JP2000296322A - Method and device for fluidizing granular or powdery body - Google Patents

Abstract

PROBLEM TO BE SOLVED: To shorten a treating time while suppressing the generation of lump particles. SOLUTION: One or plural spray nozzles 8 for spraying a spray soln. in mist-like by spray air are provided in a treating chamber 4a. The spray nozzle 8, enables a high volume soln. injection of >=700 NL/min spray air flow rate and 360 g/min spray soln. flow rate per one spray nozzle. The treating time per one batch can be shortened compared with the conventional method while suppressing the generation of the lump particles by executing high concn. soln. injection and the high volume soln. injection by using the high volume spray nozzle 8.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method and an apparatus for fluidizing a granular material, which sprays a spray liquid onto a particle group in a fluidized state to form a coating layer on the surface of the particle.

[0002]

2. Description of the Related Art For example, in the field of manufacturing foods, pharmaceuticals, agricultural chemicals, etc., many studies on a drug release control system (drug delivery system) have been made. In particular, in oral dosage forms, granules show no difference in solids in gastric emptying rate and absorbability compared to tablets, and are hardly affected by meals. In view of this, granules are used for oral administration, granules are mixed with tablets, and capsules are filled with granules in capsules.

[0003] As for granules, Japanese Patent Application Laid-Open No. 2-179331 proposes a method of spraying a dispersion of low-substituted hydroxypropylcellulose onto core granules to obtain nucleated granules. Granules obtained by this method have high strength and excellent disintegration.

[0004] Also, European Patent Publication No. 04528 is disclosed.
62A2 is composed of at least 50% by weight of microcrystalline cellulose and has an average particle diameter of 100 to 10%.
Disclosed are spherical granules obtained by spraying a powder containing an active ingredient onto 00 μm and inert spherical core particles and spraying a solution or dispersion containing a binder or an excipient.

[0005] Granules obtained by these methods are characterized in that most of the particle diameter is 500 µm or more.
Further, the granules have a large and uniform particle diameter. Therefore, when the elution control substrate is coated to control the elution of the drug, the dispersion of the coating is small and advantageous. However, since the particle size is large, not only is the dispensing property inferior, but also when added to tablets and capsules, the amount of granules to be added varies widely. Furthermore, for the dosage form of granules, a particle size test and a disintegration test are required in the section of "11th Revised Japanese Pharmacopoeia (hereinafter sometimes referred to as Japanese Pharmacopoeia) / General Rules for Preparation 5 Granules". It is not easy to formulate drug release control that satisfies those requirements.

[0006] On the other hand, powders (fine granules) are not regulated by the disintegration test of the Japanese Pharmacopoeia, and have a small particle size of 500 µm or less, so that they have excellent dispensing properties as compared with granules, and are incorporated into tablets and capsules. In this case, the variation in the amount of addition becomes small. However, in powders having a small particle size,
It is not easy to precisely control the release of the drug.

[0007] Regarding powders, Japanese Patent Application Laid-Open No. 5-92918 discloses that a fine-grained nucleus contains at least one core together with a water-soluble polymer.
Coated with a kind of physiologically active substance, and the particle size is substantially 500μ.
It has been proposed to obtain m or less nucleated powders. This nucleated powder has an advantage that the release of a drug can be controlled with relatively high accuracy even if the powder has a small particle size.

[0008]

SUMMARY OF THE INVENTION Nuclear particles in a flowing state include:
Fine particles produced by spraying a spray liquid containing a main ingredient etc. to form a coating layer are more spherical than the fine particles produced by extrusion molding, stirring granulation, etc. It is excellent in terms of smoothness, particle size distribution, etc., so that it is possible to form a coating layer of uniform thickness,
As a result, there are many advantages in product quality (elution, specific solution, content uniformity). However, on the other hand, the processing time per batch is long, aggregates are easily formed, the yield is poor, and the variation in each operating condition affects the quality.
There is a problem in industrialization, and particularly, a long processing time per batch has been a major problem in terms of productivity.

