JP2000080048A - Water-based enteric coating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a water-based enteric coating agent having small particle diameters, a few coarse particles, temperature uniformity of coating film, excellent solubility at pH 4, capable of being prepared even in a simple system yet showing stable water dispersibility even at a high concentration (>=10 wt.%) in comparison with a conventional water-based enteric coating agent. SOLUTION: This water-based enteric coating agent comprises a water dispersion of a carboxyalkylalkyl cellulose having 1.6-2.6 alkylation degree, 0.4-0.6 carboxyalkylation degree, the ratio of carboxy group to carboxylate group in carboxyalkyl group of 2.3-19 and the ratio of carboxylate group to alkylation degree in the carboxyalkyl group of 0.01-0.08.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an enteric coating agent, and more particularly, to an enteric coating agent comprising an aqueous dispersion of carboxyalkylalkylcellulose and a method for producing the same.

[0002]

2. Description of the Related Art In this field, in order to effectively exert the medicinal effect of a drug, a control release for releasing the drug at a target site is performed. Until now it was important to dissolve at pH 6.8 to dissolve in the intestine,
At this pH, the effect is delayed, and it has been desired to elute at around pH 4, which is the pH of the small intestine and duodenum. In addition, in pharmaceutical production sites, there is a demand for solvent-free (water-based) systems to ensure worker safety. In response to such needs, there are the following various improvement reports. For the need to dissolve at pH 4, a method has been reported in which a fine product of carboxymethyl ethyl cellulose of 1 to 2 μm is partially neutralized, a film aid is added, and the mixture is dispersed in water and coated.
(Japanese Patent Application Laid-Open No. 59-193832) As a method for eliminating the solvent, there is a method of increasing the dispersibility by pulverization and emulsion polymerization, but the pulverization does not improve the working environment because the powder is severely dusted. For emulsion polymerization, there is an emulsion of an acrylic polymer. (Sho 60-
No. 43334) Also, after dissolving a cellulosic polymer in an organic solvent,
There is a method of substituting water with a poor solvent, controlling the particle size to submicron, and dispersing in water. (JP-A-7-23
No. 3092)

[0003]

However, in the method disclosed in JP-A-59-193832, the particle size of the aqueous dispersion is too large to form a uniform film, and the film is locally dissolved and dropped, and There is a problem that unevenness is caused in the dissolution rate of the compound. In the method disclosed in Japanese Patent Publication No. 60-33434, there is a problem in physical properties and safety of the film due to the influence of the remaining monomer, catalyst and surfactant. JP-A-7-23
In the method of No. 3092, a stable aqueous dispersion is prepared at a low concentration (10%).
(% By weight or less), and the solubility of the film is problematic. The present invention solves the above-mentioned problems at a stretch, and can produce a stable aqueous dispersion even at a high concentration (10% by weight or more) in a simple system without adding an emulsifier, a plasticizer, etc. Good homogeneity, PH4 of film
It is an object of the present invention to obtain an aqueous enteric coating agent comprising an aqueous dispersion having good solubility in water.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have neutralized carboxyalkylalkylcellulose having a defined structure in a specific ratio range and specified a specific production method. Thus, an aqueous enteric coating agent comprising a target aqueous dispersion having a particle size distribution of That is, the present invention is an aqueous enteric coating agent comprising an aqueous dispersion of carboxyalkylalkylcellulose satisfying the following requirements (1) to (4). (1) The degree of alkylation is 1.6 to 2.6 (2) The degree of carboxyalkylation is 0.4 to 0.6 (3) The ratio of the carboxylate group to the carboxylate group in the carboxyalkyl group is 2.3. (4) The ratio of the carboxyalkyl group to the degree of alkylation of the carboxylate group is 0.01 to 0.08.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION

[0006]

Embedded image

In the formula, a: degree of alkylation b: degree of carboxyalkylation R: alkyl group having 1 to 5 carbon atoms M: hydrogen or a salt-forming cation.

The degree of alkylation of carboxyalkylalkylcellulose is the number (average value) of alkyl etherified ones out of three hydroxyl groups per glucose skeleton. In the general formula (1), a corresponds to this. R in the formula represents an alkyl group having 1 to 5 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and n-amyl group. Preferred are methyl and ethyl groups. In the formula, A represents an anhydrous glucose unit skeleton of cellulose of C ₆ H ₇ O ₂ .

The carboxyalkylation degree is the number (average value) of carboxyalkylated ones of the three hydroxyl groups, and corresponds to b in the above general formula (1).
-C _n H _2n COOM in formula is carboxyalkyl group, n is 1~5, -C _n H _2n - as methylene, ethylene, propylene, butylene, be amylene group. Preferably it is a methylene group.

