Preparation method of acetylcysteine oral solution

Abstract

The invention relates to a preparation method of an acetylcysteine oral solution. The preparation method comprises the following steps: preparing an initial solution from acetylcysteine, a thickening agent, a bacteriostatic agent, a stabilizer, a flavoring agent, a pH regulator and water; and filtering the primary solution to obtain a liquid medicine of the acetylcysteine oral solution, and then carrying out mechanical filling to obtain a finished product of the acetylcysteine oral solution. Before mechanical filling, primary nitrogen purging is carried out on the borosilicate bottle, so that the residual oxygen content in the borosilicate bottle is 12-21%; after the acetylcysteine oral solution is filled, the borosilicate bottle is subjected to nitrogen purging again, so that the residual oxygen content in the borosilicate bottle is 8 + / -0.5%; afterwards, the borosilicate bottle reaches the nitrogen dripping position through nitrogen curtain protection on the conveying track, liquid nitrogen dripping is carried out, finally, the residual oxygen content in the borosilicate bottle is 2%-3%, and capping is carried out. According to the invention, a packaging bottle is changed into a borosilicate bottle, and a liquid nitrogen dropping process is matched, so that the residual oxygen content in the sealed bottle can be reduced to 1.8%, and the generation of impurity C is inhibited.

Description

Technical Field

[0001] The invention relates to a method for preparing an acetylcysteine ​​oral solution, and belongs to the technical field of pharmaceutical preparations. Background Art

[0002] Acetylcysteine ​​is a mucolytic agent with a strong mucolytic effect. The sulfhydryl group contained in its molecule can break the disulfide bonds in the glycoprotein polypeptide chain in the sputum, thereby reducing the viscosity of the sputum and making the sputum liquid and easier to cough up. It is suitable for respiratory diseases characterized by excessive viscous secretions, such as COPD, bronchiectasis, etc.

[0003] Since acetylcysteine ​​contains sulfhydryl groups in its molecular structure, its chemical properties are unstable, it is prone to oxidation reactions, and it is sensitive to moisture and heat. Therefore, the stability of acetylcysteine-related preparations is poor, which seriously affects the efficacy of acetylcysteine.

[0004] At present, the packaging bottles of acetylcysteine ​​original research manufacturers are sodium-calcium bottles. Generally, nitrogen is filled into the sodium-calcium bottles to expel the air when filling the oral solution. However, this method is not very effective in expelling air. Even if the nitrogen filling time is extended or auxiliary nitrogen purging is used, the residual oxygen content in the sodium-calcium bottle is still above 7%, which makes the residual oxygen content in the sealed sodium-calcium bottle at a relatively high level. After extensive research by the inventors, it is found that this is easy to lead to the generation of oxidative impurities and the quality stability of the drug is poor.

[0005] Based on this, the present invention is proposed. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention provides a method for preparing an acetylcysteine ​​oral solution, and the specific technical scheme is as follows:

[0007] A method for preparing an acetylcysteine ​​oral solution comprises the following steps:

[0008] Step 1, weighing acetylcysteine, thickener, antibacterial agent, stabilizer, flavoring agent, pH regulator and water according to the prescription amount;

[0009] Step 2, pour a portion of water into the liquid preparation container, preheat, fill with nitrogen for protection, and then add the antibacterial agent, stabilizer and flavoring agent into the liquid preparation container and stir to dissolve;

[0010] Step 3, after dispersing acetylcysteine ​​and thickener in a portion of water, add them into a liquid preparation container and stir to dissolve;

[0011] Step 4, dissolving a pH adjusting agent in a portion of water to prepare a pH adjusting solution, pouring the pH adjusting solution into a liquid preparation container and stirring, and adjusting the pH of the solution in the liquid preparation container to 7.5±0.2;

[0012] Step 5, add the remaining water to the liquid preparation container, make up to the full volume, mix well, and obtain the initial liquid;

[0013] Step 6: Filter the initial liquid to obtain an acetylcysteine ​​oral solution, and then perform mechanical filling to obtain an acetylcysteine ​​oral solution finished product.

[0014] In a further improvement, the thickener is sodium carboxymethylcellulose.

[0015] In a further improvement, the antibacterial agent is one or more of sodium benzoate and methylparaben.

[0016] In a further improvement, the stabilizer is disodium edetate.

[0017] In a further improvement, the flavoring agent is one or more of saccharin sodium and peach essence.

[0018] In a further improvement, the pH adjuster is sodium hydroxide.

