JPS6355526B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing easily water-dispersible oxycarboxylic acid type cellulose derivatives. For more details,
The present invention relates to a method for providing an easily water-dispersible oxycarboxylic acid type cellulose derivative that is effective for preparing an aqueous enteric coating solution.

BACKGROUND ART Conventionally, when coating solid pharmaceutical products such as granules and tablets with enteric coating agents, the method of dissolving them in a single or mixed solvent such as an organic solvent, such as a halogenated hydrocarbon, alcohol, or ketone, and then spray coating the agent is carried out. Generally adopted. However, this method requires a large amount of organic solvent to prepare the coating liquid, which is difficult to recover and is economically disadvantageous. There were problems with the safety of users due to residual solvent in the drug.

From this point of view, the importance of making enteric coating liquids water-based has recently been recognized, and various methods have been proposed. Incidentally, enteric coating agents are generally polymeric compounds that do not dissolve in water or gastric juices, but have the property of dissolving in intestinal fluids, and generally have an anionic group. Since such polymer compounds have the property of becoming water-soluble only by forming a salt in an alkaline aqueous solution, the reality is that they cannot simply be made into an aqueous solution.

Therefore, the aqueous coating solution for enteric coating agents having such properties is generally prepared by dispersing fine powder of enteric coating agents pulverized to 100 μm or less in water. Needless to say, it is desirable that the particle size of the enteric coating agent be as small as possible from the viewpoint of water dispersibility and film-forming properties of the dispersion when preparing such a dispersion. Various proposals have been made. Conventional techniques related to atomization methods include dry pulverization of dried products using a jet mill, etc.
It is broadly classified into the physicochemical pulverization method described in No. 54331.

However, the former method has problems such as the extremely large power required during pulverization and the resulting product being a fine powder that is extremely inconvenient to handle, which is a major drawback in practical use. On the other hand, the latter method is characterized by pulverizing by a physicochemical method, that is, a method of neutralizing an alkaline solution while applying sharp cutting force, instead of mechanical dry pulverization, and the solid content at the time of pulverization is This method is not economically advantageous because it requires a significantly low concentration and requires the use of a homogenizer that requires strong power.

Means and Effects for Solving the Problems In view of the above situation, the present inventors have developed an industrially advantageous water-based enteric coating solution which is industrially advantageous and effective for preparing a good water-based enteric coating liquid in order to solve the problems of the prior art. However, as a result of intensive studies on a method for producing enteric coating agent powder that produces less powder, we found that when producing a water-insoluble oxycarboxylic acid type cellulose derivative, the oxycarboxylic acid type cellulose derivative is used as at least one component in water. By performing solid-liquid separation from a solvent system containing the compound, wet-pulverizing it, and drying it, it is possible to industrially advantageously obtain a product in a form that satisfies the purpose with less dust and is easily water-dispersible. This discovery led to the completion of the present invention.

In this application, the oxycarboxylic acid type cellulose derivative is defined as follows.

At least a portion of the three hydroxyl groups per glucose skeleton of cellulose or hydroxyalkylcellulose are selected from carboxyalkyl ether groups (-OCnH ₂ nCOOH), half-ester groups based on dibasic carboxylic acids, and ether groups (-OCnH _2o+1 ) Cellulose derivative substituted with one selected from ester groups (-OCR).
However, alkyl is an alkyl having 1 to 5 carbon atoms, and n is 1.
-5, and R represents an alkyl or higher fatty acid residue having 1 to 5 carbon atoms. Examples of the oxycarboxylic acid type cellulose derivatives include cellulose ethers, cellulose esters, and cellulose ether esters. The term ether group or ester group refers to an atomic group introduced into cellulose through etherification or esterification of cellulose, and examples of the ester group include acetate, propionate, butyrate, and higher fatty acid ester.

