JPS60130527A - Production of solid pharmaceutical - Google Patents

Abstract

PURPOSE:To obtain industrially and advantageously a solid pharmaceutical, by treating sodium carboxymethyl cellulose (CMC-Na) with an alkali and then an acid, purifying the resultant CMC, drying the purified CMC, and pulverizing the dried CMC, and incorporating the resultant CMC powder having improved bulk density, angle of repose and powder fluidity as a disintegrating agent in a composition. CONSTITUTION:Sodium carboxymethyl cellulose (CMC-Na) having 0.2-1.2 substitution degree of carboxymethyl groups per flucose unit is treated with an alkali and then an acid, and the resultant converted CMC is purified, dried and pulverized to give CMC powder having 400-700g/l bulk density and 35-45 degrees angle of repose. The alkali agent in an amount of 10-120wt% based on the CMC-Na and in 15-60wt% concentration based on water must be used to treat the CMC-Na at 30-80 deg.C. Thus, the aimed CMC powder having a high bulk density, small angle of repose and improved powder fluidity is obtained with advantages of disintegration and compression moldability as they are. If the above-mentioned powder is incorporated as the disintegrating agent, a solid pharmaceutical having improved disintegration property and pressure moldability is obtained with improved operability.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a solid drug that is easy to work with during preparation, has excellent disintegration properties, and is excellent in pressure moldability. Sodium methylcellulose (hereinafter referred to as Na-CMC)
After treating H-CMC with an alkaline agent, converting it to carboxymethylcellulose (hereinafter referred to as H=CMCa) with an acid treatment, purifying it, drying it, and pulverizing it, and blending the resulting H-CMC powder into a composition containing a medicinal ingredient. The present invention relates to a method for producing a solid drug characterized by:

Conventionally, solid sugar preparations for medical use such as tablets, pills, capsules, granules, and fine granules have disintegrated to quickly disintegrate in the digestive juices of the stomach and intestines after taking them, speeding up the absorption of medicinal ingredients. It is necessary to add an agent. Disintegrants are also added to solid drugs such as agricultural chemicals, disinfectants, and bleaching agents to ensure quick action.

Those used as disintegrants include unmodified starch, 5
ta-Rx 1500 (physically modified starch), EC
G505 (carboxymethylcellulose calcium),
NS-300 (H-CMC), L-I+pc (low ftt
hydroxypropyl cellulose), Polypla
Examples include sdon XL (cross-linked polyvinylpyrrolidone). However, these disintegrants still do not fully satisfy the requirements. That is, unmodified starch and physically processed starch require the addition of relatively much winter melon in order to provide a solid drug with a sufficient disintegration rate, but on the other hand, addition of a large amount significantly reduces tablet hardness and becomes a practical obstacle. L
-1-11) C has relatively good tablet formability.

It has poor powder fluidity and relatively weak disintegration promoting effect, so it is not used much. Although it is not necessary to add a large amount of cross-linked polyvinylpyrrolidone, it tends to cause capping during high-pressure molding.

Carboxymethyl cellulose calcium is a tasteless and odorless white powder that has relatively good disintegration and compression moldability, and is currently used in large amounts as a disintegrant. However, depending on the medicinal ingredients, there may be concerns about interactions with the calcium salts they contain. H-CMC is currently only commercially available as NS-300 (manufactured by Chirin Kagaku Kogyo Co., Ltd.). It has strong disintegration properties and good compression moldability, and unlike carboxymethyl cellulose calcium, it has no interaction with medicinal ingredients. Although there are few concerns, the NS-300 currently available on the market has a low bulk density and a large angle of repose, resulting in poor powder fluidity, and particularly when the amount added is increased, it may impede the fluidity of drug mixture compositions. However, this may cause problems in workability, such as impairing uniform flow in the hopper during tabletting. This is especially important when tabletting is performed at extremely high speeds these days. In addition, the low bulk density means that when used in fine granules, granules, capsules, etc., whose production volumes have increased in recent years, the particle size becomes large and it becomes difficult to form fetal heads into capsules of a certain volume. Therefore, there has been a desire to develop H-CMC that has a high bulk density and excellent fluidity, but to date no product has been published that meets this demand.

The present inventor focused on the outstanding properties of H-CMC in that it does not interfere with the disintegration and compression moldability and does not inhibit the medicinal ingredients. As a result of extensive research on developing H-CMC, Na-CM
After treating C with an alkali agent, H-CMC is formed by acid treatment.
H obtained by converting into H
-CMC retains its characteristic advantages of disintegration and compression moldability, while also having a large bulk density, a small angle of repose, and excellent powder fluidity, making it difficult to mix drugs even when the amount added is increased. ) It was discovered that it does not inhibit the fluidity of the body.

