JP2001347153A - Method for preparing tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for preparing a tablet having small weight dispersion and excellent in moldability and collapsibility. SOLUTION: This method for preparing the tablet comprises wet-granulating powder containing 2-30 wt.% cellulose powder to prepare granulated powder having 60-300 &mu;m average particle size, <=3.0 particle size uniformity, 1.5-2.5 ml/g apparent specific volume and 35-42 deg. repose angle and then compressing the granulated powder by a wet compressing method.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a tablet having a small weight variation and good moldability and disintegration properties.

[0002]

2. Description of the Related Art In a direct tableting method or a tableting method in which wet cellulose powder is added (a method in which granules are produced and then tableted with microcrystalline cellulose), both functions of moldability and disintegration are considered. An excipient that also has However, when the powder is wet-granulated and granulated by adding crystalline cellulose in advance, the moldability and disintegration function may be reduced.

According to US Pat. No. 5,866,166, this phenomenon may be caused by pseudo-keratinization of cellulose particles in the granulation and drying steps.
It has been proposed to use a composition in which a small amount of colloidal silica is mixed with cellulose particles. However, in the case of a mixture, it is expected that the performance will change due to the unevenness of the mixing state, and there is also a problem of incompatibilities with the mixture, which is not preferable.

[0004]

SUMMARY OF THE INVENTION The present invention provides a wet tableting method in which cellulose powder is added at the time of granulation, followed by tableting. By producing granules having specific granular properties, weight variation is small. It is intended to provide a method for producing a tablet having good moldability and disintegration properties.

[0005]

Means for Solving the Problems As a result of intensive studies, the present inventor has granulated a powder containing a cellulose powder, and controlled the physical properties of the granules to a specific range, so that the weight variation was small, the moldability was low, and The inventors have found that tablets having good disintegration properties can be produced, and have completed the present invention. That is, the present invention
It is as follows. A method for producing tablets by wet granulation of a powder containing 2 to 30% by weight of a cellulose powder to produce granules, followed by tableting, wherein the granules have an average particle size of 60 to 300 μm, A method for producing a tablet, characterized by having a particle size uniformity of 3.0 or less, a crude specific volume of 1.5 to 2.5 ml / g, and a repose angle of 35 to 42 degrees.

Hereinafter, the present invention will be described in detail. The cellulose powder used in the present invention includes crystalline cellulose, powdered cellulose, and the like, and is obtained by decomposing cellulosic substances such as linters and pulp by acid hydrolysis and / or alkali oxidative decomposition, and then purifying and drying. . It can also be obtained by mechanical pulverization without decomposition with an acid or alkali. Among them, crystalline cellulose is preferred.

[0007] The compounding amount of the cellulose powder in the powder is 2 to
30% by weight. 2% by weight of cellulose powder
If it is less than 1, the weight variation of the tablet obtained by tableting the obtained granules is slightly large, and the tablet hardness is not sufficient. Further, when the amount of the cellulose powder exceeds 30% by weight,
Since the granules are hard to be dense, the coarse specific volume increases. Accordingly, the fluidity is deteriorated, and the weight of the tablet varies widely. The physical properties of the cellulose powder suitable for the present invention will be described. The average particle size is preferably from 15 to 200 μm. If it is less than 15 μm, sufficient tablet hardness tends not to be obtained. On the other hand, if it exceeds 200 μm, the mixing property with other powders is poor, and the components tend to be easily separated. More preferably, it is 30 to 150 μm. More preferably, it is 40 to 120 μm.

The crude specific volume is 2.0-3.8 ml / g.
It is preferred that If it is less than 2.0 ml / g, the tablet hardness tends to be insufficient. If it exceeds 3.8 ml / g, the granules are less likely to be dense, so that the fluidity of the granules deteriorates and the variation in tablet weight tends to increase.
Particularly preferably, it is 2.2 to 3.4 ml / g. Also,
The degree of polymerization is preferably from 100 to 350. 100
If it is less than 3, the tablet hardness tends to be insufficient. Also,
Tablet disintegration tends to deteriorate. If it exceeds 350, the granules are less likely to be dense, so that the fluidity of the granules deteriorates and the variation in tablet weight tends to increase. Particularly preferably, it is 120 to 300.

The water retention is preferably from 150 to 300 g / g. If it is less than 150, the tablet hardness tends to be insufficient. In addition, the disintegration of tablets tends to be poor. Three
If it exceeds 00, the granules are hard to be dense, so that the fluidity of the granules is deteriorated and the variation in tablet weight tends to be large. Particularly preferably, it is 180 to 280. The physical properties of granules will be described. The average particle size of the granules is 60 to 30
It needs to be 0 μm. If it is less than 60 μm, the fluidity of the granules is not sufficient, and the weight variation of the tablets becomes large. If it exceeds 300 μm, the disintegration of the tablet will deteriorate.
Preferably it is 60 to 250 μm. Particularly preferably 8
0 to 200 μm. The particle size uniformity of the granules needs to be 3.0 or less. The particle size uniformity is defined by the following equation.

