JP2994956B2 - Low-substituted hydroxypropylcellulose, composition thereof and tablet thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition containing a low-substituted hydroxypropylcellulose, which is added to a tablet such as a pharmaceutical product as a binder, and a tablet bound with the low-substituted hydroxypropylcellulose. It is about.

[0002]

2. Description of the Related Art Tablets such as pharmaceuticals disintegrate due to swelling of a binder contained in the tablet. Tablet binders include:
Examples thereof include low-substituted hydroxypropylcellulose, carboxymethylcellulose and its calcium salt, starch and its derivatives. Among them, low-substituted hydroxypropylcellulose is a nonionic binder having little interaction with a drug. The use of low-substituted hydroxypropylcellulose as a binder is described in JP-B-46-42792 and JP-B-57-53100.

[0003] In recent years, tablets have been reduced in size so that they can be easily taken, and the addition of binders and the like tends to be suppressed. For this reason, a binder that enhances the disintegration of tablets with a small amount of addition is desired. Further, in order for the main ingredient to be uniformly dispersed in the tablet and to reduce the weight deviation of the tablet, the binder must have excellent fluidity.

[0004] In the production of tablets, a base composition and various additives are blended to prepare a tablet composition, and tablets are formed from the composition. Tableting methods include a method in which the composition is directly compressed and a method in which the composition is granulated and then compressed.
When the composition is granulated prior to tableting, fluidized-bed granulation is performed in which the composition mixed with fine powder is fluidized to form a granulated product because of easy operation. In the case of fluidized bed granulation, if a composition to which a large amount of low-substituted hydroxypropylcellulose is added is granulated, a granulated product having a low density and a high bulk may be obtained. When tableting bulky granules, the tablet weight is limited when the tableting speed is increased.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and provides a tablet with excellent disintegration and binding properties even with a small amount of addition, and has a high density even when the amount of addition is large. It is an object of the present invention to provide a composition containing a low-substituted hydroxypropylcellulose that can produce a high-granulated product, and a tablet combined with the low-substituted hydroxypropylcellulose.

[0006]

The low-substituted hydroxypropylcellulose of the present invention, which has been made to achieve the above object, has an angle of repose of less than 45 ° and activated alumina 80%.
20 parts by weight with respect to the parts by weight are mixed and molded into a disk having a diameter of 15 mm at a molding pressure of 1 ton. The volume increase rate when absorbing water and swelling rate is 100% or more.

The method of measuring the angle of repose is as follows. The hydroxypropylcellulose powder is allowed to flow down from a height of 75 mm onto a disk-shaped table having a diameter of 80 mm. The contact angle between the deposited powder and the table is measured. A powder having good fluidity spreads greatly, and therefore has a small angle of repose. The powder having poor fluidity accumulates, so that the angle of repose increases. When the angle of repose is less than 45 °, a tablet having a small weight deviation and a high hardness can be obtained. When the temperature is 45 ° or more, when tableting is performed by the direct tableting method, the fluidity of the components is poor, and the weight fluctuation of the tablet to be tableted is large. In the case of fluidized bed granulation, the bulk density of the granulated powder is low.

[0008] The swelling ratio is the rate of increase in volume when the low-substituted hydroxypropylcellulose absorbs water and swells. Low-substituted hydroxypropylcellulose, which is 20 parts by weight based on 80 parts by weight of activated alumina and has a swelling ratio of 100% or more when molded into a disk having a diameter of 15 mm at a molding pressure of 1 ton, is added with a small amount. Provides excellent disintegration to tablets. The low-substituted hydroxypropylcellulose having a swelling ratio of 100% or less cannot disintegrate tablets unless added in a large amount. Since commercially available low-substituted hydroxypropylcellulose has a swelling ratio of 100% or less,
Requires a large amount of addition.

