JP2012214417A - Disintegrating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a disintegrating agent capable of absorbing a large amount of water in a short time, to be swollen, by quickening a water permeation speed into the disintegrating agent, since the disintegrating agent of high water absorption speed is required to attain quick disintegration of an oral disintegrating tablet.SOLUTION: Hydrophobic powder (B) is mixed with a water-swelling polymer (A) swollen preliminarily by water, a mixture therein is dried thereafter to be granulated, and the disintegrating agent includes thereby the hydrophobic powder (B) in an inside of the water-swelling polymer (A).

Description

The present invention relates to a disintegrant. More specifically, the present invention relates to a disintegrant that exhibits excellent disintegration properties by rapidly absorbing water.

In the fields of pharmaceuticals and foods, various substances called disintegrants are used as additives for rapidly disintegrating solid preparations in the oral cavity, stomach, intestine and the like and releasing active ingredients. The disintegrant absorbs moisture and expands to disintegrate the tablet, and has a function of facilitating the release of the active ingredient.
At present, as the disintegrant, naturally derived polymers such as starch derivatives and cellulose derivatives and synthetic polymers such as crosslinked polyvinylpyrrolidone are mainly used.

In order to develop excellent disintegration performance, the disintegrant needs to absorb the liquid quickly and swell appropriately. Increasing the disintegration rate of a solid preparation can be achieved by increasing the amount of disintegrant added, but this increases the solid preparation, making oral administration difficult, and reducing the hardness of the solid preparation. Problems occur.
As means for improving the disintegration rate by improving the disintegrant, a disintegrant obtained by surface-treating a cellulose derivative with a surfactant or the like (Patent Document 1), or a method of impregnating a cellulose derivative with a water-soluble substance such as sugar (Patent Document) 2) is known.

JP 2000-351737 A Japanese Patent Laid-Open No. 2002-104956

However, by developing a dosage form that is easy to take for the elderly and children with low swallowing function, patients with restricted water intake, etc., to further improve the quality of life and improve compliance The current orally disintegrating tablet does not have a sufficient disintegration rate, and there is a need for an orally disintegrating tablet with a shorter disintegration time.
Therefore, by providing a specific substance in the water-swellable polymer, the water penetration rate into the water-swellable polymer is increased, and a disintegrant that absorbs and swells a large amount of water in a short time is provided. It is an object of the present invention.

The inventors of the present invention have reached the present invention as a result of studies to achieve the above object.
That is, in the present invention, the hydrophobic powder (B) is mixed with the water-swellable polymer (A) previously swollen with water and then dried to form particles, whereby the hydrophobic powder (B) is converted into water. The disintegrant is contained in the swellable polymer (A) and has a water swell ratio of 200 to 1000%.

When the disintegrant of the present invention is applied to an orally disintegrating tablet, it has a high water absorption rate, and therefore can exhibit excellent disintegration performance.

In the present invention, the hydrophobic powder (B) is water-swellable by mixing the hydrophobic powder (B) with the water-swellable polymer (A) previously swollen with water and then drying to form particles. It is a composition present inside the polymer (A).
The hydrophobic powder (B) is present inside the water-swellable polymer (A), so that the water absorption rate of the composition is increased. Therefore, when the composition is used as a disintegrant, excellent disintegration performance is exhibited. To do.
That is, in the disintegrant of the present invention, since the hydrophobic powder (B) is present inside the water-swellable polymer (A), the water-swellable polymer (A) alone or the hydrophobic powder ( Compared with the case where B) is present on the surface of the water-swellable polymer (A), it is possible to absorb water and swell in a short time.

The water-swellable polymer (A) of the present invention has a water swelling rate defined by the following formula (1) of 200 to 1000%, preferably 200 to 800. If it is less than 200, the volume increase when water is sucked is too small, and the disintegration property becomes insufficient.

Water swelling rate (%) = [W ₁ −W ₀ ] / W ₀ × 100 (1)

Where W ₁ is the weight (g) of the water-swellable polymer or disintegrant after absorbing water for 30 minutes, and W ₀ is the weight of the dried water-swellable polymer or disintegrant before water absorption ( g).

  Further, the water swelling rate after 5 seconds defined by the following formula (2) is defined as the initial water swelling rate.