[0019] As a further improvement, in step 2, preheat to 40±5°C;

[0020] and / or,

[0021] In step 6, filtration is performed using a 0.45 μm polypropylene filter element.

[0022] A further improvement is that the packaging bottles used for the finished acetylcysteine ​​oral solution are borosilicate bottles. Before mechanical filling, the borosilicate bottles are purged with nitrogen once, so that the residual oxygen content in the borosilicate bottles is 12-21%; after filling the acetylcysteine ​​oral solution, the borosilicate bottles are purged with nitrogen again, so that the residual oxygen content in the borosilicate bottles is 8±0.5%; thereafter, the borosilicate bottles are protected by a nitrogen curtain on a conveying track and reach a nitrogen dripping position, where liquid nitrogen is dripped, and finally the residual oxygen content in the borosilicate bottles is 2%-3%, and then the bottles are capped.

[0023] As a further improvement, when dripping liquid nitrogen, the dripping amount of nitrogen is 0.25-0.38 g / bottle.

[0024] As a further improvement, when dripping liquid nitrogen, the transmission belt conveying the borosilicate bottle is subjected to megasonic vibration for a duration of 1 s and a megasonic frequency of 2.3 MHz.

[0025] The present invention adopts changing the packaging material (the original sodium calcium bottle is changed to a borosilicate bottle, and the stability is improved) and adopts nitrogen purge-assisted liquid nitrogen dripping process (especially liquid nitrogen dripping process) to effectively reduce the generation of oxidative impurities.

[0026] Beneficial effects of the present invention:

[0027] The present invention further optimizes the mechanical filling process on the basis of the existing preparation process of acetylcysteine ​​oral solution, and by changing the packaging bottle to a borosilicate bottle and combining it with a liquid nitrogen dripping process, the residual oxygen content in the bottle after capping can be reduced to 1.8%, thereby inhibiting the generation of impurity C.

[0028] In addition, by improving the process, the mechanical filling of each batch can be stable and the product quality is highly stable. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the chromatogram corresponding to different residual oxygen contents in the borosilicate bottle after the stability test;

[0030] Figure 2 This is a curve chart showing the variation of the variance of megasonic frequency and residual oxygen content. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0032] Example 1

[0033] Prescription 1:

[0034] Material Name Prescription Quality Ratio effect Acetylcysteine 2％ Active substances Sodium carboxymethylcellulose 0.2％ Thickener Sodium Benzoate 0.1 Antibacterial Agents Methylparaben 0.2％ Antibacterial Agents Edetate Disodium 0.2％ Stabilizer Saccharin Sodium 0.05％ Flavoring agents Peach flavor 0.05％ Flavoring agents Sodium hydroxide Adjust pH to 7.0 pH Adjusters Purified water Make up to 10ml Solvents

[0035] Step 1, weigh acetylcysteine, thickener, antibacterial agent, stabilizer, flavoring agent, pH adjuster and water according to prescription 1;

[0036] Step 2, pour a portion of water into the liquid preparation container, preheat to 40±5°C, fill with nitrogen for protection, and then add the antibacterial agent, stabilizer and flavoring agent into the liquid preparation container and stir to dissolve;

[0037] Step 3, after dispersing acetylcysteine ​​and thickener in a portion of water, add them into a liquid preparation container and stir to dissolve;

[0038] Step 4, dissolving a pH adjusting agent in a portion of water to prepare a pH adjusting solution, pouring the pH adjusting solution into a liquid preparation container and stirring, and adjusting the pH of the solution in the liquid preparation container to 7.5±0.2;

[0039] Step 5, add the remaining water to the liquid preparation container, make up to the full volume, mix well, and obtain the initial liquid;

[0040] Step 6: Filter the initial solution using a 0.45 μm polypropylene filter to obtain an acetylcysteine ​​oral solution, and then perform mechanical filling to obtain a finished acetylcysteine ​​oral solution.

[0041] Among them, the packaging bottles used for the finished product of acetylcysteine ​​oral solution are borosilicate bottles. Before mechanical filling, the borosilicate bottles are purged with nitrogen once, so that the residual oxygen content in the borosilicate bottles is 12-21%; after filling the acetylcysteine ​​oral solution, the borosilicate bottles are purged with nitrogen again, so that the residual oxygen content in the borosilicate bottles is 8±0.5%; thereafter, the borosilicate bottles are protected by a nitrogen curtain on a conveying track and then reach a nitrogen dripping position for liquid nitrogen dripping, and finally the residual oxygen content in the borosilicate bottles is 2%-3%, and then the bottles are capped.

