Erythromycin thiocyanate solution and preparation method thereof

Abstract

The invention provides an erythromycin thiocyanate solution and a preparation method thereof, every 100 mL of the erythromycin thiocyanate solution contains 5-30 g of erythromycin thiocyanate (based on erythromycin), 7.8-31.4 g of a cosolvent, 0.2-0.5 g of a preservative, 0.1-0.4 g of an antioxidant, 0.5-1.4 g of a pH regulator, and the balance of a solvent, the cosolvent comprises L-arginine, the preservative comprises sorbic acid, and the pH regulator comprises sodium hydroxide. The solubility of erythromycin thiocyanate can be remarkably improved by combining sorbic acid and L-arginine. The erythromycin thiocyanate solution is stable in property and remarkable in effect, the preparation method is simple, the existing technical problems of erythromycin thiocyanate are effectively solved, and the erythromycin thiocyanate solution is suitable for large-scale industrial production and clinical use.

Description

Technical Field

[0001] The invention relates to a preparation method of a veterinary drug preparation, in particular to an erythromycin thiocyanate solution and a preparation method thereof. Background Art

[0002] Erythromycin thiocyanate is the thiocyanate of erythromycin, a commonly used macrolide antibiotic. It is very slightly soluble in water and has a strong antibacterial effect in alkaline solutions, but the antibacterial effect almost completely disappears when the pH is lower than 4. At present, the main dosage form of this veterinary drug on the market is powder, which is often used to treat infections caused by Gram-positive bacteria and mycoplasma, and is suitable for drinking water administration in intensive breeding of broilers and laying hens.

[0003] Erythromycin thiocyanate has poor water solubility and cannot meet clinical usage requirements. Currently, in order to solve the problem of soluble powder being difficult to dissolve in water, many manufacturers and patents have changed the solubility-aiding technology or the type of solubilizing agent, but there are still problems such as long dissolution time and complex preparation technology. Summary of the invention

[0004] The object of the present invention is to provide an erythromycin thiocyanate solution and a preparation method thereof. The preparation method of the present invention effectively solves the problems existing in the current erythromycin thiocyanate - in the prior art, erythromycin thiocyanate preparations are all solid preparations, and erythromycin thiocyanate soluble powders are difficult to dissolve during use. The present invention overcomes this difficulty in the prior art by changing the dosage form, and proposes an erythromycin thiocyanate solution dosage form for the first time.

[0005] In order to achieve the above object, the present invention provides an erythromycin thiocyanate solution.

[0006] Every 100 mL of the erythromycin thiocyanate solution contains: 5-30 g of erythromycin thiocyanate (calculated as erythromycin), 7.8-31.4 g of a cosolvent, 0.2-0.5 g of a preservative, 0.1 g-0.4 g of an antioxidant, 0.5-1.4 g of a pH regulator, and the remainder is a solvent.

[0007] Preferably, in the erythromycin thiocyanate solution, the cosolvent is L-arginine.

[0008] Preferably, in any of the above items, in the erythromycin thiocyanate solution, the preservative is sorbic acid.

[0009] The combination of sorbic acid and L-arginine can significantly improve the solubility of erythromycin thiocyanate. The mass percentage concentration of the erythromycin thiocyanate solution is as high as 30%.

[0010] Preferably, in any of the above items, the pH of the erythromycin thiocyanate solution is 5.5 to 6.5.

[0011] Preferably, in any of the above items, the antioxidant is one or more of ascorbic acid, sodium bisulfite, sodium thiosulfate and glycine.

[0012] Preferably, any of the above items is that the pH adjuster is one or more of citric acid and sodium citrate.

[0013] Preferably, in any of the above items, the solvent is water.

[0014] The present invention also provides a method for preparing the erythromycin thiocyanate solution, comprising the following steps:

[0015] Step 1: Grinding: Grind erythromycin thiocyanate in an amount larger than the prescribed amount, control the particle size to be below 40 μm, and obtain erythromycin thiocyanate powder for later use;

[0016] Step 2: Weigh the prescribed amount of erythromycin thiocyanate powder, L-arginine, and sorbic acid, add them to part of the solvent, and stir to dissolve. After the erythromycin thiocyanate is completely dissolved, add the prescribed amount of antioxidant and pH adjuster, and the rest is the solvent, and stir evenly.

