JP2512302B2 - Method for producing nicorandil-stabilized preparation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a nicorandil [chemical name: N (2-hydroxyethyl) nicotinic acid amide nitrate] stabilized preparation.

That is, the present invention provides nicorandil with one or more organic acids selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acid, and glutaric acid, and one or more kinds of saturated higher fatty acids solid at room temperature, and And / or a method for producing a nicorandil-stabilized preparation, which comprises mixing one or more saturated higher alcohols that are solid at room temperature.

Conventional Technology Nicorandil is a drug effective as a therapeutic agent for angina pectoris of various disease types, which has a coronary vasodilatory effect and a coronary artery contraction suppressing effect, and has little effect on cardiac hemodynamics and cardiac function (Japanese Patent Publication No. 58).
-17463, JP-A-53-9323, etc.).

However, although nicorandil formulations are relatively stable in the dry state, they are unstable, especially with respect to humidity,
Regarding the manufacturing method and storage method of the preparation, special consideration must be given to humidity, and a great deal of cost is required such as complete moisture-proof packaging.

It is known that nicorandil is unstable and its content is apt to decrease when it is compression-molded into tablets by an ordinary formulation method, although the crystal itself is relatively stable.

As a countermeasure against this, there is known a method in which crystals of nicorandil are coated with one or a mixture of two or more kinds of fat-and-waxy substances which are solid at room temperature and then tableted (Japanese Patent Laid-Open No. 57-145659).

Problems to be Solved by the Invention Although the above-described method of coating a crystal is an excellent method,
The equipment for coating the crystals of nicorandil is required for the equipment, and the coating process is time-consuming, which is very expensive.

Therefore, as a result of intensive studies on the method for producing a formulation that is stable against humidity and stable even when compression-molded into tablets, the present inventors have found that the stability decreases as the compression pressure increases. In consideration of the deformation of crystal particles and the distortion of crystal lattice due to compressive force, magnesium stearate or calcium stearate, which is usually used for the purpose of reducing friction between particles during compression molding of powder, is several times the normal dose to 10 times. The amount was gradually increased up to several times and tableting was performed, but it was still not improved.

However, surprisingly, a new finding was obtained that, when a certain organic acid and saturated higher fatty acid that is solid at room temperature and / or saturated higher alcohol that is solid at room temperature are mixed and then tableted, the stability thereof is significantly improved. It was

The present invention has been completed on the basis of these new findings, and is completely different from the method of coating and protecting nicorandil crystals with a solid waxy substance at room temperature, in which 0.1% by weight or more of an organic acid and solid at room temperature are solid. Saturated higher fatty acids and /
Or 0.5% by weight of saturated higher alcohol that is solid at room temperature
By mixing the above, a stable nicorandil preparation can be obtained.

Further, according to the present invention, since the step of coating the nicorandil crystal is unnecessary, the apparatus and equipment for coating are also unnecessary.

Means for Solving Problems For a composition comprising a crystal of nicorandil and a pharmaceutical carrier such as an excipient, a disintegrating agent, a lubricant, a coloring agent, and a binder,
0.1% by weight or more of a mixture of one or more kinds of organic acids, and one or more kinds of a saturated higher fatty acid solid at room temperature and / or a mixture of one or more kinds of a saturated higher alcohol solid at room temperature. 0.5% by weight or more can be mixed to obtain a desired form, that is, a solid preparation such as tablets, capsules, granules and suppositories by a conventional method.

As the organic acid used in the present invention, dibasic acids such as fumaric acid, oxalic acid, salicylic acid, tartaric acid and glutaric acid are particularly preferable. Furthermore, as the saturated higher fatty acid which is solid at room temperature, palmitic acid stearic acid and the like are particularly preferable, and as the saturated higher alcohol which is solid at room temperature, cetyl alcohol, stearyl alcohol and the like are particularly preferable. Also,
Examples of the above-mentioned pharmaceutical carrier include lactose, corn starch, mannitol, kaolin, crystalline cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, talc, anhydrous calcium hydrogen phosphate,
Calcium carbonate, calcium citrate, calcium stearate, magnesium stearate and the like are used.

