JP3017412B2 - Method for producing base for coating solid enteric preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a base for coating a solid enteric preparation.

[0002]

2. Description of the Related Art A solid enteric preparation is one in which a drug is covered with a film-like enteric polymer. Enteric polymers protect acid-sensitive drugs from stomach acid, protect gastric mucosa from drugs, and dissolve inside the small intestine. The dissolution of the enteric polymer releases the drug inside the small intestine.

[0003] Cellulose polymers are one of the enteric polymers used as a coating base for solid enteric preparations. Specifically, cellulose acetate phthalate,
Examples include cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and carboxymethylethylcellulose.

[0004] The cellulose-based polymer is dissolved in an organic solvent, or an aqueous latex or an aqueous dispersion is used as a coating liquid. This coating liquid is applied to a drug and dried to form a film, whereby a solid enteric preparation can be obtained.

[0005] These cellulosic polymers have a dissolving pH
Is 5 to 7, and the solubility is not high. At this level of solubility, the solid enteric formulation passes through the upper small intestine before the drug is completely released. In order for the solid enteric formulation to completely release the drug, it is necessary to lower the dissolution pH to increase the solubility of the cellulosic polymer.

[0006] Cellulose polymers having improved solubility include cellulose trimellitates and cellulose acetate malates having a dissolution pH of 3-4. Cellulose trimellitates are prepared by reacting a cellulose derivative with trimellitic anhydride in solution using sodium acetate as a catalyst, heating the resulting reaction solution for several hours, cooling, and mixing with excess water. Precipitates out.

[0007] 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, cooling it, and cooling Precipitates when mixed with water.

[0008] Japanese Patent Application No. 4-151939 discloses that a mixed solution of a reaction solution and excess water is charged into a stirring and mixing tank provided with two stirring blades, and the mixture is supplied to a stirring blade and a stirring blade. A method is described in which a liquid mixture is stirred with a fixed stator to precipitate a cellulosic polymer. The reaction liquid and water can be uniformly mixed by stirring, and the cellulosic polymer can be precipitated.

[0009]

The cellulosic polymer is easily soluble in a mixed solution containing a large amount of salts as a by-product. For this reason, a large amount of the cellulosic polymer could not be precipitated in the mixed solution.

[0010] The present invention has been made to solve the above-mentioned problems, and a large amount of a cellulosic polymer serving as a coating base is precipitated in a solution to efficiently recover the solid base enteric coating. It is intended to provide a manufacturing method.

[0011]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that when a coating base having a dissolution pH of 3 to 4 is precipitated, if the pH of the solution is adjusted to 2 or less, the coating base is dissolved in the solution. The inventors have found that precipitation is easy and completed the present invention.

That is, the method for producing a base 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 reacting the obtained reaction solution with an excess. Mix with water and dissolve pH
In a method for producing a base for coating a solid enteric preparation which precipitates a cellulosic polymer of 3.0 to 4.0,
After the reaction of the cellulose derivative with the acid anhydride, 80 to 110 mol of the inorganic acid is added to the reaction solution or excess water and mixed with 100 mol of the alkali metal salt.

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

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

Examples of the cellulose derivative include hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose and hydroxyethylcellulose.

The cellulosic polymer synthesized from the acid anhydride and the cellulose derivative is a cellulose acetate malate or a cellulose trimellitate. 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 Trimellitate, hydroxypropylcellulose trimellitate, and hydroxyethylcellulose trimellitate are exemplified.

The alkali metal salt added as a catalyst includes, for example, sodium acetate.

The inorganic acids added to lower the pH include, for example, hydrochloric acid and sulfuric acid.

An example of a method for producing hydroxypropylmethylcellulose acetate malate as a coating base will be described below. First, hydroxypropyl methylcellulose 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 and cooled,
Terminate the reaction of maleic anhydride and acetic anhydride with hydroxypropyl methylcellulose. 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 hydroxypropyl methylcellulose acetate malate is washed with purified water until the washing liquid no longer shows acidity, and then dried with a fluid 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. Dissolve the cellulosic polymer in an organic solvent and cast it on a glass plate.
m film is cut into 1 cm x 1 cm. The film is placed in a solvent for dissolution using an auxiliary cylinder according to the disintegration test method of the Japanese Pharmacopoeia, and the pH of the solvent in which the film dissolves is investigated. As a dissolution solvent, several kinds of McValin buffers having different pHs are used.

The coating process is completed by spraying the coating liquid onto the medicine by a coating apparatus and simultaneously drying the liquid to form a film. The coating liquid may be prepared by dissolving a cellulosic polymer in a solvent such as acetone, methylene chloride / alcohol, or alcohol / water.
Below is what was finely pulverized and dispersed in water. Pharmaceutically acceptable additives such as plasticizers, colorants, pigments and anti-adhesives may be added to the coating solution or combined with existing coating bases to alter the dissolution and solubility.

Examples of the coating device include a fluidized bed coating device, a pan coating device, and a ventilated rotary drum type coating device.

[0023]

By adding an inorganic acid, the pH of the mixture of the reaction solution and excess water becomes lower than the dissolution pH of the cellulose-based polymer, and the dissolution of the cellulose-based polymer is prevented. Since the amount of the polymer precipitated in the liquid mixture increases, the cellulosic polymer can be efficiently recovered. Cellulosic polymers are used as coating bases for solid enteric formulations.