H-CMC obtained in the present invention has a bulk density of 400 to 70
0 y/l, the angle of repose is 35 to 45 degrees, and conventionally commercially available H
-CMC (NS-:300) bulk density 300~4 (
10 y/l and an angle of repose of around 50 degrees, the powder fluidity is extremely excellent. Therefore, when the H-CMC of the present invention is used as a disintegrant and tablets are compressed, the fluidity of the drug mixed powder is good even when the amount of addition (■) is increased. They discovered that the head of the fetus can be moved smoothly, leading to the present invention.

The bulk density and angle of repose mentioned here are measured by the following method.

(Bulk density) Prepare a zoom graduated cylinder and add 2 g of powder sample.
Q Gradually add up to the ml mark and stack. Lift the cylinder so that the distance between the bottom of the cylinder and the floor is 5 cm, release your hand, and let the cylinder fall. After repeating this operation 10 times and reading the volume (mt), the weight of the powder sample is measured.

Bulk density (g/l) - [weight 1LCf)/volume ji (ml
)], X 1,000 (angle of repose) Based on a three-wheeled cylindrical rotation method angle of repose measuring instrument.

The present invention will be specifically explained below.

Raw material Na-CMC is crude product, purified product 1. It is not necessary to specifically limit the amount by 1I).Even if purified M is used, it is necessary to purify it again, and it is more advantageous in terms of cost to use a crude product. The degree of substitution of Na-CMC is 0.2 to 1.
2 is good, and if it is less than 0.2, there are few hydrophilic groups, the swelling ratio becomes small, and the disintegrability is insufficient. On the other hand, even if it is set to 1.2 or more, no improvement over the present invention is seen and there is no economic advantage. The alkaline agent used is preferably a strongly alkaline agent such as caustic soda or caustic potash, which is inexpensive and available in large quantities. The alkaline agent in the treatment system is Na-C.
10-120 heavy type 3% for MC, 15~ for water
It is necessary to process at a concentration of 60% by weight.

If the content is less than 10% by weight relative to Na-CMC or less than 15% by weight relative to water, the high density and angle of repose of the present invention cannot be obtained. If it is 120% by weight or more based on Na-CMC or 60% by weight or more based on water, it will be colored due to alkali burning, and the whiteness will be lost, which is unfavorable in terms of appearance.

The treatment temperature must be in the range of 30 to 80°C, preferably 50 to 70°C.

If it is below 30°C, the reaction time will be long and it will be uneconomical.
If the temperature exceeds 0°C, cleaning during purification, which is a post-process, becomes difficult and purification is sometimes impossible.

The treatment time varies depending on the alkali concentration and reaction temperature.
It is preferable to carry out within 10 hours.

The acid used in the acid treatment is preferably an aqueous solution of strong acids such as sulfuric acid, hydrochloric acid, and nitric acid. This acid treatment only needs to convert Na-CMC into H-CMC, and may be performed using an aqueous alcohol solution of these acids, for example, a water-containing organic solvent such as a water-containing nitric acid methanol solution, in addition to an aqueous solution of the acid. In particular, it is preferable to use non-volatile sulfuric acid from the viewpoint of the working environment.

The H-CMC obtained in the above manner was purified, dried,
The bulk density of crushed and classified through 200 mesh sieve is 4.
00 to 700 y/l and a repose angle of 35 to 45 degrees can be obtained.

Next, the present invention will be explained with reference to Examples.

<Examples I to 3> 700 g of 40% monochloroacetic acid sodium aqueous solution is added to linter pulp 500F and crushed.

To this was added 320 g of 48% caustic soda, cooled to below 15°C and mixed for 2 hours, followed by an etherification reaction at 50°C for 3 hours. 48% caustic soda 3001 was added to the obtained product, and alkali treatment was performed at 60°C for 5 hours. After the reaction is completed, immerse in 3N sulfuric acid 61 to remove Na-C.
Convert MC to H-CMC. Subsequently, the sulfuric acid solution is removed, and the product is thoroughly washed with water. Next, this wet H-CMC
is dried and pulverized until 95% or more passes through a Japanese Industrial Standard 200 mesh sieve.

Similarly, by changing the amounts of caustic soda and sodium monochloroacetate used in the etherification reaction, Na-CM with different degrees of substitution
Three types of H-CM C powders were prepared and subjected to alkali treatment in the same manner as described above to obtain H-CM C powders shown in Table (1) below.

Table (1) These H-CMCs are conventional commercially available H-CMCs (NS-3
00), the angle of repose was smaller and the powder fluidity was extremely good.

<Examples 4 to 6> 7,507 g of a 40% monochloroacetic acid aqueous solution was added to 500 g of wood pulp and crushed. To this was added 350 g of 48% caustic soda, cooled to below 15°C and mixed for 2 hours, followed by an etherification reaction at 50°C for 3 hours. Add 510 g of 48% caustic soda to the obtained product,
Alkali treatment is carried out at °C for 3 hours. Below, Example 1~
The same operation as in 3 was performed to obtain H7CMC powder.

