WO2022021769A1 - 一种盐酸氨溴索口腔喷雾溶液及其制备方法 - Google Patents

一种盐酸氨溴索口腔喷雾溶液及其制备方法 Download PDF

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WO2022021769A1
WO2022021769A1 PCT/CN2020/138891 CN2020138891W WO2022021769A1 WO 2022021769 A1 WO2022021769 A1 WO 2022021769A1 CN 2020138891 W CN2020138891 W CN 2020138891W WO 2022021769 A1 WO2022021769 A1 WO 2022021769A1
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ambroxol hydrochloride
spray solution
mass ratio
oral spray
ambroxol
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PCT/CN2020/138891
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English (en)
French (fr)
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克利泽特·克里斯蒂娜
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德国吉麦医疗技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to an oral spray solution of ambroxol hydrochloride and a preparation method thereof.
  • Ambroxol is a metabolite of bromhexine, and drugs containing ambroxol have been registered and marketed for many years. This material is used as the hydrochloride salt. Ambroxol has been shown to improve mucus transport and clearance mechanisms on the epithelial surface of the respiratory tract and stimulate surfactant synthesis and secretion by class II alveolar parietal cells. Ambroxol is used as an expectorant in acute and chronic bronchopulmonary diseases characterized by abnormal sputum secretion or impaired expectoration.
  • Ambroxol Hydrochloride is a white or slightly yellow crystalline powder with a unique bitter taste and numbness after taking it.
  • the material is slightly soluble in water, soluble in methanol, and practically insoluble in dichloromethane. Substances are stable in aqueous suspension when exposed to heating, acidic and basic conditions, but are sensitive to oxides, such as hydrogen peroxide, chemical name: trans ⁇ 4 ⁇ [(2 ⁇ amino ⁇ 3,5 ⁇ di Bromobenzyl)amino]cyclohexanol hydrochloride, molecular formula: C 13 H 18 Br 2 N 2 O ⁇ HCl, molecular weight: 414.57, structural formula:
  • Mucosolvan which has been listed abroad, was developed and marketed by Boehringer Ingelheim in Germany in 1979, and has been listed in nearly 20 countries including Italy, Switzerland, Argentina and Japan.
  • Transbroncho produced by a large pharmaceutical company in California, USA; Losolvan, produced by Taiwan Quanfu Chemical Co., Ltd.; Lambroxol Capsules (75mg/day) (Lambroxol) , which is produced by French Aidefa, and imported and packaged by No. 4 Pharmaceutical Factory in Changzhou, China.
  • the original research and marketed dosage forms are injection, tablet, syrup, oral liquid, and sustained-release capsule. my country began to approve import in 1991.
  • the trade name is "Mucosolvan”, and the specifications of ambroxol hydrochloride injection are 2ml: 15mg, and ambroxol
  • the injection is suitable for acute and chronic respiratory diseases accompanied by abnormal sputum secretion and poor expectoration function, such as the expectorant treatment of acute exacerbation of chronic bronchitis, asthmatic bronchitis and bronchial asthma, and the treatment of pulmonary complications after surgery.
  • Prophylactic treatment treatment of infant respiratory distress syndrome (IRDS) in premature infants and neonates.
  • IRDS infant respiratory distress syndrome
  • ambroxol hydrochloride For the research of ambroxol hydrochloride, domestic and foreign mostly focus on the research of preparation dosage form and the development of new clinical indications. At present, there are many types of preparations of ambroxol hydrochloride in my country, such as ambroxol hydrochloride tablet, ambroxol hydrochloride Capsules, Ambroxol Hydrochloride Oral Solution, Ambroxol Hydrochloride Sustained-Release Capsules, etc. Oral controlled-release tablets or capsules and other solid preparations often have problems such as discomfort in taste or difficulty in swallowing and difficulty in dividing doses, which leads to inconvenience for such patients, which affects the completion of normal treatment plans and the exertion of drug efficacy, such as ordinary tablets.
  • Liquid preparations have the characteristics of fast absorption, can be taken in divided doses, and are easily accepted by the elderly and children. Therefore, the research and development of liquid sustained-release preparations with good taste and stable drug efficacy have been highly valued by pharmacists and clinicians.
  • ambroxol hydrochloride oral solution is composed of ambroxol hydrochloride, water, ethanol and other flavoring agents, and is widely used clinically because of its convenience in taking.
  • the product has unpleasant tastes such as bitterness, astringency, and numbness, which can be tolerated by adults, but difficult for children.
  • oral solutions are mainly used for children and patients with dysphagia. At present, there is no better solution for this contradictory clinical application, which greatly reduces the compliance of the product, that is, some patients are reluctant to take the medicine and cannot take the medicine regularly according to the regulations, so that the therapeutic effect of the medicine cannot achieve the expected effect.
  • the present invention has been made in view of this.
  • the present invention is to solve the technical problem of poor clinical demand/compliance in the prior art, and provides a kind of oral spray solution of ambroxol hydrochloride, which can make the dosage more accurate and effective.
  • the adjustment can greatly improve the stability, and the taste is better, which can effectively improve the patient's compliance.
  • ambroxol hydrochloride oral spray solution calculated in 1 ml
  • the ambroxol hydrochloride oral spray solution includes the following components: 45-55 mg of ambroxol hydrochloride, and also includes pharmaceutically acceptable excipients and additives. to a sufficient amount of purified water.
  • Ambroxol hydrochloride oral spray solution greatly increases the convenience of taking medicine for patients with acute exacerbation of chronic bronchitis, asthmatic bronchitis and bronchial asthma.
  • many patients with dysphagia cannot take oral solid preparations and solutions of ambroxol hydrochloride.
  • This product is very easy to enter the gastrointestinal tract every time it is sprayed into the oral cavity, so it can be used by many patients with dysphagia.
  • the ambroxol hydrochloride oral spray solution of the present invention is a new prescription
  • the concentration of the ambroxol hydrochloride in the prescription is 45-55mg/ml, preferably 50mg/ml
  • the ambroxol hydrochloride oral spray solution has two packaging specifications, At 1250mg/25ml and 650mg/13ml respectively, the oral spray solution can make the dosing more precise and effectively improve patient compliance.
  • the spray solution of the present invention has convenient and flexible usability, does not require a special environment, and is portable to use.
  • the pharmaceutically acceptable adjuvants include one or more of solvents, surfactants, preservatives, flavoring agents, and pH adjusting agents.
  • the adjuvants include solvents, surfactants, preservatives, flavoring agents and pH adjusters.
  • the buffer includes tromethamine and/or sodium hydroxide, preferably, the buffer includes tromethamine and sodium hydroxide; the mass ratio of the tromethamine to ambroxol hydrochloride is 0.06 ⁇ 0.08:1, preferably, the mass ratio of described tromethamine to ambroxol hydrochloride is 0.072:1; the mass ratio of described 0.01N sodium hydroxide to ambroxol hydrochloride is 0.12 ⁇ 0.14:1, more Preferably, the mass ratio of the 0.01N sodium hydroxide to ambroxol hydrochloride is 0.125:1.
  • the present invention finds through repeated experiments that adding a certain amount of tromethamine to the active ingredient ambroxol hydrochloride can greatly improve the stability of the solution system.
  • the mass ratio of tromethamine to ambroxol hydrochloride is 0.06 ⁇ 0.08:1, with the increase of the amount of tromethamine, the product stability increases, but when it increases to a certain amount, there is almost no change, but the total impurities increase.
  • the mass ratio of ambroxol is 0.072:1, and the stability is the best.
  • the solvent includes glycerol and/or ethanol; the solvent includes glycerol and 96% ethanol, and the mass ratio of the glycerol to ambroxol hydrochloride is 0.54-0.6:1.
  • the mass ratio of ambroxol hydrochloride is 0.58:1; the mass ratio of described 96% ethanol and ambroxol hydrochloride is 0.08 ⁇ 0.14:1, preferably, the mass ratio of described 96% ethanol and ambroxol hydrochloride is 0.1 :1.
  • the surfactant comprises polyethylene glycol pentahydroxystearate; the mass ratio of the polyethylene glycol pentahydroxystearate to ambroxol hydrochloride is 1.8-2.2:1, preferably The mass ratio of the polyethylene glycol pentahydroxystearate to ambroxol hydrochloride is 2:1.
  • the formaldehyde content in the polyethylene glycol pentahydroxystearate of the present invention is less than or equal to 5ppm, so as to avoid the generation of the impurity B.
  • the present invention adopts glycerin and polyethylene glycol pentahydroxystearate to dissolve the active ingredient ambroxol hydrochloride.