[0017] Preferably, in any of the above items, in step 2, a pH adjuster is added to adjust the pH of the solution to 5.5 to 6.5.

[0018] The beneficial effects of the present invention are:

[0019] 1. The solubility of erythromycin thiocyanate solution cannot be changed by using the cosolvent L-arginine. However, it is unexpected that the solubility of erythromycin thiocyanate can be significantly improved by using sorbic acid and L-arginine together.

[0020] 2. The erythromycin thiocyanate solution saves the dissolution time of the soluble powder when used by changing the dosage form, thus facilitating clinical use.

[0021] 3. The erythromycin thiocyanate solution has stable properties and significant effects.

[0022] 4. The preparation method of the erythromycin thiocyanate solution has a simple process, and the raw materials of each component are easily available, which greatly reduces the production cost and is suitable for modern large-scale production. DETAILED DESCRIPTION

[0023] The present invention is further described in detail below through specific implementation modes.

[0024] Example 1

[0025] The invention discloses an erythromycin thiocyanate solution. Each 100 mL of the erythromycin thiocyanate solution contains: 5 g of erythromycin thiocyanate (calculated as erythromycin), 7.8 g of L-arginine, 0.2 g of sorbic acid, 0.1 g of ascorbic acid, 0.5 g of citric acid, 0.8 g of sodium citrate, and the balance is a solvent.

[0026] The preparation method of erythromycin thiocyanate solution is as follows:

[0027] (1) crushing: taking erythromycin thiocyanate in an amount larger than the prescribed amount and crushing it, controlling the crushing particle size to be less than 40 μm, and obtaining erythromycin thiocyanate powder for use;

[0028] (2) Weigh an appropriate amount of water for injection, add the prescribed amount of erythromycin thiocyanate powder, L-arginine, and sorbic acid, and stir to dissolve. After the erythromycin thiocyanate is completely dissolved, add the prescribed amount of ascorbic acid, citric acid, and sodium citrate, adjust the pH to 5.5-6.5, and make up to 100 mL.

[0029] Example 2

[0030] The invention discloses an erythromycin thiocyanate solution. Each 100 mL of the erythromycin thiocyanate solution contains: 10 g of erythromycin thiocyanate (calculated as erythromycin), 15.7 g of L-arginine, 0.3 g of sorbic acid, 0.2 g of sodium bisulfite, 0.8 g of citric acid, 1 g of sodium citrate, and the balance is a solvent.

[0031] The preparation method of erythromycin thiocyanate solution is as follows:

[0032] (1) crushing: taking erythromycin thiocyanate in an amount larger than the prescribed amount and crushing it, controlling the crushing particle size to be less than 40 μm, and obtaining erythromycin thiocyanate powder for use;

[0033] (2) Weigh an appropriate amount of water for injection, add the prescribed amount of erythromycin thiocyanate powder, L-arginine, and sorbic acid, stir to dissolve, and after the erythromycin thiocyanate is completely dissolved, add the prescribed amount of sodium bisulfite, citric acid, and sodium citrate, adjust the pH to 5.5-6.5, and make up to 100 mL;

[0034] Example 3

[0035] The invention discloses an erythromycin thiocyanate solution. Each 100 mL of the erythromycin thiocyanate solution contains: 20 g of erythromycin thiocyanate (calculated as erythromycin), 31.4 g of L-arginine, 0.4 g of sorbic acid, 0.3 g of sodium thiosulfate, 1 g of citric acid, 1.2 g of sodium citrate, and the balance is a solvent.

[0036] The preparation method of erythromycin thiocyanate solution is as follows:

[0037] (1) crushing: taking erythromycin thiocyanate in an amount larger than the prescribed amount and crushing it, controlling the crushing particle size to be less than 40 μm, and obtaining erythromycin thiocyanate powder for use;

[0038] (2) Weigh an appropriate amount of water for injection, add the prescribed amount of erythromycin thiocyanate powder, L-arginine, and sorbic acid, stir to dissolve, and after the erythromycin thiocyanate is completely dissolved, add the prescribed amount of sodium thiosulfate, citric acid, and sodium citrate, adjust the pH to 5.5-6.5, and make up to 100 mL;

[0039] Example 4

[0040] The invention discloses an erythromycin thiocyanate solution. Each 100 mL of the erythromycin thiocyanate solution contains: 30 g of erythromycin thiocyanate (calculated as erythromycin), 31.4 g of L-arginine, 0.5 g of sorbic acid, 0.4 g of glycine, 1.2 g of citric acid, 1.4 g of sodium citrate, the pH value of which is adjusted to 5.5-6.5, and the balance is a solvent.