The method for producing low-substituted hydroxypropylcellulose is as follows. The substitution reaction of propylene oxide with cellulose is carried out using alkali hydroxide as a catalyst. Next, an alkali is added in the presence of the alkali used as a catalyst or if necessary, water is added and mixed, and all or a part of the product is dissolved to reduce the fiber quality. After neutralizing this solution with an acid such as acetic acid or hydrochloric acid, purification,
Hydroxypropylcellulose is obtained through the steps of drying and pulverization. Hydroxypropylcellulose particles become spherical due to the decrease in fiber, and hydroxypropylcellulose having a swelling ratio of 100% or more and an angle of repose of less than 45 ° is produced.

The hydroxypropoxyl group content of the low-substituted hydroxypropylcellulose is preferably in the range of 5 to 16% by weight, particularly 7 to 13% by weight. Content is 5% by weight
In the following cases, the swelling ratio of hydroxypropylcellulose becomes low, and the disintegration of the tablet becomes insufficient. 16 content
If it is greater than or equal to weight percent, the hydroxypropyl cellulose will eventually become water-soluble. Average particle size is 5-1
It is preferably 50 μm, and particularly preferably in the range of 40 to 100 μm. If it is less than 5 μm, the fluidity of hydroxypropylcellulose will be poor, making it difficult to perform fluidized bed granulation. If it is 150 μm or more, the mixing of hydroxypropylcellulose and the drug is not uniform, and the binding property is reduced. For this reason, the bulk density of the granulated powder decreases, and the hardness of the tablet decreases.

The low-substituted hydroxypropylcellulose composition contains the above-mentioned low-substituted hydroxypropylcellulose as a component, and other components such as an excipient, a binder, a lubricant, and a colorant. .

The tablet is bound by the above-mentioned low-substituted hydroxypropylcellulose, and is obtained by directly tableting the low-substituted hydroxypropylcellulose composition or by tableting through fluid bed granulation. In the case of direct compression, 2% or more of low-substituted hydroxypropylcellulose is blended, and in the case of fluidized-bed granulation, 5% or more is blended.

[0013]

The low-substituted hydroxypropylcellulose of the present invention has fewer fibrous particles than the commercially available hydroxypropylcellulose, and the particle shape is nearly spherical. When hydroxypropylcellulose absorbs water and swells,
Pressure is generated inside the particles. In the case of fibrous particles, the pressure at the time of swelling is absorbed by the pores of the tablet, whereas in the case of spherical particles, the pressure is transmitted throughout. For this reason, the swelling of hydroxypropylcellulose in the tablet increases, and the disintegration of the tablet increases.

The angle of repose greatly affects the bulk density of the granulated powder obtained through fluidized bed granulation. Low-substituted hydroxypropylcellulose having an angle of repose of less than 45 ° has excellent fluidity, and the bulk density of the granulated powder obtained by fluidized bed granulation becomes high. By tableting granulated powder having a high bulk density, the weight of the tablet can be maintained even when the tableting speed is high.

[0015]

Industrial Applicability The low-substituted hydroxypropylcellulose of the present invention imparts excellent disintegration to tablets by being slightly added to a composition for direct compression. Since the proportion of hydroxypropylcellulose contained in the tablet is reduced, the tablet is reduced in size and becomes easier to take. Even when a large amount is added to the fluidized bed granulation composition, a granulated product having a high bulk density can be produced.

[0016]

Embodiments of the present invention will be described below in detail.