Initial water swelling rate (%) = [W ₂ −W ₀ ] / W ₀ × 100 (2)

Where W ₂ is the weight (g) of the water-swellable polymer or disintegrant after absorbing water for 5 seconds, and W ₀ is the weight of the dried water-swellable polymer or disintegrant before water absorption ( g).
This initial water swelling rate is an index of the ease of water absorption in a short time and affects the disintegration rate of the disintegrant.
Further, the initial water swelling ratio / water swelling ratio is an index of the water absorption rate, and is usually 0.8 to 1.0, preferably 0.9 to 1.0.

The water swelling rate and initial water swelling rate of the water-swellable polymer (A) or disintegrant are measured by the following method and calculated according to the mathematical formula.
<Water swelling ratio measurement method>
(1) About 2 g of the test sample is placed on a pulp paper (Nippon Paper Crecia Kimwipe S-200; 12.0 cm × 21.5 cm), folded so as not to spill, and then stapled.
(2) After being immersed in ion exchange water at 20 ° C. for 30 minutes, it is taken out.
(3) The sample taken out is placed on a wire mesh (aperture 1 to 10 mm) and drained for 30 seconds, and then the weight w ₁ is measured. The same measurement is performed three times for one type of sample, and the average value is obtained.
(4) Perform operations (1) to (3) in the same manner even with only pulp paper without a test sample, and set the total weight of pulp paper and stapler after operation (1) to p ₀ , and _then operate (3) the sum of the weight of the pulp paper and stapler after the p _1.
(5) weight increase of pulp paper and stapler from _{w 1} you are prompted to minus _(p 1 -p ₀₎ and _{W 1.}
(6) In the case of the initial water swelling rate, the immersion time is 5 seconds, and the weight W ₂ is measured in the same manner.

The weight average molecular weight of the water-swellable polymer (A) in the present invention is usually 10,000 to 1,000,000.
The conditions for measuring the weight average molecular weight of the water-swellable polymer (A) are determined by gel permeation chromatography (GPC) using an appropriate solvent capable of dissolving the water-swellable polymer (A). However, the type of solvent and the standard substance are not particularly limited.

For example, when the water-swellable polymer (A) is croscarmellose sodium, the weight average molecular weight is measured under the following conditions.
(Examples of weight average molecular weight measurement conditions)
GPC device: HLC-8120GPC manufactured by Tosoh Corporation
Calibration curve material: Polyethylene glycol (TSK STANDARD POLYETHYLENE OXIDE manufactured by Tosoh Corporation)
Column: TSK gel G5000pwXL, TSK gel G3000pwXL, manufactured by Tosoh Corporation
Column temperature: 40 ° C
Detector: RI
Solvent: water / methanol (volume ratio 70/30)
Flow rate: 1.0 ml / min Sample concentration: 0.25%
Injection volume: 200 μl

The type of water-swellable polymer (A) is not particularly limited, and natural polymers such as cellulose derivatives and starch derivatives and derivatives thereof, polyvinylpyrrolidone crosslinked products, poly (meth) acrylic acid crosslinked products, and the like A molecule etc. can be used.

Examples of natural polymers used as the water-swellable polymer (A) include croscarmellose sodium, carmellose potassium, carmellose calcium, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, low-substituted hydroxypropyl cellulose; hydroxypropyl Starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, starch acrylate; gelatin, hydrolyzed gelatin, succinylated gelatin, soybean lecithin, dextran, pullulan and the like.

Examples of the synthetic polymer used as the water-swellable polymer (A) include povidone, crospovidone, carboxyvinyl polymer, sodium polyacrylate, partially neutralized polyacrylic acid, and polyvinyl alcohol.

Among the water-swellable polymers (A), croscarmellose sodium, carmellose calcium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, partially pregelatinized starch, and crospovidone are preferable from the viewpoint of swelling degree.
The water-swellable polymer (A) may be used alone or in combination of two or more.

Water-swellable polymers (A) used as raw materials for disintegrants for pharmaceutical tablets are those listed in the pharmacopoeia and pharmaceutical additive standards of each country, or food additives stipulated by the Food Sanitation Law It is preferable to select from products.

