Ambroxol Hydrochloride Solution and Its Preparation Method and Application

Abstract

The present invention relates to the field of pharmaceutical preparations, and particularly to an ambroxol hydrochloride solution, a preparation method thereof and an application thereof. In the present invention, diethylenetriaminepentaacetic acid is used as a stabilizer component of the ambroxol hydrochloride solution in a relatively small amount. Diethylenetriaminepentaacetic acid has strong coordination ability and can interact with other molecules in the solution, thereby greatly improving the stability of the ambroxol hydrochloride solution. The preparation method provided by the present invention is simple and easy to operate, does not require a light-proof environment, has low production cost, and is easy to industrialize. When the ambroxol hydrochloride solution provided by the present invention is used alone or applied to an inhalation preparation, no preservative component needs to be added, the quality is reliable, the safety is good, and it is more suitable for clinical use requirements.

Description

Technical Field

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

[0002] Respiratory diseases generally manifest as cough, sputum, asthma, 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 fibrosis (CF). Children and the elderly often have difficulty expectorating sputum. In mild cases, it interferes with people's daily lives, and in severe cases, it even endangers the lives of patients. At the same time, in the case of thoracic and abdominal surgeries, patients often produce a large amount of sputum. The presence of sputum can block the respiratory tract, easily cause coughing, wheezing, and even lead to dyspnea. The blockage of the respiratory tract by sputum results in uneven distribution of inhaled gas in the lungs, imbalance of ventilation-perfusion ratio, aggravation of hypoxia, and sputum is also a good culture medium for bacteria. The poor discharge of sputum can promote the reproduction and growth of bacteria, causing the development and aggravation of inflammation. The mucus cilia of the sputum transport system are thus weakened or damaged. Therefore, the application of expectorant drugs to promote the rapid external discharge of airway secretions is an important adjuvant measure and necessary treatment means for treating airway inflammation.

[0003] Ambroxol Hydrochloride, also known as Bromhexine Hydrochloride, has the 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] 。

[0005] Ambroxol Hydrochloride was discovered by Boehringer Ingelheim GmbH in Germany in 1965 during the study of the metabolites of bromhexine, and was developed and launched in 1979. It has been launched in nearly twenty countries such as Italy, Switzerland, Argentina, and Japan. The original research marketed dosage forms are injection, tablets, syrup, oral solution, and sustained-release capsules. In China, it was approved for import in 1991, with the trade name "Mucosolvan". The specification of ambroxol hydrochloride injection is 2ml:15mg. Ambroxol hydrochloride injection is applicable to the expectorant treatment of acute and chronic respiratory diseases accompanied by abnormal sputum secretion and poor expectoration function, such as acute exacerbation of chronic bronchitis, asthmatic bronchitis, and bronchial asthma, preventive treatment of postoperative pulmonary complications, and treatment of infant respiratory distress syndrome (IRDS) in premature infants and neonates.

[0006] Ambroxol hydrochloride is a new generation of respiratory mucus regulator. By decomposing the polysaccharide part in mucin, which is a viscoelastic component of airway mucus, and increasing the secretion of serous glands in the respiratory mucosa while reducing the secretion of mucus glands, it can lower the viscosity of sputum, thereby improving expectoration. It also has the effect of promoting the production of pulmonary surfactant, airway secretion, and ciliary movement. The precursor of this type of drug, bromhexine, was extracted from vasicine. Vasicine comes from an Asian plant and has been proven to be very effective in expectoration. It can promote the elimination of thick secretions in the respiratory tract and reduce mucus retention, thus significantly promoting expectoration and improving the respiratory condition. When this product is used for treatment, the secretion of mucus in patients can return to normal. Cough and sputum volume usually decrease significantly, and the surfactant on the respiratory mucosa can thus play its normal protective function. It is applicable to 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.

[0007] The inhalation solution is sprayed into the patient's mouth through a suitable medical compressed atomizer, which is 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 the drug effect. Inhalation administration is a very important non-oral and non-injection administration method, with the following advantages: (1) The inhalant can directly enter the bloodstream from the lungs, with a rapid onset of action; (2) Local administration can increase the accumulation of the drug in the target organ, increasing the therapeutic effect while reducing toxic and side effects; (3) There is no first-pass effect, and the bioavailability is high. Currently, it has a relatively wide application in the global market and is well received by clinicians and patients.

[0008] The inhalation solution of ambroxol hydrochloride was launched in Germany and Italy in 1978 and 1981 respectively. In China, Yunnan Longhai Natural Plant Pharmaceutical Co., Ltd., Yingu Pharmaceutical Co., Ltd., Hebei Kaiwei Pharmaceutical Co., Ltd., and Hanmi Pharm. Co., Ltd. have launched generic products, all of which are single-dose packages with a specification of 2ml:15mg. The original research product has not been imported.

[0009] The chemical structure of ambroxol hydrochloride contains groups such as aryl primary amine, alkyl secondary amine, and bromoarene. Structure determines properties, resulting in its sensitivity to light and oxygen, and it is prone to free radical and redox reactions, leading to the generation of degradation impurities. Therefore, ambroxol hydrochloride is unstable to light and oxygen. The marketed ambroxol hydrochloride inhalation solutions at home and abroad are available in two specifications: multi-dose and single-dose, and are packaged in brown glass bottles or ampoules, with pillow packaging made of polyethylene plus an aluminum foil bag, all of which have a light-shielding effect. CN110870854B discloses a borosilicate glass ampoule containing a certain content of iron(III) oxide and titanium dioxide, which has an obvious light-shielding effect. The original multi-dose product is 100 ml per bottle and is packaged in a brown glass bottle, while the single-dose product is packaged in a brown ampoule, 2 ml per vial. Among the domestic marketed products, except for Hanmi Pharm. Co., Ltd. which uses pillow packaging made of polyethylene plus an aluminum foil bag, other companies all use brown ampoules, 2 ml per vial. Before the production and filling-sealing process of the product, nitrogen filling is required for protection to isolate oxygen and prevent the product from oxidative degradation. During the use of ambroxol hydrochloride inhalation solution, it needs to be diluted with 0.9% sodium chloride solution for atomization use. At this time, the original packaging protection effect will disappear, and it will be exposed to light and oxygen during the preparation and atomization processes, leading to the degradation of the main drug ingredient ambroxol and the risk of adverse reactions. Therefore, the light and oxygen stability of ambroxol hydrochloride inhalation solution is a relatively prominent problem for the existing prescriptions and processes.