Particle size uniformity = (d50 / d10 + d90 / d50) / 2 where d90 is a particle size obtained when the average particle size is measured and the cumulative weight percentage is 90%, and d10 is a product weight. This is the particle size when the percentage is 10%. If the particle size uniformity exceeds 3.0, the fluidity of the granules deteriorates because the particle size distribution is wide. Preferably it is 2.8 or less. Especially preferably, it is 2.5 or less. The coarse specific volume of the granules is between 1.5 and 2.5 ml / g. If the amount is less than 1.5 ml / g, the plastic deformability of the granules decreases, so that the tablet hardness is not sufficient. 2.5 ml
/ G, the filling of the mortar during tableting does not proceed smoothly, and the variation in tablet weight increases. Preferably it is 1.5-2.2 ml / g. Particularly preferably, it is 1.5 to 2.0 ml / g. Angle of repose of granules is 35 ~
42 degrees. If the temperature is less than 35 degrees, when excipients are further blended with the granules and tableting is performed, the excipients and the granules are separated, which is not preferable. If it exceeds 42 degrees, the weight variation of the tablets becomes large. The control of the physical properties of these granules is carried out by changing the amount of the binding solution and the rate of addition thereof, or the granulation conditions (stirring speed, stirring time, tank temperature, etc.).

As the powder to be compounded in addition to the cellulose powder, the following may be mentioned in addition to the medicinal ingredient. Excipients include sugars such as lactose, D-mannitol, sucrose, erythritol, trehalose, sugar alcohols, starches such as corn starch, potato starch, partially pregelatinized starch, calcium hydrogen phosphate, talc, light anhydrous silica. Acids, inorganic substances such as hydrous silicon dioxide, and the like. Examples of disintegrants include carmellose Ca, low-substituted hydroxypropylcellulose, cellulose derivatives such as croscarmellose Na, corn starch, carboxymethyl starch Na, hydroxypropyl starch, starch and starch derivatives such as partially pregelatinized starch. And synthetic polymers such as crospovidone.

Examples of the binder include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carmellose Na and methylcellulose; starches such as starch paste; and synthetic polymers such as povidone. In addition, components that are usually blended as additives such as pharmaceuticals such as coloring agents and flavors can be added.
Granule production method is usually granulation of powder, such as stirring granulation method, high speed stirring granulation method, fluidized bed granulation method, tumbling fluidized bed granulation method, extrusion granulation method, crushing granulation method, etc. The granulation method used can be used, and among them, the stirring granulation method, the high-speed stirring granulation method, and the tumbling fluidized bed granulation method are preferable. Particularly preferred is a high-speed stirring granulation method. The point that granulation is completed in a short time, the point that the fluidity is relatively good even if the average particle size of the granules is adjusted small,
It is suitable as a granulation method used in the present invention.

As the binding liquid at the time of granulation, an aqueous solution of the binder described above may be prepared and added to the powder by dripping or spraying. Alternatively, the binder powder may be mixed with another powder, and only water may be dropped or sprayed. Alternatively, since the cellulose powder in the powder has a binding effect, only water may be dropped or sprayed without adding a binder. The wet granules after granulation may be taken out of the granulator and dried in a tray, or may be charged in a fluidized bed dryer and dried.

A lubricant such as magnesium stearate is added to the obtained granules, and tableting is carried out in a usual manner. Before adding the lubricant, a cellulose powder such as crystalline cellulose or powdered cellulose, an excipient such as lactose, or a disintegrant may be added as necessary.

[0015]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in more detail by way of examples. In addition, cellulose powder, granules,
The method for evaluating the physical properties of the tablet is as follows.

Method for evaluating physical properties of cellulose powder ・ Average particle size (μm) 30 g of cellulose powder is opened with openings 500, 300, and 15
Using a sieve of 0, 106, 75, or 45 μm, the mixture is sieved for 15 minutes by a low tap sieving machine, and 5 g of cellulose powder is sieved by an air jet sieve. ) And the cumulative weight percentage is 50%
At the time of (d50).・ Rough specific volume (ml / g) Determined using a powder tester. -Degree of polymerization Determined by the method of measuring the degree of polymerization described in the section of crystalline cellulose or powdered cellulose in the Japanese Pharmacopoeia 13, revised. Water retention (g / g) After dispersing 5 g of cellulose powder in 50 ml of distilled water, the mixture is centrifuged at 2,000 G for 10 minutes using a centrifugal sedimenter. Subsequently, after the supernatant is gently removed, the weight of the wet cellulose powder is measured, the weight of the contained water is determined, and the value divided by 5 is defined as the water retention.

