Ambroxol hydrochloride solution as well as preparation method and application thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to an ambroxol hydrochloride solution and a preparation method and application thereof. According to the invention, the diethylenetriaminepentaacetic acid is used as a stabilizer component of the ambroxol hydrochloride solution in a small amount, and the diethylenetriaminepentaacetic acid has strong coordination ability and can interact with other molecules in the solution, so that the stability of the ambroxol hydrochloride solution is greatly improved. The preparation method provided by the invention is simple and easy to operate, does not need a dark environment, is low in production cost and is easy for industrial production. The ambroxol hydrochloride solution provided by the invention does not need to be added with preservative components or when the ambroxol hydrochloride solution is applied to an inhalation preparation, is reliable in quality and good in safety, and is more suitable for clinical use requirements.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to an ambroxol hydrochloride solution and a preparation method and application thereof. Background Art

[0002] Respiratory diseases are generally manifested as cough, sputum, wheezing, and inflammation. In particular, increased sputum volume and difficulty in expectoration are common symptoms of many respiratory diseases such as chronic obstructive pulmonary disease (COPD), bronchial asthma, and cystic pulmonary fibrosis (CF). Children and the elderly often have difficulty spitting, which interferes with people's daily lives in mild cases and even endangers the patient's life in severe cases. At the same time, in the case of chest and abdominal surgery, patients often produce a large amount of sputum, and the presence of sputum can block the respiratory tract, easily causing coughing, wheezing, and even causing dyspnea. Sputum blocking the respiratory tract leads to uneven distribution of inhaled gas in the lungs, imbalance of ventilation and blood flow ratio, and aggravation of hypoxia. Sputum is also a good culture medium for bacteria. Its poor discharge can promote the reproduction and growth of bacteria, causing the development and aggravation of inflammation. The mucus cilia of the sputum transport system are therefore weakened or destroyed. Therefore, the use of expectorants to promote the excretion of airway endocrines as soon as possible is an important auxiliary measure and necessary treatment for the treatment of airway inflammation.

[0003] Ambroxol Hydrochloride is also known as bromocyclohexanol hydrochloride, chemical name: trans-4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol hydrochloride, molecular formula: C 13 H 18 Br2N2O·HCl, molecular weight: 414.57, CAS: 23828-92-4, structural formula: .

[0004] Ambroxol hydrochloride was discovered by Boehringer Ingelheim in Germany in 1965 when studying the metabolites of bromhexine. It was developed and marketed in 1979 and has been launched in nearly 20 countries including Italy, Switzerland, Argentina, Japan, etc. The original marketing dosage forms are injection, tablets, syrup, oral solution, and sustained-release capsules. my country began to approve its import in 1991 under the trade name "Mucosolvan". The specifications of ambroxol hydrochloride injection are 2ml:15mg. Ambroxol hydrochloride injection is suitable for acute and chronic respiratory diseases accompanied by abnormal sputum secretion and poor sputum function, such as acute exacerbation of chronic bronchitis, expectorant treatment of asthmatic bronchitis and bronchial asthma, preventive treatment of postoperative pulmonary complications, and treatment of infant respiratory distress syndrome (IRDS) in premature infants and newborns.

[0005] Ambroxol hydrochloride is a new generation of respiratory mucus regulator. It reduces the viscosity of sputum by decomposing the polysaccharide part of mucin, the viscoelastic component of airway mucus, and increasing the secretion of serous glands in the respiratory mucosa, reducing the secretion of mucus glands, thereby improving expectoration. It also has the effect of promoting pulmonary surfactant and airway secretion and ciliary movement. The predecessor of this type of drug, bromhexine, was extracted from syringa alkaloids. Syringa alkaloids come from an Asian plant and have been proven to be very effective in expectoration. It can promote the removal of viscous secretions in the respiratory tract and reduce mucus retention, thereby significantly promoting expectoration and improving respiratory conditions. When this product is used for treatment, the patient's mucus secretion can be restored to normal. Cough and sputum volume are usually significantly reduced, and the surfactant on the respiratory mucosa can thus play its normal protective function. It is suitable for acute and chronic respiratory diseases accompanied by abnormal sputum secretion and poor expectoration function. It is used for the treatment of acute and chronic respiratory diseases, abnormal bronchial secretion, etc.

[0006] The inhalation solution is sprayed into the patient's mouth through a suitable medical compressed nebulizer, an air pump-driven device, to form a drug mist. The drug components in the mist adhere to the respiratory epithelium and then penetrate into the cells to exert their drug effects. Inhalation administration is a very important non-oral and non-injection drug administration method. It has the advantages of (1) inhalation agents can enter the blood directly from the lungs and take effect quickly; (2) local administration can increase the accumulation of drugs in target organs, increase efficacy and reduce toxic side effects; (3) no first-pass effect and high bioavailability. It is currently widely used in the global market and is very popular among clinicians and patients.

[0007] Ambroxol hydrochloride solution for inhalation was launched in Germany in 1978 and Italy in 1981. In China, Yunnan Longhai Natural Plant Pharmaceutical Co., Ltd., Yingu Pharmaceutical Co., Ltd., Hebei Kaiwei Pharmaceutical Co., Ltd., and Hanmi Pharm. Co., Ltd. have already launched generic versions of the drug, all in single-dose packaging with a specification of 2ml:15mg. The original drug was not imported.

