JP2003238448A - Low substitution degree hydroxypropylcellulose and binder/disintegrator - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a binder/disintegrator for dry direct compressing, having excellent bondability and fluidity. <P>SOLUTION: The low substitution degree hydroxypropylcellulose comprising coiled fiber and having 0.1-0.5 substituted molar number of hydroxypropoxy is provided. The low substitution degree hydroxypropylcellulose preferably has ≥60 flow index and ≥130 N tablet hardness in evaluating fracture strength of a tablet obtained by compression molding of the hydroxypropylcellulose. A binder/disintegrator for dry direct compressing and a solid preparation each containing the hydroxypropylcellulose are provided. A method for producing the low substitution degree hydroxypropylcellulose, characterized by pelletizing a washed low substitution degree hydroxypropylcellulose with a kneader, is provided, wherein the hydroxypropylcellulose comprises the coiled fiber and has 0.1-0.5 substituted molar number of hydroxypropoxy. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a low-substituted hydroxypropylcellulose added for imparting disintegrating property or binding property when a preparation is manufactured in the fields of medicine or food, etc., and a method for manufacturing the same.

[0002]

2. Description of the Related Art In solid preparations such as pharmaceuticals or foods, preparations made only of the main drug do not show sufficient disintegration even when the drug is administered, resulting in insufficient efficacy or binding. Since it is inferior, there is a problem that the shape cannot be maintained when it is made into a tablet or granule. In such a case, disintegrating property and binding property can be imparted by adding low-substituted hydroxypropyl cellulose to the preparation.

As a device used for such a purpose,
In addition to low-substituted hydroxypropyl cellulose, there are calcium salts of carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, carboxymethyl starch, etc., but since low-substituted hydroxypropyl cellulose is non-ionic, It has the advantage that it is less likely to be altered by the reaction with substances.

[0004] Taking advantage of the above advantages, a method of dry-mixing low-substituted hydroxypropylcellulose powder with a drug or other excipient and then tableting or kneading with water or an aqueous solution of a water-soluble binder is used. There is a method of molding granules by granulating. This low-substituted hydroxypropyl cellulose is a pharmaceutical additive listed in the Japanese Pharmacopoeia, and its use as a pharmaceutical additive is described in Patent Documents 1 and 2.

The shape of the low-substituted hydroxypropyl cellulose is a powder consisting of a mixture of fibrous material and granular material, and it is said that the binding property when molding into tablets etc. is obtained by the entanglement of the fibrous material. It is being appreciated. On the other hand, if the amount of such fibrous substances is increased in order to increase the binding property, the powder becomes bulky and its fluidity is lowered. Therefore, in the method of tableting after dry-mixing low-substituted hydroxypropylcellulose and drugs or other excipients, generally in the method called dry direct-pressing, due to the low fluidity, the hopper of the tablet machine There was a problem that the tablet could not be pressed without flowing out from the tablet, or the weight deviation of the tablet was significantly increased. Patent Document 3 discloses low-substituted hydroxypropyl cellulose having a repose angle of 45 degrees or less and a swelling rate of 100% or more. in this case,
Although the fluidity is improved, there is a problem that the fibrous material is reduced and the binding property is reduced.

[0006]

[Patent Document 1] Japanese Patent Publication No. 46-42792

[Patent Document 2] Japanese Patent Publication No. 57-53100

[Patent Document 3] Japanese Patent Laid-Open No. 7-324101

[0007]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and the low-substituted hydroxypropylcellulose used as a binder and a disintegrating agent to be added when a tablet is molded has a high binding property. Its purpose is to be a binder and a disintegrating agent for dry direct pressing, which has high fluidity.

[0008]

Means for Solving the Problems As a result of intensive studies for achieving the above-mentioned object, the present inventors have found that the low-substituted hydroxypropylcellulose fibers are preferably formed into a coil shape by granulation to improve binding property and fluidity. The present inventors have found that it can be a binder / disintegrator for dry direct hitting with improved properties, and have completed the present invention.

