JPH10279601A - Low-substitution-degree hydroxypropylcellulose powder - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a low-substitution-degree hydroxypropylcellulose powder which is a powdery drug used as a disintegrator used in combination with medicinal components in the production of e.g. granulated medicines, can give granules of good disintegrability at a high granulation rate when used in an extrusion granulation and can give granules having a high bulk density when used in a fluidized bed granulation method. SOLUTION: This powder has a viscosity of 5-100 cP (as measured in a 2 wt.% concentration solution in a 10 wt.% aqueous sodium hydroxide solution at 20 deg.C), a content of water-solubles of 2-6 wt.%, a tapped apparent density of 0.55 g/cc or above, an angle of repose of 48 deg. or below and a mean particle diameter of 45 μm or below.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a low-substituted hydroxypropylcellulose which is added as a disintegrant or a binder to pharmaceutical granules or tablets.

[0002]

[0002] Pharmaceutical granules and tablets are disintegrated by swelling of a disintegrant contained therein. Examples of the disintegrant include low-substituted hydroxypropylcellulose, carboxymethylcellulose and its calcium salt, starch and its derivatives, and the like. Among these disintegrants, low-substituted hydroxypropylcellulose is a nonionic disintegrant with little interaction with the drug. The use of low-substituted hydroxypropylcellulose as an additive for pharmaceuticals is disclosed in JP-B-48-38858 and JP-B-57-5310.
No. 0 publication.

[0003] Granules are required to have good disintegration properties in the body. As a result, the active ingredient of the medicament is rapidly released into the body. Further, the granulated product for tableting, which is a raw material of the tablet, needs to have a large bulk density, a high filling property to a die of a tableting machine, and an excellent fluidity. Thereby, the tablet can be manufactured efficiently.

[0004] Granules are produced by blending an active ingredient of a medicine and various additives to prepare a composition for granules, and then granulating the composition. The granulation method includes a wet method such as a stirring granulation method, an extrusion granulation method, and a fluidized bed granulation method, and a dry method in which a composition once compressed is crushed. Extrusion granulation of the wet method can produce granules having a relatively large bulk density, but when low-substituted hydroxypropylcellulose is added and a fine screen is used, the granulation speed may decrease. is there.

[0005] In the fluidized bed granulation method of the wet method, the operation is easy, but when a composition containing a large amount of low-substituted hydroxypropylcellulose is granulated, the bulk density of the granulated product is low. May be. When such a granulated product having a small bulk density is used as a granule, it becomes difficult to handle it during packaging or taking, and when it is used as a granulated product for tableting in order to make a tablet, a mill of a tableting machine is used. Filling becomes difficult.

[0006]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned drawbacks of the prior art, and when used in an extrusion granulation method, a granulation speed is high and a granule having good disintegration properties is obtained. It is an object of the present invention to provide a low-substituted hydroxypropylcellulose powder capable of producing granules and producing granules having a large bulk density when used in a fluidized bed granulation method.

[0007]

In order to solve the above-mentioned problems, the low-substituted hydroxypropylcellulose powder of the present invention was dissolved in a 10% by weight aqueous sodium hydroxide solution to a concentration of 2% by weight. The viscosity at 20 ° C. is 5 to 100 centipoise, and the water-soluble content is 2 to 6
% By weight, the solidified apparent density is 0.55 g / cc or more, the angle of repose is 48 degrees or less, and the average particle size is 45 μm.
m or less.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The low-substituted hydroxypropylcellulose powder of the present invention has a viscosity at 20 ° C. of 5% when dissolved in a 10% by weight aqueous sodium hydroxide solution to a concentration of 2% by weight. -100 centipoise, preferably 10-60 centipoise. The reason why the measurement is performed by dissolving the low-substituted hydroxypropylcellulose in an alkaline aqueous solution is that the low-substituted hydroxypropylcellulose swells in water and does not dissolve.

[0009] The viscosity is an index indicating the degree of polymerization. In general, the lower the degree of polymerization of a polymer substance, the easier it is to be absorbed into the body. Therefore, the viscosity of low-substituted hydroxypropylcellulose that is absorbed into the body and has little concern for pharmacological action needs to be 5 centipoise or more. On the other hand, if the viscosity exceeds 100 centipoise, the molecular chain becomes longer, the affinity for water decreases, and
Since the low molecular weight portion is reduced, the water-soluble content is reduced, which is disadvantageous in that the bulk density of the granulated product in the fluidized bed granulation is reduced.

