JPH0873379A - Powder for coating solid formulations - Google Patents

Abstract

(57) [Summary] [Objective] It is not necessary to add a polymerization initiator, a chain transfer agent, salts, etc., and after being put in water, it is easily dispersed to have an average particle size of 1 µm or less to form an aqueous coating solution. (EN) A powder for coating a solid preparation, which is excellent in stability and film-forming property, and can form a coating excellent in acid resistance and stability on the solid preparation. [Structure] The coating powder of the solid preparation is prepared by dissolving a cellulosic polymer in an organic solvent that can be mixed with water at an arbitrary ratio or a mixed solvent of the organic solvent and water to prepare a polymer solution, and then adding the polymer solution to water. To the concentrated liquid obtained by removing the organic solvent from the emulsion self-emulsified by dispersing in an aqueous solution and adding 2 to 17 weight% of anionic surfactant to 83 to 98 weight% of the actual amount of the cellulosic polymer, and then drying. It is a powder for coating a solid preparation which has been made into a powder and is dispersed into an average particle size of 1 μm or less after re-introducing it into water.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a powder for enteric 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 sensitive to acid from gastric acid, protects the gastric mucosa from a drug having irritation or damage to the stomach wall, dissolves in the intestine, and exerts a pharmacological action there. In addition, the sustained release formulation with an insoluble coating controls the release of the drug,
It exerts its medicinal effect continuously. One of the coating bases is a cellulosic polymer. Examples of the water-insoluble cellulosic polymer include enteric-based bases such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and carboxymethylethylcellulose. In addition, examples of the sustained-release base include ethyl cellulose. These polymers are dissolved in an organic solvent or used as an aqueous latex or an aqueous dispersion for 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.

Many techniques are known for water-based coating processes. JP-B-60-43334 describes an emulsion of an acrylic polymer. This acrylic polymer is an emulsion copolymer of methacrylic acid and ethyl acrylate, and is a stable emulsion having a particle size of 1 μm or less. However, emulsifiers, polymerization initiators, chain transfer agents, unreacted monomers, etc. remain in this emulsion, which is not preferable in terms of safety for coating solid preparations.

To disperse a cellulosic polymer in water, there are a method in which salts are added together with the polymer or a carboxyl group in the polymer is neutralized, and a method in which the polymer is made into fine particles and dispersed in water.

Regarding the former method, Japanese Patent Publication No. 61-56221 discloses a polymer powder which is redispersed in water by emulsifying cellulose acetate phthalate and then adding phosphate as an anti-agglomeration agent and spray-drying. A method of obtaining is described. Emulsification of ethyl cellulose and cellulose acetate phthalate is carried out by the method described in US Pat. No. 4,177,177. JP-A-56-30913 describes a method in which cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate is used for coating as an aqueous solution neutralized with ammonia. JP-A-58-135807 describes a method in which cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate is neutralized with an alkali and dissolved, and then a carboxylic acid is added. In all of these methods, the alkali salt or ammonium salt of carboxylic acid remained in the coating film of the solid enteric preparation, so that the hygroscopicity was high and it was not stable.

Regarding the latter method, Japanese Patent Publication No. 56-12614 discloses that a cellulose-based polymer having an average particle diameter of 100 μm or less is added to a gelling agent (plasticizer) at a boiling point of 100.
A method of dispersing in water at a temperature of ℃ or above is described. JP-B-57-53329 and JP-B-58-55125 describe the use of triacetin or triethyl citrate as a gelling agent. However, when these dispersions are used for coating, since the enteric preparation is mechanically pulverized, the particle size becomes at least 1 μm or more. When the particle size is 1 μm or more, a large amount of plasticizer is required, so that the polymer is softened by the temperature increase and coagulates and precipitates in the dispersion liquid, and the coating base has a large particle size, so that the film-forming property is not good. .

Japanese Patent Publication No. 3-39490 discloses a method of reducing the particle size of the cellulosic polymer in water by emulsification to improve the drawbacks of the cellulosic water coating technique. This emulsification is carried out by the method described in US Pat. No. 4,177,177. Specifically, a cellulose-based polymer is dissolved in a water-immiscible organic solvent to prepare a polymer solution. A hydrocarbon having 8 or more carbon atoms (such as cetyl alcohol) as a stabilizer and a surfactant are added to a polymer solution, and the polymer solution is treated with a special emulsifier such as a high pressure homogenizer to obtain an emulsion. in this way,
This method not only requires a special emulsifier, but it is difficult to completely remove the solvent used. In addition, the composition of the aqueous coating liquid contains components other than the cellulosic polymer, such as a stabilizer and a surfactant, and often impairs the acid resistance and stability of the enteric preparation.

