JPH09249563A - Tizanidin-containing composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a stabilized oral medicine which contains tizanidin hydrochloride and a specific carboxylic acid and inhibits the tizanidin from discoloration. SOLUTION: This oral medicine contains tizanidin hydrochloride and a non- volatile carboxylic acid which is crystalline at room temperature and has a pKa value of 2-6 (for example, tartaric acid or succinic acid). In addition, conventional excipient, binder, disintegrator, lubricant are appropriately formulated to prepare tablets, granules, fine particles, powder, dry syrup and the like. The amount of the organic acid is 0.005-1wt.% based on the whole preparation. Tizanidin hydrochloride is chemically 5-chloro-4-[(2-imidazolin-2-yl)amino]2,1,3- benzothiadiazole hydrochloride, known as a centrally acting muscle relaxant having polysynaptic reflex inhibitory action and antinociceptive property and is useful for treatment of spasmus with pain and chromic myotonia caused by cerebral and spinal diseases.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to stabilization of a pharmaceutical composition containing tizanidine hydrochloride, which is a central muscle relaxant. The present invention relates to a composition for oral administration containing tizanidine hydrochloride and a carboxylic acid, which prevents coloration.

[0002]

2. Description of the Related Art Tizanidine hydrochloride, which is a pharmacologically active substance of the present invention, is 5-chloro-4-[(2-imidazoline-
2-yl) amino] -2,1,3-benzothiadiazole is a compound represented by the chemical name. Tizanidine hydrochloride is known as a central muscle relaxant having polysynaptic reflex suppressive action, anti-nociceptive action, etc., and is widely used for the treatment of painful myotonic symptoms and chronic spasticity caused by cerebral and spinal cord diseases. .

The conventional formulation is tizanidine hydrochloride and a diluent,
It is orally administered after directly blending it with an excipient such as a binder and a disintegrant to form a tablet.

[0004]

However, the direct compression method for powders largely depends on the physical properties of the raw materials,
In addition, formulation technology requires a high degree of control, and it is difficult to secure sufficient content uniformity and mechanical strength of the formulation.
Due to such problems as described above, a method of tableting after wet granulation using water or an organic solvent is widely adopted as a general manufacturing method.

Therefore, the present inventors examined the production of a tizanidine hydrochloride formulation by the wet granulation method, and found that this formulation had a problem that it was colored during the production process or after the formulation due to the properties of tizanidine hydrochloride. . This degree of coloring was more remarkable when the drug contacted water or an organic solvent in the manufacturing process.

[0006] In order to provide medicines that are liable to be altered, it is necessary to take preventive measures so as not to reduce the effects of the main drug and not to have a harmful effect on the user.

In order to solve this problem, Japanese Patent Laid-Open No. 7-22
3952 discloses a technique for preventing yellowing of tizanidine hydrochloride by using pullulan or gum arabic as a binder. However, in this method, since the use of the binder used is limited, imparting moldability and improving brittleness of the preparation are insufficient.

Further, Japanese Patent Application Laid-Open No. 7-157429 discloses a technique for a patch preparation containing an organic acid, and the detailed description includes a statement that coloration is prevented. However, this method is intended to prevent coloration on the skin, and although the skin permeation promoting effect of organic acids has been shown, the coloration preventing effect of carboxylic acids is slightly affected by acetic acid and acetic acid. Only the effect on sodium is shown.

[0009]

Means for Solving the Problems In order to solve the above problems, the present inventors have conducted extensive studies on various pharmaceutically acceptable combination agents, and as a result, by combining tizanidine hydrochloride with a specific carboxylic acid, The inventors have found that the coloring of tizanidine hydrochloride is prevented and have completed the present invention. That is, the present invention comprises a composition for oral administration characterized by containing a nonvolatile carboxylic acid and tizanidine hydrochloride as a pharmacologically active substance.

Another feature of the present invention relates to a method for preventing discoloration of a drug containing tizanidine hydrochloride, which comprises blending a non-volatile carboxylic acid with tizanidine hydrochloride.

Here, the pharmaceutically acceptable non-volatile carboxylic acid is a compound which is crystalline at room temperature and has a pKa value of 2 to 6.

Examples of the non-volatile carboxylic acid used in the present invention include carboxylic acids such as succinic acid, citric acid, malic acid, tartaric acid and fumaric acid, of which tartaric acid is particularly preferable.

The ratio of organic acid in the whole preparation is 0.00
A sufficient effect is obtained at 5 to 1.0% by weight.

