JP2594395B2 - Stabilization method and formulation of sodium azulene sulfonate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a long-term stable sodium azulene sulfonate preparation and a method for producing the same.

[0002]

2. Description of the Related Art Sodium azulene sulfonate (Sodium 5-isopropyl-3,8-d
Imethyl-1-azulene sulfonate) has an anti-inflammatory action, an anti-allergic action, and an anti-ulcer action, and is widely used as an active ingredient in gargles and gastrointestinal drugs. However, sodium azulene sulfonate is easily decomposed with time by heat, light or moisture, and it has been difficult to store it in a usual preparation for a long period of time. As a method for stabilizing sodium azulene sulfonate, a method of making it amorphous and stabilizing it by using freeze-drying or the like (JP-A-58-1554547, JP-A-58-15447)
154548) and a method of hermetically packaging together with an oxygen scavenger (Japanese Patent Application Laid-Open No. Sho 59-176247). These methods require a lot of equipment and labor. On the other hand, a method of adding an amino acid and a weakly basic alkali salt as a stabilizer (Japanese Patent Publication No. 49-11219),
A method of adding an aluminum salt (aluminum lactate, aluminum phosphate, etc.) (JP-A-59-157014), a method of adding edetic acid and its salts (JP-A-1-121216), and adding propylene glycol Although a method (Japanese Patent Publication No. 2-42811) has been studied, its effect is not yet sufficient. By the way, although sodium azulene sulphonate preparations containing whisker powder are known, the stabilizing effect of the whisker powder was not known.

[0003]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for obtaining a practical sodium azulene sulfonate preparation which is easy and economical to produce and can maintain stability for a long period of time. However, it has been discovered that crude drugs containing silicaldehyde contribute to stabilization of sodium azulene sulfonate, and that addition of various amino acids and weakly basic alkali salts can stabilize sodium azulene sulfonate for a long time. The invention has been completed. That is, the present invention provides a herbal medicine containing silicide as a stabilizer, various amino acids and a weakly basic alkali salt as a stabilizer in order to suppress the chemical decomposition of sodium azulene sulfonate. It relates to a stabilization method and to the preparations thus obtained. The preparations of the present invention are particularly stable to heat as compared with conventional preparations, and exhibit a decrease in sodium azulene sulfonate content even at a temperature of 50 ° C. or higher, which is a guideline for stability tests as described later. I will not admit it.

The preparation of the present invention can be obtained by mixing sodium azulene sulfonate with a crude drug containing silicide, an amino acid and a weakly basic alkali salt. Alternatively, it may be appropriately dissolved in a solvent together with other components, mixed, and dried. Silicic aldehyde used in the present invention is an essential oil component contained in the crude drug, cinnamon, and accounts for 80 to 90% of the essential oil content. Examples of the form include cinnamon powder, cinnamon oil, cinnamon fluid extract, and cinnamon tincture, and these can be used alone or in combination of two or more. The amount of the cinnamon powder is usually 5 to 200 parts per 1 part by weight of sodium azulene sulfonate.
Parts by weight are used, preferably 10 to 100 parts by weight. The amount of cassia oil is usually 2.5 to 5 parts by weight based on 1 part by weight of sodium azulene sulfonate. You should refer to.