Accordingly, the present invention provides a low-substituted hydroxypropylcellulose having a coiled fiber, a binder / disintegrator for dry direct compression and a solid preparation containing the same, and a low-substituted degree having a coiled fiber. A method for producing hydroxypropyl cellulose is provided.

[0010]

The present invention will be described in more detail below. The binder / disintegrant for dry direct compression of the present invention refers to the binder / disintegrator used when producing tablets and the like by the dry method. Dry direct pressing means mixing a drug and one or more selected from an excipient, a binder, and a disintegrant without using water or a solvent as a powder, and compression-molding the mixture using a tablet molding machine. This means a method of producing tablets and the like, which has an advantage that the process is simple because powder is simply mixed and compression molded.

The low-substituted hydroxypropyl cellulose used in the present invention has a substitution number of hydroxypropoxyl groups of 0.1 to 0.
It is 5. If the substitution mole number of the hydroxypropoxyl group is less than 0.1, the desired binding property is not exhibited, and if it exceeds 0.5, the desired disintegration property is not exhibited, and the disintegration time of the formulation such as a molded tablet is prolonged. .

The low-substituted hydroxypropylcellulose of the present invention needs to have high fluidity because powder is continuously supplied from the hopper of a tableting machine in dry direct compression, and a fluidity index of 60 or more is required. preferable. The upper limit of the flow index is not particularly limited as long as the bondability is obtained, but about 80 is particularly preferable. The above-mentioned fluidity index is an index of powder fluidity proposed by Carr. In addition to the degree of compression obtained from the following equation, the angle of repose, the spatula angle, and the uniformity are measured, and the index is calculated for each value. Ask. The details are described in “Revised Supplementary Powder Physical Property Illustration”, Powder Engineering Society of Japan, Japan Powder Industrial Technology Association, Nikkei Technical Book, 1985, p. 151. Compressibility (%) = {(solidified bulk density-relaxed bulk density) / solidified bulk density} × 100

Here, the loose bulk density means a bulk density of loose packing, and the loose bulk density is measured by a diameter of 5.03c.
m, height 5.03 cm (volume 100 ml), the sample was passed through a sieve of JIS22 mesh (710 μm) for 2
It can be measured by uniformly supplying from 3 cm above, scraping the upper surface and weighing the weight, and most typically, using a powder tester (PT-D) manufactured by Hosokawa Micron.

After measuring the loosened bulk density, a dedicated cap, which is an equipment of a powder tester manufactured by Hosokawa Micron Co., is attached to the upper part of the container after the loosened bulk density is measured, and a sample is added to the upper edge of the cap, and the tap height of 1.8 cm is applied 180 times. After tapping, the cap can be removed, the sample can be scraped off on the upper surface of the container, and measurement can be performed by the sample filling amount in a 100 ml container.

The angle of repose, the angle of Subatura and the uniformity are as described in R.S.
L. Carr, Jr. , Chemical Engi
neering, pp. 163-168, Janua
ry 18, measured in 1965. The angle of repose is JIS22 mesh (71
0.5 μm from a height of 11 cm through a 0 μm sieve.
It is obtained by dropping through a funnel having a diameter of cm, and measuring the angle between the ridgeline of the formed powder mountain and the table. The subatura angle is a ridge line and a plate of a powder formed by placing a subatula having a plate (blade) of 10 cm in the vertical direction and 2 cm in the horizontal direction on a lifting table, placing the powder on the lifting table and lowering the table. After obtaining the first measurement angle of the angle, the weight of 5 g was dropped from the height of 10 cm at one end of the subatula and the powder was formed by vibrating the subatula. It is possible to obtain 2 measurement angles and obtain the average value of both measurement angles. The uniformity is measured by measuring the particle size distribution of the powder and measuring 60%.
It is determined by the ratio of the integrated particle size and the 10% integrated particle size. As a method for measuring the particle size distribution, there are a measuring method using a sieve and a measuring method using a laser diffractometer. For example, in the case of a measuring method using a sieve, several sieves having different sieve openings are vertically stacked on top of each other, and the sample 50 is placed there.
After adding g and shaking for 20 minutes, the particle size distribution can be measured by measuring the weight on each sieve.

