COMPOSITION FOR SUSTAINED-RELEASE SOLID DOSAGE FORM, SUSTAINED-RELEASE TABLET USING THE SAME, AND MANUFACTURING METHOD THEREOF

Abstract

A composition for sustained-release solid dosage form that contains (A) a polyvinyl alcohol-based resin having an average saponification degree of 78 to 96 mol % and an average polymerization degree of 800 or more and (B) a polyhydric phenol compound, preferably tannic acid. A sustained-release tablet having an intended hardness can be produced by a method that includes mixing a granulate prepared from a composition containing (A) a polyvinyl alcohol-based resin powder and a pharmaceutical ingredient with a tannic acid powder, and compressing the mixture into a tablet.

Claims

1. A composition for sustained-release solid dosage form comprising (A) a polyvinyl alcohol-based resin having an average saponification degree of 78 to 96 mol % and an average polymerization degree of 800 or more; and (B) a polyhydric phenol compound.

2. The composition for sustained-release solid dosage form according to claim 1, wherein the polyhydric phenol compound (B) is tannic acid.

3. The composition for sustained-release solid dosage form according to claim 1, wherein the content of the polyhydric phenol compound (B) is from 0.1 to 35 parts by weight with respect to 100 parts by weight of the polyvinyl alcohol-based resin (A).

4. The composition for sustained-release solid dosage form according to claim 1, wherein the polyvinyl alcohol-based resin (A) has a modification degree of less than 10 mol %.

5. The composition for sustained-release solid dosage form according to claim 1, wherein the polyvinyl alcohol-based resin (A) is a powder having an average particle size of 40 to 200 m.

6. The composition for sustained-release solid dosage from according to claim 1, wherein the polyvinyl alcohol-based resin (A) is a mixture of a first polyvinyl alcohol-based resin having an average polymerization degree of 1500 or more to 3000 and a second polyvinyl alcohol-based resin having an average polymerization degree of 100 to less than 1500.

7. A composition for sustained-release solid dosage form comprising (A) a polyvinyl alcohol-based resin having an average saponification degree of 78 to 96 mol % and an average polymerization degree of 800 or more; (B) a polyhydric phenol compound; and (C) crystalline cellulose wherein the crystalline cellulose (C) is contained in an amount of 1 to 50 parts by weight with respect to 100 parts by weight of the polyvinyl alcohol-based resin (A).

8. A method for producing a sustained-release tablet, comprising mixing tannic acid powder with a granule of a composition containing a pharmaceutical ingredient and a polyvinyl alcohol-based resin having an average polymerization degree of 800 or more; and tableting the mixture.

9. The method for producing a sustained-release tablet according to claim 8, wherein the polyvinyl alcohol-based resin has an average polymerization degree of 1500 to 3000 and is in form of powder having an average particle size of 40 to 200 m.

10. The method for producing a sustained-release tablet according to claim 8, wherein the granules are prepared by a fluid bed granulation process.

11. The composition for sustained-release solid dosage form according to claim 7, wherein the polyhydric phenol compound (B) is tannic acid.

12. The composition for sustained-release solid dosage form according to claim 7, wherein the content of the polyhydric phenol compound (B) is from 0.1 to 35 parts by weight with respect to 100 parts by weight of the polyvinyl alcohol-based resin (A).

13. The composition for sustained-release solid dosage form according to claim 7, wherein the polyvinyl alcohol-based resin (A) has a modification degree of less than 10 mol %.

14. The composition for sustained-release solid dosage form according to claim 7, wherein the polyvinyl alcohol-based resin (A) is a powder having an average particle size of 40 to 200 m.

15. The composition for sustained-release solid dosage from according to claim 7, wherein the polyvinyl alcohol-based resin (A) is a mixture of a first polyvinyl alcohol-based resin having an average polymerization degree of 1500 or more to 3000 and a second polyvinyl alcohol-based resin having an average polymerization degree of 100 to less than 1500.

Description

EXAMPLES

[0100] The present invention will be further described below with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[Measurement and Evaluation Method]

(1) Tablet Hardness (N)

[0101] A hardness of a tablet manufactured by compression was measured using a PC-30 hardness tester (manufactured by OKADA SEIKO.CO., LTD.).

(2) Release Rate

[0102] Dissolution Test 1 of USP41 Metformin Hydrochloride Extended-Release Tablets was conducted on a tablet containing metformin which is a readily water-soluble pharmaceutical ingredient.