[0008] The chemical structure of ambroxol hydrochloride contains a group such as an aromatic primary amine, an alkyl secondary amine, and a bromoaromatic hydrocarbon. The structure determines the properties, which makes it sensitive to light and oxygen, and is prone to free radicals and redox reactions, resulting in the generation of degradation impurities. Therefore, ambroxol hydrochloride is unstable to light and oxygen. The ambroxol hydrochloride solutions for inhalation that have been marketed at home and abroad have two specifications: multi-dose and single-dose. They use brown glass bottles or ampoules, polyethylene pillow packaging plus aluminum foil bags, all of which have a light-shielding effect. CN110870854B discloses a borosilicate glass ampoule containing a certain amount of ferric oxide and titanium dioxide, which has a significant light-shielding effect. The original multi-dose specification product is 100ml per bottle, packaged in brown glass bottles, and the single-dose specification product is packaged in brown ampoules, each 2ml. Except for Hanmi Pharm. Co., Ltd., which uses polyethylene pillow packaging plus aluminum foil bags, other companies use brown ampoules for domestic marketed products, each 2ml. Before the production and filling process of the product, nitrogen filling is required for protection to isolate oxygen and prevent oxidation and degradation of the product. During the use of ambroxol hydrochloride solution for inhalation, it needs to be diluted with 0.9% sodium chloride solution for atomization. At this time, the protective effect of the original packaging will disappear. During the preparation and atomization process, it will be exposed to light and oxygen, causing the main drug ingredient ambroxol to degrade and trigger the risk of adverse reactions. Therefore, the light and oxygen stability of ambroxol hydrochloride solution for inhalation is a more prominent problem for existing prescriptions and processes.

[0009] CN103462942B discloses an ambroxol hydrochloride solution for inhalation, which contains ambroxol hydrochloride, a surfactant, and an appropriate amount of an antioxidant and a preservative. The inhalation solution is added with a preservative to improve the stability of the preparation during use, but the addition of the preservative greatly increases the risk of adverse reactions such as bronchospasm.

[0010] CN108159026B discloses a stable ambroxol hydrochloride solution for inhalation and a preparation method thereof, wherein the room temperature and light stability are improved by adding a metal chelating agent, and no investigation or study on oxygen stability is involved.

[0011] CN103492642B discloses an ambroxol hydrochloride solution for inhalation, in which the content of the main drug component is low (0.15-0.3%), and contains a large amount of antioxidant components such as sulfurous acid and sodium sulfite, resulting in a large amount of atomization and easy side effects, poor patient compliance, and difficulty in ensuring drug efficacy. At the same time, it does not involve the investigation and research on photostability.

[0012] CN110755413B discloses an ambroxol hydrochloride solution for inhalation, which uses a large amount of stabilizers (chitosan, sodium pyrosulfite) and surfactants (tylosin, lecithin), which are easy to irritate the respiratory mucosa and induce asthma, and the patient's compliance is poor. At the same time, it does not involve the investigation and research on photostability.

[0013] Therefore, it is of great significance to develop a prescription and preparation process for ambroxol hydrochloride solution for inhalation that has good light and oxygen stability, is easy to operate, and has good repeatability. Summary of the invention

[0014] In order to solve the problems existing in the prior art, the purpose of the present invention is to provide a stable ambroxol hydrochloride solution for atomization inhalation and a preparation method and application thereof.

[0015] Specifically, the technical solution provided by the present invention is as follows: In a first aspect, the present invention provides an ambroxol hydrochloride solution, comprising: ambroxol hydrochloride, a stabilizer and water, wherein the stabilizer comprises 7%-12% by mass of diethylenetriaminepentaacetic acid; and the total amount of the stabilizer in the ambroxol hydrochloride solution is 27.5-192.5 mg / L.

[0016] Diethylenetriaminepentaacetic acid (DTPA), also known as diethyltriaminepentaacetic acid, diethylenetriaminepentaacetic acid, molecular formula: C 14 H 23 N3O 10 , molecular weight: 393.35, CAS: 67-43-6, white crystalline powder or colorless crystals, soluble in water, with good chemical stability and oxidation resistance, and high coordination ability under acidic conditions. In the present invention, diethylenetriaminepentaacetic acid is used as a component of the stabilizer, and its mass percentage in the stabilizer is 7%-12%, preferably 7.7%-11.1%, more preferably 8.3%-10.0%, and more preferably 9.1%.

[0017] The present invention uses diethylenetriaminepentaacetic acid as a stabilizer component of the ambroxol hydrochloride solution in a relatively small amount (the amount used in the ambroxol hydrochloride solution after conversion is about 2.5-17.5 mg / L). The diethylenetriaminepentaacetic acid has a relatively strong coordination ability and can interact with other molecules in the solution, thereby greatly improving the stability of the ambroxol hydrochloride solution.

[0018] In addition to diethylenetriaminepentaacetic acid, the stabilizer of the present invention preferably further comprises sodium bisulfite in an amount not exceeding 93% by mass. Compared with other stabilizer ingredients, the effect of using sodium bisulfite and diethylenetriaminepentaacetic acid in combination is better.

[0019] In the present invention, the stabilizer is preferably a mixture of sodium bisulfite and diethylenetriaminepentaacetic acid. The mass ratio of sodium bisulfite to diethylenetriaminepentaacetic acid is preferably (50-350): (5-35); more preferably (100-300): (10-30); further preferably (150-250): (15-25); most preferably (170-230): (18-22). Alternatively, the mass ratio of sodium bisulfite to diethylenetriaminepentaacetic acid is 8-12:1; preferably 10:1.

[0020] Sodium bisulfite and diethylenetriamine pentaacetic acid have a synergistic effect in the dispersed system of ambroxol hydrochloride solution, proton exchange occurs between molecules, and the hydrogen bonding effect with the amine group and hydroxyl hydrogen in ambroxol is enhanced, so that the electron cloud density of the ambroxol molecule is redistributed. When the stabilizer is sodium bisulfite and diethylenetriamine pentaacetic acid in the above preferred mass ratio, the effect of improving the photostability and antioxidant properties of the ambroxol hydrochloride solution is more significant, and the stability of the drug during storage and processing can be greatly improved (good stability is shown in the accelerated 6-month and long-term 24-month stability test tests).

[0021] In the present invention, the mass ratio of ambroxol hydrochloride to stabilizer is preferably (12500-17500): (55-385); more preferably (13000-17000): (110-330); further preferably (13500-16500): (165-275); most preferably (14500-15500): (188-252). The ambroxol hydrochloride solution obtained by the above preferred ratio has better stability.