Similarly, H-
A prototype of CMC powder was produced. These properties are shown in the table below (2
).

Table (2) These H-CMCs are conventionally commercially available H-CMCs (NS-
:J o 0 ), the angle of repose was smaller and the powder fluidity was extremely good.

<Example 7> Mercerization was carried out by adding 320 y of 48% caustic soda to 500 g of pulverized pulp. Next, 700 g of a 40% monochlorosodium acetate aqueous solution was added and the mixture was mixed at 15°C or lower for 3 hours, followed by an etherification reaction at 60°C for 3 hours. 550 g of 48% caustic soda was added to the obtained product and alkali treatment was carried out at 70"C for 3 hours. The following operations were carried out in the same manner as in Examples 3 to 3. The properties of the obtained H-CMC powder were determined by the degree of substitution. 0.52, bulk density 606 f/l,
.

The angle of repose was 380 degrees.

These I-1-CM Cs are conventional commercially available I-I-CMs.
The angle of repose was smaller than that of C(N S-3o 0 ), and the powder fluidity was extremely good.

<Example 8 and Comparative Example 1> H-CM C of Examples 1 to 7 and NS-300 of Comparative Example were used as disintegrants to prepare simulated tablets, and the physical properties of the tablets and the flow of the powder mixture composition were evaluated. The angle of repose was measured as a characteristic.

In addition, the properties of NS-300, which is a comparative example, are that the degree of substitution is 0.5.
2. The bulk density is 392 y/l and the angle of repose is 495 degrees.

Tablet Composition Lactose 88.5 Disintegrant 10.0 Tar 10 Total 100.0 Weight % Tableting Conditions 0.7 g of the powder mixture composition was crushed using a 15 ronrφ punch (
7) Tablet compression pressure 4 H10s2 The physical properties of the molded tablet were measured by the following method.

Hardness Monsanoto hardness tester Disintegration Measured according to the Japanese Pharmacopoeia Measurement temperature: 37±2°C Test liquid: Pharmacopoeia No. 1 liquid (artificial gastric juice) The measurement results are shown in Table (3).

Table (8) Example shows angle of repose Kata MS even in case of body mixture composition
-300, excellent powder fluidity, and no difference in hardness and disintegrability, giving good results.

<Example 9 and comparative example 2> MS was added to H-CMC of Example 1 and comparative example as a disintegrant.
-300 was used extensively and aspirin was used as the medicinal ingredient.13
) Tablets were molded from the composition using a blood punching method.

In addition, the properties of NS-300, which is a comparative example, are that the degree of substitution is 0.5.
0, bulk density 3 s o q/l, and angle of repose 49.0 degrees.

Next, a similar tablet compression test was conducted in which the medicinal ingredient was extracted from aspirin by sanarmin (alumina/magnesium hydroxide) I.

b) Body composition and tableting conditions are as follows.

Powder composition Aspirin (manufactured by Mitsui Toatsu) 55.0 Avinyl I) HIOl (manufactured by Asahi Kasei) 250 Lactose 12.0 Disintegrant 5.0 Talli 2.5 Sanarmin (manufactured by VJJ Wa Kagaku) 50.0 Lactose 44
．． 5 Disintegrant 5.0 Tableting conditions Tableting machine Rotary tablet machine Clean Press Collect 24 Manufactured by Usui Seisakusho Molding conditions Tablet diameter 3 nmtφ, tableting pressure 1.81/72
Rotation speed: 35 rpm Tablet hardness and disintegration time were measured by the method described above.

The measurement results are shown in Table (4).

Table (4) H-CMC obtained by alkali treatment with disintegrant and 1
7, the tableting operation was extremely smooth and no occurrence of capping, chino pink, etc. was observed.

Furthermore, the hardness and disintegration properties shown in Table (4) were as good as those of conventional products.

Procedural amendment (direction) August 1978/711 1 Indication of case Patent application No. 237671, 1988 3
Relationship with the case of the person making the amendment Patent applicant

Claims (1)

[Claims] The degree of carboxine methyl group substitution per glucose unit is 0,
Bulk density 400-700 f/l, angle of repose 35-45 degrees obtained by treating sodium carboxymethylcellulose of 2-1.2 with an alkali agent, converting it to carboxymethylcellulose by acid treatment, purifying, drying, and pulverizing. Method 2 for manufacturing a solid drug, characterized by blending carboxymethylcellulose powder into a composition containing a medicinal ingredient and molding it, the alkaline agent used is 10 to 120% by weight based on sodium carboxymethylcellulose, and 4% by weight based on sodium carboxymethylcellulose. A method 3 for producing a solid drug according to claim 1, characterized in that the concentration is 15 to 60% by weight, and a patent characterized in that the treatment with an alkaline agent is carried out at a temperature of 30 to 80°C. Method for producing a solid drug according to claim 1