JP2017081859A - Methods for producing telmisartan-containing tablets - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide methods for producing telmisartan-containing tablets in which dissolution of telmisartan is improved.SOLUTION: A method for producing a tablet containing telmisartan, a diluent, meglumine, and an excipient comprises a first granulation step of granulating telmisartan, a diluent, and meglumine to obtain a primary granulated material, a second granulation step of granulating the primary granulated material and a diluent to obtain a second granulated material, a mixing step of mixing the second granulated material and an excipient to obtain a mixture, and a tableting step of tableting the mixture to obtain a tablet.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a telmisartan-containing tablet. In particular, the present invention relates to a method for producing a telmisartan-containing tablet with improved dissolution of telmisartan.

  Telmisartan, an angiotensin II receptor antagonist, is widely used as one of the therapeutic agents for hypertension. Since telmisartan has low solubility in the physiological pH range between 1 and 7 in the gastrointestinal tract, a technology to improve the solubility of telmisartan by adding meglumine, which is a basic substance, and a surfactant to telmisartan is reported. (See Patent Document 1).

JP-T-2006-502194

  However, meglumine, which is a basic substance, has the property of easily absorbing moisture. Therefore, when telmisartan and meglumine are granulated, telmisartan absorbs moisture and crystallizes, and thus there is a problem that the dissolution property of telmisartan in the tablet decreases.

  Therefore, in the present invention, by performing secondary granulation using a diluent, telmisartan in the granulated product is suppressed from absorbing moisture and crystallized, and the dissolution property of telmisartan in the tablet is improved. It aims at providing the manufacturing method of a telmisartan containing tablet.

The present invention is as follows.
[1] A method for producing a tablet comprising telmisartan, a diluent, meglumine, and an excipient,
A primary granulation step of granulating telmisartan, a diluent, and meglumine to obtain a primary granulated product,
A secondary granulation step of granulating the primary granulated product and a diluent to obtain a secondary granulated product;
A mixing step of mixing the secondary granulated product and an excipient to obtain a mixture;
A tableting step of tableting the mixture to obtain a tablet;
The manufacturing method of the tablet containing this.
[2] The method for producing a tablet according to [1], wherein the primary granulated product further contains a binder.
[3] The method for producing a tablet according to [2], wherein the binder of the primary granulated product is hydroxypropylmethylcellulose.

  According to the present invention, telmisartan in the granulated product is moisture-absorbed and crystallized by performing secondary granulation using a diluent, despite containing meglumine that easily absorbs moisture. The manufacturing method of the telmisartan containing tablet which suppressed that and improved the dissolution property of the telmisartan in a tablet is provided.

About the tablet of Example 1 and the tablet of Comparative Example 1, the dissolution behavior of telmisartan was measured by a dissolution test (test solution pH 1.2: Japanese Pharmacopoeia Second Solution, paddle rotation speed 50 rpm), and the results were displayed. Is. About the tablet of Example 1 and the tablet of Comparative Example 1, the dissolution behavior of telmisartan was measured by a dissolution test (test solution pH 1.2: Japanese Pharmacopoeia Second Solution, paddle rotation speed 100 rpm), and the results were displayed. Is. For the tablet of Example 1 and the tablet of Comparative Example 1, the dissolution behavior of telmisartan was measured by a dissolution test (test solution pH 3.0: Japanese Pharmacopoeia Second Solution, paddle rotation speed 50 rpm), and the results were displayed. It is. For the tablet of Example 1 and the tablet of Comparative Example 1, the dissolution behavior of telmisartan was measured by a dissolution test (test solution pH 6.8: Japanese Pharmacopoeia Second Solution, paddle rotation speed 50 rpm), and the results were displayed. It is. About the tablet of Example 3 and the tablet of Example 4, the dissolution behavior of telmisartan was measured by a dissolution test (test solution pH 3.0: Japanese Pharmacopoeia Second Solution, paddle rotation speed 50 rpm), and the results were displayed. It is. For the tablet of Example 3 and the tablet of Example 4, the dissolution behavior of telmisartan was measured by a dissolution test (test solution pH 1.2: Japanese Pharmacopoeia Second Solution, paddle rotation speed 100 rpm), and the results were displayed. It is. About the tablet of Example 3 and the tablet of Example 4, according to a dissolution test (test solution pH 1.2: Japanese Pharmacopoeia Second Solution, paddle rotation speed 100 rpm) after storage for 1 week at 25 ° C. and 50% RH. The elution behavior of telmisartan was measured and the results were displayed.