  • the mass ratio of bromoxol is 0.54 ⁇ 0.6:1 ⁇ 3:1
  • the solubility of ambroxol hydrochloride increases, but when the increase exceeds a certain amount In the future, there will be impurities.
  • the mass ratio of glycerol, polyethylene glycol pentahydroxystearate and ambroxol hydrochloride is 0.58:2:1, ambroxol hydrochloride is completely dissolved.
  • the preservative includes sodium benzoate, and the mass ratio of the sodium benzoate to ambroxol hydrochloride is 0.08-0.12:1, more preferably, the mass ratio of the sodium benzoate to ambroxol hydrochloride is 0.1:1 .
  • the oral spray solution of the present invention contains 5 mg/ml of sodium benzoate, a preservative, which is superior to benzoic acid because of its better solubility in water, and sodium benzoate is superior to paraben preservatives because the latter generally requires Combination of two preservatives (such as methylparaben and propylparaben) to combat bacteria and fungi.
  • Sodium benzoate was chosen at a concentration of 5 mg/ml due to the high concentration of active ingredient contained in the formulation and supplied in a multi-dose container equipped with a metering pump. Concentrations of preservatives are higher than comparable products such as Syrup, but since the dosage of the formulation is small, the dosage of preservative is also low. In fact, at a daily dose of 90 mg of ambroxol hydrochloride, the amount of preservative given by this product is about 3-6 times lower than that of other products.
  • the present invention finds through repeated experiments that the mass ratio of the levomenthol, ammonium glycyrrhizinate, acesulfame potassium, xylitol and ambroxol hydrochloride is 0.08-0.15: 0.01-0.05: 0.2-0.6: 3.82-4.12: 1 hour, can effectively cover the bitter taste of ambroxol hydrochloride, when the mass ratio of described levomenthol, ammonium glycyrrhizinate, acesulfame potassium, xylitol and ambroxol hydrochloride is 0.1: 0.0128: 0.3: 4: 1 It can effectively mask the bitter taste of ambroxol hydrochloride and make the spray solution taste fresh.
  • the spray solution of the invention has fresh taste, and acceptable taste is obtained by adding acesulfame potassium, xylitol, levomenthol and ammonium glycyrrhizinate, and the combination of flavoring agents can effectively mask the bitter taste of ambroxol hydrochloride, and obtain excellent taste, Mouth spray solution with acceptable taste.
  • the ambroxol hydrochloride oral spray solution includes the following components by weight: ambroxol hydrochloride 50mg, tromethamine 3.6mg, polyethylene glycol pentahydroxystearate 100mg, glycerin 29mg , Acesulfame potassium 15mg, xylitol 200mg, sodium benzoate 5mg, levomenthol 5mg, ammonium glycyrrhizinate 0.64mg, 96% ethanol 5mg, 0.01N sodium hydroxide 6.25mg, the balance is purified water.
  • ambroxol hydrochloride spray solution of the present invention under a specific ratio and composition, has been shown through tests, and it has been surprisingly found that various index properties, pH value, content, and related substances have no obvious changes compared with 0 months, indicating that the present invention has no obvious changes.
  • the ambroxol hydrochloride spray solution sample under the ratio and composition of the invention has good stability.
  • the pH value of the ambroxol hydrochloride oral spray solution is 6.1-6.6, and preferably, the pH value of the ambroxol hydrochloride oral spray solution is 6.5.
  • the present invention ensures that the pH of the oral spray solution is between 6.1 and 6.6, preferably the pH value is 6.5, so that the stability of ambroxol hydrochloride is good, and the pH of the oral spray solution is more suitable for oral spray administration, that is, the hydrochloric acid of the present invention Ambroxol oral spray solution not only has high stability of active ingredients, but also is more suitable for oral administration.
  • the invention also discloses a preparation method of ambroxol hydrochloride oral spray solution, comprising the following steps:
  • ambroxol hydrochloride, macrogol pentahydroxystearate, glycerol, tromethamine, levomenthol of recipe quantity are mixed and stirred and heated to obtain mixture A;
  • step (1) heating to 60-70° C. and maintaining the temperature for about 30-45 minutes to obtain mixture A;
  • step (2) heating to 60-70° C. and maintaining the temperature for about 10-20 minutes to obtain mixture B;
  • step (3) at 60-70° C., stirring for 5-15 minutes, continuously stirring and cooling to 20-30° C., and then adding mixture C under stirring;
  • step (3) a 10-micron box filter is used for filtration, and the relative density of the ambroxol hydrochloride solution is 1.098-1.117.
  • ambroxol hydrochloride, polyethylene glycol pentahydroxystearate, glycerin, tromethamine, levomenthol of recipe quantity are mixed and stirred, and heated to 60 ⁇ 70 °C, maintain this temperature about 30 ⁇ 45 minutes to obtain mixture A;
  • step (3) get the ammonium glycyrrhizinate of recipe quantity, 96% ethanol, 0.001N sodium hydroxide and mix and stir, obtain mixture C
  • the mixture B obtained in step (2) is slowly added to the mixture A obtained in step (1), at 60 ⁇ At 70 °C, stir for 5 to 15 minutes to obtain a milky white mixture, continue to stir and cool to 20 to 30 °C to obtain a clear, colorless solution, then add mixture C, continue to add purified water to the full amount, and use a 10-micron box filter Filtration, and then potting, that is.
  • Mixture B made of sodium benzoate, potassium acesulfame, xylitol was then added to mix A for preservation and flavoring, and finally a mix made of ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide was added C carry out flavoring and pH correction, and finally, after filtering and filling, the oral spray solution of ambroxol hydrochloride is obtained, which is filled in a spray bottle with a quantitative valve, and it can be used. The volume of each spray is 0.2 ml (equivalent to 10 mg of ambroxol hydrochloride).
  • step (1) when the stirring temperature in step (1) is 60-70°C, preferably 65°C or in step (3), when the cooling temperature is 20-30°C, preferably 25°C, it can Make the obtained product more stable.
  • the present invention has the following beneficial effects compared with the prior art:
  • ambroxol hydrochloride oral spray solution of the present invention can be widely used for the treatment of thick sputum and difficulty expectorating sputum caused by various acute and chronic respiratory diseases, and can be applied to patients in need of treatment through the oral spray route, and the dosage is generally 10 mg / times, the specific can be determined by the doctor according to the patient's condition, age, etc.
  • ambroxol hydrochloride oral spray solution of the present invention can enter the gastrointestinal tract through the oral cavity after being administered by oral spray, and has rapid absorption, rapid onset of effect and high bioavailability. At the same time, the spray solution is easy to use, does not need to be taken with water during administration, and has good compliance.
  • the present invention Compared with the existing ambroxol hydrochloride dosage forms (such as tablets, capsules, etc.), the present invention has more convenient and flexible usability by preparing the ambroxol hydrochloride solution into an oral spray solution, and does not require special environment and auxiliary
  • the equipment has a wide range of use, and can also unify the dosage standard, with less dosage and less waste.
  • the present invention completely dissolves all the components and has good stability, and obtains a liquid preparation with a higher concentration than the current commercially available oral solution.
  • the values all meet the requirements of 95.0-105.0% of the labeled amount of 5.00g/ml.
  • the high-concentration prescription makes the packaging size smaller, 25ml and 13ml, which are convenient to carry and use.
  • the taste of the solution of the invention is fresh, and acceptable taste is obtained by adding acesulfame potassium, xylitol, levomenthol and ammonium glycyrrhizinate, and the combination of sweetener and flavoring agent can effectively mask the bitter taste of ambroxol hydrochloride, and obtain Good mouthfeel, liquid formulation with acceptable taste.
  • the test of formaldehyde is added on the basis of the quality standard of the European Pharmacopoeia, and the limit is "no more than 5 ppm" to avoid the generation of impurity B.
  • the solution prepared by the invention can be well stored and meets the microbial limit requirements of oral pharmaceutical preparations in the European Pharmacopoeia.
  • Step 1 Mix and stir Ambroxol hydrochloride, polyethylene glycol pentahydroxystearate, glycerin, tromethamine, and levomenthol in the recipe quantity, and heat to 60° C., maintain the temperature for about 30 minutes, to obtain mixture A;
  • Step 2 Mix and stir the purified water, sodium benzoate, acesulfame potassium, and xylitol in the prescribed amount, heat to 65° C., and maintain the temperature for about 10 minutes to obtain mixture B, and obtain mixture B;
  • Step 3 Take the recipe amount of ammonium glycyrrhizinate, 96% ethanol, 0.001N sodium hydroxide and mix and stir to obtain mixture C, slowly add mixture B obtained in step (2) to mixture A obtained in step (1), and at 65° C. Under stirring for 5 minutes, a milky white mixture was obtained, which was continuously stirred and cooled to 25° C. to obtain a clear, colorless solution, then mixture C was added, and purified water was added to the full amount to obtain a bulk solution.