[0042] Example 2

[0043] Prescription 2:

[0044] Material Name Prescription Quality Ratio effect Acetylcysteine 2％ Active substances Sodium carboxymethylcellulose 0.5％ Thickener Sodium Benzoate 0.3％ Antibacterial Agents Methylparaben 0.5％ Antibacterial Agents Edetate Disodium 0.5％ Stabilizer Saccharin Sodium 0.08％ Flavoring agents Peach flavor 0.05％ Flavoring agents Sodium hydroxide Adjust pH to 7.0 pH Adjusters Purified water Make up to 10ml Solvents

[0045] Step 1, weigh acetylcysteine, thickener, antibacterial agent, stabilizer, flavoring agent, pH adjuster and water according to prescription 2;

[0046] Step 2, pour a portion of water into the liquid preparation container, preheat to 40±5°C, fill with nitrogen for protection, and then add the antibacterial agent, stabilizer and flavoring agent into the liquid preparation container and stir to dissolve;

[0047] Step 3, after dispersing acetylcysteine ​​and thickener in a portion of water, add them into a liquid preparation container and stir to dissolve;

[0048] Step 4, dissolving a pH adjusting agent in a portion of water to prepare a pH adjusting solution, pouring the pH adjusting solution into a liquid preparation container and stirring, and adjusting the pH of the solution in the liquid preparation container to 7.5±0.2;

[0049] Step 5, add the remaining water to the liquid preparation container, make up to the full volume, mix well, and obtain the initial liquid;

[0050] Step 6: Filter the initial solution using a 0.45 μm polypropylene filter to obtain an acetylcysteine ​​oral solution, and then perform mechanical filling to obtain a finished acetylcysteine ​​oral solution.

[0051] Among them, the packaging bottles used for the finished product of acetylcysteine ​​oral solution are borosilicate bottles. Before mechanical filling, the borosilicate bottles are purged with nitrogen once, so that the residual oxygen content in the borosilicate bottles is 12-21%; after filling the acetylcysteine ​​oral solution, the borosilicate bottles are purged with nitrogen again, so that the residual oxygen content in the borosilicate bottles is 8±0.5%; thereafter, the borosilicate bottles are protected by a nitrogen curtain on a conveying track and then reach a nitrogen dripping position for liquid nitrogen dripping, and finally the residual oxygen content in the borosilicate bottles is 2%-3%, and then the bottles are capped.

[0052] Example 3

[0053] Prescription 3:

[0054]

[0055]

[0056] Step 1, weigh acetylcysteine, thickener, antibacterial agent, stabilizer, flavoring agent, pH adjuster and water according to prescription 3;

[0057] Step 2, pour a portion of water into the liquid preparation container, preheat to 40±5°C, fill with nitrogen for protection, and then add the antibacterial agent, stabilizer and flavoring agent into the liquid preparation container and stir to dissolve;

[0058] Step 3, after dispersing acetylcysteine ​​and thickener in a portion of water, add them into a liquid preparation container and stir to dissolve;

[0059] Step 4, dissolving a pH adjusting agent in a portion of water to prepare a pH adjusting solution, pouring the pH adjusting solution into a liquid preparation container and stirring, and adjusting the pH of the solution in the liquid preparation container to 7.5±0.2;

[0060] Step 5, add the remaining water to the liquid preparation container, make up to the full volume, mix well, and obtain the initial liquid;

[0061] Step 6: Filter the initial solution using a 0.45 μm polypropylene filter to obtain an acetylcysteine ​​oral solution, and then perform mechanical filling to obtain a finished acetylcysteine ​​oral solution.

[0062] Among them, the packaging bottles used for the finished product of acetylcysteine ​​oral solution are borosilicate bottles. Before mechanical filling, the borosilicate bottles are purged with nitrogen once, so that the residual oxygen content in the borosilicate bottles is 12-21%; after filling the acetylcysteine ​​oral solution, the borosilicate bottles are purged with nitrogen again, so that the residual oxygen content in the borosilicate bottles is 8±0.5%; thereafter, the borosilicate bottles are protected by a nitrogen curtain on a conveying track and then reach a nitrogen dripping position for liquid nitrogen dripping, and finally the residual oxygen content in the borosilicate bottles is 2%-3%, and then the bottles are capped.