The hydrophobic powder (B), which is another essential component of the disintegrant of the present invention, is not particularly limited as long as it is a hydrophobic powder, but its solubility in water at 20 ° C. is 1000 mg / 100 mL. Hereinafter, the powder is preferably 900 mg / 100 mL or less.
If it is not hydrophobic, the penetration rate of water into the disintegrant will not be improved.

Specific examples of suitable hydrophobic powder (B) that can be used in the disintegrant of the present invention include polyolefin resin, polyolefin resin derivative, polystyrene resin, polystyrene resin derivative, long chain fatty acid ester, long chain fatty acid or salt thereof, long Examples include chain aliphatic alcohols.

Of the hydrophobic powder (B), fatty acids having 8 to 30 carbon atoms and metal salts thereof are preferable from the viewpoint of safety in the body.

Specific examples of the fatty acid having 8 to 30 carbon atoms include lauric acid, palmitic acid, stearic acid, oleic acid, dimer acid, and behenic acid.
Examples of the metal salt include salts with zinc, calcium, magnesium, aluminum {eg, calcium palmitate, aluminum palmitate, zinc stearate, calcium stearate, magnesium stearate, aluminum stearate, etc.).

Of the fatty acids and metal salts thereof used as the hydrophobic powder (B), zinc stearate, calcium stearate, magnesium stearate, and aluminum stearate are preferable from the viewpoint of hydrophobicity, and more preferably magnesium stearate. It is.

Hydrophobic powder (B) may be used alone or in combination of two or more.

The weight average particle diameter of the hydrophobic powder (B) is preferably 1 to 100 μm, more preferably 2 to 50 μm, and particularly preferably 3 to 20 μm. Within this range, the dispersibility of the hydrophobic powder (B) in the disintegrant will be good.

In addition, the weight average particle diameter was measured using a low-tap test sieve shaker and a standard sieve (JIS Z8801-1: 2006), Perry's Chemical Engineers Handbook, 6th edition (McGlow Hill Book Company, 1984). , Page 21).
That is, JIS standard sieves are combined in the order of 1000 μm, 850 μm, 710 μm, 500 μm, 425 μm, 355 μm, 250 μm, 150 μm, 125 μm, 75 μm and 45 μm, and a tray from the top. About 50 g of the measured particles are put in the uppermost screen and shaken for 5 minutes with a low-tap test sieve shaker. Weigh the measured particles on each sieve and the pan, and calculate the weight fraction of the particles on each sieve with the total as 100% by weight. This value is the logarithmic probability paper {the horizontal axis is the sieve aperture (particle size ), The vertical axis is plotted in the weight fraction}, a line connecting the points is drawn, and the particle diameter corresponding to the weight fraction of 50% by weight is obtained, and this is defined as the weight average particle diameter.

The water-swellable polymer (A) and the hydrophobic powder (B) do not exhibit performance if they are simply blended, and the hydrophobic powder (B) is present inside the water-swellable polymer (A). Must be mixed.
However, the mixing method is not particularly limited as long as the hydrophobic powder (B) is mixed so that it exists inside the water-swellable polymer (A). In addition, it is preferable to mix uniformly so that mixing may be carried out.

  When the hydrophobic powder (B) is a fatty acid salt, a metal hydroxide such as magnesium hydroxide and a fatty acid may be mixed and added, or may be added individually.

The hydrophobic powder (B) is mixed with a water-containing gel of a water-swellable polymer (A) swollen in advance with water.
The water-containing gel of the water-swellable polymer (A) containing the hydrophobic powder (B) can be shredded as necessary.

When the hydrophobic powder (B) is mixed during the drying of the water-swellable polymer (A) pre-swelled with water, as a mixing device, a Bexmill, a rubber chopper, a Pharmamill, a mincing machine, an impact pulverizer And usual apparatuses, such as a roll-type grinder, can be used.

The content of the hydrophobic powder (B) with respect to the water-swellable polymer (A) is usually 0.1 to 520% by weight, preferably 0.2 to 10% by weight, more preferably 0.5 to 5% by weight. is there. If the amount is less than 0.1% by weight, the effect of improving the absorption rate is low, and if it exceeds 20% by weight, the amount of the hydrophobic powder (B) present on the surface of the water-swellable polymer (A) increases and the water absorption is inhibited.

