JP2936376B2 - Nicorandil tablet manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an improved method for producing nicorandil tablets. That is, the present invention has been improved to produce nicorandil tablets having extremely good stability.

[0002]

2. Description of the Related Art Nicorandil itself is relatively stable in crystals, but it is apt to be decomposed and reduced in content by compression in a usual tableting method, and because nicorandil has a nitrate group in the molecule, it may be contained in a formulation. It is known that the presence of natural fats and oils containing a large amount of unsaturated hydrocarbons causes coloring and a slight decrease in the content, which significantly impairs the commercial properties of the obtained tablets.

[0003] As a countermeasure, a method of coating a nicorandil crystal with one or a mixture of two or more selected from stearyl alcohol, cetanol and stearic acid, followed by tableting (Japanese Patent Application Laid-Open No. 57-145659), a method in which nicorandil and normal temperature And tableting of one or more kinds of solid saturated higher fatty acids or saturated higher alcohols (JP-A-62-252723) with one or more organic acids and one or more solid acids. A method of stabilizing by mixing and compressing a saturated higher fatty acid or a saturated higher alcohol (JP-A-63-270624).
No.) is known.

[0004]

[Problems to be Solved by the Invention] Since the content is reduced due to the pressure during compression molding in a conventional preparation method, an attempt was made to investigate a lubricant for the purpose of reducing friction between particles during compression molding. Was. Tableting after coating with several kinds of lubricants was examined, but the content reduction and coloring were not improved. However, besides, natural waxes Carnauba wax containing a large amount of unsaturated hydrocarbons and a lubricant magnesium stearate are preliminarily mixed, and this mixture (hereinafter, referred to as a mixed lubricant) is mixed with nicorandil and tableted. A new finding was obtained that the stability was significantly improved.

[0005] The present invention has been completed based on these new findings.
By containing 5% by weight, stable nicorandil tablets can be obtained.

Further, according to the present invention, natural waxes such as carnauba wax and hydrogenated castor oil can be used, and no apparatus or equipment for coating nicorandil crystals is required.

[0007]

Means for Solving the Problems For a crude product comprising a pharmaceutical carrier such as an excipient, a disintegrant, a lubricant, a binder, etc.,
A mixed lubricant in which nicorandil crystals are mixed with one or two selected from carnauba wax and hydrogenated castor oil and one or two or more selected from magnesium stearate, calcium stearate, magnesium oxide and talc, % By weight or more, and can be made into tablets by a usual preparation method.

The above-mentioned pharmaceutical carriers include, for example,
Lactose, corn starch, mannitol, glucose, dextrin, sucrose, crystalline cellulose, carboxymethylcellulose calcium, hydroxypropylcellulose, ethylcellulose, magnesium stearate, calcium stearate, magnesium oxide, talc and the like are used.

[0009]

The tablet obtained by the present invention is excellent in stability against temperature and humidity and stability during compression molding.
This is because carnauba wax containing a large amount of unsaturated hydrocarbons is mixed and coated in advance with magnesium stearate to prevent direct contact between nicorandil and carnauba wax, etc., suppress coloring, and this operation also provides moisture-proof and lubricating effects. It is presumed that the decrease in the content due to the moisture absorption and the pressure during the compression molding can be suppressed. Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited thereto.

[0010]

Example 1 Tablet formulation (in one tablet) Nicorandil 5 (mg) Carnauba wax 0.75 Magnesium stearate 0.25 Mannitol 40.2 Low substituted hydroxypropylcellulose 0.8 Carboxymethylcellulose calcium 2.5 Magnesium stearate 0 ─────────────────────────── Total 50mg

[0011] 40.2 g of mannitol, 0.8 g of low-substituted hydroxypropylcellulose and 2.5 g of calcium carboxymethylcellulose were mixed in a mortar and kneaded with water. The kneaded product was granulated with a 48-mesh sieve and then dried at 40 ° C. for 6 hours. The dried product was sized with a 48-mesh sieve to obtain a granulated product.