[0063] Test Example 1

[0064] On the basis of Example 1, the amount of liquid nitrogen dripping was optimized, and the process parameters were as shown in Table 1:

[0065] Table 1

[0066] Group No. Nitrogen drop volume (single bottle) Residual oxygen Bottle bulging Group 1 0.04-0.10 (about 0.05g) 5.5±0.05％ 5ml bottle (rubber cap does not bulge) Group 2 0.17-0.22g (about 0.20g) 3.4±0.05％ 5ml bottle (slightly bulging rubber cap) Group 3 0.25-0.29g (about 0.27g) 1.9±0.05％ 5ml bottle (slightly bulging rubber cap) Group 4 0.33-0.38g (about 0.35g) 1.8±0.05％ 5ml bottle (severe bulging of rubber bottle cap) Group 5 0.40-0.45g (about 0.42g) 2.0±0.05％ 10ml bottle (slightly bulging rubber cap)

[0067] In Table 1, because liquid nitrogen will evaporate in large quantities, if the amount of nitrogen dripping is not properly controlled, the residual liquid nitrogen may cause the rubber bottle cap to bulge to varying degrees; among them, slight bulging refers to a bulging height of about 1 to 1.5 mm; severe bulging refers to a bulging height of more than 2 mm. If the bulging is severe, it will easily affect the stability of the subsequent capping.

[0068] If screening is performed based on the residual oxygen content index, when liquid nitrogen is dripped, the dripping amount of nitrogen is preferably 0.25 to 0.38 g / bottle.

[0069] Test Example 2

[0070] When the residual oxygen content in the borosilicate bottle was 1.8%, 1.9%, 2.0%, 3.4%, and 5.5%, respectively, it was placed at 60°C for 10 days, and then the impurities were detected by high performance liquid chromatography. The results are shown in Figure 1 :

[0071] exist Figure 1 In the figure, curve 1 represents a residual oxygen content of 1.8%, curve 2 represents a residual oxygen content of 1.9%, curve 3 represents a residual oxygen content of 2.0%, curve 4 represents a residual oxygen content of 3.4%, and curve 5 represents a residual oxygen content of 5.5%. The impurity C contents corresponding to curves 1 to 5 are 0.3%, 0.6%, 0.7%, 0.9%, and 1.1%, respectively.

[0072] The chemical formula of impurity C is: 10 H 16 N 2 O 6 S 2 , the structural formula is shown in Formula I:

[0073]

[0074] From this we can see that the lower the residual oxygen content in the borosilicate bottle, the lower the content of impurity C.

[0075] In the reproduction study of the original drug of acetylcysteine ​​oral solution, it was found that when the residual oxygen content in the bottle was too high, the impurity content would increase significantly during the stability period (the content of impurity C would increase from 0 to 2.0%). Therefore, it is particularly important to control the oxygen environment during the production process.

[0076] Example 4

[0077] In the test of group 4, the residual oxygen content in the bottle can be reduced to the lowest (1.8%), but the amount of liquid nitrogen dripped in is not the highest. However, too much liquid nitrogen remains before capping, resulting in serious bulging of the rubber bottle cap. Therefore, to solve this problem, when dripping liquid nitrogen, the transmission belt conveying the borosilicate bottle is subjected to megasonic vibration for a duration of 1s, and the megasonic frequency is 2.3MHz.

[0078] This is because under the same conditions, oxygen is heavier than nitrogen, so when liquid nitrogen vaporizes, although the impact generated can expel some oxygen, it is not completely discharged. The small-amplitude, high-frequency vibration generated by megasonic vibration can assist the droplet-shaped liquid nitrogen to "shake" and "stir" around the bottle mouth, thereby prompting oxygen to flow out of the bottle mouth together with the vaporized nitrogen, thereby ensuring the oxygen discharge effect, and the residual oxygen content can be reduced to 1.7-1.8% (already close to the lowest level, even if more liquid nitrogen is dripped in, it cannot be reduced lower).

[0079] In actual production, it is found that if the liquid nitrogen drop cannot fall exactly into the center of the bottle mouth due to the deviation of the bottle body position and the drop position of the liquid nitrogen, the oxygen discharge effect at some bottle mouths may be unsatisfactory, and the residual oxygen content of the bottle mouth after the final capping may not reach 1.8%, and in severe cases it may be around 2.5%, which will significantly affect the production quality of the batch. For example, in the random sampling process, it was found that, taking 100 samples as an example, the variance of the residual oxygen content (calculated as a percentage) is generally greater than 0.45 (such as 0.4611); if megasonic vibration is used to assist the liquid nitrogen dripping, the variance of the residual oxygen content (calculated as a percentage) is 0.0054.

