JPS62132B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing granules. More specifically, the present invention relates to a method for producing granules with highly uniform particle size.

Conventionally, for example, in the pharmaceutical field, the method for manufacturing granular digestive enzymes involves mixing digestive enzyme drugs, excipients, etc., kneading them in a suspended state, granulating, drying, and pulverizing them. A method of sieving to obtain only a certain range of granules is known.

However, when using such a method, it is difficult to obtain particles with a relatively uniform particle size, and therefore,
The yield of granular products is low because it is necessary to make the particle size uniform through sieving, and for example, in the case of the digestive enzymes mentioned above, the product yield is currently only around 70 to 80% at most. It is.

Furthermore, in the case of the above-mentioned digestive enzymes, they generally consist of gastric-soluble digestive enzyme drugs and enteric-coated digestive enzyme drugs that are made into different granules and then mixed together to form a product. Differences in particle size, specific gravity, and shape of these two particulates undesirably result in promoting separation of these two particulates.

Therefore, the present inventors have improved the above-mentioned drawbacks and produced 98 to 99% of granules with uniform particle size and shape.
As a result of intensive research in order to provide a method for manufacturing with a high yield (high yield) reaching The inventors have discovered that the above objectives can be fully achieved and have arrived at the present invention.

That is, in the present invention, non-toxic carbohydrate crystal fine particles that exhibit no medicinal efficacy are rotated by centrifugal force, and the fine particles are coated with carbohydrates of the same type or different type as the carbohydrates in the fine particles, thereby forming a convex spherical nucleus as a whole. This is a method for producing granules, which comprises obtaining a drug, and then coating the drug component on the core agent while rotating the core agent by centrifugal force.

A method in which fine powder produced with or without a nucleating agent acts as a nucleating agent, is rotated by centrifugal force, and is coated with a coating component to granulate it is, for example, a centrifugal method. It is known that this can be done using a granulator known as a fluidized coating granulator.

However, in this case, there is no known method of using a generally convex spherical nucleating agent as the nucleating agent.

The above-mentioned centrifugal fluid coating granulator is a bucket-shaped granulator as a whole, in which the bottom of the inner mold, which rises somewhat along the inner wall surface, rotates, and during granulation it is circular. The bottom of the mold is rotated, and the coating component (active ingredient) containing the glue is slowly dropped from above, either by charging a nucleating agent therein in advance or without charging the nucleating agent, to form the nucleating agent. Alternatively, a powder obtained by agglomerating and growing the naturally produced coating components is used as a nucleating agent, and the coating components are gradually attached thereon to grow and granulate particles.

According to the above-mentioned granulation method using this granulator, relatively spherical or elliptical granules can be produced, but when a nucleating agent is not used, particularly fine particles with a wide particle size distribution can be produced. There is a disadvantage that a large amount of granular material with many bodies is easily generated.Also, even when a nucleating agent is used, the nucleating agent is generally a fine powder and is crystalline, so It is difficult to coat uniformly, and especially when producing relatively small granules, there is a drawback that granules with a portion of the nucleating agent covered on the surface are likely to be produced with low product value.

However, when using a spherical nucleating agent that has an arbitrary cross-sectional shape such as a circular or elliptical shape and is convex as a whole, the above-mentioned fine powder in which only the coating components aggregate and grow is generated. In addition, since the nucleating agent used has a spherical shape, it is easy to obtain one with a uniform shape and particle size.
Therefore, it is possible to uniformly complete the coating of the coating component and obtain granules with uniform particle size, and moreover, granules with small product value in which a part of the nucleating agent used is exposed on the surface are hardly produced. I understood.

Any method may be used to produce the generally convex spherical nucleating agent used in the present invention, but the method may include mechanically crushing solid crystals or crystallizing solid microcrystals as described above. Since this is difficult to obtain, it is necessary to devise ways to manufacture spherical objects.

As described above, the present invention is a method of granulating a nucleating agent by coating it with a coating component while rotating it by centrifugal force. Therefore, in producing the nucleating agent as described above, , it is convenient to apply this method.

