JP2017200958A - Tablet containing irbesartan with improved chemical stability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide technical means for producing a tablet containing irbesartan with highly improved chemical stability when stored under a high-temperature and high-humidity environment.SOLUTION: There is provided a tablet containing irbesartan in which content of disintegrant in an uncoated tablet portion is within a range of 4.5 to 15.0 wt.% with respect to the total weight of an uncoated tablet, and disintegrant is selected from carmellose, carmellose calcium, croscarmellose sodium, crospovidone and the like. It is desirable that the tablet is a film-coated tablet.SELECTED DRAWING: None

Description

  The present invention relates to tablets containing irbesartan and discloses a detailed method for improving the stability of irbesartan during storage.

Irbesartan (generic name) has the chemical name 2-butyl-3- {4- [2- (1H-tetrazol-5-yl) phenyl] benzyl} -1,3-diazaspiro [4.4] non-1- It is a long acting angiotensin II receptor antagonist denoted as en-4-one. It is particularly useful for the treatment of cardiovascular diseases such as hypertension and heart failure. A preferred pharmaceutical composition of this drug is a tablet containing irbesartan as an active ingredient, and is administered as a tablet containing 50 to 200 mg of irbesartan.
Irbesartan is a fluffy substance, which has a relatively low substantial weight and very low density. These properties make it difficult to include large amounts of drug in small tablets and to have the desired amount of consistency, hardness, and other desirable tablet properties. Irbesartan also has undesired flow characteristics, causing poor powder flowability and sticking to the surface of a punch or mortar during tableting at high speed, making it difficult to guarantee tablet weight uniformity.

  On the other hand, pharmaceutical preparations such as tablets are not administered to a patient immediately after production, and are generally provided to a patient after being stored for an appropriate period after production. The quality characteristics of pharmaceutical preparations such as tablets are evaluated at the time of the shipping test immediately after production, but the same characteristics must be maintained even when the patient takes them, and the quality characteristics of the preparation change over time. Must not. Therefore, it is naturally necessary to ensure the chemical stability of the drug substance, that is, to suppress the degree of formation of decomposition products to an allowable limit or less.

Prior art of tablets containing irbesartan is disclosed in various documents including Patent Documents 1 to 5 below.
Patent Document 1 discloses a technique relating to a tablet containing irbesartan and about 1 to 5 w / w% of croscarmellose sodium (disintegrant) as an example. Patent Document 2 discloses, as an example, a technique relating to a tablet comprising more than 70 w / w% irbesartan and about 3 to 4 w / w% croscarmellose sodium (disintegrant). Patent Document 3 discloses, as an example, a technique relating to a tablet containing irbesartan and about 25 to 50 w / w% D-mannitol and about 4 to 5 w / w% croscarmellose sodium or crospovidone (disintegrant). Has been. Patent Document 4 discloses, as an example, a technique relating to a tablet containing irbesartan, about 19 to 32 w / w% D-mannitol and about 4.5 w / w% crospovidone (disintegrant). Patent Document 5 discloses a technique relating to a tablet containing irbesartan and about 2.5 w / w% of croscarmellose sodium (disintegrant) as an example. The invention described in these prior art documents is intended to produce a tablet containing irbesartan having effects such as improvement of the dissolution property of irbesartan and improvement of bitterness.
With respect to these prior arts, the present inventor aimed to develop a technique for improving the chemical stability of irbesartan under severe storage conditions.

Japanese Patent No. 3162626 Japanese Patent No. 4880591 Japanese Patent No. 5296456 JP 2010-53048 A Japanese Patent Laid-Open No. 2015-3901

"Avapro (R) Tablets 50mg Avapro (R) Tablets 100mg Avapro (R) Tablets 200mg" Drug Interview Form Revised October 2014 (9th Edition)

  The present invention provides a technical means for producing a tablet containing irbesartan having high chemical stability and improved when stored in a high temperature and high humidity environment.

  As a result of intensive studies to solve the above-mentioned problems, the present inventor produced an irbesartan-containing tablet having a high disintegrant content in the uncoated tablet. It has been found that the stability is improved. The inventor has conducted further intensive studies based on the findings, and has completed the present invention described below.