[0008]

The present invention has been made to solve the above-mentioned problems, and it is not necessary to add a polymerization initiator, a chain transfer agent, salts, etc., and the average particle diameter can be easily obtained after charging in water. An object of the present invention is to provide a powder for coating a solid preparation, which is dispersed in a particle size of 1 μm or less to form an aqueous coating liquid, which is excellent in stability and film-forming property and which can exhibit a desired effect with a low coating amount. And

[0009]

The powder for coating a solid preparation of the present invention made to achieve the above-mentioned object is an organic solvent capable of mixing a cellulosic polymer with water at an arbitrary ratio, or with this organic solvent. A polymer solution was prepared by dissolving it in a mixed solvent with water, and the polymer solution was dispersed in water and the organic solvent was removed from the self-emulsified emulsion. It is a powdered product. This powder is re-introduced into water and dispersed to have an average particle diameter of 1 μm or less to form an aqueous coating liquid.

Cellulosic polymers serve as a base for coating solid formulations. Examples of enteric bases for the cellulosic polymers include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, and carboxymethylethylcellulose. In addition, examples of the sustained-release base include ethyl cellulose.
These cellulosic polymers may be used alone or in combination.

Examples of the anionic surfactant include sulfonic acid salts such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and sodium dodecylbenzene sulfonate, and fatty acid salts such as sodium stearate.
Particularly, sodium lauryl sulfate is preferable. Further, the addition amount thereof is preferably 2 to 17 weight ratio, more preferably 5 to 12 weight ratio with respect to the actual amount of cellulose polymer of 83 to 98 weight ratio. Addition of this concentration of the anionic surfactant improves the dispersibility of the emulsion and thus improves the film forming property, that is, the coating performance. Moreover, the addition of an anionic surfactant also improves the temperature stability of the aqueous coating liquid.

If the amount of the anionic surfactant added is less than 2% by weight, the redispersibility of the powder is low, and if it is more than 17% by weight, the surfactant is water-soluble, so that the water of the coating film formed is formed. Increases permeability and impairs acid resistance.

Examples of the organic solvent include solvents that can be mixed with water at an arbitrary ratio, for example, alcohols such as methanol, ethanol and isopropanol, and ketones such as acetone and methyl ethyl ketone, which are used in an amount capable of dissolving the cellulosic polymer. . Further, these solvents can be used as a mixed solvent with water, and the mixing ratio thereof varies depending on the kind of the cellulosic polymer dissolved in the mixed solvent, but the ratio of water in the mixed solvent is 60% by weight or less. It is also free to use a small amount of water immiscible solvent.

The concentration of the polymer solution in the organic solvent is 10
It is preferably not more than 10% by weight, more preferably 2 to 10% by weight. If it is 10% by weight or more, the viscosity becomes too high, and it becomes impossible to emulsify into fine particles of 1 μm or less. When it is 2% by weight or less, the concentration of the finally obtained aqueous emulsion becomes too low, so that the productivity is lowered.

The amount of water mixed with the polymer solution is preferably 80% by weight, more preferably 80 to 150% by weight, based on the polymer solution. If it is less than 80% by weight, the dispersion of the solvent is insufficient and the emulsification is incomplete. 15
When it is 0% by weight or more, the concentration of the finally obtained aqueous emulsion becomes too low, so that the productivity is lowered.

The emulsification method is to dissolve the cellulosic polymer in an organic solvent or a mixed solvent to prepare a polymer solution,
The polymer solution is mixed with water in a predetermined ratio. During that time, it is sufficient to continue the stirring gently with an ordinary stirring device, and there is no influence by the strength of stirring. However, when the polymer solution is mixed with the aqueous phase, if the feeding speed is slow, the concentration of the aqueous phase is low and the dispersion is not sufficiently performed, so that an emulsion having an average particle diameter of 1 μm or less cannot be obtained. Further, the organic solvent is removed by distillation or vacuum distillation according to a conventional method to obtain an aqueous emulsion. Also remove organic solvent,
There is also a method of performing concentration using an ultrafiltration membrane.