The low-substituted hydroxypropylcellulose powder of the present invention has a water-soluble content of 2 to 6% by weight, preferably 3% by weight.
~ 5% by weight. When the water-soluble content is less than 2% by weight,
The granulation speed in the extrusion granulation method is reduced, and the bulk density of the granulated product obtained by the fluidized bed granulation method is reduced. When the water-soluble content exceeds 6% by weight, the granulation speed and the bulk density are good, but the time required for disintegration of the obtained granulated product becomes long. The water-soluble component is a low molecular weight part and a high substitution degree part in the low substituted hydroxypropylcellulose. The water-soluble component dissolves at the time of granulation and acts in the same manner as the sizing agent (binder). The water-soluble content is calculated by suspending low-substituted hydroxypropylcellulose in water, shaking the suspension, centrifuging the suspension, and measuring the solid content of the supernatant.

The solid apparent density (also referred to as "apparent density" in the present specification) of the low-substituted hydroxypropylcellulose powder of the present invention is 0.55 g / cc or more, preferably 0.60 g. / Cc or more. If the apparent density is less than 0.55 g / cc, the granulation properties will deteriorate.
Here, the hardened apparent density refers to the apparent density when a sample is lightly filled in a certain container and then hardened by the impact of tapping, and is performed at 50 times / minute using a powder tester (manufactured by Hosokawa Micron Corporation). 100cc after tapping for 3 minutes
Is determined by measuring the weight of the sample filled in the container.

The angle of repose of the low-substituted hydroxypropylcellulose powder of the present invention is 48 degrees or less. The angle of repose is
It is a value to evaluate the fluidity of the powder.
Granulation property deteriorates. Here, the angle of repose refers to the angle between the horizontal line and the conical generating line formed by dropping the sample on a plane and using a powder tester on a disk-shaped table with a diameter of 80 mm from a height of 75 mm. It is determined by measuring the angle between the outflow and the accumulated powder and the table.

The average particle size of the low-substituted hydroxypropylcellulose of the present invention is 45 μm or less, preferably 20 to 40 μm. If it exceeds 45 μm, in the extrusion granulation method, the molecules of the low-substituted hydroxypropylcellulose are difficult to pass through the screen, so that the granulation speed is reduced. On the other hand, when the thickness is 20 μm or more, the fluidity is improved, and the handling is facilitated. Here, the average particle diameter is 50% of the number-based cumulative distribution curve.
The diameter corresponding to the cumulative value is referred to as the laser diffraction measuring device H
It is measured by ELOS & DOROS (manufactured by Shinpac).

To produce the low-substituted hydroxypropylcellulose powder of the present invention, first, sodium hydroxide is allowed to act on cellulose as a raw material to form alkali cellulose, and the alkali cellulose and propylene oxide are subjected to a substitution reaction. Next, the sodium hydroxide used as a catalyst is neutralized with an acid such as acetic acid or hydrochloric acid, and then purified, dried and pulverized to obtain hydroxypropylcellulose powder.

In order to reduce the viscosity of the aqueous solution of sodium hydroxide in which the low-substituted hydroxypropylcellulose powder is dissolved, alkali cellulose is heated to 40 to 80 ° C. under humidification with steam or the like, if necessary. The method may be performed according to a method of allowing to stand for about 4 hours to age, a method of depolymerizing simultaneously with the reaction in the presence of oxygen in the air during the reaction, or a method of treating the purified product with an acid such as acetic acid or hydrochloric acid.

The content of the hydroxypropoxyl group in the low-substituted hydroxypropylcellulose is 5 to 16% by weight, preferably 7 to 13% by weight. If it is less than 5% by weight, the hydroxypropyl cellulose is similar in properties to the raw material cellulose, and if it exceeds 16% by weight, the water-solubility of the hydroxypropylcellulose becomes large, so that the swelling ratio becomes small and both When used, the disintegration becomes insufficient.

[0017]

The present invention will be described below with reference to examples and comparative examples. (1) The method of synthesizing the low-substituted hydroxypropyl cellulose powder; Sample No. Synthesis of Synthesis Example 1 (Synthesis Example 1) Pulp was immersed in a 49% by weight aqueous solution of sodium hydroxide and then squeezed to obtain alkali cellulose containing 24.5% by weight of sodium hydroxide. After leaving the alkali cellulose at 40 ° C. overnight, 100 parts by weight of the alkali cellulose was charged into the reactor, and the atmosphere was replaced with nitrogen gas. After the replacement, 9.5 parts by weight of propylene oxide was charged into the reactor and stirred at 40 ° C. for 1 hour for 50 hours.
Reaction for 1 hour at 70 ° C. and 1 hour at 70 ° C.
9.5 parts by weight of the reaction product were obtained. This reaction product is
The product was charged into 2,000 parts by weight of hot water at 95 ° C. containing an equivalent of acetic acid equivalent to the amount of sodium hydroxide remaining with the product, neutralized, and dehydrated. The low-substituted hydroxypropylcellulose obtained by dehydration is washed with 3000 parts by weight of hot water at 90 ° C., dehydrated, dried, crushed with a vibration mill for 3 hours, and sieved with a 75 μm mesh sieve. Sample No. 1 shown in FIG. One sample was obtained.

