JP3969585B2 - Azulene sulfonate sodium preparation - Google Patents

Description

  The present invention relates to an aqueous solution preparation containing sodium azulene sulfonate as an active ingredient, and in particular, azulene sulfonic acid that can be used as a prophylactic and therapeutic agent for inflammatory diseases in areas such as the oral cavity, throat, and ophthalmology. The present invention relates to an aqueous solution preparation containing sodium stably.

  Conventionally, many aqueous solution preparations for sterilization and disinfection containing iodine, povidone iodine and the like are commercially available as solutions for oral and throat diseases. Oral / throat preparations containing anti-inflammatory ingredients that suppress inflammation such as stomatitis are also commercially available, and examples of such anti-inflammatory ingredients include sodium azulene sulfonate and dipotassium glycyrrhizinate.

  Among them, sodium azulene sulfonate is a component extracted from the plant chamomile of the family Asteraceae, and chamomile decoction extract has long been used as a folk medicine for various inflammatory diseases. At present, oral anti-gastric and gastric ulcer treatments containing sodium azulene sulfonate as an active ingredient, as well as gargles and ophthalmic preparations for the treatment of stomatitis, pharyngitis, tonsillitis and the like are provided.

  By the way, for a preparation containing sodium azulene sulfonate, solid dosage forms such as tablets, granules, powders and the like are basically adopted in addition to the liquid preparation as an eye drop, and it is used as an aqueous solution preparation. Even if it is a gargle, the dosage form is a dissolution type at the time of use. This is because sodium azulene sulfonate is unstable in an aqueous solution and is easily decomposed in the aqueous solution.

  Therefore, even in an eye drop which is an aqueous liquid, means for eliminating instability in an aqueous solution of sodium azulene sulfonate which is an active ingredient has been adopted, for example, sodium thiosulfate which is an antioxidant, EDTA, which is a chelating agent, is blended and then filled with an expensive closed container, but its degradability has not yet been completely eliminated.

  For this reason, various studies have been conducted on stable aqueous solution preparations containing sodium azulenesulfonate as an active ingredient. For example, a method for producing a stable aqueous solution of a water-soluble azulene derivative obtained by adding a cationic surfactant or chlorhexidine and a nonionic surfactant to an aqueous solution of sodium azulenesulfonate (Patent Document 1), azulenes and benzalkonium chloride Alternatively, a solution preparation containing a quaternary ammonium salt such as cetylpyridinium chloride and further containing a nonionic surfactant and alcohol (Patent Document 2), an aqueous preparation containing sodium azulenesulfonate and a polyhydric alcohol ( Patent Document 3) has been proposed.

Japanese Patent Publication No. 1-227060 Japanese Patent Publication No. 8-32626 Patent No. 2724943 publication

  However, these aqueous solution preparations contain a surfactant together with sodium azulene sulfonate, and in particular, a white turbidity phenomenon that occurs when used in combination with a bactericidal agent that is a quaternary ammonium salt. Needless to say, the use of a surfactant should be avoided as much as possible. In addition, an aqueous solution formulation that stabilizes sodium azulenesulfonate by using in combination with a polyhydric alcohol is effective when the amount of sodium azulenesulfonate is very small, but it is effective. When sodium acid is contained, the present situation is that the stabilization is not necessarily achieved.

  Accordingly, an object of the present invention is to provide a stable aqueous solution preparation containing a high concentration of sodium azulene sulfonate without using a surfactant under the present situation.

  In order to solve this problem, the present inventors have intensively studied. As a result, a substance having a buffering action together with a polyhydric alcohol, that is, a buffering agent is used in an aqueous solution containing sodium azulenesulfonate without using a surfactant. In this case, it has been found that even an aqueous solution containing sodium azulenesulfonate at a high concentration can be an extremely stable aqueous solution, and that further stabilization can be achieved when polyethylene glycol is added. The present invention has been completed.

  Therefore, a basic aspect of the present invention is an aqueous solution preparation characterized by containing 0.07 to 10% sodium azulenesulfonate and further containing a polyhydric alcohol, a lower alcohol and a buffer.

  More preferably, the present invention is an aqueous solution preparation containing 0.4 to 4% sodium azulenesulfonate and further containing polyethylene glycol.

  More specifically, the aqueous solution preparation of the present invention is an aqueous solution preparation in which the polyhydric alcohol is selected from ethylene glycol, propylene glycol, butylene glycol, glycerin, sorbitol, mannitol, and xylitol.

  In a more specific aqueous solution preparation of the present invention, the buffer having a buffering action is selected from a combination consisting of an organic acid salt, an organic acid and a salt thereof or sodium hydrogen carbonate, The organic acid salt is sodium citrate, potassium sorbate, sodium maleate, sodium benzoate, sodium hydrogen phosphate or anhydrous disodium phosphate, and the organic acid is citric acid, sorbic acid, maleic acid or benzoic acid An aqueous solution formulation.

  That is, the present invention is an aqueous solution preparation stably containing sodium azulenesulfonate, but does not use a cationic or nonionic surfactant that has been added for stabilization so far. It is characterized in that stabilization can be achieved by using a polyhydric alcohol and a lower alcohol in combination, and further containing a buffer.

