JP5503192B2 - Method for producing bioactive substance-containing particles - Google Patents

Description

  The present invention relates to a method for granulating a medicine, that is, a method for producing a bioactive substance-containing particle.

  Depending on the physiologically active substance, it may become chemically unstable by mixing and contacting with moisture, liquidity, temperature, and other materials, and decomposition, deactivation, etc. may occur (such a physiologically active substance is described below). Called "unstable substances"). Thus, when processing particles (granulation / coating, tableting, etc.) of a substance that becomes unstable under certain conditions, it takes a lot of time, labor, and cost to select conditions that do not affect the stability. Further, in order to keep the quality of the processed particles stable, a more complicated manufacturing method is required, and in order to satisfy the request, the productivity of the granulated product is extremely deteriorated and the processing cost is also increased.

Specific examples of the prior art, a method of manufacturing is disclosed a nuclear material blended with stabilizer chemically unstable substances by a conventional method (patent documents 1 and 2).
In addition, in the production of a nuclear material suitable for coating in the subsequent process, in order to prevent the quality deterioration of unstable drugs, only unstable substances or stabilizer powders are added without adding other granular materials. It is proposed to spray and add an aqueous solution in which the unstable substance is dissolved (Patent Document 3). However, when the unstable substance is unstable in water, it is inconvenient because the substance becomes unstable when dissolved in water.
In addition, the blending ratio of the physiologically active substance in the raw material is small. For example, a granulation operation in which the drug content in a 200 mg tablet is 5 to 30 mg and the additive is mixed with about 65% of the total weight of the tablet is performed. However, processing of particles containing additives requires a large amount of processing, requires a large amount of film agent and binder, and further requires a large processing apparatus.
The particles that require stabilization treatment are physiologically active substances that are the main agent , and after treatment with a high content, it is more reasonable to add other additives to the final treatment in the subsequent steps.
In Patent Document 4, primary granulation is performed using about 52 g (about 6.5 wt%) of HPC-L in solid content with respect to 800 g of acetaminophen, and a part of the granulated product obtained (300 g) In contrast, 371.3 g of the HPC-L solution wets the surface of the acetaminophen granulated product, and 300 g of acetaminophen powder is supplied almost quantitatively to adhere to the surface of the primary granulated product. . However, it is somewhat difficult to control the wet state of the core particles (primary granulated product), and the adhesion efficiency is poor when dry, and excessive wetting causes generation of coarse particles due to adhesion and aggregation of the core particles (primary granulated product). Connected.
Although it is described that depending on the raw material powder, it may be dispersed / suspended in the binder liquid, the inventors made a supplementary examination of the example, and as a result, the obtained granulated product was a core particle (primary granulation). Product) and raw material particles, and the geometric standard deviation (Non-Patent Document 1) ["D (84.1) / D (50)": σg] was found to be greater than about 1.4. . That is, there were fine particles having a particle diameter of 75 microns or less and particles larger than 300 microns, and irregularities derived from the raw material particles were also observed.
Further, Patent Document 5 describes an example of a jet fluidized bed, but the coating layer has a thin thickness of several microns, and a bitterness mask (dissolution delay of about 60 seconds in order not to feel bitterness in the oral cavity). ) Is effective but acid- and water-unstable substances such as rabeprazole sodium are deactivated if they do not retain acid resistance during retention in the stomach (generally referred to as 2 hours) To do. For this purpose, the enteric film agent is coated on the particle surface, but since the water-based enteric film agent is acidic, it penetrates during the coating operation and rabeprazole sodium is deactivated, so in the middle of the enteric film agent, It is essential to form a dense and homogeneous barrier layer. Further, if the surface is uneven, a thin portion is formed on the film, and the acid resistance becomes unstable. Therefore, there is a demand for smooth surface core particles with less unevenness.