That is, the present invention is described in the following (1) to (6).
(1) The disintegrant content in the uncoated tablet part is 4.5 to 15.0% by weight with respect to the total weight of the uncoated tablet, and the disintegrant is corn starch, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium Film coated tablet containing irbesartan selected from sodium carmellose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone.
(2) The film-coated tablet according to (1), wherein the content of the disintegrant in the uncoated tablet part is 6.0 to 12.0% by weight based on the total weight of the uncoated tablet.
(3) The film-coated tablet according to (1) or (2), wherein the content of irbesartan in the uncoated tablet part is 35.0 to 65.0% by weight based on the total weight of the uncoated tablet.
(4) The film-coated tablet according to any one of (1) to (3), wherein the disintegrant is selected from carmellose, carmellose calcium, croscarmellose sodium, and crospovidone.
(5) The film-coated tablet according to any one of (1) to (3), wherein the disintegrant is croscarmellose sodium.
(6) A disintegrant containing 2.5 to 5.0% by weight of a disintegrant and irbesartan based on the total weight of the uncoated tablet, and a disintegrant of 2.5 to 5.0% by weight based on the total weight of the uncoated tablet A method for producing a film-coated tablet according to any one of the above (1) to (5), wherein a tablet is produced after mixing with a step of producing an uncoated tablet.

  The tablet containing irbesartan of the present invention has an effect that the generation amount of related substances is suppressed and the chemical stability is high and improved when stored in a high temperature and high humidity environment, and is high quality in the medical field. Makes it possible to provide tablets.

  Hereinafter, the formulation and production method of tablets containing irbesartan of the present invention will be described in detail. However, the following description is an example for explaining the present invention, and is not intended to specifically limit the present invention to this description range.

<Physical properties of irbesartan>
The average particle diameter (d ₅₀ ) of irbesartan used for producing the tablet of the present invention is preferably 1.0 to 15.0 μm, more preferably 7.0 to 12.0 μm. Irbesartan can be adjusted to an arbitrary particle size by appropriately performing dry or wet pulverization as necessary. Irbesartan is contained only in the uncoated tablet (referring to a tablet not covered with a film coating layer) portion, preferably in the range of 35.0 to 65.0% by weight with respect to the total weight of the uncoated tablet, more preferably It is contained in the range of 45.0 to 55.0% by weight.

<Additives that can be used in the manufacture of uncoated tablets>
Examples of the pharmaceutically acceptable additive used for the production of the uncoated tablet according to the present invention include commonly used excipients, disintegrants, binders, lubricants, surfactants, and coloring agents. Etc. can be used.

<Excipient>
The usable excipient is, for example, selected from lactose hydrate, crystalline cellulose, anhydrous lactose and D-mannitol, preferably selected from lactose hydrate and crystalline cellulose, more preferably lactose hydrate and crystals. It is a mixture of cellulose. The excipient is preferably contained in the range of 25.0 to 65.0% by weight, more preferably 35.0 to 45.0% by weight, based on the total weight of the uncoated tablet.

<Disintegrant>
Usable disintegrants are selected from, for example, corn starch, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, more preferably carmellose, It is selected from carmellose calcium, croscarmellose sodium and crospovidone, most preferably croscarmellose sodium. The disintegrant is preferably contained in the range of 4.5 to 15.0% by weight, more preferably in the range of 6.0 to 12.0% by weight, and even more preferably 7%, based on the total weight of the uncoated tablet. 0.5 to 10.0% by weight.

<Binder>
The binder according to the present invention is selected from, for example, hypromellose, hydroxypropylcellulose, povidone, and gelatinized starch, preferably hypromellose. The binder is preferably contained in the range of 1.0 to 5.0% by weight based on the total weight of the uncoated tablet.

<Lubricant>
The lubricant according to the present invention is selected from, for example, magnesium stearate, calcium stearate, and sodium stearyl fumarate, and is preferably magnesium stearate. The lubricant is preferably contained in the range of 0.5 to 3.0% by weight based on the total weight of the uncoated tablet.

