JP2716619B2 - Midodrine hydrochloride-containing preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention is stable midodrine hydrochloride containing
It relates chromatic formulations, more particularly, be prepared by wet granulation of midodrine hydrochloride with Man <br/> Nitoru
Stable midodrine hydrochloride containing preparations can, and to a manufacturing method <br/>.

[0002]

2. Description of the Related Art Midodrine hydrochloride is commonly used as an excipient, disintegrant, binder, lubricant, etc., lactose, carboxymethylcellulose calcium, methylcellulose, hydroxypropylcellulose, light silicic anhydride, magnesium stearate, etc. And marked contraindications. Therefore, only limited additives such as starch and microcrystalline cellulose are used in the formulation.

[0003]

Therefore, there is a great limitation in the formulation design. Particularly for tablets, the tableting pressure must be increased in order to obtain sufficient hardness. Further, the tablet easily absorbs moisture, and when the tablet absorbs moisture, the hardness is reduced, which causes the tablet to break. Therefore, mass production is difficult, and packaging of the preparation requires special consideration for preventing moisture absorption.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, wet granulation of midodrine hydrochloride and mannitol in advance has been carried out .
By finding solid particles dispersed in ninitol matrix, the contraindications of midodrine hydrochloride can be eliminated and the properties of tablets can be improved, and the present invention has been completed. It was just.

[0005] Thus, the present invention relates to a midodrine hydrochloride crystal.
Particles dispersed in mannitol matrix
To provide a stable midodrine hydrochloride-containing preparation containing
It is. Furthermore, the present invention is, after granulation by a wet method with Man'ni <br/> torr midodrine hydrochloride, the preparation of stable midodrine hydrochloride-containing preparation characterized by formulating
Is provided.

The mixing ratio of mannitol used in wet granulation which is a feature of the present invention is 1 to 200 parts by weight, more preferably 2 to 100 parts by weight, based on 1 part by weight of midodrine hydrochloride.
Parts by weight.

[0007] In the preparation of the present invention, in addition to the above-mentioned components, other pharmaceutically acceptable additives can be used. These include excipients, disintegrants, binders,
Includes those essential for formulation technology such as lubricants, or those intended to increase the commercial value of pigments, flavors, and the like.

Examples of excipients and disintegrants include sorbitol, glucose, sucrose, lactose, crystalline cellulose, calcium hydrogen phosphate, starch, sodium carboxymethyl starch, dextrin, carboxyvinyl polymer, polyethylene glycol, carboxymethyl cellulose, carboxy And methylcellulose calcium. As the binder, for example, methyl cellulose,
Examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyvinyl alcohol, pullulan and the like. Examples of the lubricant include magnesium stearate, calcium stearate, polyoxyl stearate, talc, sucrose fatty acid ester, hydrogenated oil, dimethylpolysiloxane and the like. In addition, as the coloring matter and the fragrance, a natural or synthetic fragrance and the like can be used. Any of these pharmaceutically acceptable additives can be used in general for solid preparations, and is not particularly limited.

[0009]

EFFECTS OF THE INVENTION The midodrine hydrochloride-containing preparation of the present invention can eliminate the contraindications for mixing with general additives. Moreover, mannitol as an additive has a high adhesive property and easily adheres to a punch for press molding during tablet production.However, it is possible to granulate midodrine hydrochloride and mannitol in advance by a wet method. Adhesion to punches during molding can be improved. Furthermore, sufficient hardness can be obtained with a lower tableting pressure than before, and moisture absorption of the preparation can be suppressed.

[0010]

EXAMPLES The present invention will be specifically described below with reference to examples and test examples.

Example 1 240 g of mannitol was added to 10 g of midodrine hydrochloride and mixed, and the mixture was granulated with a fluidized bed granulator using purified water as a granulation solvent. The crystalline cellulose 1 sieved through No. 30 sieve
40g, lactose 100g, calcium stearate 10g
Was added and mixed, followed by press molding to obtain a preparation having a diameter of 7 mm and containing 3 mg of midodrine hydrochloride in one tablet.

Example 2 After adding 40 g of mannitol to 10 g of midodrine hydrochloride and mixing, kneaded with purified water as a granulating solvent with a Shinagawa-type universal mixing stirrer, sieved with a No. 8 sieve, and dried with a fluidized bed drier. And dried. After sieving the dried product through No. 24 sieve, 280 g of crystalline cellulose sieved through No. 30 sieve, lactose 160 g,
10 g of hardened oil was added and mixed, followed by press molding to obtain a preparation having a diameter of 7 mm and containing 3 mg of midodrine hydrochloride in one tablet.

Example 3 240 g of mannitol was added to 10 g of midodrine hydrochloride, mixed, kneaded with a kneader using purified water as a granulating solvent, sieved with a No. 8 sieve, and dried with a fluid bed dryer. After the dried product was sieved through a No. 24 sieve, 140 g of crystalline cellulose sieved through a No. 30 sieve, 100 g of starch, and 10 g of magnesium stearate were added and mixed, and the mixture was pressed and molded into a tablet having a diameter of 7 mm and hydrochloric acid in one tablet. A formulation containing 3 mg of midodrine was obtained.

