JPH08333401A - Method for producing base for coating solid enteric preparation - Google Patents

Abstract

(57) [Abstract] [PROBLEMS] To provide a method for producing a coating base for a solid enteric preparation, which enables efficient precipitation of a large amount of a cellulosic polymer serving as a coating base in a solution. [Structure] An acid anhydride and a cellulose derivative are reacted in a solution using an alkali metal salt as a catalyst. After the reaction, 80 to 110 mol of an inorganic acid is added to the reaction liquid with respect to 100 mol of an alkali metal salt, the reaction liquid and excess water are mixed, and a cellulose-based polymer having a dissolution pH of 3.0 to 4.0 is mixed. Precipitate in.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing a base material for coating a solid enteric preparation.

[0002]

2. Description of the Related Art A solid enteric preparation is a drug coated with a film-shaped enteric polymer. The enteric polymer protects the acid-sensitive drug from gastric acid, protects the gastric mucosa from the drug, and dissolves inside the small intestine. Dissolution of the enteric polymer releases the drug inside the small intestine.

Cellulose-based polymers are known as one of the enteric polymers as a base for coating solid enteric preparations. Specifically, cellulose acetate phthalate,
Examples thereof include cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, and carboxymethyl ethyl cellulose.

The above cellulose-based polymer is dissolved in an organic solvent, or an aqueous latex or an aqueous dispersion is prepared to obtain a coating liquid. A solid enteric preparation can be obtained by applying this coating liquid to a drug and drying it to form a film.

These cellulosic polymers have a dissolution pH
Is 5 to 7 and the solubility is not high. With this degree of solubility, the solid enteric preparation will pass through the upper small intestine before the drug is completely released. In order for the solid enteric preparation to completely release the drug, it is necessary to lower the dissolution pH to enhance the solubility of the cellulosic polymer.

Examples of the cellulosic polymers having improved solubility include cellulose trimellitates and cellulose acetate malates having a dissolution pH of 3 to 4. Cellulose trimellitates are prepared by reacting a cellulose derivative with trimellitic anhydride in a solution using sodium acetate as a catalyst, heating the obtained reaction solution for several hours, then cooling it, and mixing with excess water. Is deposited.

Cellulose acetate malates are prepared by reacting a cellulose derivative with acetic anhydride and maleic anhydride in a solution using sodium acetate as a catalyst, heating the resulting reaction solution for several hours and then cooling it to obtain an excess amount. Precipitates by mixing with water.

In Japanese Patent Application No. 4-151939, a mixed solution of a reaction solution and excess water is introduced into a stirring and mixing tank having two stirring blades, and the stirring blade and the stirring blades are charged. A method of precipitating a cellulosic polymer by stirring a mixed solution with a fixed stator is described. The reaction liquid and water can be uniformly mixed by stirring, and the cellulose-based polymer can be precipitated.

[0009]

The cellulosic polymer is easily dissolved in a mixed liquid containing a large amount of salts as by-products. Therefore, it was not possible to deposit a large amount of the cellulosic polymer in the mixed liquid.

The present invention has been made to solve the above-mentioned problems, and a coating base for a solid enteric preparation capable of efficiently recovering a large amount of a cellulosic polymer as a base for coating is precipitated in a solution. It is intended to provide a manufacturing method.

[0011]

Means for Solving the Problems As a result of intensive studies by the present inventors, when a coating base having a dissolution pH of 3 to 4 is deposited, if the pH of the solution is adjusted to 2 or less, the coating base becomes a solution. The present invention has been completed by finding that it is easy to deposit.

That is, the method for producing a base material for coating a solid enteric preparation of the present invention comprises reacting an acid anhydride with a cellulose derivative in a solution using an alkali metal salt as a catalyst, and then reacting the obtained reaction solution with an excess amount. Mix with water and dissolve pH
A method for producing a base for coating a solid enteric preparation, which comprises depositing a cellulose-based polymer of 3.0 to 4.0,
After the reaction between the cellulose derivative and the acid anhydride, 80 to 110 mol of the inorganic acid is added to the reaction liquid or excess water with respect to 100 mol of the alkali metal salt and mixed.