The usual low-substituted hydroxypropyl cellulose is a mixture of fibrous material and granular material, and the binding property is mainly obtained by the fibrous material and the fluidity is obtained by the granular material. The low-substituted hydroxypropyl cellulose can enhance this fluidity by utilizing the property of being soluble in an alkaline aqueous solution. More specifically, the alkali-containing low-substituted hydroxypropylcellulose reaction product that takes over the fibrous morphology of the raw material pulp is dissolved in water and neutralized and precipitated with an acid to change the morphology from a fibrous material to a granular material. It is achieved by However, the low-substituted hydroxypropylcellulose in a granular form obtained by once dissolving and then neutralizing in this way has a dense structure and the binding property during compression molding is reduced.

The low-substituted hydroxypropyl cellulose of the present invention has a form in which a linear fiber in a fibrous or granular form is rolled into a coil. Therefore, the apparent shape is spherical and excellent in fluidity. Further, when this is compression-molded, the fibers have high bondability. As an index of its connectivity, IR (infrare
d) Using a tablet molding machine, compression-mold 200 mg of low-substituted hydroxypropylcellulose in 9.8 MPa and 30 seconds,
A 10 mmφ tablet is produced, and the breaking strength in the major axis direction of the tablet can be evaluated. Generally, this strength is called tablet hardness. As a binder for dry direct compression, this tablet hardness is 13
It is preferably 0 N or higher, more preferably 150 N or higher. The upper limit of the tablet hardness is not particularly limited as long as disintegration is obtained, but is preferably 300 N or less.

The low-substituted hydroxypropyl cellulose of the present invention can be produced by granulating a washed product of low-substituted hydroxypropyl cellulose. The washed product of low-substituted hydroxypropyl cellulose is not particularly limited, and a known method for producing low-substituted hydroxypropyl cellulose can be used.

For example, after immersing the pulp in an aqueous solution of caustic soda and pressing, the alkali cellulose produced by pressing is reacted with propylene oxide, or the powdered pulp is reacted with caustic soda in an organic solvent such as isopropyl alcohol, tert-butyl alcohol and hexane. A reaction product can be obtained by adding an aqueous solution to prepare alkali cellulose, and adding propylene oxide to cause a reaction.

The low-substituted hydroxypropyl cellulose is soluble in an alkaline aqueous solution, and caustic soda used as a catalyst remains in the reaction product. After water is added to this reaction product to dissolve it, the remaining alkali is neutralized with an acid (for example, acetic acid, hydrochloric acid, sulfuric acid, etc.) to form neutralized precipitated particles of low-substituted hydroxypropylcellulose. Washing with water or hot water to remove salts and other impurities produced in this step, and removing water to obtain a washed product of low-substituted hydroxypropylcellulose can be performed.

The washed product of low-substituted hydroxypropyl cellulose is further subjected to a drying step and a crushing step to produce a conventional low-substituted hydroxypropyl cellulose. In the present invention, the low-substituted hydroxypropyl cellulose is subjected to the low-substituted hydroxypropyl cellulose before these steps. It is characterized by granulating a washed product of propylcellulose.

As the granulating device used for granulating the washed product of low-substituted hydroxypropyl cellulose, a vertical stirring granulating device, a horizontal stirring granulating device, a batch type kneading device, a horizontal short axis continuous kneading device, a horizontal type A biaxial continuous kneading device and the like can be mentioned, but a horizontal biaxial continuous kneading device is particularly preferable. In the case of a continuous kneading device, the apparent density and fluidity of the product can be adjusted by the residence time of the washed product in the machine.

The residence time in the case of using this continuous kneading device can be adjusted by the arrangement of the built-in paddles, the number of rotations, the opening of the discharge port, and the like. In addition, as a method for measuring the residence time, after adding a dye to the supply port, the reaction product granulated powder that comes out from the discharge port with time is sampled, and the highest concentration of the dye can be measured as the average residence time. . The residence time is about 30 to 300 seconds, although it varies depending on the desired apparent density of the product.