Therefore, the present invention aims at shortening the processing time while paying attention to the stabilization of product quality, thereby achieving an improvement in productivity.

[0010]

In order to improve the productivity, it is necessary to increase the spraying capacity per unit time (high-concentration injection, high-volume injection), but it contains component substances (solid content). The spray liquid mist not only adheres to and coats the surfaces of the core particles, but also acts as a liquid bridge between the particles. Therefore, an increase in the spraying ability (scale-up) causes the generation of aggregates due to aggregation of the particles. It can be a cause. The generation of aggregates leads to a decrease in product quality and a decrease in yield. Therefore, the increase in spraying capacity needs to be optimized under conditions that do not cause aggregation. In particular, the coating operation takes several times or more the time of a normal granulation operation, and there are many operation parameters. Therefore, there is a concern that a large amount of time is required for optimization design for scale-up.

Therefore, first, from the analysis of the mechanism of the generation of aggregates in the fluidized-granulation coating process, the formulation of the spray liquid, the concentration conditions and all the operating conditions were changed to the thermal equilibrium coefficient RW and the spray liquid mist diameter (maximum mist diameter). The following examination was performed by reducing the results to two parameters. Here, the thermal equilibrium coefficient RW is the injection amount Lp per unit time excluding the solids (component substances) in the spray injection with respect to the thermal equilibrium state between the fluidizing air in the processing container and the spray injection. Is divided by the maximum theoretical moisture evaporable amount Lt per unit time, and is calculated by the following equation. Thermal equilibrium coefficient RW
Indicates a dry / wet state inside the processing container, and indicates that the smaller the RW, the more the inside of the processing container is dry.

Thermal equilibrium coefficient RW = Lp / Lt Lp: Injection rate (excluding solid content) [kg / min] Lt: Maximum theoretical water evaporation per unit time [kg / m]
in] Lp = F (1−α / 100) Lt = Q (Cin · Tin−Cout · Tout) / Δ
H Q: fluidizing air flow rate [kg dryair / min] Tin: fluidizing air temperature [° C.] Tout: exhaust temperature [° C.] C: specific heat [Kcal / ° C./kg dryair] ΔH: latent heat of vaporization [kcal / kg dryair] F: Spray liquid flow rate [kg / min] α: Solid content concentration (%) In general, the exhaust temperature is an index indicating the dry / wet state inside the processing container. FIG. 4 shows the relationship between the exhaust temperature and the aggregate generation rate. However, exhaust temperature is not an absolute index,
If the supply air temperature, the supply air humidity, and the supply air volume are different, the relationship shown in FIG. 4 is different. Therefore, consideration was made using the thermal equilibrium coefficient RW as an index.

FIG. 5 shows a case where a coating treatment is performed using a fluidized-granulation apparatus and a tumbling fluidized-granulation apparatus (a type in which a blade is provided on a rotating disk: tangential spray method).
Thermal equilibrium coefficient R when coating is performed using
The relationship between W and the amount of aggregate generation is shown. Comparing the two, at the same thermal equilibrium coefficient RW (the same dry / wet state in the processing vessel), the latter produces a smaller amount of aggregates, and in the latter case, the larger thermal equilibrium coefficient RW (the It is understood that the amount of aggregates is small and stable coating treatment is performed. This is considered to be influenced by the spray method and the size of the shear by the rotating disk. It was also found that there was a critical point of the thermal equilibrium coefficient RW at which the amount of aggregates increased. In the latter case, the amount of aggregates is small when RW = 0.7 or less, but the amount of aggregates is sharply increased when RW = 0.7 or more. In this test, in the latter case (rolling fluidized granulation coating), 0.5 ≦ RW ≦ 0.7
Within the range, it was confirmed that the amount of aggregate generated was small and stable treatment was performed.