[0080] In the process of using vibration to assist liquid nitrogen dripping, ultrasonic vibration was initially used to assist. When the ultrasonic frequency increased from 20kHz to 80kHz, it was found that ultrasonic vibration had a great impact on the acetylcysteine ​​oral solution in the bottle, causing it to fluctuate violently, resulting in the residual oxygen content in the bottle after the final capping to always be greater than 6.1% (the amount of nitrogen dripped was calculated as 0.33-0.38g / bottle). Therefore, when using megasonic vibration to assist liquid nitrogen dripping, when the megasonic frequency varied between 2 and 3MHz, it was found that although the minimum residual oxygen content in the bottle after capping could be reduced to 1.8% (the amount of nitrogen dripped was calculated as 0.33-0.38g / bottle), the variance (in percentage) of the residual oxygen content in a batch of borosilicate bottles was quite different, as shown in the change curve. Figure 2 .Depend on Figure 2 It can be seen that the megasonic frequency is preferably 2.3 MHz.

[0081] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing an acetylcysteine ​​oral solution, characterized in that: The following steps are involved: Step 1, weighing acetylcysteine, thickener, antibacterial agent, stabilizer, flavoring agent, pH regulator and water according to the prescription amount; Step 2, pour a portion of water into the liquid preparation container, preheat, fill with nitrogen for protection, and then add the antibacterial agent, stabilizer and flavoring agent into the liquid preparation container and stir to dissolve; Step 3, after dispersing acetylcysteine ​​and thickener in a portion of water, add them into a liquid preparation container and stir to dissolve; Step 4, dissolving a pH adjusting agent in a portion of water to prepare a pH adjusting solution, pouring the pH adjusting solution into a liquid preparation container and stirring, and adjusting the pH of the solution in the liquid preparation container to 7.5±0.2; Step 5, add the remaining water to the liquid preparation container, make up to the full volume, mix evenly, and obtain the initial liquid; Step 6: Filter the initial liquid to obtain an acetylcysteine ​​oral solution, and then perform mechanical filling to obtain a finished acetylcysteine ​​oral solution.

2. The method for preparing an acetylcysteine ​​oral solution according to claim 1, wherein: The thickener is sodium carboxymethylcellulose.

3. The method for preparing an acetylcysteine ​​oral solution according to claim 1, wherein: The antibacterial agent is one or more of sodium benzoate and methylparaben.

4. The method for preparing an acetylcysteine ​​oral solution according to claim 1, wherein: The stabilizer is edetate disodium.

5. The method for preparing an acetylcysteine ​​oral solution according to claim 1, wherein: The flavoring agent is one or more of saccharin sodium and peach essence.

6. The method for preparing an acetylcysteine ​​oral solution according to claim 1, wherein: The pH adjuster is sodium hydroxide.

7. The method for preparing an acetylcysteine ​​oral solution according to claim 1, characterized in that: In step 2, preheat to 40 ± 5 °C; and / or, In step 6, filtration is performed using a 0.45 μm polypropylene filter element.

8. The method for preparing an acetylcysteine ​​oral solution according to claim 1, characterized in that: The packaging bottles used for the finished product of the acetylcysteine ​​oral solution are borosilicate bottles. Before mechanical filling, the borosilicate bottles are purged with nitrogen once, so that the residual oxygen content in the borosilicate bottles is 12-21%; after the acetylcysteine ​​oral solution is filled, the borosilicate bottles are purged with nitrogen again, so that the residual oxygen content in the borosilicate bottles is 8±0.5%; thereafter, the borosilicate bottles are protected by a nitrogen curtain on a conveying track and then reach a nitrogen dripping position, where liquid nitrogen is dripped, and finally the residual oxygen content in the borosilicate bottles is 2%-3%, and then the bottles are capped.

9. The method for preparing an acetylcysteine ​​oral solution according to claim 8, characterized in that: When liquid nitrogen is dripped, the amount of nitrogen dripped is 0.25 to 0.38 g / bottle.

10. The method for preparing an acetylcysteine ​​oral solution according to claim 8, characterized in that: When liquid nitrogen was dripped, the transmission belt conveying the borosilicate bottle was subjected to megasonic vibration for a duration of 1 s and a megasonic frequency of 2.3 MHz.

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