CN108159026B - Stable ambroxol hydrochloride solution for inhalation and preparation method thereof - Google Patents

Stable ambroxol hydrochloride solution for inhalation and preparation method thereof Download PDF

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CN108159026B
CN108159026B CN201810117660.6A CN201810117660A CN108159026B CN 108159026 B CN108159026 B CN 108159026B CN 201810117660 A CN201810117660 A CN 201810117660A CN 108159026 B CN108159026 B CN 108159026B
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ambroxol hydrochloride
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金方
郭升
史亚茹
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JOINCARE PHARMACEUTICAL INDUSTRY GROUP Co.,Ltd.
SHANGHAI FANGYU HEALTH PHARMACEUTICAL TECHNOLOGY Co.,Ltd.
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Abstract

A stable ambroxol hydrochloride solution for inhalation and a preparation method thereof, wherein the solution comprises 0.5-0.9% (w/v) of ambroxol hydrochloride, 0.5-0.8% (w/v) of isotonic agent, 0.001-0.003% (w/v) of metal ion complex serving as a stabilizing agent, a pH regulator and a solvent. The inhaled ambroxol hydrochloride solution has higher portability, obviously enhanced light stability and inhalation performance, can greatly improve the stability of the medicine in the storage process, and is more suitable for clinical use requirements.

Description

Stable ambroxol hydrochloride solution for inhalation and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutics, and particularly relates to a stable ambroxol hydrochloride solution for inhalation and a preparation method thereof.
Background
Ambroxol Hydrochloride (Ambroxol Hydrochloride), also known as bromocyclohexanol Hydrochloride, is a new generation of phlegm-resolving agent, an in vivo active metabolite of bromhexine used as a drug in respiratory system. Ambroxol hydrochloride is introduced by the company of Boringer Yiger and marketed in Germany at the end of the 70 th 20 th century, and is marketed in dozens of countries such as Europe, Japan and China, and is clinically used for treating patients with thick sputum and difficult expectoration. The molecular formula is C13H18Br2N2O.HCl with molecular weight of 414.47 and chemical name of trans-4- [ (2-amino-3, 5-dibromo benzyl) amino]Cyclohexanol hydrochloride of the formula:
Figure BDA0001571079710000011
the medicine becomes an expectorant with stronger clinical effect at present, has definite clinical curative effect and less toxic and side effect, and is widely applied in domestic and foreign markets. The action mechanism is to decompose polysaccharide part in airway mucus mucin, increase secretion of respiratory tract mucous serous gland and reduce mucus gland secretion, thereby playing the roles of reducing sputum viscosity and promoting mucus elimination, having remarkable promoting effect on synthesis and secretion of alveolar surface active substances, and being capable of remarkably discharging phlegm and improving respiratory condition by increasing bronchus cilium movement. The phlegm-eliminating traditional Chinese medicine is mainly used for eliminating phlegm and treating acute and chronic respiratory diseases, in particular chronic bronchitis in clinic. In addition, ambroxol hydrochloride also has obvious curative effect on Chronic Obstructive Pulmonary Disease (COPD) and neonatal respiratory distress syndrome (ARDS).
Ambroxol hydrochloride inhalation solutions were developed by the company brilin bergham and were marketed in germany and italy in 1978 and 1981, respectively. No inhalation solution products are imported and sold in the market at home. Ambroxol hydrochloride recorded in the Chinese pharmacopoeia of 2015 edition has six dosage forms of oral solution, tablets, injection, capsules, sustained-release capsules and syrup, and in addition, the literature reports of new dosage forms of oral fast disintegrating tablets, effervescent tablets, compound preparations, solid dispersions and the like. Compared with intravenous administration and oral administration, inhalation administration directly acts on the lung, has higher local concentration, can avoid adverse reaction caused by larger systemic administration dosage, and has higher compliance for children and the elderly, so the inhalation administration is the first choice for respiratory diseases such as acute and chronic bronchial and pulmonary diseases.