That is, a method of producing a mechanically pulverized solid material is rotated by centrifugal force, and a mixed coating component of a finer pulverized material, which is the same as or different from the above-mentioned solid component, and a sizing agent is adhered thereto and granulated. It is. According to such a method, a part of the surface of the initially mechanically pulverized material may be exposed, but a convex granular material is obtained as a whole. Since this material is used as a nucleating agent and is completely included in the product granules, there is no problem with the part of the surface being exposed as described above. There is an advantage that a generally convex spherical nucleating agent suitably used as the nucleating agent of the invention can be produced in high yield. Specifically, for example, a fine powder of crystals such as lactose or granulated sugar (e.g., 32 to 42 mesh) is put into a centrifugal fluid coating granulator and rotated by centrifugal force, while forming a sizing agent. For example, by using polyvinylpyrrolidone and coating it with lactose, granulated sugar, etc., which is even more finely powdered than the above-mentioned finely ground material, a spherical core agent having a convex shape as a whole (for example, 24 to 32 mesh) is obtained.
can be produced at a yield of about 96 to 99% at a desired particle size.

The spherical nucleating agent having a convex shape as a whole produced in this way can be suitably used as a nucleating agent in the method of the present invention. In particular, the nucleating agent is made of non-toxic lactose or granulated sugar that does not exhibit medicinal efficacy as described above. If it is a carbohydrate such as sucrose or an inorganic mineral salt such as calcium phosphate, it can be administered to animals including humans.
Since this can be used as a nucleating agent and a medicinal ingredient can be used as a coating component, it is desirable as a nucleating agent-forming component for producing granular drugs with uniform particle size.

Therefore, when producing a nucleating agent consisting of the above-mentioned ingredients, by rotating non-toxic carbohydrate crystal particles with no medicinal effect by centrifugal force, the carbohydrate crystals are placed on the fine particles of the same kind or with the carbohydrate that is the constituent of the fine particles. It has been found that when coating different types of carbohydrates, it is desirable to have a spherical nucleating agent that not only has a uniform particle size but also has a relatively uniform specific gravity and has a convex shape as a whole.

The method of the present invention is carried out by coating the coating component on the nucleating agent and granulating it to a larger particle size while rotating the generally convex spherical nucleating agent preformed as described above by centrifugal force. .

Therefore, by selecting the nucleating agent component and the coating component, granules can be manufactured according to the field of application. For example, granular materials, preferably granular materials with uniform particle size, can be used in digestive enzymes, antibiotics, medicines such as anti-inflammatory analgesics, fertilizers, animal feed, and certain confectionery, seasonings, and recreational foods. be.

The method for producing granules according to the method of the present invention will be specifically described as follows.

A predetermined amount of the generally convex spherical nucleating agent produced as described above is put into a centrifugal fluid coating granulator, and while this spherical nucleating agent is rotated by centrifugal force (by rotation of the rotor), At the same time, the air flow blown out from between the side wall and the rotating body (slit) of the centrifugal fluid coating granulator is sucked upward to a controlled height, and a spray gun (for example, For example, use a pen type spray gun (0.5 m/mφ) to spray syrup made by appropriately mixing sugar and water, water alone, or low boiling point substances such as methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc. In a single solvent or a mixed solvent such as an organic solvent or water,
For example, a solution (coating liquid) in which an organic polymer such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. By carrying out the operation of introducing the coating powder from the coating powder inlet located at the coating powder inlet and adhering it to the wet spherical nucleating agent for a certain period of time, it is possible to produce granules with a desired particle size at a yield of about 97 to 99%. It can be done. In the above method, the rotation of the spherical nucleating agent, blowing up with air, spraying of the coating liquid, and charging of the coating powder are generally performed simultaneously in a steady state, but in some cases, they may be performed intermittently. Good too. Machine operating conditions such as spray gun air pressure, air volume, rotor rotational speed and temperature, air volume from the slit, air pressure and air temperature, type and amount of coating powder, type and concentration of coating liquid, etc. The base material conditions can be easily determined by repeated tests depending on the target product, and for example, these specific operating conditions are as described in the examples. .

The object produced by the method of the present invention is to use a preformed, generally convex spherical nucleating agent, and to coat the coating component thereon while rotating it by centrifugal force. Therefore, it is clear from the purpose of the present invention that the type of object does not matter, and for products requiring a relatively uniform coating with uniform particle size, for example, It extends to.

