JP2009275041A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable carvedilol-containing solid preparation which is a β-blocker even in long term preservation and preservation under severe conditions and has effects on patients suffering from chronic heart failure based on essential hypertension, renal parenchymal hypertension, angina pectoris, ischemic heart disease or extension type cardiomyopathy. <P>SOLUTION: Generation of carvedilol homologues can be markedly reduced even in long term preservation and preservation under severe conditions by blending tocopherol, an antioxidant, with the carvedilol-containing solid preparation to prevent oxidation of carvedilol. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a solid preparation containing stable carvedilol.

As a preparation containing carvedilol, which is a β-blocker, as an active ingredient, a solid preparation containing a cellulosic binder and a disintegrant is already known (see, for example, Patent Document 1).
. Artist tablets (Daiichi Sankyo Co., Ltd.) are commercially available as tablets containing hydroxypropylcellulose and croscarmellose sodium.

As a result of conducting research on the tablet and conducting stability tests (long-term, accelerated, severe), the present inventors have found a problem that a related substance of carvedilol is generated. However, there is no known method for reducing the generation of carvedilol-related substances in a solid preparation containing carvedilol.

JP 2005-187464 A

In the present invention, in a solid preparation containing carvedilol (hereinafter also referred to as carvedilol-containing solid preparation), the occurrence of carvedilol-related substances when the solid preparation is stored for a long time and under severe conditions is further reduced. A solid preparation is provided.

The present inventors have found that the generation of carvedilol-related substances can be remarkably reduced by adding an antioxidant to the carvedilol-containing solid preparation, thereby completing the present invention.

That is, the present invention
1. A solid formulation containing carvedilol and an antioxidant,
2. The solid preparation according to 1, wherein the content of carvedilol is 0.1% to 20%,
3. The solid preparation according to 1 or 2, wherein the content of the antioxidant is 0.1% to 2% of the total weight of the solid preparation,
4). The solid preparation according to any one of 1 to 3, wherein the antioxidant is tocopherol,
5. The solid preparation according to any one of 1 to 4, wherein the dosage form is a tablet,
6). A method for reducing the occurrence of carvedilol-related substances in a solid preparation, characterized by comprising an antioxidant;
It is.

By adding an antioxidant to the solid preparation containing carvedilol, the generation of carvedilol-related substances in the solid preparation could be reduced. That is, by blending an antioxidant, a stable carvedilol-containing solid preparation can be produced and provided even when stored under long-term storage and severe conditions.

Carvedilol according to the present invention has a chemical name of (±) -1- (carbazol-4-y
loxy) -3-[[2- (o-methoxyphenoxy) ethyl] amino]
It is called 2-propanol and is known as a compound having a β-blocking action and the like. In addition, carvedilol according to the present invention is an ethical drug that has an effect on patients with chronic heart failure based on essential hypertension, renal parenchymal hypertension, angina pectoris, ischemic heart disease or dilated cardiomyopathy (first Sankyo Co., Ltd., trade name: Artist) active ingredient. The solid preparation of the present invention is
This carvedilol is contained as an active ingredient.

The content of carvedilol according to the present invention is not particularly limited. In the present invention, the content of carvedilol in the solid preparation is preferably low, and the content ratio of carvedilol in the solid preparation is preferably 0.1% to 20% of the total weight of the solid preparation. It is preferably 1% to 2%. In particular, when the dosage form of the solid preparation of the present invention is a tablet, the content of carvedilol per tablet is preferably 1.25 mg to 50 mg, more preferably 1.25 mg to 20 mg, and further 1.25 to 6.25 mg. Preferably
1.25 mg to 2.5 mg is particularly preferred.

The antioxidant according to the present invention includes, for example, ascorbic acids or salts thereof (ascorbic acid, calcium ascorbate, ascorbic acid stearates or salts thereof, etc.)
, Tocopherols or salts thereof (natural vitamin E, tocopherol (dl-α-tocopherol), β-tocopherol, γ-tocopherol, σ-tocopherol, tocopherol acetate, tocopherol nicotinate ester, calcium tocopherol succinate, concentrated Mixed tocopherols, etc.), sodium edetate, erythorbic acid, cysteine hydrochloride, dry sodium sulfite, citric acid, potassium dichloroisocyanurate, dibutylhydroxytoluene, soybean lecithin, sodium thioglycolate, sodium thiomalate, ascorbic acid palmitate, Butyl hydroxyanisole, 1,3-
Butylene glycol, benzotriazole, propyl gallate, 2-mercaptobenzimidazole, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate], sodium pyrosulfite, sodium nitrite Sodium sulfite, sodium hydrogen sulfite, alpha thioglycerin, β-carotene and the like.

These antioxidants are known compounds, and commercially available ones can be used. For example, those produced by the production method described in the 15th revision Japanese Pharmacopoeia can also be used. As the antioxidant according to the present invention, tocopherols are preferable, and tocopherol is more preferable.

The content of the antioxidant added to the solid preparation of the present invention is usually 0.01 of the total weight of the solid preparation.
% To 10%, preferably 0.1% to 2%. When the antioxidant according to the present invention is tocopherol, the content of tocopherol is usually 0.01% to 10%, preferably 0.1% to 2%, of the total weight of the solid preparation.

