Ambroxol orally disintegrating film composition, method of preparation and use thereof

Abstract

The application provides an ambroxol oral dissolving film composition, a preparation method and application thereof. The ambroxol oral dissolving film composition comprises an active drug, a film forming material and a taste masking agent, and the active drug is 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl) benzylamine and / or a pharmaceutically acceptable salt thereof, for example, ambroxol hydrochloride. The ambroxol oral dissolving film composition provided by the application has the advantages of thin thickness, good taste, stable properties, immediate dissolution in the oral cavity without drinking water, and fast oral absorption speed. Moreover, the ambroxol oral dissolving film composition has the advantages of simple process, high drug loading, good drug content uniformity, and good market prospect.

Description

[0001] This application claims priority to the earlier application filed on November 14, 2022, with the China National Intellectual Property Administration, patent application number 202211420255.4, entitled "Ambroxol Hydrochloride Oral Dissolution Film Composition, Preparation Method Thereof and Application". The entire contents of that application are incorporated herein by reference.

[0002] This application is a divisional application filed on November 14, 2023, by the China National Intellectual Property Administration, with patent application number 2023115140899 and invention title "Ambroxol Hydrochloride Oral Dissolution Film Composition, Preparation Method Thereof and Application". Technical Field

[0003] This invention relates to an oral solution composition of ambroxol hydrochloride, its preparation method and application. Background Technology

[0004] Ambroxol hydrochloride is the active metabolite of the expectorant bromhexine, exhibiting lower toxicity and higher activity than bromhexine. Developed by Boehringer Ingelheim in Germany, ambroxol hydrochloride is a mucolytic agent that was first marketed in Germany in the early 1980s, followed by its introduction to many other countries including France, Italy, Japan, and Spain. It is a new generation of mucolytic agent that improves expectoration and promotes pulmonary surfactant, airway secretion, and ciliary movement. Clinically, it regulates mucus and mucus secretion, activates ciliary movement, facilitates sputum thinning, enhances mucus transport, and facilitates expectoration. It also promotes pulmonary surfactant synthesis to maintain alveolar tone and ensure lung function indicators; promotes antibiotic penetration into tissues to increase concentration and enhance bactericidal effects; acts as an antioxidant, reducing the release of inflammatory mediators to alleviate inflammatory responses; and works synergistically with bronchodilators to improve the efficacy of antispasmodic drugs. Therefore, this drug can be widely used in clinical practice for acute and chronic respiratory diseases accompanied by abnormal respiratory secretions, especially for expectorant treatment of chronic bronchitis, neonatal respiratory distress syndrome, and as an adjunct treatment for lung surgery. It has the advantages of low toxicity, definite efficacy, and good synergistic effect when used with antibiotics, making it one of the most commonly used expectorants.

[0005] Currently, the original drug manufacturer has marketed it in China in the form of injections, tablets, sustained-release capsules, and oral solutions. The drug has been authorized in the following countries through various approval processes: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and the Netherlands.

[0006] In addition, generic drugs such as injections, oral solutions, syrups, granules, regular tablets, capsules, sustained-release tablets, sustained-release capsules, orally disintegrating tablets, dispersible tablets, and chewable tablets have been launched in China.

[0007] Ambroxol is popular among clinicians due to its significant expectorant effect, and its injectable form is widely used for nebulized therapy in patients with respiratory diseases (off-label). However, the weakly acidic ambroxol injection solution itself can irritate the airways after nebulization, leading to airway spasm and difficulty breathing. This adverse effect is more pronounced in COPD patients. Furthermore, the saline-based injection solution, regardless of the nebulized particle diameter or excipients (including preservatives), may pose a risk of lung infection or exacerbation of asthma after nebulization. However, in 2019, Hanmi's marketing application (JXHS1700033) for inhaled ambroxol hydrochloride solution, submitted under a Class 5.2 new drug category (granted priority review on the grounds of "pediatric use"), was approved by the National Medical Products Administration. This application addresses the pain point of pediatric patients requiring large doses of ambroxol, where existing formulations cannot meet clinical needs.