[0022] In the present invention, based on a total amount of 2000 ml, the ambroxol hydrochloride solution preferably comprises 12.5-17.5 g of ambroxol hydrochloride, 50-350 mg of sodium bisulfite and 5-35 mg of diethylenetriaminepentaacetic acid; More preferably, each 2000 ml of ambroxol hydrochloride solution contains 13.0-17.0 g of ambroxol hydrochloride, 100-300 mg of sodium bisulfite and 10-30 mg of diethylenetriaminepentaacetic acid; Further preferably, each 2000 ml of ambroxol hydrochloride solution contains 13.5-16.5 g of ambroxol hydrochloride, 150-250 mg of sodium bisulfite and 15-25 mg of diethylenetriaminepentaacetic acid; Most preferably, each 2000 ml of ambroxol hydrochloride solution contains 14.5-15.5 g of ambroxol hydrochloride, 170-230 mg of sodium bisulfite and 18-22 mg of diethylenetriaminepentaacetic acid.

[0023] The ambroxol hydrochloride solution provided by the invention has stable properties, does not require the addition of additional preservative components, has reliable quality and good safety.

[0024] In the present invention, the ambroxol hydrochloride solution can be further added with other pharmaceutically acceptable functional excipients as required.

[0025] Preferably, the functional auxiliary material comprises at least one of a pH regulator and an osmotic pressure regulator.

[0026] Preferably, the pH adjuster is at least one of anhydrous disodium hydrogen phosphate and citric acid.

[0027] The pH regulator is mainly used to adjust the ambroxol hydrochloride solution to a weak acidity (the pH range is preferably 4.5 to 5.5), which is more conducive to the coordination effect of diethylenetriaminepentaacetic acid and enhances its role as a stabilizer.

[0028] Preferably, the osmotic pressure regulator is sodium chloride.

[0029] In a more preferred and more specific embodiment provided by the present invention, the ambroxol hydrochloride solution contains 12.5-17.5g of ambroxol hydrochloride, 1.5-4.5g of anhydrous disodium hydrogen phosphate, 1.0-3.0g of citric acid, 12.0-16.0g of sodium chloride, 50-350mg of sodium bisulfite and 5-35mg of diethylenetriaminepentaacetic acid, based on a total amount of 2000ml.

[0030] Further preferably, the ambroxol hydrochloride solution comprises 13.0-17.0 g of ambroxol hydrochloride, 2.0-4.0 g of anhydrous disodium hydrogen phosphate, 1.5-2.5 g of citric acid, 12.5-15.5 g of sodium chloride, 100-300 mg of sodium bisulfite, and 10-30 mg of diethylenetriaminepentaacetic acid in a total amount of 2000 ml.

[0031] Further preferably, the ambroxol hydrochloride solution comprises 13.5-16.5 g of ambroxol hydrochloride, 2.5-3.5 g of anhydrous disodium hydrogen phosphate, 1.6-2.4 g of citric acid, 13.0-15.0 g of sodium chloride, 150-250 mg of sodium bisulfite, and 15-25 mg of diethylenetriaminepentaacetic acid in a total amount of 2000 ml.

[0032] Further preferably, the ambroxol hydrochloride solution comprises 14.5-15.5 g of ambroxol hydrochloride, 2.7-3.3 g of anhydrous disodium hydrogen phosphate, 1.8-2.2 g of citric acid, 14.0-14.9 g of sodium chloride, 170-230 mg of sodium bisulfite, and 18-22 mg of diethylenetriaminepentaacetic acid in a total amount of 2000 ml.

[0033] In a second aspect, the present invention provides a method for preparing the above-mentioned ambroxol hydrochloride solution, which comprises the step of dissolving each raw material component in water for injection.

[0034] Preferably, the temperature of the water for injection is 40-70°C.

[0035] Preferably, after each raw material is dissolved in water for injection, a filtering and / or sterilization step is further included.

[0036] Preferably, the present invention uses a polyethersulfone filter membrane for filtration, and the pore size of the filter membrane is 0.22±0.02 μm.

[0037] Preferably, the present invention adopts moist heat sterilization, and the conditions of moist heat sterilization are: 121±5°C, 15±3min, F0≥12.

[0038] In one optional specific embodiment of the present invention, the preparation method comprises the following steps: (1) Add about 80% of the total amount of water for injection into the liquid preparation container, dissolve citric acid, disodium hydrogen phosphate, sodium bisulfite, diethylenetriaminepentaacetic acid, ambroxol hydrochloride and sodium chloride in appropriate amounts of water for injection in sequence, and add the mixture to the liquid preparation container, stir evenly, and obtain mixed solution I.

[0039] (2) Adding water for injection to the mixed solution I obtained in step (1), adjusting the volume to the total weight of the prepared solution, and stirring evenly to obtain a mixed solution II; (3) The mixed solution II obtained in step (2) is filtered through two sterilization-grade filters connected in series, and then sealed in a 2 ml ampoule for sterilization.

[0040] Furthermore, in step (1), the temperature of the water for injection added to the liquid preparation container, which accounts for about 80% of the total amount of the preparation, is preferably controlled at 40-70°C.

[0041] Furthermore, the filter membrane material of the filter in step (3) is preferably polyethersulfone; and the pore size of the filter membrane micropores is preferably 0.22 μm.

[0042] Furthermore, in step (3), a moist heat sterilization process of 121°C for 15 min (F0≥12) is adopted.

[0043] The preparation method provided by the present invention is simple and easy to operate, has good repeatability, does not require a light-proof environment, has low production cost, and is easy to promote industrialization. The prepared product does not need to add preservatives, has high safety, stable quality, and has no obvious side effects.

[0044] In a third aspect, the present invention further provides the use of the ambroxol hydrochloride solution or the ambroxol hydrochloride solution prepared by the preparation method in the preparation of an inhalation preparation.

[0045] Preferably, the inhalation preparation is used to treat respiratory diseases accompanied by abnormal sputum secretion and poor sputum discharge function.

[0046] Based on the medicinal activity of ambroxol hydrochloride, the ambroxol hydrochloride solution provided by the present invention is prepared into an inhalation preparation, and the active pharmaceutical ingredient is sprayed into the patient's oral cavity by atomization, which can effectively treat respiratory diseases accompanied by abnormal sputum secretion and poor expectoration function (such as common acute and chronic respiratory diseases, postoperative pulmonary complications, infant respiratory distress syndrome of premature infants and newborns, etc.), and exert a good expectorant effect.

