Phlegm-reducing chemical medicine composition and preparation process thereof

Abstract

The invention relates to the technical field of pharmaceutical compositions, in particular to a phlegm-reducing chemical pharmaceutical composition and a preparation process thereof.The preparation process includes the steps of weighing, preparation before liquid preparation, liquid preparation, circulation, filtration, filling and sterilization. A comparison result shows that the prepared acetylcysteine injection and a reference preparation have no obvious difference in various inspection results, the quality is equivalent, and a strong sputum dissolving effect can be exerted, so that the viscosity of sputum is reduced, and the sputum is easy to cough.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical compositions, in particular to a phlegm-resolving chemical pharmaceutical composition and a preparation process thereof. Background Art

[0002] Acetylcysteine ​​(NAC) is a cysteine ​​derivative, belonging to a mucolytic agent, which mainly breaks the disulfide bond (-SS) of the acidic glycoprotein polypeptide in the mucous sputum and cleaves the DNA in the purulent sputum through the sulfhydryl group in the molecule. It can play a strong sputum dissolving effect on white mucous sputum or mucopurulent sputum, thereby reducing the viscosity of sputum and making it easy to cough up. In addition, NAC is a precursor substance for synthesizing glutathione (GSH) in the human body, has a strong oxygen free radical scavenging effect, has a protective effect on lipid peroxidation damage and inflammatory response of the liver, and then slows down the process of liver fibrosis; the preparation of acetylcysteine ​​is widely used clinically, and is also used or studied for the treatment of other indications, including liver failure, accidental poisoning with acetaminophen, the alleviation of nephropathy induced by radiocontrast, and the alleviation of reperfusion injury during cardiac bypass surgery. At present, the acetylcysteine ​​pharmaceutical dosage forms listed at home and abroad include oral preparations, injections, and atomized inhalers.

[0003] At present, acetylcysteine ​​is available in the United States, Europe, Japan, etc. and has been widely used. Acetylcysteine ​​injection (trade name: Fluimuc il; specification: 3ml: 300mg) was first developed by Zambon GmbH and obtained EU marketing authorization in August 1991. At present, the original acetylcysteine ​​injection (trade name: Fluimuc il; specification: 3ml: 300mg) has not been imported and marketed in my country. Therefore, the present invention provides a generic drug with the acetylcysteine ​​injection (Fluimuc il) marketed in the EU as a reference preparation. Summary of the invention

[0004] The invention provides a phlegm-resolving chemical medicine composition. Each vial of acetylcysteine ​​injection contains 280-350 mg of acetylcysteine, 2-5 mg of edetate disodium, 2000-3000 mg of a pH regulator and 2000-5000 mg of injection water. The pH regulator is a 20% (w / v) sodium hydroxide solution.

[0005] In a possible implementation, each vial of acetylcysteine ​​injection contains 300 mg of acetylcysteine, 3 mg of edetate disodium, 2000 mg of a pH adjuster, and 3000 mg of water for injection.

[0006] The present invention also provides a preparation process of a phlegm-resolving chemical medicine composition, comprising the following steps: S1, weighing: weighing edetate disodium, sodium hydroxide, and acetylcysteine ​​respectively according to the batch feeding amount;

[0007] S2. Preparation before mixing

[0008] S3, liquid preparation

[0009] S31, preparation of 20% (w / v) sodium hydroxide solution: weigh 2.8 kg of sodium hydroxide, slowly add it into 10000 ml of water for injection, stir while adding to dissolve, add water to make up to 14000 ml, and set aside;

[0010] S32, 0.35mol / L glacial acetic acid solution preparation: measure 20ml glacial acetic acid, add injection water to 1000ml, mix well;

[0011] S33, preparation of the combined drug solution: first inject 75.0±0.4kg of water for injection into the preparation tank, turn on the stirrer, stir at a frequency of 40Hz throughout the process, continue to introduce nitrogen until the dissolved oxygen is ≤1.68mg / L, and after the temperature of the water for injection drops to 30±5°C, add the weighed disodium edetate into the preparation tank and stir for 10min to completely dissolve;

[0012] The weighed acetylcysteine ​​raw material was put into the liquid preparation tank and stirred for 10 minutes to completely dissolve; the pH value of the liquid was adjusted to 6.5±0.2 with 20% (w / v) sodium hydroxide solution. After adding 20% ​​sodium hydroxide solution each time, the stirring time was 10 minutes. The liquid was taken from the sampling port of the liquid preparation tank to test the pH value. After the pH adjustment was qualified, the stirring and nitrogen were stopped, and nitrogen was added for injection; the volume was adjusted to 104.6±0.4kg, and the stirrer and nitrogen were turned on. The stirring frequency was 40Hz and the nitrogen pressure was>0.1Mp;

[0013] S4, circulation and filtration

[0014] Start the circulation for 30 minutes, and the drug solution returns to the liquid preparation tank through a 0.45μm precision filter and a 0.22μm sterilizing filter. Samples are taken at the sampling port of the 0.45μm precision filter to test the properties, pH, content, visible foreign matter, and insoluble particles of the drug solution. Samples are taken at the sampling port of the 0.22μm terminal filter to test bacterial endotoxins. After the semi-finished product is tested and qualified, the drug solution is passed through a 0.45μm precision filter, a 0.22μm sterilizing filter, and a 0.22μm terminal filter to the buffer tank for filling.