In a preferred embodiment of the present invention, in view of the characteristics and objects of the present invention, the pre-formed, generally convex spherical core agent is formed from a non-toxic component that does not exhibit medicinal efficacy; The generally convex spherical core agent is made of non-toxic carbohydrates or inorganic mineral salts that exhibit no medicinal efficacy, and more preferably, the preformed generally convex spherical core agent exhibits no medicinal efficacy. A mode in which a non-toxic carbohydrate crystal fine particle that does not exhibit a chemical reaction is rotated by centrifugal force, and a generally convex spherical nucleating agent is coated on the fine particle with a carbohydrate of the same type or a different type as the carbohydrate of the fine particle. be.

Hereinafter, the method of the present invention will be explained in detail with reference to Examples. These Examples are illustrative examples in a limited field, and the present invention is not limited thereto.

Example 1 (1) Centrifugal fluid coating granulator (inner volume approx. 10
) was used to produce a generally convex spherical nucleating agent (basic granules) under the following conditions.

Operating conditions of centrifugal fluid coating granulator: Spray gun pen type 0.5m/mφ Spray air pressure 1.5~2.0Kg/cm ² Spray air volume 35~40/min Rotor rotation speed 150~170r.pm Slit air volume 150 /min Slit air temperature 50-70℃ Base materials used for base granule production (four levels below): (1) Fine powder nucleating agent Lactose 32-42 mesh 2.5Kg Coating powder Lactose 200 mesh 2.5Kg Coating liquid 1% polyvinylpyrrolidone aqueous solution 1.2 (2) Fine powder nucleating agent Lactose 32-42 mesh 2.5Kg Coating powder Cornstarch 200 mesh 2.5Kg Coating liquid 1% polyvinylpyrrolidone aqueous solution 1.2 (3) Fine powder nucleating agent Granium sugar 32-42 mesh
2.5Kg Coating powder Lactose 200 mesh 2.5Kg Coating liquid 1% polyvinylpyrrolidone aqueous solution 1.2 (4) Fine powder nucleating agent Granium sugar 32-42 mesh
2.5Kg Coating powder Corn starch 200 mesh 2.5Kg Coating liquid 1% polyvinylpyrrolidone aqueous solution 1.2 Using the above operating conditions and base material, put the entire amount of fine powder nucleating agent into a centrifugal fluid coating fluidizer, and blow air through the slit while rotating the rotor. The fine powder nucleating agent is blown up by air and rotated as a whole by centrifugal force, and the coating powder and coating liquid are gradually added thereto, and the coating liquid is adhered onto the fine powder nucleating agent to cover the coating powder. I forced it. As a result, the fine nucleating agent had sharp angular parts because it was a crystalline fine powder, but the base granules produced as described above were all convex spherical nucleating agents with 20 to 36 meshes. (yield 98%).

In addition, at the level of (4) above, the coating liquid was replaced with 1% polyvinylpyrrolidone aqueous solution, 3% polyvinylpyrrolidone ethanol solution, 3% polyvinylpyrrolidone isopropanol solution, 30% polyvinylpyrrolidone ethanol solution, 30% polyvinylpyrrolidone isopropanol solution, 1 A similar experiment was conducted using a 1% hydroxypropyl cellulose ethanol solution and a 1% hydroxypropyl cellulose isopropanol solution (however, the slit air temperature was 25 to 30°C).
Almost the same results as above were obtained.

(2) Using the base granules produced as described above, granules (gastric granules) were produced using a centrifugal fluid coating granulator under the following conditions.

Operating conditions of centrifugal flow coating granulator: Spray gun Pen type 0.5m/mφ Spray air pressure 1.5-2.0Kg/cm ² Spray air amount 35-40/min Rotor rotation speed 150-170r.pm Slit air amount 100/min Slit Air temperature: 25-30℃ Base material used for producing gastric granules: Spherical core with a convex shape as a whole (standard (1) above) 1.2Kg Coating powder gastric soluble digestive enzyme (100 mesh) 2.25Kg Coating liquid 3 % polyvinylpyrrolidone isopropanol solution 1 The actual production was carried out according to the method (1) of Example 1 above. The obtained gastric granules were generally convex spherical particles, and the entire surface of the spherical nucleating agent used was coated with the coating powder, and no spherical nucleating agent was seen forming the outer surface. Ta. Its size is 16 to 32 meters (yield
97%).

