JPS61213201A - Spherical granule of fine crystalline cellulose and production thereof - Google Patents

Abstract

PURPOSE:To obtain the titled granule having excellent granule characteristics such as smooth surface, compact texture, high density and nearly complete sphericity, and useful in the fields of pharmaceuticals and foods, etc., by controlling the rotational speed of an aeration rotary disk and the feeding rate of a binder in a granulation apparatus. CONSTITUTION:Fine crystal cellulose powder is charged to a granulation apparatus furnished with an aeration rotary disk 4 having aeration means from the upper part 12 of the aeration rotary disk 4. A gas is supplied from the lower part 9 of the rotary disk 4, and the aeration rotary disk 4 is rotated at a circumferential speed of 1.5-15m/sec. A binder (e.g. a solution obtained by dissolving propylene glycol in a mixture of water and an alcohol) is added to the powder in an amount to give a moistened powder having a liquid content of 40-65%. The rotary fluidized granulation of the powder is carried out after or during the feeding of the binder to obtain the objective granule having an apparent density of >=0.65g/ml and a sphericity of >=0.8.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to spherical microcrystalline cellulose granules having excellent granule properties and used in pharmaceuticals, foods, etc., and a method for producing the same.

[Prior art]

Spherical granules have traditionally been manufactured in fields such as pharmaceuticals and food.
available for use. Particularly in the field of pharmaceuticals, drug-containing powders are made into spherical granules, and a plurality of spherical granules are used as a dosage unit, and formulations are designed to ensure reliable drug efficacy. In addition, in recent years, as a drug sustained sustained release preparation, a preparation with a spherical granule as a core and a drug coated on its surface has been proposed and is attracting attention.

To meet these needs, spherical granules composed of sucrose and sucrose corn starch have been commonly used. However, sucrose has drawbacks such as being relatively highly active, reacting with some drugs as a drug and producing deterioration or impurities, and low strength in processing pharmaceuticals.

Against this background, there has been a demand for spherical granules that are composed of substances that are chemically inert, safe to the living body, and not absorbed by the living body, have high physical strength, and are easy to process into pharmaceutical preparations.

On the other hand, microcrystalline cellulose is widely used in the pharmaceutical and food fields as a chemically inert, biosafe, and non-absorbable substance, and it is also known that it can be formed into spherical granules. [
Avicel Jiho No. 4, page 6 (June 30, 1960, published by Asahi Kasei Kogyo Co., Ltd.), etc.).

Spherical granules of microcrystalline cellulose are conventionally produced through a process of humidifying microcrystalline cellulose powder, a process of producing cylindrical granules by extrusion granulation of the humidified raw material, and a rolling granulation method of forming cylindrical granules. They were manufactured using different types of equipment using a method consisting of four steps: forming spherical granules using a spherical granule, and drying the spherical granules.

However, when microcrystalline cellulose is granulated by the conventional rolling granulation method, the resulting granules have irregular particle sizes and a wide particle size distribution, and the sphericity (short axis length/ The length of the long axis) is small and the shape is irregular, the particle surface is not smooth,
It is light with low density. Therefore, conventional microcrystalline cellulose spherical granules are unsatisfactory in terms of granule properties applicable to the above-mentioned uses, and have problems in the formulation process or economically.

In addition, in the conventional manufacturing method, each of the four steps mentioned above needs to be performed using separate equipment, which requires a large number of equipment, and cannot be performed as a continuous process, which requires a lot of work time and is expensive. There were drawbacks such as the fact that it had no choice but to become a product.

Furthermore, the water content may differ between columnar granules obtained by extrusion granulation and spherical granules obtained by rolling granulation based on this. If there is a lot of moisture in the granules, when the granules are made into spheres using the rolling granulation method, the moisture contained in the granules may come out to the surface of the granules due to centrifugal force. Undesirable. In order to prevent this, it is necessary to dry the extrusion granulated product in advance to reduce the moisture contained in the granulated product before rolling granulation. Therefore, it is necessary to add a drying step between extrusion granulation and rolling granulation, which further increases the number of steps.

In the case of rolling granulation, it is not economical because only a very small amount can be processed compared to the volume of the processing container, and it requires manpower and is often carried out depending on the intuition of a particularly skilled person.