Method for evaluating physical properties of granules: Average particle size (μm) After sieving the dried granules at 1410 μm, 30 g of the granules are opened to 1000, 710, 500, 300, 212, and 1,
Using a 50, 106, or 75 μm sieve, the mixture is sieved for 15 minutes using a low-tap sieving machine, and the weight percentage (%) on the sieve is determined, and is represented by the particle size (d50) when the cumulative weight percentage is 50%. Particle size uniformity Using the particle size when the cumulative weight percentage is 90% (d90) and the particle size when the cumulative weight percentage is 10% (d10), which is obtained when measuring the average particle size, is given by the following formula. Ask. Particle size uniformity = (d50 / d10 + d90 / d50) / 2 Coarse specific volume (ml / g) Using a granule passing through 1410 μm, measured by a powder tester and expressed as an average of five measurements. Angle of repose (degree) Measured with a powder tester using granules passing through 1410 μm, and expressed as an average of 5 measurements.

Method for evaluating physical properties of tablets: Tablet weight variation (CV value) The weight of 10 tablets is weighed and determined by the following formula.

CV value (%) = 100 × standard deviation (mg)
/ Average weight (mg) Hardness (N) Measured using a Schleunigel hardness tester (manufactured by Freund Corporation). Expressed as an average of ten. -Disintegration time (sec) Measure using distilled water in accordance with the disintegration time measurement method of the Japanese Pharmacopoeia 13 revision. Expressed as an average of six.

Table 1 shows the physical properties of the cellulose samples used in the present invention.

[0021]

Example 1 240 g of cellulose A (15 g in powder)
%), 1040 g of 200 mesh lactose (manufactured by DMV),
160 g of phenacetin (manufactured by Yamamoto Chemical Co., Ltd.) and 160 g of corn starch (manufactured by Nichien Chemical Co., Ltd.) were charged into a new speed kneader (model SK250, manufactured by Powtex),
Stir at 500 rpm for 1 minute and mix. Next, while stirring under the same conditions, 400 g of a 6% aqueous solution of hydroxypropylcellulose (low viscosity type: manufactured by Nippon Soda Co., Ltd.) was added in about 30 seconds, and the mixture was further stirred for 5 minutes. The obtained wet granules were dried at 40 ° C. overnight to obtain granules. Granules 1410 μm
After sieving, the physical properties of the granules were measured. Table 2 shows the results.

Subsequently, 800 g of the granules and 4 g of magnesium stearate were gently mixed in a polyethylene bag for 30 seconds, and then, using a rotary tableting machine (manufactured by Kikusui Seisakusho, Collect 12HUK), 2 g of 8 mm in diameter and 12R in size were used.
A 00 mg tablet was formed at a compression pressure of 100 MPa. Table 2 shows the physical properties of the obtained tablets.

[0023]

Example 2 The same operation as in Example 1 was carried out except that the amount of the 6% aqueous solution of hydroxypropylcellulose added during granulation was 290 g. Table 2 shows the results of the physical properties of the granules and tablets.

[0024]

Example 3 The same operation as in Example 1 was carried out except that the amount of the 6% aqueous solution of hydroxypropylcellulose added during granulation was 460 g. Table 2 shows the results of the physical properties of the granules and tablets.

[0025]

Example 4 The procedure of Example 1 was repeated, except that cellulose B was used instead of cellulose A, and the amount of the 6% aqueous solution of hydroxypropylcellulose was changed to 320 g.
Table 2 shows the results of the physical properties of the granules and tablets.

[0026]

Example 5 The same procedure as in Example 1 was carried out except that cellulose B was used instead of cellulose A and the amount of the 6% aqueous solution of hydroxypropylcellulose was changed to 380 g.
Table 2 shows the results of the physical properties of the granules and tablets.

[0027]

Example 6 80 g of cellulose A (5% in powder), 2
Using 1160 g of 00 mesh lactose (manufactured by DMV), 200 g of phenacetin (manufactured by Yamamoto Kagaku Kogyo), and 160 g of corn starch (manufactured by Nisseki Chemical) as powders, the addition amount of a 6% hydroxypropylcellulose aqueous solution was 240 g.
Except for that, the procedure was performed in the same manner as in Example 1. Table 2 shows the results of the physical properties of the granules and tablets.