Japanese Examined Patent Publication No. 7-68125 JP 2000-355540 A JP 2006-131548 A Japanese Patent No. 3354172 (heavy granulation of high drug content powder) Japanese Patent No. 3352059

Introduction to Powder Engineering, edited by Japan Powder Industrial Technology Association, published on April 10, 1995, pages 3 to 5 (1.1.3 Particle size distribution) Michitaka Suzuki, Journal of Powder Engineering, Vol. 27, 693-699 (1990)

  An object of the present invention is to provide a method for producing a granular material capable of stably holding a chemically unstable physiologically active substance over a long period of time by a simple method in terms of formulation operation. It is an object of the present invention to provide a granulated product for a solid preparation in which the elution rate of a physiologically active substance can be easily controlled.

As a result of intensive studies to solve the above problems, the present inventors have dissolved and sprayed an unstable substance in an aqueous solution of a stabilizer on a stabilizer or additive particle in a jet flow state. Thus, it was found that a stable granulated product can be obtained.
Further, the geometric standard deviation of the granulated product produced by the above granulated product production method is in the range of 1.0 to 1.4, and the fractal dimension (non-patent document 2) is in the range of 1.0 to 1.2. It was found that a tablet with easy-to-control dissolution rate can be obtained by compression molding.
Therefore, further studies were made to complete the present invention.

(1) A seed particle comprising an additive is charged into a spouted fluidized bed granulator and sprayed with a solution in which a chemically unstable physiologically active substance is dissolved or suspended in an aqueous solution of a stabilizer while maintaining a fluid state. In the method for producing a granulated product, a liquid containing 2 to 18 parts by weight of a physiologically active substance and a stabilizer with respect to 1 part by weight of seed particles charged in the spouted fluidized bed apparatus is spouted fluidized bed granulated. Sprayed as homogeneous and fine droplets with a discharge speed of the compressed gas body at the nozzle tip of the apparatus of 300 m / second or more and a discharge liquid speed of 1 m / second or less, with an average particle diameter of 150 microns or less and a geometric standard deviation [“ D (84.1) / D (50) ": σg] is a method for producing a granulated product having a value of 1.1 to 1.5.
(2) A single layer or a plurality of layers in a spouted fluidized bed granulator using a mixture of fine particles in a water-based binder or polymer film agent liquid on the surface of the granulated product obtained by the method of (1) The manufacturing method of the granulated material which makes geometric standard deviation ["D (84.1) / D (50)" :( sigma) g] 1.1-1.5 particle | grains by giving the barrier layer film of a layer.
(3) The liquid which mix | blended 1 type or multiple types of aqueous polymer film agent with the elution control film agent liquid which does not mix | blend a plasticizer on the surface of the granulated material obtained by the method as described in (1) or (2) Is added by spraying, the average particle diameter is 200 microns or less, and the geometric standard deviation [“D (84.1) / D (50)”: σg] is 1.1 to 1.4. A method for producing a granulated product having a smooth particle having a dimension of 1.0 to 1.2.
(4) The granulated product according to any one of (1) to ( 3 ), wherein the stabilizer is an alkaline substance, and the chemically unstable physiologically active substance is a substance that is unstable under neutral or acidic conditions. Manufacturing method.
(5) The stabilizer is an alkali metal or alkaline earth metal hydroxide, oxide or carbonate, and the chemically unstable physiologically active substance is a proton pump inhibitor (1) to ( 4 The manufacturing method of the granulated material in any one of.
(6) The stabilizer according to any one of (1) to ( 5 ), wherein the stabilizer is sodium hydroxide, potassium carbonate, sodium carbonate, or potassium hydroxide, and the chemically unstable physiologically active substance is rabeprazole sodium. A method for producing a granulated product.
(7) The manufacturing method of the granulated material in any one of (1)-( 6 ) whose stabilizer amount in the aqueous solution of a stabilizer is 0.01 to 10 weight% with respect to a granulated material.
(8) The manufacturing method of the granulated material in any one of (1)-(7) whose density | concentration of the stabilizer in the aqueous solution of a stabilizer is 0.1 to 33 weight%.
(9) The method for producing a granulated product according to any one of (1) to ( 8 ), wherein the surface of the seed particles is subjected to stabilization treatment with a stabilizer.
(10) Seed particles are lactose, crystalline cellulose, corn starch, potato starch, partially pregelatinized starch, D-mannitol, sucrose, sucrose, glucose, light anhydrous silicic acid, calcium silicate, carboxymethyl starch sodium, cloth The manufacturing method of the granulated material in any one of (1)-( 9 ) which is a particle | grains of povidone (cr-PVP) or a low substituted hydroxypropyl cellulose (L-HPC).
(11) The polymer compound of the water-based polymer film agent is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymer, aminoalkyl methacrylate polymer (E, RL, RS), methacrylic acid copolymer (L, LD, S) methyl copolymer dispersion of ethyl acrylate-methacrylic acid, Metolose, hydroxypropylmethylcellulose phthalate, one selected from hydroxypropylmethylcellulose acetate succinate and the group consisting of ethyl cellulose compound or at two or more (3) - (10) The manufacturing method of the granulated material in any one.
(12) A normal tablet or an orally disintegrating tablet that is tableted by mixing the granulated product obtained by the method for producing a granulated product according to any one of (1) to ( 11 ) with another additive. Production method.

