JPS6215058B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a basic amino acid salt of acetylsalicylic acid (hereinafter referred to as aspirin). More specifically, the present invention relates to a method for producing a sterile basic amino acid salt of aspirin.

Aspirin is a drug with a long history and is recognized as a useful analgesic and hypothermic agent when administered systemically; however, aspirin has low solubility in gastric juices and is therefore slow to be absorbed by the body when administered orally. Undesirable effects have also been observed as a result of hydrolysis in the gastric or intestinal secretions.

Therefore, a method of increasing the absorption rate of aspirin by adding a buffer or a solubilizing agent to aspirin has been proposed and is known. However, although it has been recognized that such buffered aspirin compositions prepared by conventional techniques increase the dissolution rate, they are not always satisfactory, as they tend to cause constipation, laxative effects, and acid reaction. In addition to the addition of buffers, water-soluble addition salts of basic compounds, particularly basic amino acids, and aspirin have been proposed and are known; It is not always satisfactory because it undergoes hydrolysis.

Therefore, in order to avoid the disadvantages of oral administration, attempts have been made to prepare water-soluble addition salts of aspirin and basic amino acids, particularly basic essential amino acids, as injections (for example, Japanese Patent Publication No. 53-8769).
issue).

However, aspirin itself is a relatively unstable compound with respect to moisture and heat, and is susceptible to hydrolysis.Additionally, addition salts with basic amino acids have poor stability with respect to moisture and heat. The industrial production of sterile preparations suitable for use in pharmaceutical preparations is fraught with many difficulties.

As a method for producing a sterile preparation of an addition salt of aspirin and a basic amino acid, for example, methanol or ethanol containing formamide is used as a reaction solvent, or the reaction is carried out in aqueous methanol or aqueous ethanol, followed by sterilization. A method is known in which ethyl ether or isopropanol is added to precipitate crystals of an addition salt of aspirin and a basic amino acid, which are filtered and vacuum dried to obtain a product.

As a result of studying this known production method, the present inventors found that it has considerable drawbacks as an industrial production method.

In other words, as mentioned above, the addition salt of aspirin and a basic amino acid has poor stability, and is particularly unstable in water or an aqueous solvent. Even if it is kept for a long time, most of it decomposes and can no longer be recovered. It was also recognized that in such a water-containing solution state, the operation must be carried out in a short time even at room temperature.

In the known production method, a sterile product is obtained by sterilizing and filtrating a water-containing solution of such an unstable addition salt of aspirin and a basic amino acid. However, as a result of studies, the present inventors found that this salt-forming mass is quite viscous, and it would take an excessively long time to sterilize it using a so-called membrane filter. It was learned that the product was decomposed during the sterilization process, reducing the yield and quality of the product. Therefore, the present inventors studied to improve this difficulty, and found that the ethyl alcohol solution of aspirin was sterilized in advance, and the aqueous solution of basic amino acids was also sterilized in advance, and both solutions It has been found that the above-mentioned difficulties can be overcome by a method of mixing aspirin and basic amino acids in a sterile container to produce an addition salt of aspirin and a basic amino acid. When using the method of the present invention, a membrane filter (0.2~
Bacterial sterilization using 0.45μ) is easy and does not require an excessively long time as described above, and decomposition can be avoided, and the workability is good and it is easy to carry out industrially, which is advantageous.

Another feature of the present invention is that the solvent is limited to ethyl alcohol. In conventionally known methods, the solvent used to dissolve aspirin and the solvent used to generate addition salts of aspirin and basic amino acids and then precipitate crystals of the addition salts (hereinafter referred to as precipitating agents) are different; A number of drawbacks can be pointed out in the known methods. That is, since the product targeted by the present invention is an injection, it is important and essential that the solvent used in its manufacture does not have any unfavorable effects on the human body. Although methyl alcohol, isopropyl alcohol, formamide, and the like have been proposed as solubilizing agents in conventionally known methods, it is clear that these are unfavorable to the human body and are not practical. Also, isopropyl alcohol, ethyl ether, and the like have been proposed as precipitating agents, but these are not preferred for the same reason. In particular, it has been pointed out that methods using ethyl ether as a precipitating agent are not industrially suitable from the standpoint of disaster prevention when large quantities are handled. Experiments have shown that when a poorly soluble aqueous solvent such as ethyl ether is used as a precipitating agent, it is difficult to obtain good results in terms of workability, yield, and quality, such as the formation of two layers. Furthermore, the use of the above-mentioned solvents as a mixed solvent is even more undesirable because it complicates the recovery of the solvent.

The inventors of the present invention conducted studies to improve this point and found that it is most suitable to use only ethyl alcohol. It can be said that ethyl alcohol has a much safer effect on the human body than the aforementioned ethyl alcohol, isopropyl alcohol, formamide, and ethyl ether.
The solvent used in this manufacturing process needs to be dissolved in water, and in addition to the above solvents, examples include acetone, dioxane, and tetrahydrofuran, but these are less safe than the ethyl alcohol of the present invention. That is clear.