  Hereinafter, the manufacturing method of the telmisartan containing tablet which concerns on this invention is demonstrated. However, the method for producing a telmisartan-containing tablet of the present invention is not construed as being limited to the description of the embodiments and examples shown below.

  The method for producing a telmisartan-containing tablet of the present invention is a method for producing a tablet comprising telmisartan, a diluent, meglumine, and an excipient, and 1) granulates telmisartan, a diluent, and meglumine. A primary granulation step for obtaining a primary granulated product, 2) a secondary granulation step for obtaining a secondary granulated product by granulating the primary granulated product and a diluent, and 3) a secondary granulated product. And a mixing step of mixing an excipient to obtain a mixture, and 4) a tableting step of tableting the mixture to obtain a tablet.

1. Primary granulation step The primary granulation step in the present invention may be a step of obtaining a primary granulated product while spraying a binder solution in which telmisartan and meglumine are dissolved by introducing a diluent into the fluidized bed granulator. .

(Fluidized bed granulation)
In fluid bed granulation, air is fed from below the packed bed of the powder composition in the fluid bed granulator, and the powder composition is suspended and dispersed in the air stream, that is, the fluid bed In this method, the particles are grown by spraying a binding liquid onto the fluidized bed from a spray nozzle to cause the particles to adhere and aggregate with each other.

(Fluidized bed granulator)
Fluidized bed granulators are classified into batch type, semi-continuous type, continuous type, etc. according to operational classification, and fluidized bed type, spouted fluidized bed type, spouted bed type, etc., depending on the position and spray direction of the spray nozzle. However, any apparatus can be used in the present invention.
The intake temperature of the fluidized bed granulator is 50 to 100 ° C., preferably 60 to 90 ° C., and the exhaust temperature is 20 to 60 ° C., preferably 30 to 50 ° C. It is good to adjust. Although the spraying time varies depending on the charged amount of the raw material powder and the spraying speed (amount), it usually ends in 240 to 480 minutes. When spraying is completed, if the suction is continued for about 5 to 30 minutes and dried, a dried granulated product is obtained.

(Diluent)
The granulated powder composition is a diluent, but it is preferable to use a diluent that has a low moisture value and can protect moisture absorption. For example, D-mannitol, dulcitol Sugar alcohols such as ribitol and xylitol, monosaccharides such as glucose, polysaccharides such as sucrose, and the like.

  On the other hand, sorbitol, a sugar alcohol, has the property of easily absorbing moisture, so when telmisartan and meglumine are granulated, telmisartan absorbs moisture and crystallizes, reducing the dissolution of telmisartan in tablets. There is a risk. Therefore, it is preferable to use a sugar alcohol as a diluent other than sorbitol. In addition, erythritol, a sugar alcohol, has a low hygroscopic property, but may be deliquescent at a certain temperature or humidity. Therefore, it is preferable to use a sugar alcohol as a diluent other than erythritol. From the above, it is preferable to use D-mannitol and dulcitol, more preferably D-mannitol, from the viewpoint of having low hygroscopicity and being difficult to deliquesce with a certain temperature or humidity above a certain level. .

  The content of the diluent when performing primary granulation in the tablet is preferably 20% by mass or more and 70% by mass or less, more preferably 30% by mass or more and 50% by mass or less.

(Binder)
In primary granulation, the diluent is granulated with a granulation liquid containing telmisartan and meglumine. The granulating liquid preferably contains a binder, and the binder may be water alone, but preferably contains other binder together with water. A binder can also be added to the diluent.

The binder used for the primary granulation is, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, popidone, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and the like.
On the other hand, hypromellose acetate succinate and carboxymethylethylcellulose, which are generally used as binders, are enteric and may reduce the dissolution of telmisartan in the stomach (pH 1.2-3). Therefore, it is preferable to use a binder other than hypromellose acetate succinate or carboxymethylethylcellulose.
From the above, from the viewpoint that telmisartan suppresses crystallization due to moisture absorption, and further improves the dissolution of telmisartan in the stomach (pH 1.2-3), hydroxypropylmethylcellulose, hydroxypropyl Preferred are cellulose and popidone, and more preferred is hydroxypropylmethylcellulose.