[0005] Examples of various amino acids include sodium L-aspartate, DL-alanine, arginine, sodium L-glutamate, L-phenylalanine, lysine and the like. These can be used alone or in combination of two or more. is there. The amount of the amino acid is usually 0.01 to 1 part by weight of sodium azulene sulfonate.
10 parts by weight are used, preferably 0.5 to 2 parts by weight. Further, the weakly basic alkali salt is blended to suppress the hydrolysis of sodium azulene sulfonate, and includes sodium hydrogen carbonate, sodium tartrate, sodium acetate, sodium polyphosphate, sodium hydrogen phosphate, potassium hydrogen phosphate and the like. These may be used alone or in combination of two or more. Usually, the amount is 0.0% with respect to 1 part by weight of sodium azulene sulfonate.
1 to 5 parts by weight is used, preferably 0.2 to 1 part by weight. The solvent used in the preparation of the preparation is preferably methanol, ethanol, water or the like, or a mixture thereof. Most preferably, ethanol and water or methanol and water (preferably purified water) in a 1: 1 volume is used. It is a specific mixture. The mixed powder is usually 60
It is obtained by drying at -70 ° C for 2 hours. Formulations of the present invention, corn starch, pharmaceutically used excipients such as crystalline cellulose, binders such as hydroxypropylcellulose, disintegrants such as calcium carboxymethylcellulose, lubricants such as magnesium stearate, For example, by adding digestive agents such as biodiastase, antacids such as synthetic hydrotalcite and funnel extract, and other active ingredients such as various vitamins, and performing conventional operations according to the dosage form, powders, fine powders, and the like can be obtained. Stabilized sodium azulene sulfonate-containing solid preparations such as granules, granules, nucleated granules, tablets (including sugar-coated tablets and film-coated tablets) and capsules can be prepared.

[0006]

EXAMPLES Next, the effects of the present invention will be described specifically with reference to examples and reference examples, but the present invention is not limited to these examples.

REFERENCE EXAMPLE 1 0.6 g of sodium azulene sulfonate was added to powder 2
It was added to 0.0 g and mixed in a mortar to prepare a powder. In the same manner, instead of Caffeine powder, a mixture of microcrystalline cellulose, lactose and corn starch, which are widely used as general additives, was prepared, and placed in a plastic container. After sealing, the solution was stored in a thermostat at 60 ° C. for 5 days and 10 days, and the degree of coloring due to a slight decomposition product of sodium azulene sulfonate was compared. Table 1 shows the results. Each symbol in the table of this specification has the following meaning. -: Coloring was not observed +: Coloring was observed ++: Strong coloring was observed

[0008]

[Table 1] 度 合 い Degree of coloring additive ───────────── 5 Sun 10th ─────────────────────────── Keihi end-+ ──────────────── ─────────── Microcrystalline cellulose ++ ++ ─────────────────────────── Lactose ++ ++ ──── Corn starch ++ ++ ─────────────────────── ────

As is clear from Table 1, in the case of a preparation using powdered cinnamon powder, coloring of the container was not observed in 5 days, but slight coloring was observed in 10 days. In the other comparative preparations, strong coloring was observed.

Reference Example 2 0.3 g of sodium azulene sulfonate, cinnamon oil 1.
5 ml and 10 g of cinnamon powder were mixed in a mortar to prepare a powder. As a comparative example, a mixed powder of microcrystalline cellulose, lactose, and corn starch (mixing ratio 2:
5: 3) was used. The prepared powder was placed in a plastic container, sealed and stored in a thermostat at 60 ° C. for one month, and the degree of coloring of the plastic container was compared. Table 2 shows the results.

[0011]

[Table 2] ───────────────────────── Additives + caffeine oil coloring degree ────────────── ─────────── Caffeine powder-結晶 Microcrystalline cellulose + lactose + corn starch-─── ──────────────────────

As is clear from Table 2, no coloring was observed in any of the formulations containing cauliflower oil.

Example 1 Sodium azulene sulfonate 0.6 g DL-alanine 0.54 g Sodium L-aspartate 0.54 g Sodium bicarbonate 0.27 g Powder powder 18.05 g ２ 20.0 g in total The above components were mixed in a mortar to prepare a powder. As a comparative example, a powder was similarly prepared using microcrystalline cellulose, lactose, and corn starch instead of cinnamon powder.
The prepared powder was put in a plastic container, sealed and stored in a thermostat at 60 ° C. for 5 days and 10 days, and the degree of coloring of the plastic container was compared. Table 3 shows the results.

