JP2009057331A - Glimepiride-containing drug product - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of preparing a solid drug product which can contain glimepiride stably for a long period of time, and to provide the solid drug product prepared thereby. <P>SOLUTION: In the method of preparing the solid drug product, the process for preparing the glimepiride-containing solid drug product is characterized by comprising a granulation step using a liquid obtained by suspending or dispersing glimepiride into a solution containing hydroxypropyl cellulose or hydroxypropylmethyl cellulose. The fine grain-, pellet- or tablet-shaped solid drug product prepared thereby is also provided. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a preparation that can stably contain glimepiride (generic name of Japanese pharmaceuticals) for a long period of time and a method for producing the same.

Glimepiride is a sulfonylurea hypoglycemic agent, and is a useful pharmaceutical agent used for the improvement of type 2 diabetes.
The inventors of the present invention developed tablets of glimepiride using conventional additives (excipients, disintegrants, binders, lubricants, etc.) and tableted them in the usual manner. It was revealed that there was a problem that the drug substance could not be held stably for a long time by the severe test. Several attempts were made with different additives, but similar results were obtained.
In addition, as a prior art of a glimepiride containing formulation, the thing regarding the formulation excellent in ingestibility is disclosed (patent document 1).

JP 2005-218876 A

  The subject of this invention is providing the formulation which can contain glimepiride stably for a long period of time, and its manufacturing method.

  The present inventors diligently studied to solve the above problems. As a result, in the production of granules containing glimepiride, when granulated with fine particles of glimepiride uniformly in a solution containing hydroxypropylcellulose or hydroxypropylmethylcellulose together with D-mannitol and low-substituted hydroxypropylcellulose, We found that there is a remarkable effect for the solution. Therefore, the present inventors have made further studies based on the findings and have completed the present invention.

That is, according to the present invention, it is possible to provide the method for producing a solid preparation described in (1) below and the solid preparation described in (2), (3) and (4).
(1) In the production process of a solid preparation containing glimepiride, a step of granulating using a liquid in which glimepiride is suspended or dispersed in a hydroxypropylcellulose or hydroxypropylmethylcellulose-containing solution is included. Production method.
(2) A solid preparation containing gourmet pyrido produced by the production method of (1).
(3) The solid preparation according to (2), wherein the solid preparation is a fine granule, a granule or a tablet.
(4) The solid preparation according to (2) or (3), wherein the weight content of hydroxypropylcellulose or hydroxypropylmethylcellulose in the solid preparation is 0.2% to 10%.

  In the solid preparation of the present invention, glimepiride is stably maintained for a long time due to the coating effect of hydroxypropylcellulose or hydroxypropylmethylcellulose.

  The bulk powder of glimepiride used in the present invention preferably has an average particle diameter (measured by a light scattering method) of 1 μm to 10 μm, more preferably 1 μm to 4 μm. The amount used is preferably about 0.2 to 5% by weight of the total weight of the solid preparation, more preferably 0.5 to 3%.

  Additives in the preparation used in the present invention include lactose, crystalline cellulose, corn starch, potato starch, partially pregelatinized starch, D-mannitol, sucrose, sucrose, glucose, low-substituted hydroxypropyl as excipients A cellulose etc. are mentioned. Of these excipients, lactose and D-mannitol are preferred. In particular, D-mannitol is preferable. The amount of excipient used is preferably about 80 to 90% by weight in the weight of the preparation.

  In the present invention, fine powder of glimepiride can be uniformly dispersed and granulated in a hydroxypropylcellulose- or hydroxypropylmethylcellulose-containing solution. The amount of hydroxypropylcellulose or droxypropylmethylcellulose used is preferably about 0.2 to 10% by weight, more preferably about 1 to 5% by weight of the total weight of the solid agent. The solvent for the solution is preferably water or a water-soluble solvent.

  Examples of the disintegrant used in the present invention include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch, and the like. Propylcellulose is preferred. The amount of disintegrant used is preferably about 0.1 to 10% by weight in the weight of the preparation.

  Furthermore, talc, magnesium stearate, calcium stearate, fatty acid glycerin ester and the like can be used as a lubricant. Of these lubricants, magnesium stearate is preferred. The amount of the lubricant used is preferably about 0.1 to 5% by weight in the weight of the preparation.

  The solid preparation of the present invention can be used in the form of fine granules, granules or tablets.

D-mannitol (443.1 g) and low-substituted hydroxypropylcellulose (15.3 g) were charged into a fluidized bed granulator (manufactured by Paul W: MP-01 type), and glimepiride (9.0 g) having an average particle size of 1.5 μm was added to hydroxypropylcellulose. It granulated using the liquid disperse | distributed to 204.0g of aqueous solution of (10.2g). For dispersion, a high-speed disperser (manufactured by Tokushu Kika Kogyo Co., Ltd .: TK Robotics f model) was used. Subsequently, fluidized bed granulation was performed by spraying a solution prepared by heating from 14.1 g of corn starch and 457 g of water. The obtained granules were dried and sieved with a JIS 24 mesh sieve. Crospovidone (2.2 g) and magnesium stearate (0.9 g) were added to a part (82.0 g) of the obtained sized product, and mixed uniformly by hand in a polyethylene bag. Subsequently, this mixture was compression-molded with a rotary tableting machine (Kikusui Seisakusho: VIRGO type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Glimepiride 3.0
D-mannitol 147.7
Low-substituted hydroxypropylcellulose 5.1
Hydroxypropyl cellulose 3.4
Cornstarch 4.7
Crospovidone 4.4
Magnesium stearate 1.7