FIG. 6 shows the relationship between the gas-liquid ratio (spray air flow rate / spray liquid flow rate): (NL / Kg)} and the aggregation rate. The agglomeration rate is 35% for particles having a particle diameter of 500 μm or more.
It was represented by the weight fraction of particles of 5 μm or more. Even if the inside of the processing container is in a sufficiently dry state (tested under the condition of thermal equilibrium coefficient RW = 0.6), if the gas-liquid ratio is small (gas-liquid ratio is 4000 or less), the maximum mist diameter becomes large and It was found to happen. Regarding the generation of aggregates, it has been reported that even a coarse mist of only about 1% can generate tens of percent of aggregates. Also, depending on the viscosity of the spray liquid, aggregates have a particle size of about nucleus particles. It has also been reported that it is caused by droplets having a mist diameter of 0.6 times or more.

In the present specification, “particle size” means
It refers to the particle size as measured by using a sieve having a given size aperture. For example, the case of passing through a sieve having an opening of 500 μm is referred to as “particle diameter of 500 μm or less”, and the case of remaining on a sieve having an opening of 500 μm is referred to as “particle diameter of 500 μm or more”.

Next, based on the results of the above basic study,
A study was conducted to increase the productivity after scale-up under conditions that do not produce aggregates.

FIG. 7 shows the relationship between the type of spray liquid and the liquid viscosity, and FIG. 8 shows the relation between the type and concentration of the spray liquid and the maximum mist diameter. When the spray liquid is an aqueous solution (dispersion, suspension, or solution) and a water-soluble polymer such as hydroxypropylcellulose (HPC) is used as a binder, its grade (M, L / M, L, It has been found that the viscosity differs depending on the SSL), and that the lower the viscosity, the higher the solid content can be for the same maximum mist diameter. Therefore, while increasing the solid content to increase the processing capacity, downsizing the processing equipment and shortening the processing time, HPC-SSL which is a low-viscosity grade is used from the viewpoint of making the maximum mist diameter that does not cause aggregation. It is effective to use

Further, a simulation of the processing capacity was performed. The sprayable amount that can be estimated from the possible spray air flow rate of the conventional spray nozzle is 150 g / min × with four spray nozzles installed.
4 = 600 g / min, and as shown in Table 1 below,
Even if the solid content concentration of the spray liquid is increased, it takes about 7 hours for the processing time (conventional example 2). It turned out to be.

[0019]

[Table 1]

Therefore, in order to improve the productivity, it is necessary to increase the spraying ability (high-concentration injection, high-volume injection) under conditions that do not generate aggregates (conditions in which the maximum mist diameter is suppressed). Requires a high gas-liquid ratio and a high spray air flow rate.

As shown in FIG. 9, the processing time per batch tends to decrease as the spray air flow rate increases. Conventionally, in this type of granulation apparatus (granulation coating apparatus), the spray air flow rate per spray nozzle is less than 700 NL / min /. Therefore, by setting the spray air flow rate of at least one spray nozzle to 700 NL / min or more, the processing time per batch can be reduced as compared with the conventional case. By the way, in the processing apparatus of the present invention that has been developed, 1400 NL / mi per spray nozzle
n spray air flow rate can be secured,
By performing high-concentration injection and high-volume injection using this large-volume spray nozzle, the processing time per batch can be significantly reduced as compared with the conventional case. For example, in Examples described later, the processing is performed under the conditions (actual results: spray air flow rate of 1300 NL / min, spray liquid flow rate of 360 g / min) shown in the right column of Table 1 above, and the processing time per batch is 2.8. Time could be reduced. That is, the processing time is reduced by half compared to the conventional example.
This was shortened to the following, in other words, the productivity could be more than doubled. As a result, the productivity is improved, and as a result, the manufacturing cost of the product is reduced, and the investment cost for manufacturing equipment can be reduced. For example, in the case of manufacturing equipment, it is possible to respond to an increase in product demand by scaling up the existing equipment line, which significantly reduces capital investment costs compared to the case of adding an equipment line can do.