When the amount of the inorganic acid added is less than 80 mol, the pH of the mixed solution of the reaction solution and excess water does not become 2 or less, and the dissolved cellulosic polymer does not precipitate in the mixed solution. If it exceeds 110 moles, the effect of adding a large amount will not be exhibited.

The acid anhydride is preferably a mixture of maleic anhydride and acetic anhydride or trimellitic anhydride.

Examples of the cellulose derivative include hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxyethyl cellulose.

Cellulosic polymers synthesized from the acid anhydride and the cellulose derivative are cellulose acetate malates and cellulose trimellitates. Cellulose acetate malates include hydroxypropyl methyl cellulose acetate malate, methyl cellulose acetate malate, hydroxypropyl cellulose acetate malate, hydroxyethyl cellulose acetate malate, and cellulose trimellitates include hydroxypropyl methyl cellulose trimellitate, methyl cellulose. Examples include trimellitate, hydroxypropyl cellulose trimellitate, and hydroxyethyl cellulose trimellitate.

Examples of the alkali metal salt added as a catalyst include sodium acetate.

Examples of the inorganic acid added to lower the pH include hydrochloric acid and sulfuric acid.

An example of a method for producing hydroxypropylmethylcellulose acetate malate as a coating base will be described below. First, hydroxypropylmethyl cellulose is dissolved in a solvent such as acetic acid, and predetermined amounts of acetic anhydride and maleic anhydride are added in the presence of an alkali metal salt. Purified water was added to the obtained reaction solution to cool it,
The reaction of maleic anhydride and acetic anhydride with hydroxypropyl methylcellulose is stopped. An inorganic acid such as hydrochloric acid or sulfuric acid is added to the reaction solution and then mixed with excess water,
Hydroxypropyl methylcellulose acetate malate is precipitated in the mixture. The hydroxypropylmethylcellulose acetate malate is washed with purified water until the washing liquid shows no acidity, and then dried with a fluidized bed dryer or the like to obtain a coating base having a dissolution pH of 3.0 to 4.0.

The dissolution pH of the cellulosic polymer is measured by the method described below. Cellulosic polymer is dissolved in organic solvent and cast on a glass plate to a thickness of 100μ
m film is made and cut into 1 cm x 1 cm. The film is put in the solvent for dissolution using an auxiliary cylinder according to the Japanese Pharmacopoeia disintegration test method, and the pH of the solvent in which the film is dissolved is investigated. As the dissolving solvent, several kinds of McValine buffer solutions having different pH are used.

The coating process is completed by spraying the coating liquid onto the drug by the coating device and simultaneously drying the liquid to form a film. For the coating liquid, dissolve the cellulosic polymer in a solvent such as acetone, methylene chloride / alcohol, alcohol / water, or
The following is finely pulverized and dispersed in water. A pharmaceutically acceptable additive such as a plasticizer, a colorant, a pigment or an anti-adhesive agent may be added to the coating liquid, or the dissolution or solubility may be changed by combining it with an existing coating base.

Examples of the coating apparatus include a fluidized bed coating apparatus, a pan coating apparatus, and an aeration type rotary drum type coating apparatus.

[0023]

By adding the inorganic acid, the pH of the mixed solution of the reaction solution and excess water becomes lower than the dissolution pH of the cellulose polymer, and the dissolution of the cellulose polymer is prevented. Since the amount of the polymer precipitated in the mixed solution is large, the cellulosic polymer can be efficiently recovered. Cellulosic polymers are used as a base for coating solid enteric preparations.

[0024]

EXAMPLES Examples of the present invention will be described in detail below.