  • Step 4 Filter the bulk solution through a 10 micron box filter, collect the filtrate in a storage vessel and proceed to step 5.
  • Step 5 Fill the solution into a Type III amber glass bottle via a filling station connected to a nitrogen line, seal using a metering pump; check the fill volume and seal integrity.
  • Step 1 Mix and stir the ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerin, tromethamine and levomenthol in the recipe quantity, and heat to 65°C, and maintain the temperature for about 40 minutes, to obtain mixture A;
  • Step 2 Mix and stir the purified water, sodium benzoate, acesulfame potassium, and xylitol in the prescribed amount, heat to 65° C., and maintain the temperature for about 15 minutes to obtain mixture B, and obtain mixture B;
  • Step 3 Take the recipe amount of ammonium glycyrrhizinate, 96% ethanol, 0.001N sodium hydroxide and mix and stir to obtain mixture C, slowly add mixture B obtained in step (2) to mixture A obtained in step (1), and at 65° C. Under stirring for 10 minutes, a milky white mixture was obtained, which was continuously stirred and cooled to 25° C. to obtain a clear, colorless solution, then mixture C was added, and purified water was added to the full amount to obtain a bulk solution.
  • Step 4 Filter the bulk solution through a 10 micron box filter, collect the filtrate in a storage vessel and proceed to step 5.
  • Step 5 Fill the solution into a Type III amber glass bottle via a filling station connected to a nitrogen line, seal using a metering pump; check the fill volume and seal integrity.
  • Step 1 Mix and stir the ambroxol hydrochloride, polyethylene glycol pentahydroxystearate, glycerin, tromethamine, and levomenthol in the recipe quantity, and heat to 70° C., maintain the temperature for about 32 minutes, to obtain mixture A;
  • Step 2 Mix and stir the purified water, sodium benzoate, acesulfame potassium, and xylitol in the prescribed amount, heat to 70° C., and maintain the temperature for about 10 minutes to obtain mixture B, and obtain mixture B;
  • Step 3 Take the recipe quantity of ammonium glycyrrhizinate, 96% ethanol, 0.001N sodium hydroxide, mix and stir to obtain mixture C, slowly add mixture B obtained in step (2) to mixture A obtained in step (1), at 70 ° C Under stirring for 8 minutes, a milky white mixture was obtained, which was continuously stirred and cooled to 30° C. to obtain a clear, colorless solution. Then, mixture C was added, and purified water was continued to be added to the full amount to obtain a bulk solution.
  • Step 4 Filter the bulk solution through a 10 micron box filter, collect the filtrate in a storage vessel and proceed to step 5.
  • Step 5 Fill the solution into a Type III amber glass bottle via a filling station connected to a nitrogen line, seal using a metering pump; check the fill volume and seal integrity.
  • Step 1 Mix and stir the ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerin, tromethamine, and levomenthol in the recipe quantity, and heat to 68° C., and maintain the temperature for about 36 minutes, to obtain mixture A;
  • Step 2 Mix and stir the purified water, sodium benzoate, acesulfame potassium, and xylitol in the prescribed amount, heat to 67° C., and maintain the temperature for about 12 minutes to obtain mixture B, and obtain mixture B;
  • Step 3 Take the recipe quantity of ammonium glycyrrhizinate, 96% ethanol, 0.001N sodium hydroxide, mix and stir to obtain mixture C, slowly add mixture B obtained in step (2) to mixture A obtained in step (1), at 67 ° C Under stirring for 15 minutes, a milky white mixture was obtained, which was continuously stirred and cooled to 28° C. to obtain a clear, colorless solution, then mixture C was added, and purified water was added to the full amount to obtain a bulk solution.
  • Step 4 Filter the bulk solution through a 10 micron box filter, collect the filtrate in a storage vessel and proceed to step 5.
  • Step 5 Fill the solution into a Type III amber glass bottle via a filling station connected to a nitrogen line, seal using a metering pump; check the fill volume and seal integrity.
  • Step 1 Mix and stir the ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerin, tromethamine, and levomenthol in the recipe quantity, and heat to 63° C., and maintain the temperature for about 42 minutes, to obtain mixture A;
  • Step 2 mixing and stirring the purified water, sodium benzoate, acesulfame potassium, and xylitol in the prescribed amount, heating to 63° C., maintaining the temperature for about 18 minutes, obtaining mixture B, obtaining mixture B;
  • Step 3 Take the recipe quantity of ammonium glycyrrhizinate, 96% ethanol, 0.001N sodium hydroxide, mix and stir to obtain mixture C, slowly add mixture B obtained in step (2) to mixture A obtained in step (1), and at 63 ° C Under stirring for 15 minutes, a milky white mixture was obtained, which was continuously stirred and cooled to 26° C. to obtain a clear, colorless solution, then mixture C was added, and purified water was added to the full amount to obtain a bulk solution.
  • Step 4 Filter the bulk solution through a 10 micron box filter, collect the filtrate in a storage vessel and proceed to step 5.
  • Step 5 Fill the solution into a Type III amber glass bottle via a filling station connected to a nitrogen line, seal using a metering pump; check the fill volume and seal integrity.
  • Step 1 Mix and stir ambroxol hydrochloride 50 mg, polyethylene glycol pentahydroxystearate 100 mg, glycerin 29 mg, the pH adjuster of the recipe, and levomenthol 5 mg, and heat to 65° C. 40 minutes to obtain mixture A;
  • Step 2 Mix and stir purified water, sodium benzoate 5 mg, acesulfame potassium 15 mg, and xylitol 200 mg, heat to 65° C., and maintain the temperature for about 15 minutes to obtain mixture B, and obtain mixture B;
  • Step 3 Take 0.64 mg of ammonium glycyrrhizinate, 5 mg of 96% ethanol, and 6.25 mg of 0.001N sodium hydroxide, mix and stir to obtain mixture C, and slowly add mixture B obtained in step (2) to mixture A obtained in step (1), in Stir at 65°C for 10 minutes to obtain a milky white mixture, continue stirring and cool to 25°C to obtain a clear, colorless solution, then add mixture C and continue to add purified water to full volume to obtain a bulk solution.
  • Step 4 Filter the bulk solution through a 10 micron box filter, collect the filtrate in a storage vessel and proceed to step 5.
  • Step 5 Fill the solution into a Type III amber glass bottle via a filling station connected to a nitrogen line, seal using a metering pump; check the fill volume and seal integrity.
  • mass ratio glycerol (mg): polyethylene glycol pentahydroxystearate (mg): ambroxol hydrochloride (mg)
  • Step 1 Mix and stir the recipe quantities of Ambroxol hydrochloride, polyethylene glycol pentahydroxystearate, glycerin, tromethamine 3.6g, and levomenthol 5mg, and heat to 65°C, maintaining the temperature about 40 minutes to obtain mixture A;
  • Step 2 Mix and stir purified water, sodium benzoate 5 mg, acesulfame potassium 15 mg, and xylitol 200 mg, heat to 65° C., and maintain the temperature for about 15 minutes to obtain mixture B, and obtain mixture B;
  • Step 3 Take 0.64 mg of ammonium glycyrrhizinate, 5 mg of 96% ethanol, and 6.25 mg of 0.001N sodium hydroxide, mix and stir to obtain mixture C, and slowly add mixture B obtained in step (2) to mixture A obtained in step (1), in Stir at 65°C for 10 minutes to obtain a milky white mixture, continue stirring and cool to 25°C to obtain a clear, colorless solution, then add mixture C and continue to add purified water to full volume to obtain a bulk solution.
  • Step 4 Filter the bulk solution through a 10 micron box filter, collect the filtrate in a storage vessel and proceed to step 5.
  • Step 5 Fill the solution into a Type III amber glass bottle via a filling station connected to a nitrogen line, seal using a metering pump; check the fill volume and seal integrity.
  • the stability of the obtained finished product was investigated: after placing the sample for 5 days and 10 days, it was detected. The results are shown in Table 5.
  • the present invention also carried out sampling detection to 3 batches of ambroxol hydrochloride spray solution in Example 2:
  • Relative density The relative density of the solution was determined by a hydrometer according to European Pharmacopoeia 2.2.5 "Relative Density”.
  • **The indicated time points refer to the filling operation, i.e. 3 samples were taken at the beginning, middle and end of the filling process.