  The content of the binder used in the primary granulation is preferably 0.3% by mass or more and 7.0% by mass or less, and more preferably 0.5% by mass or more and 5.0% by mass or less with respect to the tablet weight. When hydroxypropylmethylcellulose is used as the primary granulating binder, the content of hydroxypropylmethylcellulose is preferably 0.5% by mass or more and 6.0% by mass or less, more preferably 1.0% by mass with respect to the tablet weight. The mass is not less than 5.0% by mass.

(Telmisartan)
The tablet in the present invention contains a predetermined amount of telmisartan, and the content of telmisartan is, for example, 20 mg, 40 mg, or 80 mg / tablet.

(Meglumine)
Meglumine in the present invention is a solubilizing agent for improving the dissolution of telmisartan.
The amount may be any amount necessary to improve the dissolution property of telmisartan. For example, the amount is the same as the content of telmisartan and is 20 mg, 40 mg or 80 mg / tablet.
Further, the content ratio of telmisartan: meglumine is preferably 0.5: 1 to 10: 1, more preferably telmisartan: meglumine = 1: 1 to 2: 1.

2. Secondary granulation step The secondary granulation step in the present invention is performed by granulating a composition containing the primary granulated product obtained in the primary granulation step and a diluent using a binding solution in which the binder is dissolved. In this step, a secondary granulated product is obtained. Secondary granulation can be performed with a fluidized bed granulator.

(Diluent)
The diluent used when performing the secondary granulation is preferably the same as the diluent used when performing the primary granulation. By performing secondary granulation using a diluent, the secondary granulated product suppresses moisture absorption and suppresses crystallization of telmisartan in the primary granulated product, thereby increasing the dissolution property of telmisartan. be able to.
The content of the diluent when performing secondary granulation with respect to the tablet weight is preferably 3.0% by mass or more and 30% by mass or less, and more preferably 5.0% by mass or more and 20% by mass or less.

(Binder)
When performing secondary granulation, the composition containing a primary granulated material and a diluent is granulated with a granulating liquid. The granulating liquid preferably contains a binder, and the binder may contain only water, but preferably contains other binder together with water. Other binders can also be added to the composition comprising the primary granulate and diluent.

The binder used for the secondary granulation is, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.
In particular, in the stomach (pH 1.2 to 3), from the viewpoint that the dissolution property of telmisartan in the tablet can be enhanced, the binder used in the secondary granulation is hydroxypropylcellulose or hydroxypropylmethylcellulose. Of these, hydroxypropylcellulose is more preferable.
Further, when performing the secondary granulation, by using hydroxypropyl cellulose as a binder, the binding force between the primary granulated product and the diluent is increased, so that the tableting property can be improved.

  The content of the binder in the secondary granulation is preferably 0.2% by mass or more and 7.0% by mass or less, and more preferably 0.3% by mass or more and 5.0% by mass or less with respect to the tablet weight. When hydroxypropylcellulose is used as a binder in secondary granulation, the content of hydroxypropylcellulose is preferably 0.2% by mass or more and 3.0% by mass or less, more preferably 0.00% by mass with respect to the tablet weight. It is 3 mass% or more and 1.0 mass% or less.

(Average particle size of secondary granulated product)
The average particle diameter of the obtained secondary granulated product is preferably 80 μm or more and 300 μm or less, more preferably 90 μm or more and 260 μm or less, and further preferably 90 μm or more and 180 μm or less. Thus, by setting the average particle diameter of the secondary granulated product to a value within the above range, tableting troubles do not occur during tablet production, and the hardness of the produced tablet can be maintained. .
The average particle size was measured by the 16th revised Japanese Pharmacopoeia Manual 2011, General Test Method, Particle Size Measurement Method 2 and Screening Method.

(Surfactant)
In the physiological pH range between pH 1 and 7 of the gastrointestinal tract, from the viewpoint of improving the dissolution of telmisartan in the tablet, it may further contain a surfactant when performing primary granulation or secondary granulation. preferable.
Surfactants are, for example, polysorbate, poloxamer or pluronic, polyethylene glycol, polyethylene glycol monostearate, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil.
From the viewpoint of further improving the dissolution property of telmisartan in the tablet, polysorbate, poloxamer or pluronic, and polyethylene glycol are preferably used, and polysorbate is more preferable.
Examples of usable polysorbates include polysorbate 20, polysorbate 40, polysorbate 80, and the like, but polysorbate 80 is preferably used.
The content of the surfactant in the tablet is preferably 2.0% by mass or more and 5.0% by mass or less, and more preferably 3.1% by mass or more and 4.7% by mass or less.

