JPS6259118B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for preparing a useful glycyrrhizin solution at room temperature. Glycyrrhizin, an active ingredient in licorice, has an excellent anti-inflammatory effect and has been considered important as an anti-allergy agent. Recently, it has been demonstrated both domestically and internationally that it has a remarkable medicinal effect in improving liver function in chronic hepatitis diseases, and it is also attracting attention as an inducer of γ-interferon.
Therefore, there is an increasing demand for the mass production of stable glycyrrhizin preparations. Here, we will briefly discuss the solubility of glycyrrhizin and its salts. Glycyrrhizin (glycyrrhizinic acid) is a diglucuronic acid conjugate of glycyrrhetinic acid and is a tribasic acid. It is slightly soluble in dilute ethanol, insoluble in ether, has a high melting point, and is extremely sparingly soluble in water even when heated. Like glycyrrhizin, the monosalt of glycyrrhizin is acidic, its surface takes on an agar-like appearance in water, and it is difficult to dissolve in water at room temperature. Although it dissolves at high temperatures, the monosalt precipitates out in the form of a gel as the temperature decreases. However, di- and tri-salts become soluble in water. Glycyrrhizin decomposes into glycyrrhetinic acid and glucuronic acid by acid decomposition, and turns yellow when heated with an alkali. It is not easy to prepare a glycyrrhizin solution at room temperature using glycyrrhizin or its monosalt, which is sparingly soluble in water, as a raw material. Usual concentration of glycyrrhizin (0.1-2.0
%) of water and an appropriate amount of an alkali neutralizing agent are stirred and heated, and an isotonic agent is added thereto.
When reacting glycyrrhizin with an alkali at a high temperature or at a high concentration, and especially when it comes into contact with an excessive amount of alkali, it may cause coloration due to trace amounts of flavonoid pigments, so careful attention is required. Currently, the raw materials for glycyrrhizin solutions are highly pure glycyrrhizin and its monosalts (ammonium, sodium, potassium), and soluble dialkali salts and trialkali salts are often colored due to alkali treatment during production, so they are not used for pharmaceuticals. It is not used for any purpose. In addition, when adding heat-labile drugs such as glucuronic acid, ascorbic acid, or cysteine to the glycyrrhizin solution,
If extreme care is not taken, there is a risk of precipitation and coloring occurring over time. In order to eliminate these difficulties, the inventors have developed a solution stabilizer for the main ingredient that is extremely advantageous as a method that can easily mass-produce glycyrrhizin solutions at room temperature, avoiding the heating process that tends to involve the above-mentioned deterioration. I've done a lot of research on this. As a result, it was found that urea and sodium benzoate are the most suitable solubilizers for glycyrrhizin or its salt. That is, if a highly concentrated solution of these solubilizers is prepared and sparingly soluble glycyrrhizin or its salt is added thereto, it will be easily dissolved at room temperature to obtain a certain acidic solution. Next, adjust the pH to 6 to 7 using an appropriate pH adjuster to prevent it from becoming alkaline, and if necessary, dilute with water to the specified glycyrrhizin concentration (0.1 to 2.0%). Able to achieve purpose. In particular, as described below, by using these two solubilizers in appropriate concentrations (urea 1-3%, sodium benzoate 1-3%), isotonicity of the glycyrrhizin solution can be obtained. There is no need to add a tonicifying agent. Furthermore, both of these solubilizers are extremely safe for living organisms, and have a large tolerance as additives for pharmaceuticals. Next, the solubility (approximate) of urea and sodium benzoate for glycyrrhizin compounds is expressed as follows.