[0010] CN103462942B discloses an ambroxol hydrochloride inhalation solution, which contains ambroxol hydrochloride, a surfactant, and appropriate amounts of antioxidants and preservatives. The stability of the preparation during use is improved by adding a preservative to this inhalation solution, but the addition of the preservative will greatly increase the risk of adverse reactions such as bronchospasm.

[0011] CN108159026B discloses a stable ambroxol hydrochloride inhalation solution and its preparation method, which improves the stability at room temperature and under light by adding a metal chelating agent, without involving the investigation and research on oxygen stability.

[0012] CN103492642B discloses an ambroxol hydrochloride inhalation solution. The content of the main drug ingredient in this solution is low (0.15 - 0.3%), and it contains a large amount of antioxidants such as sulfurous acid and sodium sulfite, resulting in problems such as a large atomization dosage, easy generation of side effects, poor patient compliance, and difficult guarantee of drug efficacy. At the same time, it does not involve the investigation and research on light stability.

[0013] CN110755413B discloses an ambroxol hydrochloride solution for inhalation. The solution uses a relatively large amount of stabilizers (chitosan, sodium metabisulfite) and surfactants (butylphenol aldehyde, lecithin), which are likely to irritate the respiratory mucosa and trigger asthma, resulting in poor compliance of patients. At the same time, there is no investigation and research on the light stability.

[0014] Therefore, for the ambroxol hydrochloride solution for inhalation, it is of great significance to develop a formulation and preparation process with good light and oxygen stability, simple operation and good repeatability. Summary of the Invention

[0015] 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 nebulized inhalation, its preparation method and application.

[0016] Specifically, the technical solution provided by the present invention is as follows:

[0017] In the first aspect, the present invention provides an ambroxol hydrochloride solution, comprising: ambroxol hydrochloride, a stabilizer and water. The stabilizer contains diethylenetriaminepentaacetic acid with a mass percentage of 7%-12%; the total amount of the stabilizer used in the ambroxol hydrochloride solution is 27.5-192.5 mg / L.

[0018] Diethylenetriaminepentaacetic acid (DTPA), also known as diethylenetriamine pentaacetic acid, diethylene triamine pentaacetic acid, molecular formula: C 14 H 23 N3O 10 , molecular weight: 393.35, CAS: 67-43-6, appearance is white crystalline powder or colorless crystal, soluble in water, has good chemical stability and antioxidant properties, and has a 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 even more preferably 9.1%.

[0019] The present invention uses diethylenetriaminepentaacetic acid as a stabilizer component in the ambroxol hydrochloride solution with a relatively small amount (the dosage in the ambroxol hydrochloride solution after conversion is about 2.5-17.5 mg / L). Diethylenetriaminepentaacetic acid has a strong coordination ability and can interact with other molecules in the solution, thus greatly improving the stability of the ambroxol hydrochloride solution.

[0020] In addition to diethylenetriaminepentaacetic acid, the composition of the stabilizer described in the present invention preferably further contains sodium bisulfite with a mass percentage not exceeding 93%. Compared with other stabilizer components, the use of sodium bisulfite in combination with diethylenetriaminepentaacetic acid shows better effects.

[0021] In the present invention, the stabilizer is preferably a mixture of sodium bisulfite and diethylenetriaminepentaacetic acid. Among them, 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.

[0022] There is a synergistic effect between sodium bisulfite and diethylenetriaminepentaacetic acid in the dispersion system of ambroxol hydrochloride solution. Proton exchange occurs between molecules, enhancing the hydrogen bond interaction with the amino and hydroxyl hydrogens in ambroxol, and redistributing the electron cloud density of ambroxol molecules. When the stabilizer is sodium bisulfite and diethylenetriaminepentaacetic acid in the above preferred mass ratio, its effect on improving the photo - stability and antioxidant properties of ambroxol hydrochloride solution is more significant, and can greatly improve the stability of the drug during storage and processing (showing good stability in both the accelerated 6 - month and long - term 24 - month stability tests).

[0023] In the present invention, the mass ratio of ambroxol hydrochloride to the 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 stability of the ambroxol hydrochloride solution obtained with the above - mentioned preferred ratio is relatively better.

[0024] In the present invention, based on a total volume of 2000 ml, the ambroxol hydrochloride solution preferably contains 12.5 - 17.5 g of ambroxol hydrochloride, 50 - 350 mg of sodium bisulfite, and 5 - 35 mg of diethylenetriaminepentaacetic acid;

[0025] 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;

[0026] 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;

[0027] Most preferably, every 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.

[0028] The ambroxol hydrochloride solution provided by the present invention has stable properties, can not add additional preservative components, has reliable quality and good safety.

[0029] In the present invention, the ambroxol hydrochloride solution can be further added with other pharmaceutically acceptable functional excipients according to needs.

[0030] Preferably, the functional excipient at least includes one of a pH regulator and an osmotic pressure regulator.

[0031] Preferably, the pH regulator is selected from at least one of disodium hydrogen phosphate anhydrous and citric acid.

[0032] The pH regulator is mainly used to adjust the ambroxol hydrochloride solution to weakly acidic (the preferred pH value range is 4.5 - 5.5), which is more conducive to the coordination of diethylenetriaminepentaacetic acid and enhances its function as a stabilizer.

[0033] Preferably, the osmotic pressure regulator is selected from sodium chloride.

[0034] In a more preferred and specific embodiment provided by the present invention, taking the total amount of 2000 ml of the ambroxol hydrochloride solution, it contains 12.5 - 17.5 g of ambroxol hydrochloride, 1.5 - 4.5 g of disodium hydrogen phosphate anhydrous, 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.