[0047] At the same time, since the ambroxol hydrochloride solution of the present invention has good light stability and antioxidant properties, when it is used to prepare an inhalation preparation, the quality is more reliable, and no preservative ingredients need to be added, so that the obtained inhalation preparation product has better safety, can be well tolerated by patients, and is more suitable for clinical use needs.

[0048] Beneficial effects: The present invention provides an ambroxol hydrochloride solution and a preparation method and application thereof. The ambroxol hydrochloride solution comprises: ambroxol hydrochloride, a stabilizer and water; the stabilizer comprises 7.7%-11.1% by mass of diethylenetriamine pentaacetic acid; the total amount of the stabilizer in the ambroxol hydrochloride solution is 27.5-192.5 mg / L. The present invention uses diethylenetriamine pentaacetic acid as a stabilizer component of the ambroxol hydrochloride solution in a relatively small amount. The diethylenetriamine pentaacetic acid has a strong coordination ability and can interact with other molecules in the solution, thereby greatly improving the stability of the ambroxol hydrochloride solution. In addition, the preparation method provided by the present invention is simple and easy to operate, has good reproducibility, does not require a light-proof environment, has low production cost, and is easy to promote industrialization. The ambroxol hydrochloride solution provided by the present invention itself or when it is applied to an inhalation preparation, does not need to add a preservative component, has reliable quality, good safety, and is more suitable for clinical use needs. DETAILED DESCRIPTION

[0049] The invention provides an ambroxol hydrochloride solution for inhalation, a preparation method thereof and an application thereof. The ambroxol hydrochloride solution for inhalation has good light and oxygen stability, and during the treatment process, the patient has good tolerance and high safety. The ambroxol hydrochloride solution for inhalation provided by the invention does not contain any preservative, has stable quality and has no side effects. The preparation process provided by the invention is simple to operate, has good repeatability and is suitable for industrial production.

[0050] The present invention is specifically implemented through the following optional technical solutions.

[0051] In one optional embodiment, the present invention provides an ambroxol hydrochloride solution for inhalation, comprising the following ingredients in every 2000 ml of water for injection: 12.5-17.5 g of ambroxol hydrochloride, 1.5-4.5 g of anhydrous disodium hydrogen phosphate, 1.0-3.0 g of citric acid, 12.0-16.0 g of sodium chloride, 50-350 mg of sodium bisulfite, and 5-35 mg of diethylenetriaminepentaacetic acid.

[0052] In one optional embodiment, the present invention provides a method for preparing an ambroxol solution preparation for inhalation, the preparation method comprising the following steps in sequence: (1) Add about 80% of the total amount of water for injection into the liquid preparation container, dissolve citric acid, disodium hydrogen phosphate, sodium bisulfite, diethylenetriaminepentaacetic acid, ambroxol hydrochloride and sodium chloride in appropriate amounts of water for injection in sequence, and add the mixture to the liquid preparation container, stir evenly, and obtain mixed solution I.

[0053] (2) Adding water for injection to the mixed solution I obtained in step (1), adjusting the volume to the total weight of the prepared solution, and stirring evenly to obtain a mixed solution II; (3) The mixed solution II obtained in step (2) is filtered through two sterilization-grade filters connected in series, and then sealed in a 2 ml ampoule for sterilization.

[0054] In one optional embodiment, the present invention provides the use of an ambroxol solution preparation for inhalation in the preparation of a preparation for treating respiratory diseases accompanied by abnormal sputum secretion and poor sputum discharge function.

[0055] Compared with the prior art, the light and oxygen stability of the ambroxol hydrochloride solution for inhalation provided by the present invention is significantly enhanced, and the stability of the drug during storage can be greatly improved. In the test experiment, after the ambroxol hydrochloride solution of the present invention is diluted with 0.9% sodium chloride solution, it can be placed for 2 days under room temperature conditions without light protection and contact with air, and the total impurities of the related substances are less than 0.2%, and the maximum single impurity is less than 0.1%. After being placed for 10 days under the light conditions of the influencing factors, the total impurities of the related substances are still less than 1.0%, and the maximum single impurity is less than 0.2%. In addition, compared with the prior art, the atomization characteristic indicators of the ambroxol hydrochloride solution for inhalation provided by the present invention are also significantly improved in delivery rate, total delivery amount and fine particle dosage. The ambroxol hydrochloride solution for inhalation provided by the present invention does not contain preservatives and has a low risk of causing adverse reactions. Therefore, the ambroxol hydrochloride solution for inhalation provided by the present invention has the advantages of reliable quality and good safety, and is more suitable for clinical use needs. The preparation process of the ambroxol hydrochloride solution for inhalation provided by the present invention is simple to operate, has good reproducibility, good product stability, and is easy to large-scale industrial production.

[0056] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0057] The endpoints and any values ​​of the ranges disclosed in this specification are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0058] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "specific implementations", or "some specific implementations" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the embodiment of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0059] In the examples provided in this specification, if no specific techniques or conditions are specified, the techniques or conditions described in the literature in this field or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels.

[0060] In the present invention, the instruments involved include waters liquid chromatograph, electronic balance, NGI, stability sample box, etc. The raw materials and auxiliary materials involved are all registered on the raw materials and auxiliary materials registration platform of the Center for Evaluation of the State Food and Drug Administration (CDE).

[0061] Example 1

[0062] The present embodiment provides a kind of ambroxol hydrochloride solution, and the formula is as follows: Based on a total volume of 2000 ml, the ambroxol hydrochloride solution contains 12.5 g of ambroxol hydrochloride, 1.5 g of anhydrous disodium hydrogen phosphate, 1.0 g of citric acid, 12.0 g of sodium chloride, 50 mg of sodium bisulfite, 5 mg of diethylenetriaminepentaacetic acid, and the remainder is water for injection.