  • sample batch SPa1 batch SPa2 batch SPa3 PH3 meets the meets the meets the PH4bot meets the meets the meets the PH4top meets the meets the meets the meets the PH5start meets the meets the meets the PH5mid meets the meets the meets the PH5end meets the meets the meets the
  • the following table shows the content of ambroxol hydrochloride in the samples taken in production process step 3 and step 4.
  • n.d. n.d. ⁇ 0.5% PH5end/2 n.d. n.d. n.d. ⁇ 0.5% PH5end/3 n.d. n.d. n.d. n.d. ⁇ 0.5%

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Abstract

涉及一种盐酸氨溴索口腔喷雾溶液及其制备方法，所述盐酸氨溴索口腔喷雾溶液包括盐酸氨溴索45-55mg/ml，还包括药学上可接受的辅料以及添加至足量的纯化水。所述盐酸氨溴索口腔喷雾溶液可广泛用于急性支气管炎、慢性支气管炎等呼吸道疾病治疗，通过口腔喷雾途径施加于需要治疗的患者，药物可经口腔进入胃肠道，吸收迅速、起效快、生物利用度高。同时，喷雾溶液使用方便、用药依从性强，尤其适用于许多吞咽困难无法服用盐酸氨溴索口服固体制剂及溶液剂的病人。

Description

一种盐酸氨溴索口腔喷雾溶液及其制备方法 技术领域
本发明属于医药技术领域，具体地说，涉及一种盐酸氨溴索口腔喷雾溶液及其制备方法。
背景技术
氨溴索为溴己新的代谢物，且含氨溴索的药物已注册和上市销售多年。该物质以盐酸盐形式使用。氨溴索经证实可改善呼吸道上皮表面的粘液传输和清除机制并通过II类肺泡壁细胞刺激表面活性剂的合成和分泌。氨溴索用作痰液分泌异常或排痰功能受损为特征的急性和慢性支气管肺病的祛痰治疗。
盐酸氨溴索，Ambroxol Hydrochloride，为白色或微黄色结晶性粉末，具有独特的苦味，且服用后具有麻痹感。该物质略溶于水，溶于甲醇，且几乎不溶于二氯甲烷。当暴露于加热、酸性和碱性条件下，物质在水悬液中稳定，但对氧化物敏感，如过氧化氢，化学名：反式～4～[(2～氨基～3，5～二溴苄基)氨基]环己醇盐酸盐，分子式：C 13H 18Br 2N 2O·HCl，分子量：414.57，结构式：
Figure PCTCN2020138891-appb-000001
国外已上市的有沐舒坦(Mucosolvan)，系1979年由德国勃林格殷格翰公司研发上市，并先后在意大利、瑞士、阿根廷、日本等近二十个国家上市。痰之保克(Transbroncho)，系美国加利福尼亚大药厂生产；全福乐舒痰液(Losolvan)，系台湾全福化学股份有限公司出品；兰勃舒缓释胶囊(75mg/天)(Lambroxol)，系法国爱的发生产，中国常州第四制药厂进口分装。
原研上市剂型为注射液、片剂、糖浆、口服液、缓释胶囊，我国于1991年开始批准进口，商品名“沐舒坦”，盐酸氨溴索注射液规格为2ml：15mg，盐酸氨溴索注射液适用于伴有痰液分泌不正常及排痰功能不良的急性、慢性呼吸道疾病，例如，慢性支气管炎急性加重、喘 息型支气管炎及支气管哮喘的祛痰治疗，手术后肺部并发症的预防性治疗，早产儿及新生儿的婴儿呼吸窘迫综合症(IRDS)的治疗。
对于盐酸氨溴索的研究，国内外多集中于制剂剂型研究及临床新适应症的开发，目前，我国盐酸氨溴索的制剂类型有多种，如盐酸氨溴索片剂、盐酸氨溴索胶囊、盐酸氨溴索口服溶液剂、盐酸氨溴索缓释胶囊等。口服控释片剂或胶囊剂等固体制剂常因为口感不适或吞咽困难以及不易分剂量等问题，而导致此类患者的服用不便，影响正常治疗方案的完成和药效的发挥，如普通片剂一日给药3次，每次1片(30mg/片)，因疼痛、怕麻烦等原因患者会有意无意改变服药方案，漏服一次或两次，血浆和组织中的药物水平浓度起伏大，即使继续用药，短期内也达不到治疗浓度，只能重复用药才能重建治疗水平，既浪费了药物又延误了治疗，更进一步的，如果儿童服用，需将一片或者一粒药物分成几份服用，剂量难以准确控制，而且，固体制剂需先溶解，再溶出，人体才能吸收，吸收速度和起效都较慢。而液体制剂具有吸收快，可分剂量服用，易被老人和儿童所接受的特点，因此研究开发口感好且药效稳定的液体缓释制剂受到药剂学家和临床医生的高度重视。
另外，盐酸氨溴索口服溶液，以盐酸氨溴索、水、乙醇及其它矫味剂组成，由于其服用方便，在临床上广泛应用。但该产品有苦、涩、麻等不愉快的口感，成人尚可忍受，对于儿童则很难接受，众所周知，口服溶液主要用于儿童和吞咽困难的患者。目前对于这一矛盾的临床应用上没有更好的解决办法，这大大降低了该产品的依从性，即有些患者不愿用药从而不能按照规定定时服药，从而导致药物的治疗疗效无法达到预期效果。
因此，所述技术领域迫切需要一种治疗效果好、口感优良、质量稳定且用药依从性强的盐酸氨溴索制剂。
有鉴于此特提出本发明。
发明内容
本发明要解决现有技术中临床需求\依从性较差的技术问题，提供一种盐酸氨溴索口腔喷雾溶液，该口腔喷雾溶液可以使给药剂量更加精确、有效，通过处方及pH值的调节，使稳定性大大提高，且口感较佳，有效改善患者的依从性。
为解决上述技术问题，本发明采用技术方案的基本构思是：
本发明公开了一种盐酸氨溴索口腔喷雾溶液，以1ml计，所述盐酸氨溴索口腔喷雾溶液 包括以下的成分：盐酸氨溴索45～55mg，还包括药学上可接受的辅料以及添加至足量的纯化水。
盐酸氨溴索口腔喷雾溶液对患有慢性支气管炎急性发作、喘息型支气管炎、支气管哮喘的患者来说大大增加了服药的方便性。在临床应用上，许多吞咽困难的病人无法服用盐酸氨溴索的口服固体制剂及溶液剂，本品每次喷雾至口腔，非常容易进入胃肠道，因此可以供许多吞咽困难的病人使用。
本发明的盐酸氨溴索口腔喷雾溶液是一种新的处方，处方中盐酸氨溴索的浓度为45–55mg/ml，优选50mg/ml，盐酸氨溴索口腔喷雾溶液有两种包装规格，分别为1250mg/25ml和650mg/13ml，该口腔喷雾溶液可以使给药剂量更加精确，有效改善患者的依从性。
此外，本发明的喷雾溶液相比现有技术具有方便灵活的使用性，不需要特殊的环境，使用便携。
进一步的，所述药学上可接受的辅料包括溶剂、表面活性剂、防腐剂、调味剂、pH调节剂中的一种或几种。
进一步的，所述辅料包括溶剂、表面活性剂、防腐剂、调味剂和pH调节剂。
本发明通过添加上述活性成分和药学上可接受的辅料，可以制备出澄清、且口感优良的液体制剂，该制剂质量稳定，无可见异物析出，用药安全。
进一步的，所述缓冲剂包括氨丁三醇和/或氢氧化钠，优选的，所述缓冲剂包括氨丁三醇和氢氧化钠；所述氨丁三醇与盐酸氨溴索的质量比为0.06～0.08：1，优选的，所述氨丁三醇与盐酸氨溴索的质量比为0.072：1；所述0.01N氢氧化钠与盐酸氨溴索的质量比为0.12～0.14：1，更优选的，所述0.01N氢氧化钠与盐酸氨溴索的质量比为0.125：1。
本发明通过反复的实验发现，在活性成分盐酸氨溴索中加入一定量的氨丁三醇，可以大大的提高溶液体系的稳定性，当氨丁三醇与盐酸氨溴索的质量比为0.06～0.08：1，随着氨丁三醇用量的增加，产品稳定性随之增加，但当增加至一定量以后，几乎不再发生变化，但总杂有所增加，当氨丁三醇与盐酸氨溴索的质量比是0.072：1，稳定性效果最好。
