JPH0460970B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to enteric coating fluids. More specifically, the present invention relates to an aqueous enteric coating liquid.

Conventionally, the method of producing enteric coating liquids is to dissolve a polymeric substance that does not dissolve in water or gastric fluid but dissolves in intestinal fluid in an organic solvent, and then add plasticizers, colorants, etc. to this as necessary. There is.

However, this method requires a large amount of organic solvent to produce the coating liquid, and it is difficult to recover the organic solvent, which is economically disadvantageous. In addition, there were problems with safety for workers during production and formulation due to the use of large amounts of organic solvents, risk of ignition, and safety for users due to residual solvent in the drug.

From this point of view, there has recently been an increasing recognition of the need for a water-based enteric coating solution, that is, a method using water as a dispersion medium, and various methods have been proposed.

However, enteric coating materials are generally polymeric compounds with carboxyl groups, and their characteristic is that they only become solubilized in water by forming a salt with water on the alkaline side, so they cannot simply be made into an aqueous solution. The reality is that it is not possible. Therefore, although various methods have been proposed for producing water-based enteric coating liquids using polymeric substances having carboxyl groups, almost no methods have been put to practical use.

The only practical method is to use methyl methacrylate/methacrylic acid copolymer in the form of an aqueous emulsion obtained by emulsion polymerization; Since it relies on the emulsion polymerization method, there are concerns about residual polymerization initiators, monomers, etc., and safety issues remain when applied to pharmaceuticals.

In order to solve the problems of the prior art, the present inventors have made extensive studies on an economical and good water-based enteric coating solution. Merely reducing the particle size of dry powder is insufficient;
It is important to plasticize the enteric base material powder, which is essentially insoluble in water, and to adhesively bond the plasticized particles together. Based on the knowledge that the affinity for the dispersion medium is an extremely important factor, we found a new combination of materials and completed the present invention.

That is, the present invention provides a solution in which a sucrose ester and a water-soluble gummy substance are dissolved or dispersed as essential components in water or an aqueous alcohol solution containing 20% by weight or less of a lower alcohol having 1 to 3 carbon atoms.
This invention relates to an enteric coating liquid whose main feature is to disperse a water-insoluble oxycarboxylic acid type cellulose derivative powder represented by the general formula (1) with a size of 100μ or less.

General formula (1) (In the formula, Gul represents an anhydroglucose unit skeleton of cellulose consisting of C ₆ H ₇ O ₂ , R ₁ is hydrogen or a carboxyalkyl group having 1 to 5 carbon atoms, R ₂ and R ₃ are
When R ₁ is hydrogen, at least one of them represents the same or different ester group or ether group having a carboxyl group, and when R ₁ is a carboxyalkyl group having 1 to 5 carbon atoms, at least one of them has a hydroxyl group. Indicates the same or different ether or ester groups. ) The oxycarboxylic acid type cellulose derivatives represented by the general formula (1) include those belonging to cellulose ethers, cellulose esters, and cellulose ether esters. The degree of substitution of substituents is determined depending on the purpose. In the above general formula (1), R ₂ ,
The ester group or ether group represented by R ₃ means an atomic group introduced into cellulose through an ester or ether bond. Examples of esters include acetate ester, propionate ester, butyrate ester, succinate ester, phthalate ester, and higher fatty acid. Examples of the ether include carboxyalkyl ether, alkyl ether, and hydroxyalkyl ether having 1 to 5 carbon atoms. Therefore, examples of the oxycarboxylic acid type cellulose derivative represented by the above general formula (1) include carboxyalkylalkylcellulose such as carboxymethylethylcellulose, carboxyethylmethylcellulose, and carboxypropylmethylcellulose, mixed ethers, hydroxypropylmethylcellulose succinate, Cellulose mixed ether esters such as hydroxypropyl methylcellulose phthalate, acidic succinoyl and acidic phthaloyl mixed esters of hydroxypropylmethylcellulose, acidic succinoyl and propionic acid esters of hydroxypropylmethylcellulose, cellulose mixed esters such as cellulose acetate phthalate, cellulose acetate succinate, etc. is included.

As mentioned above, the oxycarboxylic acid type cellulose derivative represented by the general formula (1) is required to be a powder of 100μ or less, but there are no particular restrictions on the method for preparing such a powder. It can be adjusted by any method among methods such as mechanical pulverization method and physicochemical pulverization method.

Further, the purpose of the present invention is to provide an aqueous enteric coating solution, and naturally the selection of the enteric coating material itself to be used is also an important factor, and the following can be the selection criteria.

(1) It is advantageous for the enteric coating material itself to be highly hydrophilic to the extent that it does not impair the enteric function.

(2) Adjust the coating liquid using an aqueous system,
Since the enteric coating material itself is used for coating, it is more practical if the enteric coating material itself is highly resistant to hydrolysis.