In addition, when the granules formed by extrusion granulation contain a large amount of water, when rolling the granules,
One possible method is to granulate the material by blowing hot air on it to dry and remove the moisture that appears on the surface.

However, in a granulating device that performs rolling granulation, it is generally not possible to perform drying in the same device, and therefore, sufficient moisture removal effects cannot be obtained through drying.

Conventional rolling granulation equipment simply rotates a rotary plate, and as mentioned above, the drying process is generally performed in a separate device, but when this is done in the same device, the drying process is performed from above the rotary plate. If air is sent or sent from below, it is done through the gap between the granulation chamber and the rotating plate, which is insufficient to evaporate the water coming out on the particle surface. For this reason, coarse particles are generated and uniform particles cannot be produced.

[Object of the invention]

The present invention has an apparent density of 0.65 P/mj or more and a sphericity of 0.
．． The object of the present invention is to provide spherical granules of microcrystalline cellulose having a particle size of 8 or more, smooth surface, dense, heavy, and having excellent granule properties that are close to true spheres.

In addition, the present invention provides a granulation device equipped with an aeration rotary plate having a ventilation mechanism, in which microcrystalline cellulose powder is introduced from the upper part of the aeration rotary plate, gas is supplied from the lower part of the aeration rotary plate, and the aeration rotary plate is surrounded. By rotating at a speed of 1.5 to 15 m/sec, tumbling fluid granulation by supplying or supplying a binder with a wet granulation rate of 40 to 65%, and then drying. The object of the present invention is to provide a method for directly producing microcrystalline cellulose having the aforementioned excellent granule properties and uniform particle size and shape.

The spherical granules of microcrystalline cellulose in the present invention may not only consist of microcrystalline cellulose alone, but may also have a composition containing 100 to 20% by weight of microcrystalline cellulose. The number and type of components to be mixed are not particularly limited, but for example, substances that adjust the disintegration and solubility of spherical granules, specifically carboxymethyl cellulose calcium (CMC-Ca).
, carboxycellulose sodium (CMC-Na
), f-pun, D-mannitol, lactose, sucrose, etc.

In addition, the binder is a substance that has binding properties to water, a solution of 1 to 50% of water mixed with an alcohol such as ethanol, a substance that has a binding property to water or a solution of water and an alcohol such as ethanol, or a substance that has a surfactant. For example, propylene glycol, polyethylene glycol, polyvinylpyrrolidone (P, V, P), volibithyl alcohol (PVA),
Hydroxypropylcellulose (RPC), hydroxypropylmethylcellulose (I (PMC), methylcellulose (MC), ethylcellulose (EC), methacrylic acid/methacrylic acid ester copolymer (Eudragit), 7N7 oxidized starch, dextrin polysorbate 80. Sorbitan mono A liquid in which fatty acid ester, sucrose fatty acid ester, stearic acid polyoxy A/40, etc. are dissolved or dispersed is used.

The microcrystalline cellulose spherical granules of the present invention can be produced by using a hanging device that performs all of the steps of supplying the binder, aeration rolling, and drying, which are equipped with an aeration rotary plate having an aeration mechanism, especially at the rotational speed of the aeration rotary plate. , by controlling the temperature and amount of gas supplied through the ventilation mechanism of the ventilation rotating plate, and the amount of binder supplied.

These controls are to control the particle size, particle shape, and granule characteristics by changing various conditions such as binder supply, aeration rolling, and drying, and are automatically performed by a computer or the like.

The main factor determining particle size is the wetting rate of the wet material before entering the aeration rolling. The moisture content is expressed as [weight of water content/(weight of water content of dry raw material powder weight)] x 100 (%). In the present invention, the moisture content of the wet material before entering the aeration rolling is controlled mainly by the supply amount of the binder, but the drying conditions due to the aeration during powder fluidization, the granule characteristics, etc. Select control conditions taking into consideration. When the moisture content is less than 40%, the particle size is 150 μm or less, which is not much different from a powder, and when it is more than 65%, it is larger than a pea-sized particle, making it unsuitable for the above-mentioned uses. The binder is usually supplied by spraying onto the microcrystalline cellulose powder in a fluidized state. Therefore, the total amount of binder supplied varies depending on the drying conditions of the fluidizing aeration in order to obtain a wet material with a wetness rate of 40-65%, but it is usually 75-200% of the weight of the microcrystalline cellulose powder ( ”
/w)% is appropriate.