  In the aqueous solution preparation provided by the present invention, sodium azulene sulfonate, which is an active ingredient to be contained, can be contained at a higher concentration than conventional aqueous solution preparations. Specifically, sodium azulenesulfonate can be contained in an amount of 0.07 to 10%, more preferably about 0.4 to 4%.

  Examples of the polyhydric alcohol blended in the aqueous solution preparation provided by the present invention include polyhydric alcohols such as glycerin, glycols, and sugar alcohols. Examples of glycols include ethylene glycol, propylene glycol, and butylene glycol. Examples of sugar alcohols include sorbitol, mannitol, and xylitol. Among these, the addition of glycerin gave the best results for the stability of the aqueous solution of sodium azulenesulfonate.

  The blending amount of these polyhydric alcohols is 20% or more, preferably about 30 to 50%. If it is less than 20%, it becomes difficult to stably maintain sodium azulenesulfonate for a long period of time.

  In the aqueous solution preparation of the present invention, a lower alcohol is blended together with these polyhydric alcohols. Examples of such lower alcohols include lower alcohols having about 1 to 4 carbon atoms, specifically, methanol, ethanol, propanol, butanol, etc. Among them, ethanol is preferably blended.

  Therefore, as the most preferable combination of the present invention, it is preferable to use glycerin as the polyhydric alcohol, ethanol as the lower alcohol, and use both in combination.

  On the other hand, the buffering agent having a buffering action formulated to stabilize sodium azulenesulfonate in the aqueous solution preparation of the present invention is a buffering agent for sodium azulenesulfonate dissolved as an aqueous solution. Examples of such a buffering agent include organic acid salt alone, or a combination of an organic acid and its salt or sodium hydrogen carbonate.

  Specifically, the organic acid salt includes sodium citrate, potassium sorbate, sodium maleate, sodium benzoate, sodium hydrogen phosphate or anhydrous disodium phosphate, and the organic acid includes citric acid, sorbic acid. And maleic acid or benzoic acid. These buffering agents can be used singly or in combination, and are blended for the purpose of maintaining 7.0 to 9.0, which is a stable pH range of sodium azulenesulfonate in an aqueous solution. . Although the compounding quantity cannot be generally limited, it is about 0.01 to 5%. Among them, it is preferable to use sodium hydrogen phosphate and anhydrous disodium phosphate in combination.

  If the blending amount of the buffering agent is less than 0.01%, the buffering effect cannot be exhibited, and stability cannot be imparted to the aqueous solution containing sodium azulenesulfonate. Moreover, even if it mixes exceeding 5%, the further buffer effect cannot be acquired, but it becomes a waste of resources on the contrary, and is not preferable.

  In the aqueous solution preparation provided by the present invention, it has been found that by adding polyethylene glycol in addition to the above, further long-term stability of sodium azulenesulfonate can be achieved. As such polyethylene glycol, those having a molecular weight of about 200 to 20,000 can be generally used, but those having a molecular weight of 400 to 6000 are preferably used from the viewpoint of safety and usability. As these polyethylene glycols, for example, those marketed under the name of “Macrogol” can be used.

  Although the compounding quantity cannot be generally limited by the kind of polyethylene glycol to be used, it is about 5 to 20%. If it is less than 5%, a further effect is not recognized, and even if it exceeds 20%, no further effect is recognized.

  In the aqueous solution preparation provided by the present invention, various additives to be blended with ordinary pharmaceutical preparations can be blended within a range not impairing the effects of the present invention. Such additives include flavoring agents such as l-menthol and mint oil, flavoring agents, preservatives such as benzethonium chloride and cetylpyridinium chloride (quaternary ammonium salt), stabilizers such as macrogol, sodium edetate, etc. And the like.

  The aqueous solution preparation of the present invention can be produced according to a conventional method. Specifically, it is manufactured by blending macrogol (polyethylene glycol) as desired with sodium azulenesulfonate, polyhydric alcohol and lower alcohol, and further mixing a buffer, a corrigent, sterile distilled water for injection, etc. can do.

  The aqueous solution formulation containing sodium azulene sulfonate provided by the present invention thus prepared contains a high concentration of sodium azulene sulfonate, which is an active ingredient, in comparison with the aqueous solution formulations provided so far. In addition, it has excellent long-term stability. Therefore, this aqueous solution preparation can be used as a liquid for internal use, a liquid for oral cavity / throat, a liquid for nose and the like.

  Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples, but it goes without saying that the present invention is not limited to these Examples.

Examples 1-5
The aqueous solution preparation containing sodium azulenesulfonate of the present invention was prepared according to the above-described production method based on the blending formulation (blending ratio:%) shown in Table 1 below.

  The stability of the aqueous solution preparation containing sodium azulenesulfonate of the present invention obtained above was evaluated by conducting the following tests.

