JPH0643300B2 - Effervescent formulation - Google Patents

Description

TECHNICAL FIELD The present invention relates to an effervescent preparation, and more particularly to a stable effervescent preparation containing guaiazulene sulfonate.

[Conventional technology]

Sodium guaiazulene sulfonate is a water-soluble azulene drug (gastrointestinal drug, mouthwash, eye drop etc.),
It is widely used in cosmetics (toothpaste, cream, etc.) for the purpose of anti-inflammatory and anti-cormorant, but is known to have poor stability. Therefore, in formulating,
Various stabilizations have been tried.

Known stabilization methods for guaizulene sulfonates include adding amino acids and weak base alkali salts (Japanese Patent Publication No. 49-11219), adding weakly alkaline glycols. Method (JP-A-51-1)
25713), a method of reacting β-, γ-cyclodextrin (JP-A-56-30927), a method of adding 6 to 20 times the amount of a water-soluble polymer (JP-A-57-108012), propylene. A method of blending and mixing glycol (JP-A-58-13513),
A method of blending 1/10 parts or more of polyvinylpyrrolidone (JP-A-59-39824) is known.

[Problems to be solved by the invention]

However, these methods are not sufficient to keep guaiazulene sulfonate stable for a long time in an effervescent preparation containing a carbonate and an acid. However, it has a drawback that its solubility in water is poor.

[Means for solving problems]

The present inventors have conducted diligent research to keep guaiazulene sulfonate stable for a long period of time in an effervescent preparation containing a carbonate and an acid, and as a result, a liquid polyhydric alcohol compound, an alkaline inorganic salt and an average of Molecular weight 2,000 ~ 20,
The present invention was completed by finding that the above object can be achieved by adding 000 polyethylene glycols.

The guaiazulene sulfonic acid salt used in the present invention is a water-soluble salt of guaiazulene sulfonic acid, and among them, alkali metal salts, particularly sodium salts are preferred. The amount of guaiazulene sulfonate in the present invention is not particularly limited, it depends on the degree of expectation of its effect and the use form of the preparation, but generally 0.
It is about 001 to 5% by weight (hereinafter simply referred to as%).

Further, the liquid polyhydric alcohol compound used in the present invention,
Among the polyhydric alcohols which are liquid at 25 ° C., propylene glycol, ethylene glycol, polypropylene glycol, glycerin, polyglycerin, polyethylene glycol and the like can be mentioned. From the viewpoint of their effect, glycerin and propylene glycol are preferable. The amount of the liquid polyhydric alcohol added to guaiazulene sulfonate is preferably 10 to 600%, particularly preferably 50 to 300%. If the addition amount is small, the stability is insufficient, and if the addition amount is large, the fluidity of the powder deteriorates, which is not preferable.

Further, as the alkaline inorganic salt, carbonates such as sodium carbonate, sodium sesquicarbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, magnesium carbonate; sodium tripolyphosphate, sodium pyrophosphate, sodium silicate and the like can be used. Water soluble carbonates are preferred. The amount of the alkaline inorganic salt added to the water-soluble azulene is preferably 20 to 2000%, particularly preferably 50 to 500%.

Furthermore, the polyethylene glycol needs to have an average molecular weight of 2,000 to 20,000, but one having an average molecular weight of 4,000 to 20,000 is more preferable. The suitable amount of polyethylene glycol added to water-soluble azulene is 50 to 2000%.

The effervescent preparation of the present invention contains a carbonate and an acid to generate carbon dioxide. Examples of the carbonate include sodium hydrogen carbonate, sodium carbonate, sodium sesquicarbonate, potassium carbonate, potassium hydrogen carbonate, and carbonic acid. Ammonium or the like is used, and these can be used alone or in combination of two or more kinds. As the acid, either an organic acid or an inorganic acid can be used, but a water-soluble and solid acid is preferable. Among these acids, organic acids include, for example, straight-chain fatty acids such as formic acid, acetic acid, propionic acid, butyric acid, and valeric acid; oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid,
Dicarboxylic acids such as pimelic acid, fumaric acid, maleic acid, phthalic acid, isophthalic acid and terephthalic acid; acidic amino acids such as glutamic acid and aspartic acid; glycolic acid,
Lactic acid, hydroxyacrylic acid, α-oxybutyric acid, glyceric acid, tartronic acid, malic acid, tartaric acid, citric acid,
Oxyacids such as salicylic acid (o, m, p), gallic acid, mandelic acid, tropic acid, ascorbic acid, gluconic acid; cinnamic acid, benzoic acid, phenylacetic acid, nicotinic acid, kainic acid, sorbic acid, pyrrolidonecarboxylic acid, Examples include trimellitic acid, benzenesulfonic acid, toluenesulfonic acid, and acidic salts of these organic acids. Further, as the inorganic acid, for example, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium sulfite, potassium sulfite, sodium pyrosulfite (sodium metabisulfite), potassium prosulfite (potassium metabisulfite), acidic Examples thereof include sodium hexametaphosphate, potassium acid hexametaphosphate, sodium acid pyrophosphate, potassium acid pyrophosphate, sulfamic acid and the like. Above all, succinic acid,
Aliphatic dicarboxylic acids such as adipic acid, fumaric acid, phosphoric acid and their acid salts are preferred.

The method for producing the effervescent preparation of the present invention is not particularly limited, and the effervescent preparation can be produced by mixing the above-mentioned components in a conventional manner. However, in order to exert more stability, it is necessary to melt-mix guaiazulene sulfonate, liquid polyhydric alcohol, alkaline inorganic salt and polyethylene glycol in advance under heating (preferably 60 to 85 ° C) and then cool, It is preferable to carry out powdering, granulation treatment, etc. On this occasion,
When a carbonate of an effervescent base is used as the alkaline inorganic salt, a part or all of the alkaline inorganic salt may be replaced with the carbonate. Further, it is preferable to add an acid and a carbonate as an effervescent base to give an effervescent preparation.