3. Mixing process The mixing process in this invention is a process of mixing a secondary granulated material and an excipient | filler, and obtaining a mixture.
As long as the secondary granulated product and the excipient are mixed, there is no particular limitation, and a known method can be appropriately selected according to the purpose. Examples thereof include a tumbler type mixer.
Examples of the excipient include a fluidizing agent, a lubricant, a disintegrant, and a coloring agent.

(Fluidizer)
Examples of the fluidizing agent used in the mixing step are light anhydrous silicic acid, talc, colloidal silica, and the like. It is preferable to use light anhydrous silicic acid from the viewpoints of low hygroscopic properties, improved tablet hardness and dissolution, and improved fluidity.
The content of the fluidizing agent in the tablet is preferably 0.03% by mass or more and 0.2% by mass or less, and more preferably 0.05% by mass or more and 0.1% by mass or less.

(lubricant)
The lubricant used in the mixing step is, for example, magnesium stearate, stearic acid, sodium stearyl fumarate or the like.
The content of the lubricant in the tablet is preferably 0.3% by mass or more and 1.5% by mass or less, and more preferably 0.4% by mass or more and 1.2% by mass or less.

(Disintegrant)
Disintegrants used in the mixing step are, for example, sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, dried corn starch, low-substituted hydroxypropylcellulose, carmellose calcium and the like.
The content of the disintegrant in the tablet is preferably 3% by mass or more and 50% by mass or less, and more preferably 5% by mass or more and 40% by mass or less.

(Coloring agent)
Examples of the colorant used in the mixing step include iron oxide red or yellow, titanium dioxide, and talc.
The content of the colorant in the tablet is preferably 0.03% by mass or more and 0.5% by mass or less, and more preferably 0.05% by mass or more and 0.3% by mass or less.

4). Tableting step The tableting step in the present invention is a step of tableting the mixture obtained in the mixing step to obtain a tablet.
There is no restriction | limiting in particular as a tableting method, According to the objective, a well-known method can be selected suitably, For example, a rotary tableting machine, a hydraulic press machine, a single tableting machine etc. are mentioned.

The tableting pressure at the time of tableting is not particularly limited, and can be appropriately adjusted depending on the device used, the principle, the size, the type of the main drug, and the like. From the viewpoint of obtaining a tablet having a very good touch when taken, the tableting pressure for tableting the mixture is preferably 600 kg / cm ² or more and 1200 kg / cm ² or less, for example.

  The temperature at the time of tableting is not particularly limited as long as the effect of the present invention is not impaired. In this invention, it is preferable to set to the grade which does not melt | dissolve or melt | dissolve the saccharide particle to be used, and it is enough to carry out normally at room temperature (for example, about 20-30 degreeC).

5. Coating process In order to coat the tablet obtained by the tableting process, a coating process may be provided. A coating process is a process of providing at least 1 layer of film coating with respect to the tablet obtained by the tableting process. There is no restriction | limiting in particular as a method of coating, A well-known method can be suitably selected according to the objective, For example, it is performed using a film coating apparatus.

  Examples of the coating agent used in the coating step include high molecular weight polyethylene glycol, hydroxypropyl cellulose, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, and methacrylic acid polymers.

6). Telmisartan-containing tablet The telmisartan-containing tablet obtained by the present invention improves the dissolution of telmisartan in the physiological pH range between pH 1 and 7 of the gastrointestinal tract and is free from tableting obstacles in industrial production. A manufacturing method can be provided.

Below, an Example, a comparative example, and a test example are given and this invention is demonstrated concretely.
The composition (Example 1, Example 2, and Comparative Example 1) of the tablet of the following Table 1 was adjusted.