进一步的，所述溶剂包括甘油和/或乙醇；所述溶剂包括甘油和96％乙醇，所述甘油、与盐酸氨溴索的质量比为0.54～0.6：1，优选的，所述甘油、与盐酸氨溴索的质量比为0.58：1；所述96％乙醇与盐酸氨溴索的质量比为0.08～0.14：1，优选的，所述96％乙醇与盐酸氨溴索的质量比为0.1：1。
进一步的，所述表面活性剂包括聚乙二醇十五羟基硬脂酸酯；所述聚乙二醇十五羟基硬脂酸酯与盐酸氨溴索的质量比为1.8～2.2：1，优选的，所述聚乙二醇十五羟基硬脂酸酯与盐酸氨溴索的质量比为2：1。
经研究发现，对于表面活性剂聚乙二醇十五羟基硬脂酸酯，若聚乙二醇十五羟基硬脂酸酯中含有痕量甲醛，则其可与氨溴索反应生成氨溴索在欧洲药典中指明的杂质B，因此，本发明所述聚乙二醇十五羟基硬脂酸酯中甲醛含量≤5ppm，以避免杂质B的生成。
本发明采用甘油和聚乙二醇十五羟基硬脂酸酯对活性成分盐酸氨溴索进行溶解，在通过反复试验后发现，当甘油、聚乙二醇十五羟基硬脂酸酯与盐酸氨溴索的质量比为0.54～0.6：1～3：1时，随着甘油、聚乙二醇十五羟基硬脂酸酯用量的增加，盐酸氨溴索的溶解度增加，但当增加超过一定量以后，会有杂质产生，当甘油、聚乙二醇十五羟基硬脂酸酯与盐酸氨溴索的质量比为0.58：2：1时，盐酸氨溴索完全溶解。
进一步的，所述防腐剂包括苯甲酸钠，所述苯甲酸钠与盐酸氨溴索的质量比为0.08～0.12：1，更优选的，所述苯甲酸钠与盐酸氨溴索的质量比为0.1：1。
本发明口腔喷雾溶液中含5mg/ml防腐剂苯甲酸钠，苯甲酸钠优于苯甲酸，因为其在水中的溶解度更好，且苯甲酸钠优于对羟基苯甲酸酯防腐剂，因为后者一般需要两种防腐剂组合(如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯)以实现对抗细菌和真菌。
鉴于制剂中所含的活性成分浓度较高，且以配备计量泵的多剂量容器供应，选择了浓度为5mg/ml的苯甲酸钠。防腐剂的浓度高于可比产品，如
Figure PCTCN2020138891-appb-000002
糖浆，但由于制剂给药量小，防腐剂的给予量同样较低。事实上，与其他产品相比，盐酸氨溴索日剂量为90mg时，本品给予的防腐剂的量低于其他产品约3-6倍。
进一步的，所述调味剂左薄荷脑、甘草酸铵、乙酰磺胺酸钾、木糖醇中的一种或几种；所述调味剂包括左薄荷脑、甘草酸铵、乙酰磺胺酸钾和木糖醇；优选的，所述左薄荷脑、甘草酸铵、乙酰磺胺酸钾、木糖醇与盐酸氨溴索的质量比为0.08～0.15：0.01～0.05：0.2～0.6：3.82～4.12：1；更优选的，所述左薄荷脑、甘草酸铵、乙酰磺胺酸钾、木糖醇与盐酸氨溴索的质量比为0.1：0.0128：0.3：4：1。
本发明通过反复实验发现，所述左薄荷脑、甘草酸铵、乙酰磺胺酸钾、木糖醇与盐酸氨溴索的质量比为0.08～0.15：0.01～0.05：0.2～0.6：3.82～4.12：1时，可有效掩盖盐酸氨溴索的苦味，当所述左薄荷脑、甘草酸铵、乙酰磺胺酸钾、木糖醇与盐酸氨溴索的质量比为0.1： 0.0128：0.3：4：1时，可有效掩盖盐酸氨溴索的苦味，使得喷雾溶液的口味清新。
本发明喷雾溶液的口味清新，通过添加乙酰磺胺酸钾、木糖醇、左薄荷脑和甘草酸铵获得可接受的口感，调味剂的组合可有效掩盖盐酸氨溴索的苦味，获得口感优良、具有可接受味道的口腔喷雾溶液。
进一步的，以1ml计，所述盐酸氨溴索口腔喷雾溶液包括以下重量的成分：盐酸氨溴索50mg，氨丁三醇3.6mg，聚乙二醇十五羟基硬脂酸酯100mg，甘油29mg，乙酰磺胺酸钾15mg，木糖醇200mg，苯甲酸钠5mg，左薄荷脑5mg，甘草酸铵0.64mg，96％乙醇5mg，0.01N氢氧化钠6.25mg，余量为纯化水。
本发明所述的盐酸氨溴索喷雾溶液在特定的配比和组成下，经过试验表明，惊奇地发现各项指标性状、pH值、含量、有关物质与0月比较，没有明显变化，说明本发明的配比和组成下的盐酸氨溴索喷雾溶液样品稳定性好。
进一步的，所述盐酸氨溴索口腔喷雾溶液的pH值为6.1～6.6，优选的，所述盐酸氨溴索口腔喷雾溶液的pH值为6.5。
本发明保证口腔喷雾溶液的pH在6.1～6.6之间，优选pH值为6.5，可以使盐酸氨溴索的稳定性好，该口腔喷雾溶液的pH更适合口腔喷雾给药，即本发明的盐酸氨溴索口腔喷雾溶液不仅活性成分的稳定性高，且更适合口腔给药。
本发明还公开了一种盐酸氨溴索口腔喷雾溶液制备方法，包括如下步骤：
(1)将处方量的盐酸氨溴索、聚乙二醇十五羟基硬脂酸酯、甘油、氨丁三醇、左薄荷脑混合搅拌并加热，获得混合物A；
(2)将处方量的纯化水、苯甲酸钠、乙酰磺胺酸钾、木糖醇混合搅拌并加热，获得混合物B；
(3)取处方量的甘草酸铵、96％乙醇、0.001N氢氧化钠混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，持续搅拌并冷却，然后添加混合物C，继续加入纯化水至全量，之后进行过滤、灌封，即得。
进一步的，步骤(1)中，加热至60～70℃，维持该温度约30～45分钟，获得混合物A；
进一步的，步骤(2)中，加热至60～70℃，维持该温度约10～20分钟，获得混合物B；
进一步的，步骤(3)中，在60～70℃下，搅拌5～15分钟，持续搅拌并冷却至20～30℃， 然后在搅拌下添加混合物C；
进一步的，步骤(3)中，采用10微米箱式过滤器过滤，所述盐酸氨溴索溶液的相对密度为1.098～1.117。
本发明一种盐酸氨溴索口腔喷雾溶液具体的制备方法如下：
(1)将处方量的盐酸氨溴索、聚乙二醇十五羟基硬脂酸酯、甘油、氨丁三醇、左薄荷脑混合搅拌，并加热至60～70℃，维持该温度约30～45分钟，获得混合物A；
(2)将处方量的纯化水、苯甲酸钠、乙酰磺胺酸钾、木糖醇混合搅拌，加热至60～70℃，维持该温度约10～20分钟，获得混合物B，获得混合物B；
(3)取处方量的甘草酸铵、96％乙醇、0.001N氢氧化钠混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，在60～70℃下，搅拌5～15分钟，得到乳白色混合物，持续搅拌并冷却至20～30℃，得到澄清、无色溶液，然后添加混合物C，继续加入纯化水至全量，采用10微米箱式过滤器过滤，之后进行灌封，即得。
本发明的上述制备方法中，首先采用在活性成分盐酸氨溴索中加入一定量的氨丁三醇，提高溶液体系的稳定性，然后添加聚乙二醇15羟基硬脂酸酯和甘油将活性成分完全溶解，并添加左薄荷脑进行掩味，得到均一的混合物A；
然后向混合物A中加入由苯甲酸钠以及乙酰磺胺酸钾、木糖醇制成的混合物B，进行防腐和调味处理，最后加入由甘草酸铵、96％乙醇和0.001N氢氧化钠制成的混合物C进行调味以及pH校正，最后，经过滤、灌封后即得到盐酸氨溴索口腔喷雾溶液，将其灌装于带有定量阀的喷雾瓶中，即可使用，每次喷出体积为0.2ml(相当于10mg盐酸氨溴索)。
此外，在制备过程中还发现，当步骤(1)中的搅拌温度为60～70℃时，优选65℃或步骤(3)中，冷却的温度为20-30℃时，优选25℃，能够使制得的产品更稳定。
采用上述技术方案后，本发明与现有技术相比具有以下有益效果：
本发明的盐酸氨溴索口腔喷雾溶液可广泛用于各种急、慢性呼吸道疾病引起的痰液粘稠、咳痰困难等治疗，可通过口腔喷雾途径施加于需要治疗的患者，剂量一般为10mg/次，具体可根据病人的病情、年龄等，由医师决定。
本发明的盐酸氨溴索口腔喷雾溶液，经口腔喷雾给药后，药物可经口腔进入胃肠道，吸收迅速、起效快、生物利用度高。同时，喷雾溶液使用方便，给药时不需用水送服，有良好的依从性。
本发明通过将盐酸氨溴索溶液制成口腔喷雾溶液，相比于现有的盐酸氨溴索剂型(如片剂、胶囊剂等)具有更方便灵活的使用性，不需要特殊的环境和辅助设备，使用范围广，还可统一剂量标准，用量少，浪费少。
本发明通过对处方成分的改进，使所有成分完全溶解，且稳定性好，获得了比当前市售口服溶液浓度更高的液体制剂，经过对3个批次盐酸氨溴索的含量检测，所有值均符合95.0～105.0％标示量5.00g/ml的要求，高浓度的处方使包装尺寸更小，25ml和13ml尺寸，携带及使用方便。