[0035] Further preferably, taking the total amount of 2000 ml of the ambroxol hydrochloride solution, it contains 13.0 - 17.0 g of ambroxol hydrochloride, 2.0 - 4.0 g of disodium hydrogen phosphate anhydrous, 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.

[0036] Further preferably, taking the total amount of 2000 ml of the ambroxol hydrochloride solution, it contains 13.5 - 16.5 g of ambroxol hydrochloride, 2.5 - 3.5 g of disodium hydrogen phosphate anhydrous, 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.

[0037] Further preferably, based on a total amount of 2000 ml, the ambroxol hydrochloride solution contains 14.5 - 15.5 g of ambroxol hydrochloride, 2.7 - 3.3 g of disodium hydrogen phosphate anhydrous, 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.

[0038] In a second aspect, the present invention provides a method for preparing the above-mentioned ambroxol hydrochloride solution, which includes the step of dissolving each raw material component in water for injection.

[0039] Preferably, the temperature of the water for injection is 40 - 70 °C.

[0040] Preferably, after each raw material is dissolved in water for injection, it further includes the steps of filtration and / or sterilization.

[0041] Preferably, a polyethersulfone membrane is used for filtration in the present invention, and the pore size of the membrane is 0.22 ± 0.02 μm.

[0042] Preferably, moist heat sterilization is adopted in the present invention, and the conditions for moist heat sterilization are: 121 ± 5 °C, 15 ± 3 min, F0 ≥ 12.

[0043] In one specific embodiment optional in the present invention, the preparation method includes the following steps:

[0044] (1) Add about 80% of the total amount of water for injection to the liquid preparation container, and successively dissolve citric acid, disodium hydrogen phosphate, sodium bisulfite, diethylenetriaminepentaacetic acid, ambroxol hydrochloride, and sodium chloride in appropriate amounts of water for injection and then add them to the liquid preparation container, stir evenly to obtain mixture I.

[0045] (2) Add water for injection to the mixture I obtained in step (1) to make up the volume to the total weight of the preparation, stir evenly to obtain mixture II;

[0046] (3) Filter the mixture II obtained in step (2) through two series-connected sterilizing-grade filters, and then seal it in 2-ml ampoules for sterilization to obtain the product.

[0047] Further, the temperature of the water for injection added to the liquid preparation container in step (1) is preferably controlled at 40 - 70 °C.

[0048] Further, the filter membrane material of the filter in step (3) is preferably polyethersulfone; the pore size of the micropores of the membrane is preferably 0.22 μm.

[0049] Further, a moist heat sterilization process at 121 °C for 15 min (F0 ≥ 12) is adopted in step (3).

[0050] 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 costs, and is easy to promote industrially. The prepared product does not need to add preservatives, has high safety, stable quality, and no obvious side effects.

[0051] In a third aspect, the present invention also 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.

[0052] Preferably, the inhalation preparation is used for treating respiratory diseases accompanied by abnormal sputum secretion and poor expectoration function.

[0053] Based on the medicinal activity of ambroxol hydrochloride, the ambroxol hydrochloride solution provided by the present invention is made into an inhalation preparation, and the active ingredient of the drug 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 complication diseases, infant respiratory distress syndrome in premature infants and neonates, etc.), and play a good expectorant effect.

[0054] At the same time, due to the good light stability and antioxidant properties of the ambroxol hydrochloride solution of the present invention, when it is applied to the preparation of an inhalation preparation, the quality is more reliable, and there is no need to add preservative components, so that the obtained inhalation preparation product has better safety, and patients can all tolerate it well, and it is more suitable for clinical use requirements.

[0055] Beneficial effects:

[0056] The present invention provides an ambroxol hydrochloride solution, its preparation method and application. The ambroxol hydrochloride solution contains: ambroxol hydrochloride, a stabilizer and water; the stabilizer contains diethylenetriaminepentaacetic acid with a mass percentage of 7.7%-11.1%; the total amount of the stabilizer used in the ambroxol hydrochloride solution is 27.5-192.5 mg / L. The present invention uses diethylenetriaminepentaacetic acid as a stabilizer component of the ambroxol hydrochloride solution in a relatively small amount. Diethylenetriaminepentaacetic acid has strong coordination ability and can interact with other molecules in the solution, thus 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 costs, and is easy to promote industrially. The ambroxol hydrochloride solution provided by the present invention itself or when it is applied to an inhalation preparation, there is no need to add preservative components, has reliable quality and good safety, and is more suitable for clinical use requirements. Specific embodiments

[0057] The present invention provides an ambroxol hydrochloride solution for inhalation, its preparation method and application. The ambroxol hydrochloride solution for inhalation has good light and oxygen stability, and during the treatment process, patients show good tolerance and high safety. The ambroxol hydrochloride solution for inhalation provided by the present invention does not contain added preservatives, has stable quality and no side effects. The preparation process provided by the present invention is simple to operate, has good repeatability and is suitable for industrial production.

[0058] The present invention is specifically realized through the following optional technical solutions.

[0059] In one optional embodiment, the present invention provides an ambroxol hydrochloride solution for inhalation. Each 2000 ml of water for injection contains the following components: 12.5 - 17.5 g of ambroxol hydrochloride, 1.5 - 4.5 g of disodium hydrogen phosphate anhydrous, 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.

[0060] In one optional embodiment, the present invention provides a preparation method for an ambroxol solution preparation for inhalation. The preparation method successively includes the following steps:

[0061] (1) Add about 80% of the total preparation amount of water for injection to a 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 then add them to the liquid preparation container, and stir evenly to obtain a mixed solution I.

[0062] (2) Add water for injection to the mixed solution I obtained in step (1) to make up the volume to the total weight of the preparation, and stir evenly to obtain a mixed solution II;

[0063] (3) Filter the mixed solution II obtained in step (2) through two series-connected sterilization-grade filters, and then fill and seal it in 2-ml ampoules for sterilization to obtain the product.

[0064] In one optional embodiment, the present invention provides the application of the ambroxol solution preparation for inhalation in the preparation of drugs for treating respiratory diseases accompanied by abnormal sputum secretion and poor expectoration function.

