JP2017001973A - Irbesartan-containing tablets - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide irbesartan-containing tablets having improved dissolution property of irbesartan after long-term storage.SOLUTION: According to one embodiment to the invention, provided is an irbesartan-containing tablet obtained by granulating a mixture containing irbesartan and a disintegrant to prepare a granulated material and further mixing the granulated material and the disintegrant, the granulated material characterized by containing 6% by weight or more of the disintegrant to 100% by weight of the irbesartan. Also provided is the irbesartan-containing tablet obtained by granulating the mixture containing irbesartan and a low substituted hydroxypropylcellulose to prepare the granulated material and further mixing the granulated material and the low substituted hydroxypropylcellulose, the granulated material containing 10% by weight of the low substituted hydroxypropylcellulose to 100% by weight of the irbesartan.SELECTED DRAWING: Figure 1

Description

The present invention relates to irbesartan-containing tablets. In particular, the present invention relates to irbesartan-containing tablets with improved dissolution properties of irbesartan after long-term storage.

Irbesartan (2-Butyl-3- [4- [2- (1H-tetrazol-5-yl) phenyl] benzyl] -1,3-diazaspiro [4.4] non-1-en-4-one) Since it selectively acts on the AT ₁ (A II type 1) receptor involved in the increase and competitively inhibits the binding of angiotensin II (A II), it is an effective drug for the treatment of hypertension.

For example, in Patent Document 1, in order to realize quick disintegration of a tablet, the density and volume of the tablet are made within a certain range, croscarmellose sodium, crospovidone, carmellose calcium, carboxymethyl starch sodium. In addition, it is described that one or more disintegrants selected from low-substituted hydroxypropylcellulose are contained in an amount of 0.5 to 10% by weight based on the total amount of the preparation.

Patent Document 2 describes an irbesartan-containing pharmaceutical composition containing one or more binders selected from hydroxypropylcellulose and polyvinyl alcohol in order to obtain rapid disintegration in an orally disintegrating tablet.

Also known is a pharmaceutical containing an ingredient effective for the treatment of hypertension together with irbesartan by an action mechanism different from that of irbesartan. For example, Patent Document 3 discloses a pharmaceutical composition containing irbesartan, amlodipine or a salt thereof. Things are listed.

JP2015-003901A JP 2010-053047 A JP 2013-078893 A

As a result of the study of the irbesartan-containing tablet by the present inventors, it has been clarified that the dissolution property of irbesartan decreases after long-term storage. Although it is also described in the above-mentioned patent document that irbesartan has low affinity for water, the decrease in the dissolution property of irbesartan due to long-term storage has not been studied so far, including the above-mentioned patent document, Not reported to date.

The present invention is the first to examine the dissolution properties of irbesartan after long-term storage, which has not been studied so far. An object of the present invention is to provide an irbesartan-containing tablet having improved dissolution properties of irbesartan after long-term storage.

According to one embodiment of the present invention, an irbesartan-containing tablet is prepared by granulating a mixture containing irbesartan and a disintegrant to prepare a granulated product, and further mixing the granulated product and the disintegrant. The granulated product contains an irbesartan-containing tablet, wherein the disintegrant is 6% by weight or more with respect to 100% by weight of the irbesartan.

In the irbesartan-containing tablet, the disintegrant comprises croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate, carmellose, carmellose calcium, corn starch, partially pregelatinized starch, and combinations thereof It may be selected from a group.

According to one embodiment of the present invention, a granulated product is prepared by granulating a mixture containing irbesartan and low-substituted hydroxypropylcellulose, and the granulated product and the low-substituted hydroxypropylcellulose are prepared. The irbesartan-containing tablet, wherein the granulated product contains 10% by weight or more of the low-substituted hydroxypropylcellulose with respect to 100% by weight of the irbesartan. Provided.