443.1 g of D-mannitol and 15.3 g of low-substituted hydroxypropylcellulose were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and 9.0 g of glimepiride having an average particle size of 1.5 μm was added to hydroxypropylmethylcellulose. It granulated using the liquid disperse | distributed to 204.0g of aqueous solution of (10.2g).
For dispersion, a high-speed disperser (manufactured by Tokushu Kika Kogyo Co., Ltd .: TK Robotics f model) was used. Subsequently, fluidized bed granulation was performed by spraying a solution prepared by heating from 14.1 g of corn starch and 457 g of water. The obtained granules were dried and sieved with a JIS 24 mesh sieve. Crospovidone (2.2 g) and magnesium stearate (0.9 g) were added to a part (82.0 g) of the obtained sized product and mixed uniformly by hand in a polyethylene bag. Subsequently, this mixture was compression-molded with a rotary tableting machine (Kikusui Seisakusho: VIRGO type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Glimepiride 3.0
D-mannitol 147.7
Low-substituted hydroxypropylcellulose 5.1
Hydroxypropyl methylcellulose 3.4
Cornstarch 4.7
Crospovidone 4.4
Magnesium stearate 1.7

[Comparative Example 1]
9.0 g of glimepiride having an average particle size of 1.5 μm, 443.1 g of D-mannitol and 15.3 g of low-substituted hydroxypropylcellulose were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Granulation was carried out using 204.0 g of an aqueous solution of cellulose (10.2 g). Subsequently, fluidized bed granulation was performed by spraying a solution prepared by heating from 14.1 g of corn starch and 457 g of water. The obtained granules were dried and sieved with a JIS 24 mesh sieve. Crospovidone (2.2 g) and magnesium stearate (0.9 g) were added to a part (82.0 g) of the obtained sized product and mixed uniformly by hand in a polyethylene bag. Subsequently, this mixture was compression-molded with a rotary tableting machine (Kikusui Seisakusho: VIRGO type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Glimepiride 3.0
D-mannitol 147.7
Low-substituted hydroxypropylcellulose 5.1
Hydroxypropyl cellulose 3.4
Cornstarch 4.7
Crospovidone 4.4
Magnesium stearate 1.7

[Comparative Example 2]
608.0 g of D-mannitol and 20.4 g of low-substituted hydroxypropylcellulose were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and 12.0 g of glimepiride having an average particle size of 1.5 μm was added to corn starch 18 Fluidized bed granulation was performed using a liquid dispersed in a solution prepared by heating from 0.8 g and 452 g of water. For dispersion, a high-speed disperser (manufactured by Tokushu Kika Kogyo Co., Ltd .: TK Robotics f model) was used. The obtained granules were dried and sieved with a JIS 24 mesh sieve. Crospovidone (2.2 g) and magnesium stearate (0.4 g) were added to a part (82.4 g) of the obtained sized product, and the mixture was uniformly mixed by hand in a polyethylene bag. Subsequently, this mixture was compression-molded with a rotary tableting machine (manufactured by Kikusui Seisakusho: Clean Press Collect 19K type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Glimepiride 3.0
D-mannitol 152.0
Low-substituted hydroxypropylcellulose 5.1
Cornstarch 4.7
Crospovidone 4.4
Magnesium stearate 0.8

表１の結果から、本発明に係る実施例１及び実施例２の錠剤は、比較例１及び比較例２の錠剤と比べ、グリメピリドを極めて効果的に安定に保持し得ることが判る。 [Test Example 1] (Measurement of increase in degradation product in tablets in severe test)
15 tablets each of the tablets obtained in Example 1, Example 2, Comparative Example 1 and Comparative Example 2 were taken, placed in glass bottles, placed in a thermostatic bath, temperature 60 ° C., temperature 60 ° C., and relative humidity 75%. Stored under the conditions of Seven days after the start of storage, the degradation product in each tablet was measured by high performance liquid chromatography. From the measurement results, the amount of decomposition product increase (%) was calculated, and the results shown in Table 1 were obtained.

From the results of Table 1, it can be seen that the tablets of Example 1 and Example 2 according to the present invention can hold glimepiride very effectively and stably as compared with the tablets of Comparative Examples 1 and 2.

  ADVANTAGE OF THE INVENTION According to this invention, the safe solid formulation which maintained glimepiride stably for a long term can be provided to a medical field.

Claims (4)

  A method for producing a solid preparation comprising the step of granulating using a liquid in which glimepiride is suspended or dispersed in a hydroxypropylcellulose or hydroxypropylmethylcellulose-containing solution in the production process of a solid preparation containing glimepiride.   The solid formulation containing the gourmet pyride manufactured by the manufacturing method of Claim 1.   The solid preparation according to claim 2, wherein the solid preparation is a fine granule, a granule or a tablet.   The solid preparation according to claim 2 or 3, wherein the weight content of hydroxypropylcellulose or hydroxypropylmethylcellulose in the solid preparation is 0.2% to 10%.