Such a continuous kneading device can shorten the granulation time and improve the processing speed as compared with the batch type mixing device. In addition, it is possible to process with a small device, and it is possible to reduce the equipment cost and installation place.

The continuous kneading apparatus which can be used in the present invention includes a uniaxial type and a biaxial type, but in the present invention, a biaxial type is preferable in terms of excellent kneading property. In such an apparatus, the residence time or the kneading state can be adjusted by combining the built-in paddles. Further, L / D, which is the ratio of the trough length to the paddle diameter of the continuous kneading device, may be about 5 to 13.

The influence of the temperature during granulation on the physical properties of the product is small and can be freely selected. The obtained granulated product may be dried by a conventional method, and the dried product thus obtained may be pulverized and classified as needed. The drying method is not particularly limited, and examples thereof include a method of drying at about 60 to 80 ° C using a blower oven and a method of drying at intake temperature of about 60 to 80 ° C by fluidized bed drying.

The low-substituted hydroxypropylcellulose of the present invention obtained in this manner serves as a binder / disintegrator for dry direct compression with improved bondability and fluidity. A solid preparation such as a tablet can be prepared by mixing the low-substituted hydroxypropylcellulose of the present invention and a drug in the form of powder and compression-molding the mixture using a tablet molding machine. The content of low-substituted hydroxypropylcellulose depends on the drug species, dosage form, etc., but is preferably 5 to 30% by weight in the solid preparation. The preferable average particle size of the powder to be mixed is determined in consideration of the mixture with the drug, the excipient, etc., but the preferable average particle size of the low-substituted hydroxypropylcellulose of the present invention is 50 to 50%. 300μ
m.

[0028]

EXAMPLES The present invention will be specifically described below by showing Examples and Comparative Examples, but the present invention is not limited to the following Examples. Example 1 Pulp was dipped in a 43 wt% caustic soda solution and pressed to obtain 22.2 wt% NaOH, 44.8 wt% cellulose,
Alkaline cellulose having a composition of 33.0% by weight of H ₂ O was obtained. 350 g of alkali cellulose in terms of cellulose was charged into a reactor having a volume of 5 L, and nitrogen substitution was performed. 79 g of propylene oxide (0.226 parts by weight:
(1 part by weight to cellulose) is added, and the jacket temperature is 45
The reaction was carried out at 65 ° C. for 2 hours and at 65 ° C. for 30 minutes, and the number of moles of hydroxypropoxyl group substitution per anhydrous glucose unit was 0.1.
857 g of 25 hydroxypropylcellulose crude reaction product was obtained. Next, add 5 L of batch type kneader with water at 45 ° C.
25 g and 52 g of glacial acetic acid were added, and all the reacted crude reaction products were added and dissolved. Then, 33 wt% acetic acid 6
Neutralization precipitation was performed by adding 33 g at a rate of 20 g / min. The neutralized precipitate was slurried with hot water and dehydrated with a centrifugal dehydrator for washing. This washed product is a biaxial continuous kneading device (KRC kneader S2 type, paddle diameter: 50 mmφ, barrel length: 660) at a rate of 300 g / min.
mm, L / D: 13.2, internal volume: 1.2 L manufactured by Kurimoto Tekko Co., Ltd., using a rotation speed of 100 rpm and a residence time of 105.
Second, granulation was performed at a jacket temperature of 60 ° C. The obtained granules are dried at 80 ° C. in a ventilation oven for 24 hours and then crushed to
The product was passed through a 50-mesh (mesh opening 100 μm) sieve, and the product on the sieve was collected to obtain the desired product. Table 1 shows the fluidity index, binding property and disintegration property of the obtained target product.