[0065] Compared with the prior art, the ambroxol hydrochloride solution for inhalation provided by the present invention has significantly enhanced light and oxygen stability, which can greatly improve the stability of the drug during storage. In the test experiment, after diluting the ambroxol hydrochloride solution with 0.9% sodium chloride solution, it can be placed for 2 days under the room temperature condition of not avoiding light and contacting with air. The total impurities of 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 condition of the influencing factors, the total impurities of 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 indexes such as the delivery rate, the total delivery amount, and the fine particle dose of the ambroxol hydrochloride solution for inhalation provided by the present invention are also significantly improved. The ambroxol hydrochloride solution for inhalation provided by the present invention does not contain preservatives and has a lower 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 the clinical use requirements. The preparation process of the ambroxol hydrochloride solution for inhalation provided by the present invention is simple in operation, good in reproducibility, good in product stability, and easy for large-scale industrial production.

[0066] In order to make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions in the present invention will be clearly and completely described below. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0067] At the endpoints and any values disclosed in this specification, the precise ranges or values are not limited, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and a single point value, and between single point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0068] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "specific embodiments", or "some specific embodiments" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the embodiments 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 can be combined in a suitable manner in any one or more embodiments or examples. In addition, without conflict, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0069] In the embodiments provided in this specification, for those without specific technologies or conditions indicated, they shall follow the technologies or conditions described in the literature in this field or the product specifications. For reagents or instruments without the manufacturer indicated, they are all conventional products that can be obtained through regular channels of purchase.

[0070] In the present invention, the instruments involved include a waters liquid chromatograph, an electronic balance, an NGI, a stability retention chamber, etc. All the raw materials, auxiliary materials, and packaging materials involved are filed and registered on the registration platform for raw materials, auxiliary materials, and packaging materials of the Center for Drug Evaluation (CDE) of the National Medical Products Administration.

[0071] Example 1

[0072] This example provides an ambroxol hydrochloride solution, and the formula is as follows:

[0073] Based on a total amount of 2000 ml, the ambroxol hydrochloride solution contains 12.5 g of ambroxol hydrochloride, 1.5 g of disodium hydrogen phosphate anhydrous, 1.0 g of citric acid, 12.0 g of sodium chloride, 50 mg of sodium bisulfite, 5 mg of diethylenetriaminepentaacetic acid, and the balance is injection water.

[0074] This example also provides a preparation method for the above-mentioned ambroxol hydrochloride solution, and the specific steps are as follows:

[0075] Weigh 12.5 g of ambroxol hydrochloride, 1.5 g of disodium hydrogen phosphate anhydrous, 1.0 g of citric acid, 12.0 g of sodium chloride, 50 mg of sodium bisulfite, and 5 mg of diethylenetriaminepentaacetic acid for standby. Add 1600 ml of injection water to the liquid preparation container, control the water temperature at 40 °C, and dissolve citric acid, disodium hydrogen phosphate, sodium bisulfite, diethylenetriaminepentaacetic acid, ambroxol hydrochloride, and sodium chloride in appropriate amounts of injection water in sequence and then add them to the liquid preparation container, and stir evenly. Make up the volume to 2000 ml with injection water. Filter the obtained liquid medicine through 2 series-connected sterilization-grade filters (the filter membrane material of the filter is polyethersulfone, and the micropores of the filter membrane are 0.22 μm), then fill the liquid medicine into 2-ml transparent ampoules, and perform moist heat sterilization at 121 °C for 15 min (F0≥12) to obtain the product.

[0076] This example conducts the following tests on the above-mentioned ambroxol hydrochloride solution:

[0077] Dilute the trial-produced sample with 0.9% sodium chloride solution according to a volume ratio of 1:1 to obtain a compatibility solution for atomization use. Place it under the conditions of room temperature, not protected from light, and in full contact with air for 2 days, and detect the related substances, pH, delivery rate, delivery total amount, and fine particle dose. The test results are shown in Table 1.

[0078] Place the trial-produced sample under the influencing factor of light conditions (① visible light 5500±500 Lux; ② near ultraviolet 90 μw / cm2 Leave it for 10 days and test its properties, related substances, pH, bacterial endotoxin and sterility. The test results are shown in Table 2.

[0079] Table 1

[0080]

[0081] Table 2

[0082]

[0083] From the data results in Tables 1 - 2, it can be seen that after the ambroxol hydrochloride solution sample provided in this example is diluted with 0.9% sodium chloride solution according to a volume ratio of 1:1 and left for 2 days at room temperature, without light protection and in full contact with air, there are no significant changes in its related substances, pH, delivery rate, total delivery amount and fine particle dose. The related substances and pH meet the requirements of the pharmacopoeia standard. Among them, the contents of related substance impurity I, other single impurities and total impurities are far lower than the standard requirements. In addition, when the trial - produced sample is placed under the influencing factor of light (① visible light 5500 ± 500 Lux; ② near - ultraviolet 90 μw / cm 2 ), leave it for 10 days, and its properties, related substances, pH, bacterial endotoxin and sterility still meet the requirements of the pharmacopoeia standard.

[0084] Example 2

[0085] This example provides an ambroxol hydrochloride solution with the following formula:

[0086] 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 balance is water for injection.

[0087] This example also provides a preparation method for the above - mentioned ambroxol hydrochloride solution, and the specific steps are as follows:

[0088] Weigh 17.5 g of ambroxol hydrochloride, 4.5 g of disodium hydrogen phosphate anhydrous, 3.0 g of citric acid, 16.0 g of sodium chloride, 350 mg of sodium bisulfite, and 35 mg of diethylenetriaminepentaacetic acid for standby. Add 1600 ml of injection water into the liquid preparation container, control the water temperature at 70 °C, dissolve citric acid, disodium hydrogen phosphate, sodium bisulfite, diethylenetriaminepentaacetic acid, ambroxol hydrochloride, and sodium chloride successively with appropriate amount of injection water and then add them into the liquid preparation container, and stir evenly. Make up the volume to 2000 ml by adding injection water. Filter the obtained liquid medicine through 2 series-connected sterilizing-grade filters (the filter membrane material of the filter is polyethersulfone, and the micropores of the filter membrane are 0.22 μm), then fill the liquid medicine into 2-ml transparent ampoules, and carry out moist heat sterilization at 121 °C for 15 min (F0≥12) to obtain the product.