Further, according to one embodiment of the present invention, there is provided a tablet manufacturing method comprising irbesartan particles containing irbesartan and a disintegrant, wherein the irbesartan is 6% by weight or more with respect to 100% by weight of the irbesartan. There is provided a method for producing an irbesartan-containing tablet, wherein a disintegrant is mixed and granulated to prepare a granulated product, and the granulated product and the disintegrant are further mixed to form a tablet.

According to the present invention, there is provided an irbesartan-containing tablet having improved dissolution properties of irbesartan after long-term storage. Furthermore, irbesartan-containing tablets also improve the storage stability under high temperature and high humidity conditions for a long time.

It is a figure which shows the elution delay rate of the irbesartan based on the Example of this invention. It is a figure which shows the saturation solubility in the water of the irbesartan based on the Example of this invention. It is a figure which shows the elution delay rate of the irbesartan based on the Example of this invention. It is a figure which shows the elution delay rate of the irbesartan based on the Example of this invention.

Hereinafter, the irbesartan-containing tablet according to the present invention will be described. However, the irbesartan-containing tablet of the present invention is not construed as being limited to the description of the embodiments and examples shown below. In the present invention, “internal addition” means addition and mixing when granulating particles containing irbesartan. In the present invention, “post-addition” means adding and mixing after granulating, drying, and sizing particles containing an active ingredient.

As described above, as a result of investigations by the present inventors, it has been clarified that the dissolution property of irbesartan is lowered after long-term storage. The present inventors can effectively improve the delay of dissolution of irbesartan after long-term storage by preparing particles containing irbesartan and a predetermined amount of disintegrant and tableting with other additives. I found a new thing. It was also found that particles granulated with the internal addition of a disintegrant also improve the storage stability of the components effective for the treatment of hypertension under long-term high-temperature and high-humidity conditions.

The irbesartan-containing tablet according to the present invention is an irbesartan-containing tablet obtained by granulating a mixture containing irbesartan and a disintegrant to prepare a granulated product, and further mixing the granulated product and the disintegrant. A granule contains 6 weight% or more of disintegrating agents with respect to 100 weight% of irbesartan. In the present embodiment, the irbesartan-containing tablet contains a predetermined amount of irbesartan, and the content of irbesartan per tablet is, for example, 50 mg, 100 mg, or 200 mg, but is not limited thereto.

In the irbesartan-containing tablet according to the present invention, the disintegrant is croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, carmellose, carmellose calcium, corn starch, partially pregelatinized starch, and combinations thereof Selected from the group consisting of

In one embodiment, the dissolution properties of irbesartan after long-term storage are improved by containing croscarmellose sodium in the granulated irbesartan before tableting in an amount of 6% by weight or more with respect to 100% by weight of irbesartan. can do.

In one embodiment, the disintegrant is preferably selected so that the saturated solubility of water is comparable to existing formulations. For example, croscarmellose sodium improves the elution rate in water after long-term storage as the content increases, but is preferable as a formulation because the saturated solubility in water becomes larger than that of existing formulations. Absent. However, by replacing some or all of croscarmellose sodium with low-substituted hydroxypropylcellulose, the dissolution of irbesartan after long-term storage is improved and the saturated solubility of water is equivalent to that of existing formulations. This is preferable. In the irbesartan-containing tablet according to the present invention, in order to improve the dissolution property of irbesartan after long-term storage, a low-substituted hydroxypropylcellulose is used alone in 100% by weight of irbesartan in the irbesartan granule before tableting. Or it is preferable that content of the disintegrant used in combination becomes 10 weight% or more.

The irbesartan-containing tablet according to the present invention may contain a therapeutically effective ingredient other than irbesartan. For example, amlodipine or a salt thereof may be contained. In one embodiment, the irbesartan-containing tablet according to the present invention may contain amlodipine besylate so as to be 5 mg or 10 mg as amlodipine per 100 mg of irbesartan, but is not limited thereto.

The irbesartan-containing tablet according to the present invention may further contain excipients, binders, lubricants and the like as additives.

