JPH0372047B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides tablets comprising novel cellulose derivatives having two or three ether or ester substituents, one of which is a calcium carboxymethyl group which may contain a free acid. It concerns disintegrants.

Calcium salts of carboxymethyl cellulose are insoluble in water, but have the property of swelling and dispersing in water, making it easier to disintegrate solids containing this in water. It is widely used as an agent. However, due to poor binding properties, capping may easily occur during tablet compression depending on the properties of the active ingredient and other ingredients.

As a result of various studies, the present inventors discovered that the above-mentioned drawbacks could be improved by introducing another kind of ester group or ether group into the calcium salt of carboxymethyl cellulose, and arrived at the present invention. Carboxymethylcellulose calcium salts having such substituents have not been known at all so far.

That is, the present invention is based on the general formula {In the formula, Gul represents the anhydroglucose unit skeleton of cellulose consisting of C ₆ H ₇ O ₂ , and OR and OR' are the same or different ether groups, ester groups, or hydroxyl groups (however, both OR and OR' are hydroxyl group), M is Ca or H (excluding when all M are H), n is
Indicates a number greater than 50. } The present invention relates to a tablet disintegrant comprising a substituted carboxymethyl cellulose calcium salt represented by:

The substituted carboxymethyl cellulose calcium salt according to the present invention has the general formula {In the formula, Gul represents the anhydroglucose unit skeleton of cellulose consisting of C ₆ H ₇ O ₂ , and OR and OR' are the same or different ether groups, ester groups, or hydroxyl groups (however, both OR and OR' are hydroxyl (except when it is a group), and n represents a number of 50 or more. } It can be produced by reacting substituted carboxymethyl cellulose represented by the following with calcium carbonate in a wet state.

In the general formula (), the substituents represented by OR and OR' include an alkyl ether group having 5 or less carbon atoms, a hydroxyalkyl ether group, and an alkyl ester group having 5 or less carbon atoms. At the same time, it may be included as a substituent.

In carrying out the method for producing substituted carboxymethylcellulose calcium salt of the present invention,
First, a carboxymethylcellulose sodium salt having a substituent is synthesized. For the synthesis method, methods disclosed in prior patent documents such as Japanese Patent Publication No. 53-8751, Japanese Patent Publication No. 48-18586, Japanese Patent Publication No. 44-15678, and US Pat. No. 2,476,331 can be used.

Next, the carboxymethylcellulose sodium salt having a substituent is treated with an acid aqueous solution to form a free acid. Suitable acids to be used include mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid, and lower fatty acids such as acetic acid.
15 when using mineral acids to avoid side reactions.
It is desirable to process at a low concentration of 20°C or less and at a temperature of 20°C or less. The acid treatment is followed by washing with water to remove the generated salt and excess acid to obtain the free acid of carboxymethyl cellulose in a wet state. The free acid is once dried and re-wetted by adding water to adjust the moisture content in the wet material to 30-80%, then mixed with powdered cowsium carbonate and subjected to a neutralization reaction at 30-40℃. to obtain calcium salt. When the quantitative relationship of moisture can be determined separately, the step of drying and rewetting the wet free acid can be omitted. The amount of calcium carbonate is preferably equivalent to or less than the equivalent amount to the free acid of carboxymethylcellulose. In this case, a portion of the carboxymethyl group will remain in the free acid form. When the thus obtained substituted carboxymethylcellulose calcium salt is used as a disintegrant for pharmaceutical tablets, it enables tablet formulations with better tablet physical properties than conventional unsubstituted carboxymethylcellulose calcium salts. It is.