[0024]

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

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.) having a viscosity of 5.5 cP of a 2% by weight aqueous solution at 20 ° C. And acetic acid 21
00g was poured into a 5-liter twin-screw kneader and dissolved at 70 ° C. After completion of the dissolution, 910 g of trimellitic anhydride was added as an esterifying agent, and 275 g of sodium acetate was further added as a catalyst, followed by reaction 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 no longer showed acidity, the product was dried with a fluidized bed drier to obtain 927 g of hydroxypropyl methylcellulose trimellitate. This yield corresponded to 81% of theory.

This hydroxypropylmethylcellulose 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 types of McLuvine buffers having different pHs,
It was confirmed that the film was dissolved in the pH 3.9 buffer solution.

From the measurement results of the dissolution pH, it was confirmed that the obtained hydroxypropylmethylcellulose trimellitate was a satisfactory 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 of a 2% by weight aqueous solution at 20 ° C. And acetic acid 21
00g was poured into a 5-liter twin-screw kneader and dissolved at 70 ° C. After the dissolution, acetic anhydride 17 is used as an esterifying agent.
6 g and 193 g of maleic anhydride were added, and 278 g of sodium acetate was further added as a catalyst and 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 after the washing liquid showed no acidity, the product was dried with a fluidized bed drier to obtain 780 g of hydroxypropylmethylcellulose acetate malate. The yield was 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 the film was investigated. The dissolution pH was 3.5. From the measurement results of the dissolution pH, it was confirmed that the obtained hydroxypropylmethylcellulose acetate malate was a satisfactory base for coating solid enteric preparations.

Example 3 Hydroxypropyl methylcellulose trimellitate was synthesized in the same manner as in Example 1 except that the amount of hydrochloric acid (36% by weight) was 370 g. The yield of the obtained hydroxypropylmethylcellulose trimellitate was 1020 g, 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 the film was examined. Dissolution pH
Was 3.9. From the measurement results of the dissolution pH, it was confirmed that the obtained hydroxypropylmethylcellulose trimellitate was satisfactory as a coating base for a solid enteric preparation.

Example 4 In the same manner as in Example 1, hydroxypropylmethylcellulose was reacted with trimellitic anhydride to synthesize hydroxypropylmethylcellulose trimellitate. Thereafter, the solution was cooled and purified water was added to stop the reaction. A mixture of this solution and excess water was charged into a stirring and mixing tank. The stator is fixed to the stirring blade installed in the stirring and mixing tank. While stirring the mixture 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
8.5 g / min.

The precipitated product was washed with purified water, and after the washing liquid showed no acidity, the product was dried with a fluidized bed drier 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 the film was investigated. Dissolution pH
Was 3.9.

From the measurement results of the dissolution pH, it was confirmed that the obtained hydroxypropylmethylcellulose trimellitate was a satisfactory 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. Thereafter, the solution was cooled and purified water was added to stop the reaction. This solution is concentrated 370 hydrochloric acid (36% by weight)
g was added to 50 liters of purified water and stirred vigorously to precipitate the product. The product was washed with purified water, and after the washing liquid no longer showed acidity, the product was dried using a fluidized bed drier to obtain 1000 g of hydroxypropyl methylcellulose trimellitate. The yield was 87% of theory.

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

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

Comparative Example 1 In the same manner as in Example 1, hydroxypropylmethylcellulose was reacted with trimellitic anhydride to synthesize hydroxypropylmethylcellulose trimellitate. Thereafter, the solution was cooled and purified water was added to stop the reaction. This solution was poured into excess purified water,
Little material precipitated.

Comparative Example 2 In the same manner as in Example 1, hydroxypropylmethylcellulose was reacted with trimellitic anhydride to synthesize hydroxypropylmethylcellulose trimellitate. Thereafter, the solution was cooled and purified water was added to stop the reaction. 150 g of concentrated hydrochloric acid (36% by weight)
Was added, and then poured into an excess of purified water to precipitate the product. The product is washed with purified water, and after the washing liquid no longer shows acidity, the product is dried in a fluidized bed drier to obtain hydroxypropyl methylcellulose trimellitate 100.
g was obtained. The yield was about 9% of theory.

────────────────────────────────────────────────── ─── of the front page continued (72) inventor Katsuyoshi Minemura Niigata Prefecture medium kubiki County kubiki village Oaza west Fukushima 28 address of 1 Shin-Etsu Chemical Co., Ltd. synthesis technology research house (58) investigated the field (Int.Cl. ⁷ , DB name) C08B 3/28 A61K 47/38 C08B 13/00

Claims (2)

(57) [Claims] 1. An acid anhydride and a cellulose derivative are reacted in a solution using an alkali metal salt as a catalyst, and the resulting reaction solution is mixed with excess water to form 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 in which a base polymer is precipitated, 80 to 110 mol of an inorganic acid is added to 100 mol of the alkali metal salt after the reaction of the cellulose derivative with the acid anhydride. Or a method for producing a base for coating a solid enteric preparation, which is mixed with an excess of water. 2. The method according to claim 1, wherein the acid anhydride is a mixture of maleic anhydride and acetic anhydride or trimellitic anhydride.