[0028]

Example 7 400 g of cellulose A (25 in powder)
%), 880 g of 200 mesh lactose (manufactured by DMV), 200 g of phenacetin (manufactured by Yamamoto Kagaku Kogyo), and 120 g of corn starch (manufactured by Nisseki Chemical) as powders,
The amount of 6% hydroxypropylcellulose aqueous solution added was 4
It carried out similarly to Example 1 except having set it to 40 g. Table 2 shows the results of the physical properties of the granules and tablets.

[0029]

Example 8 240 g of cellulose A (15 g in powder)
%), 400 g of 200 mesh lactose (manufactured by DMV), 800 g of ascorbic acid (manufactured by Hoei Pharmaceutical Co., Ltd.), and 160 g of corn starch (manufactured by Nisseki Chemical) are charged in a new speed kneader (model SK250, manufactured by Powtex) at 500 rpm for 1 minute. Stir and mix. Next, while stirring under the same conditions, 350 g of a 6% aqueous solution of hydroxypropylcellulose (low-viscosity type: manufactured by Nippon Soda Co., Ltd.) was added in about 30 seconds, and the mixture was further stirred for 5 minutes. The obtained wet granules are heated at 40 ° C.
And dried overnight to obtain granules. After sieving the granules at 1410 μm, the physical properties of the granules were measured. Table 2 shows the results.

Subsequently, 800 g of the granules and 4 g of magnesium stearate were gently mixed in a polyethylene bag for 30 seconds, and then, using a rotary tableting machine (manufactured by Kikusui Seisakusho, Collect 12HUK), 2 g of 8 mm in diameter and 12R in size were used.
A 00 mg tablet was formed at a compression pressure of 100 MPa. Table 2 shows the physical properties of the obtained tablets.

[0031]

Example 9 The procedure of Example 8 was repeated, except that cellulose B was used instead of cellulose A, and the amount of the 6% aqueous solution of hydroxypropylcellulose was changed to 180 g.
However, for drying the wet granules, 1.3 kg of the wet granules were charged into a multiplex MP-01 equipped with a fluidized bed attachment, and were allowed to flow at an inlet temperature of 75 ° C. and an air flow of 500 L / min.
It dried until exhaust temperature reached 50 degreeC. Also, granules 80
After mixing 0 g and 100 g of cellulose A in a plastic bag for 2 minutes, 4 g of magnesium stearate was mixed, followed by tableting. Table 2 shows the results of the physical properties of the granules and tablets.

[0032]

Comparative Example 1 The same operation as in Example 1 was carried out except that 200 g of a 6% aqueous solution of hydroxypropylcellulose was added without adding cellulose powder. Table 3 shows the results of physical properties of granules and tablets.
Shown in

[0033]

Comparative Example 2 The same operation as in Example 1 was carried out except that the amount of the 6% aqueous solution of hydroxypropylcellulose used during granulation was changed to 200 g. Table 3 shows the results of the physical properties of the granules and tablets.

[0034]

Comparative Example 3 The same operation as in Example 1 was performed except that the amount of the 6% aqueous hydroxypropylcellulose solution added during granulation was changed to 550 g. Table 3 shows the results of the physical properties of the granules and tablets.

[0035]

Comparative Example 4 The operation was performed in the same manner as in Example 5, except that the granulation time was changed to 10 minutes. Table 3 shows the results of the physical properties of the granules and tablets.

[0036]

Comparative Example 5 560 g of cellulose A (35 in powder)
%), 740 g of 200 mesh lactose (manufactured by DMV), 200 g of phenacetin (manufactured by Yamamoto Kagaku Kogyo), and 100 g of corn starch (manufactured by Nisseki Chemical) as powders.
The amount of 6% hydroxypropylcellulose aqueous solution
It carried out similarly to Example 1 except having set it to 20 g. Table 3 shows the results of the physical properties of the granules and tablets.

[0037]

[Table 1]

[0038]

[Table 2]

[0039]

[Table 3]

[0040]

According to the tablet manufacturing method of the present invention in which a powder containing 2 to 30% by weight of a cellulose powder is granulated into granules having specific physical properties and the granules are compressed, the flowability of the granules is improved. Is good, the weight variation of the tablet is small,
In addition, a practical tablet having a fast disintegration time despite high tablet hardness can be produced.

Claims (1)

[Claims] 1. A method for producing tablets by wet granulation, comprising granulating granules by wet granulation of a powder containing 2 to 30% by weight of cellulose powder, and then compressing the granules. A method for producing a tablet, characterized by having a diameter of 60 to 300 µm, a particle size uniformity of 3.0 or less, a coarse specific volume of 1.5 to 2.5 ml / g, and a repose angle of 35 to 42 degrees.