According to the present invention, there is provided a method for producing a granular material that can hold a chemically unstable physiologically active substance having an average particle size of 200 microns or less , for example , in a stable manner over a long period of time by a simple method for formulation operation. Can do. In addition, the method of the present invention can provide a granulated product for a solid preparation in which the elution rate of a physiologically active substance can be easily controlled.

It is a scanning electron micrograph (magnification 200 times) of the granulated material manufactured in Example 1-C of the present invention. It is a scanning electron micrograph (magnification 200 times) of the granulated material manufactured in Example 1-D of the present invention. It is a scanning electron micrograph (magnification 200 times) of the granulated material manufactured by Comparative Example 1-A of the present invention. It is a scanning electron micrograph (magnification 200 times) of the granulated material manufactured by Comparative Example 1-B of the present invention.

In implementing the present invention, while checking the proper flow state according to the particle diameter and the particle properties of charged particles in the jet fluidized bed apparatus (avoiding particularly excessive air volume), powder properties (particle size, which is a seed Select the spray mist diameter, liquid viscosity, etc. according to the shape, solubility, etc. Fine particle size particles while suppressing the agglomeration of larger particles when the discharge speed of the gas body (generally compressed air) at the nozzle tip is 300 m / sec or more and the discharge liquid speed is 1 m / sec or less. By performing an operation to promote adhesion and aggregation of the particles (main factor is adjustment of the mist diameter), the geometric standard deviation [“D (84.1) / D (50)”: σg] of the granulated product is 1.0 to The range is 1.5, more preferably 1.1 to 1.5.
In other words, if the size of the adhering binder droplet is larger than the size of the jet flowing particle, it adheres to nearby particles. This is due to the separation force caused by the kinetic energy of the particles and the combination of spray droplets Determined by balance with power. That is, when the separation force is larger than the binding force, the adhesion / aggregation of particles is suppressed, and when the separation force is smaller than the coupling force, the particles adhere / aggregate. However, even with the same droplet size, when the initial particle size is small, even if it contributes to adhesion / aggregation, if the particle size grows to a certain size, the separation force increases as the mass increases. Growth is suppressed, and as a result, a granulated product having a sharp particle size distribution is obtained.
Depending on the viscosity and adhesion of the liquid to be sprayed, the geometric standard deviation [“D (84.1) / D (50)”: σg] can be controlled by controlling the droplet diameter. I found what I could do for the first time .

In the present invention, the average particle diameter of the fine particles blended in the liquid constituting the barrier layer is preferably about 1/10 of the average particle diameter of the granulated product. By blending the fine particles, irregularities on the surface of the granulated product are reduced, and smooth particles can be obtained. When this is expressed by a fractal dimension, a granulated product having a smooth particle surface of 1.0 to 1.2 is obtained.
If the surface of the particles is uneven, a lot of film agent necessary for barrier properties and elution control is required. This is because the film thickness of the convex part becomes thin, so that the elution is accelerated. To ensure the film thickness of the convex part, excessive addition is made in the concave part. For this purpose, core particles having a smooth surface state are important.
A more preferable granulated product of the present invention has a geometric standard deviation [“D (84.1) / D (50)”: σg] within a range of 1.1 to 1.5, and a fractal dimension. Is within the range of 1.0 to 1.2.