To give more specific examples, examples of oxycarboxylic acid type cellulose derivatives include carboxyalkylalkylcellulose mixed ethers such as carboxymethylethylcellulose, carboxyethylmethylcellulose, and carboxypropylmethylcellulose, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose phthalate, and hydroxypropyl. Included are cellulose mixed ether esters such as acidic succinoyl and acidic phthaloyl mixed esters of methylcellulose, acidic succinoyl and propionic acid esters of hydroxypropylmethylcellulose, and cellulose mixed esters such as cellulose acetate phthalate and cellulose acetate succinate.

Among these, when using an oxycarboxylic acid type cellulose derivative as an aqueous enteric coating agent, carboxyalkylalkylcelluloses, which are highly hydrophilic and have excellent hydrolysis resistance, are particularly preferred. Examples include carboxymethylethylcellulose, carboxyethylethylcellulose, carboxybutylethylcellulose, carboxypropylmethylcellulose, and the like.

When carboxymethylethylcellulose is used, it is produced by etherifying carboxymethylcellulose in the presence of a quaternary ammonium salt as a phase transfer catalyst, especially carboxymethylcellulose is pre-dispersed in an organic solvent that is not freely miscible with an aqueous caustic solution. After that, it is preferably mixed with caustic alkali and subjected to etherification reaction by adding a phase transfer catalyst, ethyl halide, because it provides a strong film with uniform distribution of substituted ethoxyl groups and less shrinkage.

Next, in the production method of the present invention, in the production of a water-insoluble oxycarboxylic acid type cellulose derivative, the oxycarboxylic acid type cellulose derivative is uniformly dissolved as at least one component in a solvent system containing water, and then the solid-liquid liquid is extracted from the solvent system. It is characterized in that it is separated, then wet-pulverized without prior drying, and then dried, and even if water is added to the dried oxycarboxylic acid type cellulose derivative and crushed, it still achieves the purpose of easy water dispersibility. cannot be achieved. In the present invention, solvent systems containing water as at least one component include, for example, lower alkanol aqueous solutions having 1 to 4 carbon atoms, organic solvent/water mixed solvent systems such as acetone aqueous solutions, and bases such as ammonia, methylamine, caustic soda, and caustic potash. Examples include aqueous solutions of sexual substances. It is not limited to these as long as it dissolves the oxycarboxylic acid type cellulose derivative.

Next, as a solid-liquid separation method for the oxycarboxylic acid type cellulose derivative, in the case of an organic solvent/water mixed solvent system such as an aqueous lower alkanol solution, solid-liquid separation can be easily performed by removing the organic solvent by distillation etc. In addition, in the case of an aqueous solution of a basic substance such as an ammonia aqueous solution, solid-liquid separation is performed by adding an acidic substance that can neutralize the basic substance used and filtering or settling the resulting precipitate. do.

By the way, the oxycarboxylic acid type cellulose derivatives used as enteric coating agents are desired to have various degrees of polymerization depending on their uses.
To this end, there are two methods: using a cellulose raw material with a degree of polymerization suitable for the purpose and a method of depolymerizing it during the manufacturing process to achieve a degree of polymerization according to the purpose.Industrially, the latter method is the depolymerization method. It is practical to adopt

As the depolymerization method, for example, the method previously proposed by the present inventors (Japanese Patent Application Laid-open No. 108401/1983 and Japanese Patent Application No. 1983/1983)
185978), that is, there is a method in which an oxycarboxylic acid type cellulose derivative is uniformly dissolved in a solvent system containing water as at least one component, and then depolymerized using a peroxide, but the method is not limited thereto. After the depolymerization is completed, the depolymerized oxycarboxylic acid type cellulose derivative is separated from the reaction solution into solid and liquid, and then wet-pulverized and dried according to the method of the present invention to achieve the desired easy water dispersibility in an extremely economical manner. It is possible to obtain oxycarboxylic acid type cellulose derivatives.

Naturally, if the oxycarboxylic acid type cellulose derivative with a degree of polymerization suitable for the purpose is available, the oxycarboxylic acid type cellulose derivative is uniformly dissolved in the solvent system specified in the present invention, and then subjected to depolymerization treatment. It goes without saying that it is better to subject the product to wet pulverization after solid-liquid separation without carrying out this step.