In the solid preparation of the present invention, in addition to carvedilol and an antioxidant, an appropriate pharmaceutical additive can be blended as necessary. For example, excipients, binders, disintegrants, lubricants and the like can be blended. Examples of excipients that can be incorporated into the solid preparation of the present invention include saccharides (lactose, mannitol, etc.), starches (corn starch, partially pregelatinized starch, etc.),
Examples thereof include celluloses (crystalline cellulose and the like). Examples of the binder that can be blended in the solid preparation of the present invention include celluloses (hydroxypropylcellulose and the like), polyvinyl alcohol, polyvinylpyrrolidone, gum arabic, agar, gelatin, macrogol, tragacanth, sodium alginate and the like. it can. Examples of the disintegrant that can be blended in the solid preparation of the present invention include celluloses (low-substituted hydroxypropylcellulose, croscarmellose sodium, etc.), crospovidone, starches (sodium carboxymethyl starch, partially pregelatinized starch) Etc.). Examples of the lubricant that can be blended in the solid preparation of the present invention include magnesium stearate, calcium stearate, stearic acid, hydrogenated oil, talc, light anhydrous silicic acid, macrogol, sucrose fatty acid ester and the like. .

Examples of the dosage form of the solid preparation of the present invention include tablets, granules, powders, capsules and the like. These solid preparations can be produced by a commonly used method for producing a known solid preparation, and can be produced, for example, by the method described in the section of the formulation of the 15th revised Japanese Pharmacopeia. When the dosage form of the solid preparation of the present invention is a granule or a powder, carvedilol, an antioxidant and a desired pharmaceutical additive are mixed by a known method, and if necessary, a fluidized bed granulation method or a stirring method is used. Granulation can be performed by a granulation method, a rolling fluid method granulation method, an extrusion granulation method, a spray granulation method, or a crushing granulation method. Furthermore, when the dosage form of the solid preparation of the present invention is a tablet, carvedilol, an antioxidant and a desired pharmaceutical additive are mixed by a known method, granulated as necessary, and then subjected to an appropriate tableting pressure. It can be manufactured by compression molding.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

(Test example)
The components shown in Table 1 were mixed, and tablets of Example 1, Example 2, and Comparative Example 1 were prepared using a tableting machine. Each of these tablets was stored in a bottle package at 60 ° C., and the increase in related substances after 2 days was examined. The results are shown in Table 2.

類縁物質の測定方法
検出器：紫外吸光光度計（測定波長：２４０ｎｍ）
カラム：内径４mm, 長さ１５cm のステンレス管に５μm の液体クロマトグラフ用オクチ
ルシリル化シリカゲルを充てんしたもの
カラム温度：４０℃付近の一定温度
移動相：メタノール／ｐＨ５.０リン酸緩衝液混液（１１：９）
流速：約１ｍＬ／ｍｉｎ
試料量：５０μＬ

表２の結果から、抗酸化剤であるα−トコフェロールを添加したカルベジロール含有固
形製剤（実施例１、２）は、α−トコフェロールを含有しないカルベジロール含有固形製
剤（比較例１）に比べ、過酷条件下におけるカルベジロールの類縁物質の発生を格段に低
減することが判明した。すなわち、抗酸化剤を添加したカルベジロール含有製剤は、安定
性において極めて優れていることがわかった。

Measuring method of related substances Detector: Ultraviolet absorptiometer (measurement wavelength: 240 nm)
Column: A stainless steel tube with an inner diameter of 4 mm and a length of 15 cm filled with 5 μm octylsilylated silica gel for liquid chromatography
Column temperature: constant temperature around 40 ° C. Mobile phase: methanol / pH 5.0 phosphate buffer mixed solution (11: 9)
Flow rate: About 1 mL / min
Sample volume: 50 μL

From the results in Table 2, the carvedilol-containing solid preparations (Examples 1 and 2) to which α-tocopherol, which is an antioxidant, was added, were severer than the carvedilol-containing solid preparations not containing α-tocopherol (Comparative Example 1). It has been found that the occurrence of carvedilol-related substances under the water is greatly reduced. That is, it was found that the carvedilol-containing preparation to which the antioxidant was added was extremely excellent in stability.

According to the present invention, in a preparation containing carvedilol, the generation of carvedilol-related substances when stored under long-term storage and harsh conditions has been significantly reduced. According to the present invention, a stable carvedilol-containing preparation can be provided, which is useful.

Claims (6)

A solid formulation containing carvedilol and an antioxidant. The solid preparation according to claim 1, wherein the content of carvedilol is 0.1% to 20%. The solid preparation according to claim 1 or 2, wherein the content of the antioxidant is 0.1% to 2% of the total weight of the solid preparation. The solid preparation according to any one of claims 1 to 3, wherein the antioxidant is tocopherol. The solid dosage form according to any one of claims 1 to 4, wherein the dosage form is a tablet. A method for reducing the generation of carvedilol-related substances in a solid preparation, which comprises blending an antioxidant.