The stabilizer in the present invention is a substance that can keep an unstable substance in a stable state under a certain chemical condition, for example, an alkaline substance, an alkaline substance against an unstable substance in a neutral or acidic region. An acidic substance can be mentioned for a substance that is unstable.
Examples of alkaline substances include alkali metal or alkaline earth metal hydroxides, oxides or carbonates, and specific examples include sodium hydroxide, magnesium oxide, potassium carbonate, sodium carbonate, or potassium hydroxide. It is done. Preference is given to sodium hydroxide.
The amount of the stabilizer used in the aqueous solution or suspension of the stabilizer is 0.01 to 10% by weight, preferably 0.05 to 7.5% by weight, based on the total weight of the granulated product. Preferably it is 0.1 to 5 weight%. The concentration of the stabilizer in the aqueous solution or suspension of the stabilizer is 0.1 to 33% by weight, preferably 0.5 to 25% by weight, more preferably 1 to 20% by weight.

When a chemically unstable substance is unstable under neutral or acidic conditions, examples of the substance unstable in the neutral or acidic region include proton pump inhibitors, and representative examples thereof include: Rabeprazole sodium is mentioned.
The amount of a chemically unstable substance in a solution in which an unstable substance is dissolved or suspended in an aqueous solution or suspension of a stabilizer is added to the additive particles. 0.5 to 95% by weight, preferably 1 to 90% by weight, more preferably 5 to 85% by weight, based on the total weight of the granulated product obtained by spraying the liquid in which the solution is dissolved or suspended .

The spouted fluidized bed granulator is composed of a fluidized bed main body, a rectifying plate, a blower, an intake filter, a heat exchanger, a spray device, a dust collector, a wind exhauster, and the like. The air supplied from the blower fan is cleaned by an air intake filter, heated by a heat exchanger, and sent to the device body through a rectifying plate.This hot air is used for seed particles made of additives charged in the device. By spraying as a binder a solution in which an unstable substance is dissolved in an aqueous solution of a stabilizer while maintaining a suspended state, that is, in a fluid state, the mist adheres to the surface of the seed particle , Through this binder mist, particle growth (granulation / coating) progresses gradually as adhesion / aggregation is repeated.

Additives used as seeds include lactose, crystalline cellulose, corn starch, potato starch, partially pregelatinized starch, D-mannitol, sucrose, sucrose, glucose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, calcium silicate Or excipient | fillers, such as carboxymethyl starch sodium, are mentioned. A part or all of these additives may be dissolved, dispersed, or suspended in the binder solution. Furthermore, these additives are preferably used after being subjected to stabilization treatment (surface modification) by a treatment method such as spraying a stabilizer solution on the surface thereof.

  In the granulation method of the present invention, stabilizer powder and additives are used as seeds for granulation. In this case, the average particle size is about 0.1 to 50 μm.

Examples of the polymer compound of the aqueous polymer film agent used in the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyvinyl alcohol copolymer. Hydroxypropyl methylcellulose, polyvinyl alcohol, and polyvinyl alcohol copolymer are preferred. Furthermore, you may mix | blend additives, such as talc.
The amount of these aqueous polymer film agents used is preferably 1 to 50% by weight, more preferably 3 to 30% by weight, based on the total weight of the tablet.
Additives in the preparation that can be used for the barrier layer coating, that is, the intermediate layer coating, include commonly used excipients, disintegrants, binders, flavoring agents, coloring agents, tonicity agents, etc. Other additives can be used as appropriate.