本发明溶液的味道清新，通过添加乙酰磺胺酸钾、木糖醇、左薄荷脑和甘草酸铵获得可接受的口感，甜味剂和调味剂的组合可有效掩盖盐酸氨溴索的苦味，获得口感优良、具有可接受味道的液体制剂。
本发明中对表面活性剂聚乙二醇十五羟基硬脂酸酯，在欧洲药典质量标准基础上增加了甲醛的检验，限度为“不超过5ppm”，避免杂质B的产生。
本发明制备的溶液可很好的贮存，并符合欧洲药典中口服药物制剂的微生物限度要求。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对实施例中的技术方案进行清楚、完整地描述，以下实施例用于说明本发明，但不用来限制本发明的范围。
实验例1
采用如表1中的处方，一种盐酸氨溴索口腔喷雾溶液的制备方法如下：
步骤1：将处方量的盐酸氨溴索、聚乙二醇十五羟基硬脂酸酯、甘油、氨丁三醇、左薄荷脑混合搅拌，并加热至60℃，维持该温度约30分钟，获得混合物A；
步骤2：将处方量的纯化水、苯甲酸钠、乙酰磺胺酸钾、木糖醇混合搅拌，加热至65℃，维持该温度约10分钟，获得混合物B，获得混合物B；
步骤3：取处方量的甘草酸铵、96％乙醇、0.001N氢氧化钠混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，在65℃下，搅拌5分钟，得到乳白色混合物，持续搅拌并冷却至25℃，得到澄清、无色溶液，然后添加混合物C，继续加入纯化水至全量，得到散装溶液。
步骤4：散装溶液通过10微米箱式过滤器过滤，在储存容器中收集滤液并继续步骤5的处理。
步骤5：通过连接氮气线的灌装站，将溶液灌装至III型琥珀色玻璃瓶中，使用计量泵密封；检查灌装体积和密封的完整性。
实施例2
采用如表1中的处方，一种盐酸氨溴索口腔喷雾溶液的制备方法如下：
步骤1：将处方量的盐酸氨溴索、聚乙二醇十五羟基硬脂酸酯、甘油、氨丁三醇、左薄荷脑混合搅拌，并加热至65℃，维持该温度约40分钟，获得混合物A；
步骤2：将处方量的纯化水、苯甲酸钠、乙酰磺胺酸钾、木糖醇混合搅拌，加热至65℃，维持该温度约15分钟，获得混合物B，获得混合物B；
步骤3：取处方量的甘草酸铵、96％乙醇、0.001N氢氧化钠混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，在65℃下，搅拌10分钟，得到乳白色混合物，持续搅拌并冷却至25℃，得到澄清、无色溶液，然后添加混合物C，继续加入纯化水至全量，得到散装溶液。
步骤4：散装溶液通过10微米箱式过滤器过滤，在储存容器中收集滤液并继续步骤5的处理。
步骤5：通过连接氮气线的灌装站，将溶液灌装至III型琥珀色玻璃瓶中，使用计量泵密封；检查灌装体积和密封的完整性。
实施例3
采用如表1中的处方，一种盐酸氨溴索口腔喷雾溶液的制备方法如下：
步骤1：将处方量的盐酸氨溴索、聚乙二醇十五羟基硬脂酸酯、甘油、氨丁三醇、左薄荷脑混合搅拌，并加热至70℃，维持该温度约32分钟，获得混合物A；
步骤2：将处方量的纯化水、苯甲酸钠、乙酰磺胺酸钾、木糖醇混合搅拌，加热至70℃，维持该温度约10分钟，获得混合物B，获得混合物B；
步骤3：取处方量的甘草酸铵、96％乙醇、0.001N氢氧化钠混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，在70℃下，搅拌8分钟，得到乳白色混合物，持续搅拌并冷却至30℃，得到澄清、无色溶液，然后添加混合物C，继 续加入纯化水至全量，得到散装溶液。
步骤4：散装溶液通过10微米箱式过滤器过滤，在储存容器中收集滤液并继续步骤5的处理。
步骤5：通过连接氮气线的灌装站，将溶液灌装至III型琥珀色玻璃瓶中，使用计量泵密封；检查灌装体积和密封的完整性。
实施例4
采用如表1中的处方，一种盐酸氨溴索口腔喷雾溶液的制备方法如下：
步骤1：将处方量的盐酸氨溴索、聚乙二醇十五羟基硬脂酸酯、甘油、氨丁三醇、左薄荷脑混合搅拌，并加热至68℃，维持该温度约36分钟，获得混合物A；
步骤2：将处方量的纯化水、苯甲酸钠、乙酰磺胺酸钾、木糖醇混合搅拌，加热至67℃，维持该温度约12分钟，获得混合物B，获得混合物B；
步骤3：取处方量的甘草酸铵、96％乙醇、0.001N氢氧化钠混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，在67℃下，搅拌15分钟，得到乳白色混合物，持续搅拌并冷却至28℃，得到澄清、无色溶液，然后添加混合物C，继续加入纯化水至全量，得到散装溶液。
步骤4：散装溶液通过10微米箱式过滤器过滤，在储存容器中收集滤液并继续步骤5的处理。
步骤5：通过连接氮气线的灌装站，将溶液灌装至III型琥珀色玻璃瓶中，使用计量泵密封；检查灌装体积和密封的完整性。
实施例5
采用如表1中的处方，一种盐酸氨溴索口腔喷雾溶液的制备方法如下：
步骤1：将处方量的盐酸氨溴索、聚乙二醇十五羟基硬脂酸酯、甘油、氨丁三醇、左薄荷脑混合搅拌，并加热至63℃，维持该温度约42分钟，获得混合物A；
步骤2：将处方量的纯化水、苯甲酸钠、乙酰磺胺酸钾、木糖醇混合搅拌，加热至63℃，维持该温度约18分钟，获得混合物B，获得混合物B；
步骤3：取处方量的甘草酸铵、96％乙醇、0.001N氢氧化钠混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，在63℃下，搅拌15分钟， 得到乳白色混合物，持续搅拌并冷却至26℃，得到澄清、无色溶液，然后添加混合物C，继续加入纯化水至全量，得到散装溶液。
步骤4：散装溶液通过10微米箱式过滤器过滤，在储存容器中收集滤液并继续步骤5的处理。
步骤5：通过连接氮气线的灌装站，将溶液灌装至III型琥珀色玻璃瓶中，使用计量泵密封；检查灌装体积和密封的完整性。
实施例1-5
处方：
表1 实施例1-5的处方
Figure PCTCN2020138891-appb-000003
对比例1-4
添加不同pH调节剂处方实验(规格3.6mg，pH调节剂见表2)
步骤1：将盐酸氨溴索50mg、聚乙二醇十五羟基硬脂酸酯100mg、甘油29mg、处方量的pH调节剂、左薄荷脑5mg混合搅拌，并加热至65℃，维持该温度约40分钟，获得混合物A；
步骤2：将纯化水、苯甲酸钠5mg、乙酰磺胺酸钾15mg、木糖醇200mg混合搅拌，加热至65℃，维持该温度约15分钟，获得混合物B，获得混合物B；
步骤3：取甘草酸铵0.64mg、96％乙醇5mg、0.001N氢氧化钠6.25mg混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，在65℃下，搅拌10分钟，得到乳白色混合物，持续搅拌并冷却至25℃，得到澄清、无色溶液，然后添加混合物C，继续加入纯化水至全量，得到散装溶液。
步骤4：散装溶液通过10微米箱式过滤器过滤，在储存容器中收集滤液并继续步骤5的处理。
步骤5：通过连接氮气线的灌装站，将溶液灌装至III型琥珀色玻璃瓶中，使用计量泵密封；检查灌装体积和密封的完整性。
表2 各对比例pH调节剂处方
Figure PCTCN2020138891-appb-000004
上述各实施例和对比例样品进行稳定性考察：将各样品放置5天、10天后，对其进行检测，结果见表3。
表3 稳定性检测结果
Figure PCTCN2020138891-appb-000005
Figure PCTCN2020138891-appb-000006
注：含量以盐酸氨溴索计。
以上实验结果显示，与对比例添加其它pH调节剂的样品相比，本发明实施例制备的盐酸氨溴索口腔喷雾溶液，添加了氨丁三醇后，总杂质含量明显降低，溶液澄清，无可见异物，产品含量提高，说明本发明制备的盐酸氨溴索口腔喷雾溶液稳定性好，质量高。
试验例1-5