Fluidization is performed by supplying gas to the granulation chamber from the lower part of the ventilation rotary plate through the ventilation mechanism of the ventilation rotary plate. Control is mainly performed by the amount of gas supplied, which is appropriately selected in consideration of the amount of microcrystalline cellulose powder supplied and the state of formation of the fluidized bed. Even when the binder supply process is set up separately from other processes, in order to achieve uniform fluidization, it is preferable to supply the fluidization gas while rotating the ventilation rotary plate. The rotation of the ventilation rotating plate is the circumferential speed (
In other words, the rotation speed in the specific equipment) is 2 to 20 m1m
It is advantageous to set and control the value to a constant value within the range of . In addition, it is appropriate to set the temperature of the fluidizing gas stream at a constant temperature to avoid the influence of the external temperature of the device, and between 0 and 0.
The temperature is controlled to be constant within a range of 80°C.

The main factors that determine the particle size distribution are the above-mentioned wetting rate, drying conditions of aerated rolling, and rolling conditions. In addition, the particle shape and granule characteristics such as surface smoothness, denseness, and sphericity are mainly determined by the rolling conditions of aerated rolling. Ventilation rolling is performed by rotating the ventilation rotary plate and supplying gas, preferably hot air, from below the ventilation rotary plate to the upper part of the ventilation rotary plate through the ventilation mechanism of the ventilation rotary plate, and the rotation of the ventilation rotary plate The purpose is to spheroidize the wet material by the rolling action caused by the container wall, and at this time remove the moisture leaching onto the surface of the spherical granules by aeration.

The rolling is mainly performed by controlling the circumferential speed of the ventilation rotary plate. The circumferential speed of the ventilation rotating plate in the rolling process is 1.5-15 m
It is set to a constant value within the range of /sec and controlled. When the circumferential speed is lower than 1.5i and higher than 15i, the particle size distribution deteriorates, granule properties such as sphericity deteriorate, and the desired spherical granules cannot be obtained.

The amount of gas supplied is appropriately set in consideration of the particle size distribution of the spherical granules, the granule characteristics, the type of raw material, the amount of gas supplied, the wetting rate of the wet material, and the like. Temperature control is carried out by setting the air flow at a constant temperature within the range of 0 to 90"C1, preferably 40 to 75C.

Drying is preferably carried out by ventilation or hot air drying.
A granulation apparatus equipped with an aeration rotary plate having the aeration mechanism is advantageous because it can be carried out with the same equipment. The temperature is set and controlled at a constant temperature within the range of room temperature to 45°C, preferably 50 to 9°C. Drying can also be carried out by rotating the aeration rotary plate in consideration of drying efficiency.

The method of the present invention is carried out using a granulation device equipped with an aeration rotary plate having a gas flow path as described above, and therefore the amount of dry air supplied to the powder through the gas flow path is reduced. It is large in size and has good drying efficiency. Therefore, moisture seeping from the inside of the granules to the surface during the granulation process is effectively removed. Furthermore, the swirling flow caused by the rotating plate is promoted by the flow of air toward the outer circumferential direction through the gas flow passage, and even if there is a large amount of raw material to be supplied, a sufficient swirling flow is formed, which promotes the rolling effect. This makes it possible to obtain spherical granules of microcrystalline cellulose with high sphericity.

Therefore, the apparatus used in the present invention has a ventilation mechanism such as a slit, a large number of small holes, or a part or all of a mesh, and is equipped with a ventilation rotating plate that can rotate at high speed at the bottom of the granulation chamber. , through the ventilation mechanism from below this ventilation rotary plate (
Alternatively, the gap between the peripheral edge of the rotating plate and the vessel wall may serve as a ventilation mechanism.) There is no particular limitation as long as it has a structure that can supply humidity-controlled gas above the ventilation rotating plate. Among these, the apparatus described below is most suitable for achieving the object of the present invention.