[0063] The present embodiment also provides a method for preparing the above-mentioned ambroxol hydrochloride solution, and the specific steps are as follows: Weigh 12.5g of ambroxol hydrochloride, 1.5g of anhydrous disodium hydrogen phosphate, 1.0g of citric acid, 12.0g of sodium chloride, 50mg of sodium bisulfite, and 5mg of diethylenetriamine pentaacetic acid for later use. Add 1600ml of water for injection into the liquid preparation container, control the water temperature at 40℃, dissolve citric acid, disodium hydrogen phosphate, sodium bisulfite, diethylenetriamine pentaacetic acid, ambroxol hydrochloride, and sodium chloride with an appropriate amount of water for injection in turn, and add them to the liquid preparation container and stir evenly. Add water for injection to make up to 2000ml. Filter the obtained drug solution through two sterilization grade filters in series (the filter membrane material is polyethersulfone, and the filter membrane micropore is 0.22μm), then fill the drug solution into a 2ml transparent ampoule, and sterilize it with wet heat at 121℃ for 15min (F0≥12).

[0064] The present embodiment carries out the following detection to above-mentioned ambroxol hydrochloride solution: The sample was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1 to obtain a compatible solution for atomization. It was placed at room temperature, not protected from light, and fully exposed to air for 2 days to test the relevant substances, pH, delivery rate, total delivery amount, and fine particle dose. The test results are shown in Table 1.

[0065] The samples were placed under the light conditions of the influencing factors (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) were placed for 10 days, and the properties, related substances, pH, bacterial endotoxins and sterility were tested. The test results are shown in Table 2.

[0066] Table 1

[0067] Table 2

[0068] From the data results in Table 1-2, it can be seen that the ambroxol hydrochloride solution sample provided in this embodiment was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1, and then placed at room temperature, not protected from light, and fully in contact with air for 2 days. The related substances, pH, delivery rate, total delivery amount, and fine particle dosage did not change significantly. The related substances and pH all met the requirements of the pharmacopoeia standards, among which the contents of related substance impurity I, other single impurities, and total impurities were far lower than the standard requirements. In addition, the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2) After being placed for 10 days, the properties, related substances, pH, bacterial endotoxins and sterility still meet the requirements of pharmacopoeia standards.

[0069] Example 2

[0070] The present embodiment provides a kind of ambroxol hydrochloride solution, and the formula is as follows: Based on a total volume of 2000 ml, the ambroxol hydrochloride solution contains 17.5 g of ambroxol hydrochloride, 4.5 g of anhydrous disodium hydrogen phosphate, 3.0 g of citric acid, 16.0 g of sodium chloride, 350 mg of sodium bisulfite, 35 mg of diethylenetriaminepentaacetic acid, and the remainder is water for injection.

[0071] The present embodiment also provides a method for preparing the above-mentioned ambroxol hydrochloride solution, and the specific steps are as follows: Weigh 17.5g of ambroxol hydrochloride, 4.5g of anhydrous disodium hydrogen phosphate, 3.0g of citric acid, 16.0g of sodium chloride, 350mg of sodium bisulfite, and 35mg of diethylenetriamine pentaacetic acid for later use. Add 1600ml of water for injection into the liquid preparation container, control the water temperature at 70℃, dissolve citric acid, disodium hydrogen phosphate, sodium bisulfite, diethylenetriamine pentaacetic acid, ambroxol hydrochloride, and sodium chloride with an appropriate amount of water for injection in turn, and add them to the liquid preparation container and stir evenly. Add water for injection to make up to 2000ml. Filter the obtained drug solution through two sterilization grade filters in series (the filter membrane material is polyethersulfone, and the filter membrane micropore is 0.22μm), then fill the drug solution into a 2ml transparent ampoule, and sterilize it with wet heat at 121℃ for 15min (F0≥12).

[0072] The present embodiment carries out the following detection to above-mentioned ambroxol hydrochloride solution: The sample was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1 to obtain a compatible solution for atomization. The solution was placed at room temperature, not protected from light, and in full contact with air for 2 days to test the relevant substances, pH, delivery rate, total delivery amount, and fine particle dose. The test results are shown in Table 3.

[0073] The samples were placed under the light conditions of the influencing factors (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) were placed for 10 days, and the properties, related substances, pH, bacterial endotoxins and sterility were tested. The test results are shown in Table 4.

[0074] Table 3

[0075] Table 4

[0076] From the data results in Table 3-4, it can be seen that the ambroxol hydrochloride solution sample provided in this embodiment was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1, and then placed at room temperature, not protected from light, and fully in contact with air for 2 days. The related substances, pH, delivery rate, total delivery amount, and fine particle dosage did not change significantly. The related substances and pH all met the requirements of the pharmacopoeia standards, among which the contents of related substance impurity I, other single impurities, and total impurities were far lower than the standard requirements. In addition, the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, the properties, related substances, pH, bacterial endotoxins and sterility still meet the requirements of pharmacopoeia standards.

[0077] Example 3

[0078] The present embodiment provides a kind of ambroxol hydrochloride solution, and the formula is as follows: Based on a total volume of 2000 ml, the ambroxol hydrochloride solution contains 15.0 g of ambroxol hydrochloride, 3.0 g of anhydrous disodium hydrogen phosphate, 2.0 g of citric acid, 14.0 g of sodium chloride, 200 mg of sodium bisulfite, 20 mg of diethylenetriaminepentaacetic acid, and the remainder is water for injection.

[0079] The present embodiment also provides a method for preparing the above-mentioned ambroxol hydrochloride solution, and the specific steps are as follows: Weigh 15.0g of ambroxol hydrochloride, 3.0g of anhydrous disodium hydrogen phosphate, 2.0g of citric acid, 14.0g of sodium chloride, 200mg of sodium bisulfite, and 20mg of diethylenetriaminepentaacetic acid for use. Add 1600ml of water for injection into the liquid preparation container, control the water temperature at 55℃, dissolve citric acid, disodium hydrogen phosphate, sodium bisulfite, diethylenetriaminepentaacetic acid, ambroxol hydrochloride, and sodium chloride with an appropriate amount of water for injection in turn, and add them to the liquid preparation container and stir evenly. Add water for injection to make up to 2000ml. Filter the obtained drug solution through two sterilization-grade filters in series (the filter membrane material is polyethersulfone, and the filter membrane micropore is 0.22μm), then fill the drug solution into a 2ml transparent ampoule, and sterilize it with wet heat at 121℃ for 15min (F0≥12).