Example 1 Synthesis of Low-Substituted Hydroxypropylcellulose Wood pulp was prepared by adding 49% by weight of caustic soda (NaOH).
After being immersed in water, compression was performed to obtain alkali cellulose having a composition of 24.6% by weight of NaOH, 48.2% by weight of cellulose, and 27.2% by weight of water. 100 g of this alkali cellulose was charged into a reactor, and the atmosphere was replaced with nitrogen. After the replacement with nitrogen, 10.7 g of propylene oxide was charged into the reactor and reacted with stirring at 40 ° C. for 1 hour and at 70 ° C. for 1 hour to obtain hydroxypropylcellulose. 265 g of warm water was put into a kneader, hydroxypropyl cellulose was dispersed in the warm water, and kneaded at a temperature of 45 ° C. for 30 minutes. Thereafter, 112 g of a 33% by weight acetic acid aqueous solution was added to precipitate hydroxypropylcellulose. After washing the precipitated hydroxypropylcellulose with hot water of about 80 ° C,
Dewatered, dried and pulverized with a high-speed rotary impact pulverizer. Aperture 7
The coarse powder was removed from the powder with a 5 μm sieve to obtain a fine powder having a hydroxypropoxyl group content of 11.0%. This fine powder was used as sample No. It was set to 1.

Physical Properties of Low-Substituted Hydroxypropylcellulose Sample No. The angle of repose of No. 1 was measured by a cone deposition method using a powder tester RT-D type (manufactured by Hosokawa Powder Engineering Laboratory). The measurement is as follows. The powder was allowed to flow down onto the powder tester table, a protractor was set on the line adjacent to the deposited powder and the table, and the contact angle between the powder and the table was measured.
It was shown to. Then, the sample No. The average particle shape and bulk density of Sample No. 1 were measured, and the results are shown in Table 1.

For 10 g of sample No. 1 and 40 g of activated alumina (200 mesh) were mixed in a V-type kneader, and 500 mg of the mixture was subjected to a molding pressure of 1 ton and a diameter of 15 m.
m tablets. Water was absorbed into the tablets, the rate of increase in volume was measured, and the swelling rate was calculated. FIG. 1 shows the measurement results.

Tableting by direct compression Aspirin granulated powder (aspirin / corn starch = 95)
/ 5) as a base, sample No. 1 was 10 parts by weight, aspirin granulated powder was 90 parts by weight, and magnesium stearate was 0.5 parts by weight to prepare a composition for direct compression.

RT-S15K-T35 (manufactured by Kikusui Seisakusho)
The composition for direct compression was tableted at a rotation speed of 30 rpm and a tableting pressure of 0.6 ton, with a diameter of 9 mm and a weight of 300 m.
g tablets were obtained. The weight deviation, hardness, and disintegration time of this tablet were measured, and the results are shown in Table 1.

Fluid bed granulation Sample No. 100 g 1 was mixed with 160 g of acetaminophen (fine powder), 98 g of lactose, and 42 g of corn starch to prepare a composition for fluidized bed granulation. AEROMAT
A 5% by weight aqueous solution of HPC-LEP (manufactured by Shin-Etsu Chemical Co., Ltd.) is sprayed onto the fluidized-bed granulating composition at a spray rate of 20 g / min with an IC STREA-1 type (manufactured by Fuji Sangyo) at an intake temperature of 70 ° C. Layer granulation was performed. After removing the obtained granulated powder with a sieve having a mesh size of 1400 μm, the average particle diameter and the bulk density were measured. The results are shown in Table 1.

Next, a tableting powder was prepared with a mixing ratio of 100 parts by weight of the granulated powder and 0.5 part by weight of magnesium stearate. The granulated powder is tableted with RT-S15K-T35 (manufactured by Kikusui Seisakusho) at a rotation speed of 30 rpm and a tableting pressure of 1 ton.
A tablet having a diameter of 8 mm and a weight of 200 mg was obtained. The hardness and disintegration time of the tablet after tableting were measured, and the results are shown in Table 1.

After tableting a tablet weighing 200 mg at a rotation speed of 30 rpm and a tableting pressure of 1 ton, only the rotation speed was increased to 45 rpm.
m and 50 rpm, the weight of the tablets compressed at each rotation speed was measured, and the results are shown in Table 2.

Example 2 Synthesis and Physical Properties of Low-Substituted Hydroxypropyl Cellulose In the same manner as in Example 1, low-substituted hydroxypropyl cellulose was synthesized. The opening was set to 180 μm, and impurities were removed from the powder to obtain a fine powder having a hydroxypropoxyl group content of 11.0%. This fine powder was used as sample No.
And 2. As in Example 1, the sample No. The average particle shape, bulk density, and angle of repose of Sample No. 2 were measured, and the results are shown in Table 1.