In the disintegrant of the present invention, in addition to the water-swellable polymer (A) and the hydrophobic powder (B), disintegrants other than the present invention, bases, excipients, lubricants, binders Further, it may contain appropriate additives such as thickeners, stabilizers, preservatives, coating agents, flavoring agents, flavoring agents, emulsifiers, flavoring agents, and coloring agents.

There is no particular limitation on the shape of the disintegrant, and examples thereof include an irregularly crushed shape, a flake shape, a pearl shape, and a rice grain shape. Among these, from the viewpoint of moldability at the time of solid preparation, an amorphous crushed shape is preferable.

The disintegrant of the present invention can be used for pharmaceuticals, foods, agricultural chemicals, fertilizers, etc., and becomes a solid pharmaceutical preparation, a solid composition for food, a solid composition for agricultural chemical, and a solid composition for fertilizer, respectively.
In particular, it is very useful as a solid pharmaceutical preparation.

Hereinafter, although an example and a comparative example explain the present invention further, the present invention is not limited to these. Hereinafter, unless otherwise specified, “%” represents “% by weight” and “parts” represents “parts by weight”.

Example 1
100 parts of croscarmellose sodium (A-1) (Kycolate ND-2HS manufactured by Asahi Kasei Chemicals Co., Ltd.) and 100 parts of ion-exchanged water were placed in a beaker, mixed and stirred to obtain a hydrous gel.
Next, while cutting 100 parts of this hydrogel with a mincing machine (12VR-400K manufactured by ROYAL), 0.05 part of magnesium stearate (B-1) was added and mixed to obtain a chopped gel. Further, the chopped gel was dried with a ventilation type band dryer (150 ° C., wind speed 2 m / sec) to obtain a dried product. The dried product was pulverized with a juicer mixer (OSTERIZER BLENDER manufactured by Oster) to obtain a disintegrant powder (X-1).

Example 2
In Example 1, the same operation as in Example 1 was performed except that 0.05 part of magnesium stearate (B-1) was changed to 2.5 parts of calcium stearate (B-2), and the disintegrant powder of the present invention Body (X-2) was obtained.

Example 3
In Example 1, 100 parts of croscarmellose sodium (A-1) was changed to 100 parts of low-substituted hydroxypropylcellulose (A-2) (manufactured by Shin-Etsu Chemical Co., Ltd .; L-HPC LH-22), and magnesium stearate ( B-1) The same operation as in Example 1 was carried out except that 0.05 part of stearic acid (B-3) (Japanese Pharmacopoeia purified stearic acid 750V manufactured by Kao Corporation) was 1.0 part. Disintegrant powder (X-3) was obtained.

Example 4
In Example 1, 100 parts of croscarmellose sodium (A-1) was taken as 100 parts of low-substituted hydroxypropylcellulose (A-2), and 0.05 part of magnesium stearate (B-1) was taken as magnesium stearate (B -1) Except for 0.25 part, the same operation as in Example 1 was performed to obtain a disintegrant powder (X-4) of the present invention.

Example 5
In Example 1, 100 parts of croscarmellose sodium (A-1) was used as 100 parts of crospovidone (A-3) (Collidon CL manufactured by BASF), and 0.05 part of magnesium stearate (B-1) was calcium stearate. (B-2) Except for 0.5 part, the same operation as in Example 1 was performed to obtain a disintegrant powder (X-5) of the present invention.

Example 6
In Example 1, 100 parts of croscarmellose sodium (A-1) was used as 100 parts of crospovidone (A-3), and 0.05 part of magnesium stearate (B-1) was magnesium stearate (B-1) 2. The same operation as in Example 1 was carried out except that the amount was changed to 5 parts to obtain a disintegrant powder (X-6) of the present invention.

Comparative Example 1 <Method for Producing Disintegrant Powder without Adding Hydrophobic Powder>
100 parts of croscarmellose sodium (A-1) and 100 parts of ion-exchanged water were stirred and mixed to obtain a hydrous gel. Next, 100 parts of this hydrogel was cut with a mincing machine to obtain a chopped gel. Further, the chopped gel was dried with a ventilation band dryer to obtain a dried product. The dried product was pulverized with a juicer mixer to obtain a disintegrant powder (X′-1).

Comparative Example 2
In Comparative Example 1, the same procedure as in Comparative Example 1 was performed, except that 100 parts of croscarmellose sodium (A-1) was changed to 100 parts of low-substituted hydroxypropylcellulose (A-2). X′-2) was obtained.