甘油和聚乙二醇十五羟基硬脂酸酯用量对活性成分盐酸氨溴索的影响
表4 甘油(mg)、聚乙二醇十五羟基硬脂酸酯(mg)和盐酸氨溴索(mg)用量
Figure PCTCN2020138891-appb-000007
Figure PCTCN2020138891-appb-000008
注：质量比＝甘油(mg)：聚乙二醇十五羟基硬脂酸酯(mg)：盐酸氨溴索(mg)
步骤1：将处方量的盐酸氨溴索、聚乙二醇十五羟基硬脂酸酯、甘油、氨丁三醇3.6g、左薄荷脑5mg混合搅拌，并加热至65℃，维持该温度约40分钟，获得混合物A；
步骤2：将纯化水、苯甲酸钠5mg、乙酰磺胺酸钾15mg、木糖醇200mg混合搅拌，加热至65℃，维持该温度约15分钟，获得混合物B，获得混合物B；
步骤3：取甘草酸铵0.64mg、96％乙醇5mg、0.001N氢氧化钠6.25mg混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，在65℃下，搅拌10分钟，得到乳白色混合物，持续搅拌并冷却至25℃，得到澄清、无色溶液，然后添加混合物C，继续加入纯化水至全量，得到散装溶液。
步骤4：散装溶液通过10微米箱式过滤器过滤，在储存容器中收集滤液并继续步骤5的处理。
步骤5：通过连接氮气线的灌装站，将溶液灌装至III型琥珀色玻璃瓶中，使用计量泵密封；检查灌装体积和密封的完整性。
对所得成品进行稳定性考察：将样品放置5天、10天后，检测，结果见表5。
表5 稳定性检测结果
Figure PCTCN2020138891-appb-000009
Figure PCTCN2020138891-appb-000010
注：含量以盐酸氨溴索计。
由上表可知，当甘油、聚乙二醇十五羟基硬脂酸酯与盐酸氨溴索的质量比为0.54～0.6：1～3：1时，随着甘油、聚乙二醇十五羟基硬脂酸酯用量的增加，盐酸氨溴索的溶解度增加，产品稳定性随之增加，异物减少，但当增加超过一定量以后，盐酸氨溴索开始析出，可见异物增多，总杂有所增加，当甘油、聚乙二醇十五羟基硬脂酸酯与盐酸氨溴索的质量比为0.58：2：1时，盐酸氨溴索完全溶解，稳定性最好。
试验例6 质量检测结果
本发明还对实施例2中盐酸氨溴索喷雾溶液3个批次进行进行了采样检测：
A、检测标准：
Figure PCTCN2020138891-appb-000011
B、过程控制方法的描述
(1)溶液外观：在无色、透明、中性玻璃试管中对溶液样品进行目视检查。
(2)PH：根据欧洲药典2.3.3“电位法测定PH”测定溶液的PH。
(3)相对密度：根据欧洲药典2.2.5“相对密度”通过比重计测定溶液的相对密度。
1)采样计划
Figure PCTCN2020138891-appb-000012
Figure PCTCN2020138891-appb-000013
*在溶液的大约中层处采集一份均匀样品。盐酸氨溴索的含量必须在±5％理论值范围内。
**指示的时间点指的是灌装操作，即在灌装工艺开始、中间和结束时各采集3份样品。
2)结果
验证研究的结果以表格形式列于下文。
a)溶液外观
样品 批次SPa1 批次SPa2 批次SPa3
PH3 符合 符合 符合
PH4bot 符合 符合 符合
PH4top 符合 符合 符合
PH5start 符合 符合 符合
PH5mid 符合 符合 符合
PH5end 符合 符合 符合
在各工艺步骤中检查各批次的溶液外观。结果符合验收标准。
b)pH和相对密度
Figure PCTCN2020138891-appb-000014
计算灌装过程中所取样品的平均值、标准偏差和相对标准偏差RSD(PH5start、PH5middle 和PH5end)。这些数值显示生产工艺具有稳健性和重复性，批次间差异较小。
C)盐酸氨溴索含量
下表显示在生产工艺步骤3和步骤4中所取样品中盐酸氨溴索的含量。
步骤3
Figure PCTCN2020138891-appb-000015
步骤4
Figure PCTCN2020138891-appb-000016
下表中报告了各批次步骤5中的盐酸氨溴索含量结果。
步骤5～批次Spa1
样品 标示量[g/100ml] 实测值[g/100ml] 实测值(标示量％)
PH5start/1 5.00 4.89 97.8
PH5start/2 5.00 5.07 101.4
PH5start/3 5.00 5.02 100.4
PH5mid/1 5.00 4.95 99.0
PH5mid/2 5.00 5.01 100.2
PH5mid/3 5.00 5.08 101.6
PH5end/1 5.00 5.05 101.0
PH5end/2 5.00 4.88 97.6
PH5end/3 5.00 5.02 100.4
均值 ～～～ 5.00 99.93
标准差 ～～～ 0.07 1.39
RSD[％] ～～～ 1.39 1.39
步骤5～批次Spa2
Figure PCTCN2020138891-appb-000017
Figure PCTCN2020138891-appb-000018
步骤5～批次Spa3
Figure PCTCN2020138891-appb-000019
对于盐酸氨溴索的含量，所有值均符合95.0～105.0％标示量5.00g/100ml的要求。此外，RSD值证实在灌装工艺期间溶液的均匀性。
D)降解产物
在下表中，报告了各批次中步骤5的代表性样品进行杂质试验的结果。
步骤5～批次Spa1
样品 杂质A[％(w/w)] 杂质B[％(w/w)] 杂质E[％(w/w)] 非特定杂质[％(w/w)] 总杂质[％(w/w)]
PH5start/1 n.d. n.d. n.d. n.d. <0.5％
PH5start/2 n.d. n.d. n.d. n.d. <0.5％
PH5start/3 n.d. n.d. n.d. n.d. <0.5％
PH5mid/1 n.d. n.d. n.d. n.d. <0.5％
PH5mid/2 n.d. n.d. n.d. n.d. <0.5％
PH5mid/3 n.d. n.d. n.d. n.d. <0.5％
PH5end/1 n.d. n.d. n.d. n.d. <0.5％
PH5end/2 n.d. n.d. n.d. n.d. <0.5％
PH5end/3 n.d. n.d. n.d. n.d. <0.5％
n.d.＝未检出
步骤5～批次Spa2
样品 杂质A[％(w/w)] 杂质B[％(w/w)] 杂质E[％(w/w)] 非特定杂质[％(w/w)] 总杂质[％(w/w)]
PH5start/1 n.d. n.d. n.d. n.d. <0.5％
PH5start/2 n.d. n.d. n.d. n.d. <0.5％
PH5start/3 n.d. n.d. n.d. n.d. <0.5％
PH5mid/1 n.d. n.d. n.d. n.d. <0.5％
PH5mid/2 n.d. n.d. n.d. n.d. <0.5％
PH5mid/3 n.d. n.d. n.d. n.d. <0.5％
PH5end/1 n.d. n.d. n.d. n.d. <0.5％
PH5end/2 n.d. n.d. n.d. n.d. <0.5％
PH5end/3 n.d. n.d. n.d. n.d. <0.5％
n.d.＝未检出
步骤5～批次Spa3
样品 杂质A[％(w/w)] 杂质B[％(w/w)] 杂质E[％(w/w)] 非特定杂质[％(w/w)] 总杂质[％(w/w)]
PH5start/1 n.d. n.d. n.d. n.d. <0.5％
PH5start/2 n.d. n.d. n.d. n.d. <0.5％
PH5start/3 n.d. n.d. n.d. n.d. <0.5％
PH5mid/1 n.d. n.d. n.d. n.d. <0.5％
