JPH0931370A - Solid form coating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a solid form coating agent that disperses easily into water in an average particle size of not more than 1μm without the need of adding a salt and the like to form an aqueous coating liquid which is superior in stability and film-forming capability and can achieve an aimed effect with a small amount of coating. SOLUTION: This solid form coating agent is made of a freeze-dried aqueous emulsion of a water-insoluble polymer containing a dispersing agent in a weight ratio of the water-insoluble polymer to the dispersing agent at 88:12-98:12 and an aqueous coating liquid is formed, as the polymer disperses into water in an average particle size of not more than 1μm, when it is put back into water.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a coating agent for coating a solid preparation.

[0002]

2. Description of the Related Art A solid preparation is coated with various bases depending on its purpose. The enteric-coated preparation having an enteric coating protects a drug that is weak against acid from gastric acid, protects the gastric mucosa from a drug that has irritation and damage to the stomach wall, and dissolves in the intestine, where it exerts a pharmacological action. In addition, the sustained release formulation with an insoluble coating controls the release of the drug,
It exerts its medicinal effect continuously.

As a base material for such a coating,
Mainly cellulosic or acrylic water-insoluble polymers are used. The enteric coating base, as a cellulosic polymer, for example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethylethyl cellulose,
Examples of acrylic polymers include copolymers of methacrylic acid and ethyl acrylate or methyl methacrylate.

Examples of the sustained-release coating base include ethyl cellulose, a copolymer of ethyl acrylate and methyl methacrylate, a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate. , A copolymer of butyl methacrylate, methyl methacrylate, and diethylaminoethyl methacrylate.

The polymers used as the coating base are dissolved in an organic solvent or used as an aqueous latex or an aqueous dispersion for the coating treatment. In recent years, the use of organic solvents has been regulated due to environmental problems, and it is becoming popular to carry out coating treatment in an aqueous system.

Aqueous latex is excellent in film-forming property, but since it contains a large amount of water, it is difficult to handle for transportation and the like, and it must be preserved so as not to destroy the latex. Since chemically unstable polymers cannot be stored for a long period of time, a method has been devised in which they are powdered, put into water and spray-dried so that they can be redispersed.

[Problems to be Solved by the Invention]

As such a technique, as a cellulosic polymer, Japanese Patent Publication No. 61-56221 discloses that cellulose acetate phthalate is emulsified, and then phosphate is added as an anti-agglomeration agent, followed by spray drying. , A method for obtaining a polymer powder that is redispersible in water is described. In this method, since the alkali salt of carboxylic acid remains in the coating film of the solid enteric preparation, the acid resistance is not sufficient, and the hygroscopicity is high and the storage stability is not sufficient.

An acrylic polymer is disclosed in Japanese Patent Laid-Open No. 63
-46229 discloses a method for spray-drying a copolymer of acrylic acid and / or methacrylic acid and a lower alkyl ester thereof, and JP-A-57-130924 discloses an alkyl of acrylic acid and / or methacrylic acid. Esters and their alkylaminoester copolymers and the like are described. However, these methods cannot obtain sufficient coating performance because they do not return to the atomized latex when they are re-dispersed by being added to water.

[0009] As a result of earnest studies in view of the above problems, the present inventor has found that when a coating agent obtained by freeze-drying an aqueous emulsion of a mixture of a water-insoluble polymer and a dispersant having a specific composition is added to water, the average particle diameter is increased. The present invention has been completed by discovering that it is dispersed in an amount of 1 μm or less to form an aqueous coating liquid, which is excellent in stability and film-forming property and can exert a desired effect with a low coating amount on a solid preparation. It was

The object of the present invention is that it is not necessary to add salts and the like, and after being poured into water, it is easily dispersed to have an average particle diameter of 1 μm or less to form an aqueous coating solution, which has stability and film-forming property. It is an object of the present invention to provide a coating agent for a solid preparation which is excellent and can exhibit a desired effect with a low coating amount.

[0011]

That is, according to the present invention, the weight ratio of the water-insoluble polymer to the dispersant is 88: 12-9.
A coating agent for a solid preparation obtained by freeze-drying an aqueous emulsion of a water-insoluble polymer containing a dispersant of 8: 2, which is re-introduced into water to disperse into an aqueous coating solution with an average particle size of 1 μm or less. The present invention provides a coating agent for a solid preparation characterized by:

In the present invention, the water-insoluble polymer is hydroxypropylmethylcellulose phthalate,
The solid preparation as described above, which is at least one or more cellulosic polymers selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose and ethylcellulose. A coating agent is provided.