Next, as the pulverizing device used in the wet pulverizing step of the present invention, conventionally known wet pulverizers such as a ball mill, attritor, disper mill, colloid mill, and vibration mill can be used, but are not limited thereto. do not have. In addition, the solid content concentration during wet pulverization varies depending on the type of pulverizer used and the target particle size of the pulverized product, but is usually 50% or less.
In particular, it is preferably 30% or less. The particle size during wet pulverization affects the dispersibility of the product in water after drying, and hence the film-forming properties, so it is desirable to make it as small as possible, but it is usually 100 μm or less, preferably 10 μm.

The wet-pulverized product thus obtained can be dried by conventionally known methods such as ventilation drying, vacuum drying, spray drying, freeze drying, and the like. Further, drying can be easily performed if the water content is reduced in advance by heating and dehydrating the slurry before drying. Oxycarboxylic acid type cellulose derivatives tend to undergo esterification under acidic or neutral conditions, which affects enteric properties, so it is desirable to process them at as low a temperature and in a short time as possible after wet grinding until obtaining a dry product. .

Effects of the Invention The oxycarboxylic acid type cellulose derivative obtained by carrying out the method concerned undergoes secondary aggregation in the drying process after wet pulverization due to water acting as a binder, etc., and remains granular even after drying. It exhibits a lump-like shape, does not have the problem of dusting, which is one of the disadvantages of dry grinding methods such as jet mills, and has excellent redispersibility in water.

That is, by carrying out the present invention, it is possible to eliminate the drawbacks of the prior art and provide an easily water-dispersible oxycarboxylic acid type cellulose derivative in an economically advantageous manner, and its industrial significance is extremely high. It's big.

The method for preparing the enteric coating liquid by dispersing the oxycarboxylic acid type cellulose derivative obtained by carrying out the present invention in water to form an aqueous system is not particularly limited.

In addition, in order to further improve the dispersion stability and film forming properties of the aqueous coating liquid, if necessary, various emulsifiers, water-soluble film forming agents such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinyl alcohol, polyethylene glycol, Plasticizers such as ethylene glycol, triacetin, and various glycerin fatty acid esters, alkali metal salts of acids with an acid dissociation constant (pKa) of 3 or more at 25°C, and colorants such as other food colors are used during or during dispersion. It can be added later.

Examples Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples.
In the following examples, parts and % indicate parts by weight and % by weight unless otherwise specified, and various measured values were determined by the following methods.

(1) Viscosity The sample was dissolved in a mixed solvent of ethanol/water (80/20) to prepare a 5% solution, and measured using a B-type viscometer at a rotor rotation speed of 30 rpm and 250°C. be.

(2) Minimum film forming temperature (hereinafter abbreviated as MFT) Sodium citrate 0.294 parts, citric acid 0.017 parts,
Emulsifier (trade name Tween 80, manufactured by Kao Atlas Co., Ltd.) 0.05 parts, 2% hydroxypropyl methyl cellulose (trade name TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) 5 parts aqueous solution, plasticizer (trade name
MGK, Nikko Chemical Co., Ltd.) 3 parts and 70
10 parts of the sample classified into ~16 meshes were dissolved or emulsified and dispersed at room temperature with 106.6 parts of water using a homomixer (manufactured by Tokushu Kika Kogyo Co., Ltd.). Next, the dispersion was passed through a 70-mesh sieve, and the MFT was determined according to a conventional method using the resulting liquid.
And so.

(3) Undispersed rate The dispersion liquid dispersed by the method in section (2) was passed through a 70 mesh sieve to determine the content of coarse particles of 70 mesh or more, and this value was calculated as the undispersed rate.

(4) Enteric coating test (a) Preparation of tablets used Microcrystalline cellulose (trade name: Avicel, manufactured by Asahi Kasei Corporation) / Rapidly disintegrating excipient for direct compression (trade name: Perfiller, manufactured by Freund Sangyo Co., Ltd.) ) = 1/1 mixture was directly compressed into tablets of about 200 mg and 8 mm in diameter.