[0080] The present embodiment carries out the following detection to above-mentioned ambroxol hydrochloride solution: The sample was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1 to obtain a compatible solution for atomization. The solution was placed at room temperature, not protected from light, and in full contact with air for 2 days, and the relevant substances, pH, delivery rate, total delivery amount, and fine particle dose were tested. The test results are shown in Table 5.

[0081] The samples were placed under the light conditions of the influencing factors (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) were placed for 10 days and tested for properties, related substances, pH, bacterial endotoxins and sterility. The test results are shown in Table 6.

[0082] Table 5

[0083] Table 6

[0084] From the data results in Table 5-6, it can be seen that the ambroxol hydrochloride solution sample provided in this embodiment was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1, and then placed at room temperature, not protected from light, and fully in contact with air for 2 days. The related substances, pH, delivery rate, total delivery amount, and fine particle dosage did not change significantly. The related substances and pH all met the requirements of the pharmacopoeia standards, among which the contents of related substance impurity I, other single impurities, and total impurities were far lower than the standard requirements. In addition, the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, the properties, related substances, pH, bacterial endotoxins and sterility still meet the requirements of pharmacopoeia standards.

[0085] Example 4

[0086] This embodiment provides an ambroxol hydrochloride solution, and its formula is compared with that of Example 3, except that sodium bisulfite is replaced by an equal amount of sodium sulfite.

[0087] The preparation method of the present embodiment ambroxol hydrochloride solution is reference example 3.

[0088] The present embodiment detects the above-mentioned ambroxol hydrochloride solution, and the detection method is the same as that in Example 3.

[0089] The test results are shown in Tables 7 and 8.

[0090] Table 7

[0091] Table 8

[0092] From the data results in Tables 7-8, it can be seen that after the ambroxol hydrochloride solution sample provided in this embodiment was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1, it was placed at room temperature, not protected from light, and fully in contact with air for 2 days. Its related substances, pH, delivery rate, total delivery amount and fine particle dosage have undergone significant changes. Although the related substances and pH still meet the requirements of the pharmacopoeia standards, the contents of related substance impurity I, other single impurities, and total impurities have shown a significant growth trend. In addition, the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, the properties, related substances, pH, bacterial endotoxins and sterility still meet the requirements of pharmacopoeia standards.

[0093] Example 5

[0094] This embodiment provides an ambroxol hydrochloride solution, and its formula is compared with that of Example 3, except that sodium bisulfite is replaced by an equal amount of sodium pyrosulfite.

[0095] The preparation method of the present embodiment ambroxol hydrochloride solution is reference example 3.

[0096] The present embodiment detects the above-mentioned ambroxol hydrochloride solution, and the detection method is the same as that in Example 3.

[0097] The test results are shown in Tables 9 and 10.

[0098] Table 9

[0099] Table 10

[0100] From the data results in Tables 9-10, it can be seen that after the ambroxol hydrochloride solution sample provided in this embodiment was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1, it was placed at room temperature, not protected from light, and fully in contact with air for 2 days. Its related substances, pH, delivery rate, total delivery amount and fine particle dosage changed significantly. Although the related substances and pH still meet the requirements of the pharmacopoeia standards, the contents of related substance impurity I, other single impurities, and total impurities have a more significant growth trend, and other single impurities are close to the limit requirements. In addition, the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, the properties, related substances, pH, bacterial endotoxins and sterility still meet the requirements of the pharmacopoeia standards, but compared with Examples 1-4, the data results of properties, related substances and pH are much worse.

[0101] Example 6

[0102] This embodiment provides an ambroxol hydrochloride solution, and its formula is compared with that of Example 3, except that anhydrous disodium hydrogen phosphate, citric acid, and sodium chloride are replaced by equal amounts of sodium acetate, glacial acetic acid, and calcium chloride.

[0103] The preparation method of the present embodiment ambroxol hydrochloride solution is reference example 3.

[0104] The present embodiment detects the above-mentioned ambroxol hydrochloride solution, and the detection method is the same as that in Example 3.

[0105] The test results are shown in Tables 11 and 12.

[0106] Table 11

[0107] Table 12

[0108] From the data results in Tables 11-12, it can be seen that the ambroxol hydrochloride solution sample provided in this embodiment was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1, and then placed at room temperature, not protected from light, and fully in contact with air for 2 days. The related substances, pH, delivery rate, total delivery amount, and fine particle dosage did not change significantly. The related substances and pH all met the requirements of the pharmacopoeia standards, among which the contents of the related substance impurity I, other single impurities, and total impurities were lower than the standard requirements. Compared with Example 1-2, the data results were not much different. In addition, the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, the properties, related substances, pH, bacterial endotoxins and sterility still meet the requirements of pharmacopoeia standards.

[0109] Comparative Example 1

[0110] An ambroxol hydrochloride solution, the formula of which is compared with that of embodiment 3, except that sodium bisulfite and diethylenetriaminepentaacetic acid are not added in the formula.

[0111] Above-mentioned Ambroxol HCl solution is detected, and detection method is with embodiment 3.

[0112] The test results are shown in Tables 13 and 14.

[0113] Table 13

[0114] Table 14

[0115] From the data results in Tables 13-14, it can be seen that after the sample prepared by the above prescription and process was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1, it was placed at room temperature, not protected from light, and fully exposed to air for 2 days. Its related substances, pH, delivery rate, total delivery amount and fine particle dosage all changed significantly. Although the related substances and pH still meet the requirements of the pharmacopoeia standards, its stability and atomization effect are relatively poor compared with the samples of Examples 1-6. In addition, the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, its properties, related substances and pH changed significantly, and the contents of related substance impurity I, other single impurities and total impurities were much higher than the standard requirements.