The effervescent preparation of the present invention can be made into a dosage form such as a gastrointestinal drug, a mouthwash, a dentifrice, a cosmetic, a bath agent, a skin external drug, etc., which is used in the expectation of the efficacy or color tone of water-soluble azulene . The effervescent preparation of the present invention is blended with commonly used medicinal agents, pigments, fragrances, etc. according to these applications, and if necessary for formulation, an excipient, a binder, a disintegrant, a lubricant, etc. Agents and the like can be added.

〔Example〕

Examples of the present invention will be shown below, but the present invention is not limited to these examples. The mixing ratios are all parts by weight.

Example 1 (i) 2 kg of guaiazulene sulfonic acid sodium salt and 2 kg of glycerin, 5 kg of sodium carbonate and PEG (average molecular weight 6
000) 5 kg was heated to 70 ° C. with a Nauta mixer (manufactured by Hosokawa Micron Co., Ltd.) and stirred for 10 minutes. After melt-mixing, the mixture was cooled and pulverized to obtain a powdery processed product.

(ii) Treated product obtained in (i) 6%, sodium bicarbonate 30%, sodium carbonate 15%, succinic acid 40%, mirabilite 5.5%, fragrance 0.5
% And dextrin 3% were mixed with the same Nauta mixer as described above, and each tablet was compressed with a tableting machine (manufactured by Masina Co., Ltd.) to give 50 g of each tablet. This was laminated on an aluminum foil on polypropylene, placed in a bag made of a film laminated with polyethylene terephthalate, and hermetically sealed with a heat sealer to obtain a bath salt.

Example 2 Guaiazulenesulfonic acid sodium salt 2 kg, glycerin 1 kg, sodium carbonate 5 kg and PEG (average molecular weight 2000
0) 5 kg and super mixer (Kawata Manufacturing Co., Ltd.)
The temperature was raised to 75 ° C. with stirring, the mixture was stirred and melt-mixed, and then cooled to obtain a powdery processed product. This treated product 8%, sodium bicarbonate 30%, sodium carbonate 20%, fumaric acid 40%,
A mixture of 10% of a fragrance of 0.5% and dextrin of 1.5% was tabletted in the same manner as in Example 1 and packaged to give a bath salt.

Example 3 2 kg of guaiazulene sulfonic acid sodium salt, 1 kg of propylene glycol, 5 kg of potassium carbonate and 5 kg of PEG (average molecular weight 6000) were treated in the same manner as in Example 1 to obtain a powdery treated product. This treated product 5%, sodium bicarbonate 25
%, Sodium carbonate 15%, succinic acid 40%, fragrance 0.5%,
Mixture of 11.5% dextrin and 3% chamomile extract 10kg
Tablets were packed and packaged in the same manner as in Example 1 to obtain a bath salt.

Comparative Example 1 2 kg of guaiazulene sulfonic acid sodium salt, 5 kg of sodium carbonate and 5 kg of PEG (average molecular weight 6000) were treated in the same manner as in Example 1 to obtain a powdery treated product. This treated product 5%, sodium bicarbonate 30%, sodium carbonate 15%, succinic acid 40%, mirabilite 5.5%, fragrance 0.5%, dextrin 4%
10 kg of a mixture consisting of
It was used as a bath salt.

Comparative Example 2 2 kg of sodium guaizulene sulfonate, 2 kg of glycerin and 5 kg of PEG (average molecular weight 20000) were treated in the same manner as in Example 1 to obtain a powdery treated product. This processed product 3.5
%, Sodium bicarbonate 30%, sodium carbonate 17.5%, succinic acid 40%, mirabilite 5.5%, fragrance 0.5%, dextrin 5.5
10 kg of a mixture of 10% was compressed and packed in the same manner as in Example 1.

Comparative Example 3 2 kg of sodium guaizulene sulfonate, 1 kg of propylene glycol, 5 kg of sodium bicarbonate and 5 kg of PEG (average molecular weight 400) were treated in the same manner as in Example 1 to obtain a powdery treated product. This treated product 5%, sodium bicarbonate 25
%, Sodium carbonate 15%, succinic acid 40%, fragrance 0.5%,
Mixture of 11.5% dextrin and 3% chamomile extract 10kg
Tablets were packed and packaged in the same manner as in Example 1 to obtain a bath salt.

Test Example The tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 2 were tested for stability of guaiazulene sulfonate.

The stability of guaiazulene sulfonate was determined by the degree of blue discoloration of the polypropylene film on the inner surface of the package and the turbidity after dissolving the tablet in water.

Degree of blue discoloration ○: No blue discoloration (no decomposition of guaiazulene sulfonate) △: Some blue discoloration (decomposition is observed) ×: Blue discoloration (clearly disintegration) Tablets at 50 g / water Turbidity of aqueous solution after dissolution in: ◯: No turbidity is observed ×: There is turbidity The results are shown in Table 1.

[Effects of the Invention] As is clear from the results of the stability test in Table 1, the water-soluble azulene-containing effervescent preparation obtained by the present invention is extremely stable as compared with the preparations obtained by other methods.

Claims (1)

[Claims] 1. A guaiazulene sulfonate, a liquid polyhydric alcohol compound, an alkaline inorganic salt and an average molecular weight of 2,
An effervescent preparation containing 000 to 20,000 polyethylene glycol.