[0014]

[Table 3] 度 合 い Coloring additive 5 days 10th ケ イ Keihi end--──────────────────結晶 Microcrystalline cellulose ++ ────────────────────────── Lactose ++ ──────── ────────────────── Corn starch ++ ──────────────────────────

As is clear from Table 3, no coloring of the container was observed in the preparation of the present invention, but coloring was observed in all of the other comparative preparations. In addition, when compared with the results of Reference Example 1, compared to the formulation of the powder of cinnamon powder alone, the addition of an amino acid and sodium hydrogencarbonate in addition to the powder of cinnamon powder as in this example makes it possible to obtain a sodium azulene sulfonate preparation which is more stable for a long period of time. It became clear that was obtained.

Example 2 10.0 g of sodium azulene sulfonate, 0.1 g of DL-alanine, 0.1 g of sodium L-aspartate
And 0.1 g of sodium bicarbonate were gently mixed in a mortar, and the mixed powder was dissolved in 120 ml of a mixture of purified water and ethanol (purified water: ethanol = 1: 1). 38.7 ml of the above solution was added to 28.7 g of cinnamon powder and kneaded.
For 2 hours to prepare a powder. In the same manner, powder using microcrystalline cellulose, lactose and corn starch in place of cinnamon powder is prepared, each powder is placed in a plastic container, sealed, stored in a thermostat at 60 ° C. for 21 days, and placed in a plastic container. The degree of coloring was compared. Table 4 shows the results
Shown in

[0017]

[Table 4] 度 合 い Degree of coloring of additives ───────────────── ─────── Caffeine powder − ──────────────────────── Microcrystalline cellulose ++ ───────────── ─────────── Lactose ++ ──────────────────────── Corn starch ++ ───────── ───────────────

As is apparent from Table 4, no coloring of the container was observed in the preparation of the present invention, but strong coloring was observed in the other comparative preparations.

Example 3 2.5 g of sodium azulene sulfonate, 1.0 g of DL-alanine, 1.0 g of sodium L-aspartate and 0.5 g of sodium hydrogen carbonate were gently mixed in a mortar, and the mixed powder was purified water. And ethanol (purified water: ethanol = 1: 1) in 50 ml. 5 ml each of the above solution was added to 5.0 g of cinnamon powder, crystalline cellulose, lactose and corn starch, and kneaded.
For 16 hours to prepare a powder. Each was placed in a glass bottle, sealed and stored in a thermostat at 60 ° C. for 16 days, and the content of sodium azulene sulfonate was measured comparatively by liquid chromatography. Table 5 shows the results.

[0020]

[Table 5] ──────────────────────────── Additive Sodium azulene sulfonate content (%) ───────ケ イ Keihi end 99.7 ────────────────────────結晶 crystalline cellulose 56.0 ──────────────────────────── lactose 51.1 ──────── Corn starch 65.4 ───────────────────────── ─── (The initial value content was 100.0%)

As is evident from Table 5, the content of the preparation containing the powder of cabbage was hardly reduced,
The other additives clearly reduced the content.