A powder for coating the solid preparation of the present invention can be obtained by adding an anionic surfactant to the thus obtained aqueous emulsion and then pulverizing it. As a powdering method, a spray dryer, a jet dryer, a medium fluidized dryer, or the like may be used according to a conventional method.

The coating treatment is carried out by spraying an aqueous coating solution on a solid preparation with a coating device,
The process is completed by drying the liquid and forming a film. It is free to add pharmaceutically acceptable drugs and additives such as plasticizers, colorants, pigments and anti-adhesives to the aqueous coating liquid. Examples of the plasticizer include triethyl citrate and triacetin. 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.

[0019]

The powder for coating the solid preparation of the present invention does not need to be added with a polymerization initiator, a chain transfer agent, salts and the like, and can be easily dispersed in water after being put into water to have an average particle diameter of 1 μm or less and thus stable. And it becomes an aqueous coating liquid having excellent film forming properties. The aqueous coating solution can form a solid formulation with excellent stability and can provide acid resistance with a low coating amount.

[0020]

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

Example 1 Hydroxypropyl methylcellulose phthalate (HP
-55: manufactured by Shin-Etsu Chemical Co., Ltd.) 0.3 kg of acetone 9.
Dissolve in 7 kg, stir at 100 rpm,
The mixture was added to 10 kg of water at a rate of 1 kg / sec for emulsification. The obtained emulsion was distilled under reduced pressure by an evaporator to remove the solvent, and then concentrated using an ultrafiltration membrane to a solid content concentration of 15% by weight.

To this concentrated solution, sodium lauryl sulfate 30 was added.
g (10% by weight with respect to HP-55) was added, and the mixture was pulverized with a spray dryer. The obtained powder had an average particle size of 10 μm and had excellent fluidity. When the powder was re-introduced into water to be dispersed into an aqueous coating liquid, the average particle diameter was 0.5 μm.

Similar to the actual coating, triethyl citrate (15% by weight) was added to this aqueous coating solution as a plasticizer and cast on a glass plate to form a transparent continuous film. 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 disintegration test method of the Japanese Pharmacopoeia, and no change was observed in the film.

Comparative Example 1 Hydroxypropylmethylcellulose phthalate (HP-55UF: manufactured by Shin-Etsu Chemical Co., Ltd.) having an average particle size of 5 μm was dispersed in water, and triethyl citrate was added to the polymer as a plasticizer in an amount of 15 with respect to the polymer as in the actual coating. When it was added to the glass plate by weight% and cast on a glass plate, about 20% by weight of the whole was a transparent film, but no film was formed on the other parts.

Example 2 0.5 kg of hydroxypropylmethyl cellulose acetate succinate (AS-MF: manufactured by Shin-Etsu Chemical Co., Ltd.)
Was dissolved in 20 kg of a mixed solvent of ethanol and water (ethanol / water = 7/3), and 20 kg of water was added to the mixture while stirring at 100 rpm to emulsify. The obtained emulsion was distilled under reduced pressure by an evaporator to remove the solvent, and then concentrated using an ultrafiltration membrane to a solid content concentration of 10% by weight.

75% sodium lauryl sulfate was added to this concentrated solution.
g (15% by weight with respect to AS-MF) was added, and the mixture was pulverized with a spray dryer. The average particle size of the obtained powder was 8 μm. When the powder was re-introduced into water to disperse it into an aqueous coating solution, the average particle size was 0.7.
was μm.

Comparative Example 2 3 g (1% by weight based on HP-55) of sodium lauryl sulfate was added to the emulsion obtained by emulsion concentration in the same manner as in Example 1, and the mixture was pulverized with a spray dryer. The average particle size of the obtained powder was 10 μm. When the powder was redispersed in water, the average particle size was 4.2 μm and it was not completely redispersed.

Comparative Example 3 90 g of sodium lauryl sulfate (30 to HP-55 was added to an emulsion obtained by emulsion concentration in the same manner as in Example 1).
% By weight) and pulverized by a spray dryer.
The average particle size of the obtained powder was 6 μm. When the powder was redispersed in water to give an aqueous coating solution, the average particle size was 0.3 μm.

In the same manner as in actual coating, 15% by weight of triethyl citrate was added to this aqueous coating solution as a plasticizer and cast on a glass plate to form a transparent continuous film. When the obtained film was immersed for 2 hours in the first liquid (artificial gastric juice) having a pH of 1.2 according to the enteric-coated preparation test defined by the disintegration test method of the Japanese Pharmacopoeia, the film disintegrated.

