Ambroxterol composition and preparation process thereof

Abstract

The invention provides an ambroxterol composition and a preparation process thereof, and particularly relates to the field of medicines. Each milliliter of the liquid preparation comprises 1-2mg of ambroxol hydrochloride, 0.5-1.5 [mu] g of clenbuterol hydrochloride, 10-20mg of sodium hydrogen sulfite, 1-4mg of hydroxyethyl cellulose and purified water. The toothpaste further comprises 243-247 mg of an amorphous sorbitol solution, 3-5 mg of pomegranate essence, 148-152 mg of glycerin, 1-3 mg of sodium benzoate and a proper amount of DL-tartaric acid. According to the preparation disclosed by the invention, the increase of an impurity B can be inhibited by adding sodium hydrogen sulfite, and the increase of an ambroxol impurity 14 and an unknown single impurity can be reduced by reducing the dosage of hydroxyethyl cellulose, so that the drug stability is improved.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to an ambroxol hydrochloride composition and a preparation process thereof. Background Art

[0002] Ambroxol hydrochloride is a selective β-receptor agonist, which has the effects of relaxing bronchial smooth muscle, enhancing ciliary movement, dissolving mucus, and promoting sputum discharge; in order to improve the stability of ambroxol hydrochloride preparations, the following two methods are generally adopted in the prior art: 1. By continuously introducing nitrogen into the liquid during liquid preparation, starting from the prescription and process of introducing aldehyde substances, reducing the residual oxygen in the container, and not using thickeners, etc., the reduction of impurities and the improvement of storage stability are achieved, especially the reduction of impurity B (4-(6,8-dibromo-3,4-dihydroquinazolin-3-yl)-cyclohexanol hydrochloride); 2. By adding alkaline substances such as ammonia water and sodium bicarbonate to improve the stability of the preparation; however, the preparation processes of the above methods are relatively cumbersome and the effects are not significant.

[0003] In view of the prior art situation, an ambroxol hydrochloride composition and a preparation process thereof are needed, which can effectively improve the above deficiencies. Summary of the Invention

[0004] The purpose of the present invention is to provide an ambroxol hydrochloride composition and a preparation process thereof. By adding sodium bisulfite, the growth of impurity B can be inhibited, and by reducing the dosage of hydroxyethyl cellulose, the growth of ambroxol impurity 14 and unknown single impurity can be reduced, thereby improving the drug stability.

[0005] The present invention provides the following technical solutions:

[0006] An ambroxol hydrochloride composition, each milliliter of the liquid preparation contains 1-2 mg of ambroxol hydrochloride, 0.5-1.5 μg of clenbuterol hydrochloride, 10-20 mg of sodium bisulfite and purified water.

[0007] Preferably, it further contains 243-247 mg of non-crystalline sorbitol solution, 1-4 mg of hydroxyethyl cellulose, 3-5 mg of pomegranate essence, 148-152 mg of glycerol, 1-3 mg of sodium benzoate, and an appropriate amount of DL-tartaric acid.

[0008] The preparation process of the ambroxol hydrochloride composition is as follows:

[0009] S1. Weigh the prescribed amount of clenbuterol hydrochloride into a beaker, add purified water, stir and dissolve it to prepare a 0.1 mg / ml clenbuterol hydrochloride solution for standby;

[0010] S2. Weigh 60% of the prescribed amount of water into a glass beaker, heat it in a water bath to 40°C ± 5°C, and slowly add the prescribed amount of hydroxyethyl cellulose under stirring to dissolve it;

[0011] Add the prescribed amount of amorphous sorbitol solution, propylene glycol, and glycerin, and stir evenly;

[0012] Slowly add the prescribed amount of sodium bisulfite and sodium benzoate, and stir until dissolved;

[0013] Add the prescribed amount of ambroxol hydrochloride, and stir until dissolved;

[0014] Add the clenbuterol hydrochloride solution, and stir for 3 - 7 min;

[0015] S3. Add purified water to make the volume up to 1 ml, measure the pH, then add DL - tartaric acid, adjust the pH to 4.0 - 4.5, stir evenly, and then fill into containers.

[0016] Preferably, add the clenbuterol hydrochloride solution, stir for 5 min at a rotation speed of 500 r / min.

[0017] Preferably, adjust the pH to 4.5

[0018] Advantages of the present invention:

[0019] In the preparation of the present invention, adding sodium bisulfite can inhibit the growth of impurity B, and reducing the dosage of hydroxyethyl cellulose can reduce the growth of ambroxol impurity 14 and unknown single impurity, thereby improving the drug stability. Detailed implementation mode

[0020] Example 1

[0021] An ambroxol and clenbuterol composition, containing 1.5 g of ambroxol hydrochloride, 0.001 g of clenbuterol hydrochloride, 10 g of sodium bisulfite, 245 g of amorphous sorbitol solution, 4 g of hydroxyethyl cellulose, 4 g of pomegranate essence, 150 g of glycerin, 2 g of sodium benzoate, an appropriate amount of DL - tartaric acid, and purified water in each milliliter of the liquid preparation.

