JPH075464B2 - Stable nicorandil formulation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a stable formulation of nicorandil and is very useful as a medicine. That is, the present invention provides nicorandil [chemical name: N- (2-hydroxyethyl) nicotinic acid amide nitrate] with one or more selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acid, and glutaric acid. A stable nicorandil preparation containing an organic acid.

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 spasm suppressing effect, and has little effect on cardiac hemodynamics and heart function (Japanese Patent Publication 58).
-17463, JP-A-53-9323).

Problems to be Solved by the Invention However, although the nicorandil preparation is relatively stable in a dry state, it is unstable especially in humidity, and special consideration is required for humidity in the manufacturing method and storage method of the preparation. Therefore, a large amount of cost is required such as completely moisture-proof packaging.

As a result of intensive studies on a method for producing a formulation stable to humidity, the present inventors have improved the stability of a nicorandil formulation by mixing and formulating a crystal or crystalline powder of a certain organic acid, particularly It has been found that stability against humidity is dramatically improved.

Further, as an organic acid effective in stabilizing the nicorandil preparation, it was found that dibasic acids such as fumaric acid, oxalic acid, glutaric acid, tartaric acid and salicylic acid show particularly excellent stabilization, and thus the present invention is completed. I arrived.

Means for Solving the Problems Crystalline or crystalline powder of nicorandil and excipient, disintegrant,
In addition to the above-mentioned fumaric acid, a composition prepared by mixing a pharmaceutical carrier such as a lubricant, a coloring agent, a binder, an ointment base, and a tape base.
Oxalic acid, salicylic acid, tartaric acid, glutaric acid, and one or more kinds of organic acids selected from the group are blended, and the desired form, that is, solid preparations such as tablets, capsules, granules and suppositories, ointments by a conventional method. It can be a transdermal agent such as a drug or a tape. In the case of solid preparations, for example, lactose, corn starch, mannitol, kaolin, crystalline cellulose, carboxymethyl cellulose calcium, talc, calcium carbonate, calcium stearate, magnesium stearate, etc. are used as the above-mentioned pharmaceutical carrier.

In the case of transdermal agents, polyvinyl alkyl ether, poly (meth) acrylate, polyurethane, polyester,
Polyamide, ethylene-vinyl acetate copolymer, acrylic acid alkyl ester-acrylic acid copolymer, and the like are used, and a tackifier, a softening agent, and the like are added as necessary.

The amount of organic acid required to stabilize the nicorandil preparation varies depending on the manufacturing method, but is 0.1% for the preparation.
The purpose can be achieved by adding at least wt%.

The formulation obtained by the present invention has excellent stability. Examples will be described below, but the present invention is not limited thereto.

Example 1 Tablet formulation (in one tablet) Nicorandil 10 (mg) Lactose 76.5 Corn starch 10 Fumaric acid 3 Magnesium stearate 0.5 Total 100 (mg) Nicorandil crystals 200 g, lactose 1530 g, corn starch 200 g and fumaric acid ground powder (average particle size) Diameter about 3μm) 60g
Place in a Shinagawa mixer, mix for 20 minutes, add 10 g of magnesium stearate and mix for 1 minute.

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 the same amount of lactose was used instead of fumaric acid in the formulation of the Examples.

Put both tablets in glass bottles and keep them tightly closed at 40 ℃
Stability was compared by accelerating for 3 months and 40 ° C.-relative humidity 61.5% -3 months respectively in the open state. Table 1 shows the residual rate with 100% before acceleration.

Example 2 Capsule (in 1 capsule) Nicorandil 10 (mg) Mannitol 44 Carboxymethylcellulose calcium 5 Salicylic acid 40 Calcium stearate 1 Total 100 (mg) Nicorandil crystals 200 g, mannitol 880 g, carboxymethylcellulose calcium 100 g, salicylic acid crystals 800 g and calcium stearate 20 g. Is uniformly mixed in a plastic bag, treated with a roller compactor, and sized with a 10-mesh sieve to give slug granules.

No. 3 capsule was filled with 100 mg of the above slug granules.

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

Put both capsules in glass bottles, respectively, and put a desiccant (silica gel) in a tightly plugged state at 40 ° C-3 months, and in a tightly plugged state without a desiccant, accelerate each at 40 ° C-3 months,
The stability was compared.

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

Example 3 Granules (1000 mg) Nicorandil 50 (mg) Mannitol 920 Oxalic acid 10 Corn Depun 20 Total 1000 mg Nicorandil crystals 100 g, mannitol 1,840 g and oxalic acid 20 g were put in a Shinagawa mixer and mixed for 20 minutes, then 10%
Add 400 g of corn starch paste and knead for 10 minutes.

The kneaded product is granulated with a cylindrical granulator equipped with a 1.0 mm diameter net. The granules were dried at 50 ° C. for 4 hours in a tray dryer. After drying, the particles were sized with a 10-mesh screen.

For comparison, granules in which the same amount of mannitol was replaced in place of the oxalic acid in the Example formulation were produced under the same conditions.

Put both granules in glass bottles respectively and keep them tightly closed at 40 ℃
The stability was compared by accelerating for 3 months and 40 ° C. in the open state −61.5% relative humidity for 3 months, respectively.

Table 3 shows the residual rate with 100% before acceleration.

Example 4 Ointment (1000 mg) Nicorandil 20 mg Fumaric acid 20 mg Plastibase 960 mg Total 1000 mg Nicorandil crystals 2 g, fumaric acid 2 g, and a small amount of plastibase are put in an Ishikawa vacuum stirrer and kneaded for 10 minutes. Furthermore, plastibase is added little by little and kneaded, and the total amount is added to 100 g to make the whole quality uniform.

For comparison, an ointment in which the same amount of plastibase was used instead of fumaric acid in the Example formulation was prepared under the same conditions.
Both ointments were placed in a plastic ointment container, and the stability was compared by accelerating with and without a desiccant (silica gel) at 40 ° C. for 2 months and 60 ° C. for 1 week in a tightly closed state. Table 4 shows the residual rate with 100% before acceleration.

Example 5 Tape formulation Nicorandil 5 parts Salicylic acid 5 parts Isooctyl acrylate-acrylic acid copolymer 100 parts Ethyl acetate 300 parts 25% Isooctyl acrylate (95% by weight) -Acrylic acid (5% by weight) copolymer ethyl acetate After dissolving 5 parts of nicorandil and 5 parts of salicylic acid in 400 parts of the solution, this is applied on the surface of a polyethylene film having a thickness of 80 μm and dried so that the thickness after drying becomes 50 μm to obtain a tape preparation.

For comparison, a tape preparation was prepared under the same conditions in which 20 parts of isooctyl acrylate (95% by weight) -acrylic acid (5% by weight) copolymer solution was replaced in place of salicylic acid in the formulation of the example.

EFFECTS OF THE INVENTION As shown in the above examples, the nicorandil preparation of the present invention is extremely stable, and in particular, the stability against humidity is dramatically improved.

Claims (1)

[Claims] 1. Nicorandil is selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acid and glutaric acid.
A stable nicorandil preparation containing one or more organic acids.