[0116] Comparative Example 2

[0117] An ambroxol hydrochloride solution, whose formula is compared with that of Example 3, except that the diethylenetriaminepentaacetic acid in the formula is replaced by an equal amount of disodium ethylenediaminetetraacetate.

[0118] Above-mentioned Ambroxol HCl solution is detected, and detection method is with embodiment 3.

[0119] The test results are shown in Tables 15 and 16.

[0120] Table 15

[0121] Table 16

[0122] From the data results in Tables 15-16, it can be seen that after the sample prepared by the above prescription and process was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1, it was placed at room temperature, not protected from light, and fully exposed to air for 2 days. Its related substances, pH, delivery rate, total delivery amount and fine particle dosage all changed significantly. Although the related substances and pH still meet the requirements of the pharmacopoeia standards, its stability and atomization effect are relatively poor compared with the samples of Examples 1-6. In addition, the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, its properties, related substances and pH value changed significantly, and the contents of related substance impurity I, other single impurities and total impurities were higher than the standard requirements.

[0123] Comparative Example 3

[0124] An ambroxol hydrochloride solution has a formula that is different from that of Example 3, except that sodium bisulfite and diethylenetriaminepentaacetic acid are not added in the formula, and the drug solution is sealed in a 2 ml brown ampoule after filtration.

[0125] The above-mentioned ambroxol hydrochloride solution was tested as follows: The samples were placed under the light conditions of the influencing factors (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) was placed for 10 days, and the properties, related substances and pH were tested. The test results are shown in Table 17.

[0126] Table 17

[0127] From the data results in Table 17, it can be seen that the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, its properties, related substances and pH value have changed significantly, and the contents of other individual impurities and total impurities of related substances have exceeded the standard requirements.

[0128] Comparative Example 4

[0129] A kind of ambroxol hydrochloride solution, its preparation method is: Weigh 15g of ambroxol hydrochloride, add it to 5000ml of water for injection, stir to dissolve, add 0.5g of sodium sulfite, 0.5g of benzoic acid, and 0.75g of tylosin, dissolve completely, add appropriate amount of phosphate to adjust the pH value, and then add appropriate amount of water for injection to make the solution system to 10000ml, then filter with a microporous filter membrane, and dispense into medical control bottles, 10mL per bottle, the concentration of ambroxol hydrochloride in each bottle is 1.5mg / ml, and the pH value is 4.7.

[0130] The above-mentioned ambroxol hydrochloride solution was tested as follows: The samples were placed under the light conditions of the influencing factors (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) was placed for 10 days, and the properties, related substances and pH were tested. The test results are shown in Table 18.

[0131] Table 18

[0132] From the data results in Table 18, it can be seen that the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2) After being placed for 10 days, its properties, related substances and pH changed significantly, and the contents of related substance impurity I, other single impurities and total impurities were much higher than the standard requirements.

[0133] Comparative Example 5

[0134] A kind of ambroxol hydrochloride solution, its preparation method is: Add 700ml of water for injection into the liquid preparation tank, control the temperature at about 40℃, add ambroxol hydrochloride, citric acid, disodium hydrogen phosphate, sodium chloride, and disodium edetate, stir until all are dissolved. Add water for injection to 1000ml, stir evenly, filter through a 0.22μm filter membrane, and seal in a 2ml low-density polyethylene bottle to obtain the product.

[0135] The above-mentioned ambroxol hydrochloride solution was tested as follows: The samples were placed under the light conditions of the influencing factors (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) was placed for 10 days, and the properties, related substances and pH were tested. The test results are shown in Table 19.

[0136] Table 19

[0137] From the data results in Table 19, it can be seen that the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, its properties, related substances and pH value changed significantly, and the contents of other single impurities and total impurities were much higher than the standard requirements.

[0138] Comparative Example 6

[0139] A kind of ambroxol hydrochloride solution, its preparation method is: Weigh 12.0g of ambroxol hydrochloride, 1.2g of disodium hydrogen phosphate, 1.0g of citric acid, 10.2g of sodium chloride, 0.5g of stabilizer (chitosan and sodium pyrosulfite in a weight ratio of 1:7) and 0.8g of surfactant (tetrabutylphenol and lecithin in a weight ratio of 6:5) for later use. Add 1200ml of water for injection into the liquid preparation container, add disodium hydrogen phosphate, citric acid, ambroxol hydrochloride and surfactant in turn, stir to dissolve, and after complete dissolution, add sodium chloride and stabilizer, and stir until completely dissolved. Add water for injection to make up to 2000ml. After filtering the drug solution through a sterilization grade filter membrane (the filter membrane material is polyvinylidene fluoride membrane, and the filter membrane micropore is 0.22μm), it is sealed in a 2ml transparent ampoule under nitrogen protection, and sterilized by wet heat at 121℃ for 12min.

[0140] The above-mentioned ambroxol hydrochloride solution was tested as follows: The samples were placed under the light conditions of the influencing factors (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) was placed for 10 days, and the properties, related substances and pH were tested. The test results are shown in Table 20.

[0141] Table 20

[0142] From the data results in Table 20, it can be seen that the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, its properties, related substances and pH value changed significantly, and the contents of other single impurities and total impurities were much higher than the standard requirements.

[0143] Comparative Example 7

[0144] A kind of ambroxol hydrochloride solution, its preparation method is: Weigh 7.5g of ambroxol hydrochloride, 0.1g of cysteine ​​hydrochloride, 0.125g of glycerol, 0.6g of citric acid, and 1.2g of disodium hydrogen phosphate for use. Add 900ml of water for injection into the liquid preparation tank, heat to 70℃, add cysteine ​​hydrochloride and citric acid, then add ambroxol hydrochloride and stir for 15min to dissolve, pH value is about 3.5, add 0.01% activated carbon and stir for 8min and filter. Slowly cool to 10℃, add disodium hydrogen phosphate solution dropwise, adjust pH to 4.8, stir for 20min, and filter through 0.45μm filter membrane to remove impurities. After adding glycerol, add water for injection to 1000ml, stir for 10min, and filter through 0.22μm for sterilization and impurity removal, and seal in 2ml transparent ampoule under nitrogen protection.