[0015] In one possible implementation, the preparation process also includes filling and sterilization. The filtered drug solution is filled into a clean 5 ml brown medium borosilicate ampoule, and then the drug solution is sterilized at a sterilization temperature of 121° C. and a sterilization time of 12 minutes.

[0016] In one possible implementation, the specific process of step S2 is as follows: before liquid preparation, the filtration pipeline is first opened with nitrogen to separate the 0.45μm precision filter section, the 0.22μm sterilizing filter section, the 0.22μm terminal filter section, and the circulating reflux section for about 1 minute of purge per section, and the dilution tank and the buffer tank are continuously filled with nitrogen 30 minutes in advance, and the nitrogen pressure is >0.1Mpa.

[0017] Weigh 12 kg of water for injection and put it into a sterilized stainless steel barrel with a lid. Continue to fill it with nitrogen until the dissolved oxygen is ≤1.68 mg / L, and then make up the volume for later use.

[0018] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects: the present invention compares multiple batches of acetylcysteine ​​injection with reference reagents. The comparison results show that the acetylcysteine ​​injection prepared by the present invention has no significant difference in various test results with the reference preparation, and the quality is equivalent. It can exert a strong sputum dissolving effect, thereby reducing the viscosity of sputum and making it easier to cough up. DETAILED DESCRIPTION

[0019] The following describes the implementation of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific implementations, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0020] Before further describing the specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the examples of the present invention are for describing specific embodiments rather than for limiting the scope of protection of the present invention.

[0021] When the embodiments give a numerical range, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by ordinary technicians in the technical field to which the present invention belongs.

[0022] A preparation process of a phlegm-resolving chemical medicine composition comprises the following steps: S1, weighing: weighing disodium edetate, sodium hydroxide and acetylcysteine ​​respectively according to the batch feeding amount.

[0023] S2. Preparation before mixing

[0024] Before liquid preparation, open the nitrogen in the filter pipeline to divide it into 0.45μm precision filter section, 0.22μm sterilizing filter section, 0.22μm terminal filter section, and circulating reflux section for about 1 minute of purge in each section. The dilution tank and buffer tank begin to be continuously filled with nitrogen 30 minutes in advance, and the nitrogen pressure is >0.1Mpa.

[0025] Weigh 12 kg of water for injection and put it into a sterilized stainless steel barrel with a lid. Continue to fill it with nitrogen until the dissolved oxygen is ≤1.68 mg / L, and then make up the volume for later use.

[0026] S3, liquid preparation

[0027] S31. Preparation of 20% (w / v) sodium hydroxide solution: Weigh 2.8 kg of sodium hydroxide, slowly add it into 10000 ml of water for injection, stirring while adding to dissolve, add water to make up to 14000 ml, and set aside.

[0028] S32, preparation of 0.35 mol / L glacial acetic acid solution: measure 20 ml of glacial acetic acid, add water for injection to 1000 ml, and mix well.

[0029] S33, preparation of the combined drug solution: first inject 75.0±0.4kg of water for injection into the preparation tank, turn on the stirrer, stir at a frequency of 40Hz throughout the process, continue to introduce nitrogen until the dissolved oxygen is ≤1.68mg / L, and after the temperature of the water for injection drops to 30±5°C, add the weighed disodium edetate into the preparation tank and stir for 10min to completely dissolve;

[0030] The weighed acetylcysteine ​​raw material is put into the liquid preparation tank and stirred for 10 minutes to completely dissolve; the pH value of the liquid is adjusted to 6.5±0.2 with 20% (w / v) sodium hydroxide solution. After adding 20% ​​sodium hydroxide solution each time, the stirring time is 10 minutes, and the liquid is taken from the sampling port of the liquid preparation tank to detect the pH value. After the pH adjustment is qualified, the stirring and nitrogen are stopped, and nitrogen is added for standby injection water; the volume is adjusted to 104.6±0.4kg, and the stirrer and nitrogen are turned on. The stirring frequency is 40Hz, and the nitrogen pressure is>0.1Mp.

[0031] S4, circulation and filtration

[0032] Start the circulation for 30 minutes, and the drug solution returns to the liquid preparation tank through a 0.45μm precision filter and a 0.22μm sterilizing filter. Samples are taken at the sampling port of the 0.45μm precision filter to test the properties, pH, content, visible foreign matter, and insoluble particles of the drug solution. Samples are taken at the sampling port of the 0.22μm terminal filter to test bacterial endotoxins. After the semi-finished product is tested and qualified, the drug solution is passed through a 0.45μm precision filter, a 0.22μm sterilizing filter, and a 0.22μm terminal filter to the buffer tank for filling.