Stability test The aqueous solution preparation of each Example obtained above was filled in a 15 mL polyethylene container, stored in a constant temperature and humidity environment at a temperature of 40 ± 2 ° C., and a humidity of 75 ± 5%, and the azulene over time. The content of sodium sulfonate was determined from the change in absorbance with a spectrophotometer, and the stability was evaluated. The results are also shown in the table.

The criteria for evaluation are as follows.
A: There is no change in the residual ratio, and the stability is extremely good.
○: Some variation in residual rate is observed, but stability is good.
(Triangle | delta): A change is recognized by residual rate and stability is a little bad.
X: Residual rate decreases and stability is poor.

Examples 6-8
The aqueous solution preparation containing sodium azulenesulfonate of the present invention was prepared according to the above-described production method based on the blending formulation (blending ratio:%) shown in Table 2 below. Moreover, the stability test was similarly performed about the obtained aqueous solution formulation of each Example, and the result was also shown in the table | surface.

Comparative Examples 1-6
Based on the blending formulation (blending ratio:%) shown in Table 3 below, according to the above-described production method, an aqueous solution preparation containing sodium azulene sulfonate of Comparative Example to which a nonionic surfactant was added was prepared. Moreover, the stability test was similarly performed about the obtained aqueous solution formulation of each comparative example, and the result was also shown in the table | surface.

Comparative Examples 7-13
Based on the blending formulation (blending ratio:%) shown in Table 4 below, according to the above-described production method, an aqueous solution preparation containing sodium azulene sulfonate of Comparative Example to which a nonionic surfactant was added was prepared. Moreover, the stability test was similarly performed about the obtained aqueous solution formulation of each comparative example, and the result was also shown in the table | surface.

Comparative Examples 14-16
Based on the blending formulation (blending ratio:%) shown in Table 5 below, a sodium azulene sulfonate-containing aqueous solution preparation of Comparative Example to which a nonionic surfactant was added was prepared according to the above-described production method. Moreover, the stability test was similarly performed about the obtained aqueous solution formulation of each comparative example, and the result was also shown in the table | surface.

  As can be seen from the examples and comparative examples shown above, Examples 1 to 5 of the present invention do not contain a nonionic surfactant, and are glycerol, which is a polyhydric alcohol, ethanol, which is a lower alcohol, and a buffer. This is an aqueous solution preparation containing sodium azulene sulfonate containing sodium hydrogen phosphate and anhydrous disodium phosphate, and further added with polyethylene glycol. The stability of sodium azulene sulfonate in water-soluble preparations is extremely high by blending polyhydric alcohol, lower alcohol and buffer, and adding polyethylene glycol instead of blending nonionic surfactant. It was confirmed to be good.

  In addition, Examples 6 to 8 of the present invention were prepared by adding glycerin, which is a polyhydric alcohol, ethanol, which is a lower alcohol, and sodium hydrogen phosphate and anhydrous disodium phosphate, which are buffer agents, without adding a nonionic surfactant. It is an aqueous solution preparation containing sodium azulenesulfonate, which is added and does not contain the polyethylene glycol added in Examples 1 to 5. Even in this case, the stability of sodium azulene sulfonate in the water-soluble preparation is extremely improved by blending a polyhydric alcohol, a lower alcohol and a buffering agent instead of blending a nonionic surfactant. It was confirmed to be good.

  On the other hand, the aqueous solution formulations containing sodium azulene sulfonate of Comparative Examples 1 to 16 are those containing a nonionic surfactant, but the aqueous solution formulations containing sodium azulene sulfonate are examples of the present invention. In comparison, the stability was poor. This decrease in stability was confirmed to originate from the nonionic surfactant to be blended.

As described above, the present invention aims to provide a stable aqueous solution preparation containing a high concentration of sodium azulene sulfonate, without using a conventionally used surfactant, A highly stable aqueous solution preparation is provided by using a substance having a buffering action together with a polyhydric alcohol, that is, a buffering agent, in an aqueous solution containing sodium azulenesulfonate. Therefore, it contributes greatly to medical treatment in terms of providing an aqueous solution preparation that stably contains sodium azulenesulfonate, which can be used as an agent for the prevention and treatment of inflammatory diseases in areas such as the oral cavity, throat, and ophthalmology. To do.

Claims (5)

No surfactant, sodium azulene sulfonate 0 . An aqueous solution preparation containing 4 to 4% and further containing a polyhydric alcohol, a lower alcohol and a buffer. The aqueous solution preparation according to claim 1 , further comprising polyethylene glycol. The aqueous solution preparation according to claim 1 or 2 , wherein the polyhydric alcohol is selected from ethylene glycol, propylene glycol, butylene glycol, glycerin, sorbitol, mannitol, and xylitol. The aqueous solution preparation according to claim 1, 2 or 3, wherein the buffer is selected from a combination consisting of an organic acid salt, an organic acid and a salt thereof or sodium hydrogen carbonate. The organic acid salt is sodium citrate, potassium sorbate, sodium maleate, sodium benzoate, sodium hydrogen phosphate or anhydrous disodium phosphate, and the organic acid is citric acid, sorbic acid, maleic acid or benzoic acid The aqueous solution formulation according to claim 4 .