Example 2 Pulp was dipped in a 43 wt% caustic soda solution and pressed to obtain alkali cellulose having a composition of 22.2 wt% NaOH, 44.8 wt% cellulose and 33.0 wt% H ₂ O. 350 g of alkali cellulose in terms of cellulose was charged into a reactor having a volume of 5 L, and nitrogen substitution was performed.
To this, 79 g (0.226 parts by weight: 1 part by weight of cellulose) of propylene oxide was added, and the reaction was carried out at a jacket temperature of 45 ° C. for 2 hours and at 65 ° C. for 30 minutes to give a hydroxypropoxyl group-substituted mole per anhydrous glucose unit. Number 0.25 hydroxypropylcellulose crude reaction product 857
g was obtained. Next, 1925 g of water at 45 ° C. and 52 g of glacial acetic acid were added to a 5 L batch type kneader, and all the crude reaction products reacted in the same manner as in Example 1 were charged and dissolved. Then, 633 g of 33 wt% acetic acid was added at a rate of 20 g / min to perform neutralization precipitation. The neutralized precipitate was slurried with hot water and dehydrated with a centrifugal dehydrator for washing. This washed product is a biaxial continuous kneading device (KRC kneader S2 type, paddle diameter: 50 m) at a speed of 300 g / min.
mφ, barrel length: 660 mm, L / D: 13.2, internal volume: 1.2 L, manufactured by Kurimoto Tekko Co., Ltd., and the number of revolutions is 100.
Granulation was carried out at a jacket temperature of 60 ° C. with a rpm of 105 seconds. The obtained granulated product was dried in a ventilation oven at 80 ° C. for one day and then crushed to obtain 150 mesh (opening 100
(μm) was passed through a sieve to obtain the target product (sieved product). Table 1 shows the fluidity index, binding property and disintegration property of the obtained target product.

Example 3 The crude reaction product obtained by carrying out the reaction in the same manner as in Example 1 was charged in a 5 L batch-type kneader with 2450 g of water at 45 ° C. and 104 g of glacial acetic acid, and in the same manner as in Example 1. All the reacted crude reaction products were added and dissolved. Then 33
Neutralization precipitation was carried out by adding 468 g of acetic acid in weight% at a rate of 20 g / min. The neutralized precipitate was slurried with hot water and dehydrated with a centrifugal dehydrator for washing.
This cleaning product is a biaxial continuous mixing device (KRC kneader S2 type, paddle diameter: 50 mmφ, barrel length: 660 mm, L / D: 13.2, internal volume: 1.2 at a rate of 300 g / min.
L Kurimoto Tekko Co., Ltd.) was used for granulation at a rotation speed of 100 rpm, a residence time of 105 seconds, and a jacket temperature of 60 ° C.
The obtained granulated product was dried in a blowing oven at 80 ° C. for one day, then pulverized, and sieved with a 150 mesh (mesh opening 100 μm) sieve to obtain a target product (sieve product). Table 1 shows the fluidity index, binding property and disintegration property of the obtained target product.

Comparative Example 1 Pulp was dipped in a 43% by weight caustic soda solution and pressed to obtain 22.2% by weight of NaOH and 44.8% by weight of cellulose.
Alkaline cellulose having a composition of 33.0% by weight of H ₂ O was obtained. 350 g of alkali cellulose in terms of cellulose was charged into a reactor having a volume of 5 L, and nitrogen substitution was performed. 79 g of propylene oxide (0.226 parts by weight:
(To cellulose) and reacted at a jacket temperature of 45 ° C. for 2 hours and at 65 ° C. for 30 minutes to obtain 857 g of a crude reaction product of hydroxypropylcellulose having 0.25 mol of hydroxypropoxyl group-substituted moles per anhydrous glucose unit. . Next, 1925 g of water at 45 ° C. and 104 g of glacial acetic acid were added to a 5 L batch type kneader, and all the crude reaction products reacted in the same manner as in Example 1 were charged and dissolved. Then, 473 g of 33 wt% acetic acid was added at a rate of 20 g / min to perform neutralization precipitation. The neutralized precipitate is slurried with hot water,
Washing was performed by dehydrating with a centrifugal dehydrator. The obtained washed product was dried in a ventilation oven at 80 ° C. for one day, crushed, and then sieved with a 150 mesh (mesh opening 100 μm) sieve to obtain an intended product (sieve product). Table 1 shows the fluidity index, binding property and disintegration property of the obtained target product.