At present, the ambroxol hydrochloride injection is generally used for atomization administration in China, and there is an improper administration mode. The recommended administration mode in the description of the ambroxol hydrochloride injection is intravenous infusion or intravenous drip, and the description uses an aerosol inhalation mode, which has a positive effect on the treatment of the disease condition, but lacks relevant experimental data in the aspect of the medication safety. Therefore, the inhaled ambroxol hydrochloride solution preparation can provide a safe and reliable brand-new treatment way, makes up the shortage of the inhaled phlegm-eliminating preparation in China, and improves the medication safety of patients.
Ambroxol hydrochloride is extremely unstable to light, is easy to degrade when being irradiated by light, and needs to be prevented from being irradiated by strong light. The ambroxol hydrochloride inhalation solution which is sold on the market abroad has two specifications of multi-dose and single dose, the package has the light-proof effect, special attention needs to be paid to light-proof during the use of the medicine, otherwise, the service life of the product is greatly shortened. The multi-dose specification product is 100ml per bottle and is packaged in brown glass bottles, and the single-dose specification product is packaged in brown ampoule bottles, and each bottle contains 2 ml. The glass packing is transported, is carried inconveniently, and the glass ampoule is easy to scratch and has the risk of easily introducing insoluble foreign matters when being opened, which brings great inconvenience to the use of patients. In addition, the multi-dose package containing the preservative benzalkonium chloride is easy to cause respiratory spasm. In addition, we have found that the preparation temperature of ambroxol hydrochloride when the ambroxol hydrochloride is absorbed into the solution also has certain influence on the stability. Therefore, the prescription and the preparation process of the ambroxol hydrochloride inhalation solution are optimized, the more convenient and safer package is adopted, and the improvement of the stability of the inhaled ambroxol hydrochloride solution under illumination becomes a research direction which needs to be developed urgently.
Patent CN103462942 discloses an ambroxol hydrochloride solution for inhalation, each 100ml of which contains 0.15-0.3g of ambroxol hydrochloride, 4-6% of surfactant and a proper amount of antioxidant and preservative, the pH value of the solution is 4.6-5.8, wherein the solvent is selected from water for injection, normal saline and isotonic glucose solution. The stability of the preparation in the using process is improved by adding the preservative into the inhalation solution, but the risk of adverse reactions such as bronchospasm and the like is greatly increased by adding the preservative.
Disclosure of Invention
In order to overcome the defect that the conventional ambroxol hydrochloride solution for inhalation is unstable under illumination, the invention discovers that the stability and the inhalation performance (delivery rate, total delivery amount and fine particle dose) of the ambroxol hydrochloride solution for inhalation after an outer package is opened in the using process can be obviously improved by adding a specific amount of metal ion complex serving as a stabilizer into the ambroxol hydrochloride solution for inhalation and selecting a specific temperature for liquid medicine preparation. The inhalation solution does not need to be protected from light after the outer package of the product is opened in the using process, the solution is placed at room temperature for 30 days, and the color, the pH value and related substances of the solution meet the requirements of quality standards.
Therefore, the invention aims to provide a stable ambroxol hydrochloride solution for inhalation and a preparation method thereof, the solution has higher light stability than the prior product, can be placed at room temperature for 30 days without being shaded after an outer package is opened in the using process, and is convenient for patients to use.
The purpose of the invention is realized by the following technical scheme:
in a first aspect, the present invention provides a stable solution of ambroxol hydrochloride for inhalation comprising 0.5-0.9% (w/v) ambroxol hydrochloride, 0.5-0.8% (w/v) isotonic agent, 0.001-0.003% (w/v) metal ion complex, pH adjusting agent and vehicle.
Preferably, the concentration of ambroxol hydrochloride is 0.7-0.85% (w/v), preferably 0.7-0.75(w/v), and most preferably 0.75% (w/v);
preferably, the concentration of the isotonicity agent is 0.55-0.75% (w/v), preferably 0.58-0.75% (w/v), more preferably 0.58-0.68% (w/v);
preferably, the concentration of the metal ion complex is 0.0015-0.003% (w/v), preferably 0.002-0.003% (w/v), and most preferably 0.002% (w/v).