M is hydrogen or a salt forming cation, ie, the cation side of a basic substance which forms a salt with a carboxylic acid. Here, the basic substance includes hydroxides of alkali metals [sodium hydroxide, potassium hydroxide, etc.], hydroxides of alkaline earth metals [calcium hydroxide, magnesium hydroxide, etc.], carbonates [sodium carbonate, carbonate Potassium, etc.], ammonia, organic amines [trimethylamine, triethylamine, triethanolamine, etc.], basic amino acids [lysine, arginine, etc.], and basic amine-containing polymers [for example, vinylamine (co) polymer, allylamine (co) Polymers having a molecular weight of 10,000 or less, such as polymers, vinylpyridine (co) polymers, vinylimidazole (co) polymers, and ethyleneimine polymers]. Preferred are hydroxides of alkali metals, and particularly preferred is sodium hydroxide.

Examples of the carboxyalkylalkylcellulose used in the present invention include carboxymethylethylcellulose, carboxyethylmethylcellulose, carboxypropylmethylcellulose, carboxyethylethylcellulose, carboxypropylethylcellulose, carboxymethylamylcellulose, carboxyethylbutylcellulose and the like. . Preferably, it is carboxymethylethylcellulose.

The degree of alkylation (a) is usually 1.6 to 2.
6, preferably 2.0 to 2.3. If it is less than 1.6, the water resistance and acid resistance of the film of the coating agent will be poor, and if it exceeds 2.6, it will not dissolve in the intestine. The carboxyalkylation degree (b) is usually 0.4 to 0.6, preferably 0.45 to 0.55. If it is less than 0.4, the coating of the coating agent will not dissolve in the intestine. If it exceeds 0.6, water resistance and acid resistance will be poor. The ratio of the carboxylic acid group (COOH) to the carboxylic acid group in the carboxyalkyl group is usually 2.3 to 19, preferably 3.0 to 5.0.
5 If it is less than 2.3, the particle size of the aqueous dispersion becomes large, which makes it unsuitable for practical use. If it exceeds 19, the water resistance and acid resistance of the coating agent film will be poor. The particle size of the aqueous dispersion becomes too large to be suitable for practical use. The ratio of the carboxyalkyl group to the degree of alkylation of the carboxyalkyl group is 0.01 to 0.08. Preferably 0.
03 to 0.07. If it is less than 0.01, the particle size of the aqueous dispersion becomes large. If it exceeds 0.08, water resistance and acid resistance become poor.

[0013] The method for producing the enteric coating agent of the present invention is as follows: water is added to a mixture of the carboxyalkylalkylcellulose and the basic substance dissolved in an organic solvent or a mixed solvent of an organic solvent and water. A method in which the carboxyalkylalkyl cellulose is added to a basic substance mixed in a mixed solvent of an organic solvent and water to form an aqueous dispersion, and an organic solvent or an organic solvent and water are added to water in which the basic substance is mixed. A method of adding the carboxyalkylalkylcellulose dissolved in the mixed solvent of the above to make an aqueous dispersion. Preferably, a water dispersion is obtained by adding water to a mixture of the carboxyalkylalkylcellulose and the basic substance dissolved in an organic solvent or a mixed solvent of an organic solvent and water.

The organic solvent used here is preferably an organic solvent soluble in water, such as methanol, ethanol,
Alcohols such as isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran; and one or more mixed solvents thereof can be used. In addition, a water-immiscible solvent such as butanol, methyl isobutyl ketone, or the like can be freely mixed and used in the above solvent. Preferably, ethanol, isopropanol and acetone are used.

As the basic substance, those described above can be used. The compounding ratio of the basic substance is 5 to 30% in a molar ratio with respect to the carboxylic acid in the carboxyalkylalkylcellulose. Preferably 10-25%,
Particularly preferably, it is 15.5 to 25%. At this time, it is important to mix the carboxyalkyl group so that the ratio of the carboxylate group to the degree of alkylation is usually 0.01 to 0.08, preferably 0.03 to 0.07.

The amount of the organic solvent or the mixed solvent of the organic solvent and water to be used depends on the amount of the carboxyalkylalkyl cellulose 10
Usually 100 to 2000 parts by weight, preferably 300 to 1000 parts by weight, particularly preferably 150 to 100 parts by weight with respect to 0 parts by weight.
400 parts by weight. The ratio of organic solvent to water is usually 1 /
The ratio is 9 to 9/1, preferably 5/5 to 8/2. After forming the aqueous dispersion, the organic solvent used may or may not be removed. When the organic solvent is present in the aqueous dispersion, the drying efficiency at the time of spray coating of the aqueous dispersion is improved, and the uniformity of the coating film is improved. The solvent in the coating agent may be a residual organic solvent, or an organic solvent may be added after preparing the aqueous dispersion. The amount of organic solvent present is from 0 to 25% by weight, preferably from 5 to 20% by weight.