Excipients include, for example, lactose, D-mannitol, crystalline cellulose, fructose, purified sucrose, sucrose, purified sucrose spherical granules, anhydrous lactose, sucrose / starch spherical granules, semi-digested starch, glucose, glucose hydrate, powder Sugar, pullulan, β-cyclodextrin, aminoethylsulfonic acid, candy powder, sodium chloride, citric acid, sodium citrate, glycine, calcium gluconate, L-glutamine, tartaric acid, potassium hydrogen tartrate, ammonium carbonate, dextran 40, dextrin , Calcium lactate, povidone, macrogol (polyethylene glycol) 1500, macrogol 1540, macrogol 4000, macrogol 6000, anhydrous citric acid, DL-malic acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, dihydrogen phosphate Sodium, L-as Laginate, alginate, carmellose sodium, hydrous silicon dioxide, crospovidone, calcium glycerophosphate, magnesium aluminate, calcium silicate, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, wheat flour, wheat starch, wheat germ Flour, wheat germ oil, rice flour, rice starch, cellulose acetate phthalate, titanium oxide, magnesium oxide, dihydroxyaluminum aminoacetate, tricalcium phosphate, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, natural aluminum silicate, corn starch Corn starch granule, potato starch, hydroxypropyl cellulose, hydroxypropyl starch, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate Examples thereof include granulated products and calcium dihydrogen phosphate, and lactose, D-mannitol and crystalline cellulose are preferable.

Examples of binders include hypromellose, corn starch, pregelatinized starch, partially pregelatinized starch, gum arabic, gum arabic powder, gelatin, agar, dextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, ethylcellulose, carboxymethylethylcellulose, carmellose , Carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose and the like, and hypromellose and polyvinyl alcohol are preferred.

The lubricant includes, for example, metal stearate, sucrose fatty acid ester, talc, light anhydrous silicic acid, hydrous silicon dioxide, hydrogenated oil, etc., preferably metal stearate, magnesium stearate preferable.

(Production method)
The irbesartan-containing tablet according to the present invention can be produced according to a production method known in the pharmaceutical field. For example, irbesartan (added with other therapeutically effective ingredients if necessary), an excipient and a disintegrant are mixed, this mixture is wet granulated, and sized to obtain a sized product. A powder before tableting containing irbesartan can be obtained by mixing a disintegrant, a binder, and a lubricant with the obtained sized product. By compressing the pre-tablet powder containing irbesartan, the irbesartan-containing tablet according to the present invention can be produced. Tableting can be performed by a conventional method using a commercially available tableting machine. In the production method of the present invention, a commercial machine such as “LFS-GS-2J” (Fukae Kogyo) can be used as the agitation granulation.

In the method for producing an irbesartan-containing tablet according to the present invention, the disintegrant was added and mixed (internal addition) when granulating the particles containing irbesartan, and the particles containing irbesartan were granulated, dried and sized. It is preferable to add and mix later (post-addition). The disintegrant added internally is preferably added in an amount of 6% by weight or more with respect to 100% by weight of irbesartan. Moreover, it is preferable that the particle | grains containing an internal additive post-add a further disintegrating agent. In the irbesartan-containing tablet according to the present invention, the post-added disintegrant can promote the disintegration of the irbesartan-containing tablet immediately after taking it and improve the dissolution delay of irbesartan. Further, the disintegrant added internally improves the dissolution delay of irbesartan from irbesartan-containing tablets produced using the present invention stored for a long time under high temperature and high humidity conditions for a predetermined time after taking, for example, 30 minutes. be able to.

(Dissolution test method)
In this specification, the dissolution rate of irbesartan is evaluated by measuring the dissolution rate of irbesartan in the tablet by the 16th revised Japanese Pharmacopoeia dissolution test method (paddle method). The dissolution test second solution or water shall be used for the dissolution test.

Specific examples and test results of the aforementioned irbesartan-containing tablet according to the present invention will be shown and described in more detail.