As shown in FIG. 10, the generation rate of aggregates tends to decrease as the gas-liquid ratio increases, but if the gas-liquid ratio is too large, the scattering rate of particles increases. Therefore, the optimal setting of the gas-liquid ratio is also important. From the test results shown in FIG. 10, it was confirmed that there was an optimal gas-liquid ratio that minimized both the aggregation rate and the scattering rate. In this test, the gas-liquid ratio was 3
Although favorable results were obtained in the range of 600 to 3800,
3000 to 50 depending on conditions such as the viscosity of the spray liquid.
It is possible to obtain a favorable result in the range of 00.

Based on the results of the above-mentioned studies, the present invention provides a spray liquid in which a required component substance is blended with particles, which have been fluidized by fluidizing air in a processing vessel, using at least one spray nozzle. In the fluidizing treatment method for a granular material, which forms at least one coating layer containing the component material on the particles by spraying in a mist state by spray air,
Spray air flow rate of 700 NL
/ Min or more solves the above problem. Here, “at least one spray nozzle” is meant to include both a case where one spray nozzle is installed and a case where a plurality of spray nozzles are installed. When one spray nozzle is installed, the spray air flow rate of one spray nozzle is set to 700 NL / min or more,
When a plurality of spray nozzles are installed, the spray air flow rate of one spray nozzle, a plurality of spray nozzles less than the number of installed spray nozzles, or a total number of each spray nozzle is 700 NL / min or more.

In order to obtain an appropriate gas-liquid ratio, the spray liquid flow rate of the at least one spray nozzle is set to 200.
g / min or more. When one spray nozzle is installed, the spray liquid flow rate of one spray nozzle is set to 200 g / min or more, and when multiple spray nozzles are installed, one spray nozzle or less than the number of spray nozzles installed The spray liquid flow rate of each of the plurality of spray nozzles or all of the spray nozzles is set to 200 g / min or more.

The above-mentioned "fluidization treatment method" is a treatment method generally called a fluid granulation method or a fluid coating method. The spray method includes a top spray method, a bottom spray method, and a tangential spray method.
As the processing device, a fluidized-granulation device (fluidized-granulation coating device) and a complex-type fluidized-granulation device (complex-type fluidized-granulation coating device) are used. In the top spray type fluidized-granulation apparatus, fluidized air is introduced into the processing vessel from a gas permeable porous plate or wire mesh placed at the bottom of the processing vessel to form a fluidized bed, and the fluidized air is formed above the fluidized particle group. Spray the spray liquid downward from. In the fluidized granulation apparatus of the bottom spray type, a guide tube is provided below the fluidized bed, a large amount of fluidizing air is introduced into the guide tube to form a spouted bed, and the fluidized particles are sprayed upward from below. In the tangential spray type composite fluidized-granulation apparatus, a rotating disk is attached to the bottom of the processing vessel, and fluidized air is introduced from, for example, a gap between the rotating disk and the bottom wall of the processing vessel to form a fluidized bed. And spray the fluidized particles tangentially (in the direction of rotation of the rotating disk) (in some cases,
The top spray method is sometimes used. ). On the upper surface of the rotating disk, a conical cone portion is provided, and in some cases, a plurality of blades (convex blades) are provided. In the composite fluidized-bed granulating apparatus, a rolling compaction effect is applied to the particle group by a rotating disk. Therefore, it is also called a tumbling fluidized-granulation device (a tumbling fluidized-granulation coating device). In particular, a rotating disk provided with a blade is characterized in that each zone of wet → consolidation → dry forms a clear circulation flow. In addition, in the complex type fluidized granulation apparatus,
Some have stirring blades (there is no rotating disk). In this type of composite fluidized-bed granulating apparatus (rolling fluidized-bed granulating apparatus), a rotating blade is added to the group of particles by the stirring blade.

In the present invention, any of the above-mentioned various granulation coating methods and apparatuses can be arbitrarily adopted. However, generation of aggregates is small, fine particle coating is possible, particle strength is high, and sharp flow distribution is obtained. From the point of being obtained,
It is preferable to employ a composite fluidized-granulation coating method and apparatus (rolling fluidized-granulation coating method and apparatus), particularly a method in which a rotating disk is provided with a blade.