[0008] In my country, oral ambroxol preparations are all over-the-counter (OTC) drugs and are among the best-selling respiratory medications, used by a wide range of people, especially infants and children. The instructions for ambroxol hydrochloride oral solution clearly state that it is suitable for infants and young children. However, internationally, the use of such products by infants and young children is highly controversial. Many organizations are concerned about the appropriateness of using ambroxol as an expectorant in children under 6 years old, believing that the benefits of this drug do not outweigh the risks in this patient population.

[0009] Ambroxol tablets and extended-release capsules require swallowing with water, which can lead to poor compliance in some elderly people, children, and patients with swallowing difficulties. Their use may be limited or less effective in certain situations (such as lack of drinking water). Injectable formulations pose safety risks and have poor patient compliance. While oral solutions have a pleasant taste, they suffer from drawbacks such as larger dosages, difficulty in dosing, and poor stability. Furthermore, they require sophisticated manufacturing processes and packaging, and their inconvenience in carrying and transporting them creates numerous inconveniences and safety risks for patients.

[0010] Ambroxol hydrochloride is slightly soluble in water. The drug has a bitter and numbing taste, and this bitterness and numbing sensation are persistent and cannot be masked by conventional addition of solubilizers and flavoring agents, resulting in poor patient compliance, especially in children. Patent document CN102846581A discloses an orally dissolving film for ambroxol hydrochloride; however, experiments have shown that the orally dissolving film prepared using this formula has poor mechanical strength, instability, slow disintegration, and a complex preparation process, which is not conducive to commercial production.

[0011] Therefore, there is an urgent need to develop a formulation of ambroxol hydrochloride that has good stability, good taste, and good patient compliance. Summary of the Invention

[0012] To overcome the shortcomings of existing ambroxol hydrochloride oral dissolving films, such as poor taste, poor stability, and / or poor patient compliance, this invention provides an ambroxol hydrochloride oral dissolving film composition, its preparation method, and its application. The ambroxol hydrochloride oral dissolving film composition provided by this invention has the advantages of thin thickness, good taste, stable properties, stable mechanical properties, and immediate dissolution in the oral cavity without the need for drinking water, as well as rapid oral absorption. Furthermore, its process is simple, it has a high drug loading capacity, good drug content uniformity, and promising market prospects.

[0013] This invention provides an ambroxol oral dissolving film composition comprising an active pharmaceutical ingredient, a film-forming material, and a flavor masking agent, wherein the active pharmaceutical ingredient contains 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzylamine (also known as ambroxol) or a pharmaceutically acceptable salt thereof, such as the hydrochloride salt of 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzylamine as shown in Formula I (also known as ambroxol hydrochloride).

[0014] I.

[0015] According to an embodiment of the present invention, the ambroxol oral solution composition of the present invention can be an ambroxol hydrochloride oral solution composition.

[0016] According to embodiments of the present invention, the ambroxol oral solution composition (such as the ambroxol hydrochloride oral solution composition) of the present invention preferably does not contain a pH adjuster.

[0017] According to embodiments of the present invention, the ambroxol oral solution composition (such as the ambroxol hydrochloride oral solution composition) preferably does not contain a free pH adjuster. The free pH adjuster refers to a pH adjuster that does not form a salt with the active drug.

[0018] According to embodiments of the present invention, the pH adjuster includes, but is not limited to, pharmaceutically acceptable acids known in the art for adjusting pH values, such as organic acids, inorganic acids, organic bases, and inorganic bases. The aforementioned inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; the aforementioned organic acids include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, formic acid, trifluoroacetic acid, etc.

[0019] According to embodiments of the present invention, the ambroxol oral soluble film composition (such as ambroxol hydrochloride oral soluble film composition) does not contain an alkaline pH adjuster, such as a pharmaceutically acceptable base known in the art for adjusting pH.