Preferably, the isotonicity agent is selected from one or more of sodium chloride, potassium chloride, glucose, mannose and sorbitol, preferably sodium chloride.
Preferably, the metal ion complex is ethylenediaminetetraacetic acid and/or ethylenediaminetetraacetate.
Preferably, the edetate is selected from one or more of disodium edetate, calcium sodium edetate and ferric sodium edetate, preferably disodium edetate.
Preferably, the pH regulator is selected from one or more of citric acid, sodium citrate, disodium hydrogen phosphate, acetic acid, sodium acetate, hydrochloric acid and sulfuric acid, preferably citric acid and disodium hydrogen phosphate;
preferably, the pH of the solution is 4.5-5.5, preferably 4.7-5.3.
Preferably, the solvent is water for injection or physiological saline.
Preferably, the solution is colorless to yellowish clear solution in appearance, more preferably colorless clear solution;
preferably, the solution has less than 1.0%, preferably less than 0.5%, most preferably less than 0.35% of the substance of interest.
Secondly, the present invention also provides a method for preparing the solution as described above, said method comprising the steps of:
(1) sequentially weighing ambroxol hydrochloride, a metal ion complex, an isotonic agent and a solvent according to the prescription amount, and stirring and dissolving at 40-70 ℃, preferably 50-60 ℃;
(2) adding pH regulator, stirring, regulating pH to 4.5-5.5, preferably 4.7-5.3, and adding solvent to full volume;
(3) performing sterile treatment, preferably filtering with 0.22 μm filter membrane, performing blow-fill-seal (BFS) integrated full-automatic encapsulation, preferably encapsulating in low density polyethylene bottle.
Preferably, the concentration of ambroxol hydrochloride is 0.5-0.9% (w/v), preferably 0.7-0.85% (w/v), more preferably 0.7-0.75(w/v), and most preferably 0.75% (w/v);
preferably, the isotonicity agent is selected from one or more of sodium chloride, potassium chloride, glucose, mannose and sorbitol, preferably sodium chloride;
preferably, the concentration of the isotonicity agent is 0.5-0.8% (w/v), preferably 0.55-0.75% (w/v), more preferably 0.58-0.75% (w/v), still more preferably 0.58-0.68% (w/v);
preferably, the metal ion complex is ethylenediamine tetraacetic acid and/or ethylenediamine tetraacetic acid salt;
preferably, the edetate is selected from one or more of disodium edetate, calcium sodium edetate and ferric sodium edetate, preferably disodium edetate;
preferably, the concentration of the metal ion complex is 0.001-0.003% (w/v), preferably 0.0015-0.003% (w/v), more preferably 0.002-0.003% (w/v), most preferably 0.002% (w/v);
preferably, the pH regulator is selected from one or more of citric acid, sodium citrate, disodium hydrogen phosphate, acetic acid, sodium acetate, hydrochloric acid and sulfuric acid, preferably citric acid and disodium hydrogen phosphate;
preferably, the solvent is water for injection or physiological saline.
Compared with the prior art, the ambroxol hydrochloride solution for inhalation provided by the invention has higher portability and obviously enhanced light stability, and can greatly improve the stability of the medicine in the storage process. The external package is opened during the use process, the solution can be placed at room temperature for 30 days without being shielded from light and can be kept stable, the solution is colorless and clear, the content of related substances is lower than 1.0 percent, the inhalation performance (delivery rate, total delivery amount and fine particle dosage) is obviously improved, and the external package is more suitable for clinical use requirements.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a high performance liquid chromatogram of example 7 (after 30 days);
FIG. 2 is a high performance liquid chromatogram of comparative example 1 (after 30 days).
Detailed Description
The invention is further illustrated below with reference to specific examples. It should be understood that the examples given herein are for illustrative purposes only and are not intended to limit the scope of the present invention.