As a film agent for elution control, for example, aminoalkyl methacrylate copolymer (E, RS), methacrylic acid copolymer (L, LD, S), ethyl acrylate / methyl methacrylate copolymer dispersion, Metrols, hydroxypropyl methylcellulose phthalate, Well-known elution control film | membrane agents, such as a hydroxypropyl methylcellulose acetate succinate and an ethyl cellulose type aqueous dispersion, can be mentioned. These film agents may be used alone or in combination.
Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose, and partially pregelatinized starch.

By covering and concealing the particle surface with a stabilizer aqueous solution mist, decomposition and alteration can be prevented even when blended with additives such as other additives. In order to enhance the effect, it is possible to suppress the adsorption of moisture in the atmosphere by applying an intermediate layer coating containing a stabilizer. Next, by applying a film agent for elution control, such as an enteric coating, to the obtained particle surface, it is possible to prevent alteration or deactivation of unstable substances due to direct contact between the enteric film and the drug. You can also. Examples of enteric film agents include known ones such as methacrylic acid copolymer, cellulose acetate phthalate, and hydroxypropylmethyl / cellulose phthalate.
A stabilizer may be added to adjust the pH of the enteric film agent.

A) 56.0 g of calcium silicate having an average particle diameter of 31.0 μm was put into a spouted fluidized bed granulator (manufactured by Paulek: MP-01-SPC type), and 80.0 g of sodium hydroxide was added to 2160 g of purified water. The dissolved solution was sprayed with a solution (solid content concentration: 28.9% by weight) in which 800.0 g of rabeprazole sodium was dissolved to obtain a granulated product.
B: Barrier layer 1) 468.0 g of the obtained granulated product was put into a jet fluidized bed granulator, and talc was added to a solution obtained by dissolving 0.24 g of sodium hydroxide and 25.2 g of HPC-L in 1430.0 g of purified water. A liquid in which 151.04 g of 75.52 g titanium oxide was dispersed and suspended was sprayed to obtain a granulated product.
C: Barrier layer 2) To 720.0 g of the granulated product obtained above, 853.3 g of ethyl acrylate / methyl methacrylate copolymer dispersion (NE30D) (solid content: 256.0 g), ethyl cellulose aqueous dispersion 426. 7 g (solid content: 128.0 g) was added to 1024.0 g of purified water and mixed and stirred. Further, 96.0 g of light anhydrous silicic acid was added, mixed, stirred and dispersed (solid content concentration: 20% by weight). Was added by spraying to obtain a granulated product.
D: Elution control layer) 180.0 g of the product obtained above was charged into a jet fluidized bed, 670.4 g of methacrylic acid copolymer LD (L30D-55) (solid content: 201.12 g), and ethyl acrylate / methacrylic acid A solution obtained by adding 670.4 g (solid content: 201.12 g) of methyl copolymer dispersion (NE30D) to 861.44 g of purified water, gently mixing and stirring, and further adding 47.76 g of glycerol monostearate (solid content concentration: 20.1% by weight) was added by spraying to obtain a granulated product.
The resulting granulated product was mixed with other additives and tableted to obtain an orally disintegrating tablet excellent in acid resistance and stability and having an oral disintegration time of about 50 seconds.

A) 56.0 g of calcium silicate having an average particle diameter of 31.0 μm was put into a spouted fluidized bed granulator (manufactured by Paulek: MP-01-SPC type), and 80.0 g of sodium hydroxide was added to 2160 g of purified water. The dissolved solution was sprayed with a solution (solid content concentration: 28.9%) in which 800.0 g of rabeprazole sodium was dissolved to obtain a granulated product.
B: Barrier layer 1) 468.0 g of the obtained granulated product was put into a jet fluidized bed granulator, and talc was added to a solution obtained by dissolving 0.48 g of sodium hydroxide and 50.4 g of HPC-L in 2788.0 g of purified water. A liquid in which 110.28 g and titanium oxide 330.84 g were dispersed and suspended was sprayed to obtain a granulated product.
C: Barrier layer 2) 480.0 g of the product obtained above, 720.0 g of ethyl acrylate / methyl methacrylate copolymer dispersion (NE30D) (solid component 216.0 g), 720.0 g of ethyl cellulose aqueous dispersion (solid content) : 216.0 g) was added to 912.0 g of purified water, mixed and stirred, and then 48.0 g of light anhydrous silicic acid was added, mixed, stirred and dispersed (solid content concentration: 20% by weight) by spraying. A granulated product was obtained.
D: Elution control layer) 240.0 g of the product obtained above was charged into a jet fluidized bed, 700.0 g of methacrylic acid copolymer LD (L30D-55) (solid content: 210.0 g), ethyl acrylate / methyl methacrylate 700.0 g of copolymer dispersion (NE30D) (solid content: 210.0 g) was added to 1420.0 g of purified water, mixed gently with stirring, and further added with 180.0 g of talc (solid content concentration: 20.0 weight) %) Was added by spraying to obtain a granulated product.
The resulting granulated product was mixed with other additives and tableted to obtain an orally disintegrating tablet excellent in acid resistance and stability and having an oral disintegration time of about 50 seconds.