[0020] According to an embodiment of the present invention, the mass percentage of the active pharmaceutical ingredient is 1.00% to 40.00%, preferably 5.00% to 30.00%, for example 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 9.09%, 10.00%, 12.45%, 15.00%, 15.23%, 16.48%, 19.23%, 19.48%, 20.00%, 21.43%, 25.00%, or 30.00%, wherein the mass percentage refers to the percentage of the mass of the active pharmaceutical ingredient to the total mass of the ambroxol oral solution composition (such as the ambroxol hydrochloride oral solution composition).

[0021] According to an embodiment of the present invention, the masking agent is a substance that masks unpleasant tastes such as bitterness and numbing sensation, and it may be selected from cation exchange resins. The cation exchange resin is selected from one, two or three of sodium polystyrene sulfonate, potassium polycrylene, and polacrine resin.

[0022] Preferably, the particle size D90 of the cation exchange resin is less than 200 μm.

[0023] Preferably, the mass percentage of the masking agent is 10.00% to 70.00%, more preferably 15.00% to 60.00%, for example 10.00%, 12.00%, 15.00%, 19.48%, 20.00%, 21.43%, 24.90%, 25.00%, 30.00%, 30.30%, 38.06%, 38.46%, 40.00%, 41.21%, 45.00%, 45.45%, 50.00%, 55.00%, or 60.00%, where the mass percentage refers to the percentage of the masking agent's mass relative to the total mass of the ambroxol oral soluble film composition (such as the ambroxol hydrochloride oral soluble film composition).

[0024] According to an embodiment of the present invention, the film-forming material is a drug carrier and is selected from one or more of xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hydroxypropyl methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, pullulan, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, acrylic acid copolymer, polylactic acid, and silicone rubber.

[0025] Preferably, the mass percentage of the film-forming material is 10.00% to 70.00%, more preferably 15.00% to 60.00%, for example 10.00%, 12.00%, 14.29%, 15.00%, 20.00%, 25.00%, 27.47%, 30.00%, 30.30%, 30.45%, 35.00%, 37.34%, 38.46%, 40.00%, 45.00%, 50.00%, 55.00%, 58.44%, or 60.00%. The mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the ambroxol oral solution composition (such as the ambroxol hydrochloride oral solution composition).

[0026] According to embodiments of the present invention, the ambroxol oral soluble film composition (such as an ambroxol hydrochloride oral soluble film composition) may further include one or more of plasticizers, flavoring agents, coloring agents, and fillers. As an example, the ambroxol oral soluble film composition (such as an ambroxol hydrochloride oral soluble film composition) may or may not contain flavoring agents.

[0027] According to an embodiment of the present invention, the plasticizer refers to a substance used to lower the glass transition temperature of the film, increase its plasticity and toughness, and improve its elongation. It may be selected from one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil, polypropylene glycol, and hexanediol.

[0028] Preferably, the plasticizer has a mass percentage content of 0-30.00%, more preferably 0-25.00%, for example 1.00%, 2.00%, 2.60%, 3.00%, 4.00%, 5.00%, 6.00%, 6.06%, 7.00%, 8.00%, 8.67%, 9.00%, 10.00%, 10.15%, 10.99%, 15.00%, 20.00%, 24.90%, 25.00%, or 30.00%. The mass percentage content refers to the percentage of the mass of the plasticizer in the total mass of the ambroxol oral film composition (such as the ambroxol hydrochloride oral film composition).

[0029] According to an embodiment of the present invention, the flavoring agent refers to a substance that performs a flavoring function, which may be selected from one, two or more of aspartame, sucralose, fructose, sucrose, steviol glycoside, neotame, glycyrrhizin, flavoring, fragrance, saccharin and sodium saccharin.