The experimental procedures, in which specific conditions are not specified, in the following examples are generally carried out under conventional conditions or under conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
Figure BDA0001571079710000051
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled to be about 40 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.0. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 2
Figure BDA0001571079710000061
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled to be about 50 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 4.7. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 3
Figure BDA0001571079710000062
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled to be about 55 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.0. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 4
Figure BDA0001571079710000063
Figure BDA0001571079710000071
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled at about 60 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.5. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 5
Figure BDA0001571079710000072
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled to be about 40 ℃, the raw and auxiliary materials are added and stirred to be completely dissolved, and the pH value is adjusted to 5.0 by hydrochloric acid. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 6
Figure BDA0001571079710000073
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled at about 70 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 4.5. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 7
Figure BDA0001571079710000081
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled to be about 50 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.3. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 8
Figure BDA0001571079710000082
The process comprises the following steps:
700ml (70 percent of prescription amount) of water for injection is added into the liquid preparation tank, the temperature is controlled at about 60 ℃, the raw and auxiliary materials are added and stirred to be completely dissolved, and the pH value is adjusted to 4.5 by sulfuric acid. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 9
Figure BDA0001571079710000083
Figure BDA0001571079710000091
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled at about 60 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.5. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 10
Figure BDA0001571079710000092
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled at about 60 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.0. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Example 11
Figure BDA0001571079710000093
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled at about 60 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.0. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Comparative example 1
Figure BDA0001571079710000101
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled to be about 80 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.0. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Comparative example 2
Figure BDA0001571079710000102
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled to be about 50 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 4.7. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Comparative example 3
Figure BDA0001571079710000103
Figure BDA0001571079710000111
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled to be about 80 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.3. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Comparative example 4
Figure BDA0001571079710000112
The process comprises the following steps:
700ml (70 percent of prescription amount) of water for injection is added into the liquid preparation tank, the temperature is controlled at about 50 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 4.5. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Comparative example 5
Figure BDA0001571079710000113
The process comprises the following steps:
700ml (prescription amount is 70%) of water for injection is added into the liquid preparation tank, the temperature is controlled to be about 35 ℃, and the raw and auxiliary materials are added and stirred to be completely dissolved, wherein the pH value is about 5.5. Adding water for injection to 1000ml, stirring, filtering with 0.22 μm filter membrane, and bottling in 2ml low density polyethylene bottle.
Experimental example 1
The samples of examples 1 to 11 of the present invention and the samples of comparative examples 1 to 5 were taken, and left under natural light for 30 days after removing the outer package at room temperature, and the stability was examined, and the samples were taken at 0, 5, 10 and 30 days, respectively, and the appearance was observed, and the contents and the related substances were measured, and the results are shown in tables 1 and 2, wherein the chromatogram of example 7 is shown in FIG. 1, and the chromatogram of comparative example 1 is shown in FIG. 2.
Wherein, the chromatographic conditions of the content determination method are as follows:
0.01mol/L diammonium hydrogen phosphate (phosphoric acid adjusted pH to 7.5): acetonitrile 50: 50;
ODS C18 chromatography column;
flow rate 1 ml/min;
the column temperature was 30 ℃.
Wherein, the related substances determine chromatographic conditions:
0.01mol/L diammonium hydrogen phosphate (phosphoric acid adjusted pH to 7.0): acetonitrile 50: 50;
ODS C18 chromatography column;
flow rate 1 ml/min;
the column temperature was 25 ℃.
Table 1: the appearance, content and related substance detection results of the ambroxol hydrochloride solutions for inhalation prepared in examples 1 to 11
Figure BDA0001571079710000121
Figure BDA0001571079710000131
Table 2: the appearance, content and related substance detection results of the ambroxol hydrochloride solutions for inhalation prepared in comparative examples 1 to 5
Figure BDA0001571079710000132
Figure BDA0001571079710000141
Wherein, the related substance% is the ratio of the peak area of the related substance in the High Performance Liquid Chromatography (HPLC) to the total peak area.
