JPH0813737B2 - Syrup - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for formulating and producing a stable syrup containing carbocysteine.

Carbocysteine has the following structural formula It is a general name for the compound represented by and is an airway mucus regulating / mucosal normalizing agent that reduces the viscosity of sputum by normalizing the content ratio of various mucins contained in airway mucus. Clinically, excellent effect on sputum of various respiratory diseases is recognized,
It is commercialized under the trade name of Mucodine (registered trademark) as tablets and syrups.

[Prior Art and Problems Thereof] Sucrose and glucose are generally used as sweeteners added to syrups. However, it is known that when such a reducing sugar is used as a syrup of carbocysteine, the solution undergoes Maillard reaction with carbocysteine, which is an amino acid, and the solution turns brown. In addition, the addition of these sugars caused a decrease in pH over time, which also had the drawback of decreasing the stability of carbocysteine.

Carbocysteine has different stability depending on pH, and is decomposed on the acidic and alkaline sides. The main decomposition products are 3-thiomorpholinone-5-carboxylic acid,
Thioglycolic acid and alanine are produced. Therefore, it is essential to maintain a stable constant pH for a long period of time.

Carbocysteine has a unique strong sour taste, and when taken as a syrup, it is essential to add a corrigent or sweetener, so it does not change even if blended with carbocysteine in consideration of the above problems. There is a need for stable flavoring or sweetening agents.

[Problems to be Solved by the Invention] In the case of producing a syrup of carbocysteine, the present invention provides a stable formulation that suppresses browning of the solution and suppresses the formation of decomposition products, and is a syrup that is easy to take. The purpose is to obtain the prescription ingredients of the drug.

[Means and Actions for Solving Problems] In order to solve the above problems, a sweetener as a corrigent was researched, and a coloring inhibitor and a stabilizer were earnestly studied to complete the present invention.

Generally, as a sweetener, sucrose, which is a natural sweetener,
Glucose, fructose, maltose, xylose, maple sugar, honey, palatinose, coupling sugar and neo sugar are known, and sugar sugars include D-sorbitol, mannitol, maltitol, xylitol,
Palatinit and lykacin are known. Glycyrrhizin, glycyrrhizic acid disodium salt, glycyrrhizinic acid trisodium salt, stevioside, α-G sweet (α-glycosylstevioside), rebaudianaside, phyllodulcin, lohancuo and the like are also known. Aspartame (α-L-aspartyl-L-phenylalanine methyl ester) and glycine are added as amino acids and peptides, and further, protein sweeteners such as thoumatin, artificial synthetic sweeteners such as saccharin sodium, acezulfarm K, cyclodextrin, etc. It is known.

The present inventors investigated the stability when the above various sweeteners were blended with carbocysteine.

Stability test was carried out by adding 0.2 to 40 W / V% of various sweeteners to a 5 W / V% carbocysteine aqueous solution (pH 6.5) at 50 °, 3
The pH, the degree of coloring (the degree of yellowness measured using a color difference meter), and the residual rate of carbocysteine after storage for 0 days were measured. The results are shown in Table 1.

As a result, the highly stable sweetener is D-sorbitol,
D-mannitol, xylitol, and sodium saccharin were D-sorbitol or xylitol, which were the most suitable as an oral sweetener in view of secondary symptoms such as diarrhea during administration. It is also possible to mix two or more sweeteners, such as adding saccharin sodium.

Next, the relationship between the amount of D-sorbitol or xylitol added to the syrup, pH, coloring degree and carbocysteine residual rate was investigated. The results are shown in Table 2.

From the above results, with respect to D-sorbitol and xylitol, addition of 10 w / v% or more did not show any change in pH, coloring degree and residual rate. As a result of considering the taste of the syrup, it was not necessary to add more than 70 w / v%. It has the best sweetness, and the most suitable concentration for use is
It was 40 W / V%.

Further, the stability of the carbocysteine aqueous solution varies depending on its pH. The stability of 5 W / V% carbocysteine syrup containing 40 W / V% D-sorbitol to pH was examined.
Table 3 shows the results.

The change in coloring degree tends to be slightly larger at pH 5.3, but
There was little change above 5.8.

The residual rate decreased slightly at pH 5.3 and pH 7.9. Almost stable in these pH ranges, but the preferred pH range is 6.
It was 0 to 7.5. As the pH adjusting agent, an alkaline agent which is usually used is good, and the most suitable one is an aqueous solution of sodium hydroxide.

In addition to the above sweetener, the syrup preparation of the present invention may contain, as a stabilizer, any one of L-cysteine, EDTA, sodium bisulfite and the like, and the addition amount thereof is 0.01 to 0.1%. Therefore, the stability of carbocysteine syrup can be increased.