Example 1 700 g of hydroxypropylmethylcellulose (HPMC: 23.3% by weight of methoxyl group, 6.4% by weight of hydroxypropoxyl group manufactured by Shin-Etsu Chemical Co., Ltd.) having a viscosity of 5.5 cP in a 2% by weight aqueous solution at 20 ° C. And acetic acid 21
00 g was put into a 5 liter twin-screw kneader and melted at 70 ° C. After completion of the dissolution, 910 g of trimellitic acid anhydride was added as an esterifying agent, and 275 g of sodium acetate was added as a catalyst, and the mixture was reacted at 85 to 90 ° C. After 5 hours, the solution was cooled, and 1180 g of purified water was added to stop the reaction. A mixture of this solution and 280 g of concentrated hydrochloric acid (36% by weight) was poured into excess purified water to precipitate a product. The product was washed with purified water, and after the washing liquid did not show acidity, the product was dried with a fluid bed dryer to obtain 927 g of hydroxypropylmethylcellulose trimellitate. This yield corresponded to 81% of theory.

This hydroxypropylmethyl cellulose trimellitate was dissolved in a 1: 1 solution of methylene chloride / ethanol, and the solution was cast on a glass plate to prepare a film having a thickness of 100 μm.

The dissolution pH was measured according to the Japanese Pharmacopoeia disintegration test method. As a result of adding the film cut into 1 cm squares to several kinds of McCluvine buffer solutions having different pH,
It was confirmed that the film was dissolved in the buffer solution of pH 3.9.

From the results of measurement of dissolved pH, it was confirmed that the obtained hydroxypropylmethylcellulose trimellitate was satisfactory as a base for coating solid enteric preparations.

Example 2 700 g of hydroxypropylmethylcellulose (HPMC: 29.1% by weight of methoxyl group, 8.9% by weight of hydroxypropoxyl group, manufactured by Shin-Etsu Chemical Co., Ltd.) having a viscosity of 5.2 cP in 2% by weight aqueous solution at 20 ° C. And acetic acid 21
00 g was put into a 5 liter twin-screw kneader and melted at 70 ° C. After dissolution, acetic anhydride 17 was used as an esterifying agent.
6 g and 193 g of maleic anhydride were added, and 278 g of sodium acetate was added as a catalyst, and the mixture was reacted at 85 to 90 ° C. After 5 hours, the solution was cooled, and 1180 g of purified water was added to stop the reaction. A mixture of this solution and 310 g of concentrated hydrochloric acid (36% by weight) was poured into excess purified water to precipitate a product. The product was washed with purified water, and when the washing liquid did not show acidity, the product was dried with a fluidized bed drier to obtain 780 g of hydroxypropylmethylcellulose acetate malate. This yield corresponded to 87% of theory.

A film was prepared from this hydroxypropylmethylcellulose acetate malate in the same manner as in Example 1 and the dissolution pH of this film was investigated. The dissolution pH was 3.5. From the measurement result of the dissolution pH, it was confirmed that the obtained hydroxypropylmethylcellulose acetate malate was satisfactory as a coating base for a solid enteric preparation.

Example 3 Hydroxypropylmethylcellulose trimellitate was synthesized in the same manner as in Example 1 except that the amount of hydrochloric acid (36% by weight) added was 370 g. The yield of the obtained hydroxypropyl methylcellulose trimellitate was 1020 g, which was an amount corresponding to 89% of the theoretical value.

A film was prepared from this hydroxypropylmethylcellulose trimellitate in the same manner as in Example 1 and the dissolution pH of this film was investigated. Dissolution pH
Was 3.9. From the measurement result of the dissolution pH, it was confirmed that the obtained hydroxypropylmethyl cellulose trimellitate was satisfactory as a coating base for a solid enteric preparation.