The above-mentioned "coating layer" is not limited to the form covering the entire surface of the particle, but also the form partially covering the surface of the particle, and further the form which is adsorbed or absorbed on the surface of the particle. Is included. The “particles” serving as nuclei are not limited to true spheres, but also include those having a curved surface such as an elliptical cross section, an oval cross section, or a drop shape.

In the present invention, at least one coating layer formed on the particles may be a main drug layer containing a physiologically active substance and a substance for controlling the dissolution of the physiologically active substance (elution controlling substance). it can.

As the above-mentioned "particles" serving as nuclei, for example, inert substance particles having a particle diameter of 1000 μm or less, preferably 500 μm or less can be used. Specifically, a spherical granulated product of crystalline cellulose (for example, Avicel SP, manufactured by Asahi Kasei Corporation), a spherical granulated product of crystalline cellulose and lactose (for example, nonpareil NP, manufactured by Freund), and stirring of lactose and pregelatinized starch Granulated product, JP-A-61-2
Microcrystalline cellulose spherical granules described in No. 13201,
Processed products such as waxes formed into a spherical shape by spray chilling and melt granulation, processed products such as gelatin beads of oil components, calcium silicate, starch, chitin,
Examples include porous particles such as cellulose and chitosan, bulk products such as granulated sugar, crystalline lactose, crystalline cellulose, and sodium chloride, and processed products thereof.
In addition, the particles may contain a physiologically active substance described below (hereinafter, may be referred to as “drug”). The shape of the core particles is not particularly limited, but is preferably spherical in order to reduce the variation of the coating and increase the coating amount.

The above "bioactive substance" is not particularly limited as long as it is orally administered, and various physiologically active substances used in the fields of foods, pharmaceuticals, agricultural chemicals and the like can be used. For example, preferred bioactive substances include central nervous system drugs (diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetylaminophen, etenzazamide, ketoprofen, etc.)
Cardiovascular drugs (molsidomine, vinpocetine, delapril hydrochloride, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide nitrate, etc.), respiratory drugs (amlexanox, Theophylline, pseudoephedrine, salbutamol, guaifenicin, etc.), digestive system drugs (benzimidazole drugs such as lansoprazole, omeprazole, cimetidine, ranitidine, pancreatin, bisacodyl, 5-aminosalicylic acid, etc.), antibiotics and chemotherapeutic agents (Cephalexin, cefaclor, cefradine, amoxicillin, ivampicillin, bacampicillin, dicloxacillin , Erythromycin, erythromycin stearate, silicon mycin, doxycycline, trimethoprim / sulfamethoxazole, etc.),
Metabolic drugs (serrapeptase, lysozyme chloride, adenosine triphosphate, glipenclamide, potassium chloride, etc.), vitamin drugs (vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C,
Fursultiamine, vitamin A, vitamin E, vitamin D, vitamin K, folic acid, etc.), antacids and the like.
One or more of these drugs can be used.

As the "elution controlling substance", for example, a water-soluble polymer can be used. Examples of the water-soluble polymer include ethanol-soluble water-soluble polymers [eg, cellulose derivatives such as hydroxypropylcellulose (HPC), polyvinylpyrrolidone, etc.],
Ethanol-insoluble water-soluble polymers [eg, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), methylcellulose, sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like]. The dissolution of a drug can be controlled by using a combination of an ethanol-soluble water-soluble polymer and an ethanol-insoluble water-soluble polymer, or by using a combination of water-soluble polymers having different viscosities.

The "main drug layer" is used to increase the strength of the nucleated powder (nucleated fine granule).
And low additives hydroxypropylcellulose (L-HPC) described in Japanese Patent Application Laid-Open Publication No. H11-209, and other additives. As the additives, additives that are generally blended when manufacturing powders can be used, for example, lactose, corn starch, sucrose, talc, crystalline cellulose, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L Excipients such as cysteine; pregelatinized starch, partially pregelatinized starch, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone,
Binders such as pullulan, dextrin, gum arabic;
Disintegrators such as calcium carboxymethylcellulose, starches, sodium crosslinked carboxymethylcellulose, and crosslinked insolvable polyvinylpyrrolidone; and coloring agents such as titanium oxide, red iron oxide, and tar dyes. Two or more of these additives may be used.