[Table] In order to increase the dissolution ability of the urea solution for the main drug glycyrrhizin, it is necessary to increase the concentration of urea. As shown in the table above, there is a large difference in solubility between 50% and 33.3%, which are close to saturated solutions. Concentrations below 33.3% are unsuitable for the purpose of this method. On the other hand, the solubility of sodium benzoate aqueous solution tends to be similar to that of urea, but there is no significant difference in concentration as seen with urea, and with the exception of glycyrrhizin, low concentrations can also be used as a solubilizing agent. Based on the above-mentioned confirmation, the present invention aims to provide an industrial manufacturing method for preparing a useful glycyrrhizin solution at room temperature without performing any heat treatment to dissolve glycyrrhizin or its salt. The gist of the present invention, taken to achieve this object, is, as shown in the claims, that glycyrrhizin or its salt is dissolved in an aqueous solution of a solubilizing agent such as urea or sodium benzoate at room temperature, and then concentrated. Obtain an acidic solution of the main drug, then adjust the PH
It is characterized by smoothly adjusting the pH to 6.0 to 7.0 with a regulator and diluting it to a predetermined concentration. As the pH adjuster, alkali carbonate, alkali hydrogen carbonate, alkali hydroxide, sodium citrate, disodium phosphate, sodium benzoate, and aqueous solutions thereof are usually used. Next, this method will be explained in detail. ~Method using urea~ As shown in the example, when 150 g of urea is dissolved in 150 ml of water, it becomes an almost saturated solution, with a concentration of 50 W/W%, 264 ml. Judging from the above table, 20g of glycyrrhizin dissolves well and first becomes an acidic urea solution of glycyrrhizin. PH is approximately 3.4. Gradually add 1N sodium hydroxide solution as a pH adjuster to adjust the pH to around 6.5. This can prevent deterioration of the main drug due to direct heating neutralization of glycyrrhizin and an alkaline agent. Then dilute it with water and make it 1, then 2
%, 10, a 0.2% glycyrrhizin solution will be obtained. When using glycyrrhizin monoammonium salt as a raw material, the ammonium salt is used in an amount approximately 1.02 times that of glycyrrhizin as in the example. In addition, when using glycyrrhizin monopotassium salt, the amount of potassium salt is about 1.046 times that of glycyrrhizin as in the example. As shown in the examples, each is dissolved in a saturated solution of urea to form a concentrated acidic solution at room temperature.
Adjust the pH with 1N potassium hydroxide solution to about 6.5, and dilute this with water to obtain 0.2% and 0.5% glycyrrhizin solutions. ~Method using sodium benzoate~ When preparing 0.2% glycyrrhizin solution 10 using 20 g of glycyrrhizin as a raw material, 20 g of glycyrrhizin is dissolved in 375 ml of a 40 W/V% sodium benzoate solution as shown in the example. As shown, it is easily dissolved to obtain a sodium benzoate solution of glycyrrhizin. In this case, the liquid property is adjusted by the liquid property of the dissolving agent and becomes PH5.4. Next, adjust the pH to around 6.5 with 1N sodium hydroxide solution and dilute with water to a total of 10 to obtain a 0.2% glycyrrhizin solution. Next, 0.2% glycyrrhizin solution using glycyrrhizin monosodium as raw material.
10, as shown in the example, use 20.5 g of glycyrrhizin monosodium, which is 1.026 times that of glycyrrhizin, and dissolve it in 550 ml of 40 W/V% sodium benzoate solution to obtain a clear weakly acidic solution (PH
5.8). In the same manner as above, adjust the pH to around 6.5 with 1N sodium hydroxide solution, and dilute with water to 10 to obtain a 0.2% glycyrrhizin solution with a pH of about 6.6. Next, the concentrations of the main drug and solubilizing agent in the various glycyrrhizin solutions obtained in the Examples and the osmotic pressure ratios of these solutions to physiological saline are as follows. Example 0.2% glycyrrhizin, 1.5% urea...