Sample No. 2-No. Synthesis Example 6 Alkaline cellulose used in Synthesis Example 1 was left at room temperature for 8 hours, reacted with propylene oxide in the same manner as in Synthesis Example 1, neutralized and dehydrated. Set the washing water volume to 6000
In the same manner as in Synthesis 1, except that the weight ratio was changed to 3000 parts by weight and 1500 parts by weight, the sample Nos. 2 to 4 were obtained. Sample No. 1 was prepared in the same manner as in Synthesis Example 1 except that the amount of washing water was 3000 parts by weight, and the pulverized material was sieved with a sieve having an opening of 150 μm. 5 was obtained. Sample N was prepared in the same manner as in Synthesis Example 1 except that the pulverizing time by the vibration mill was 1.5 hours.
o. 6 was obtained.

Sample No. The alkali cellulose was used in 7 Synthesis Example 1 was allowed to stand at room temperature for 3 hours, following the procedure of Synthesis Example 1, a sample shown in Table 1 No. 7 was obtained.

Sample No. Synthesis Example 8 Alkaline cellulose used in Synthesis Example 1 was charged into a reactor immediately after production, and the same operation as in Synthesis Example 1 was performed.
Sample No. shown in FIG. 8 was obtained.

[0021]

[Table 1]

Each numerical value in Table 1 was obtained by the following method. (1) Method for quantifying hydroxypropoxyl group ; The content of hydroxypropoxyl group was calculated according to the method of the Japanese Pharmacopoeia shown below. (2) Measurement method of average particle diameter: The average particle diameter was measured by a laser diffraction measuring device HELOS & DOROS (manufactured by Shinpac). (3) Viscosity measuring method : 6 g of a sample is dispersed in 147 g of water, and a 20% aqueous sodium hydroxide solution 14 is stirred while stirring.
After adding and dissolving 7 g, it was measured at 20 ° C. using a B-type viscometer.

(4) Method for measuring water-soluble content : 10 g of a sample was dispersed in 100 g of water, shaken for 30 minutes, centrifuged, and the solid content concentration in the supernatant was measured. (5) Method for measuring compact apparent density ; Powder Tester PD-T
It was measured by a mold (manufactured by Hosokawa Micron Corporation). (6) Method of measuring angle of repose : Measured with a powder tester PD-T type (manufactured by Hosokawa Micron Corporation).

Examples 1 and 2 and Comparative Examples 1 to 3 1 to No. For each of No. 5, 10 parts by weight of the sample and 90 parts by weight of phenacetin were mixed with a kneader, and water 3
After adding 5 parts by weight and kneading, the mixture was granulated using a 5-inch cylindrical extruder having a 0.6 mmφ screen. Table 2 shows the granulation speed. From Table 2, in Examples 1 and 2, both the granulation speed and the disintegration were excellent, while Comparative Examples 1 to
In No. 3, it can be seen that either the granulation speed or the disintegration property is inferior.

[0025]

[Table 2]

Examples 3 and 4, Comparative Examples 4 and 5 3, No. 6-No. For each of Nos. 8, 25 parts by weight of a sample, 40 parts by weight of acetaminophen, 24.5 parts by weight of lactose, and 10.5 parts by weight of corn starch were blended, and the mixture was charged into an AEROMATIC STREA-1 type (manufactured by Powrex Corporation). When the temperature is 70 ° C, HPC-L
240 parts by weight of a 5% aqueous solution of EP (manufactured by Shin-Etsu Chemical Co., Ltd.) was sprayed to perform fluidized bed granulation. The obtained granules were sieved with a sieve having an opening of 1400 μm, and the specific volume was measured. Table 3 shows the results. From Table 3, Examples 3 and 4 are Comparative Examples 4,
It can be seen that the specific volume is smaller (the bulk density is larger) than that of No. 5.

[0027]

[Table 3]

[0028]

When the low-substituted hydroxypropylcellulose powder of the present invention is used in an extrusion granulation method, a granulated product having a high granulation speed in the process of producing a granulated product and having good disintegration properties can be obtained. When used in the fluidized bed granulation method, a granulated product having a large bulk density can be obtained.

Claims (1)

[Claims] 1. A solution having a viscosity at 20 ° C. of 5 to 100 centipoise and a water-soluble content of 2 to 6% by weight when dissolved in a 10% by weight aqueous solution of sodium hydroxide to a concentration of 2% by weight. And the apparent apparent density is 0.55 g / c.
c or more, the angle of repose is 48 degrees or less, and the average particle diameter is 45 μm or less.