Further, among the organic acids having the above-described stabilizing effect, fumaric acid is used in a nicorandil preparation, whereby nicorandil is gradually released over a long period of time.

This stabilized sustained-release preparation is prepared by weighing predetermined amounts of nicorandil and an excipient, and further containing fumaric acid in an amount of about 10% or more of the total weight of the preparation and one or more kinds of saturated higher fatty acids solid at room temperature. And / or one or a mixture of two or more saturated higher alcohols which are solid at room temperature are mixed by a usual method. A lubricant, for example, magnesium stearate, calcium stearate, talc, or the like is added to the thus obtained mixed powder, and the mixture can be compression-molded to give a tablet.

Furthermore, sucrose, an aromatic agent, a coloring agent, etc. may be added and compression-molded into a predetermined shape to prepare a troche.

In addition, a layer A containing nicorandil and a layer B not containing nicorandil are laminated and compression-molded, whereby a laminated tablet with enhanced dissolution of nicorandil after a certain period of time can be obtained.

Further, an enteric coated granule can be prepared by coating a granule, a capsule or hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose or the like by a usual method.

Action The preparation obtained according to the present invention has excellent stability against temperature and stability when compressed into tablets.

Examples will be described below, but the present invention is not limited thereto.

Example 1 Tablet formulation (in one tablet) Nicorandil 10 (mg) Lactose 65.5 Stearic acid 8 Croscarmellose sodium 5 Fumaric acid 10 Corn starch 1Magnesium stearate 0.5 Total 100 mg lactose 65.5 g, stearic acid 8 g and croscarmellose
Sodium (Ac-Di-Sol : FMC) 5g in a mortar
After mixing, add 20 g of 5% corn starch paste and smelt
It matched. After passing the kneaded product through a 30-mesh screen,
It was dried for 4 hours. Sift the dried product with 30 mesh and
Granules were obtained.

10 g of nicorandil, 10 g of fumaric acid, 79.5 g of granules and 0.5 g of magnesium stearate were mixed in a plastic bag.

The mixed powder was compression-molded with a total pressure of about 1 ton using a single-punch tableting machine equipped with a die having a diameter of 7 mm and a flat punch to give 100 mg per tablet.

For comparison, tablets were prepared under the same conditions, in which stearic acid and fumaric acid in the Example formulation were replaced by the same amount of lactose.

Put both tablets in glass bottles and keep them tightly closed at 40 ℃.
The stability was compared by accelerating for 3 months and at 40 ° C. in the open state −61.5% relative humidity for 3 months, respectively. 100 before acceleration
It is as shown in Table 1 when it is shown by the residual rate as%.

Example 2 Capsule (in 1 capsule) Nicorandil 10 mg Mannitol 40 Fumaric acid 10 Stearyl alcohol 30 Carboxymethylcellulose calcium 10 Total 100 mg Nicorandil 10 g, Mannitol 40 g, Fumaric acid 10 g,
30 g of stearyl alcohol and 10 g of calcium carboxymethyl cellulose were placed in a mortar and mixed, and then 22 g of 20% ethanol was added and kneaded well. The kneaded product was passed through a 14-mesh screen and then dried at 40 ° C. for 6 hours. Dried food
The granules were obtained by sizing with a 10-mesh sieve.

 No. 3 capsules were filled with 100 mg of the above granules.

For comparison, capsules in which the fumaric acid and stearyl alcohol in the Example formulation were replaced by the same amount of mannitol were produced under the same conditions.

Both capsules were put in glass bottles respectively, and a desiccant (silica gel) was put therein, and the stability was compared by accelerating at 40 ° C-3 months in a tightly plugged state and 40 ° C-3 months in a tightly plugged state without a desiccant. .

Table 2 shows the residual rate with 100% before acceleration.