Comparative Example 3
In Comparative Example 1, the same procedure as in Comparative Example 1 was performed, except that 100 parts of croscarmellose sodium (A-1) was changed to 100 parts of crospovidone (A-3), and the disintegrant powder (X′-3 )

Comparative Example 4 <Manufacturing Method Simply Mixing B>
Disintegrating powder (X′-4) was obtained by adding 2.5 parts of calcium stearate (B-2) to 100 parts of croscarmellose sodium (A-1) and mixing.

Comparative Example 5
In Comparative Example 4, 100 parts of croscarmellose sodium (A-1) was used as 100 parts of low-substituted hydroxypropyl cellulose (A-2), and 2.5 parts of calcium stearate (B-2) was used as magnesium stearate (B- 1) Except for 5.0 parts, the same operation as in Comparative Example 4 was performed to obtain a disintegrant powder (X′-5).

Comparative Example 6
In Comparative Example 4, 100 parts of croscarmellose sodium (A-1) was changed to 100 parts of crospovidone (A-3), 2.5 parts of calcium stearate (B-2) was added to magnesium stearate (B-1) 0. Except for 5 parts, the same operation as in Comparative Example 4 was performed to obtain a disintegrant powder (X′-6).

Comparative Example 7
In Example 1, 100 parts of croscarmellose sodium (A-1) was used as 100 parts of crospovidone (A-3), and 0.05 part of magnesium stearate (B-1) was used as mannitol (B′-1) (Towa). A disintegrant powder (X′-7) was obtained in the same manner as in Example 1, except that 2.5 parts of Mannite P) manufactured by Kasei Kogyo Co., Ltd. was used.

Disintegrant powders (X-1) to (X-6) of the present invention prepared in Examples 1 to 6, and disintegrant powder (X′-1) for comparison prepared in Comparative Examples 1 to 7 About (X′-7), the initial water swelling ratio and the water swelling ratio were measured by the above-described method for measuring the water swelling ratio, and the results are shown in Table 1.
The value of initial water swelling ratio / water swelling ratio was used as an index of absorption rate.

The disintegrants of Examples 1 to 6 of the present invention showed a very high absorption rate because the difference between the values of the water swelling rate and the initial water swelling rate was small.
On the other hand, Comparative Examples 1 to 3, which are disintegrants not containing the hydrophobic powder (B), have a large difference between the initial water swelling rate and the water swelling rate and a low water absorption rate.
In Comparative Examples 4 to 6, in which the hydrophobic powder is simply mixed, the difference between the water swelling rate and the initial water swelling rate is large because the hydrophobic powder does not exist inside the water-swellable polymer. Low.
In Comparative Example 7, since the solubility of the kneaded powder in water is high, both the initial water swelling rate and the water swelling rate are low, and the difference between the initial water swelling rate and the water swelling rate is large, so the water absorption rate is low. .

  Since the disintegrant of the present invention has an excellent water absorption rate, it is useful as a disintegrant for orally disintegrating tablets. Moreover, the solid formulation using the disintegrant of this invention can be used for various uses, such as a food use, an agrochemical use, and a fertilizer use.

Claims (8)

The hydrophobic powder (B) and the water-swellable polymer (A) swollen in advance with water are mixed and then dried to form particles, whereby the hydrophobic powder (B) is converted into a water-swellable polymer (A). ), And the water-swellable polymer (A) has a water swelling ratio of 200 to 1000%. The disintegrant according to claim 1, comprising 0.1 to 20% by weight of the hydrophobic powder (B) with respect to the water-swellable polymer (A). The disintegrant according to claim 1 or 2, wherein the hydrophobic powder (B) has a solubility in water at 20 ° C of 1000 mg / 100 mL or less. The disintegrant according to any one of claims 1 to 3, wherein the hydrophobic powder (B) is a fatty acid having 8 to 30 carbon atoms or a metal salt thereof. An orally disintegrating composition containing the disintegrant according to any one of claims 1 to 4. A solid pharmaceutical preparation comprising the disintegrant according to any one of claims 1 to 4. The solid composition for foods containing the disintegrating agent in any one of Claims 1-4. The solid composition for agricultural chemicals or fertilizer containing the disintegrating agent in any one of Claims 1-4.