Example 3 The powder produced in Example 1 was re-introduced into water at a temperature of 15 ° C. so that the polymer concentration was 10% by weight to disperse the powder to obtain an aqueous coating solution. The aqueous coating liquid 80
0 ml using a Japanese Pharmacopoeia dissolution tester (paddle method) at 40 ° C
The mixture was stirred at a rotation speed of 200 rpm for 1 hour under the temperature of 1. The composition of this aqueous coating liquid was 10 parts by weight of polymer, 3.5 parts by weight of triethyl citrate, 1 part by weight of sodium lauryl sulfate, and 85.5 parts by weight of water. The aqueous coating solution was passed through a 60-mesh sieve, the remaining agglomerates were dried, and the weight was measured to determine the ratio (aggregation rate) to the solid content in the aqueous coating solution.
It was found to be as small as 0.1% by weight and good in temperature stability.

Comparative Example 4 An aqueous coating solution was prepared in the same manner as in Example 3 except that HP-55UF having an average particle size of 5 μm was added to water. The composition of this aqueous coating solution was such that the polymer was 10 parts by weight, triethyl citrate was 3.5 parts by weight, and water was 86.5 parts by weight. This aqueous coating solution was passed through a 60-mesh sieve, and the remaining agglomerates were dried and weighed.
When the aggregation rate was determined, it was as large as 50.5% by weight and the temperature stability was poor.

Comparative Example 5 HP-55UF having an average particle size of 5 μm was put into water to form HP-
An aqueous coating solution was prepared in the same manner as in Example 3, except that 10% by weight of sodium lauryl sulfate was added to 55UF. The composition of this aqueous coating solution is 10 parts by weight of polymer, 3.5 parts by weight of triethyl citrate,
It was 1 part by weight of sodium lauryl sulfate and 85.5 parts by weight of water. This dispersion was passed through a 60-mesh sieve, and the remaining agglomerates were dried and weighed, and the agglomeration rate was determined to be 10.2% by weight, indicating a poor temperature stability.

Example 4 Ethyl cellulose (N-7-G: manufactured by Shin-Etsu Chemical Co., Ltd.)
A polymer solution was prepared by dissolving 0.05 kg of ethanol in 2.45 kg. The emulsion was emulsified by adding 10 kg of water at a speed of 5 kg / sec while stirring at a rotation speed of 100 rpm. The solvent was removed from the obtained emulsion under reduced pressure by an evaporator, and then the emulsion was concentrated to a polymer concentration of 10% by weight using an ultrafiltration membrane.

5 g of sodium lauryl sulfate was added to this concentrated liquid.
(10% by weight with respect to ethyl cellulose) was added, and the mixture was pulverized with a spray dryer. The average particle size of the obtained powder was 10 μm. When this powder was re-introduced into water and dispersed, the average particle diameter was 0.6 μm.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shinichiro Nakamura 28, Nishi-Fukushima, Kubiki-mura, Nakakubiki-gun, Niigata Prefecture 1 Shin-Etsu Chemical Co., Ltd.

Claims (4)

[Claims] 1. A water-insoluble cellulosic polymer is dissolved in an organic solvent that can be mixed with water at an arbitrary ratio or a mixed solvent of the organic solvent and water to prepare a polymer solution, and the polymer solution is dispersed in water. Powder obtained by adding 2 to 17 weight ratio of anionic surfactant to 83 to 98 weight ratio of the actual amount of the cellulosic polymer to a concentrated liquid obtained by removing the organic solvent from the self-emulsified emulsion. A powder for coating a solid preparation, wherein the powder for coating a solid preparation is characterized by being dispersed into an average particle diameter of 1 μm or less after being re-introduced into water. 2. The cellulose-based polymer is at least one selected from hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, and ethylcellulose. The powder for coating the solid preparation according to claim 1. 3. The powder for coating a solid preparation according to claim 1, wherein the anionic surfactant comprises sodium lauryl sulfate and / or dioctylsodium sulfosuccinate. 4. The organic solvent is at least one solvent selected from methanol, ethanol, isopropanol, acetone, and methyl ethyl ketone, the ratio of water in the mixed solvent is 60% by weight or less, and the polymer solution The powder for coating a solid preparation according to claim 1, wherein the concentration is 10% by weight or less, and the water in which the polymer solution is dispersed is 80% by weight or more based on the polymer solution.