0.75 g of Carnauba wax and 0.25 g of magnesium stearate corresponding to one third of the amount were mixed in a mortar to obtain a mixed lubricant.

Nicorandil 5 g, granulated product 43.5 g, mixed lubricant 1 g and magnesium stearate 0.5 g
Was mixed in a plastic bag.

The above-mentioned mixed powder was compression-molded to 50 mg per tablet using a single-shot tableting machine in which a die having a diameter of 5 mm and a flat punch were set.

For comparison, tablets prepared by substituting the same amount of mannitol in place of the mixed lubricant in the formulation of the Examples (hereinafter referred to as Control 1) and using stearyl alcohol in accordance with JP-A-57-144569 were used. The tablets were manufactured (hereinafter referred to as Control 2).

Each tablet is placed in a glass bottle, and 4
0 ° C. for 3 months and at 40 ° C., 75% RH-
Each accelerated for three months and compared for stability. Table 1 shows the residual rates with the pre-acceleration as 100%.

[0017]

[Table 1]

[0018]

Example 2 Tablet formulation (in one tablet) Nicorandil 5 (mg) Hardened castor oil 0.75 Magnesium stearate 0.25 Mannitol 40.2 Low substituted hydroxypropylcellulose 0.8 Carboxymethylcellulose calcium 2.5 Stearic acid Magnesium 0.5 ─────────────────────────── Total 50mg

40.2 g of mannitol, 0.8 g of low-substituted hydroxypropylcellulose and 2.5 g of calcium carboxymethylcellulose were mixed in a mortar and kneaded with water. The kneaded product was granulated with a 48-mesh sieve and then dried at 40 ° C. for 6 hours. The dried product was sized with a 48-mesh sieve to obtain a granulated product.

[0027] 0.75 g of hydrogenated castor oil and 0.25 g of magnesium stearate corresponding to 1/3 thereof were mixed in a mortar to obtain a mixed lubricant.

5 g of Nicorandil, 43.5 g of granules, 1 g of mixed lubricant and 0.5 g of magnesium stearate
Was mixed in a plastic bag.

The mixed powder was compression-molded to 50 mg per tablet using a single-shot tableting machine in which a die having a diameter of 5 mm and a flat punch were set.

For comparison, tablets were prepared under the same conditions by replacing the mixed lubricant in the formulation of the example with the same amount of mannitol.

Put both tablets in a glass bottle and seal 4
0 ° C. for 3 months and at 40 ° C., 75% RH-
Each accelerated for three months and compared for stability. Table 2 shows the residual rate with the value before acceleration set to 100%.

[0025]

[Table 2]

From the results of Examples 1 and 2, the present invention clearly suppressed the decrease in nicorandil content more than the control group, and no coloring of the tablet was observed.

Carnauba wax and hydrogenated castor oil are natural waxes, are easily available, and do not require equipment or equipment for coating nicorandil. Tablets can be manufactured at low cost by a conventional preparation method. Was.

Continuing from the front page (72) Yukari Higashi, No. ⁶ , Kobayashi Chemicals Co., Ltd. No. 6, No. 6, Kanatsu-cho, Sakai-gun, Fukui Pref. A61K 31/455 A61K 9/20 A61K 47/02 A61K 47/12 A61K 47/44 CA (STN)

Claims (2)

(57) [Claims] 1. A stable nicorandil tablet comprising the steps of mixing groups (A) and (B) in a ratio of 1: 5 to 3: 1, and then mixing and tableting nicorandil using this mixture. Recipe. Group (A): One or two kinds of mixtures selected from carnauba wax and hydrogenated castor oil Group (B): One or more kinds of mixtures selected from magnesium stearate, calcium stearate, magnesium oxide and talc 2. A stable nicorandil tablet according to claim 1, wherein the mixture of groups (A) and (B) comprises at least 0.5% by weight of the total weight of the nicorandil preparation .
Law .