As a result of various studies from the above points of view, we found that among the oxycarboxylic acid type cellulose derivatives represented by the general formula (1), the general formula (2), which is highly hydrophilic and has excellent hydrolysis resistance, was selected as the enteric coating material to be used. ) was found to be preferable. Examples of the oxycarboxylic acid type cellulose derivative represented by the general formula (2) include carboxymethylethylcellulose, carboxyethylethylcellulose, carboxybutylethylcellulose, and carboxypropylmethylcellulose.

General formula (2) (In the formula, Gul represents an anhydroglucose unit skeleton of cellulose consisting of C ₆ H ₇ O ₂ , m is an integer of 1 to 5, and R ₄
represents a hydroxyl group and a methoxyl group or an ethoxy group. ) Next, although sucrose ester is an essential component of the present invention, fatty acid esters of sucrose having a monoester content of about 10% or more and a di-, tri-, and polyester content of about 90% or less may be arbitrarily selected. For example, DK ester F-160, F-140, etc. (trade name, manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.) are used.
Such sucrose esters have the effect of both a plasticizer and an emulsifier, and in some cases also have the effect of an antifoaming agent, and the amount used is preferably 30% by weight or less based on the enteric base material. It is appropriate that the amount is 10% by weight or less.

In the present invention, water-soluble gums include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose, water-soluble gums such as polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate, polyethylene glycol, and polyethylene oxide. It means synthetic polymers and natural gums such as carrageenan, guar gum, xanthan gum, sodium alginate, gelatin, and gum arabic, and one or a combination of any one or more of these can be selected. The amount of the water-soluble gummy substance varies depending on the type of the oxycarboxylic acid type cellulose derivative represented by general formula (1) or (2) and the dosage form of the product to be coated, but generally the oxycarboxylic acid type cellulose derivative 50% by weight or less.

Although water alone is mainly used as the dispersion medium, base materials that have a strong affinity for lower alcohols having 1 to 3 carbon atoms, such as oxycarboxylic acid type cellulose mixed ethers represented by the general formula (2), are also used. In some cases, as long as the base particles do not aggregate during dispersion,
The use of water containing a lower alcohol having 1 to 3 carbon atoms is advantageous in improving the uniformity of the coating film. In such cases, the alcohol content is generally 20
It is preferable to adjust the amount to % by weight or less.

When carrying out the present invention, the method for dispersing the oxycarboxylic acid type cellulose derivative powder in the dispersion medium referred to in the present invention is not particularly limited, and general dispersion means can be applied.

Furthermore, various emulsifiers can be used in combination for the purpose of further improving the dispersion stability of the powder. Also,
For the purpose of further improving the film-forming properties of the coating liquid, it is optional to add a plasticizer such as polyethylene glycol, propylene glycol, various phthalic acid esters, or various glycerin fatty acid esters during or after dispersion. This does not contradict the spirit of the present invention in any way.

The enteric coating liquid of the present invention does not have a very high minimum film forming temperature and provides a stable continuous coating under mild drying conditions, so it can be used for solid drugs, tablets, multilayer tablets, granules, etc.
Excellent enteric-coated preparations can be obtained by coating the surface or inner layer of capsules, blending them into capsule materials, or kneading and molding powdered or granular drugs.

Next, the present invention will be further explained with reference to Examples.
The present invention is not limited to the following examples unless it exceeds the spirit thereof. In the following examples, parts and % both mean parts by weight and % by weight.

Example 1 After dissolving 2 g of sucrose ester (trade name F-160, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) in 168 parts of water, hydroxypropyl methyl cellulose (trade name TC
-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) 2% aqueous solution
10 parts were added to form a separation medium. While stirring this dispersion medium using a homomixer, the carboxymethyl group
After gradually adding 20 parts of carboxymethylethylcellulose powder (average particle size 30μ) with DS 0.52 and ethoxyl group DS 1.95 and further thorough dispersion, a white dispersion of carboxymethylethylcellulose was obtained.

The minimum film forming temperature (abbreviated as MFT) of this dispersion is
A transparent uniform film was formed at a temperature of 46°C, which was higher than the MFT.

Next, 1 kg of tablets with a diameter of 8 mm and a weight of 150 mg, mainly composed of Japanese lactose/crystalline cellulose, were placed in an automatic pan coating machine EF-2 manufactured by Freund Sangyo, and the solid content was approximately 15 mg per tablet using the above dispersion.
Coated.

When the coated tablet was tested according to the disintegration test method for enteric-coated preparations of the Japanese Pharmacopoeia (10th revision), there was no change in the first liquid, and the test with the second liquid showed 13
It collapsed in ~16 minutes.

Example 2 Add 2 sucrose esters (trade name F-160) to 166 parts of water.
After dissolving g, 10 parts of a 2% aqueous solution of hydroxypropyl methyl cellulose (trade name TC-5R) was added to form a dispersion medium. Two parts of glycerin fatty acid ester (trade name MGK, manufactured by Nisshin Oil Co., Ltd.) was added to this dispersion medium and emulsified using a homomixer. Next, 20 parts of the same carboxymethylethylcellulose used in Example 1 was gradually added and further dispersed, to obtain a white dispersion of carboxymethylethylcellulose.

The MFT of this dispersion was 38°C, and a transparent uniform film was formed at temperatures above the MFT.