Example 3 Tablet formulation (in one tablet) Nicorandil 10 mg Mannitol 52 Salicylic acid 5 Palmitic acid 2 Corn starch 10 Crystalline cellulose 20 Calcium stearate 1 total 100 mg Nicorandil 10 g, Mannitol 52 g, Salicylic acid 5 g,
2 g of palmitic acid, 10 g of corn starch, 20 g of crystalline cellulose and 1 g of calcium stearate were mixed in a plastic bag.

The mixed powder was compression-molded with a single-shot tableting machine equipped with a die having a diameter of 7 mm and a flat punch at a total pressure of about 1 ton so as to give 100 mg per tablet.

For comparison, a tablet was produced under the same conditions, in which the salicylic acid and palmitic acid in the Example formulation were replaced by the same amount of mannitol.

Put both tablets in glass bottles and keep them tightly closed at 40 ℃.
The stability was compared by accelerating for 3 months and at 40 ° C. in the open state −61.5% relative humidity for 3 months, respectively. 100 before acceleration
Table 3 shows the residual rate in%.

Example 4 Sustained-release pharmaceutical formulation (in one tablet) Lower layer (mg) Upper layer (mg) Nicorandil 10-fumaric acid 85.5 39.8 Stearate 4- calcium stearate 0.5 0.2 Total 100 mg 40 mg Nicorandil 10 g, fumaric acid 85.5 g, stearic acid 4 g And 0.5 g of calcium stearate were mixed well in a plastic bag. This mixed powder is referred to as a mixed powder.

39.8 g of fumaric acid and 0.2 g of calcium stearate were mixed well in a plastic bag. This mixed powder is referred to as b mixed powder.

With a single-shot tableting machine with a die with a diameter of 8 mm and a flat punch,
First, 100 mg of the mixed powder a was filled in a die and lightly pre-pressed, then 40 mg of the mixed powder b was filled thereon, and compression molded at a total pressure of 1.3 tons.

Comparative Example Sustained release formulation (in 1 tablet) Lower layer (mg) Upper layer (mg) Nicorandil 10-hydroxypropyl cellulose 89.5 39.8
Calcium stearate 0.5 0.2 Total 100 mg 40 mg Nicorandil 10 g, Hydroxypropyl cellulose (H
PC-L: Nippon Soda KK) 89.5 g and calcium stearate 0.5 g were mixed well in a plastic bag. This mixed powder is a
Use mixed powder.

39.8 g of hydroxypropyl cellulose (HPC-L) and 0.2 g of calcium stearate were mixed well in a plastic bag. This mixed powder is referred to as b mixed powder.

Using a single-shot tableting machine set with a die with a diameter of 8 mm and a flat punch, first, fill 100 mg of a mixed powder into a die, lightly precompress, and then
b Mixed powder (40 mg) was filled thereon and compression molded at a total pressure of 1.3 tons. The results of the dissolution test of both sustained release preparations are as shown in FIG.

The dissolution test was carried out at a basket rotation speed of 100 rpm using a test device of the 10th revision, Japanese Pharmacopoeia, dissolution test method, method 1 (rotating basket method), using 500 ml of distilled water as the dissolution test solution. is there.

Both sustained-release preparations were put in glass bottles, respectively, and a desiccant (silica gel) was put therein to accelerate each at 50 ° C. for 10 days in the sealed state and at 50 ° C.-relative humidity 50% for 5 days in the open state,
The stability was compared. Table 4 shows the residual rate with 100% before acceleration.

Claims (4)

(57) [Claims] 1. A mixture of nicorandil with one or more organic acids and one or more saturated higher fatty acids solid at room temperature and / or one or more saturated higher alcohols solid at room temperature. A method for producing a nicorandil-stabilized preparation, comprising: 2. The method according to claim 1, wherein the organic acid is a dibasic acid selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acid and glutaric acid. 3. The amount of organic acid added is 0.1% by weight based on the total weight of the preparation.
The manufacturing method according to claim 1, which is as described above. 4. A saturated higher fatty acid solid at room temperature and a saturated higher alcohol solid at room temperature are added in an amount of 0.5 of the total weight of the preparation.
The manufacturing method according to claim 1, which is at least wt%.