The central muscle relaxant of the present invention containing tizanidine hydrochloride and carboxylic acid can be obtained by blending a non-volatile carboxylic acid with a physiologically active ingredient consisting of tizanidine hydrochloride.

The formulation may contain a diluent, a binder, a disintegrating agent, a lubricant and the like which are commonly used in the art.

Examples of the dosage form include tablets, capsules, granules, fine granules, powders and dry syrups.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION Tizanidine hydrochloride, carboxylic acid and various excipients were mixed and granulated, and tablets were prepared for use in the test.

[0018]

The present invention will be described in more detail below by showing Examples of the present invention, but the present invention is not limited to these Examples.

Example 1 Tizanidine hydrochloride tablets were prepared according to the formulation shown in Table 1 and the following production method.

Preparation method: A mixture of tizanidine hydrochloride, lactose, crystalline cellulose, and low-substituted hydroxypropyl cellulose (L-HPC) was mixed with an aqueous solution of tartaric acid and hydroxypropyl cellulose (HPC-L), and then granulated. , Magnesium stearate (St-Mg)
Was added and tableted to produce a flat tablet having a diameter of 6.0 mm and a weight of 95 mg.

Composition:

[Table 1]

Comparative Example 1 The procedure of Example 1 was repeated except that the tartaric acid of Example 1 was omitted.

Comparative Example 2 (Blank) The procedure of Example 1 was repeated except that the amount of tartaric acid added in Example 1 was 0.1% by weight and the tizanidine hydrochloride was omitted.

Formulation test: For each formulation of Example 1 and Comparative Examples 1 and 2, color difference measurement and appearance change were observed. Color difference was measured using a Nippon Denshoku SZ-Σ80 type color difference meter with La
The method b was used. Table 2 shows the results. In the table, the value in parentheses is the weight% of tartaric acid in the whole preparation, L is the lightness, a,
b is the hue saturation, and ΔE is the chromaticity difference. The symbol of visual change indicates the result of comparison with Comparative Example 2 (blank).

[0025]

[Table 2]

Example 2 The procedure of Example 1 was repeated except that 0.1% by weight of citric acid was added instead of the tartaric acid of Example 1.

Example 3 The procedure of Example 1 was repeated except that 0.1% by weight of malic acid was added instead of the tartaric acid of Example 1.

Example 4 The procedure of Example 1 was repeated, except that 0.1% by weight of succinic acid was added instead of the tartaric acid of Example 1.

Example 5 The procedure of Example 1 was repeated, except that 0.1% by weight of fumaric acid was added instead of the tartaric acid of Example 1.

Stability test A: 0.1 wt% tartaric acid preparation of Example 1, each preparation prepared in Examples 2-5 and Comparative Examples 1-2 were stored at 40 ° C. and 75% RH. The color difference and the appearance change of each preparation before and after the observation were observed. The measurement method was in accordance with the method of the above formulation test. The results are shown in Table 3.

[0031]

[Table 3]

Example 6 Granules were prepared as follows. To a mixture of tizanidine hydrochloride, lactose, corn starch, and hydroxypropyl cellulose, 20% ethanol-water solution (V / V) of tartaric acid and polysorbate 80 was added and kneaded, and then granulated.

Stability test B: The granules of Example 6 were stored under the conditions of 40 ° and 75% RH for 1 month, and then the appearance was observed. No coloration was observed.

[0034]

From the above results, it was confirmed that tartaric acid, citric acid, malic acid, succinic acid and fumaric acid have remarkable effects in preventing the coloration of the tizanidine hydrochloride preparation. Since these acids are effective even when added in an extremely small amount, there are few restrictions on the excipients used, and they can be made into a formulation by a usual production process.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 9/48 A61K 9/48 F 47/12 J 47/12 C07D 417/12 233 C07D 417/12 233 A61K 9/14 L // (C07D 417/12 233: 44 285: 14)

Claims (4)

[Claims] 1. A composition for oral administration containing tizanidine hydrochloride and a carboxylic acid. 2. The composition of claim 1 wherein the carboxylic acid is a non-volatile carboxylic acid. 3. The composition of claim 1, wherein the non-volatile carboxylic acids are succinic acid, tartaric acid, malic acid, citric acid, and fumaric acid. 4. The composition according to any one of claims 1 to 3, wherein the dosage form of the composition for oral administration is a tablet, a granule, a fine granule, or a capsule.