〔Example〕

An example of manufacturing microcrystalline cellulose spherical granules of the present invention is shown.

First, the main components of the granulation equipment used in the following examples are:
Explain the structure.

Figure 1 is a diagram showing the entire granulation device, in which 1 is a granulation chamber, 2 is a bag filter case, 3 is a scraper,
Reference numeral 4 denotes a ventilation rotating plate having a structure to be described later, and is fixed to a rotating shaft 6 supported by a bearing 5. This rotating shaft 6 is rotated by a drive motor 7 via a rotation transmission mechanism such as a pulley or a belt, and the rotation of this rotating shaft 6 causes the rotating plate 4 to rotate.
is rotated. Reference numeral 8 indicates a plurality of inclined plates for enhancing the granulation effect attached to the surface of the rotating plate 4, and 9 indicates the rotating plate 4 of the granulation chamber 2.
1o is a spray gun for spraying the binder, 11 is a bag filter, 12 is a raw material inlet, and 13 is a granulated material outlet.

The rotating plate 4 has a structure as shown enlarged in FIGS. 2 and 3, and 20 is a disc-shaped substrate having a large opening 20a and fixed to the rotating shaft 6, with a gap of 21°. 24 are formed respectively. Each of the gaps 24 has a shape in which the upper opening 24b of the rotary plate 4 is located on the outer side farther from the center than the lower opening 24a, and the openings 24b and 24a communicate with each other through a gap running substantially horizontally. Therefore, arrow A shown in FIG.
Air from below enters from the lower opening 24a,
After flowing almost horizontally away from the center, the upper mouth 2
It has a structure that forms a gas flow passage that exits from 4b.

When producing microcrystalline cellulose granules using such a granulating device, the raw material microcrystalline cellulose is introduced from the raw material input port 12, a predetermined amount of binder is sprayed from the spray gun 1o, and the mixture is heated at a predetermined rotation speed. This is carried out by rotating the rotary plate 4 and supplying a predetermined amount of gas at a predetermined temperature from the blast pipe 9. Further, the gas from the blow pipe 9 passes from below the rotary plate 4 through the gas flow path of the rotary plate 4 and onto the rotary plate 4. Pass through. Here, the centrifugal force due to the rotation of the rotary plate 4 is also applied, and the gas rises from the center toward the periphery.

Due to this action, the microcrystalline cellulose on the rotary plate 4 is given appropriate moisture and is moved upwards from the center to the periphery due to the rotation and rotation of the rotary plate 4 and the gas flowing through the flow path of the plate 4. Then, it falls towards the center and moves in a swirling flow that rotates as a whole. Therefore, the raw material moving along with this swirling flow rotates and revolves, and is granulated by the rolling action, and gas (preferably hot air when rolling)
However, since it moves in the flow as described above, it promotes the movement of the raw material in a swirling flow and adds an appropriate drying effect, and the wetting of the surface of the raw material powder causes the raw material powder to True spherical particles are formed without adhering to each other to form irregularly shaped lumps. Furthermore, the inclined plate 8 provided on the rotary plate 4 for enhancing the granulation effect enables granulation even if a large amount of raw material is introduced compared to the volume of the granulation chamber.

An example of a method for manufacturing crystalline cellulose particles using the above-mentioned granulation apparatus will be shown below.

Example 1' A rotary aeration plate with a diameter of 500fi was rotated, and air at 0 to 60°C was supplied into the granulation chamber from 3 to 8rnζ from the bottom of the aeration rotary plate, and water was added as a binder. 0.
The mixture was granulated for 75 minutes by spraying at 24/mis. The spraying of the drained water was stopped, and the temperature of the hot air supplied into the granulation chamber was gradually increased to 80"C, while the rotational speed of the ventilation rotating plate was gradually lowered to 50 R, P, M, and 80" C. Microcrystalline cellulose particles were obtained by drying for 1 minute. The particle size distribution of the microcrystalline cellulose particles thus formed is as follows.

12-24 mesh 2.2% 24-48 mesh 97.1% 48 mesh passing 0.6% Apparent density 0.781 Shoulder sphericity
0.96 Angle of repose 29° Example 2 Using the same granulating device as in Example 1 and under the same granulating conditions, the granulating time was 7.
0 minutes, that is, further reducing the total amount of water supplied, the particle size distribution of the microcrystalline cellulose particles was as follows.