In addition, as a preservative commonly added to syrups, sorbic acid is added in an amount of 0.05 to 0.2%, preferably
0.1W / V% and the addition amount of caramel as a coloring agent 0.02
~ 0.1%, preferably 0.06 W / V% and fruit essence may be added as a trace amount of fragrance.

[Examples] Hereinafter, various modes of embodying the present invention will be described with reference to Examples, but the present invention is not limited to these exemplifications.

Example 1. Carbocysteine 50 g and sorbic acid 1.0 g were added to purified water 600
Add 20 ml / ml of sodium hydroxide aqueous solution 58m
l was added and dissolved by stirring. To this, D-sorbitol 400
Add g to dissolve with stirring, adjust the pH to 6.5 by adding 20 W / V% sodium hydroxide aqueous solution, add 0.6 g of caramel and a small amount of fruit essence, and add purified water to a total volume of 1000 ml.
And carbocysteine 5w / v% syrup preparation was prepared.

Example 2. Carbocysteine 100g and sorbic acid 2.0g purified water 12
Add to 00 ml and stir, 20 W / V% sodium hydroxide aqueous solution 1
15 ml was added and dissolved by stirring. To this, xylitol 1200
Add g and dissolve with stirring, adjust the pH to 7.0 by adding 20 W / V% sodium hydroxide aqueous solution, add a small amount of caramel and fruit essence, add purified water to a total volume of 2000 ml, and carbocysteine 5 w / v % Syrup was prepared.

Example 3 Carbocysteine 100 g and sorbic acid 2.0 g purified water 12
Add to 00 ml and stir-mix, add 115 W of 20 W / V% sodium hydroxide aqueous solution and dissolve with stirring. To this, add 800 g of D-sorbitol and 4 g of sodium saccharin and dissolve with stirring to obtain 20 W / V% aqueous sodium hydroxide solution. In addition to pH 7.0
After adjusting to, a small amount of caramel and fruit essence was added, and purified water was added to a total amount of 2000 ml to prepare a carbocysteine 5w / v% syrup.

Example 4. Carbocysteine 50 g and sorbic acid 1 g purified water 500 ml
Then, 115 ml of a 10% aqueous sodium hydroxide solution is added to this and dissolved. Next, 400 g of D-sorbitol, 0.2 g of sodium hydrogen sulfite and a small amount of fragrance were added, and the mixture was dissolved with stirring to give 10%
The pH was adjusted to 6.8 with an aqueous sodium hydroxide solution, and purified water was added to adjust the total amount to 1 to prepare a carbocysteine 5 w / v% syrup preparation.

Example 5. Carbocysteine 1000 g and sorbic acid 20 g were added to purified water 10
And stir to add 10% aqueous sodium hydroxide solution.
After adding 2300 ml and stirring to dissolve, D-sorbitol 8000
Add g, 12 g caramel and a small amount of flavor to dissolve. Ten%
An aqueous sodium hydroxide solution was added to adjust the pH to 6.8, and purified water was added to adjust the total amount to 20 to prepare carbocysteine 5w / v% syrup agent.

The carbocysteine syrups produced by the above examples were syrups with almost no color change and excellent stability and high stability.

[Effects of the Invention] As described above, according to the present invention, by adding a sugar alcohol to an aqueous solution of carbocysteine and adjusting the pH, a highly stable syrup having suppressed color change could be produced. . The carbocysteine syrup thus obtained had a good taste and was highly useful.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References Osaka Prefectural Hospital Pharmacists' Edition, Completed Manual of Pharmaceuticals, September 10, 1986, Osaka Prefectural Hospital Pharmacists Association, pp. 504-505 Officially-established foundation Japan Supervised by the Book Association, 11th Revised Japanese Pharmacopoeia, July 18, 1986, Hirokawa Shoten, A-99 to A-103

Claims (9)

[Claims] 1. A carbocysteine syrup preparation containing 10 to 70 w / v% of at least one sweetener selected from the group consisting of D-sorbitol, D-mannitol, xylitol and sodium saccharin. 2. The carbocysteine syrup preparation according to claim 1, wherein the sweetening agent is D-sorbitol and / or xylitol. 3. The carbocysteine syrup preparation according to claim 1 or 2, wherein the concentration of carbocysteine is 5 w / v%. 4. The carbocysteine syrup composition according to any one of claims 1 to 3, which has a pH of 6.0 to 7.5. 5. The carbocysteine syrup according to any one of claims 1 to 4, which contains a preservative, a coloring agent, a fragrance, and a stabilizer. 6. The carbocysteine syrup preparation according to claim 5, wherein the preservative is sorbic acid. 7. The carbocysteine syrup preparation according to claim 5, wherein the coloring agent is caramel. 8. The carbocysteine syrup preparation according to claim 5, wherein the fragrance is fruit essence. 9. The carbocysteine syrup preparation according to claim 5, wherein the stabilizer is at least one selected from L-cysteine, EDTA and sodium bisulfite.