[0041] The preparation method of erythromycin thiocyanate solution is as follows:

[0042] (1) crushing: taking erythromycin thiocyanate in an amount larger than the prescribed amount and crushing it, controlling the crushing particle size to be less than 40 μm, and obtaining erythromycin thiocyanate powder for use;

[0043] (2) Weigh an appropriate amount of water for injection, add the prescribed amount of erythromycin thiocyanate powder, L-arginine, and sorbic acid, stir to dissolve, and after the erythromycin thiocyanate is completely dissolved, add the prescribed amount of glycine, citric acid, and sodium citrate, adjust the pH to 5.5-6.5, and make up to 100 mL;

[0044] Comparative Example 1

[0045] The components and preparation method are basically the same as those in Example 1, except that sorbic acid is not added and the amount of L-arginine is increased to 8 g.

[0046] Comparative Example 2

[0047] The components and preparation method are basically the same as those in Example 2, except that L-arginine is not added and the amount of sorbitol is increased to 16 g.

[0048] Comparative Example 3

[0049] The components and preparation method are basically the same as those in Example 3, except that benzoic acid is used instead of sorbic acid.

[0050] Comparative Example 4

[0051] The components and preparation method are basically the same as those in Example 4, except that citric acid and sodium citrate are not added to adjust the pH of the solution.

[0052] The solubility test, aqueous solution stability test, high temperature test (60°C), strong light test (4500±500lx, 10d total illumination ≥1.2×10 6lx·h) and accelerated test (40±2℃) to determine the basic characteristics of erythromycin thiocyanate solution.

[0053] The experimental results of each embodiment are as follows:

[0054]

[0055]

[0056] As can be seen from the results of the above examples, Examples 1-4 are completely dissolved, and under high temperature, illumination, and accelerated test conditions, the solution properties are stable. This shows that the present invention significantly improves the solubility of erythromycin thiocyanate. Comparative Example 1 does not add sorbic acid, Comparative Example 2 does not add L-arginine, Comparative Example 3 uses benzoic acid instead of sorbic acid, and Comparative Example 4 does not add citric acid and sodium citrate. These four comparative examples of erythromycin thiocyanate are not dissolved, indicating that L-arginine can improve the solubility of erythromycin thiocyanate when used in combination with sorbic acid, and erythromycin thiocyanate is dependent on pH.

[0057] The above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. An erythromycin thiocyanate solution, characterized in that: Every 100 mL of the erythromycin thiocyanate solution contains: 5-30 g of erythromycin thiocyanate, calculated as erythromycin, 7.8-31.4 g of a cosolvent, 0.2-0.5 g of a preservative, 0.1 g-0.4 g of an antioxidant, 0.5-1.4 g of a pH adjuster, and the remainder is a solvent; the cosolvent is L-arginine, and the preservative is sorbic acid.

2. The erythromycin thiocyanate solution according to claim 1 is characterized in that: The pH of the erythromycin thiocyanate solution is 5.5-6.

5.

3. The erythromycin thiocyanate solution according to claim 1 is characterized in that: The antioxidant is one or more of ascorbic acid, sodium bisulfite, sodium thiosulfate and glycine.

4. The erythromycin thiocyanate solution according to claim 1 is characterized in that: The pH regulators are citric acid and sodium citrate.

5. The erythromycin thiocyanate solution according to claim 1 is characterized in that: The solvent is water.

6. The method for preparing the erythromycin thiocyanate solution according to claim 1, characterized in that: The following steps are involved: Step 1: Grinding: Grind erythromycin thiocyanate in an amount larger than the prescribed amount, control the particle size to be below 40 μm, and obtain erythromycin thiocyanate powder for later use; Step 2: Weigh the prescribed amount of erythromycin thiocyanate powder, L-arginine, and sorbic acid, add them to part of the solvent, and stir to dissolve. After the erythromycin thiocyanate is completely dissolved, add the prescribed amount of antioxidant and pH adjuster, and the rest is the solvent, and stir evenly.

7. The preparation method according to claim 6, characterized in that: In step 2, a pH adjuster is added to adjust the pH of the solution to 5.5-6.5.

Images