On the outer layer of the above-mentioned "main drug layer", a "functional coating layer" such as a moisturizing property, a light-shielding property, a sustained release property, a gastric solubility and an enteric coating is formed directly or via another coating layer. You may.
In a state where at least one coating layer is formed on the core particles, the total particle diameter is preferably 1000 μm or less, and more preferably 500 μm or less.

The spray nozzle is supplied with spray air from "spray air supply means". The "spray air supply means" includes a compressed air supply source such as a compressor, a piping system, and control means and measurement means for pressure, flow rate, dew point, etc. as necessary, and a flow rate of 700 NL / mi.
It is configured such that n or more spray air can be supplied to at least one spray nozzle.

A spray liquid is supplied to the above-mentioned spray nozzle from "spray liquid supply means". The "spray liquid supply means" includes a liquid injection source such as a metering pump and a piping system, and if necessary, control means and measurement means such as pressure, flow rate, and liquid temperature, and at least one spray liquid having a flow rate of 200 g / min or more. It can be configured so that it can be supplied to a book spray nozzle.

[0036]

Embodiments of the present invention will be described below with reference to the drawings.

FIG. 1 schematically shows the structure of a pharmaceutical fine granule produced by the fluidizing treatment method and apparatus of this embodiment. For example, on the surface of core particles 1 which are spherical granules of an inert substance such as cellulose, lactose, and granulated sugar,
A main drug layer 2 containing a drug (bioactive substance) such as vinpocetine and a water-soluble polymer such as HPC-SSL as a binder (elution controlling substance) is formed by coating, and the surface of the main drug layer 2 is gradually coated. A film layer having functions of releasing, enteric, gastric, moisturizing and light-shielding properties, for example, a light-shielding film layer 3
Is coated. The particle diameter of the core particle 1 is, for example, 25
0-300 μm, the thickness of the main drug layer 2 is, for example, 15 μm
The thickness of the film layer 3 is, for example, about 3 μm.
However, the particle diameter of the core particles 1 may be 1000 μm or less, preferably 500 μm or less, and the total particle diameter including the core particles and the coating layer may be 1000 μm or less, preferably 500 μm or less.

FIG. 2 conceptually shows an example of the configuration of a tumbling fluidized-granulation apparatus (rolling fluidized-granulation coating apparatus) used in this embodiment.

Above the processing chamber 4a of the processing container 4, a bag filter 5 (a twin-shaking filter system is exemplified; there is also a filter system of a single shaking system or a pulse removing system) is installed. A rotating disk 6 is attached to the bottom of the. On the upper surface of the rotating disk 6, a conical cone portion and a plurality of blades (convex blades) are provided. Fluidized air is supplied at a predetermined temperature, air volume, etc. from a fluidized air supply unit 7 (provided with an air supply source such as a blower, and control means for temperature, air volume, etc.). Of the processing chamber 4a through the gap between the outer peripheral portion of the rotating disk 6 and the bottom wall surface of the processing container 4.
Introduced within. The granular material on the rotating disk 6 is strongly subjected to the rolling consolidation effect of the cone and the blade, and when rolling to the outer periphery, it is blown up to the upper center by the fluidized air when rolling to the outer periphery, and the conical taper surface of the cone is formed. Circulates along.
In the processing chamber 4a, one or a plurality of spray nozzles 8 are provided for spraying a spray liquid in a mist state by spray air.