(Preparation method of Example 1)
In a fluidized bed granulator / dryer (FD-WSG-15 type, manufactured by Paulek), a solution prepared by dissolving 144 mg of telmisartan, 144 g of meglumine, and 21.6 g of polysorbate 80 in 233.64 g of D-mannitol in about 2. While spraying at 0 g / min, primary granulation was performed while maintaining the inside of the machine at around 70 ° C., and a primary granulated product was obtained.
The resulting primary granulated product was sprayed with a solution obtained by dissolving 57.6 g of D-mannitol and 3.6 g of hydroxypropylcellulose in purified water at a rate of about 5.0 g / min while keeping the inside of the apparatus at around 70 ° C. Granulation was performed to obtain a secondary granulated product (average particle size: 260 μm).
The obtained secondary granulated product was sized with a screen diameter of 500 mm to obtain a sized product.
To the obtained sized product, 0.36 g of light anhydrous silicic acid and 7.2 g of magnesium stearate were added and mixed in a polyethylene bag to obtain a mixture.
Subsequently, the obtained mixture was compression-molded to a diameter of 10 mm with a tableting pressure of 900 kg / cm ² using a rotary tableting machine (VIRGO19 type, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a telmisartan-containing tablet having a tablet mass of 340 mg. .

(Preparation method of Example 2)
In a fluidized bed granulator / dryer (FD-WSG-15 type, manufactured by Paulek), a solution obtained by dissolving 237.24 g of D-mannitol, 144 g of telmisartan, 144 g of meglumine, and 21.6 g of polysorbate 80 in purified water was about 2. While spraying at 0 g / min, primary granulation was performed while maintaining the inside of the machine at around 70 ° C., and a primary granulated product was obtained.
The resulting primary granulated product is subjected to secondary granulation while keeping the inside of the apparatus at around 70 ° C. while spraying a solution obtained by dissolving only 57.6 g of D-mannitol in purified water at about 5.0 g / min. The next granulated product (average particle size: 230 μm) was obtained.
The obtained granulated and dried product was sized with a screen diameter of 500 mm to obtain a sized product.
To the obtained sized product, 0.36 g of light anhydrous silicic acid and 7.2 g of magnesium stearate were added and mixed in a polyethylene bag to obtain a mixture.
Subsequently, although the obtained mixture was compression-molded using the rotary type tableting machine (VIRGO19 type | mold by Kikusui Seisakusho Co., Ltd.), the case where the tableting trouble generate | occur | produced was also seen.

(Preparation method of Comparative Example 1)
In a fluidized bed granulator / dryer (FD-WSG-15 type, manufactured by Paulek), a solution obtained by dissolving 3600 g of telmisartan, 3600 g of meglumine, and 540 g of polysorbate 80 in 725 g of D-mannitol at about 40 g / min. However, primary granulation was performed while maintaining the interior of the machine at around 70 ° C. to obtain a primary granulated product.
The obtained primary granulated product was sized with a screen diameter of 500 mm to obtain a sized product.
To the obtained sized product, 9 g of light anhydrous silicic acid and 126 g of magnesium stearate were added and mixed in a polyethylene bag to obtain a mixture.
Subsequently, the obtained mixture was compression-molded to a diameter of 10 mm with a tableting pressure of 900 kg / cm ² using a rotary tableting machine (VELA type 5 manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a telmisartan-containing tablet having a tablet mass of 340 mg. .

Dissolution evaluation test (Test Example 1)
About the telmisartan containing tablet obtained in Example 1 and Comparative Example 1, using a Japanese Pharmacopoeia dissolution tester (paddle method), dissolution test (test solution pH 1.2: Japanese Pharmacopoeia Second Solution, paddle rotation speed) The elution behavior of telmisartan was measured at 50 rpm), and the results are shown in FIG.
From FIG. 1, it was found that the dissolution rate of telmisartan of the tablet of Example 1 was higher than that of the tablet of Comparative Example 1 over 15 minutes after the start of the test.

(Test Example 2)
About the telmisartan containing tablet obtained in Example 1 and Comparative Example 1, using a Japanese Pharmacopoeia dissolution tester (paddle method), dissolution test (test solution pH 1.2: Japanese Pharmacopoeia Second Solution, paddle rotation speed) The elution behavior of telmisartan was measured at 100 rpm, and the results are shown in FIG.
From FIG. 2, the dissolution rate of telmisartan of the tablet of Example 1 is about 60% by weight 30 minutes after the start of the test, whereas the dissolution rate of telmisartan of the tablet of Comparative Example 1 is about 40%. It was found that it was far below the weight percent.