[0089] The following tests were carried out on the above-mentioned ambroxol hydrochloride solution in this example:

[0090] Dilute the trial-produced sample with 0.9% sodium chloride solution according to the volume ratio of 1:1 to obtain the compatible solution for atomization. Place it for 2 days under the conditions of room temperature, not protected from light, and sufficient contact with air, and test the related substances, pH, delivery rate, total delivery amount, and fine particle dose. The test results are shown in Table 3.

[0091] Place the trial-produced sample under the influencing factor of light (① visible light 5500±500 Lux; ② near ultraviolet 90 μw / cm 2 ) for 10 days, and test the appearance, related substances, pH, bacterial endotoxin, and sterility. The test results are shown in Table 4.

[0092] Table 3

[0093]

[0094] Table 4

[0095]

[0096] From the data results in Tables 3-4, it can be seen that after the ambroxol hydrochloride solution sample provided in this example is diluted with 0.9% sodium chloride solution according to the volume ratio of 1:1 and placed for 2 days under the conditions of room temperature, not protected from light, and sufficient contact with air, there are no significant changes in its related substances, pH, delivery rate, total delivery amount, and fine particle dose. The related substances and pH meet the requirements of the pharmacopoeia standard, and the contents of related substance impurity I, other single impurities, and total impurities are far lower than the standard requirements. In addition, when the trial-produced sample is placed for 10 days under the influencing factor of light (① visible light 5500±500 Lux; ② near ultraviolet 90 μw / cm 2 ), the appearance, related substances, pH, bacterial endotoxin, and sterility still meet the requirements of the pharmacopoeia standard.

[0097] Example 3

[0098] This example provides an ambroxol hydrochloride solution with the following formula:

[0099] Based on a total volume of 2000 ml, the ambroxol hydrochloride solution contains 15.0 g of ambroxol hydrochloride, 3.0 g of disodium hydrogen phosphate anhydrous, 2.0 g of citric acid, 14.0 g of sodium chloride, 200 mg of sodium bisulfite, 20 mg of diethylenetriaminepentaacetic acid, and the balance is water for injection.

[0100] This example also provides a method for preparing the above-mentioned ambroxol hydrochloride solution, and the specific steps are as follows:

[0101] Weigh 15.0 g of ambroxol hydrochloride, 3.0 g of disodium hydrogen phosphate anhydrous, 2.0 g of citric acid, 14.0 g of sodium chloride, 200 mg of sodium bisulfite, and 20 mg of diethylenetriaminepentaacetic acid for standby. Add 1600 ml of water for injection to the liquid preparation container, control the water temperature at 55°C, and dissolve citric acid, disodium hydrogen phosphate anhydrous, sodium bisulfite, diethylenetriaminepentaacetic acid, ambroxol hydrochloride, and sodium chloride in appropriate amounts of water for injection in sequence, and then add them to the liquid preparation container and stir evenly. Make up the volume to 2000 ml with water for injection. Filter the obtained liquid medicine through two series-connected sterilization-grade filters (the filter membrane material of the filter is polyethersulfone, and the micropores of the filter membrane are 0.22 μm), and then fill the liquid medicine into 2-ml transparent ampoules, and carry out moist heat sterilization at 121°C for 15 min (F0≥12) to obtain the product.

[0102] This example conducts the following tests on the above-mentioned ambroxol hydrochloride solution:

[0103] Dilute the trial-produced sample with 0.9% sodium chloride solution at a volume ratio of 1:1 to obtain a compatible solution for atomization use. Place it under the conditions of room temperature, not protected from light, and in full contact with air for 2 days, and detect the related substances, pH, delivery rate, delivery total amount, and fine particle dose. The test results are shown in Table 5.

[0104] Place the trial-produced sample under the influencing factor of light (① visible light 5500±500 Lux; ② near ultraviolet 90 μw / cm 2 ) for 10 days, and detect the appearance, related substances, pH, bacterial endotoxin, and sterility. The test results are shown in Table 6.

[0105] Table 5

[0106]

[0107] Table 6

[0108]

[0109] As can be seen from the data results in Table 5-6, after the ambroxol hydrochloride solution sample provided in this example was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1 and placed for 2 days at room temperature, without light protection and in full contact with air, there were no significant changes in its related substances, pH, delivery rate, total delivery amount and fine particle dose. The related substances and pH met the requirements of the pharmacopoeia standard. Among them, the contents of related substance impurity I, other individual impurities and total impurities were far lower than the standard requirements. In addition, when the trial-produced sample was placed under the influencing factor of light (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), after 10 days, the appearance, related substances, pH, bacterial endotoxin and sterility still met the requirements of the pharmacopoeia standard.

[0110] Example 4

[0111] This example provides an ambroxol hydrochloride solution. Compared with the formulation in Example 3, the only difference is that sodium bisulfite is replaced with sodium sulfite in the same amount.

[0112] The preparation method of the ambroxol hydrochloride solution in this example refers to Example 3.

[0113] This example detects the above-mentioned ambroxol hydrochloride solution, and the detection method is the same as that in Example 3.

[0114] The detection results are shown in Tables 7 and 8.

[0115] Table 7

[0116]

[0117] Table 8

[0118]

[0119] As can be seen from the data results in Tables 7-8, after the ambroxol hydrochloride solution sample provided in this example was diluted with 0.9% sodium chloride solution at a volume ratio of 1:1 and placed for 2 days at room temperature, without light protection and in full contact with air, there were obvious changes in its related substances, pH, delivery rate, total delivery amount and fine particle dose. Although the related substances and pH still met the requirements of the pharmacopoeia standard, the contents of related substance impurity I, other individual impurities and total impurities showed an obvious increasing trend. In addition, when the trial-produced sample was placed under the influencing factor of light (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), after 10 days, the appearance, related substances, pH, bacterial endotoxin and sterility still met the requirements of the pharmacopoeia standard.