Comparative Example 2 Crude reaction was carried out in the same manner as in Example 1 by reacting the crude reaction product obtained by the reaction in the same manner as in Example 1 with 2450 g of water at 45 ° C. in a 5 L batch type kneader. All the products were added and dissolved. Then, 33 wt% acetic acid 78
Neutralization precipitation was performed by adding 0 g at a rate of 20 g / min.
The neutralized precipitate was slurried with hot water and dehydrated with a centrifugal dehydrator for washing. After neutralization and washing, the washed product is dried at 80 ° C. in a ventilation oven for one day and then pulverized, and then sieved with a 150 mesh (opening 100 μm) sieve to obtain a target product (sieved product). It was Table 1 shows the fluidity index, binding property and disintegration property of the obtained target product.

The evaluation test method will be described below. A fluidity index powder tester (manufactured by Hosokawa Micron Co., Ltd.) was used to measure the degree of compression, the angle of repose, the spatula angle, and the homogeneity, and the respective indexes were summed.

Bondability 200 mg of each target product was weighed and pressed with an IR tablet molding machine at 9.8 MPa for 30 seconds to prepare a tablet having a diameter of 10 mm, and the hardness of the tablet was measured.

Disintegration According to the disintegration test of Japanese Pharmacopoeia 13, 37 as a test solution
The disintegration time was measured using water at ° C. The above test results are shown in Table 1.

[0036]

[Table 1]

From the above results, it can be seen that the low-substituted hydroxypropyl cellulose of the present invention is a powder having a high binding property and an excellent fluidity. Further, it can be used as a base material for dry direct hitting which is excellent in its disintegration property.

SEM photographs of the low-substituted hydroxypropyl cellulose obtained in Example 1 and Comparative Example 1 are shown in FIGS. 1 and 2, respectively. In the SEM photograph of FIG. 1, a state in which fibers of low-substituted hydroxypropylcellulose, which is a feature of the present invention, were granulated in a coil shape, and this had high fluidity and high binding property. In the SEM photograph of FIG. 2, many fibrous substances of low-substituted hydroxypropyl cellulose were observed, and these had high binding properties but low fluidity.

[0039]

EFFECTS OF THE INVENTION By forming a fiber of low-substituted hydroxypropylcellulose into a coil, it can be used as a base material for dry direct-casting as a binder and a disintegrant having high bondability and fluidity.

[Brief description of drawings]

FIG. 1 shows a 75 times SEM photograph of the low-substituted hydroxypropyl cellulose obtained in Example 1.

FIG. 2 shows a 75 times SEM photograph of the low-substituted hydroxypropyl cellulose obtained in Comparative Example 1.

Continued front page    (72) Inventor Hiroshi Umezawa             28, Nishi-Fukushima             1 Shin-Etsu Chemical Co., Ltd. Synthesis Technology Laboratory             Within F-term (reference) 4B035 LE01 LG26 LK09                 4C076 AA37 BB01 EE32A EE32B                       FF05 FF06 GG12                 4C090 AA02 AA08 BA34 BB03 BB12                       BB33 BB36 BB52 DA08 DA11                       DA23 DA27

Claims (6)

[Claims] 1. A low-substituted hydroxypropyl cellulose having coil-shaped fibers and having a hydroxypropoxyl group substitution mole number of 0.1 to 0.5. 2. The low-substituted hydroxypropyl cellulose according to claim 1, which has a flow index of 60 or more. 3. The low-substituted hydroxypropyl group according to claim 1, which has a tablet hardness of 130 N or more for evaluating the breaking strength of a tablet obtained by compression molding hydroxypropyl cellulose. cellulose. 4. A binder / disintegrator for dry direct compression, which comprises the low-substituted hydroxypropylcellulose according to claim 1. 5. A solid preparation comprising the dry direct hitting binder / disintegrator according to claim 4 and a drug. 6. A coil-shaped fiber characterized in that a washed product of low-substituted hydroxypropylcellulose having a hydroxypropoxyl group substitution mole number of 0.1 to 0.5 is granulated by a kneading device. A method for producing a low-substituted hydroxypropyl cellulose having the same.