The results show that after the ambroxol hydrochloride solution for inhalation prepared in the embodiments 1 to 11 of the invention is unpacked and placed at room temperature for 30 days, the content of related substances is less than 1 percent, the content change is not obvious, the photostability is obviously enhanced, and the drug use portability of patients is greatly improved. The color of the samples of comparative examples 1-3 is obviously changed after the samples are placed for 10 days, and the content of related substances is more than 1 percent after the samples are placed for 30 days, which does not meet the requirements of pharmacopoeia and causes great waste of medicines. The dosage of the stabilizer added into the sample and the sample preparation temperature are strictly screened, and the stability of the product is not suitable to be improved when the temperature of the stabilizer and the sample preparation is too high or too low. Especially when the sample preparation temperature is lower than 40 ℃, the sample preparation time is obviously increased, and the protective effect of the stabilizing agent on the sample solution is obviously weakened. Therefore, the stability of the sample of the embodiment of the invention is better than that of the sample of the comparative example after the sample is opened and placed for 30 days at room temperature, and the sample is more suitable for clinical use requirements.
Experimental example 2
According to the preparation method of example 1, samples containing disodium ethylenediaminetetraacetate 0.001% (w/v), 0.002% (w/v), 0.003% (w/v), 0.005% (w/v) and the stabilizer disodium ethylenediaminetetraacetate were prepared in the prescription by changing the amount of disodium ethylenediaminetetraacetate in the prescription, respectively, and the samples were left for 30 days at room temperature by removing the outer package and leaving it under natural light, and the stability was examined, and the samples were taken at 0, 5, 10 and 30 days, and the appearance was observed, and the pH value, the content and the related substances were measured, and the results are shown in Table 3.
Table 3: the appearance, content and related substance inspection results of the inhaled ambroxol hydrochloride solution
Figure BDA0001571079710000142
Figure BDA0001571079710000151
The result shows that when the content of the disodium ethylene diamine tetraacetate is 0.001-0.003% (w/v), the color content of the sample is not obviously changed, and related substances are less than 1%. The appearance of the sample without the disodium ethylene diamine tetraacetate and related substances are obviously changed after the sample is placed for 10 days, the stability of the sample is obviously reduced, and the sample with the content of the disodium ethylene diamine tetraacetate exceeding 0.003 percent (w/v) has no obvious improvement effect on the stability but causes the stability of the sample to be reduced compared with the sample with the content of 0.001 to 0.003 percent (w/v). Therefore, from the aspects of appearance, content, safety of related substances and auxiliary material dosage and the like, the content of the disodium ethylene diamine tetraacetate is preferably 0.002%.
Experimental example 3
Samples of inventive examples 1-11 and comparative examples 1-5 were taken and left at room temperature for 30 days after opening the package, and the delivery rate and the total amount delivered, and the fine particle dose were measured, and the results are shown in Table 3.
Delivery rate versus total delivered amount: the delivery rate and total delivery amount of the liquid formulation for the nebulizer were determined according to method 0113, the general rule of pharmacopoeia of china (2015 edition).
Fine particle dose: the determination was carried out by 0951 fine particle aerodynamic property measurement method according to the general rules of Chinese pharmacopoeia (2015 edition).
TABLE 3 delivery Rate vs Total delivered amount, Fine particle dose determination results
Figure BDA0001571079710000152
Figure BDA0001571079710000161
The result shows that the sample of the embodiment of the invention is prepared by adding the stabilizer and at a proper temperature, and the inhalation performance is better than that of the sample of the comparative example after the sample is opened and placed for 30 days at room temperature, so that the sample is more suitable for clinical use requirements.