The present invention will be explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 Powdered carboxymethyl cellulose sodium salt (carboxymethyl substitution degree DS 0.49, 1% viscosity
118cps) 50g, t-butanol 328.9g, water 63.3
After dispersing the mixture in a mixed system of 50%, 21.9g of a 50% caustic soda aqueous solution was added and stirred at 15°C for 45 minutes. Thereafter, 24.5 g of propylene oxide was added, and the mixture was reacted at 50°C for 1 hour and then at 70°C for 1 hour. After the reaction was completed, the caustic soda was neutralized with acetic acid, washed twice with 80% methanol, and dried. The degree of substitution (MS) of hydroxypropyl groups per anhydroglucose unit of the produced carboxymethylhydroxypropylcellulose was 0.20. Next, this derivative was treated with 10% sulfuric acid, washed with water, deliquified, the wetting water was replaced with acetone, and vacuum dried. After drying, 55 parts of water was added to 40 parts of the powdered sample (by weight, the same applies hereinafter), and after mixing well, 4 parts of calcium carbonate powder was added, and the mixture was reacted by stirring at a temperature of 30 to 40°C for 2 hours. .
After the reaction was completed, the mixture was dried and ground. This product is a carboxymethyl hydroxypropylcellulose calcium salt, with a degree of carboxymethyl substitution.
DS was 0.49, and degree of substitution of hydroxypropyl was MS 0.20. The infrared absorption spectrum (IR spectrum) of this product is shown in FIG. For comparison, the IR spectrum of commercially available carboxymethylcellulose calcium salt is shown in FIG.

Example 2 50 g of powdered carboxymethyl cellulose sodium salt (degree of substitution DS 0.49, 1% viscosity 118 cps)
- After dispersing in a mixed system of 328.9 g of butanol and 63.3 g of water, 21.9 g of a 50% caustic soda aqueous solution was added and stirred at 15°C for 45 minutes. Thereafter, 5.5 g of ethylene oxide was added and reacted at 60°C for 1.5 hours. After the reaction was completed, the caustic soda was neutralized with acetic acid, washed twice with 80% methanol, and dried. The degree of substitution (MS) of hydroxyethyl groups per anhydroglucose unit of the produced carboxymethyl hydroxyethyl cellulose was 0.23. Next, this derivative was treated with 10% sulfuric acid, washed with water, deliquified, the wet moisture was replaced with acetone, and vacuum dried. After drying, 80 parts of water was added to 50 parts of the powdered sample, and after mixing well, 4.9 parts of calcium carbonate powder was added and reacted by stirring at a temperature of 30 to 40°C for 2 hours. After the reaction was completed, it was dried and pulverized. The product was carboxymethyl hydroxyethyl cellulose calcium salt, with a carboxymethyl substitution degree DS of 0.49 and a hydroxyethyl substitution degree MS of 0.23. The IR spectrum of this product is shown in FIG.

Example 3 After dispersing 493 g of powdered carboxymethylcellulose sodium salt (degree of substitution DS 0.64, 1% viscosity 1850 cps) in 2264 g of toluene in an autoclave, 320 g of a 50% ethanol aqueous solution was gradually added while stirring. Then flaked caustic soda
After adding 142 g, the autoclave was thoroughly stirred, the autoclave was purged with nitrogen, 260 g of methyl chloride was added, the autoclave was closed, and the reaction was carried out at 80°C for 1 hour and at 90°C for 2 hours. After the reaction was completed, the mixture was neutralized with acetic acid, the liquid was removed, and the mixture was washed three times with 80% methanol. The substitution degree DS of the methoxyl group of the produced carboxymethylmethylcellulose was 0.7. Next, this derivative was treated with 10% sulfuric acid, washed with water, dehydrated, replaced with acetone, and dried in vacuum. After drying, add 80 parts of water to 50 parts of the powdered sample, mix well, add 5.7 parts of calcium carbonate powder, and mix at a temperature of 30 to 40°C.
The mixture was stirred for some time and allowed to react. After the reaction was completed, it was dried and pulverized. The product is carboxymethyl methylcellulose calcium salt, with a degree of carboxymethyl substitution.
The DS was 0.64 and the degree of methoxyl substitution was DS 0.7. The IR spectrum of this product is shown in FIG. Mock tablets were molded using the carboxymethylmethyl cellulose calcium salt obtained in this example as a disintegrant.

The tablet composition is as follows.