As an apparatus for producing the coating agent of the present invention, any apparatus capable of stirring can be used, but it is more preferable that a dropping apparatus or a topping apparatus capable of removing an organic solvent and a pressure reducing apparatus are provided. Although the production temperature of the aqueous dispersion is sufficient at room temperature, it is generally 0 to 70 ° C, preferably 10 to 50 ° C. When the organic solvent is removed, the organic solvent can be removed at a normal pressure or higher than the boiling point of the organic solvent used or at a reduced pressure if the operation is performed under reduced pressure.

The solid content of the enteric coating agent comprising the aqueous dispersion of the present invention is usually 5 to 40%, preferably 1 to 40%.
1 to 30%. This is a solid concentration that is stable as an aqueous dispersion. The solid concentration can be adjusted by removing the solvent on the high concentration side. Any concentration on the low concentration side can be achieved by diluting with water. The median size of the particle size distribution of the particles in the aqueous dispersion is usually 0.1 to 5 μm, preferably 0.2 to 2 μm, particularly preferably 0.1 to 1 μm. Maximum particle size is usually 10μ
m, preferably 5 μm or less, particularly preferably 2 μm
It is as follows. The amount of the particles having a particle diameter of more than 5 μm is 15% or less, preferably 10% or less, and particularly preferably 5% or less based on volume. In particular, when the median diameter is 0.1 to 1 μm, the solubility of the film at PH4,
The effect of the aqueous dispersion stability of the aqueous dispersion is good. If the median diameter is less than 0.1 μm, the effect of the solubility of the film at PH4 and the effect of the aqueous dispersion stability of the aqueous dispersion are good and do not change, and it is not necessary to further reduce the effect. The median diameter exceeds 5 μm, the maximum particle size exceeds 10 μm, or the particle size is 5 μm
If the amount of the particles exceeding 15% by volume exceeds 15% of the total volume, the solubility of the film in PH4 becomes poor and the aqueous dispersion stability of the aqueous dispersion becomes poor. The surface of the treated film loses homogeneity, causing unevenness in the elution rate of the drug. The measured values of the above particle size distribution (median diameter, maximum particle size and particle size distribution%) are
This is a value measured by a size analyzer. The median diameter represents a diameter that becomes 50% of the volume.

The enteric coating agent comprising the aqueous dispersion according to the present invention may contain conventionally used additives such as plasticizers, activators and excipients in addition to the above-mentioned composition. Examples of the plasticizer include polyethylene glycol, polypropylene glycol, glycerin, monoacetyl glycerin, triacetin, and triethyl citrate. Examples of the activator include a fatty acid ester-based nonionic activator. Excipients include water-soluble cellulose derivatives, polyvinyl alcohol, gelatin, gums and the like.

In order to coat a solid drug such as a pharmaceutical tablet or a granule using the enteric coating agent obtained as described above, a conventional device such as a bank coating device, a drum type coating device or a fluid coating device is used. This is completed by spraying the solid medicine with the device and drying the liquid to form a film. The concentration of the liquid used as the coating agent is adjusted to 2 to 35% by weight, particularly 3 to 20% by weight. The coating agent of the present invention has a solid content concentration of 5 to 40, and can be used as it is or diluted with water when used. Although it is economical to process at a high concentration, it is a trade-off with the uniformity of the coating. Even if the coating agent of the present invention is treated at a high concentration, a uniform film can be obtained.
The required coating amount varies depending on factors such as the type of cellulose used, the shape and size of the solid preparation, and the type of the main drug contained therein.
mm to 0.2 mm. When the enteric coating agent of the present invention is used, a solid enteric preparation having excellent solubility in PH4 can be obtained.

Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited to these examples. Hereinafter, "part" indicates "part by weight".

Example 1 70 parts of ethanol and 30 parts of water were put into a 200 mL kolben, 30 parts of carboxymethylethylcellulose (ethylation degree 2.2, carboxymethylation degree 0.50) was added and dissolved at room temperature. With stirring, sodium hydroxide (4
(8% concentration), and after stirring for 5 minutes, 100 parts of water was added dropwise over 30 minutes. Thereafter, the mixture was stirred at room temperature for 1 hour.
The solid concentration of the obtained aqueous dispersion was 13%, and the particle size distribution of the obtained aqueous dispersion was measured with a Particle size analyzer (LA-700, manufactured by HORIBA, Ltd.). The median diameter was 0.4 μm and the maximum particle size was 2 μm.