[0030] Preferably, the flavoring agent has a mass percentage content of 0-50.00%, more preferably 0-45.00%, for example, 1.00%, 1.10%, 1.20%, 1.30%, 1.33%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50%, 2.60%, 2.70%, 2.80%, 2.90%, 3.00%, 3.05%. 3.50%, 3.85%, 4.00%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 9.09%, 10.00%, 12.00%, 15.00%, 20.00%, 25.00%, 30.00%, 35.00%, 40.00%, 42.87%, 45.00%, or 50.00%, where the mass percentage refers to the percentage of the flavoring agent's mass to the total mass of the ambroxol oral soluble film composition (such as the ambroxol hydrochloride oral soluble film composition).

[0031] According to an embodiment of the present invention, the colorant refers to a substance that can improve the appearance color of the preparation, can be used to identify the concentration of the preparation, distinguish the method of application, and reduce the patient's aversion to taking the medication, and is selected from one, two or more of titanium dioxide, pigments, and lakes.

[0032] Preferably, the colorant has a mass percentage content of 0-2.00%, for example, 0, 0.02%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.41%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.65%, 1.70%, 1.80%, 1.90%, or 2.00%, where the mass percentage content refers to the percentage of the colorant's mass in the total mass of the ambroxol oral solution composition (such as the ambroxol hydrochloride oral solution composition).

[0033] According to an embodiment of the present invention, the filler refers to a solid substance that, when added to a material, can improve the material's properties, or increase its volume or weight, thereby reducing the material's cost. It may be selected from one or more of sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose.

[0034] Preferably, the filler has a mass percentage content of 0-20.00%, for example, 0%, 1.00%, 5.00%, 10.00%, 15.00%, or 20.00%; the mass percentage content refers to the percentage of the filler mass in the total mass of the ambroxol oral soluble film composition (such as the ambroxol hydrochloride oral soluble film composition).

[0035] According to an embodiment of the present invention, the ambroxol oral solution composition (such as ambroxol hydrochloride oral solution composition) is selected from the following formulations 1-1 to 1-5, by weight percentage: Formulation 1-1 contains: 15-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 18-52% polycrylene potassium, 18-35% film-forming material, 8-12% plasticizer, 0.3-7% flavoring agent and / or coloring agent; Formulations 1-2 contain: 15-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 18-46% polycrylene potassium, 18-60% film-forming material, 2-22% plasticizer and 0-0.05% flavoring agent and / or coloring agent; Formulas 1-3 contain: 17-21% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 35-40% polycrylene potassium, 34-41% film-forming material and 2-6% flavoring agent and / or coloring agent; Formulas 1-4 contain: 9-13% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 22-48% sodium polystyrene sulfonate, 30-40% film-forming material, 5-25% plasticizer, and 0.2-10% flavoring agent and / or coloring agent; Formulas 1-5 contain: 18-24% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 20-24% sodium polystyrene sulfonate, 13-15% film-forming material, and 40-45% flavoring agent.

[0036] According to an embodiment of the present invention, in formulations 1-1 to 1-5, the film-forming material is one, two or more of xanthan gum, polyvinyl alcohol, hydroxypropyl methylcellulose, pullulan, and sodium alginate.

[0037] According to an embodiment of the present invention, in formulations 1-1 to 1-5, the plasticizer is glycerin.

[0038] According to an embodiment of the present invention, in formulations 1-1 to 1-5, the colorant is a lake.

[0039] The ambroxol hydrochloride oral solution film composition of the present invention can be any of the following formulations: Formulation 2-1: 18-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 48-52% polycrylene potassium, 14-32% film-forming material, 6-10% plasticizer and 1-3% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulation 2-2: 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 39-43% polycrylene potassium, 25-29% film-forming material, 9-13% plasticizer, 1.5-6% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulations 2-3: 13-17% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 36-40% polycrylene potassium, 28-32% film-forming material, 8-12% plasticizer, 1-11% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulations 2-4: 17-21% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 17-21% polycrylene potassium, 58-52% film-forming material and 0.5-4% plasticizer, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulations 2-5: 17-21% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 36-40% polycrylene potassium, 34-41% film-forming material and 2-6% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulations 2-6: 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 38-42% polycrylene potassium, 30-34% film-forming material, 9-13% plasticizer and 0-0.02% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.