Example 1
In Example 1, 50.0 g of irbesartan, 20.0 g of lactose hydrate (DFE, pharmatose (200M)), 10.0 g of crystalline cellulose (Asahi Kasei, ph101), croscarmellose sodium (FMC, Akizol) 3.0 g and 1.0 g of light anhydrous silicic acid (Freund Sangyo, Ad Solider 101) were added to a mortar and mixed with a pestle. To this mixture, 33.3 g of an aqueous solution of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5E) was added and kneaded. After the kneaded material was crushed with a No. 8 sieve, a small hot-air circulating thermostat (mini jet oven) / Dried by Toyama Sangyo MO-921) and sized with sieve No. 22 to obtain a sized product. To the obtained sized product, 11.0 g of croscarmellose sodium (FMC, Akzisol), 1.0 g of light anhydrous silicic acid (Freund Sangyo, Adsolider) and 1.0 g of magnesium stearate (Taihei Chemical) were added to add vinyl. It mixed with the bag and the powder before tableting containing irbesartan was obtained. Using a tableting machine (VELA5, Kikusui Seisakusho), the powder before tableting was tableted to a weight of 200 mg, and the irbesartan-containing tablet of Example 1 was obtained.

(Example 2)
In Example 2, except that a mixture was prepared by changing to 18.0 g of lactose hydrate (DFE, pharmatose (200M)) and 16.0 g of croscarmellose sodium (FMC, axizol). In the same manner as in 1, irbesartan-containing tablets were obtained.

(Example 3)
In Example 3, 150.0 g of irbesartan, 44.6 g of lactose hydrate (DFE, pharmatose (200M)), 23.4 g of crystalline cellulose ph101, low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd., L- 15.0 g of HPC (21)) was added to the mortar and mixed with a pestle. To this mixture, 78.4 g of an aqueous solution of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5E) was added and kneaded. After the kneaded material was crushed with a No. 8 sieve, a small hot-air circulating thermostat (mini jet oven) / Dried by Toyama Sangyo MO-921) and sized with sieve No. 22 to obtain a sized product. To the obtained sized product, croscarmellose sodium (FMC, Akzizol) 18.0 g, low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (21)) 15.0 g, light anhydrous silicic acid (Freund Industrial, Adsolider 101) 2.25 g and magnesium stearate (Taihei Chemical) 2.25 g were added and mixed in a plastic bag to obtain a pre-tablet powder containing irbesartan. Using a tableting machine (VELA5, Kikusui Seisakusho), the powder before tableting was tableted to a weight of 185 mg to obtain an irbesartan-containing tablet of Example 3.

(Comparative Example 1)
As comparative example 1, lactose hydrate (DFE, pharmatose (200M)) was changed to 23.0 g and croscarmellose sodium (FMC, azizol) was changed to 11.0 g. In the same manner as in 1, irbesartan-containing tablets were obtained.

(Comparative Example 2)
As Comparative Example 2, Example 1 was prepared except that a mixture was prepared by changing to 22.0 g of lactose hydrate (DFE, pharmatose (200M)) and 12.0 g of croscarmellose sodium (FMC, Akizol). In the same manner as above, tablets containing irbesartan were obtained.

(Dissolution test)
The irbesartan-containing tablets of Examples 1-2 and Comparative Examples 1-2 were stored at 40 ° C. and 75% humidity for 1 month. Using 900 ml of the second dissolution test solution as the test solution, the irbesartan-containing tablets of Examples 1 and 2 and Comparative Examples 1 and 2, according to the 16th revised Japanese Pharmacopoeia dissolution test method (paddle method) 5, 10, The mixture was stirred for 15, 30, 45, 60 and 90 minutes, and the dissolution rate was measured. In the dissolution test, the dissolution rate at the above time was measured for the irbesartan-containing tablets of Examples 1-2 and Comparative Examples 1-2 immediately after production, and irbesartan of Examples 1-2 and Comparative Examples 1-2 after storage. The difference from the dissolution rate for the contained tablets was determined and used as the dissolution delay rate. The measurement result of the elution delay rate is shown in FIG.