FIG. 3 illustrates a spray nozzle 8 used in this embodiment. The spray nozzle 8 is configured as a so-called two-fluid nozzle, having a liquid passage 8a for ejecting a spray liquid at a center portion, and an air passage 8b for ejecting spray air outside the liquid passage 8a.
A spray liquid is supplied to the liquid passage 8a at a predetermined flow rate, liquid temperature, and the like from a spray liquid supply unit 9 (constituted of a constant-rate injection source such as a constant-quantity pump, control means for liquid temperature and the like, and a piping system). Is done. The air passage 8b is supplied from the spray air supply unit 10 (composed of a compressed air supply source such as a compressor, control means for controlling pressure, flow rate, dew point, and the like, and a piping system) at a predetermined pressure and air volume. Is done. The spray liquid ejected from the liquid injection port 8a1 at the tip through the liquid passage 8a is converted into mist by the spray air ejected from the air outlet 8b1 at the tip through the air path 8b, and the processing chamber 4
A is sprayed in a tangential direction toward the powdery material in the fluidized state in a.

The mist of the spray liquid sprayed from the spray nozzle 8 causes the nucleus particles to be wet, and at the same time, the solid component contained in the spray liquid adheres to the surface of the nucleus particles, forms a compacted sphere, and is dried and solidified. Thus, a coating layer (such as a layering layer) is formed on the surface of the core particles.

The spray nozzle 8 of this embodiment has a spray air flow rate of 700 NL / min or more per one nozzle.
For example, 1400 NL / min, spray liquid flow rate 200 g
/ Min, for example, 360 g / min high-volume injection is possible, and the spraying ability is twice or more as compared with the conventional spray nozzle. The spray air supply unit 10
Is a flow rate of 700 NL / min or more, for example, 1400 NL
/ Min spray air can be supplied to the spray nozzle 8 (per nozzle), and the spray liquid supply unit 9 has a flow rate of 200 g / min or more, for example, 360 g / min.
spray nozzle 8 (per nozzle)
It can be supplied to For example, by installing four spray nozzles 8, the amount of spray liquid required for one batch can be sprayed in less than four hours, thereby enabling a pre-process such as liquid adjustment and a post-process such as clean-up. And processing per batch can be completed in a one-day process.

[0043]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Referring to FIG.
Was manufactured, and the treatment time and the particle size distribution of the recovered fine granules were measured. Table 2 below shows the processing conditions, and Table 3 below shows the raw material name of the main chemical solution (the solution to be sprayed on the core particles 1) and the amount charged per 132 kg (kg),
Table 4 below shows the raw material names of the film liquid (the solution to be sprayed after the formation of the main chemical layer 2) and the amount charged per 132 kg (kg).
Are respectively shown. In addition, as a core particle, nonpareil NP
, And the charged amount for one batch was 79.2 kg.

As shown in Table 2 below, in this embodiment, the spray air flow rate for one spray nozzle was 13
00 NL / min, spray liquid flow rate 360 g / min
Set to. Therefore, as shown in the right column of Table 1 described above, the treatment could be completed by spraying the entire amount of the main chemical solution and the film solution for one batch in 2.8 hours.

[0045]

[Table 2]

[0046]

[Table 3]

[0047]

[Table 4]

The coating treatment was carried out under the above conditions, and the particle size distribution of the recovered fine granules was measured. As shown in Table 5 below, 0.2% by weight of coarse particles having a particle diameter of 500 μm or more was obtained.
0.1% by weight of fine particles having a particle diameter of 150 μm or less, and 9 particles having an appropriate particle diameter of 150 μm to 500 μm.
It was 9.7% by weight. From this test result, it was confirmed that by employing the production process of the present invention, fine granules having an appropriate particle size and a sharp particle size distribution can be obtained in a short time.

[0049]

[Table 5]

[0050]

As described above, according to the present invention,
In the fluidization process of forming a coating layer on the particles,
Aggregation can be suppressed to achieve stable product quality and a high yield, and at the same time, to shorten the processing time and improve productivity. As a result, the manufacturing cost of the product can be reduced, and the cost of manufacturing equipment investment can be reduced.

[Brief description of the drawings]

FIG. 1 is a diagram schematically showing a tissue structure of a pharmaceutical fine granule manufactured by a processing method and an apparatus of an embodiment.

FIG. 2 is a cross-sectional view conceptually illustrating a configuration example of a tumbling fluidized-granulation apparatus used in the embodiment.

FIG. 3 is a sectional view showing a spray nozzle used in the embodiment.