Example 2 70 parts of ethanol and 30 parts of water were put into a 200 mL kolben, 30 parts of carboxymethylethylcellulose (ethylation degree 2.2, carboxymethylation degree 0.50) was added and dissolved at room temperature. With stirring, sodium hydroxide (4
(8% concentration), and after stirring for 5 minutes, 200 parts of water was added dropwise over 50 minutes. Thereafter, the mixture was stirred at room temperature for 1 hour.
The mixture was heated to 50 ° C., the mixture of ethanol and water was removed under a reduced pressure of 300 mmHg, and the mixture was concentrated to a solid concentration of 15%. The obtained aqueous dispersion is subjected to Particlesize anal
The particle size distribution was measured with a yzer (LA-700, manufactured by Horiba, Ltd.). Median diameter 0.4μm, maximum particle size 2μm
Met.

Examples 3 to 6 and Comparative Examples 1 to 3 In the same manner as in Example 1 or 2, enteric coating agents shown in Tables 1 to 3 were obtained.

Comparative Example 4 97 parts of acetone and 3 parts of carboxymethylethylcellulose (degree of ethylation 2.2, degree of carboxymethylation 0.50) were charged into a 200 mL kolben and dissolved at room temperature. While stirring, 100 parts of water was added and emulsified. The mixture was heated to a temperature of 50 ° C., and acetone was distilled off under reduced pressure of 500 mmHg. The concentrate was filtered through a 200 mesh wire screen. The solid content of this liquid was 10%.

Comparative Example 5 Into a 200 mL kolben, 45 parts of methanol, 45 parts of dichloromethane, and 10 parts of carboxymethylethylcellulose (degree of ethylation 2.2, degree of carboxymethylation 0.50) were added and dissolved at room temperature.

[0027]

[Table 1]

[0028]

[Table 2]

[0029]

[Table 3]

(Description of abbreviations) AL degree: degree of alkylation CAL degree: carboxyalkylation H / M ratio: carboxylic acid group / carboxylate base ratio M / AL ratio: carboxylate base / alkylation degree ratio CMEC: carboxy Methyl ethyl cellulose CPMC: carboxypropyl methyl cellulose

The coating evaluation tests of the enteric coating agent of the present invention (Examples 1 to 6) and Comparative Examples 1 to 3 prepared as described above are shown in Tables 4 to 6. [Coating evaluation test method] (Creation of coating) Samples prepared in Examples and Comparative Examples were
It was applied on a smooth plate (material: glass), dried at 40 ° C. for 24 hours to form a film, and cut into 1 cm square to prepare a test piece. (The coating amount was adjusted so that the film thickness after drying became 100 μm.) (Evaluation method) The time until the test piece disintegrated using an apparatus conforming to the Japanese Pharmacopoeia (12th revision) general test method and disintegration test method (Min) was measured.

[0032]

[Table 4]

[0033]

[Table 5]

[0034]

[Table 6] * 1: Defined in the Japanese Pharmacopoeia (Revised 12th) General Tests and Disintegration Tests PH1, Liquids of PH1, * 2: Same as above, Liquid of PH6.8 * 3: Mcllvain buffer * 4: Same as above

[0035]

The aqueous enteric coating agent of the present invention has the following advantages: 1) Since the particle size is small and the number of coarse particles is small, the homogeneity of the film is good and the solubility in PH4 is excellent. High concentration (more than 10%)
However, it has the effect of exhibiting stable water dispersibility.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification FI FI Theme Court ゛ (Reference) (72) Inventor Tokunori Yokota 11-1, Nobashinohoncho, Higashiyama-ku, Kyoto Sanyo Chemical Industry Co., Ltd.

Claims (7)

[Claims] An aqueous enteric coating agent comprising an aqueous dispersion of carboxyalkylalkylcellulose which satisfies the following requirements (1) to (4). (1) The degree of alkylation is 1.6 to 2.6 (2) The degree of carboxyalkylation is 0.4 to 0.6 (3) The ratio of the carboxylate group to the carboxylate group in the carboxyalkyl group is 2.3. (4) The ratio of the carboxyalkyl group to the degree of alkylation of the carboxylate group is 0.01 to 0.08. 2. The aqueous enteric coating agent according to claim 1, wherein the median diameter of the particle size distribution of the particles in the aqueous dispersion is 0.1 to 5 μm. 3. The maximum particle size of the particles in the aqueous dispersion is 10 μm.
The aqueous enteric coating agent according to claim 1 or 2, which is: 4. The aqueous enteric coating agent according to claim 1, wherein the amount of the particles having a particle size of more than 5 μm in the aqueous dispersion is 15% or less of the total volume. 5. The aqueous enteric coating agent according to claim 1, wherein the aqueous dispersion has a solid content of 11 to 35% by weight. 6. The method according to claim 1, wherein said carboxyalkylalkylcellulose is carboxymethylethylcellulose.
5. The aqueous enteric coating agent according to any one of 5. 7. The aqueous dispersion according to claim 1, wherein water is added to a mixture of the carboxyalkylalkylcellulose and the basic substance dissolved in an organic solvent or a mixed solvent of an organic solvent and water to form an aqueous dispersion. Aqueous enteric coating agent.