From the results of FIG. 1, in the irbesartan-containing tablets of Comparative Examples 1 and 2 in which the content of croscarmellose sodium is less than 6% by weight relative to 100% by weight of irbesartan, the dissolution delay after storage is sufficiently improved. There wasn't. On the other hand, in the irbesartan-containing tablets of Examples 1 and 2 containing croscarmellose sodium in an amount of 6% by weight or more with respect to 100% by weight of irbesartan particles, the dissolution delay after storage was improved. From this result, it became clear that the irbesartan-containing tablet according to this example improves the dissolution properties of irbesartan after long-term storage.

About the irbesartan containing tablet of Examples 1-3 and Comparative Examples 1-2, the saturation solubility with respect to water was confirmed. Using 900 ml of water as the test solution, the irbesartan-containing tablets of Examples 1 to 3 and Comparative Examples 1 and 2 were subjected to 5, 16, 15, 30, according to the 16th revised Japanese Pharmacopoeia Dissolution Test Method (Paddle Method). It stirred for 45, 60, 90, 120, 240, 300, and 360 minutes, and measured the elution rate, respectively. FIG. 2 shows the measurement results of saturation solubility in water.

From the results shown in FIG. 2, it was revealed that the saturation solubility increases as the content of croscarmellose sodium increases. For this reason, disintegrants that can be controlled to an equivalent saturation solubility in irbesartan formulations were investigated. The appropriate saturation solubility in the irbesartan preparation means that the saturation solubility is about 20% in the 16th revised Japanese Pharmacopoeia dissolution test method (paddle method). In Example 3, in which low-substituted hydroxypropylcellulose was added as a disintegrant added in place of croscarmellose sodium, a value indicating an appropriate saturation solubility was shown, and it was revealed that the saturation solubility could be controlled. .

The effect of adding low-substituted hydroxypropylcellulose was further verified. The irbesartan-containing tablets of Examples 2 and 3 were stored at 40 ° C. and 75% humidity for 3 months. Using the second solution of 900 ml of dissolution test as the test solution, the dissolution delay rate was determined by the dissolution test method described above. The measurement result of the elution delay rate is shown in FIG.

From the results shown in FIG. 3, the irbesartan-containing tablet of Example 2 containing only 10% by weight of croscarmellose sodium and croscarmellose sodium in 100% by weight of irbesartan in irbesartan particles even after storage for 3 months. Instead, it became clear that the dissolution properties of irbesartan were improved in the irbesartan-containing tablet of Example 3 containing 10% by weight of low-substituted hydroxypropylcellulose.

Example 4
In addition to irbesartan, irbesartan-containing tablets containing amlodipine besylate as an active ingredient were verified to be able to improve the dissolution properties of irbesartan. In Example 4, 60.0 g of irbesartan, 14.4 g of D-mannitol (Mitsubishi Foodtech, Mannit (P)), 8.36 g of crystalline cellulose (Asahi Kasei ph101), low-substituted hydroxypropylcellulose (Shin-Etsu) Chemical industry, L-HPC (31)) 6.0 g was added to a mortar and mixed with a pestle. After adding 20.4 g of an aqueous solution of polyvinyl alcohol (Nippon Synthetic Chemical Co., EG-05) to this mixture and kneading, the kneaded material was crushed with a No. 8 sieve, and then a small hot air circulation type incubator (minijet Oven / Toyama Sangyo MO-921) and sized with sieve No. 22 to obtain a sized product. To the obtained sized product, 8.32 g of amlodipine besylate, 6.0 g of low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (31)), and 1.08 of magnesium stearate (Taihei Chemical) g was added and mixed with a plastic bag to obtain a powder before tableting. Using a tableting machine (VELA5, Kikusui Seisakusho), the powder before tableting was tableted to a weight of 177 mg, and the irbesartan-containing tablet of Example 4 was obtained. In Example 4, irbesartan-containing tablets were stored at 60 ° C. and 60% humidity for 2 weeks.