[0040] Formulations 2-7: 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 37-41% polycrylene potassium, 29-33% film-forming material, 8-12% plasticizer, 0-6% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.

[0041] Formulations 2-8: 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 38-42% polycrylene potassium, 30-34% film-forming material, 9-13% plasticizer, 0-0.5% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.

[0042] Formulations 2-9: 13-17% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 43-47% polycrylene potassium, 18-22% film-forming material and 18-22% plasticizer, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulation 2-10: 7-11% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 44-48% sodium polystyrene sulfonate, 26-34% film-forming material, 4-8% plasticizer, 1-15% flavoring agent and / or colorant, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulation 2-11: 10-14% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 21-25% sodium polystyrene sulfonate, 35-39% film-forming material, 23-27% plasticizer and 0-0.5% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulation 2-12: 20-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 20-22% sodium polystyrene sulfonate, 12-16% film-forming material, 30-50% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.

[0043] According to embodiments of the present invention, in formulations 2-1 to 2-12, the film-forming material is one, two or more of xanthan gum, polyvinyl alcohol, hydroxypropyl methylcellulose, pullulan, and sodium alginate.

[0044] According to an embodiment of the present invention, in formulations 2-1 to 2-12, the plasticizer is glycerin.

[0045] According to an embodiment of the present invention, in formulations 2-1 to 2-12, the colorant is a lake.

[0046] The ambroxol oral solution film composition of the present invention can be any of the following formulations: Formulation 3-1: 18-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 48-52% polycrylene potassium, 11-15% xanthan gum, 4-8% polyvinyl alcohol, 6-10% glycerin and 1-3% aspartame, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulation 3-2: 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 39-43% polycrylene potassium, 25-29% polyvinyl alcohol, 9-13% glycerin, 0.5-1.5% steviol glycoside, 0.5-1.5% fragrance and 0.5-3% lake, wherein the percentages refer to the mass of each component as a percentage of the total mass of the composition; Formulation 3-3: 13-17% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 36-40% polycrylene potassium, 28-32% polyvinyl alcohol, 8-12% glycerin, 1-5% sucralose, 1-5% flavoring and 0-0.05% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulations 3-4: 17-21% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 17-21% polycrylene potassium, 58-52% hydroxypropyl methylcellulose and 0.5-4% glycerol, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulations 3-5: 17-21% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 36-40% potassium polycrylene, 23-27% polyvinyl alcohol, 11-14% pullulan and 2-6% sucralose, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulations 3-6: 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 38-42% polycrylene potassium, 30-34% polyvinyl alcohol, 9-13% glycerol and 0-0.02% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.

[0047] Formulations 3-7: 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 37-41% polycrylene potassium, 29-33% polyvinyl alcohol, 8-12% glycerol, 1-5% sucralose and 0-0.05% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.

[0048] Formulations 3-8: 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 38-42% polycrylene potassium, 30-34% polyvinyl alcohol, 9-13% glycerol, 0-0.1% neotame and 0-0.05% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.

[0049] Formulations 3-9: 13-17% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 43-47% polycrylene potassium, 18-22% xanthan gum and 18-22% glycerin, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formula 3-10: 7-11% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 44-48% sodium polystyrene sulfonate, 16-20% sodium alginate, 10-14% polyvinyl alcohol, 4-8% glycerin, 1-5% sucralose, 1-5% steviol glycoside and 1-5% fragrance, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulation 3-11: 10-14% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 21-25% sodium polystyrene sulfonate, 35-39% hydroxypropyl methylcellulose, 23-27% glycerol and 0-0.5% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formula 3-12: 20-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 20-22% sodium polystyrene sulfonate, 12-16% xanthan gum, 12-16% sucralose, 12-16% steviol glycoside and 12-16% flavoring, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.