[0103] The dissolution test was conducted by dissolving 500 mg of tablets in 900 mL of distilled water at 37 C. and measuring the amount of the pharmaceutical ingredient (metformin) with a dissolution tester NTR-6400ACT (manufactured by Toyama Sangyo Co., Ltd.) after 1 hour, 3 hours, and 10 hours from the start of the test. The release rate (%) after 1 hour and 3 hours was calculated when the dissolution amount after 10 hours was taken as 100%.

[Manufacturing of Tablets]

[0104] A PVA-based resin for a matrix material, metformin hydrochloride as a pharmaceutical ingredient, and crystalline cellulose (PH102 manufactured by Asahi Kasei Chemicals) were mixed at a ratio shown in Table 1. This mixture was fed to a granulator (MP-01 manufactured by Powrex Corporation) and fluidized. A PVA aqueous solution having a concentration of 6%, which was used as a liquid binder, was also fed to the granulator and produce granules. The PVA aqueous solution (6%) was prepared by dissolving 1.0 part of a PVA-based resin (average polymerization degree of 600 and saponification degree of 88 mol %) in water and had a viscosity 5.0 mPa.Math.s in the case of 4% aqueous solution. The conditions for granulation process were as follows: supply air temperature 70 C., supply air volume 0.9 m.sup.3/min, atomizing air pressure 0.5 MPa, and atomizing air volume 30 NL/min. To the granules, tannic acid and magnesium stearate were added in the respective amounts shown in Table 1. Thus prepared composition for tableting was pressed with a rotary tableting machine (HT-EX12SS-U manufactured by Hata Iron Works Co., Ltd.) at a pressure of 25 N to obtain a tablet with 11 mm in diameter and 500 mg in weight.

TABLE-US-00001 TABLE 1 ingredient amount (weight part) composition matrix PVA 39.9 for metformin 48.8 granulation crystalline cellulose 10.3 binder PVA 1.0 added when tannic acid Variable amount tableting magnesium stearate 1.0

[0105] The following two types of PVA were used for the matrix PVA-based resin. [0106] PVA1: average polymerization degree 2500, saponification degree 88 mol %, alkali metal salt content 0.03% by weight, and average particle size 48 m, 78 m, or 97 m [0107] PVA2: average polymerization degree 600, saponification degree 88 mol %, alkali metal salt content 0.03% by weight, and average particle size 320 m

[0108] Tablets No. 1 to No. 7 were manufactured with use of the matrix PVA-based resins shown in Table 2. Tablets No. 1 to No. 7 differed in a mixing ratio of tannic acid to the matrix PVA-based resin as shown in Table 2. Table 2 also shows the measurement results of hardness and release rate of the produced tablets.

[0109] The average polymerization degree of the PVA-based resin each contained in tablets Nos. 1 to 6 was 2454 according to the calculation by the equation shown below. While the average polymerization degree of the PVA-based resin contained in tablet No. 7 was 600.

Average polymerization degree=250039.9/40.9+6001/40.9=2454

TABLE-US-00002 TABLE 2 matrix PVA amount of tannic acid average of particle per evaluation Tablet polymerization diameter matrix per release rate (%) hardness No degree (m) amount PVA*.sup.1 metformin*.sup.2 1 h 3 h 10 h (N) 1 2500 48 4.0 0.1 0.08 40.5 67.4 100.0 123 2 2500 78 4.0 0.1 0.08 39.3 65.7 100.0 101 3 2500 97 4.0 0.1 0.08 39.8 65.5 100.0 96 4 2500 48 8.0 0.2 0.16 35.3 61.1 100.0 137 5 2500 48 12.0 0.3 0.25 38.7 66.4 100.0 151 6 2500 48 0 0 0 45.4 79.6 100.0 147 7 600 43 4.0 0.1 0.08 83.4 100.0 100.0 101 *.sup.1amount of tannic acid per 1 weight part of matrix PVA *.sup.2amount of tannic acid per 1 weight part of metformin

[0110] A comparison between No. 1 and No. 6 shows that coexistence of tannic acid contributed to sustained-release of the tablet.

[0111] From Nos. 1, 4 and 5 differing only in the content of tannic acid, it can be understood that the hardness increases as the increase of tannic acid content.

[0112] From the comparison between No. 1 and No. 7, when a PVA having a low average polymerization degree like a binder PVA is used as a matrix polyvinyl alcohol-based resin, the resulting tablet is not considered to assure a desirable sustained-release performance.

INDUSTRIAL APPLICABILITY

[0113] Solid dosage form such as a tablet produced using a composition for solid dosage form of the disclosure have a sustained-release property and desirable hardness. Therefore, the composition for solid dosage form of the disclosure is useful because combining a variety of pharmaceutical ingredients requiring sustained-release with the composition of the disclosure would provide a desired sustained-release tablet containing the pharmaceutical ingredient.