JP2856485B2 - Granule-containing tablets - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a tablet containing granules. More particularly, the present invention relates to tablets containing coated granules.

[Conventional technology]

As a means of improving the stability of medicinal ingredients and masking taste,
Alternatively, the drug is often coated as a means of controlling the release of a long-acting drug or as a means of enteric solubilization. In most cases, this coating is applied to tablets and granules, but when it is turned into granules, it is almost always filled into capsules to form capsules from the viewpoint of handleability. From the viewpoint of cost, ease of drinking, etc., it is preferable to add excipients and compress them into tablets, rather than filling them into capsules.However, they have a coating such as long-acting coated granules or enteric coated granules. When the granules are compressed into tablets, there is a problem that the coating film is damaged by the compressive stress and the dissolution rate of the drug in a medium such as gastric juice is increased. To prevent this, lactose, microcrystalline cellulose,
Japanese Patent Application Laid-Open No. 53-142520 describes that it is sufficient to use a large amount of starch.
No. in the official gazette. Among them, it is stated that crystalline cellulose is particularly effective. JP-A-61-221115 discloses a method using about 10 to about 50% of crystalline cellulose to a tablet.

[Problems to be solved by the invention]

It is said that if a large amount of crystalline cellulose or starch is used, damage to the coating film during compression can be suppressed, but conventionally used crystalline cellulose and starch are not yet sufficient, and the damage to the coating film on the compressor is not sufficient. This causes a problem that the dissolution rate of the drug increases.
For example, FIG. 2 of JP-A-61-221115 describes that enteric-coated granules are tableted by mixing 20% of crystalline cellulose with respect to the total tablet weight. However, elution of about 20% of the drug was observed at an elution time of 1 hour, and the coating film was damaged by tableting, and it was insufficient to suppress the film damage with crystalline cellulose.

[Means and actions for solving the problems]

It is an object of the present invention to provide tableted pharmaceutical tablets in which granules with a coating, especially granules with a long-lasting or enteric coating, are compressed without damaging the coating film.

That is, the present invention is a granule-containing tablet containing, in a granule having a coating, crystalline cellulose and a processed starch having a swelling volume of 3 ml / g or more.

According to the present invention, when tableting granules having a coating, damage to the coating film is extremely small as compared with conventional crystalline cellulose, or a combination of crystalline cellulose and raw starch, and an increase in drug dissolution rate due to tableting is suppressed. It became possible.

 Hereinafter, the present invention will be described in detail.

The granules having a coating according to the present invention can be obtained by film-coating granules containing one or more drugs. As a coating film,
There are special-effect coatings and enteric coatings. Specifically, cellulose-based coating agents such as ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate, or acrylic polymer-based coating agents such as Eudragit R
There are S, Eudragit L, Eudragit NE, or shellac, silicone resin, and the like. These may be used alone or in combination of two or more. Further, a water-soluble substance, a plasticizer, a stabilizer and the like for adjusting the dissolution rate may be added as required. These coating agents may be coated on granules after being dissolved in an organic solvent, or may be coated on granules after being suspended in water.

 The crystalline cellulose used in the present invention has been conventionally used.
Crystalline cellulose, such as Asahi Kasei Kogyo Co., Ltd.
Product Name: Avicel PH-101, PH-102, PH-301, PH-3
02, or their crushed products.

The modified starch used in the present invention is not subjected to a chemical treatment,
A pregelatinized starch obtained by thermally or mechanically treating starch is required to have a swelling volume of 3 ml / g or more. If the swelling volume is less than 3 ml / g, there is no significant difference from the raw starch and the desired result cannot be obtained. Such a modified starch includes a modified starch described in JP-B-59-47600. In particular, partially pregelatinized starch which substantially maintains the outer shell thin film structure of raw starch granules is preferable. Partially pregelatinized starch refers to a shell thin film of raw starch particles obtained by heating raw starch particles such as corn starch and rice starch at a temperature slightly higher than the gelatinization start temperature specific to the raw starch particles in the presence of moisture. It is obtained by swelling without destroying the structure and then drying without destroying the outer shell thin film structure.

 Of partially pregelatinized starch that can be used in the present invention.
As commercially available products, for example, PCS manufactured by Asahi Kasei Corporation
Is raised.

When granules having a coating are tabletted, when microcrystalline cellulose and a processed starch having a swelling volume of 3 ml / g or more are used as an excipient, microcrystalline cellulose or a combination of microcrystalline cellulose and raw starch is used as an excipient. As compared with the case where the granules are used, damage to the coating film during compression is suppressed, and long-lasting granules maintain long-lasting properties, while enteric-coated granules maintain gastric juice resistance. It is presumed that the starch has an amorphous structure due to thermal or mechanical treatment, and the compression pressure during tableting is greatly relaxed, so that damage to the coating film is suppressed. There is no particular limitation on the blending ratio of crystalline cellulose and modified starch, but it seems that a weight ratio of about 9/1 to 3/7 is good. When the ratio is larger than 9/1, the effect of blending the modified starch is small, and when the ratio is smaller than 3/7, the amount of crystalline cellulose is small, so that the tablet has a weak binding property and is brittle. The total amount of the crystalline cellulose and the modified starch is 2% by weight or more, preferably about 5 to 20% by weight, based on the weight of the tablet.

In addition, by blending the processed starch that swells by absorbing water, when the tablet is introduced into the body, the tablet is rapidly disintegrated into granules, and the granules are easily dispersed in the stomach.

The granule-containing tablet of the present invention is prepared by mixing microcrystalline cellulose and modified starch with granules having a coating and, if necessary, adding other additives and drugs. The granule-containing tablets can be freely coated with a film for the purpose of, for example, moisture proofing.

〔Example〕

Hereinafter, the present invention will be described with reference to examples. The methods for measuring the physical properties of the powder and tablet in the examples are shown below.

<Swelling volume (ml / g)> 5 g of starch (equivalent to anhydrous) is taken in a 100 ml measuring cylinder with a stopper, about 80 ml of pure water at 25 ° C is added, and the mixture is shaken gently to remove bubbles. Make 100 ml. The sample was sealed and allowed to stand for 24 hours. The volume of the sample that had swollen with water was read, and the volume was divided by 5 to obtain the swollen volume.

<Tablet hardness (kg)> Weight was applied in the radial direction of the tablet with a Schleinger hardness tester manufactured by Freund Sangyo Co., Ltd., and it was expressed as the load at the time of breaking. The number of repetitions was 10, and the average was taken.

<Tablet disintegration time (min)> Using a disintegration degree tester NT-2HS manufactured by Toyama Sangyo Co., Ltd., a Japanese Pharmacopoeia artificial gastric juice (hereinafter abbreviated as 1 Japanese Pharmacopoeia) was used as a test solution. The number of repetitions was 6, and the average was taken.

<Drug dissolution rate (%)> The paddle method (100 rpm) was employed using an automatic dissolution tester DT-600 manufactured by Toyama Sangyo. The test solution was performed with 1 JP solution for 2 hours, and the sustained-release granules were further processed with the Japanese Pharmacopoeia artificial intestinal juice (hereinafter abbreviated as 2 JP solutions). Number of repetitions is 3
The average was taken. Table 1 shows the swelling volumes of the starch samples used in Examples and Comparative Examples.

Example 1 300 g of theophylline (Wako Pure Chemical Industries, first grade reagent) crystal cell
350 g of loin [Asahi Kasei Kogyo Co., Ltd., trade name: Avicel
PH-101], lactose 350g (DMV, 200 mesh) and pure water 7
Add 00g and use a planetary mixer (Shinagawa Seisakusho)
Ek Peret kneaded and equipped with a 0.8 mm caliber screen
Extruder with a turret (made by Fuji Paudal)
(Made by Fuji Paudal Co., Ltd.)
900 g of elementary granules of μm to 840 μm were obtained.

Ethyl cellulose (Hercules, 10 cps), hydroxypropyl methylcellulose (Shin-Etsu Chemical, TC-5, 6 cps) and triacetin (Wako Pure Chemical Industries, Ltd.) were applied to the elementary granules using a CF coating machine (Freund Sangyo, CF-360). 10% by weight (special grade reagent) (weight ratio 8/1/1)
The contained ethanol / methylene chloride (1 /) solution was coated at 15% by weight to the elementary granules to obtain granules having a long-lasting type coating (coated granules 1). The elution rate after 4 hours of elution is shown in Table-2.

 Next, 60% of coated granule 1 is crystalline cellulose [Asahi Kasei Corporation
Trade name: Avicel PH-101] 29.5%
10% of sample A, magnesium stearate (Taihei Chemical
) Is mixed at a ratio of 0.5% and mixed.
Using a tableting machine (Correct 12, manufactured by Kikusui Seisakusho), press pressure 40
0kg / cm^TwoTo give tablets of 10 mmφ, 400 mg / tablet. Tablets
Table 2 shows the hardness, disintegration time and dissolution rate after 4 hours of dissolution.
Show.

Comparative Example 1 Crystalline cellulose [Asahi Kasei Kogyo Co., Ltd.] was used without using sample A.
Product name: Avicel PH-101] 39.5%
Tableting was performed in the same manner as in Example 1. Table 2 shows the results.

Comparative Example 2 Tableting was performed in the same manner as in Example 1 except that Sample B was used instead of Sample A. Table 2 shows the results.

Example 2 Acrylic polymer coating agent Eudragit L30D-55 (manufactured by Higuchi Shokai, water dispersion, gastric juice coating agent) was applied to the elementary granules prepared in Example 1 using a fluidized bed coating machine (manufactured by Okawara Seisakusho, UNI GLATT). 39.6 parts, 1.2 parts of triethyl citrate (Wako Pure Chemical Industries, reagent grade)
After mixing 59.2 parts of pure water, the resulting granules were coated with 10% to obtain granules having an enteric coating (coated granules 2). Elution time 2 in JP 1 solution
The elution rate after time is shown in Table-3.

 Next, 60% of coated granules 2 were added to crystalline cellulose [Asahi Kasei
Industrial Co., Ltd., trade name: Avicel PH-101) to 29.5
%, Sample A 10%, magnesium stearate 0.5%
After mixing and mixing, tableting was performed according to Example 1.
Was. The tablet hardness, disintegration time, and dissolution rate 2 hours after dissolution are shown.
-3.

Comparative Example 3 Crystalline cellulose [Asahi Chemical Industry Co., Ltd.] was used without using sample A.
Product name: Avicel PH-101] 39.5%
Was tableted in the same manner as in Example 2. Table 3 shows the results.
You.

Comparative Example 4 Tableting was performed in the same manner as in Example 2 except that Sample B was used instead of Sample A. Table 3 shows the results.

[Effect of the Invention] The granule-containing tablet containing the granule having the coating of the present invention suppresses the damage of the coating film at the time of tableting as compared with the granule-containing tablet containing crystalline cellulose and raw starch, and dissolves the drug by tableting. The rate increase can be suppressed to about 1/10 to 1/5. As a result, granules having a coating, which have been conventionally filled in capsules, can be easily made into tablets, and the merit of easy taking and cost reduction can be provided.

Claims (1)

(57) [Claims] 1. A tablet containing granules, characterized by containing coated granules, crystalline cellulose, and a modified starch having a swelling volume of 3 ml / g or more.