That is, the method of the present invention uses water to dissolve basic amino acids and only ethyl alcohol to dissolve aspirin, and each solution is sterilized in advance and then mixed to form an addition salt, which is then mixed with ethyl alcohol. is added as a precipitating agent to precipitate addition salt crystals, filtered, washed with ethyl alcohol if necessary, and dried under reduced pressure below room temperature with nitrogen gas if necessary. This is a method for producing addition salts.

In carrying out the present invention, good results are obtained when the addition salt of aspirin and a basic amino acid is formed at a temperature below room temperature, preferably below 10°C. Furthermore, since the temperature at which aspirin is dissolved in ethyl alcohol is preferably room temperature or lower, it is preferable to use an amount of ethyl alcohol that is compatible with that temperature. The basic amino acid aqueous solution may have an appropriate concentration, for example, 15 to 50%, particularly 19 to 30%, but if a large amount of water is used, the amount of precipitating agent added will naturally increase, making it impossible to obtain favorable results. Therefore, it is natural to avoid using diluted materials more than necessary. If necessary, after performing a normal decolorization process using decolorizing charcoal, a sterilization process is further performed. Sterilization can be easily removed using a membrane filter (0.2-0.45μ). An ethyl alcohol solution of aspirin is also sterilized in the same manner as above. In this case as well, mistakes can be easily made.

If necessary, the ethyl alcohol used as a precipitating agent is desirably sterilized and filtered. Ethyl alcohol may be undenatured or may be used for industrial purposes, for example, ethyl alcohol modified with a small amount of benzene or the like. The amount of ethyl alcohol added as a precipitating agent greatly influences the amount of addition salt precipitated.

Preferably, the ethyl alcohol concentration of the addition salt precipitation solution is about 85 to 95%, preferably 88 to 93%. The temperature at which the precipitating agent ethyl alcohol is added is preferably below room temperature, preferably below 10°C, as in the case of addition salt formation. In this case, either a method of gradually dropping ethyl alcohol into the addition salt solution or a method of dropping the addition salt solution into ethyl alcohol may be used. During the crystallization operation, it is necessary to avoid rapid stirring, stir slowly, and add the precipitating agent gradually in order to grow the crystals and adjust the crystal shape. After the addition of the precipitant is finished, if necessary, let it stand for an appropriate period of time, filter out the added salt, wash with cold ethyl alcohol (sterilized), and immediately transfer it to a vacuum dryer and dry it under vacuum at room temperature or below. This provides a sterile basic amino acid addition salt of aspirin.

Basic amino acids used in the method of the present invention include L-lysine, DL-lysine, L-arginine, L-lysine, and L-lysine.
- Histidine, creatinine, etc. can be used.

The method of the present invention will be specifically explained below with reference to Examples and Comparative Examples of the present invention.

Example 1 72 g (0.40 mol) of aspirin was stirred and dissolved in 320 ml of ethyl alcohol, and filtered through a membrane filter (TM-2p manufactured by Toyo Shisha Co., Ltd., 0.45μ, size 47).
Sterilization was carried out at room temperature using (m/m). The time required was approximately 3 minutes.

Next, add 58.4g (0.40mol) of LD-lysine to pure water.
The solution was dissolved in 240 ml, added with 4 g of activated carbon, stirred for a while, and then filtered with ordinary industrial paper.
Furthermore, this liquid was sterilized at room temperature using the same membrane filter as above. The time required was approximately 4 minutes.

The above sterilized aqueous solution of DL-lysine was placed in a reaction container that had been cleaned in a sterile state, and cooled to 5° C. from the outside while being gently stirred. The above sterilized aspirin ethyl alcohol solution was gradually dropped into the solution. During dripping, keep the internal temperature at 5~5
The solution was kept at 10°C and added dropwise over about 15 minutes, and stirred at the same temperature for about 30 minutes to complete the salt-forming reaction. The reaction solution was an almost clear homogeneous solution (hereinafter referred to as salt formation mass). Next, 2400 ml of ethyl alcohol, which had been sterilized in advance, was added dropwise into the solution over a period of about 3 hours. During the addition, the temperature was maintained at 5 to 10°C and the mixture was gently stirred. As the addition of ethyl alcohol progressed, crystals of aspirin-DL-lysine salt began to precipitate and the amount of crystals gradually increased. After the dropwise addition of ethyl alcohol was completed, the mixture was gently stirred at 5 to 10°C for about 3 hours to complete crystallization. The crystals were filtered in a clean bench (clarity level 100) and washed four times with 50 ml of ethyl alcohol that had been sterilized in advance.
The crystals were transferred to a vacuum dryer, taking care to avoid contamination due to contact with the outside air, and dried under reduced pressure (10 to 20 mmHg abs.
) at room temperature (25-30°C) for about 20 hours to obtain aspirin-DL-lysine salt. The yield was 115.5 g, yield 88.6%, and melting point 138-139°C. The results of a sterility test (Japanese Antibiotic Pharmaceutical Standards, membrane filter method) for this product were negative for both bacteria and fungi. It was also negative in the progel method and the pyrodiene test using rabbits.