[0033] S5, filling and sterilization

[0034] The filtered liquid medicine was filled into a clean 5 ml brown medium borosilicate ampoule, and then sterilized at a temperature of 121°C for 12 minutes.

[0035] Quality attribute comparison experiment

[0036] The various information indicators of the reference preparation and the self-made product were tested and compared. The information table of the reference preparation and the self-made product are shown in Table 1 and Table 2, and the test results are shown in Table 3

[0037] Table 1

[0038]

[0039] Table 2

[0040]

[0041] Table 3

[0042]

[0043]

[0044]

[0045] Among them, impurity A is cystine, impurity B is cysteine, impurity C is N,N'-diacetyl-L-cystine, impurity D is N,S-diacetyl-L-cysteine, and impurity E is N,N'-diacetyl L-lanthionine.

[0046] As can be seen from Table 3, there is no significant difference in the test results between the acetylcysteine ​​injection prepared in Example and the reference preparation, and the quality is equivalent.

Claims

1. A phlegm-resolving chemical pharmaceutical composition, characterized in that: Each vial of acetylcysteine ​​injection contains 280-350 mg of acetylcysteine, 2-5 mg of edetate disodium, 2000-3000 mg of pH adjuster and 2000-5000 mg of water for injection, wherein the pH adjuster is 20% (w / v) sodium hydroxide solution.

2. The expectorant chemical pharmaceutical composition according to claim 1, characterized in that: Each vial of acetylcysteine ​​injection contains 300 mg of acetylcysteine, 3 mg of edetate disodium, 2000 mg of pH adjuster and 3000 mg of water for injection.

3. A process for preparing the expectorant chemical pharmaceutical composition according to claim 1, characterized in that: The following steps are involved: S1. Weighing: Weigh edetate disodium, sodium hydroxide and acetylcysteine ​​according to the batch feeding amount; S2. Preparation before mixing S3, liquid preparation S31, preparation of 20% (w / v) sodium hydroxide solution: weigh 2.8 kg of sodium hydroxide, slowly add it into 10000 ml of water for injection, stir while adding to dissolve, add water to make up to 14000 ml, and set aside; S32, 0.35mol / L glacial acetic acid solution preparation: measure 20ml glacial acetic acid, add injection water to 1000ml, mix well; S33, preparation of the combined drug solution: first inject 75.0±0.4kg of water for injection into the preparation tank, turn on the stirrer, stir at a frequency of 40Hz throughout the process, continue to introduce nitrogen until the dissolved oxygen is ≤1.68mg / L, and after the temperature of the water for injection drops to 30±5°C, add the weighed disodium edetate into the preparation tank and stir for 10min to completely dissolve; The weighed acetylcysteine ​​raw material was put into the liquid preparation tank and stirred for 10 minutes to completely dissolve; the pH value of the liquid was adjusted to 6.5±0.2 with 20% (w / v) sodium hydroxide solution. After adding 20% ​​sodium hydroxide solution each time, the stirring time was 10 minutes. The liquid was taken from the sampling port of the liquid preparation tank to test the pH value. After the pH adjustment was qualified, the stirring and nitrogen were stopped, and nitrogen was added for injection; the volume was adjusted to 104.6±0.4kg, and the stirrer and nitrogen were turned on. The stirring frequency was 40Hz and the nitrogen pressure was>0.1Mp; S4, circulation and filtration Start the circulation for 30 minutes, and the drug solution returns to the liquid preparation tank through a 0.45μm precision filter and a 0.22μm sterilizing filter. Samples are taken at the sampling port of the 0.45μm precision filter to test the properties, pH, content, visible foreign matter, and insoluble particles of the drug solution. Samples are taken at the sampling port of the 0.22μm terminal filter to test bacterial endotoxins. After the semi-finished product is tested and qualified, the drug solution is passed through a 0.45μm precision filter, a 0.22μm sterilizing filter, and a 0.22μm terminal filter to the buffer tank for filling.

4. The preparation process of the expectorant chemical pharmaceutical composition according to claim 3, characterized in that: The preparation process also includes filling and sterilization. The filtered liquid medicine is filled into a clean 5 ml brown medium borosilicate ampoule, and then the liquid medicine is sterilized at a sterilization temperature of 121° C. and a sterilization time of 12 minutes.

5. The preparation process of the expectorant chemical pharmaceutical composition according to claim 3, characterized in that: The specific process of step S2 is as follows: before liquid preparation, the filtration pipeline is first opened with nitrogen to separate the 0.45μm precision filter section, the 0.22μm sterilizing filter section, the 0.22μm terminal filter section, and the circulating reflux section for about 1 minute of purge in each section, and the dilution tank and the buffer tank are continuously charged with nitrogen 30 minutes in advance, and the nitrogen pressure is>0.1Mpa; Weigh 12 kg of water for injection and put it into a sterilized stainless steel barrel with a lid. Continue to fill it with nitrogen until the dissolved oxygen is ≤1.68 mg / L, and then make up the volume for later use.

6. Use of the composition according to claim 1 in expectoration.

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