Further, in the present invention, the water-insoluble polymer is a copolymer of acrylic acid or methacrylic acid and a lower alkyl ester of acrylic acid and / or methacrylic acid, a lower alkyl ester of acrylic acid and a lower alkyl of methacrylic acid. At least one selected from the group consisting of a copolymer with an ester, a copolymer of a lower alkyl ester of acrylic acid and / or methacrylic acid and a diethylaminoethyl or trimethylammonium ethyl ester of acrylic acid and / or methacrylic acid. The present invention provides a coating agent for the solid preparation as described above, which is an acrylic polymer.

In the present invention, the dispersant is at least one selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose and sodium lauryl sulfate.
It provides a coating agent for the solid preparation as described above, which is one or more kinds of dispersants.

Further, the present invention provides the coating agent for the solid preparation as described above, wherein the saponification degree of the polyvinyl alcohol is in the range of 76 to 96 mol%.

In the present invention, the aqueous emulsion of the water-insoluble polymer containing the dispersant is dissolved in an organic solvent capable of mixing the water-insoluble polymer with water at an arbitrary ratio or a mixed solvent of the organic solvent and water. A water-insoluble polymer solution is prepared by mixing the water-insoluble polymer solution with water, and the water-insoluble polymer solution is self-emulsified to obtain an aqueous emulsion. is there.

The coating agent for the solid preparation of the present invention is a freeze-dried aqueous emulsion of a water-insoluble polymer for coating containing a dispersant in a specific composition ratio. This coating agent is re-introduced into water and dispersed to have an average particle size of 1 μm or less to form an aqueous coating liquid.

The water-insoluble polymer used as a base for coating the solid preparation used in the present invention includes enteric-based bases such as cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and the like. Cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose
Examples of acrylic polymers include copolymers of methacrylic acid and ethyl acrylate or methyl methacrylate.

Examples of the sustained-release base include ethyl cellulose, a copolymer of ethyl acrylate and methyl methacrylate, a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate, A copolymer of methyl methacrylate, butyl methacrylate and diethylaminoethyl acrylate may be mentioned.

Even if these polymers are used alone, 2
You may mix and use more than seeds.

As the dispersant used in the present invention, polyvinyl alcohol, hydroxypropyl cellulose and sodium lauryl sulfate are preferable, and polyvinyl alcohol is particularly preferable.

The degree of saponification and the degree of polymerization of polyvinyl alcohol are not particularly limited, but those having a degree of saponification of 76 to 96 mol% are preferable. If the degree of saponification is higher than this range, the solubility of polyvinyl alcohol in water tends to be low, so the average particle size tends to increase after reintroduction into water, and if it is lower than this range, polyvinyl alcohol will dissolve in water. Then it becomes difficult to add. The degree of polymerization is preferably low in both cases of polyvinyl alcohol and hydroxypropyl cellulose.

The amount of the dispersant added to the water-insoluble polymer, that is, the composition ratio of the water-insoluble polymer and the dispersant must be 88:12 to 98: 2 by weight, and more preferably 92 :. The weight ratio is 8 to 97: 3. When the content of the dispersant is less than 2% by weight, the redispersibility of the coating agent is deteriorated, and when it is more than 12% by weight, the water permeability of the formed coating film is high because the dispersant is water-soluble. Impairs acid resistance.

An aqueous emulsion of a water-insoluble polymer and a dispersant is a method of emulsifying an organic solvent solution of the polymer in a cellulosic polymer (JP-A-6-293633), an organic solvent solution which can be mixed with water at an arbitrary ratio. Is mixed with water and diffused (Japanese Patent Application No. 5-331431, Japanese Patent Application No. 5-331432) and the like.
Further, the organic solvent is removed by distillation or vacuum distillation according to a conventional method to obtain an aqueous emulsion. There is also a method of removing and concentrating the organic solvent using an ultrafiltration membrane. In the case of acrylic polymers, a usual emulsion polymerization method (Japanese Patent Publication No. 3-37562, Japanese Patent Publication No. 4-192).
09, JP-A-61-100527).