12-32 mesh 1.8% 32-60 mesh 91.6% 60 mesh passing 7.1% Apparent density 0.762 Shoulder sphericity
0.97 Angle of repose 30° Example 3 Using the same granulation device as in Example 1, microcrystalline cellulose 9.
5, put 1.67 kg of Eudragit L30D (manufactured by Rohm and Haas, Eudragit is a registered trademark) and rotate the ventilation rotating plate at 25 OR, P, M to blow air at 35°C from the bottom of the ventilation rotating plate. ~8I was supplied into the granulation chamber and water was sprayed at 0.217 m for 67 minutes, then the spraying was stopped and air at 40"C was supplied into the granulation chamber at 3-3 m"/-t for 30 minutes. Then, the temperature of the hot air was gradually increased to 80"C, while the rotation speed of the ventilation rotating plate was gradually lowered to 150 R, P, M, and dried for 90 minutes to form microcrystalline cellulose spherical granules. I got it.

Particle size distribution 12-16 mesh 2% 16-32 mesh 97% Passage through 32 mesh 1% Apparent density 0.782 Shoulder sphericity 0.96 Angle of repose 28° Example 4 Microcrystalline cellulose 6 kg, lactose 5 K? , the total water supply amount is 14.2 to 9 binder supply process, the air flow temperature in the rolling process is 70 ° C1, the binder supply method is interval spraying, and the rotation speed of the ventilation rotary plate during the rolling process. 30
Microcrystalline cellulose spherical granules were obtained in substantially the same manner as in Example 3, except that OR, P, M, and the air flow temperature during drying were 90° C. and the drying time was 60 minutes.

Particle size distribution 20-24 mesh 2% 24-42 mesh 91% Passed through 42 mesh 7% Apparent density 0.76? hawk.

Sphericity 0.90 Angle of repose 33° Example 5 Microcrystalline cellulose spherical granules were obtained in almost the same manner as in Example 4, except that 8 kg of microcrystalline cellulose, 4 kg of sucrose (powdered sugar), and 12 kg of total water supply were used. .

Particle size distribution 20-24 mesh 3% 24-42 mesh 92% Passage through 42 mesh 5% Apparent density 0.77 Sphericity 0.95 Angle of repose 31° In the above example, water was used as the binder. Other binders as described above may also be used. Furthermore, granulation is also possible by spraying a coating liquid as a binder.

The granulator used in the examples was equipped with a rotary plate provided with an inclined plate as shown in Fig. 2, but even a granulator equipped with a rotating plate without an inclined plate could produce microcrystalline cellulose. Granulation can be performed. Also, Figures 5, 6, and 7
A granulating device having a rotary plate having the structure shown in the figure may be used.

Among these rotary plates, the one shown in FIG. 5 has an inclined plate 25 for promoting granulation extending diagonally upward from the center toward the periphery as shown in the figure. The rotating plate 26 shown in FIG.
The outflow port 24b, which looks like a rotating plate shown in the figure, is the inflow port, and the inflow port 74a
Only the opening 2 is provided without providing the gas flow passage 24 located on the outer side.
7.

In addition, the inclined plate 28 covers the opening 27 and rises in the direction opposite to the rotating direction of the rotary plate, and its end 211
A large number of small holes 29 are provided in &. When this ventilation rotary plate is used, air from the air pipe passes through the opening 27 and is supplied into the granules through the small holes 29 of the inclined plate 28.

〔Effect of the invention〕

As is clear from the above examples, the spherical granules of microcrystalline cellulose provided by the present invention have a smooth surface, a dense and heavy structure, and are almost true spheres. That is,
The spherical granules of the present invention have granule characteristics such as an apparent density of 0.6597 m1 or more, preferably 0.7 r/i or more, and a sphericity of 0.8 or more, preferably 0.90 or more.

Spherical granules of microcrystalline cellulose having such granule characteristics have not been previously available, and offer many pharmaceutical and economical advantages as listed below.