Lactose 100 parts Disintegrant 10 Calcium suraate 0.5 Talc 0.5 Tablets with a diameter of 8 mm and a thickness of 4 mm were molded by a direct compression method at a compression pressure of 2000 kg/cm ² . For comparison, tablets using a commercially available carboxymethyl cellulose calcium salt as a disintegrant were compressed. The Monsanto hardness was 2.2 kg for the present invention product and 1.4 kg for the comparative product, and there was no significant difference in the rate of disintegration in water.

Example 4 50 g of carboxymethyl cellulose sodium salt with a degree of carboxymethyl substitution (DS) of 0.63 was immersed in 1.5 kg of 20% sulfuric acid for 2 hours at room temperature, washed with water, and then immersed in 1.5 kg of acetic acid.
The sample was washed three times with acetic acid and the moist water was replaced with acetic acid to make it wet with acetic acid. After removing the liquid, put it in a small kneader and add 250% acetic acid.
g, 5.6 g of sulfuric acid, and 150 g of acetic anhydride, and heated to 48-50℃.
It reacted for 4 hours. As the reaction progressed, the raw materials dissolved in the reaction medium and became a homogeneous system. The reaction solution was added to water to cause precipitation, and the resulting precipitate was thoroughly washed with water and dried in vacuum. The degree of acetylation of the product was measured by a saponification method and found to be DS2.34. After drying, 15 parts of water was added to 10 parts of the powdered sample, and after mixing well, 0.8 parts of calcium carbonate powder was added and reacted at a temperature of 30 to 40°C for 2 hours. After the reaction was completed, it was dried and pulverized. The product was carboxymethyl acetylcellulose calcium salt, with a carboxymethyl substitution degree DS of 0.63 and an acetyl substitution degree DS of 2.34.
The IR spectrum of this product is shown in FIG.

Example 5 514 g of carboxymethyl cellulose sodium salt with a degree of carboxymethyl substitution (DS) of 0.52 (water 23
) was added to the autoclave together with 2194 g of toluene, and while stirring, a 50% ethanol aqueous solution was added.
Add 460g and additionally 404 flaked caustic soda
After adding 1,005 g of ethyl chloride and purging with nitrogen, the autoclave was sealed and reacted at 120° C. for 6 hours. After the reaction, cool to around room temperature, add 225g of flaky caustic soda and heat to 120℃.
It reacted for 6 hours. After the reaction was completed, the solution was deliquified and the wet solvent was evaporated, followed by treatment with 10% sulfuric acid, thorough washing with water, and deliquification. The dehydrated sample was vacuum dried. The degree of ethoxyl substitution DS of this carboxymethylethyl cellulose was 2.0. After drying, add 100 parts of water to 100 parts of the powdered sample, mix well, add 8 parts of calcium carbonate powder, and mix at a temperature of 30 to 40°C.
The mixture was stirred for some time and allowed to react. After the reaction was completed, it was dried and pulverized. The product is a carboxymethyl ethyl cellulose calcium salt with a degree of carboxymethyl substitution.
The DS was 0.52, and the degree of ethoxyl substitution was DS 2.0. The IR spectrum of this product is shown in FIG.

[Brief explanation of drawings]

Figure 1 is the product of Example 1, Figure 2 is the commercially available carboxymethylcellulose calcium salt, Figure 3 is the product of Example 1,
Figure 6 is the IR spectrum of the products of Examples 2 to 5, respectively.

Claims (1)

[Claims] 1. General formula {In the formula, Gul represents the anhydroglucose unit skeleton of cellulose consisting of C ₆ H ₇ O ₂ , and OR and OR' are the same or different ether groups, ester groups, or hydroxyl groups (however, both OR and OR' are hydroxyl group), M is Ca or H (excluding when all M are H), n is
Indicates a number greater than 50. } A tablet disintegrant consisting of a substituted carboxymethyl cellulose calcium salt represented by: 2. The tablet disintegrant according to claim 1, wherein the ether group or ester group represented by OR or OR' is an alkyl ether group, hydroxyalkyl ether group, or alkyl ester group having 5 or less carbon atoms.