Example 4 After 40 g of mannitol was added to 10 g of midodrine hydrochloride and mixed, the mixture was granulated with a fluidized bed granulator using purified water as a granulation solvent. The crystalline cellulose 28 sieved through No. 30 sieve
0 g, lactose 160 g, and hydrogenated oil 10 g were added and mixed, followed by press molding to obtain a preparation having a diameter of 7 mm and containing 3 mg of midodrine hydrochloride in one tablet.

Example 5 180 g of mannitol was added to 10 g of midodrine hydrochloride, mixed, kneaded with a kneader using purified water as a granulating solvent, sieved with a No. 8 sieve, and dried with a fluid bed dryer. After the dried product was sieved through a No. 24 sieve, 200 g of crystalline cellulose sieved through a No. 30 sieve, 100 g of starch, and 10 g of sucrose fatty acid ester were added and mixed.
No. capsule was filled with 150 mg to obtain a capsule containing 3 mg of midodrine hydrochloride.

Example 6 500 g of mannitol was added to and mixed with 30 g of midodrine hydrochloride, and the mixture was granulated with a fluidized bed granulator using purified water as a granulation solvent, followed by sieving with a No. 30 sieve to produce a granulated product. This was mixed with 200 g of mannitol and 270 g of starch, granulated in a fluidized bed using purified water as a granulating solvent, and then granulated through a No. 30 sieve to obtain a powder containing 3% of midodrine hydrochloride.

Comparative Example 1 To 10 g of midodrine hydrochloride, 240 g of mannitol, 50 g of starch and 100 g of lactose were added and mixed, and then granulated in a fluidized bed using purified water as a granulating solvent. 60 g of crystalline cellulose sieved through No. 30 sieve, partially pregelatinized starch 30
After adding and mixing 10 g of hardened oil, the mixture was molded under pressure to obtain a preparation having a diameter of 7 mm and containing 3 mg of midodrine hydrochloride in one tablet.

Comparative Example 2 290 g of starch was added to 10 g of midodrine hydrochloride and mixed, and the mixture was granulated in a kneader using heated purified water as a granulation solvent. The crystalline cellulose 1 sieved through No. 30 sieve
After adding and mixing 60 g, partially pregelatinized starch 30 g, and hardened oil 10 g, the mixture was molded under pressure to obtain a preparation having a diameter of 7 mm and containing 3 mg of midodrine hydrochloride in one tablet.

Comparative Example 3 To 10 g of midodrine hydrochloride, 240 g of mannitol, 100 g of crystalline cellulose, 150 g of partially pregelatinized starch, and 10 g of magnesium stearate were added and mixed, followed by press molding and 3 mg of midodrine hydrochloride in a tablet having a diameter of 7 mm. The resulting formulation was obtained.

Test Example 1 The tablets obtained in Examples 1 to 4 and Comparative Examples 1 and 2 were subjected to a stability test for 2 weeks at a temperature of 65 ° C. and a relative humidity of 75%. As shown in Table 1, the results are as follows: Examples 1 to 5 in which midodrine hydrochloride and mannitol were wet granulated in advance.
No. 4 showed good stability with respect to Comparative Examples 1 and 2.

[0021]

[Table 1]

Test Example 2 With respect to the tablets obtained in Examples 1 to 4 and Comparative Examples 1 to 3, adhesion to a punch and the like at the time of tablet press molding was observed. As a result, except for Comparative Example 3, no adhesion to the punch was observed, but in Comparative Example 3, adhesion to the punch was observed, and continuous pressure molding was not possible.

Test Example 3 For the tablets obtained in Example 2 and Comparative Example 2, changes in weight and hardness due to moisture absorption were measured at a temperature of 25 ° C. and a relative humidity of 93%, 84%, 62.6%, 45%, and 22%. % Was measured under each condition. As a result, as shown in FIGS. 1 to 4, Example 2 showed good properties with less change in weight and change in hardness due to moisture absorption than Comparative Example 2.

[Brief description of the drawings]

1 to 4 show the test results of Example 2 and Comparative Example 2 obtained in Test Example 3.

FIG. 1 shows the measurement results of weight change due to moisture absorption at each relative humidity in Example 2.

FIG. 2 shows measurement results of weight change due to moisture absorption at each relative humidity in Comparative Example 2.

FIG. 3 shows measurement results of changes in tablet hardness at each relative humidity in Example 2.

FIG. 4 shows the results of measurement of tablet hardness change at each relative humidity in Comparative Example 2.

Claims (2)

(57) [Claims] 1. The method of claim 1, wherein the midodrine hydrochloride crystal is mannitol mat.
Stable salt containing solid particles dispersed in ritux
Preparations containing acid midodrine. Wherein After granulated by midodrine hydrochloride <br/> formula Method humidity with mannitol, granulation method manufacturing of a stable midodrine hydrochloride-containing preparations, characterized in that the formulation.