Example 4 A mixture of 21.6 g of sodium L-aspartate, 21.6 g of DL-alanine and 10.8 g of sodium bicarbonate in a mixture of ethanol and purified water (ethanol: purified water = 1: 1)
1) Dissolved in 700 ml. This was heated to 60 ° C. while adding sodium azulene sulfonate and dissolved by stirring for 30 minutes, then kneaded with kneaded powder and dried at 60 ° C. for 3 hours. A formulation was made. Separately, funnel extract 3 times powder, biodiastase 2000 and corn starch are mixed, and granules produced by adding corn starch as a binder, synthetic hydrotalcite, carboxymethyl cellulose calcium and crystalline cellulose are mixed,
Two preformulations of granules made with the addition of hydroxypropylcellulose as a binder were made. Three kinds of pre-formulations are mixed with magnesium stearate to obtain a tableting powder, and each tablet has the following composition (diameter: 10.0
mm). 9. Sodium azulene sulfonate 0.7 mg L-sodium aspartate 0.6 mg DL-alanine 0.6 mg sodium bicarbonate 0.3 mg Caffeine powder 57.7 mg Caffeine oil 0.2 mg Roto extract 3 times 0 mg Biodiastase 2000 10.0 mg Corn starch 62.1 mg Synthetic hydrotalcite 144.4 mg Carboxymethylcellulose calcium 7.8 mg Crystalline cellulose 57.9 mg Hydroxypropylcellulose 6.7 mg Magnesium stearate 1.0 mg ───────────────────────────── Total 360.0 mg Put the above tablets in a glass bottle, stopper tightly, then at 40 ℃, 75% relative. Store in a humidity (RH) thermostat / humidifier and a 50 ° C thermostat. The content of sodium lensulfonate was measured by liquid chromatography. Table 6 shows the results.

[0023]

[Table 6] ───────────────────────────── Storage period 40 ℃ ・ 75% RH 50 ℃ ─────── ────────────────────── Initial value 100.0 100.0 ──────────────────── １ 1 month 99.4 100.5 ───────────────────────────── 3 months 99. 499.2 ───────────────────────────── 6 months 99.5- ────────────────── (Initial value content was 100.0%)

As is evident from Table 6, no decrease in the sodium azulene sulfonate content was observed under any of the storage conditions.

Example 5 Sodium azulene sulfonate, powdered cinnamon, cinnamon oil,
Sodium L-aspartate, DL-alanine and sodium bicarbonate were mixed, dry-pressed, crushed and granulated to produce a pre-formulation. To this preformulation were added synthetic hydrotalcite, Roh extract 3 times powder, Bio-Astase 2
000, corn starch, crystalline cellulose, carboxymethyl cellulose calcium, hydroxypropyl cellulose, and magnesium stearate were added, mixed and dry-pressed again, crushed to give a tableting powder,
Tablets having the same composition as in Example 4 per tablet (diameter 1
0.0 mm). The tablets are placed in a glass bottle, sealed, and stored in a constant temperature / humidifier at 40 ° C. and 75% relative humidity (RH) and a constant temperature at 50 ° C., and the content of sodium azulene sulfonate is determined by liquid chromatography over time. Measured. Table 7 shows the results.

[0026]

[Table 7] ───────────────────────────── Storage period 40 ℃ ・ 75% RH 50 ℃ ─────── ────────────────────── Initial value 100.0 100.0 ──────────────────── １ 1 month 99.2 99.7 ３ 3 months 99. 5 100.6 {6 months 99.7-} ────────────────── (The initial value content was 100.0%)

As is clear from Table 7, no decrease in the sodium azulene sulfonate content was observed under any of the storage conditions.

[0028]

EFFECTS OF THE INVENTION The sodium azulene sulfonate-containing preparation obtained by the method of the present invention is particularly stable against heat as compared with conventional preparations, and changes its appearance even when stored at a temperature of 50 ° C. or more for a long time. It is useful without lowering the sodium azulene sulfonate content.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 47/08 A61K 47/08 J 47/16 47/16 A J C07C 303/42 C07C 303/42 (72) Inventor: Fumihiro Ikeda 955, Koichiku, Yoshitomi-cho, Chikami-gun, Fukuoka Prefecture Inside the Central Research Laboratory, Tochi Pharmaceutical Co., Ltd. (72) Inventor: Hiroshi Kono 955; In the laboratory

Claims (2)

(57) [Claims] 1. A method for stabilizing sodium azulene sulfonate, comprising blending a crude drug containing silicide, various amino acids and a weakly basic alkali salt with sodium azulene sulfonate. 2. A solid preparation containing a herbal medicine containing sodium azulene sulfonate and silicic aldehyde, various amino acids and a weakly basic alkali salt.