In the same manner as in Example 1, the sample No. 2 was compression-molded into a tablet, and the swelling ratio was measured. The result is shown in FIG.

Tableting by direct compression Sample No. 2
A tableting composition was prepared and tableted directly in the same manner as in Example 1 except that The weight deviation, hardness and disintegration time of the tablets were measured, and the results are shown in Table 1.

Fluid bed granulation The low-substituted hydroxypropylcellulose was obtained from Sample No. 2
In the same manner as in Example 1, fluidized-bed granulation and tableting of the granulated powder were carried out. The average particle size, bulk density, tablet hardness and disintegration time of the granulated powder having a weight of 200 g were measured, and the results are shown in Table 1.

After tableting a tablet weighing 200 mg at a rotation speed of 30 rpm and a tableting pressure of 1 ton, only the rotation speed was increased to 45 rpm.
m and 50 rpm, the weight of the tablets compressed at each rotation speed was measured, and the results are shown in Table 2.

Comparative Example 1 Physical Properties of Low-Substituted Hydroxypropyl Cellulose Low-substituted hydroxypropyl cellulose was used as a commercially available product, LH-11 (manufactured by Shin-Etsu Chemical Co., Ltd.). The average particle diameter, bulk density, and angle of repose of LH-11 were measured in the same manner as in Example 1, and the results are shown in Table 1.

LH-11 was compression molded in the same manner as in Example 1, and the swelling ratio was measured. The result is shown in FIG. LH-
The swelling ratio of No. 11 was 100% or less.

Tableting by Direct Compression A composition for direct compression was prepared and directly tableted in the same manner as in Example 1 except that the low-substituted hydroxypropylcellulose was LH-11. Table 1 shows the weight deviation, hardness, and disintegration time of the tablets.

Fluid bed granulation Fluid bed granulation and tableting of the granulated powder were carried out in the same manner as in Example 1 except that the low-substituted hydroxypropylcellulose was LH-11. The average particle size, bulk density, tablet hardness and disintegration time of the granulated powder having a weight of 200 g were measured, and the results are shown in Table 1.

After tableting a tablet weighing 200 mg at a rotation speed of 30 rpm and a tableting pressure of 1 ton, only the rotation speed was increased to 45 rpm.
m and 50 rpm, the weight of the tablets compressed at each rotation speed was measured, and the results are shown in Table 2.

Comparative Example 2 Physical Properties of Low-Substituted Hydroxypropylcellulose Low-substituted hydroxypropylcellulose was used as a commercial product, LH-21 (manufactured by Shin-Etsu Chemical Co., Ltd.). The average particle size, bulk density, and angle of repose of LH-21 were measured in the same manner as in Example 1, and the results are shown in Table 1.

As in Example 1, LH-21 was compression molded and the swelling ratio was measured. The result is shown in FIG.

Tableting by Direct Compression A composition for direct compression was prepared and directly tableted in the same manner as in Example 1 except that the low-substituted hydroxypropylcellulose was LH-21. Table 1 shows the weight deviation, hardness, and disintegration time of the tablet.

Fluid bed granulation Fluid bed granulation and tableting of the granulated powder were carried out in the same manner as in Example 1 except that the low-substituted hydroxypropylcellulose was LH-21. Table 1 shows the average particle size, bulk density, tablet hardness and disintegration time of the granulated powder having a weight of 200 g.
Shown in

After tableting a tablet weighing 200 mg at a rotation speed of 30 rpm and a tableting pressure of 1 ton, only the rotation speed was increased to 45 rpm.
m and 50 rpm, the weight of the tablets compressed at each rotation speed was measured, and the results are shown in Table 2.