[0120] Example 5

[0121] This example provides an ambroxol hydrochloride solution. Compared with Example 3, the only difference in its formulation is that sodium bisulfite is replaced with an equal amount of sodium metabisulfite.

[0122] The preparation method of the ambroxol hydrochloride solution in this example refers to Example 3.

[0123] This example detects the above-mentioned ambroxol hydrochloride solution, and the detection method is the same as that in Example 3.

[0124] The test results are shown in Tables 9 and 10.

[0125] Table 9

[0126]

[0127] Table 10

[0128]

[0129] From the data results in Tables 9 - 10, it can be seen that after the sample of the ambroxol hydrochloride solution provided in this example is diluted with 0.9% sodium chloride solution at a volume ratio of 1:1 and placed for 2 days at room temperature, without light protection, and in full contact with air, its related substances, pH, delivery rate, total delivery amount, and fine particle dose change significantly. Although the related substances and pH still meet the requirements of the pharmacopoeia standards, the contents of related substance impurity I, other individual impurities, and total impurities show a relatively significant increasing trend, and the content of other individual impurities is close to the limit requirement. In addition, when the trial-produced sample is placed for 10 days under the influencing factor of light (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 )), the appearance, related substances, pH, bacterial endotoxin, and sterility still meet the requirements of the pharmacopoeia standards, but compared with Examples 1 - 4, the data results of the appearance, related substances, and pH are much worse.

[0130] Example 6

[0131] This example provides an ambroxol hydrochloride solution. Compared with Example 3, the only difference in its formulation is that disodium hydrogen phosphate anhydrous, citric acid, and sodium chloride are replaced with an equal amount of sodium acetate, glacial acetic acid, and calcium chloride.

[0132] The preparation method of the ambroxol hydrochloride solution in this example refers to Example 3.

[0133] This example detects the above-mentioned ambroxol hydrochloride solution, and the detection method is the same as that in Example 3.

[0134] The test results are shown in Tables 11 and 12.

[0135] Table 11

[0136]

[0137] Table 12

[0138]

[0139] From the data results in Tables 11 - 12, it can be seen that after the ambroxol hydrochloride solution sample provided in this example is diluted with 0.9% sodium chloride solution according to a volume ratio of 1:1 and placed for 2 days under the conditions of room temperature, not protected from light, and in full contact with air, there are no significant changes in its related substances, pH, delivery rate, total delivery amount, and fine particle dose. The related substances and pH both meet the requirements of the pharmacopoeia standards. Among them, the contents of related substance impurity I, other individual impurities, and total impurities are lower than the standard requirements. Compared with the samples in Examples 1 - 2, the data results show little difference. In addition, when the trial - produced sample is placed under the influencing factor of light conditions (① visible light 5500 ± 500 Lux; ② near - ultraviolet 90 μw / cm 2 ) for 10 days, the appearance, related substances, pH, bacterial endotoxin, and sterility still meet the requirements of the pharmacopoeia standards.

[0140] Comparative Example 1

[0141] An ambroxol hydrochloride solution, compared with the formulation in Example 3, is different in that sodium bisulfite and diethylenetriaminepentaacetic acid are not added to the formulation.

[0142] The above - mentioned ambroxol hydrochloride solution is detected, and the detection method is the same as that in Example 3.

[0143] The detection results are shown in Tables 13 and 14.

[0144] Table 13

[0145]

[0146] Table 14

[0147]

[0148] From the data results in Tables 13 - 14, it can be seen that after the sample prepared by the above - mentioned prescription and process is diluted with 0.9% sodium chloride solution according to a volume ratio of 1:1 and placed for 2 days under the conditions of room temperature, not protected from light, and in full contact with air, there are significant changes in its related substances, pH, delivery rate, total delivery amount, and fine particle dose. Although the related substances and pH still meet the requirements of the pharmacopoeia standards, compared with the samples in Examples 1 - 6, its stability and atomization effect are relatively poor. In addition, when the trial - produced sample is placed under the influencing factor of light conditions (① visible light 5500 ± 500 Lux; ② near - ultraviolet 90 μw / cm 2After being placed for 10 days, its properties, related substances, and pH changed significantly. Among them, the contents of related substance impurity I, other individual impurities, and total impurities were much higher than the standard requirements.

[0149] Comparative Example 2

[0150] An ambroxol hydrochloride solution, compared with Example 3 in terms of its formulation, is different in that diethylenetriaminepentaacetic acid in the formulation is replaced with disodium ethylenediaminetetraacetate in the same amount.

[0151] The above-mentioned ambroxol hydrochloride solution was tested, and the testing method was the same as that in Example 3.

[0152] The test results are shown in Tables 15 and 16.

[0153] Table 15

[0154]

[0155] Table 16

[0156]

[0157] 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 and then placed for 2 days at room temperature, without light protection, and in full contact with air, its related substances, pH, delivery rate, total delivery amount, and fine particle dose all changed significantly. Although the related substances and pH still met the requirements of the pharmacopoeia standards, compared with the samples in Examples 1 - 6, its stability and atomization effect were relatively poor. In addition, when the trial-produced sample was placed for 10 days under the influencing factor of light (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), its properties, related substances, and pH changed significantly, and the contents of related substance impurity I, other individual impurities, and total impurities were higher than the standard requirements.

[0158] Comparative Example 3

[0159] An ambroxol hydrochloride solution, compared with Example 3 in terms of its formulation, is different in that sodium bisulfite and diethylenetriaminepentaacetic acid are not added in the formulation, and the filtered liquid medicine is filled and sealed in 2 - ml brown ampoules.

[0160] The above-mentioned ambroxol hydrochloride solution was tested as follows:

[0161] When the trial-produced sample was placed for 10 days under the influencing factor of light (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), the properties, related substances, and pH were tested, and the test results are shown in Table 17.

[0162] Table 17

[0163]

[0164] From the data results in Table 17, it can be seen that when the trial-produced samples are placed under the influencing factor of light conditions (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), for 10 days, significant changes occur in their properties, related substances, and pH. Among them, the contents of other individual impurities and total impurities in the related substances have exceeded the standard requirements.