(Test Example 3)
About the telmisartan containing tablet obtained in Example 1 and Comparative Example 1, using a Japanese Pharmacopoeia dissolution tester (paddle method), dissolution test (test solution pH 3.0: Japanese Pharmacopoeia Second Solution, paddle rotation speed) The dissolution behavior of telmisartan was measured at 50 rpm), and the results are shown in FIG.
From FIG. 3, the dissolution rate of telmisartan of the tablet of Example 1 was about 90% by weight 15 minutes after the start of the test, whereas the dissolution rate of telmisartan of the tablet of Comparative Example 1 was about 80%. It was found that it was less than wt%.

(Test Example 4)
About the telmisartan containing tablet obtained in Example 1 and Comparative Example 1, using a Japanese Pharmacopoeia dissolution tester (paddle method), dissolution test (test solution pH 6.8: Japanese Pharmacopoeia Second Solution, paddle rotation speed) The elution behavior of telmisartan was measured at 50 rpm), and the results are shown in FIG.
From FIG. 4, the dissolution rate of telmisartan in the tablet of Example 1 was about 90% by weight 15 minutes after the start of the test, whereas the dissolution rate of telmisartan in the tablet of Comparative Example 1 was about 80%. It was found that it was less than wt%.

  From the results of Test Examples 1 to 4, the telmisartan-containing tablet of Example 1 produced by secondary granulation was more dissolved than the telmisartan-containing tablet of Comparative Example 1 produced only by primary granulation. Has been found to be excellent and can effectively improve the problem of poor solubility in water.

Tabletability evaluation test (Test Example 5)
Subsequently, in Example 1 and Comparative Example 1, the tableting failure when each mixture was tableted was evaluated.
Continuous tableting for 20 minutes at a speed of 12 rotations per minute on a rotary tableting machine capable of tableting 18 tablets under the conditions of 20 ° C, 50% RH and 30 ° C, 65% RH (after 1 day) The adhesion and appearance of the specified three sets of punches and mortars were visually evaluated, and tableting properties were evaluated according to the following criteria.
○: Remarkable adhesion to the wrinkles and mortars is not observed, and no remarkable unevenness is observed on the tablet surface.
Δ: One or more of wrinkles, adhesion to the mortar, and irregularities on the tablet surface are observed, but are mild.
X: Any one or more of adhesion to the wrinkles and mortars and irregularities on the tablet surface is observed, and the degree is remarkable.
The evaluation results are shown in Table 2 below.

  From the results in Table 2, the tablet of Example 1 produced by secondary granulation can suppress the tableting trouble, while Comparative Example 1 showed the tableting trouble.

  From the above results, in the tablet of Example 1 produced by secondary granulation, dissolution of telmisartan is improved in the test solution pH 1.2 to 6.8, and a tablet free from tableting troubles can be obtained. did it.

  Subsequently, when producing a tablet by secondary granulation, in order to confirm the effect at the time of including a binder in a primary granulated material, the composition of the tablet of the following Table 3 (Examples 3 and 4) was adjusted.

(Preparation method of Example 3)
About 40 g of a solution obtained by dissolving 3200 g of telmisartan, 3200 g of meglumine, 4432 g of polysorbate 80, 240 g of hydroxypropyl methylcellulose in 5048 g of D-mannitol in a fluidized bed granulator / dryer (type FD-WSG-15 manufactured by Paulec) Primary granulation was carried out while keeping the inside of the machine at around 70 ° C. while spraying at a rate of / min, and a primary granulated product was obtained.
The resulting primary granulated product was subjected to secondary granulation while keeping the inside of the apparatus at around 80 ° C. while spraying a solution obtained by dissolving 1280 g of D-mannitol and 80 g of hydroxypropyl cellulose in purified water at about 40 g / min. The next granulated product (average particle size: 167 μm) was obtained.
The obtained secondary granulated product was sized with a screen diameter of 500 mm to obtain a sized product.
To the obtained sized product, 8 g of light anhydrous silicic acid and 112 g of magnesium stearate were added and mixed in a polyethylene bag to obtain a mixture.
Subsequently, the obtained mixture was compression-molded to a diameter of 10 mm with a tableting pressure of 900 kg / cm ² using a rotary tableting machine (VIRGO19 type, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a telmisartan-containing tablet having a tablet mass of 340 mg. .