In addition, the above coating solution was replaced with 3% polyvinylpyrrolidone ethanol solution, 30% polyvinylpyrrolidone isopropanol solution, 30% polyvinylpyrrolidone ethanol solution, 1% hydroxypropyl cellulose isopropanol solution, and 1% hydroxypropyl cellulose ethanol solution, and the same as above. When gastric granules were produced using the same method, excellent results almost the same as those described above were obtained.

Comparative Example 1 This comparative example describes the case where gastric granules were produced using the fluidized coating granulator used in Example 1 and using finely crystalline lactose as a nucleating agent as it was.

Operating conditions of centrifugal flow coating granulator: Spray gun Pen type 0.5m/mφ Spray air pressure 1.6Kg/cm ² Spray air amount 30/min Rotor rotation speed 160r.pm Slit air amount 100/min Slit air temperature 20 to 25℃ Base materials used for gastric granule production: Crystal fine powder nucleating agent Lactose 35-40 mesh 1.2Kg Coating powder Gastric soluble digestive enzyme agent (200 mesh) 2.25Kg Coating liquid 30% polyvinylpyrrolidone isopropanol solution 700ml The above experiment was carried out in Example 1 above. However, the obtained gastric granules were found to be due to the fact that the crystal fine powder nucleating agent used was not a convex spherical granule as a whole, but had some acute angles. Therefore, a part of the nucleating agent was exposed on the surface, making it difficult to use as a product.

Example 2 Intestinal granules were produced in the same manner as in Example 1 (1) under the following conditions using a centrifugal fluid coating granulator.

Operating conditions of centrifugal fluid coating granulator: Spray gun Pen type 0.5m/mφ Spray air pressure 1.5~2.0Kg/cm ² Spray air amount 35~40/min Rotor rotation speed 150~170r.pm Slit air amount 100/min Slit Air temperature: 25-35°C Base material used for producing intestinal granules: Overall convex spherical core agent (level (4) of Example 1 (1) above) 0.6Kg Coating powder enteric-coated digestive enzyme agent ( 200 mesh) 1.334Kg Coating liquid 3% polyvinylpyrrolidone isopropanol solution 1.8 The obtained intestinal granules were convex spherical particles as a whole, and the entire surface of the spherical nucleating agent used was coated with the coating powder, resulting in a spherical shape. No nucleating agent was observed forming the outer surface. The size was 16 to 32 meshes (yield 97.5%).
In addition, the above coating solution was replaced with 3% polyvinylpyrrolidone ethanol solution, 30% polyvinylpyrrolidone isopropanol solution, 30% polyvinylpyrrolidone ethanol solution, 1% hydroxypropyl cellulose isopropanol solution, and 1% hydroxypropyl cellulose ethanol solution, and the same as above. When intestinal granules were produced using
Almost the same excellent results as above were obtained.

In addition, when the intestinal granules obtained in the above experiment were tested according to the Japanese Pharmacopoeia No. 1 General Test Method Section 33 Disintegration Test Method, all intestinal granules disintegrated within 3 minutes.

Example 3 The intestinal granules obtained in Example 2 above were coated with an enteric coating that was poorly soluble in the stomach according to the method (1) of Example 1.

The experimental conditions are as follows.

Centrifugal flow coating granulator: Spray gun Pen type 0.5m/mφ Spray air pressure 1.5-2.0Kg/cm ² Spray air amount 35-40/min Rotor rotation speed 150-170r.pm Slit air amount 400/min Slit air temperature 25 ~30℃ Base material used for enteric coating: Intestinal granules 1.5 kg Coating liquid (methylene chloride/ethanol mixed solvent solution containing hydroxypropyl methyl cellulose phthalate as the main coating component) 6 The enteric coating coated intestinal granules obtained were approximately It was completely coated (yield 100%), and when tested according to the Japanese Pharmacopoeia General Test Method Section 33 disintegration test method, it disintegrated within 3 minutes after passing the test for 60 minutes.

Claims (1)

[Claims] 1. While rotating non-toxic carbohydrate crystal fine particles that do not exhibit medicinal efficacy by centrifugal force, the fine particles are coated with carbohydrates of the same type or different type as the carbohydrates in the fine particles to obtain a spherical nucleating agent having an overall convex shape, and then While rotating the obtained nucleating agent by centrifugal force,
A method for producing a granular material, which comprises coating the core with a drug component.