(Example 5)
As Example 5, the irbesartan-containing tablet of Example 4 described above was stored at 60 ° C. and 60% humidity for 1 month.

Using the second solution of 900 ml of dissolution test as the test solution, the dissolution delay rate was determined by the dissolution test method described above. The measurement results of the elution delay rate are shown in FIG. In the irbesartan-containing tablet of Example 4, no dissolution delay was observed, and almost no dissolution delay was observed when stirring for 30 minutes. Also, no dissolution delay was observed in the irbesartan-containing tablet of Example 5 stored for 1 month. From this result, even in irbesartan-containing tablets containing amlodipine besylate as an active ingredient in addition to irbesartan, elution of irbesartan by containing 10% by weight or more of low-substituted hydroxypropylcellulose with respect to 100% by weight of irbesartan It became clear that there was no delay.

(Example 6)
It was verified whether the stability of irbesartan-containing tablets containing irbesartan and amlodipine besylate as active ingredients could be improved. In Example 6, irbesartan 500.0 g, D-mannitol (Mitsubishi Foodtech, Mannit (P)) 82.85 g, crystalline cellulose (Asahi Kasei ph101) 110.00 g, croscarmellose sodium (FMC, Akzizol) ) 50.0 g was added to a mortar and mixed with a pestle. To this mixture, 13.50 g of an aqueous solution of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5M) was added and kneaded. The kneaded product was crushed with a No. 8 sieve, and then a small hot-air circulating thermostat (mini jet oven) / Dried by Toyama Sangyo MO-921) and sized with sieve No. 22 to obtain a sized product. Amlodipine besylate 34.65 g, croscarmellose sodium (FMC, Akzizol) 50.0 g, and magnesium stearate (Taihei Chemical) 9.00 g were added to the obtained sized product, and mixed in a plastic bag. A powder before tableting was obtained. Using a tableting machine (VELA5, Kikusui Seisakusho), the powder before tableting was tableted to a weight of 170 mg, and the irbesartan-containing tablet of Example 6 was obtained.

(Related substances)
As an evaluation of the stability of the irbesartan-containing tablet of Example 6, the formulation of Example 6 which was stored in an unwrapped state under the condition of a temperature of 40 ° C. and a humidity of 75% was subjected to liquid chromatography using irbesartan and amlodipine besylate. Purity was evaluated. The ratio to the respective peak areas was calculated from the peak areas of the related substances derived from irbesartan and amlodipine besylate to obtain the total related substances. The measurement results of the related substances of Example 6 are shown in Table 1. In Example 6, not only irbesartan but also amlodipine besylate, no increase in total related substances was observed after storage, and it was revealed that the preparation can withstand unwrapping.

Claims (4)

An irbesartan-containing tablet in which a mixture containing irbesartan and a disintegrant is granulated to prepare a granulated product, and the granulated product and the disintegrant are further mixed,
The granulated product contains 6% by weight or more of the disintegrant with respect to 100% by weight of the irbesartan. The disintegrant is selected from the group consisting of croscarmellose sodium, low substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, carmellose, carmellose calcium, corn starch, partially pregelatinized starch and combinations thereof The irbesartan-containing tablet according to claim 1, wherein A granule is prepared by granulating a mixture containing irbesartan and low-substituted hydroxypropylcellulose, and is an irbesartan-containing tablet in which the granulated product and the low-substituted hydroxypropylcellulose are further mixed,
The granulated product contains 10% by weight or more of the low-substituted hydroxypropylcellulose with respect to 100% by weight of the irbesartan. A method for producing an irbesartan-containing tablet containing irbesartan and a disintegrant,
The irbesartan and 6% by weight or more of the disintegrant with respect to 100% by weight of the irbesartan are mixed and granulated to prepare a granulated product, and the granulated product and the disintegrant are further mixed to form a tablet. A method for producing an irbesartan-containing tablet.

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