<Manufacturing method of uncoated tablet>
The manufacturing method of the uncoated tablet according to the tablet of the present invention is, for example, through a step of manufacturing a granule by adding a binder to a powder obtained by mixing irbesartan, a diluent and a disintegrant and performing wet high-speed stirring granulation. The high-speed agitation granulator used in the present invention is, for example, a vertical granulator (Paurec Co., Ltd.) or a high-speed mixer (Earth Technica). There may be a stirring blade that rotates horizontally at the bottom of the stirring vessel, and an auxiliary blade for crushing the granulated material on the side surface. The mixed powder is charged into the stirring layer, and granulated by adding a solution in which the binder is dissolved in water while rotating the stirring blade at high speed. The rotational speed of the stirring blade is 50 to 500 revolutions per minute. The obtained granules are dried by a fluidized bed dryer or vacuum dryer, sized by a granulator, mixed with a disintegrant and a lubricant, and then compressed into tablets by a tableting machine. Is preferred. The granule preferably contains about 2.5 to 5.0% by weight of a disintegrant based on the total weight of the uncoated tablet.

<Film-coated tablets>
The form of the tablet of the present invention is either an uncoated tablet or a form in which the uncoated tablet is covered with a film coating layer (film coated tablet), preferably a film coated tablet. The film-coated tablet of the present invention can be produced by an ordinary method for producing a film-coated tablet. For example, an uncoated tablet containing irbesartan is charged into a film coating machine, and additives such as a coating agent and a light-shielding agent are added to water or the like. The film-coated tablet of the present invention can be obtained by spraying an uncoated tablet with a solution dispersed in the above solvent and drying.
Usable coating agents include, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), carmellose sodium, ethyl acrylate / methyl methacrylate copolymer dispersion, polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol, macro Hypromellose is most preferably selected from the goals. The coating agent is preferably contained in the range of 90.0 to 99.9% by weight based on the total weight of the film coating layer.
Examples of the light-shielding agent that can be used include titanium oxide, talc, yellow ferric oxide, ferric oxide, and the like, and most preferred is titanium oxide. The light-shielding agent is preferably contained in the range of 0.01 to 10.0% by weight based on the total weight of the film coating layer.

  EXAMPLES The present invention will be described below with reference to examples and the like, but the present invention is not limited to these examples and the like.

The preparation of one tablet of 408.0 mg containing 200 mg of irbesartan will be described.
The tablet of Example 1 was prepared by the wet high speed stirring granulation method using the components shown in Table 1.
Irbesartan 100.0 g, lactose hydrate 64.0 g, crystalline cellulose 20.0 g, and croscarmellose sodium 5.0 g were mixed with a high-speed agitation granulator (VG-01, manufactured by Paulek). Separately, 4.0 g of hypromellose was dissolved in 66 mL of water, added to the mixed powder in the high-speed stirring granulator, and stirred at 370 rpm for 5 minutes to perform wet granulation. The obtained granule was dried with a fluidized bed dryer (MP-01, manufactured by Paulek), and the dried granule was sized by passing through a pulverizer / classifier (Commir, manufactured by Paulek).
To 193.0 g of the obtained sized powder, 5.0 g of croscarmellose sodium and 2.0 g of magnesium stearate were added and mixed with a mixer. The mixed powder was compression-molded with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho) to obtain an uncoated tablet having a weight of 400.0 mg.
Next, the uncoated tablet is put into a coating machine (DRC-200, manufactured by Paulek), to which 19.0 g of hypromellose and 1.0 g of titanium oxide are added in advance to 180 g of purified water, and a uniformly dispersed liquid is sprayed. It was coated to a tablet weight of 408.0 mg and dried to obtain a single-layer film-coated tablet.