A disintegration test was conducted on tablets coated with this dispersion in the same manner as in Example 1.
There was no change in the liquid, and the test with the second liquid was 12 to 15.
It collapsed in minutes.

Example 3 In Example 1, carboxyethyl ethyl cellulose powder (average particle size 30μ) with carboxyethyl group DS 0.56 and ethoxyl group DS 1.81 was used instead of carboxymethyl ethyl cellulose, and polyvinyl cellulose was used instead of the 2% aqueous solution of hydroxypropyl methyl cellulose. Alcohol (product name Gohsenol)
A white dispersion of carboxyethyl cellulose was obtained in the same manner as in Example 2, except that a 2% aqueous solution (NL-05, manufactured by Nippon Gosei Kagaku Kogyo Co., Ltd.) was used.

The MFT of this dispersion was 35°C, and a transparent uniform film was formed at temperatures above the MFT.

A disintegration test was conducted on tablets coated with this dispersion in the same manner as in Example 1.
There was no change in the liquid, and in the test with the second liquid, it disintegrated in 10 to 13 minutes.

Example 4 In Example 1, instead of carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) powder (average particle size 30μ) was used,
A white dispersion of hydroxypropyl methylcellulose phthalate was obtained by carrying out the same procedure as in Example 2 except that a 2% aqueous solution of sodium alginate was used instead of a 2% aqueous solution of hydroxypropyl methylcellulose.

The MFT of this dispersion was 50°C, and a transparent uniform film was formed at temperatures above the MFT.

A disintegration test was conducted on tablets coated with this dispersion in the same manner as in Example 1.
There was no change in the liquid, and in the test with the second liquid, it disintegrated in 14 to 16 minutes.

Example 5 A white dispersion of carboxymethylethylcellulose was obtained in the same manner as in Example 2 except that 2% ethanol aqueous solution was used instead of 166 parts of water.

The MFT of this dispersion was 36°C, and a transparent uniform film was formed at temperatures above the MFT.

A disintegration test was conducted on tablets coated with this dispersion in the same manner as in Example 1.
There was no change in the liquid, and in the test with the second liquid, it disintegrated in 11 to 14 minutes.

Comparative Example 1 A white dispersion of carboxymethylethyl cellulose was obtained in the same manner as in Example 1 except that sucrose ester was not added.

The MFT of this dispersion was 80°C or higher, and if it was lower than 80°C, the powder simply adhered and no continuous film was formed, so it could not be used in a coating test.

Comparative Example 2 A white dispersion of carboxymethylethylcellulose was obtained in the same manner as in Example 2 except that sucrose ester and hydroxypropylmethylcellulose were not added.

The MFT of this dispersion was 70°C, but even above the MFT, it did not become a completely transparent film, but was only a semi-transparent, rough, and poorly slippery film, which could not be used for coating tests. Ta.

Claims (1)

[Scope of Claims] 1. Particle size in a liquid obtained by dissolving or dispersing sucrose ester and water-soluble gummy substance as essential components in water or an aqueous alcohol solution containing 20% by weight or less of a lower alcohol having 1 to 3 carbon atoms. General formula (1) below 100μ
An enteric coating liquid characterized by dispersing a water-insoluble oxycarboxylic acid type cellulose derivative powder represented by: General formula (1) (In the formula, Gul is an anhydroglucose unit skeleton of cellulose consisting of C ₆ H ₇ O _2, R ₁ is hydrogen or a carboxyalkyl group having 1 to 5 carbon atoms, R ₂ and R ₃ are R ₁
is hydrogen, at least one of them represents the same or different ester group or ether group having a carboxyl group, and when R ₁ is a carboxyalkyl group having 1 to 5 carbon atoms, at least one of them represents the same or different ester group or ether group having a hydroxyl group. or represents a different ether or ester group. 2. The enteric coating liquid according to claim 1, wherein the water-insoluble oxycarboxylic acid type cellulose derivative is an oxycarboxylic acid type mixed ether represented by the general formula (2). General formula (2) (In the formula, Gul represents an anhydroglucose unit skeleton of cellulose consisting of C ₆ H ₇ O ₂ , m is an integer of 1 to 5, and R ₄ represents a hydroxyl group and a methoxyl group or an ethoxyl group.) 3 The water-soluble gum substance is methyl cellulose, The enteric coating liquid according to claim 1 or 2, wherein the enteric coating liquid is a cellulose derivative such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose. 4 Water-soluble gums include polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate,
The enteric coating liquid according to claim 1 or 2, which is a synthetic gum material such as polyethylene glycol or polyethylene oxide. 5 Aqueous solution gums include carrageenan, guar gum,
3. The enteric coating liquid according to claim 1 or 2, which is a natural gum such as xanthan gum, sodium alginate, gelatin, or gum Larabia. 6 Sucrose ester, water-soluble gum, particle size
An enteric-coated preparation in which the drug is treated with a continuous coating formed from a dispersion liquid containing oxycarboxylic acid type cellulose derivative powder of 100μ or less as an essential ingredient and water as the main dispersion medium.