[0022] The preparation process of ambroxol and clenbuterol is as follows:

[0023] S1. Weigh the prescribed amount of clenbuterol hydrochloride into a beaker, add purified water, stir until dissolved, and prepare a 0.1 mg / ml clenbuterol hydrochloride solution for standby;

[0024] S2. Weigh 60% of the prescribed amount of water into a glass beaker, heat it in a water bath to 40°C, slowly add the prescribed amount of hydroxyethyl cellulose under stirring until dissolved; add the prescribed amount of amorphous sorbitol solution, propylene glycol, and glycerin, and stir evenly; slowly add the prescribed amount of sodium bisulfite and sodium benzoate, and stir until dissolved; add the prescribed amount of ambroxol hydrochloride, and stir until dissolved; add the clenbuterol hydrochloride solution, and stir for 5 min at a rotation speed of 500 r / min;

[0025] S3. Add purified water to make the volume up to 1000 ml, measure the pH, then add DL-tartaric acid to adjust the pH to 4.5, stir evenly, and then fill into containers.

[0026] Example 2

[0027] An ambroxol hydrochloride and clenbuterol hydrochloride composition, in each milliliter of the liquid preparation, there are 1.5 g of ambroxol hydrochloride, 0.001 g of clenbuterol hydrochloride, 20 g of sodium bisulfite, 245 g of non-crystalline sorbitol solution, 4 g of hydroxyethyl cellulose, 4 g of pomegranate essence, 150 g of glycerol, 2 g of sodium benzoate, an appropriate amount of DL-tartaric acid and purified water.

[0028] The preparation process of ambroxol hydrochloride and clenbuterol hydrochloride is as follows:

[0029] S1. Weigh the prescribed amount of clenbuterol hydrochloride into a beaker, add purified water, stir to dissolve, and prepare a 0.1 mg / ml clenbuterol hydrochloride solution for later use.

[0030] S2. Weigh 60% of the prescribed amount of water into a glass beaker, heat it in a water bath to 40 °C, slowly add the prescribed amount of hydroxyethyl cellulose under stirring, and stir to dissolve; add the prescribed amount of non-crystalline sorbitol solution, propylene glycol, and glycerol, and stir evenly; slowly add the prescribed amount of sodium bisulfite and sodium benzoate, and stir to dissolve; add the prescribed amount of ambroxol hydrochloride, and stir to dissolve; add the clenbuterol hydrochloride solution, and stir for 5 min at a rotation speed of 500 r / min.

[0031] S3. Add purified water to make the volume up to 1000 ml, measure the pH, then add DL-tartaric acid to adjust the pH to 4.5, stir evenly, and then fill into containers.

[0032] Example 3

[0033] An ambroxol hydrochloride and clenbuterol hydrochloride composition, in each milliliter of the liquid preparation, there are 1.5 g of ambroxol hydrochloride, 0.001 g of clenbuterol hydrochloride, 10 g of sodium bisulfite, 245 g of non-crystalline sorbitol solution, 1 g of hydroxyethyl cellulose, 4 g of pomegranate essence, 150 g of glycerol, 2 g of sodium benzoate, an appropriate amount of DL-tartaric acid and purified water.

[0034] The preparation process of ambroxol hydrochloride and clenbuterol hydrochloride is as follows:

[0035] S1. Weigh the prescribed amount of clenbuterol hydrochloride into a beaker, add purified water, stir to dissolve, and prepare a 0.1 mg / ml clenbuterol hydrochloride solution for later use.

[0036] S2. Weigh 60% of the prescription water into a glass beaker, heat it in a water bath to 40 °C, and slowly add the prescribed amount of hydroxyethyl cellulose under stirring until it is dissolved; add the prescribed amount of amorphous sorbitol solution, propylene glycol, and glycerol, and stir evenly; slowly add the prescribed amount of sodium bisulfite and sodium benzoate, and stir until dissolved; add the prescribed amount of ambroxol hydrochloride and stir until dissolved; add the clenbuterol hydrochloride solution and stir for 5 min at a rotation speed of 500 r / min.

[0037] S3. Add purified water to make the volume up to 1000 ml, measure the pH, then add DL-tartaric acid to adjust the pH to 4.5, stir evenly, and then fill.