The tablet of Example 2 was prepared by the wet high speed stirring granulation method using the components shown in Table 1.
Irbesartan 100.0 g, lactose hydrate 59.0 g, crystalline cellulose 20.0 g, and croscarmellose sodium 7.5 g were mixed with a high-speed agitation granulator (VG-01, manufactured by POWREC). Separately, 4.0 g of hypromellose was dissolved in 76 mL of water, added to the mixed powder in the high-speed stirring granulator, and stirred at 370 rpm for 5 minutes to perform wet granulation. The obtained granule was dried with a fluidized bed dryer (MP-01, manufactured by Paulek), and the dried granule was sized by passing through a pulverizer / classifier (Commir, manufactured by Paulek).
To 190.5 g of the obtained sized powder, 7.5 g of croscarmellose sodium and 2.0 g of magnesium stearate were added and mixed with a mixer. The mixed powder was compression-molded with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho) to obtain an uncoated tablet having a weight of 400.0 mg.
Next, the uncoated tablet is put into a coating machine (DRC-200, manufactured by Paulek), and 19.0 g of hypromellose and 1.0 g of titanium oxide are added to 180.0 g of purified water in advance and sprayed with a uniformly dispersed solution. One tablet was coated to a mass of 408.0 mg and dried to obtain a single-layer film-coated tablet.

The tablet of Example 3 was prepared by the wet high speed stirring granulation method using the components shown in Table 1.
Irbesartan 100.0 g, lactose hydrate 54.0 g, crystalline cellulose 20.0 g, and croscarmellose sodium 10.0 g were mixed with a high-speed agitation granulator (VG-01, manufactured by Paulek). Separately, 4.0 g of hypromellose was dissolved in 81 mL of water, and this was added to the mixed powder in the high speed stirring granulator and stirred at 370 rpm for 5 minutes to perform wet granulation. The obtained granule was dried with a fluidized bed dryer (MP-01, manufactured by Paulek), and the dried granule was sized by passing through a pulverizer / classifier (Commir, manufactured by Paulek).
To 188.0 g of the obtained sized powder, 10.0 g of croscarmellose sodium and 2.0 g of magnesium stearate were added and mixed with a mixer. The mixed powder was compression-molded with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho) to obtain an uncoated tablet having a weight of 400.0 mg.
Next, the uncoated tablet is put into a coating machine (DRC-200, manufactured by Paulek), and 19.0 g of hypromellose and 1.0 g of titanium oxide are added to 180.0 g of purified water in advance and sprayed with a uniformly dispersed solution. One tablet was coated to a mass of 408.0 mg and dried to obtain a single-layer film-coated tablet.

The preparation of 320.0 mg tablets each containing 200 mg irbesartan will be described.
Irbesartan (100.0 g), lactose hydrate (24.0 g), crystalline cellulose (20.0 g), and croscarmellose sodium (5.0 g) were mixed with a high-speed agitation granulator (VG-01, manufactured by POWREC). Separately, 4.0 g of hypromellose was dissolved in 50 mL of water, and this was added to the mixed powder in the high-speed stirring granulator and stirred at 370 rpm for 5 minutes to perform wet granulation. The obtained granule was dried with a fluidized bed dryer (MP-01, manufactured by Paulek), and the dried granule was sized by passing through a pulverizer / classifier (Commir, manufactured by Paulek).
To 153.0 g of the obtained sized powder, 5.0 g of croscarmellose sodium and 2.0 g of magnesium stearate were added and mixed with a mixer. The mixed powder was compression-molded with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho) to obtain a tablet having a weight of 320.0 mg.
Next, the uncoated tablet is put into a coating machine (DRC-200, manufactured by Paulek), and 19.0 g of hypromellose and 1.0 g of titanium oxide are added to 180.0 g of purified water in advance and sprayed with a uniformly dispersed solution. One tablet was coated to a mass of 328.0 mg and dried to obtain a single-layer film-coated tablet.

[Comparative Example 1]
Tablets were prepared by the wet high speed agitation granulation method using the composition shown in Table 1.
Irbesartan 100.0 g, lactose hydrate 64.0 g, crystalline cellulose 22.0 g, and croscarmellose sodium 4.0 g were mixed with a high-speed agitation granulator (VG-01, manufactured by Paulek). Separately, 4.0 g of hypromellose was dissolved in 81 mL of water, and this was added to the mixed powder in the high speed stirring granulator and stirred at 370 rpm for 5 minutes to perform wet granulation. The obtained granule was dried with a fluidized bed dryer (MP-01, manufactured by Paulek), and the dried granule was sized by passing through a pulverizer / classifier (Commir, manufactured by Paulek).
To 194.0 g of the obtained sized powder, 4.0 g of croscarmellose sodium and 2.0 g of magnesium stearate were added and mixed with a mixer. The mixed powder was compression-molded with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho) to obtain an uncoated tablet having a weight of 400.0 mg.
Next, the uncoated tablet is put into a coating machine (DRC-200, manufactured by Paulek), to which 19.0 g of hypromellose and 1.0 g of titanium oxide are added in advance to 180 g of purified water, and a uniformly dispersed liquid is sprayed. It was coated to a tablet weight of 408.0 mg and dried to obtain a single-layer film-coated tablet.