Osmotic pressure ratio 0.73; Example 0.2% glycyrrhizin,
2% urea...osmotic pressure ratio 1.04; Example 0.5% glycyrrhizin, 2% urea...osmotic pressure ratio 1.05; Example
0.2% glycyrrhizin, 1.5% sodium benzoate...osmotic pressure ratio...0.64; Example 0.2% glycyrrhizin, 2.2% sodium benzoate...osmotic pressure ratio 1.08. The concentration of glycyrrhizin used is 0.1-2.0%
In this case, the concentration of the lytic agent may range over a wide range other than those listed above. When a solution like the example is prepared, its osmotic pressure ratio to physiological saline is 1.0.
The solubilizing agent acts as a tonicity agent, and there is no need to add other drugs for isotonicity. The effects obtained by this method are as follows. Being able to prepare glycyrrhizin or its salt at a high concentration at room temperature makes it possible to mass-produce products on a small scale, which is advantageous as an industrial method, and at the same time eliminates the heating process, so there is no loss of quality.
Product uniformity is maintained. This is particularly advantageous when other hot and weak drugs are to be combined. The urea or sodium benzoate that brings about the dissolution effect by this method not only serves as a solubilizing agent but also as an isotonic agent, ensuring product safety. Example When 150 g of urea is dissolved in 150 ml of water and a small amount of 20 g of glycyrrhizin is added to the solution at room temperature, a clear, free-flowing acidic solution (PH3.4) is obtained in a short period of time. Next, add approximately 70ml of 1N sodium hydroxide solution.
0.2% glycyrrhizin solution (PH
6.8) is obtained. Example: Dissolve 200 g of urea in 200 ml of water and gradually add 20.4 g of glycyrrhizin monoammonium at room temperature to obtain a clear acidic solution (PH4.2). Then carefully add ammonia TS to bring the pH to 6.5.
If you dilute this with water and make it 1, it will be 2%.
If the solution is further increased to 10, a 0.2% glycyrrhizin solution (PH6.8) will be obtained. Example When 160 g of urea is dissolved in 160 ml of water and 41.8 g of glycyrrhine monopotassium is gradually added thereto at room temperature, a clear and free-flowing acidic solution (PH4.5) is obtained in a short period of time. Next, carefully add about 90 ml of 1N potassium hydroxide solution to adjust the pH to around 6.5, and dilute this with water to a pH of 8 to obtain a 0.5% glycyrrhizin solution with a pH of 6.8. Example 4 375 ml of 0W/V% sodium benzoate solution is taken and 20 g of glycyrrhizin is gradually added thereto, resulting in a clear acidic solution (PH5.4) in a short period of time. To that
Add about 50ml of 1N sodium hydroxide solution to adjust the pH to around 6.5, then dilute with water to make it 10, then 0.2
% glycyrrhizin solution (PH6.6) is obtained. Example 4 Take 550 ml of a 0W/V% sodium benzoate solution and add 20.5 g of glycyrrhizin monosodium to it at room temperature, which instantly turns into a clear acidic solution (PH5.8). Next, add about 46 ml of 1N sodium hydroxide solution to adjust the pH to around 6.5, and dilute with water to a concentration of 10 to create a 0.2% glycyrrhizin solution (PH
6.8) is obtained.

Claims (1)

[Claims] 1. Glycyrrhizin, an active ingredient of licorice, or a salt thereof,
Urea or sodium benzoate and PH at room temperature
1. A useful method for preparing a glycyrrhizin solution, characterized by the action of a regulator. 2 Dissolve glycyrrhizin or its salt in a concentrated solution of urea at room temperature, and dissolve the resulting acidic concentrated solution.
Claim 1, characterized in that the solution is made approximately neutral with a pH adjuster and diluted with water to a predetermined concentration.
Method for preparing useful glycyrrhizin solutions as described in Section 1. 3 Glycyrrhizin or its salt is dissolved in a concentrated solution of sodium benzoate at room temperature, the resulting acidic concentrated solution is made into an approximately neutral solution with a PH adjuster, and the solution is diluted with water to a predetermined concentration. A method for preparing a useful glycyrrhizin solution according to claim 1.