[0145] The above-mentioned ambroxol hydrochloride solution was tested as follows: The samples were placed under the light conditions of the influencing factors (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) were placed for 10 days, and the properties, related substances and pH were tested. The test results are shown in Table 21.

[0146] Table 21

[0147] From the data results in Table 21, it can be seen that the trial samples were placed under the influencing factors of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90μw / cm 2 ) After being placed for 10 days, its properties, related substances and pH value changed significantly, and the contents of other single impurities and total impurities were much higher than the standard requirements.

[0148] Experimental Example 1

[0149] In this experimental example, the ambroxol hydrochloride solution provided in Example 3 was used as a sample, and its safety as a hydrochloric acid solution for inhalation was evaluated through local irritation, acute toxicity test and long-term toxicity test.

[0150] The test method is as follows: The ambroxol hydrochloride solution for inhalation prepared in Example 3 was sprayed into the guinea pig oral cavity for local irritation test, acute toxicity test and long-term toxicity test. Each test was respectively set up with a blank control group, a vehicle control group and an experimental group, and 5 guinea pigs were used in each group. The experimental group was sprayed into the guinea pig oral cavity with 2.5 ml of the ambroxol hydrochloride solution for inhalation prepared in Example 3 by a spray device, 2 times a day, and the vehicle control group was sprayed into an equal volume of solvent (water for injection) twice a day, and the blank control group was not sprayed with any substance.

[0151] In the local irritation test and acute toxicity test, the drug was administered for 1 day, and the tissue structure of the mucous membranes and internal organs of the nasal cavity, pharynx and larynx was detected after 14 days of culture. In the long-term toxicity experiment, the mucous membranes and internal organs of the nasal cavity, pharynx and larynx were detected after 30 days of administration, as well as the serum physiological and biochemical indicators. The mucous membranes and internal organs of the nasal cavity, pharynx and larynx were fixed with 10% neutral formalin solution, and routine pathological preparation was performed, followed by light microscopy observation.

[0152] The test results show that the histopathological results of all experimental groups and control groups in the local toxicity test, acute toxicity test and long-term toxicity test are similar, and no obvious toxic pathological damage occurs. In the long-term toxicity test, the serum physiological and biochemical indices of the experimental group are all within the normal physiological range, and there is no significant difference with all control groups. The above experimental results show that the inhalation ambroxol hydrochloride solution provided in Example 3 has no side effects on the nasal cavity, pharyngeal mucosa and internal organs of guinea pigs, and the inhalation ambroxol hydrochloride solution of the present invention has good safety.

[0153] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An ambroxol hydrochloride solution comprising: ambroxol hydrochloride, a stabilizer and water, characterized in that: The stabilizer contains 7%-12% of diethylenetriaminepentaacetic acid by mass; the total amount of the stabilizer in the ambroxol hydrochloride solution is 27.5-192.5 mg / L.

2. according to the described ambroxol hydrochloride solution of claim 1, it is characterized in that, The stabilizer also contains sodium bisulfite in an amount not exceeding 93% by mass.

3. according to claim 1 or 2 described ambroxol hydrochloride solution, it is characterized in that, The stabilizer is a mixture of sodium bisulfite and diethylenetriaminepentaacetic acid, and the mass ratio of sodium bisulfite to diethylenetriaminepentaacetic acid is 8-12:1, preferably 10:

1.

4. According to any one of claims 1 to 3, the ambroxol hydrochloride solution is characterized in that: The mass ratio of ambroxol hydrochloride to the stabilizer is (12500-17500): (55-385); preferably (13000-17000): (110-330).

5. The ambroxol hydrochloride solution according to any one of claims 1 to 4, characterized in that: Based on a total amount of 2000 ml, the ambroxol hydrochloride solution comprises 12.5-17.5 g of ambroxol hydrochloride, 50-350 mg of sodium bisulfite and 5-35 mg of diethylenetriaminepentaacetic acid; Preferably, each 2000 ml of ambroxol hydrochloride solution contains 13.0-17.0 g of ambroxol hydrochloride, 100-300 mg of sodium bisulfite and 10-30 mg of diethylenetriaminepentaacetic acid.

6. The ambroxol hydrochloride solution according to any one of claims 1 to 5, characterized in that: It also contains at least one functional auxiliary material selected from the group consisting of a pH regulator and an osmotic pressure regulator; Preferably, the pH regulator is at least one of anhydrous disodium hydrogen phosphate and citric acid; and / or the osmotic pressure regulator is sodium chloride.

7. The ambroxol hydrochloride solution according to any one of claims 1 to 6, characterized in that: Based on a total volume of 2000 ml, the ambroxol hydrochloride solution comprises 12.5-17.5 g of ambroxol hydrochloride, 1.5-4.5 g of anhydrous disodium hydrogen phosphate, 1.0-3.0 g of citric acid, 12.0-16.0 g of sodium chloride, 50-350 mg of sodium bisulfite and 5-35 mg of diethylenetriaminepentaacetic acid.

8. The method for preparing the ambroxol hydrochloride solution according to any one of claims 1 to 7, characterized in that: The method comprises the steps of dissolving various raw material components in water for injection.

9. The preparation method according to claim 8, characterized in that: The temperature of the injection water is 40-70°C; Preferably, after each raw material is dissolved in water for injection, the process further comprises: filtering using a polyethersulfone filter membrane with a pore size of 0.22±0.02 μm; and / or sterilizing using a wet heat method, wherein the conditions for wet heat sterilization are: 121±5°C, 15±3min, F0≥12.

10. Use of the ambroxol hydrochloride solution according to any one of claims 1 to 7 or the ambroxol hydrochloride solution prepared by the preparation method according to claim 8 or 9 in preparing an inhalation preparation; Preferably, the inhalation preparation is used to treat respiratory diseases accompanied by abnormal sputum secretion and poor sputum discharge function; More preferably, the inhalation preparation is used to treat acute or chronic respiratory diseases, postoperative pulmonary complications, or infant respiratory distress syndrome in premature infants and newborns.

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