Then add 8% of TC-5R to this tablet.
Automatic film coating device for aqueous solution (FM-type, manufactured by Freund Sangyo Co., Ltd.)
The uncoated tablets were coated with a 2.5% coating film using a conventional method and subjected to a coating test.

(b) Preparation of coating liquid An aqueous dispersion obtained by processing in the same manner as in the preparation method of the dispersion prepared for MFT measurement described in section (2) was subjected to a coating test.

(c) Coating test Automatic film coating equipment (High coater mini type, manufactured by Freund Sangyo Co., Ltd.)
0.35 kg of the above tablets were charged, and the coating dispersion was sprayed at a rate of about 5 ml/min to cover the uncoated tablets with a coating film of about 12%. During this time, the coating pan was rotating (approximately 32 rpm) and drying was performed using dry air at 80-85°C. After a predetermined amount of coating was completed, drying was further performed using dry air for 20 minutes. Enteric properties of the obtained coated tablets were evaluated according to the disintegration test method described in the Japanese Pharmacopoeia (10th edition).

Reference example: 84.7 g of CMC with a carboxymethyl group substitution degree of 0.48, solution viscosity characteristics (ratio of viscosity at rotor rotation speeds of 6 and 30) η ₆ /η ₃₀ = 1.050, and water content of 5.6% was dissolved in toluene in an autoclave. Disperse the mixture in 320g of the mixture, add 71.1g of a 48% aqueous sodium hydroxide solution while stirring and keeping the temperature at 30-40℃, then add 51.1g of flaked sodium hydroxide, and stir at 35-45℃ for 10 minutes to ensure sufficient It was made into a slurry.

Then tetraethylammonium chloride
3.4g and 204g of ethyl chloride were added and reacted at 115±5°C for 10 hours. The reaction system was in a good slurry state from beginning to end.

After cooling, most of the solvent was distilled and recovered, about 200 g of water was added, and the pH of the system was adjusted to about 1 with 12N sulfuric acid, followed by washing with water to obtain CMEC. Solution viscosity 84cps, solution viscosity
A CMEC of 30.0 cps, a degree of ethoxyl group substitution of 2.01, and a degree of carboxymethyl group substitution of 0.48 was obtained.

Example 1 Degree of carboxymethyl group substitution (hereinafter abbreviated as DS)
After dispersing 50 parts of carboxymethylethyl cellulose (hereinafter abbreviated as CMEC) of 0.48, ethoxyl group DS 2.01, and viscosity 30.0 cps in 606.7 parts of water, 8.4 parts of 25% ammonia water and 1.66 parts of caustic soda were added and completely dissolved at room temperature. I let it happen. After dissolving, raise the temperature to 50℃ and
% hydrogen peroxide solution was added, and the mixture was stirred at 50 to 55°C for 5.5 hours.

Then cool to room temperature and add soypropyl alcohol.
After adding 10 parts, 3.6N sulfuric acid was added until the pH of the system reached 3.0 to precipitate the solid content, which was then heated to 80°C and held at the same temperature for 5 minutes. Next, it is filtered by suction using a hot nuttie, thoroughly washed with warm water at 70°C to 80°C, and made into a wet powder with a particle size of 1 to 2 mm and a moisture content of 50%.
Got CMEC.

25 parts of water was added to 50 parts of this wet CMEC, and the mixture was wet-milled using a ball mill until the average particle size was 30 μm. Thereafter, it was dried at 70°C in a ventilation dryer. The dry product was obtained as a lump. 70~
When crushed into 16 pieces, there is no powder and the viscosity is low.
It was depolymerized to a low viscosity product of 12.6 cps.

This material was dispersed in water according to the MFT measurement method, and the MFT of the dispersion was 27° C. or less, the undispersed rate was 0.0%, and the dispersibility and film forming properties showed good results.