Example 2 The same procedure as described in Example 1 was carried out, except that instead of dropping ethyl alcohol into the salt-forming mass in Example 1, the salt-forming mass was dropped at 5 to 10°C into 2400 ml of ethyl alcohol that had been sterilized in advance. Aspirin-DL-lysine salt was obtained by carrying out the same procedure. Yield 113.0g, yield 86.7. The melting point was 138-139°C. The results of the sterility test (mentioned above; membrane filter method) for this product were negative for both bacteria and fungi.

Comparative Example 1 72 g (0.40 mol) of aspirin was dissolved in 320 ml of ethyl alcohol. To this, 58.4 g (0.40 mol) of DL-lysine was dissolved in 240 ml of pure water, 4 g of activated carbon was added, and the mixture was stirred. Then, a normal decolorized DL-lysine aqueous solution was added at 5 to 10°C, and the procedure described in Example 1 was added. Salt mass was produced in the same manner. When this salt-forming mass was subjected to sterilization using a membrane filter (the same one as described in Example 1), crystals were precipitated during the filtration, and the overspeed was extremely low. It took time. The same procedure as described in Example 1 was carried out, but the yield of aspirin-DL-lysine salt was 101 g, a yield of 77.4%, which was considerably lower.

Comparative Example 2 72 g (0.40 mol) of aspirin was dissolved in 384 ml of ethyl alcohol. 256 ml of cooled pure water was gradually added to this and stirred at 10°C. Then, 58.4 g of DL-lysine was gradually added and stirred at 5 to 10°C for about 30 minutes to obtain a salt-forming solution. When this was sterilized using the same membrane filter as described in Example 1, it took 3 hours and 20 minutes. Add this solution to 10℃
2,560 ml of ethyl ether, which had been cooled, was gradually added over a period of 3 hours, and the mixture was left to cool overnight. Two layers, an ethyl ether layer and a water-containing ethyl alcohol layer, were formed, and the apparent amount of precipitated crystals was also small. After washing with a mixed solvent of ethyl alcohol and isopropyl alcohol that had been filtered and cooled at 10°C, it was dried under reduced pressure under the same conditions as described in Example 1. The yield of aspirin-DL-lysine salt was 50.8 g. rate
The yield was 38.9%, which was extremely low compared to the results of Example 1.

Example 3 10 g (0.088 mol) of creatinine was warmed and dissolved in 50 ml of pure water, and then sterilized using a membrane filter (same as described in Example 1). Separately, 15.7 g (0.087 mol) of aspirin powder was dissolved in 70 ml of ethyl alcohol and sterilized using a membrane filter (the same one as described in Example 1 was used). The above creatinine aqueous solution was transferred into a reaction vessel that had been cleaned in a sterile state, and the above aspirin ethyl alcohol solution was added dropwise at 5°C while stirring. Further, 500 ml of sterilized ethyl alcohol was added at 5 to 10°C to crystallize the creatinine salt of aspirin. After stirring gently at 5-10°C for 3 hours, the crystals were filtered, washed with cold ethyl alcohol, and dried at room temperature under reduced pressure to obtain aspirin creatinine salt. Yield 16g, yield
62.6%, melting point 130-131°C.

The results of the sterility test (same as described in Example 1) of this product were negative for both bacteria and fungi.

Example 4 75.6 g (0.42 mol) of aspirin was stirred and dissolved in 320 ml of ethyl alcohol, and filtered through a membrane filter (manufactured by Toyo Shisha Co., Ltd., 0.2μ, size 47m/
Sterilization was carried out at room temperature using m). The time required was approximately 3 minutes.

Next, add 58.4 g (0.40 mol) of DL-lysine to pure water.
The solution was dissolved in 240 ml, added with 4 g of activated carbon, stirred for a while, and then filtered using ordinary industrial paper. Furthermore, this liquid was sterilized at room temperature using the same membrane filter as above. The time required was approximately 4 minutes.

Pour the above sterilized aspirin ethyl alcohol solution into a reaction container that has been cleaned in a sterile condition, and heat the mixture from the outside at 0 to 5°C while stirring gently.
It was cooled to In this, the above sterilized DL-
An aqueous solution of lysine was gradually added dropwise. During dropping, keep the internal temperature at 0 to 5℃ and drip for about 15 minutes.
The salt formation reaction was completed by stirring for a minute. The reaction solution was an almost clear homogeneous solution. Thereafter, the same operation as in Example 1 was performed to obtain aspirin-DL-lysine salt.

Yield: 109 g, yield: 83.5% (based on DL-lysine). The melting point was 138-139°C. The results of the sterility test (see Example 1) for this product were negative for both bacteria and fungi. It was also negative in the progel method and the pyrodiene test using rabbits.

Claims (1)

[Claims] 1. In producing the basic amino acid salt of acetylsalicylic acid, a basic amino acid salt of acetylsalicylic acid is prepared by mixing an ethyl alcohol solution of acetylsalicylic acid that has been sterilized in advance and an aqueous solution of a basic amino acid that has been sterilized in advance. After the ethyl alcohol concentration of this solution is increased, crystals of the basic amino acid salt of acetylsalicylic acid are precipitated and separated, washed with ethyl alcohol, and then dried under reduced pressure. Production method.