[0165] Comparative Example 4

[0166] An ambroxol hydrochloride solution, and its preparation method is as follows:

[0167] Weigh 15 g of ambroxol hydrochloride, add it to 5000 ml of injection water, stir to dissolve, add 0.5 g of sodium sulfite, 0.5 g of benzoic acid, and 0.75 g of tributylphenol aldehyde, dissolve completely, add an appropriate amount of phosphate to adjust the pH value, then add an appropriate amount of injection water to make the solution system reach 10000 ml, then filter through a microporous membrane, and dispense into medical control bottles, with 10 mL dispensed into each bottle. The concentration of ambroxol hydrochloride in each bottle is 1.5 mg / ml, and the pH value is 4.7.

[0168] The above ambroxol hydrochloride solution is detected as follows:

[0169] When the trial-produced samples are placed under the influencing factor of light conditions (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), for 10 days, the properties, related substances, and pH are detected, and the detection results are shown in Table 18.

[0170] Table 18

[0171]

[0172] From the data results in Table 18, it can be seen that when the trial-produced samples are placed under the influencing factor of light conditions (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), for 10 days, significant changes occur in their properties, related substances, and pH. Among them, the contents of impurity I, other individual impurities, and total impurities in the related substances are much higher than the standard requirements.

[0173] Comparative Example 5

[0174] An ambroxol hydrochloride solution, and its preparation method is as follows:

[0175] Add 700 ml of injection water into the liquid dispensing tank, control the temperature at about 40 °C, add raw and auxiliary materials such as ambroxol hydrochloride, citric acid, disodium hydrogen phosphate, sodium chloride, and disodium edetate, and stir to completely dissolve. Make up the injection water to 1000 ml, stir evenly, filter through a 0.22 μm filter membrane, and seal it in a 2 ml low-density polyethylene bottle to obtain the product.

[0176] Conduct the following tests on the above-mentioned ambroxol hydrochloride solution:

[0177] Place the trial-produced sample under the influencing factor of light (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ) for 10 days, and test the appearance, related substances, and pH. The test results are shown in Table 19.

[0178] Table 19

[0179]

[0180] From the data results in Table 19, it can be seen that when the trial-produced sample is placed under the influencing factor of light (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ) for 10 days, its appearance, related substances, and pH change significantly, and the contents of other individual impurities and total impurities are much higher than the standard requirements.

[0181] Comparative Example 6

[0182] An ambroxol hydrochloride solution, and its preparation method is as follows:

[0183] Weigh 12.0 g of ambroxol hydrochloride, 1.2 g of disodium hydrogen phosphate, 1.0 g of citric acid, 10.2 g of sodium chloride, 0.5 g of stabilizer (chitosan and sodium metabisulfite in a weight ratio of 1:7), and 0.8 g of surfactant (tetrabutylphenol aldehyde and lecithin in a weight ratio of 6:5) for standby. Add 1200 ml of injection water into the liquid dispensing container, and successively add disodium hydrogen phosphate, citric acid, ambroxol hydrochloride, and surfactant, and stir to dissolve. After complete dissolution, add sodium chloride and stabilizer, and stir until completely dissolved. Make up the injection water to a constant volume of 2000 ml. Filter the liquid medicine through a sterilizing-grade filter membrane (the filter membrane material of the filter is polyvinylidene fluoride membrane, and the micropores of the filter membrane are 0.22 μm), and then seal it in a 2 ml transparent ampoule under nitrogen protection, and carry out moist heat sterilization at 121 °C for 12 minutes to obtain the product.

[0184] Conduct the following tests on the above-mentioned ambroxol hydrochloride solution:

[0185] Place the trial-produced sample under the influencing factor of light (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2Leave it for 10 days and test its properties, related substances and pH. The test results are shown in Table 20.

[0186] Table 20

[0187]

[0188] From the data results in Table 20, it can be seen that when the trial-produced sample is placed under the influencing factor of light conditions (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), leave it for 10 days, and its properties, related substances and pH have significant changes. Among them, the contents of other individual impurities and total impurities are much higher than the standard requirements.

[0189] Comparative Example 7

[0190] An ambroxol hydrochloride solution, and its preparation method is as follows:

[0191] Weigh 7.5 g of ambroxol hydrochloride, 0.1 g of cysteine hydrochloride, 0.125 g of glycerol, 0.6 g of citric acid, and 1.2 g of disodium hydrogen phosphate for standby. Add 900 ml of injection water into the liquid preparation tank, heat it to 70 °C, add cysteine hydrochloride and citric acid, then add ambroxol hydrochloride and stir for 15 min to dissolve. The pH value is about 3.5. Add 0.01% activated carbon and stir for 8 min, then filter. Slowly cool down to 10 °C, and at the same time dropwise add the disodium hydrogen phosphate solution to adjust the pH to 4.8. Stir for 20 min, and then filter through a 0.45 μm filter membrane to remove impurities. Add glycerol and make up the injection water to 1000 ml. Stir for 10 min and then filter through a 0.22 μm filter membrane to remove bacteria and impurities. Under nitrogen protection, it is sealed in a 2 ml transparent ampoule.

[0192] The above-mentioned ambroxol hydrochloride solution is tested as follows:

[0193] When the trial-produced sample is placed under the influencing factor of light conditions (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), leave it for 10 days, and test its properties, related substances and pH. The test results are shown in Table 21.

[0194] Table 21

[0195]

[0196] From the data results in Table 21, it can be seen that when the trial-produced sample is placed under the influencing factor of light conditions (① visible light 5500 ± 500 Lux; ② near ultraviolet 90 μw / cm 2 ), leave it for 10 days, and its properties, related substances and pH have significant changes. Among them, the contents of other individual impurities and total impurities are much higher than the standard requirements.

[0197] Experimental Example 1

[0198] In this experimental example, the ambroxol hydrochloride solution provided in Example 3 was used as a sample, and its safety as an inhaled hydrochloric acid solution was evaluated through local irritation, acute toxicity tests, and long-term toxicity tests.