(Preparation method of Example 4)
In a fluidized bed granulator / dryer (FD-WSG-15 type, manufactured by Paulek), a solution prepared by dissolving 3200 g of telmisartan, 3200 g of meglumine, and 432 g of polysorbate 80 in purified water was sprayed at about 40 g / min. However, primary granulation was performed while maintaining the interior of the machine at around 70 ° C. to obtain a primary granulated product.
The resulting primary granulated product was subjected to secondary granulation while keeping the inside of the apparatus at around 80 ° C. while spraying a solution obtained by dissolving 1280 g of D-mannitol and 80 g of hydroxypropyl cellulose in purified water at about 40 g / min. The next granulated product (average particle size: 153 μm) was obtained.
The obtained secondary granulated product was sized with a screen diameter of 500 mm to obtain a sized product.
To the obtained sized product, 8 g of light anhydrous silicic acid and 112 g of magnesium stearate were added and mixed in a polyethylene bag to obtain a mixture.
Subsequently, the obtained mixture was compression-molded to a diameter of 10 mm with a tableting pressure of 900 kg / cm ² using a rotary tableting machine (VIRGO19 type, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a telmisartan-containing tablet having a tablet mass of 340 mg. .

Dissolution evaluation test (Test Example 6)
About the telmisartan-containing tablet obtained in Example 3 and Example 4, using a Japanese Pharmacopoeia dissolution tester (paddle method), dissolution test (test solution pH 3.0: Japanese Pharmacopoeia Second Solution, paddle rotation speed) 50 rpm), and the elution behavior of telmisartan was measured, and the results are shown in FIG.
From FIG. 5, it was found that the dissolution rates of telmisartan in the tablets of Example 3 and Example 4 were almost the same.

(Test Example 7)
About the telmisartan-containing tablet obtained in Example 3 and Example 4, dissolution test (test solution pH 1.2: Japanese Pharmacopoeia second solution, paddle rotation speed 100 rpm) using a dissolution tester (paddle method) of Japanese Pharmacopoeia The elution behavior of telmisartan was measured, and the results are shown in FIG.
From FIG. 6, the dissolution rate of telmisartan of the tablet of Example 3 is about 80% by weight 30 minutes after the start of the test, whereas the dissolution rate of telmisartan of the tablet of Example 4 is about 60% by weight. Met.

(Test Example 8)
The telmisartan-containing tablets obtained in Example 3 and Example 4 were stored at 25 ° C. and 50% RH for 1 week, and then the dissolution test (test solution) was performed using a dissolution tester (paddle method) of the Japanese Pharmacopoeia. pH 1.2: Japanese Pharmacopoeia second solution, paddle rotation speed 100 rpm), and the elution behavior of telmisartan was measured, respectively, and the results are shown in FIG.
From FIG. 7, the dissolution rate of telmisartan of the tablet of Example 3 was about 90% by weight 30 minutes after the start of the test, whereas the dissolution rate of telmisartan of the tablet of Example 4 was about 60% by weight. It was.

  From the results of Test Examples 6 to 8, the tablet of Example 3 containing a binder in the primary granulated product has a significantly improved dissolution rate of telmisartan at a test solution pH of 1.2, and has a problem of poor solubility in water. It has been found that it can be effectively improved.

Tabletability evaluation test (Test Example 9)
In Example 3 and Example 4, the tableting failure when each mixture was tableted was evaluated.
Tableting property was evaluated in the same manner as in Test Example 5 under the conditions of 50% RH or 70% RH.
The evaluation results are shown in Table 4 below.

  From the results in Table 4, it was found that the tabletability of the tablet of Example 3 containing a binder in the primary granulated product was also improved.

  From the above results, it was found that the tablet of Example 3 containing the binder in the primary granulated product has an improved dissolution rate of telmisartan and improved tabletability at the test solution pH 1.2.

The specific contents of each component used in Examples 1 to 4 and Comparative Example 1 are as shown in Table 5.

Claims (3)

A method for producing a tablet comprising telmisartan, a diluent, meglumine, and an excipient,
A primary granulation step of granulating telmisartan, a diluent, and meglumine to obtain a primary granulated product,
A secondary granulation step of granulating the primary granulated product and a diluent to obtain a secondary granulated product;
A mixing step of mixing the secondary granulated product and an excipient to obtain a mixture;
A tableting step of tableting the mixture to obtain a tablet;
The manufacturing method of the tablet containing this.   The tablet production method according to claim 1, wherein the primary granulated product further contains a binder. The method for producing a tablet according to claim 2, wherein the binder of the primary granulated product is hydroxypropylmethylcellulose.

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