It is desirable to concentrate these aqueous emulsions to a high concentration from the viewpoint of the economical efficiency of the subsequent freeze-drying step. In the present invention, the concentration is usually 8 to 3
0% is used. The dispersant may be added as an aqueous solution after the above emulsion is produced, or may be added as a solution to water when the above emulsion is produced.

The aqueous emulsion thus obtained is further freeze-dried to obtain the coating agent for the solid preparation of the present invention. Freeze drying may be performed according to a conventional method. As a drying method, there are methods such as spray drying,
A coating agent having excellent redispersibility cannot be obtained by any method other than freeze-drying. The coating agent obtained by freeze-drying may be in the form of powder or plate, which may be used as it is or may be crushed before use.

By adding the coating agent of the present invention thus obtained to water and dispersing it with stirring, an aqueous coating solution in which a water-insoluble polymer is dispersed with an average particle size of 1 μm or less can be obtained.

The aqueous coating solution contains pharmaceutically acceptable drugs and additives such as plasticizers, colorants and pigments.
It is free to add an anti-sticking agent or the like. As the plasticizer, for example, triethyl citrate or triacetin can be added.

The coating treatment of the solid preparation with the aqueous coating solution is completed by spraying the aqueous coating solution onto the solid preparation with a coating device and then drying the solution to form a film. The coating may be performed according to a conventional method using, for example, a fluidized bed coating device, a pan coating device, an aeration type rotary drum type coating device, or the like.

[0030]

EXAMPLES The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[Example 1] Hydroxypropyl methylcellulose phthalate (HP-55: manufactured by Shin-Etsu Chemical Co., Ltd.)
1.06 kg is the weight ratio (ethanol) / (water)
Was dissolved in 25.74 kg of a mixed solvent of 7/3 to prepare a polymer solution. The polymer solution was emulsified by adding 153.36 kg of water at a speed of 10 kg / sec while stirring the polymer solution at a strength of 100 rpm. The obtained emulsified stock solution was concentrated at room temperature with a flat membrane made of polysulfone having a molecular weight cutoff of 200,000 and a filtration area of 0.65 m ² until the solid content concentration reached 15% by weight.

This emulsion having a concentration of 15% by weight was diluted with 4 times the amount of water, and further concentrated to a solid concentration of 15% by weight in the same manner as in the above method. Further, 9 times the amount of water was added to the concentrated solution to dilute and concentrate the solution to obtain an aqueous emulsion having a solid content concentration of 10% by weight.

To 10 g of this emulsion, 0.5 g of a 10% aqueous solution of polyvinyl alcohol (PA-05: manufactured by Shin-Etsu Chemical Co., Ltd.) was added, and the mixture was dried at -40 ° C. by a freeze dryer (RLE-52: manufactured by Kyowa Vacuum Technology Co., Ltd.). A coating agent was obtained by drying at a vacuum degree of -4 torr for 16 hours. When this was re-introduced into water and dispersed to give an aqueous coating liquid, the average particle diameter was 0.2 μm.

This lyophilized product was made into a 10% aqueous dispersion as in the actual coating, and triethyl citrate as a plasticizer was added to hydroxypropylmethylcellulose phthalate (HP-55: manufactured by Shin-Etsu Chemical Co., Ltd.) at 15% by weight.
When added and cast on a glass plate, a transparent continuous film was formed. When the obtained film was immersed in the first liquid (artificial gastric juice) having a pH of 1.2 for 2 hours according to the enteric-coated preparation test defined by the Japanese Pharmacopoeia, no change was observed in the film.

Example 2 In place of the 10% aqueous polyvinyl alcohol solution of Example 1, 1.0 g of a 10% aqueous sodium lauryl sulfate solution was added, and freeze-drying was carried out in the same manner as in Example 1. A coating agent having an average particle diameter of 0.7 μm when charged and dispersed was obtained.

Example 3 Aqueous copolymer emulsion of methacrylic acid and ethyl acrylate (L-30D55:
Rohm Pharma, solid content 30%) 10g, 0.75
% Polyvinyl alcohol (PA-05: manufactured by Shin-Etsu Chemical Co., Ltd.) aqueous solution (20 g) was added, and lyophilization was performed in the same manner as in Example 1.