[0038] Experimental analysis:

[0039] The control group did not add sodium bisulfite, and other implementation conditions were the same as those in Example 1;

[0040] Sodium bisulfite was added in Example 1 and Example 2, and the amount of hydroxyethyl cellulose was reduced in Example 3 for experimental testing. The data are as follows:

[0041] Name Control Group Example 1 Example 2 Example 3 Ambroxol Hydrochloride 1.5g 1.5g 1.5g 1.5g Clenbuterol Hydrochloride 0.001g 0.001g 0.001g 0.001g Non-crystalline Sorbitol Solution 245.0g 245.0g 245.0g 245.0g Glycerol 150g 150g 150g 150.0g Hydroxyethyl Cellulose 4.0g 4.0g 4.0g 1.0g Propylene Glycol 32.0g 32.0g 32.0g 32.0g Pomegranate Flavor 4.0g 4.0g 4.0g 4.0g Sodium Benzoate 2.0g 2.0g 2.0g 2.0g Sodium Bisulfite / 10.0g 20.0g 10.0g DL-Tartaric Acid Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified Water Make up to 1000 ml Make up to 1000 ml Make up to 1000 ml Make up to 1000 ml

[0042] The commercially available sodium bisulfite used in the present invention has a sulfur dioxide content of 61.5% to 67.4%. The reference preparation of ambroxol and clenbuterol is held by Sanofi-Aventis Deutschland GmbH. The comparison of related substances with and without the addition of sodium bisulfite is as follows:

[0043]

[0044] Effect of the amount of hydroxyethyl cellulose on impurities

[0045]

[0046] It can be seen from the above experimental data that for the samples with sodium bisulfite added to the prescription compared with the samples without sodium bisulfite added, impurity B is significantly reduced, and there is no significant difference in impurity B for the samples prepared with the dosages of 1.0 mg / ml and 2.0 mg / ml of sodium bisulfite; in addition, after reducing the amount of hydroxyethyl cellulose to 1 mg / ml, the increase of ambroxol impurities 14 and unknown single impurities can also be reduced. Therefore, adding sodium bisulfite and reducing the amount of hydroxyethyl cellulose in the prescription can improve the stability of the preparation.

[0047] Perform stability tests on the product prepared in Example 3, and the stability data are as follows:

[0048]

[0049] As can be seen from the above data, the sample prepared by adding sodium bisulfite at a dosage of 1.0 mg / ml to the prescription was accelerated for 6 months, and all indicators met the regulations, showing good stability.

[0050] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or perform equivalent replacements on some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. An ambroxol composition, characterized in that: Each milliliter of the liquid preparation contains 1 - 2 mg of ambroxol hydrochloride, 0.5 - 1.5 μg of clenbuterol hydrochloride, 10 - 20 mg of sodium bisulfite, 1 - 4 mg of hydroxyethyl cellulose and purified water.

2. The ambroxol composition according to claim 1, characterized in that: 1.5 mg of ambroxol hydrochloride, 1 μg of clenbuterol hydrochloride, 10 mg of sodium bisulfite, 1 mg of hydroxyethyl cellulose.

3. The ambroxol composition according to claim 1, characterized in that: It also contains 243 - 247 mg of amorphous sorbitol solution, 3 - 5 mg of pomegranate essence, 148 - 152 mg of glycerol, 1 - 3 mg of sodium benzoate, and an appropriate amount of DL-tartaric acid.

4. The ambroxol composition according to claim 3, wherein: 245 mg of amorphous sorbitol solution, 4 mg of pomegranate essence, 150 mg of glycerol, 2 mg of sodium benzoate.

5. A process for preparing an ambroxol and clenbuterol composition according to claim 1, characterized in that: The specific steps are as follows: S1. Weigh the prescribed amount of clenbuterol hydrochloride into a beaker, add purified water, stir and dissolve to prepare a 0.1 mg / ml clenbuterol hydrochloride solution for later use. S2. Weigh 60% of the prescribed amount of water into a glass beaker, heat it in a water bath to 40°C ± 5°C, and slowly add the prescribed amount of hydroxyethyl cellulose under stirring until dissolved. Add the prescribed amount of amorphous sorbitol solution, propylene glycol, and glycerol, and stir evenly. Slowly add the prescribed amount of sodium bisulfite and sodium benzoate, and stir until dissolved. Add the prescribed amount of ambroxol hydrochloride, and stir until dissolved. Add the clenbuterol hydrochloride solution, and stir for 3 - 7 min. S3. Add purified water to make up the volume to 1 ml, measure the pH, then add DL-tartaric acid to adjust the pH to 4.0 - 4.5, stir evenly, and then fill.

6. The preparation method of metronidazole tablets according to claim 5, characterized in that: Add the clenbuterol hydrochloride solution, stir for 5 min at a rotation speed of 500 r / min.

7. The preparation method of metronidazole tablets according to claim 5, characterized in that: Adjust the pH to 4.5.

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