Comparative Example 3 Physical Properties of Low-Substituted Hydroxypropylcellulose The low-substituted hydroxypropylcellulose was used as a commercial product, LH-31 (manufactured by Shin-Etsu Chemical Co., Ltd.). Commercially available LH-31 (manufactured by Shin-Etsu Chemical Co., Ltd.) was used for the low-substituted hydroxypropylcellulose. LH-3 in the same manner as in Example 1.
The average particle size, bulk density, and angle of repose of Sample No. 1 were measured, and the results are shown in Table 1.

As in Example 1, LH-31 was compression molded and the swelling ratio was measured. The result is shown in FIG.

Tableting by Direct Compression A composition for direct compression was prepared and directly tableted in the same manner as in Example 1 except that the low-substituted hydroxypropylcellulose was LH-31. The weight deviation, hardness and disintegration time of the tablets were measured, and the results are shown in Table 1.

Fluid bed granulation Fluid bed granulation and tableting of the granulated powder were carried out in the same manner as in Example 1 except that the low-substituted hydroxypropylcellulose was LH-31. Table 1 shows the average particle size, bulk density, tablet hardness and disintegration time of the granulated powder having a weight of 200 g.
Shown in

As in Example 1, direct compression and fluidized-bed granulation were performed. The physical properties of the tablets produced by direct compression, and the average particle size, bulk density, tablet hardness and disintegration time of the granulated powder obtained by fluidized bed granulation were measured, and the results are shown in Table 1.

After tableting a tablet weighing 200 mg at a rotational speed of 30 rpm and a tableting pressure of 1 ton, only the rotational speed was increased to 45 rpm.
m and 50 rpm, the weight of the tablets compressed at each rotation speed was measured, and the results are shown in Table 2.

[0046]

[Table 1]

[0047]

[Table 2]

The tablets of Examples 1 and 2 compressed by the direct compression method had smaller weight deviations than the tablets of Comparative Examples 1 to 3,
High hardness. It also has excellent disintegration properties. As can be seen in FIG. 1, this is the low-substituted hydroxypropylcellulose of Examples 1 and 2, sample No. 1 and No. This is because the swelling ratio of No. 2 is 100% or more.

The granulated powders of Examples 1 and 2 obtained by fluidized bed granulation have a higher bulk density than the granulated powders of Comparative Examples 1 to 3. In addition, the tablets of Examples 1 and 2 obtained by fluidized bed granulation
The hardness is higher and the disintegration is superior to the tablet of No. 3. This corresponds to the sample Nos. 1 and No. This is because the angle of repose of No. 2 is less than 45 °. When the number of rotations is increased, the weights of Examples 1 and 2 are stable, but the weights of Comparative Examples 1 to 3 are reduced. This is because in Examples 1 and 2, the filling amount is kept constant because of the high bulk density.

[Brief description of the drawings]

FIG. 1 is a graph showing the change over time in the swelling ratio of low-substituted hydroxypropylcellulose.

Claims (3)

(57) [Claims] 1. An angle of repose of less than 45 °, 20 parts by weight of 80 parts by weight of activated alumina, and a molding pressure of 1 part.
A low-substituted hydroxypropylcellulose for tablet binding, characterized in that a volume formed when a disc having a diameter of 15 mm is swollen by absorbing water is 100% or more. 2. An angle of repose of less than 45 °, 20 parts by weight of 80 parts by weight of activated alumina, and a molding pressure of 1 part.
Low-substituted hydroxypropyl cellulose having a low-substituted hydroxypropylcellulose having a volume increase rate of 100% or more when absorbing water and swelling into a disk having a diameter of 15 mm in tons. Propyl cellulose composition. 3. An angle of repose of less than 45 °, 20 parts by weight of 80 parts by weight of activated alumina, and a molding pressure of 1 part.
A tablet characterized by being bonded to a low-substituted hydroxypropylcellulose, which is formed into a disk having a diameter of 15 mm by ton and having a volume increase of 100% or more when absorbing water and swelling.