.

--Measurement and calculation of the amount of eluted azilsartan--
[Preparation of standard solution]
Azilsartan drug substance 22.22 mg was added to methanol and dissolved to make 100 mL (solution (A)). 10 mL of the solution (A) was taken and methanol was added to make 50 mL (solution (B)). The solution (B) and the dissolution test solution were mixed at 1: 1 (volume ratio) to obtain a standard solution.

[Preparation of sample solution]
A liquid sampled from the vessel at a predetermined time (5 minutes, 10 minutes, or 15 minutes) and methanol were mixed at 1: 1 (volume ratio) to obtain a sample solution to be subjected to UPLC.

[Analysis conditions]
Apparatus: UPLC (manufactured by Waters)
Detection wavelength: 250 nm
Column temperature: 30 ° C
Mobile phase: Buffer (10 mM potassium dihydrogen phosphate solution adjusted to pH 3.0 with phosphoric acid): A mixture of acetonitrile = 30: 70 (volume ratio) Injection volume: 0.5 μL
Flow rate: 0.3 mL / min Column: ACQUITY UPLC BEH C18 (manufactured by Waters, particle size 1.7 μm, 2.1 mm × 100 mm)

[Calculation of the amount of azilsartan]
From the results of the analysis, the amount of azilsartan (dissolution rate of azilsartan) was calculated from the following formula.
Dissolution rate of azilsartan (%) = (ru / rs) × (Cs / L) × V × 100
In the above formula, “ru” represents the area of azilsartan in the sample solution, “rs” represents the area of azilsartan in the standard solution, and “Cs” represents the concentration (mg / mL of azilsartan in the standard solution). "L" indicates the azilsartan content of the sample, and "V" indicates the amount of the test solution.

  From the results of Table 2, it was confirmed that Tablets 3 to 6 using azilsartan having an average particle size of less than 14.3 μm showed rapid dissolution. On the other hand, in tablets-1 and 2 using azilsartan having an average particle size of 14.3 μm or more, appropriate elution was not obtained.

-Stability test-
About each of tablet -1-6, after storing at 60 degreeC (open | release) for 1 week, the quantity of the related substance of azilsartan, ie, the quantity of the decomposition substance of azilsartan, was measured using HPLC as follows. did. 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. The results are shown in Table 4.

--Measurement of amount of related substances of azilsartan--
[Preparation of sample solution]
90% acetonitrile was added to the tablet after storage to make 20 mL.
A solution obtained by filtering the obtained 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]
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: 10 mM potassium dihydrogen phosphate solution, adjusted to pH 3.0 with 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 3 below

  From the results of Table 4, it was considered that the stability tends to decrease as the average particle size of azilsartan decreases. In particular, the stability is drastically reduced between tablet-5 using azilsartan with an average particle size of 5.3 μm and tablet-6 using azilsartan with an average particle size of 1.6 μm. It was.

-Verification of the influence of average particle size-
Based on tablet 1 which had the largest average particle size of azilsartan used and was stable, for each tablet, “difference (A) from the total amount of related substances in tablet-1” and “tablet-1 The difference (B) from the average particle size of azilsartan was determined, and the ratio ((A) / (B)) between them was calculated. The ratio can be considered as a parameter that contributes to a decrease in the stability of azilsartan when the average particle size of azilsartan is reduced by a certain amount. The results are shown in Table 5 and FIG.

The horizontal axis of FIG. 1 shows the average particle diameter (μm) of azilsartan, and the vertical axis shows the ratio ((A) / (B)).
From the results shown in Table 5 and FIG. 1, there is a dramatic difference between Tablet-5 using azilsartan having an average particle size of 5.3 μm and Tablet-6 using azilsartan having an average particle size of 1.6 μm. It was confirmed that the stability was lowered.

From the above results, by using azilsartan having an average particle size of more than 1.6 μm and less than 14.3 μm, it is possible to maintain rapid dissolution of azilsartan in a pharmaceutical composition and to stabilize azilsartan. confirmed.
In general, it is not known that there is a correlation between reducing the average particle size of the drug substance and reducing the stability of the drug substance.

Claims (6)

A pharmaceutical composition containing azilsartan,
The azilsartan-containing pharmaceutical composition, wherein the average particle size of the azilsartan is more than 1.6 μm and less than 14.3 μm.   The azilsartan-containing pharmaceutical composition according to claim 1, wherein the average particle size of the azilsartan is 5.0 µm to 12.0 µm.   A method for producing an azilsartan-containing pharmaceutical composition comprising using an azilsartan having an average particle size of more than 1.6 μm and less than 14.3 μm.   The method for producing an azilsartan-containing pharmaceutical composition according to claim 3, wherein the average particle size of the azilsartan is 5.0 μm to 12.0 μm. A method of maintaining rapid dissolution of azilsartan in a pharmaceutical composition and stabilizing said azilsartan,
A method comprising using azilsartan having an average particle diameter of more than 1.6 μm and less than 14.3 μm.   The method according to claim 5, wherein the average particle size of the azilsartan is 5.0 μm to 12.0 μm.