Example 4 In the same manner as in Example 1, hydroxypropylmethylcellulose and trimellitic anhydride were reacted to synthesize hydroxypropylmethylcellulose trimellitate. Then, the solution was cooled and purified water was added to stop the reaction. A mixed solution of this solution and excess water was put into a stirring and mixing tank. A stator is fixed to the stirring blade installed in the stirring / mixing tank. While stirring the mixed solution with a stirring blade and a stator, concentrated hydrochloric acid (36% by weight) was added to precipitate a product. The rate of adding concentrated hydrochloric acid is 1
It is 8.5 g / min.

The precipitated product was washed with purified water, and when the washing solution became acidic, the product was dried with a fluidized bed dryer to obtain 1005 g of hydroxypropylmethylcellulose trimellitate. This yield corresponded to 88% of theory.

A film was prepared from this hydroxypropylmethylcellulose trimellitate in the same manner as in Example 1, and the dissolution pH of this film was investigated. Dissolution pH
Was 3.9.

From the results of measurement of dissolution pH, it was confirmed that the obtained hydroxypropylmethylcellulose trimellitate was satisfactory as a base for coating solid enteric preparations.

Example 5 In the same manner as in Example 1, hydroxypropylmethylcellulose was reacted with trimellitic anhydride to synthesize hydroxypropylmethylcellulose trimellitate. Then, the solution was cooled and purified water was added to stop the reaction. This solution was added to concentrated hydrochloric acid (36% by weight) 370
50 g of purified water containing g was added and vigorously stirred to precipitate a product. The product was washed with purified water, and after the washing liquid did not show acidity, the product was dried with a fluid bed dryer to obtain 1000 g of hydroxypropylmethylcellulose trimellitate. This yield corresponded to 87% of theory.

A film was prepared from this hydroxypropylmethylcellulose trimellitate in the same manner as in Example 1 and the dissolution pH of this film was investigated. Dissolution pH
Was 3.9.

From the results of measurement of dissolution pH, it was confirmed that the obtained hydroxypropylmethylcellulose trimellitate was satisfactory as a coating base for solid enteric preparations.

Comparative Example 1 In the same manner as in Example 1, hydroxypropylmethylcellulose was reacted with trimellitic anhydride to synthesize hydroxypropylmethylcellulose trimellitate. Then, the solution was cooled and purified water was added to stop the reaction. This solution was poured into excess purified water,
Almost no material precipitated.

Comparative Example 2 In the same manner as in Example 1, hydroxypropylmethylcellulose was reacted with trimellitic anhydride to synthesize hydroxypropylmethylcellulose trimellitate. Then, the solution was cooled and purified water was added to stop the reaction. 150 g of concentrated hydrochloric acid (36% by weight) in this solution
Was added and then poured into an excess of purified water to precipitate the product. After washing the product with purified water so that the washing liquid does not show acidity, the product is dried in a fluidized bed drier to obtain hydroxypropyl methylcellulose trimellitate 100.
g was obtained. This yield corresponded to about 9% of theory.

Front Page Continuation (72) Inventor Katsuyoshi Minemura 28, Nishi-Fukushima, Kikugi Village, Nakakubiki District, Niigata Prefecture 1 Shin-Etsu Chemical Co., Ltd.

Claims (2)

[Claims] 1. An acid anhydride and a cellulose derivative are reacted in a solution using an alkali metal salt as a catalyst, and the obtained reaction solution and excess water are mixed to obtain a cellulose having a dissolution pH of 3.0 to 4.0. In the method for producing a base for coating a solid enteric preparation for precipitating a base polymer, 80-110 mol of an inorganic acid is added to 100 mol of the alkali metal salt after the reaction of the cellulose derivative with an acid anhydride. Alternatively, a method for producing a base for coating a solid enteric preparation, which comprises adding to and mixing with excess water. 2. The method for producing a base material for coating a solid enteric preparation according to claim 1, wherein the acid anhydride is a mixture of maleic anhydride and acetic anhydride or trimellitic anhydride.