A) 160.0 g of carboxymethyl starch sodium having an average particle size of 44.9 μm was charged into a spouted fluidized bed granulator (manufactured by Paulek: MP-01-SPC type), and 80.0 g of sodium hydroxide was added to 2160 g of purified water. A solution in which 800.0 g of rabeprazole sodium was dissolved (solid content concentration: 28.9% by weight) was sprayed on the solution dissolved in 1 to obtain a granulated product.
B: Barrier layer 1) 520.0 g of the obtained granulated product was put into a jet fluidized bed granulator, and talc was added to a solution obtained by dissolving 0.24 g of sodium hydroxide and 24.0 g of HPC-L in 1733.36 g of purified water. A liquid in which 127.88 g and 127.88 g of titanium oxide were dispersed and suspended was sprayed to obtain a granulated product.
C: Barrier layer 2) To 400.0 g of the product obtained above, 360.0 g of ethyl acrylate / methyl methacrylate copolymer dispersion (NE30D) (solid content: 180.0 g), 360.0 g of ethyl cellulose aqueous dispersion ( Solid content: 108.0 g) was added to 456.0 g of purified water, mixed and stirred, and then 24.0 g of light anhydrous silicic acid was added, mixed, stirred and dispersed (solid content concentration: 20% by weight) by spray addition. To obtain a granulated product.
D: Elution control layer) 320.0 g of the product obtained above was charged into a jet fluidized bed, 1400.0 g of methacrylic acid copolymer (L30D-55) (solid content: 420.0 g), ethyl acrylate / methyl methacrylate copolymer A dispersion (NE30D) (1400.0 g, solid content: 420.0 g) was added to purified water (1880.0 g), and the mixture was gently mixed and stirred, and then light anhydrous silicic acid (120.0 g) was added (solid content concentration: 20. 0% by weight) was added by spraying to obtain a granulated product.
The obtained particles were mixed with other additives and tableted to obtain an orally disintegrating tablet excellent in acid resistance and stability and having an oral disintegration time of about 50 seconds.

Comparative Example 1

A) A solution in which 800 g of acetaminophen (manufactured by Tyco Healthcare) was charged into a rolling fluidized bed apparatus (manufactured by Paulec: multiplex MP-01 type), and 51.2 g of HPC-L was dissolved in 588.8 g of purified water. Was added by spraying to obtain a granulated product.
B) 300 g of the obtained granulated product was put into a rolling fluidized bed apparatus, and 300 g of acetaminophen and 60.0 g of HPC-L were dissolved and dispersed in 1640.0 g of purified water (solid content concentration: 18% by weight) ) Was added by spraying to obtain a granulated product.

The granule produced in Examples 1-A, B, C and D and the granule produced in Comparative Examples 1-A and B were measured for particle diameter and shape, and the average particle diameter, geometric standard deviation, Fractal dimensions and circularity coefficients were calculated and are shown in Table 1.

  From Table 1, it can be seen that the granulated product according to the present invention has a sharp particle size distribution, little surface irregularities, and is nearly spherical.