(1) Surface smoothness provides free-flowing properties to the spherical granules, eliminates coating unevenness when coating the spherical granules with a drug or coating liquid, and increases the yield of coated particles. Therefore, the ease of handling and economical efficiency of formulation are greatly improved.

(2) Being dense and heavy increases the physical strength of the spherical granules, eliminates bulk, facilitates handling in formulations, and increases stability against impact during processing and transportation.

(3) High sphericity is similar to surface smoothness,
Improves free flow properties, coating economy, and improves product aesthetics.

Furthermore, since microcrystalline cellulose is inert, it is possible to obtain smooth, hard granules with high sphericity as described above by using not only crystalline cellulose alone but also a mixture of other materials. . In addition, since it has a swellable property, when used for medicine, it is possible to formulate a drug with excellent long-acting properties and controlled release properties, which are required for drugs, and it dissolves uniformly during use. The desired medicinal effect will be obtained.

In addition, according to the production method of the present invention, as is clear from the above experimental data, the particle size distribution is such that an extremely large number of particles are concentrated in a narrow range of particle sizes, meaning that the target particle size is almost non-uniform. It is clear that it can be obtained without

Furthermore, by controlling the supply amount (supply time) of the binder, particles of a desired particle size can be obtained. That is, if the binder supply time is short, particles with a small particle size can be obtained, and if the binder supply time is long, particles with a large particle size can be obtained.

According to the method for producing microcrystalline cellulose spherical granules of the present invention,
The raw material for microcrystalline cellulose moves toward the outer circumference of the rotating plate and rotates as a whole due to the centrifugal force caused by the rotation of the aeration rotating plate, which creates a swirling flow and is granulated by spraying the binder. It will be done. In addition, the hot air supplied below the ventilation rotary plate flows through the gas flow passage of the rotary plate and becomes a flow in the outer circumferential direction due to the centrifugal force of the rotary plate, promoting a swirling flow including rotation and revolution of the raw material. This increases the granulation effect of the raw material. Moreover, the moisture generated by the spraying of the binder and released onto the surface of the powder by centrifugal force is appropriately dried by the hot air passing through the raw material. Therefore, microcrystalline cellulose, which conventionally could not be directly granulated from raw material powder, can be directly made into hard microcrystalline cellulose spherical granules with a smooth surface and high sphericity, and the desired particle size can also be obtained. .

In addition, it is possible to produce a sufficient amount of granulation according to the volume of the processing container (granulation chamber), and all processes can be performed continuously with the same equipment, so the microcrystalline cellulose raw material can be It can be processed in one continuous step until the final granulated product is formed. Moreover, the desired result can be obtained accurately by automatic control by a computer. Furthermore, since the binder has extremely good dispersibility, uniform particles can be obtained.

Furthermore, if the obtained spherical granules are further coated, this can be done in the same equipment.

[Brief explanation of the drawing]

FIG. 1 is a sectional view and a plan view showing a part of the part used during granulation by the granulation method of the present invention, and FIG. 5 and 6 are views showing other rotating plates, respectively, and FIG. 7 is a cross-sectional view taken along the line ■--■ in FIG. 6.

Claims (1)

[Claims] 1. Spherical granules of microcrystalline cellulose having granule characteristics of an apparent density of 0.65 g/ml or more and a sphericity of 0.8 or more. 2. A granulation device equipped with an aeration rotary plate having an aeration mechanism. Microcrystalline cellulose powder is introduced from the top of the ventilation rotating plate, gas is supplied from the bottom of the ventilation rotating plate, and the ventilation rotating plate is rotated at a circumferential speed of 1.
．． Granules characterized by rotating at 5 to 15 m/sec, tumbling fluid granulation by supplying or supplying a binder in an amount such that the wetness ratio of the wet granules is 40 to 65%, and then drying. Apparent density 0.6 with narrow diameter distribution and uniform grain shape
Method 3 for producing spherical granules of microcrystalline cellulose having granule characteristics of 5 g/ml or more and sphericity of 0.8 or more. A ventilation rotating plate having a gas flow path, an inclined plate attached to the ventilation rotating plate, a blower pipe provided at the bottom of the rotating plate, a raw material input port disposed at the top of the rotating plate, and a spray gun for spraying a binder. The manufacturing method according to claim 2, which is an apparatus comprising: