JP2781442B2 - Granule-containing tablets - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a tablet containing granules. For more information,
It 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 for controlling the release of a specific-effect drug or as a means for enteric solubilization. In most cases, this coating is applied to tablets and granules. However, when applied to granules, capsules are often filled into capsules from the viewpoint of handleability and the like. From the viewpoints of cost, ease of drinking, etc., it is preferable to add excipients and compress them into tablets, rather than filling them into capsules. 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. In order to prevent this, Japanese Patent Application Laid-Open No. Sho 53-53 describes that lactose, ordinary crystalline cellulose, and starch may be used in large amounts as excipients.
142520 publication. Among them, it is stated that crystalline cellulose is particularly effective. Also, JP-A-61-221115
The publication discloses a method using about 10 to about 50% of normal crystalline cellulose based on a tablet.

[Problems to be Solved by the Invention] If a large amount of crystalline cellulose is used, it is possible to suppress the damage of the coating film at the time of compression. However, conventional crystalline cellulose which has been conventionally used is still not enough, and the coating film at the time of compression is not enough. There is a problem that the dissolution of the drug occurs and the dissolution rate of the drug increases. For example, JP-A-61-
FIG. 2 of Japanese Patent No. 221115 discloses that enteric-coated granules are tableted by mixing 20% of crystalline cellulose with respect to the total tablet weight. However, at the elution time of 1 hour, about 20% of the drug was eluted, and the coating film was damaged by tableting. It was not sufficient to suppress the damage of the film with ordinary crystalline cellulose.

[Means and actions for solving the problem]

An object of the present invention is to provide a pharmaceutical tablet containing a specific excipient in order to granulate a coated granule, particularly a granule having a long-lasting or enteric coating, without causing damage to the coating film. Is to provide.

That is, the present invention, after mixing a specific crystalline cellulose having an average particle diameter of 30 μm or less and a specific surface area of 1.3 m ² / g or more measured by the BET method as an excipient, to a granule having a coating, , A granule-containing tablet obtained by compression.

According to the present invention, when tableting granules having a coating, damage to the coating film is extremely small as compared with the conventional method, and it is possible to suppress an increase in drug dissolution rate due to tableting.

 Hereinafter, the present invention will be described.

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 long-acting films and enteric films. Specifically, cellulosic coating agents such as ethyl cellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate sexinate, cellulose acetate phthalate, cellulose acetate, etc., acrylic polymer coating agents such as Eudragit RS, Eudragit L, Eudragit NE Or, or shellac, silicone resin, etc., even if these are used alone,
Two or more may be used in combination, but are not limited thereto. 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.

Crystalline cellulose having an average particle size of 30 μm or less and a specific surface area of 1.3 m ² / g or more (hereinafter abbreviated as “microcrystalline cellulose fine powder”) as used in the present invention refers to acid-hydrolyzing cellulose such as linters and pulp. Decomposition, alkali oxidative decomposition or a combination of both, followed by purification and purification, after drying, drying or before drying, which is obtained by pulverization or grinding, and has an average particle size of 30 μm or less. It is necessary that the measured specific surface area is not less than 1.3 m ² / g.

When the tablet is compressed at the same compression pressure, the smaller the average particle size of the crystalline cellulose fine powder is, the smaller the destruction of the coating film is, and the increase in the dissolution rate is suppressed. This is presumed to be because the crystalline cellulose fine powder has good adhesion to the granules and the surface of the granules is covered with the crystalline cellulose fine powder, so that the destruction of the coating film due to contact between the granules is reduced. In addition, the smaller the average particle size of the microcrystalline cellulose powder, the higher the hardness of the tablet obtained when the tablet is compressed at the same compression pressure. It is presumed that the damage of the film is further reduced. However, when the average particle size of the crystalline cellulose exceeds 30 μm, a significant result cannot be obtained as compared with the case where the conventional crystalline cellulose is used.
Even if the average particle size is 30 μm or less, a desired result cannot be obtained if the specific surface area measured by the BET method is less than 1.3 m ² / g. The amount of the microcrystalline cellulose fine powder is 2% by weight or more, preferably 5 to 50% by weight, based on the weight of the tablet.

The crystalline cellulose fine powder referred to in the present invention is produced, for example, by the following methods, but is not limited to these methods. Hydrolysis of lignite, pulp and other cellulosic materials in hydrochloric acid, immersion in aqueous sodium hydroxide solution, oxidative decomposition or decomposition by a combination of the two, followed by filtration, washing and purification of the insoluble residue, followed by drying and grinding or grinding and drying. Get it. In the case of pulverization after drying, the dried product is obtained by pulverizing the dried product with a high-speed rotary impact type or airflow type pulverizer. When drying after grinding, the cellulose slurry is treated with a ball mill and then dried rapidly. If it is desired to obtain a powder having a smaller average particle size, classification may be carried out after the pulverizing step, if necessary.

The granule-containing tablet of the present invention is prepared by mixing microcrystalline cellulose fine powder with granules having a coating, adding other additives and drugs if necessary, and mixing and compressing to obtain a tablet. It is also possible to apply a film coating to the granule-containing tablet for the purpose of moisture prevention and the like.

〔Example〕

 Hereinafter, the present invention will be described in detail with reference to examples.

 The methods for measuring the physical properties of the powder and the tablet are described below.

-Average particle size (μm) The particles were sieved using an air jet sieve manufactured by ALPINE, West Germany, using a JIS standard sieve, and the particle size at a cumulative 50% by weight was defined as the average particle size. When the 400 mesh pass exceeds 50% by weight, the particle size distribution of the powder that has passed through the 400 mesh is determined using a SK laser micron sizer manufactured by Seishin Enterprise and combined with the particle size distribution of 400 mesh or more determined by sieving. The cumulative particle size of 50% by weight was taken as the average particle size.

・ Specific surface area (m ² / g) Measured by BET method using Shimadzu Flowsorb 2300 and nitrogen gas as adsorption gas.

Tablet hardness (kg) Weight was applied in the radial direction of the tablet with a Schroinger hardness tester manufactured by Freund Corporation and expressed as the load at the time of breaking. The number of repetitions was 10, and the average was taken.

-Tablet disintegration time (minutes) Using a disintegration degree tester NT-2HS manufactured by Toyama Sangyo Co., Ltd., an artificial gastric juice (Japanese Pharmacopoeia) (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 adopted using an automatic dissolution tester DT-600 manufactured by Toyama Sangyo. The test solution was administered for one hour in the Japanese Pharmacopoeia for 2 hours, and for the sustained-release granules, the test was further performed using the artificial intestinal juice of the Japanese Pharmacopoeia. The number of repetitions was 3, and the average was taken.

Table 1 shows the average particle size and specific surface area of the crystalline cellulose samples used in Examples and Comparative Examples.

Example 1 300 g of theophylline (manufactured by Wako Pure Chemical Industries, first grade), crystalline cellulose 350 g (manufactured by Asahi Kasei Kogyo, PH-101), lactose 350 g (D
700 g of pure water was added to MV Corporation, 200 mesh), kneaded with a planetary mixer (manufactured by Shinagawa Seisakusho), extruded with an Ek Pelletter (manufactured by Fuji Paudal) equipped with a 0.8 mm caliber screen, Powdered product) and dried and classified.
0 g was obtained.

Ethyl cellulose (manufactured by Hercules, 10 cps), hydroxypropylmethylcellulose (manufactured by 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 (manufactured by Freund Corporation, CF-360). 10% by weight (special grade reagent) (weight ratio 8/1/1)
The contained ethanol / methylene chloride (1/1) solution was coated at 15% by weight based on the elementary granules to obtain granules having a long-lasting type coating (coated granules 1). Table 2 shows the elution rate after 4 hours of elution.

Next, 70% of the coated granules 1 were used for the samples (A), (B),
(C) 28.5% each, disintegrant (Asahi Kasei Corporation)
And trade name: Ac-Di-Sol) 1.0% and magnesium stearate (Taihei Chemical Co., Ltd.) at a ratio of 0.5%, and then using a rotary tableting machine (manufactured by Kikusui Seisakusho, Correct12),
The tablets were compressed at a tableting pressure of 400 kg / cm ² to give tablets of 10 mmφ, 400 mg / tablet. Table 2 shows the tablet hardness, disintegration time, and dissolution rate after 4 hours of dissolution.

Comparative Examples 1 and 2 Using the coated granules 1 of Example 1, samples (D)
For each of (E), tablets were prepared according to the method of Example 1. Table 2 shows the results.

From Table 2, it can be seen that, compared to the existing crystalline cellulose of Comparative Example 2, the dissolution rate of Example 1 after 4 hours of dissolution was considerably suppressed, and the dissolution by tableting was smaller than that of coated granules 1 before tableting. The rate increase was negligible. Assuming that the degree of increase in the dissolution rate in the case of the existing crystalline cellulose of Comparative Example 2 was 100, the degree of increase in the dissolution rate in the case of Sample A was as small as 6. Further, from Comparative Example 1, in the case of Sample D having a specific surface area of less than 1.3 m ² / g even though the average particle size was small, the dissolution rate was considerably increased by tableting. In addition, as the results of Example 1 show, the smaller the average particle size is, the higher the tablet hardness is. To obtain tablets having the same hardness as Comparative Examples 1 and 2,
It is believed that better results may be obtained by compressing at a lower pressure.

Example 2 An acrylic polymer-based 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 (UNI GLATT, manufactured by Okawara Seisakusho). 39.6 parts, triethyl citrate (Wako Pure Chemicals, reagent special grade) 1.2 parts, pure water 5
The mixture obtained by mixing 9.2 parts was coated at 10% on the elementary granules to obtain granules having an enteric coating (coated granules 2). Table 3 shows the elution rate after 2 hours of elution time for 1 solution of JP.

Next, coated granules 2 were mixed at a ratio of 70%, sample (B) 28.5%, croscarmellose sodium 1.0%, and magnesium stearate 0.5%, and tableted according to Example 1. Table 3 shows the hardness, disintegration time and dissolution rate of the tablet after 2 hours.

Comparative Example 3 Using the coated granules of Example 2, tablets were prepared for sample (E) according to the method of Example 2. Table 3 shows the results.

From Table 3, as compared with the existing crystalline cellulose of Comparative Example 3, the dissolution rate of Example 2 after 2 hours of dissolution was considerably suppressed, and the destruction of the coating film by tableting was small.

〔The invention's effect〕

The granule-containing tablet of the present invention contains a special crystalline cellulose as compared with a conventional granule-containing tablet containing microcrystalline cellulose, thereby suppressing damage to a coating film at the time of tableting and reducing the drug dissolution rate by tableting. The rise 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 granule having a coating and an average particle size
A granule-containing tablet comprising crystalline cellulose having a particle size of 30 μm or less and a specific surface area of 1.3 m ² / g or more.