[0199] The test methods are as follows:

[0200] The inhaled ambroxol hydrochloride solution prepared in Example 3 was sprayed into the oral cavity of guinea pigs for local irritation tests, acute toxicity tests, and long-term toxicity tests respectively. Each test was set up with a blank control group, a solvent control group, and an experimental group. Each group used 5 guinea pigs. In the experimental group, 2.5 ml of the inhaled ambroxol hydrochloride solution prepared in Example 3 was sprayed into the oral cavity of guinea pigs each time through a spraying device, twice a day. The solvent control group was sprayed with an equal volume of solvent (injectable water) twice a day, and the blank control group was not sprayed with any substance.

[0201] For the local irritation test and the acute toxicity test, after administering the drug for 1 day and culturing for 14 days, the tissue structures of the nasal cavity, pharynx, and larynx mucosa and internal organs were detected. In the long-term toxicity experiment, after administering the drug for 30 days, the tissue structures of the nasal cavity, pharynx, and larynx mucosa and internal organs, as well as serum physiological and biochemical indexes, were detected. 10% neutral formalin solution was used to fix the tissues such as the nasal cavity, pharynx, and larynx mucosa and internal organs, and routine pathological sections were made, and then observed under a light microscope.

[0202] The test results showed that the histopathological results between all experimental groups and the control groups in the local toxicity test, acute toxicity test, and long-term toxicity test were similar, and no obvious toxic pathological damage occurred. In the long-term toxicity test, the serum physiological and biochemical indexes of the experimental group were all within the normal physiological range and showed no significant difference from all control groups. The above experimental results indicate that the inhaled ambroxol hydrochloride solution provided in Example 3 has no side effects on the nasal cavity, pharyngeal and laryngeal mucosa, and internal organs of guinea pigs, and the inhaled ambroxol hydrochloride solution of the present invention has good safety.

[0203] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Ambroxol Hydrochloride Solution, comprising: ambroxol hydrochloride, a stabilizer and water, characterized in that, The stabilizer contains diethylenetriaminepentaacetic acid in a mass percentage of 7% - 12%; the total dosage of the stabilizer in the ambroxol hydrochloride solution is 27.5 - 192.5 mg / L; Based on a total volume of 2000 ml, the ambroxol hydrochloride solution contains 12.5 - 17.5 g of ambroxol hydrochloride and the stabilizer, and the stabilizer consists of 50 - 350 mg of sodium bisulfite and 5 - 35 mg of diethylenetriaminepentaacetic acid.

2. The ambroxol hydrochloride solution according to claim 1, wherein, 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.

3. The ambroxol hydrochloride solution according to claim 2, wherein, The mass ratio of sodium bisulfite to diethylenetriaminepentaacetic acid is 10:

1.

4. The ambroxol hydrochloride solution according to any one of claims 1-3, characterized in that, The mass ratio of ambroxol hydrochloride to the stabilizer is (12500 - 17500):(55 - 385).

5. The ambroxol hydrochloride solution according to claim 4, characterized in that, The mass ratio of ambroxol hydrochloride to the stabilizer is (13000 - 17000):(110 - 330).

6. The ambroxol hydrochloride solution according to any one of claims 1-3, characterized in that, Every 2000 ml of the 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.

7. The ambroxol hydrochloride solution according to any one of claims 1-3, characterized in that, It further contains at least one functional auxiliary material such as a pH regulator and an osmotic pressure regulator.

8. The ambroxol hydrochloride solution according to claim 4, characterized in that, It further contains at least one functional auxiliary material such as a pH regulator and an osmotic pressure regulator.

9. The ambroxol hydrochloride solution according to claim 7, wherein The pH regulator is selected from at least one of disodium hydrogen phosphate anhydrous and citric acid; and / or, the osmotic pressure regulator is selected from sodium chloride.

10. The ambroxol hydrochloride solution according to any one of claims 1-3, 5, 8, and 9, characterized in that, Based on a total volume of 2000 ml, the ambroxol hydrochloride solution contains 12.5 - 17.5 g of ambroxol hydrochloride, 1.5 - 4.5 g of disodium hydrogen phosphate anhydrous, 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.

11. The ambroxol hydrochloride solution according to claim 4, wherein Based on a total volume of 2000 ml, the ambroxol hydrochloride solution contains 12.5 - 17.5 g of ambroxol hydrochloride, 1.5 - 4.5 g of disodium hydrogen phosphate anhydrous, 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.

12. The ambroxol hydrochloride solution according to claim 6, wherein, Based on a total volume of 2000 ml, the ambroxol hydrochloride solution contains 12.5 - 17.5 g of ambroxol hydrochloride, 1.5 - 4.5 g of disodium hydrogen phosphate anhydrous, 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.

13. The ambroxol hydrochloride solution according to claim 7, wherein Based on a total volume of 2000 ml, the ambroxol hydrochloride solution contains 12.5 - 17.5 g of ambroxol hydrochloride, 1.5 - 4.5 g of disodium hydrogen phosphate anhydrous, 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.

14. The preparation method of the ambroxol hydrochloride solution according to any one of claims 1-13, characterized in that, It includes the step of dissolving each raw material component in water for injection.

15. The preparation method according to claim 14, characterized in that, The temperature of the water for injection is 40 - 70 °C.

16. The preparation method according to claim 14, wherein, After each raw material is dissolved in water for injection, it further includes: filtering with a polyethersulfone membrane, the pore size of the membrane being 0.22 ± 0.02 μm; and / or, sterilizing by the moist heat method, the conditions for moist heat sterilization being: 121 ± 5 °C, 15 ± 3 min, F0 ≥ 12.

17. Use of the ambroxol hydrochloride solution according to any one of claims 1-13 or the ambroxol hydrochloride solution prepared by the preparation method according to any one of claims 14-16 in the preparation of an inhalation preparation.

18. The application according to claim 17, wherein The inhalation preparation is used for treating respiratory diseases accompanied by abnormal sputum secretion and poor sputum excretion function.

19. The application according to claim 17, wherein The inhalation preparation is used for treating acute and chronic respiratory diseases, postoperative pulmonary complication diseases, or infant respiratory distress syndrome in premature infants and neonates.

Images