In addition, when a tablet coated with 12% of this product was subjected to a disintegration test according to the 10th edition of the Japanese Pharmacopoeia according to the coating test method, there was no change in the test with the first liquid, and it took 8 to 10 minutes in the test with the second liquid. It was found that the product completely disintegrated and was found to be a good water-based enteric coating agent.

Example 2 50 parts of water was added to 50 parts of depolymerized CMEC with a particle size of 1 to 2 mm and a water content of 50% obtained in Example 1, and the average particle size was adjusted to 10 μm using Mycolloider (manufactured by Tokushu Kika Kogyo Co., Ltd.). It was wet-milled until it became . Thereafter, it was dried at 70°C in a ventilation dryer to obtain depolymerized CMEC with a viscosity of 12.5 cps. 70~
The MFT of the dispersion, which was crushed into 16 meshes and dispersed in water according to the MFT measurement method, was 27°C or less, the undispersed rate was 0.0%, and the dispersibility and film-forming properties showed good results.

In addition, when a tablet coated with 12% of this product was subjected to a disintegration test according to the 10th edition of the Japanese Pharmacopoeia according to the coating test method, there was no change in the test with the first liquid, and it took 7 to 11 minutes in the test with the second liquid. It was found that the product completely disintegrated and was found to be a good water-based enteric coating agent.

Comparative Example 1 The depolymerized CMEC with a particle size of 1 to 2 mm and a water content of 50% obtained in Example 1 was dried at 70°C using a ventilation dryer without wet grinding, and the resulting lumps were dried.
The MFT of the dispersion liquid dispersed in water according to the MFT measurement method after being crushed and classified into 70 to 16 meshes is 70.
℃ or higher, and the undispersed rate was 13%, indicating that both dispersibility and film-forming properties were insufficient.

Example 3 Carboxymethyl group DS0.42, ethoxyl group
50 parts of CMEC with a DS of 2.10 and a viscosity of 13.1 cps was dissolved in 450 parts of an 80% aqueous methanol solution. After complete dissolution,
Methanol was distilled and recovered at normal pressure until the temperature in the system reached 98°C to precipitate CMEC. This material was suctioned and filtered using a hot nuttie, and further thoroughly washed with warm water at 70 to 80°C to obtain wet CMEC with a water content of 54%.

50 parts of water was added to 50 parts of this wet CMEC and wet milled using a ball mill until the average particle size was 20 μm. After that, dry in a ventilation dryer at 70℃ to remove the lumps.
Got CMEC.

Crush this into 70 to 16 mesh pieces and MFT
MFT of a dispersion in water according to the measurement method
The temperature was 32°C, the undispersed rate was 0.2%, and the dispersibility and film forming properties showed good results.

In addition, when a tablet coated with 12% of this product was subjected to a disintegration test according to the 10th edition of the Japanese Pharmacopoeia according to the coating test method, there was no change in the test with the first liquid, and it took 7 to 9 minutes in the test with the second liquid. It was revealed that the product completely disintegrated and became a good water-based enteric coating agent.

Comparative Example 2 Obtained in the same manner as in Example 3 except for drying without wet grinding in Example 3.
After crushing and classifying the CMEC lumps into 70 to 16 meshes, the MFT of the dispersion liquid dispersed in water according to the MFT measurement method was 70°C or higher, and the undispersed rate was 27%, showing excellent dispersibility and film-forming properties. Both were inadequate.

Example 4 50 parts of water was added to 50 parts of depolymerized CMEC with a particle size of 1 to 2 mm and a water content of 50% obtained in Example 1, and a vibration mill (manufactured by Chuo Kakoki Shoji Co., Ltd., Model B-1) was used. Wet milling was carried out until the average particle size was 4.0μ. Thereafter, the mixture was heated to 80°C and then suctioned through a hot Nutssie to obtain a CMEC cake with a solid content of 53%.