Claims (23)

1. A stable solution of ambroxol hydrochloride for inhalation, said solution comprising ambroxol hydrochloride 0.5-0.9% (w/v), isotonic agent 0.58-0.8% (w/v), metal ion complex 0.001-0.003% (w/v), pH regulator and vehicle;
the preparation method of the solution comprises the following steps:
(1) sequentially weighing ambroxol hydrochloride, a metal ion complex, an isotonic agent and a solvent according to the prescription amount, and stirring and dissolving at 40-70 ℃;
(2) adding one or more pH regulator selected from citric acid, sodium citrate, sulfuric acid and disodium hydrogen phosphate, stirring, regulating pH to 4.5-5.5, and adding solvent to full dose;
(3) sterile processing, filtering with 0.22 μm filter membrane, and blow-filling-sealing (BFS) integrated full-automatic filling and sealing in low density polyethylene bottle.
2. The solution according to claim 1, wherein the concentration of ambroxol hydrochloride is 0.7-0.85% (w/v).
3. The solution according to claim 1, wherein the concentration of ambroxol hydrochloride is 0.7-0.75% (w/v).
4. The solution according to claim 1, wherein the concentration of ambroxol hydrochloride is 0.75% (w/v).
5. The solution of claim 1, wherein the concentration of the isotonicity agent is 0.58-0.68% (w/v).
6. The solution of claim 1, wherein the concentration of the metal ion complex is 0.0015-0.003% (w/v).
7. The solution of claim 1, wherein the concentration of the metal ion complex is 0.002-0.003% (w/v).
8. The solution of claim 1, wherein the concentration of the metal ion complex is 0.002% (w/v).
9. The solution according to claim 1, characterized in that the isotonicity agent is selected from one or more of sodium chloride, potassium chloride, glucose, mannose and sorbitol.
10. The solution of claim 1, wherein the isotonicity agent is sodium chloride.
11. The solution of claim 1, wherein the metal ion complex is ethylenediaminetetraacetic acid and/or an ethylenediaminetetraacetate salt.
12. The solution of claim 11, wherein the edetate is selected from one or more of disodium edetate, calcium sodium edetate and iron sodium edetate.
13. The solution of claim 11, wherein the edetate is disodium edetate.
14. The solution of claim 1, wherein the pH adjusting agent is citric acid and disodium hydrogen phosphate.
15. The solution of claim 1, wherein the solution has a pH of 4.7 to 5.3.
16. The solution of claim 1, wherein the vehicle is water for injection or saline.
17. The solution according to any one of claims 1 to 16, wherein the solution is a colorless clear solution with less than 1.0% of related substances.
18. The solution of claim 17, wherein the concentration of the substance of interest in the solution is less than 0.5%.
19. The solution of claim 17, wherein the concentration of the substance of interest in the solution is less than 0.35%.
20. The solution of claim 1, wherein the temperature for stirring and dissolving in step (1) is 50-60 ℃.
21. A method of preparing the solution of any one of claims 1 to 20, the method comprising the steps of:
(1) sequentially weighing ambroxol hydrochloride, a metal ion complex, an isotonic agent and a solvent according to the prescription amount, and stirring and dissolving at 40-70 ℃;
(2) adding one or more pH regulator selected from citric acid, sodium citrate, sulfuric acid and disodium hydrogen phosphate, stirring, regulating pH to 4.5-5.5, and adding solvent to full dose;
(3) sterile processing, filtering with 0.22 μm filter membrane, and blow-filling-sealing (BFS) to obtain the final product.
22. The method according to claim 21, wherein the temperature for the stirring dissolution in the step (1) is 50-60 ℃.
23. A stable solution of ambroxol hydrochloride for inhalation, said solution prepared from the following components:
Figure FDA0002703206180000031
the preparation process of the solution comprises the following steps:
adding 700ml of water for injection into the liquid preparation tank, controlling the temperature at 50 ℃, adding the raw and auxiliary materials, stirring to completely dissolve, controlling the pH to be 5.3, adding the water for injection to 1000ml, stirring uniformly, filtering through a 0.22 mu m filter membrane, and filling and sealing in a 2ml low-density polyethylene bottle to obtain the product.
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