[Comparative Example 2]
Tablets were prepared by the wet high speed agitation granulation method using the composition shown in Table 1.
Irbesartan 100.0 g, lactose hydrate 64.0 g, crystalline cellulose 24.0 g, and croscarmellose sodium 3.0 g were mixed with a high-speed agitation granulator (VG-01, manufactured by Paulek). Separately, 4.0 g of hypromellose was dissolved in 66 mL of water, added to the mixed powder in the high-speed stirring granulator, and stirred at 370 rpm for 5 minutes to perform wet granulation. The obtained granule was dried with a fluidized bed dryer (MP-01, manufactured by Paulek), and the dried granule was sized by passing through a pulverizer / classifier (Commir, manufactured by Paulek).
To 195.0 g of the obtained sized powder, 3.0 g of croscarmellose sodium and 2.0 g of magnesium stearate were added and mixed with a mixer. The mixed powder was compression-molded with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho) to obtain an uncoated tablet having a weight of 400.0 mg.
Next, the uncoated tablet is put into a coating machine (DRC-200, manufactured by Paulek), to which 19.0 g of hypromellose and 1.0 g of titanium oxide are added in advance to 180 g of purified water, and a uniformly dispersed liquid is sprayed. It was coated to a tablet weight of 408.0 mg and dried to obtain a single-layer film-coated tablet.

(Test Example 1)
For each of the tablets obtained in Examples 1, 2, and 3 and Comparative Examples 1 and 2, the total affinity of irbesartan was immediately after production and after storage for 2 weeks in an environment at a temperature of 60 ° C. and a relative humidity of 75% for 2 weeks. The amount of substance was measured by HPLC method. The measured results are shown in Table 2.

  The content of the disintegrant (croscarmellose sodium) relative to the total weight of the uncoated tablet is 5.0% in Example 1, 7.5% in Example 2, 10.0% in Example 3, and Comparative Example 1 4.0% and Comparative Example 2 is 3.0%. From Table 2, the tablets of Examples 1 to 3 had significantly lower amounts of increase in related substances after storage in a high temperature and high humidity environment as compared with Comparative Examples 1 and 2. Therefore, it is surprisingly suggested that the chemical stability of irbesartan can be remarkably improved in the range where the disintegrant content is more than 4.0% based on the total weight of the uncoated tablet.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the medical field the high quality tablet containing the irbesartan which has the effect which the chemical stability under the storage conditions was high and was improved.

Claims (6)

The disintegrant content in the uncoated tablet part is 4.5 to 15.0% by weight based on the total weight of the uncoated tablet, and the disintegrant is corn starch, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose A film-coated tablet containing irbesartan selected from sodium, sodium carboxymethyl starch, croscarmellose sodium and crospovidone. The film-coated tablet according to claim 1, wherein the content of the disintegrant in the uncoated tablet part is 6.0 to 12.0% by weight based on the total weight of the uncoated tablet. The film-coated tablet according to claim 1 or 2, wherein the content of irbesartan in the uncoated tablet part is 35.0 to 65.0% by weight based on the total weight of the uncoated tablet. The film-coated tablet according to any one of claims 1 to 3, wherein the disintegrant is selected from carmellose, carmellose calcium, croscarmellose sodium, and crospovidone. The film-coated tablet according to any one of claims 1 to 3, wherein the disintegrant is croscarmellose sodium. After mixing granules containing 2.5-5.0% by weight disintegrant and irbesartan with respect to the total weight of the uncoated tablet with 2.5-5.0% by weight disintegrant with respect to the total weight of the uncoated tablet The method for producing a film-coated tablet according to any one of claims 1 to 5, through a step of producing an uncoated tablet by tableting.