This material is dried at 70℃ in a ventilation dryer to reduce the viscosity.
A bulk CMEC depolymerized to 12.4 cps was obtained. This material was crushed into 70 to 16 meshes, and the MFT of the dispersion liquid dispersed in water according to the MFT measurement method was 27.
℃ or less, and the amount of undispersed matter was 0.0%, showing good results in both dispersibility and film-forming properties.

In addition, when tablets coated with 12% of this product were tested according to the 10th edition of the Japanese Pharmacopoeia according to the coating test method, there was no change in the test with the first liquid, and the test with the second liquid completely completed in 8 to 12 minutes. It was revealed that this product was a good water-based enteric coating agent.

Example 5 Carboxyethyl group DS0.50, ethoxyl group
Depolymerization treatment was carried out in the same manner as in Example 1 except that 50 parts of carboxyethyl ethyl cellulose (hereinafter abbreviated as CEEC) having a DS of 1.81 and a viscosity of 68 cps was used and 5 parts of 30% hydrogen peroxide solution was used. Next, everything was treated in the same manner as in Example 1 except that 5 parts of isopropyl alcohol was added, and the particle size was about 0.5 to 1 mm and the water content was 52.
% wet CEEC was obtained.

50 parts of water was added to 50 parts of this wet CEEC, and the mixture was wet-pulverized using a Mycolloider (manufactured by Tokushu Kika Kogyo Co., Ltd.) until the average particle size was 10 μm. Thereafter, it was dried using a spray dryer (manufactured by Okawara Kakoki Co., Ltd.) at a hot air temperature of 150°C to obtain a granular product.

The viscosity of the obtained granular CEEC is 13.7 cps, and the MFT of the dispersion of the 70 to 16 meshes dispersed in water according to the MFT measurement method is
At 27°C or lower, the amount of undispersed matter was 0.0%, showing good results in terms of dispersibility and film-forming properties.

In addition, when tablets coated with 12% of this product were subjected to a disintegration test according to the 10th edition of the Japanese Pharmacopoeia according to the coating test method, there was no change in the test with the first liquid, and the disintegration occurred in 10 to 12 minutes in the test with the second liquid. It became clear that the product completely disintegrated and became a good water-based coating agent.

Example 6 Hydroxypropyl methyl cellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.)
After dissolving everything under the same conditions as in Example 1 except that 50 parts was used, the process was carried out in the same manner as in Example 1 except that the depolymerization step was omitted and the amount of isopropyl alcohol added was 5 parts. Wet hydroxypropyl methylcellulose phthalate with a water content of 48% was obtained.

50 parts of water was added to 50 parts of this wet hydroxypropyl methylcellulose phthalate, and the mixture was wet-milled using a ball mill until the average particle size was 30 μm. Thereafter, it was dried in the same manner as in Example 1 using a ventilation dryer to obtain a dried block. (Viscosity 14.1cps) After crushing this lump into 70 to 16 meshes,
of a dispersion in water according to the MFT measurement method.
The MFT was 38°C, the undispersed rate was about 0.5%, and the dispersibility and film forming properties showed good results.

In addition, when a tablet coated with 12% of this product was subjected to a disintegration test according to the 10th edition of the Japanese Pharmacopoeia according to the coating test method, there was no change in the test with the first liquid, and it took 8 to 11 minutes in the test with the second liquid. It was found that the product completely disintegrated and was found to be a good water-based enteric coating agent.

Claims (1)

[Scope of Claims] 1. Easy water dispersibility characterized by producing a water-insoluble oxycarboxylic acid type cellulose derivative and separating it into solid and liquid from a water-containing solvent system, which is wet-pulverized without prior drying and then dried. A method for producing an oxycarboxylic acid type cellulose derivative. 2. The method for producing an easily water-dispersible oxycarboxylic acid type cellulose derivative according to claim 1, wherein the oxycarboxylic acid type cellulose derivative is carboxyalkyl methyl cellulose or carboxyalkyl ethyl cellulose. However, alkyl refers to an alkyl having 1 to 5 carbon atoms.