This lyophilized product was made into a 10% aqueous dispersion as in the case of actual coating, and 15% by weight of triethyl citrate as a plasticizer was added to the solid content and cast on a glass plate to give a transparent solution. A continuous film was formed. When the obtained film was immersed in the first liquid (artificial gastric juice) having a pH of 1.2 for 2 hours according to the enteric-coated preparation test defined by the Japanese Pharmacopoeia, no change was observed in the film.

Example 4 Ethyl cellulose (N-1
0: manufactured by Shin-Etsu Chemical Co., Ltd.) 0.3 kg acetone 9.7 kg
To prepare an organic solvent solution of ethyl cellulose. The organic solvent solution of ethyl cellulose was emulsified by adding 10 kg of water at a speed of 1 kg / sec while stirring at a strength of 100 rpm. The obtained emulsion is jacketed with an evaporator at a temperature of 50 ° C. and a vacuum degree of −500 mm.
Distilled under reduced pressure with Hg to remove solvent, solid content concentration 10% by weight
An aqueous emulsion of

0.7 g of a 10% aqueous solution of polyvinyl alcohol (PA-18: manufactured by Shin-Etsu Chemical Co., Ltd.) was added to 10 g of this emulsion, and freeze-dried in the same manner as in Example 1. When this was re-introduced into water and dispersed to make an aqueous coating liquid, the average particle diameter was 0.3 μm.

This lyophilized product was made into a 10% aqueous dispersion as in the case of actual coating, and triethyl citrate as a plasticizer plasticizer was 30% by weight with respect to ethyl cellulose (N-10: manufactured by Shin-Etsu Chemical Co., Ltd.). Thus, it was cast on a glass plate to prepare a transparent continuous film.
When the film was tested for the first liquid as in Example 1, no change was observed in the film.

"Comparative Example 1" The emulsion to which polyvinyl alcohol used in Example 1 was added was spray-dried (Pu
The powder was pulverized by using lvis Mini Spray YAMATO Co., Ltd. at an intake temperature of 120 ° C. and an exhaust temperature of 60 ° C. When the obtained powder is poured into water, the powder has an average particle size of 5.1 μm.
And was not redispersed.

[0042]

The coating agent for the solid preparation of the present invention comprises:
It is not necessary to add a polymerization initiator, a chain transfer agent, salts and the like, and after being added into water, the particles are easily dispersed to have an average particle size of 1 μm or less, and an aqueous coating solution excellent in stability and film-forming property is obtained. The aqueous coating liquid can provide a solid formulation with excellent stability and can provide acid resistance with a low coating amount.

Claims (6)

[Claims] 1. A coating agent for a solid preparation obtained by freeze-drying an aqueous emulsion of a water-insoluble polymer containing a dispersant having a weight ratio of the water-insoluble polymer to the dispersant of 88:12 to 98: 2, A coating agent for a solid preparation, which is re-introduced into water and dispersed into an aqueous coating solution with an average particle diameter of 1 μm or less. 2. The water-insoluble polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose and ethylcellulose. The coating agent for a solid preparation according to claim 1, which is a cellulosic polymer. 3. The water-insoluble polymer is a copolymer of acrylic acid or methacrylic acid and a lower alkyl ester of acrylic acid and / or methacrylic acid, and a copolymer of a lower alkyl ester of acrylic acid and a lower alkyl ester of methacrylic acid. Polymer, lower alkyl ester of acrylic acid and / or methacrylic acid and acrylic acid and / or
2. The coating agent for a solid preparation according to claim 1, which is at least one acrylic polymer selected from the group consisting of copolymers of methacrylic acid with diethylaminoethyl or trimethylammoniumethyl ester. 4. The dispersant is polyvinyl alcohol,
The coating agent for a solid preparation according to claim 1, which is at least one dispersant selected from the group consisting of hydroxypropyl cellulose and sodium lauryl sulfate. 5. The coating agent for a solid preparation according to claim 4, wherein the degree of saponification of the polyvinyl alcohol is in the range of 76 to 96 mol%. 6. An aqueous emulsion of a water-insoluble polymer containing the dispersant is water-insoluble by dissolving the water-insoluble polymer in an organic solvent capable of mixing water in an arbitrary ratio or a mixed solvent of the organic solvent and water. The coating of the solid preparation according to claim 1, 2, 3, 4 or 5, which is an aqueous emulsion obtained by preparing a polymer solution, mixing the water-insoluble polymer solution and water, and self-emulsifying the mixture. Agent.