FIG. 4 shows the relationship between the exhaust gas temperature and the aggregate generation rate.

FIG. 5 is a diagram showing the relationship between the thermal equilibrium coefficient RW and the amount of aggregate generation.

FIG. 6 is a diagram showing the relationship between the gas-liquid ratio and the aggregation rate.

FIG. 7 is a diagram showing the relationship between the type of spray liquid and the liquid viscosity.

FIG. 8 shows the relationship between the type and concentration of the spray liquid and the maximum mist diameter.

FIG. 9 is a diagram showing a relationship between a spray air flow rate and a processing time.

FIG. 10 is a diagram showing the relationship between the gas-liquid ratio and the aggregation rate and the scattering rate.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Particle (nuclear particle) 2 Main drug layer 3 Film layer 4 Processing container 6 Rotating disk 7 Fluidizing air supply part 8 Spray nozzle

Continuation of front page (72) Inventor Hiroshi Sakamoto 1455-5 Tsujiyuki Sakai, Osaka Prefecture F-term (reference) 4C076 AA62 AA67 BB01 CC11 DD28 DD29 DD38 DD51 DD70 EE32 FF21 GG17 GG33 4D075 AA02 AA73 AA83 CA48 DA11 DB32 DB33 DB70 DC30 EB60 EC11 4G004 BA02 JA01 KA03

Claims (12)

[Claims] 1. A spray liquid containing a required component substance is sprayed in a mist state by spray air using at least one spray nozzle to a particle group which has been fluidized by fluidizing air in a processing vessel. Thereby, in the method for fluidizing particles for forming at least one coating layer containing the component substance on the particles, a spray air flow rate of the at least one spray nozzle is set to 700 NL / min or more. Fluidization treatment method for powders. 2. The spray liquid flow rate of said at least one spray nozzle is set to 200 g / min or more.
The fluidization treatment method of the granular material according to the above. 3. The method for fluidizing a granular material according to claim 1, wherein a rolling operation is added to the particle group in parallel with the fluidization. 4. The method according to claim 1, wherein the at least one coating layer is a main drug layer containing a physiologically active substance and a substance for controlling the dissolution property of the physiologically active substance. . 5. The method for fluidizing powdery and granular materials according to claim 4, wherein a coating layer having a function of protecting such as moisturizing and light shielding and a function of sustained release is formed on an outer layer than the main drug layer. 6. The particle serving as a nucleus has a particle diameter of 500 μm.
The method for fluidizing a granular material according to claim 1, which is as follows. 7. The fluidizing treatment method for a granular material according to claim 6, wherein the particle diameter including the core particles and the coating layer is 500 μm or less. 8. The fluidizing device, wherein at least one of a processing container, air supply means for supplying fluidized air into the processing container, and exhaust means for discharging air in the processing container to the outside, At least one spray nozzle for spraying a spray liquid in which required component substances are blended into a fluidized particle group by air in a mist state by spray air, and spray air for supplying spray air to the spray nozzle A fluidizing treatment apparatus for granular material including a supply unit and a spray liquid supply unit for supplying a spray liquid to the spray nozzle, wherein the at least one spray nozzle has a flow rate of 700N.
A fluidizing treatment apparatus for a granular material, which is capable of ejecting spray air of L / min or more. 9. The method according to claim 9, wherein said spray air supply means has a flow rate of 7.
The fluidizing treatment apparatus for a granular material according to claim 8, wherein a spray air of 00 NL / min or more can be supplied to the at least one spray nozzle. 10. The fluidized particle processing apparatus according to claim 8, wherein the at least one spray nozzle is capable of injecting a spray liquid having a flow rate of 200 g / min or more. 11. The method according to claim 11, wherein the spray liquid supply means has a flow rate of 20.
The fluidizing treatment apparatus for a granular material according to claim 10, wherein a spray liquid of 0 g / min or more can be supplied to the at least one spray nozzle. 12. The fluidized particle processing apparatus according to claim 8, further comprising a rotating disk at the bottom of the processing container for applying a rolling consolidation effect to the group of fluidized particles.