  ADVANTAGE OF THE INVENTION According to this invention, the method of manufacturing the granular material which can hold | maintain a chemically unstable physiologically active substance stably over a long period of time by a simple method on formulation operation can be provided. In addition, the method of the present invention is suitable for the production of a granulated product for a solid preparation in which the dissolution rate of a physiologically active substance can be easily controlled, and can be used for the production of an orally rapidly disintegrating tablet for a medicine.

Claims (12)

Granulation in which seed particles consisting of additives are charged into a spouted fluidized bed granulator and sprayed with a solution in which a chemically unstable physiologically active substance is dissolved or suspended in an aqueous solution of a stabilizer while maintaining a fluid state. In the method for producing a product, a liquid containing 2 to 18 parts by weight of a physiologically active substance and a stabilizer is added to 1 part by weight of seed particles charged in the spouted fluidized bed apparatus. Sprayed as homogeneous and fine droplets having a discharge speed of a compressed gas body at the tip of 300 m / sec or more and a discharge liquid speed of 1 m / sec or less, an average particle diameter of 150 microns or less and a geometric standard deviation [“D (84 .1) / D (50) ”: σg] is 1.1 to 1.5. A single layer or a plurality of layers of barriers in a spouted fluidized bed granulator using a liquid obtained by blending fine particles in a water-based binder or polymer film agent liquid on the surface of the granulated product obtained by the method of claim 1 A method for producing a granulated product in which a geometric standard deviation [“D (84.1) / D (50)”: σg] is 1.1 to 1.5 by applying a layer coating. Spray-adding a liquid in which one or a plurality of water-based polymer film agents are mixed with an elution control film agent liquid not containing a plasticizer to the surface of the granulated product obtained by the method according to claim 1 or 2. The average particle size is 200 microns or less, the geometric standard deviation [“D (84.1) / D (50)”: σg] is 1.1 to 1.4, and the fractal dimension is 1.0. The manufacturing method of the granulated material which makes the particle | grains of -1.2 smooth. The method for producing a granulated product according to any one of claims 1 to 3 , wherein the stabilizer is an alkaline substance, and the chemically unstable physiologically active substance is a substance which is unstable under neutral or acidic conditions. Hydroxide stabilizing agent is an alkali metal or alkaline earth metal, an oxide or carbonate, in any one of claims 1-4 chemically unstable physiologically active substance is a proton pump inhibitor The manufacturing method of the granulated material of description. The stabilizer is sodium hydroxide, potassium carbonate, sodium carbonate or potassium hydroxide, and the chemically unstable physiologically active substance is rabeprazole sodium. Production method. The method for producing a granulated product according to any one of claims 1 to 6 , wherein the amount of the stabilizer in the aqueous solution of the stabilizer is 0.01 to 10% by weight based on the granulated product. The method for producing a granulated product according to any one of claims 1 to 7, wherein the concentration of the stabilizer in the aqueous solution of the stabilizer is 0.1 to 33% by weight. The method for producing a granulated product according to any one of claims 1 to 8 , wherein the surface of the seed particles is subjected to stabilization treatment with a stabilizer. Seed particles are lactose, crystalline cellulose, corn starch, potato starch, partially pregelatinized starch, D-mannitol, sucrose, sucrose, glucose, light anhydrous silicic acid, calcium silicate, carboxymethyl starch sodium, crospovidone (cr -PVP) or low substituted hydroxypropyl cellulose (L-HPC) particles. The method for producing a granulated product according to any one of claims 1 to 9 . The polymer compound of the water-based polymer film agent is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymer, aminoalkyl methacrylate polymer (E, RL, RS), methacrylic acid copolymer (L, LD, S), acrylic acid ethyl methyl methacrylate copolymer dispersion, Metolose, hydroxypropylmethylcellulose phthalate, according to any one of claims 3-10 one selected from the group consisting of hydroxypropylmethylcellulose acetate succinate and ethylcellulose compounds or at two or more A method for producing a granulated product. Granules usual production method of a tablet or orally disintegrating tablet tabletting is mixed with granules of other additives obtained by the method according to any one of claims 1 to 11.

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