PH5mid/2 n.d. n.d. n.d. n.d. <0.5％
PH5mid/3 n.d. n.d. n.d. n.d. <0.5％
PH5end/1 n.d. n.d. n.d. n.d. <0.5％
PH5end/2 n.d. n.d. n.d. n.d. <0.5％
PH5end/3 n.d. n.d. n.d. n.d. <0.5％
n.d.＝未检出
对于各批次，杂质试验结果符合验收标准。
E)苯甲酸钠含量测定
在下表中，报告了各批次中步骤5的代表性样品进行苯甲酸钠含量测定的结果。
步骤5～批次Spa1
Figure PCTCN2020138891-appb-000020
步骤5～批次Spa2
Figure PCTCN2020138891-appb-000021
Figure PCTCN2020138891-appb-000022
步骤5～批次Spa3
Figure PCTCN2020138891-appb-000023
对于苯甲酸钠含量测定，所有数值均满足95.0～105.0％标示量。即0.50g/100ml的要求。此外，RSD值证实灌装工艺过程中溶液的均匀性。
F)微生物
在下表中，报告了各批次中步骤5的代表性样品进行微生物试验的结果。
步骤5～批次Spa1
样品 需氧菌[cfu/ml] 需氧真菌[cfu/ml] 大肠杆菌
PH5start/1 ＜10 ＜10 不存在
PH5start/2 ＜10 ＜10 不存在
PH5start/3 ＜10 ＜10 不存在
PH5mid/1 ＜10 ＜10 不存在
PH5mid/2 ＜10 ＜10 不存在
PH5mid/3 ＜10 ＜10 不存在
PH5end/1 ＜10 ＜10 不存在
PH5end/2 ＜10 ＜10 不存在
PH5end/3 ＜10 ＜10 不存在
步骤5～批次Spa2
样品 需氧菌[cfu/ml] 需氧真菌[cfu/ml] 大肠杆菌
PH5start/1 ＜10 ＜10 不存在
PH5start/2 ＜10 ＜10 不存在
PH5start/3 ＜10 ＜10 不存在
PH5mid/1 ＜10 ＜10 不存在
PH5mid/2 ＜10 ＜10 不存在
PH5mid/3 ＜10 ＜10 不存在
PH5end/1 ＜10 ＜10 不存在
PH5end/2 ＜10 ＜10 不存在
PH5end/3 ＜10 ＜10 不存在
步骤5～批次Spa3
样品 需氧菌[cfu/ml] 需氧真菌[cfu/ml] 大肠杆菌
PH5start/1 ＜10 ＜10 不存在
PH5start/2 ＜10 ＜10 不存在
PH5start/3 ＜10 ＜10 不存在
PH5mid/1 ＜10 ＜10 不存在
PH5mid/2 ＜10 ＜10 不存在
PH5mid/3 ＜10 ＜10 不存在
PH5end/1 ＜10 ＜10 不存在
PH5end/2 ＜10 ＜10 不存在
PH5end/3 ＜10 ＜10 不存在
结果满足各批次中各样品的验收限度。
以上所述仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专利的技术人员在不脱离本发明技术方案范围内，当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明方案的范围内。

Claims (10)

  1. 一种盐酸氨溴索口腔喷雾溶液，其特征在于：以1ml计，所述盐酸氨溴索口腔喷雾溶液包括以下的成分：盐酸氨溴索45-55mg，还包括药学上可接受的辅料以及添加至足量的纯化水。
  2. 根据权利要求1所述的盐酸氨溴索口腔喷雾溶液，其特征在于：以1ml计，所述盐酸氨溴索的含量为50mg。
  3. 根据权利要求1或2所述的盐酸氨溴索口腔喷雾溶液，其特征在于：所述药学上可接受的辅料包括溶剂、表面活性剂、防腐剂、调味剂、pH调节剂中的一种或几种；
    优选的，所述辅料包括溶剂、表面活性剂、防腐剂、调味剂和pH调节剂。
  4. 根据权利要求3所述的盐酸氨溴索口腔喷雾溶液，其特征在于：
    所述溶剂包括甘油和/或乙醇，优选的，所述溶剂包括甘油和96％乙醇；
    所述pH调节剂包括氨丁三醇和/或氢氧化钠，优选的，所述pH调节剂包括氨丁三醇和氢氧化钠；
    所述表面活性剂包括聚乙二醇十五羟基硬脂酸酯；
    所述防腐剂包括苯甲酸钠；
    所述调味剂左薄荷脑、甘草酸铵、乙酰磺胺酸钾、木糖醇中的一种或几种，优选的，所述调味剂包括左薄荷脑、甘草酸铵、乙酰磺胺酸钾和木糖醇。
  5. 根据权利要求4所述的盐酸氨溴索口腔喷雾溶液，其特征在于：
    所述甘油与盐酸氨溴索的质量比为0.54～0.6：1，优选的，甘油与盐酸氨溴索的质量比为0.58：1，所述96％乙醇与盐酸氨溴索的质量比为0.08～0.14，优选的，96％乙醇与盐酸氨溴索的质量比为0.1：1；
    所述氨丁三醇与盐酸氨溴索的质量比为0.06～0.08：1，优选的，所述氨丁三醇与盐酸氨溴索的质量比为0.072：1；所述0.01N氢氧化钠与盐酸氨溴索的质量比为0.12～0.14：1，优选的，所述0.01N氢氧化钠与盐酸氨溴索的质量比为0.125：1；
    所述聚乙二醇十五羟基硬脂酸酯与盐酸氨溴索的质量比为1.8～2.2：1，优选的，所述聚乙二醇十五羟基硬脂酸酯与盐酸氨溴索的质量比为2：1；
    所述苯甲酸钠与盐酸氨溴索的质量比为0.08～0.12：1，优选的，所述苯甲酸钠与盐酸氨溴索的质量比为0.1：1；
    所述左薄荷脑、甘草酸铵、乙酰磺胺酸钾、木糖醇与盐酸氨溴索的质量比为0.08～0.15：0.01～0.05：0.2～0.6：3.82～4.12：1，优选的，所述左薄荷脑、甘草酸铵、乙酰磺胺酸钾、木糖醇与盐酸氨溴索的质量比为0.1：0.0128：0.3：4：1。
  6. 根据权利要求1～5任一所述的盐酸氨溴索口腔喷雾溶液，其特征在于：以1ml计，所述盐酸氨溴索口腔喷雾溶液包括以下重量的成分：盐酸氨溴索50mg，氨丁三醇3.6mg，聚乙二醇十五羟基硬脂酸酯100mg，甘油29mg，乙酰磺胺酸钾15mg，木糖醇200mg，苯甲酸钠5mg，左薄荷脑5mg，甘草酸铵0.64mg，96％乙醇5mg，0.01N氢氧化钠6.25mg，余量为纯化水。
  7. 根据权利要求1～6任一所述的盐酸氨溴索口腔喷雾溶液，其特征在于：所述盐酸氨溴索口腔喷雾溶液的pH值为6.1～6.6，优选的，所述盐酸氨溴索口腔喷雾溶液的pH值为6.5。
  8. 一种如权利要求1-7任一所述的盐酸氨溴索口腔喷雾溶液的制备方法，其特征在于：包括如下步骤：
    (1)将处方量的盐酸氨溴索、聚乙二醇十五羟基硬脂酸酯、甘油、氨丁三醇、左薄荷脑混合搅拌并加热，获得混合物A；
    (2)将处方量的纯化水、苯甲酸钠、乙酰磺胺酸钾、木糖醇混合搅拌并加热，获得混合物B；
    (3)取处方量的甘草酸铵、96％乙醇、0.001N氢氧化钠混合搅拌，获得混合物C，将步骤(2)所得混合物B缓慢添加至步骤(1)所得混合物A中，持续搅拌并冷却，然后添加混合物C，加入纯化水至全量，之后进行过滤、灌封，即得。
  9. 根据权利要求8所述的盐酸氨溴索溶液的制备方法，其特征在于：
    步骤(1)中，加热至60～70℃，维持该温度约30～45分钟，获得混合物A；
    步骤(2)中，加热至60～70℃，维持该温度约10～20分钟，获得混合物B。
  10. 根据权利要求8或9所述的盐酸氨溴索溶液的制备方法，其特征在于：步骤(3)中，在60～70℃下，搅拌5～15分钟，持续搅拌并冷却至20～30℃，然后在搅拌下添加混合物C；
    优选的，步骤(3)中，采用10微米箱式过滤器过滤，所述盐酸氨溴索溶液的相对密度为1.098～1.117。
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