[0050] The ambroxol hydrochloride oral solution film composition of the present invention can be any of the following formulations: Formula 1: 20.00% ambroxol hydrochloride, 50.00% polycrylene potassium, 13.33% xanthan gum, 6.67% polyvinyl alcohol, 8.67% glycerin and 1.33% aspartame, where the percentages refer to the mass of each component as a percentage of the total mass of the composition; Formula 2: 16.48% ambroxol hydrochloride, 41.21% potassium polycrylene, 27.47% polyvinyl alcohol, 10.99% glycerin, 1.10% steviol glycoside, 1.10% fragrance and 1.65% lake, where the percentages refer to the mass percentage of each component to the total mass of the composition; Formula 3: 15.23% ambroxol hydrochloride, 38.06% potassium polycrylene, 30.45% polyvinyl alcohol, 10.15% glycerin, 3.05% sucralose, 3.05% flavoring and 0.02% lake, where the percentages refer to the mass percentage of each component to the total mass of the composition; Formula 4: 19.48% ambroxol hydrochloride, 19.48% polycrylene potassium, 58.44% hydroxypropyl methylcellulose and 2.60% glycerin, where the percentages refer to the mass percentage of each component to the total mass of the composition; Formula 5: 19.23% ambroxol hydrochloride, 38.46% potassium polycrylene, 25.64% polyvinyl alcohol, 12.82% pullulan and 3.85% sucralose, where the percentages refer to the mass of each component as a percentage of the total mass of the composition; Formula 6: 16.21% ambroxol hydrochloride, 40.53% polycrylene potassium, 32.43% polyvinyl alcohol, 10.81% glycerol and 0.02% lake, where the percentages refer to the mass of each component as a percentage of the total mass of the composition.

[0051] Formula 7: 15.70% ambroxol hydrochloride, 39.26% potassium polycrylene, 31.41% polyvinyl alcohol, 10.47% glycerol, 3.14% sucralose and 0.02% lake, where the percentages refer to the mass of each component as a percentage of the total mass of the composition.

[0052] Formula 8: 16.16% ambroxol hydrochloride, 40.40% polycrylene potassium, 32.32% polyvinyl alcohol, 10.77% glycerol, 0.32% neotame and 0.02% lake, where the percentages refer to the mass of each component as a percentage of the total mass of the composition.

[0053] Formula 9: 15.00% ambroxol hydrochloride, 45.00% polycrylene potassium, 20.00% xanthan gum and 20.00% glycerin, where the percentages refer to the mass percentage of each component to the total mass of the composition; Formula 10: 9.09% ambroxol hydrochloride, 45.45% sodium polystyrene sulfonate, 18.18% sodium alginate, 12.12% polyvinyl alcohol, 6.06% glycerin, 3.03% sucralose, 3.03% steviol glycoside and 3.03% fragrance, where the percentages refer to the mass of each component as a percentage of the total mass of the composition; Formula 11: 12.45% ambroxol hydrochloride, 24.90% sodium polystyrene sulfonate, 37.34% hydroxypropyl methylcellulose, 24.90% glycerin and 0.41% lake, where the percentages refer to the mass of each component as a percentage of the total mass of the composition; Formula Twelve: 21.43% ambroxol hydrochloride, 21.43% sodium polystyrene sulfonate, 14.29% xanthan gum, 14.29% sucralose, 14.29% steviol glycoside and 14.29% flavoring, where the percentages refer to the mass of each component as a percentage of the total mass of the composition.

[0054] Formula 13: 15.22% ambroxol hydrochloride, 38.06% potassium polycrylene, 30.45% polyvinyl alcohol, 10.15% glycerin, 3.05% sucralose, 3.05% flavoring and 0.02% lake, where the percentages refer to the mass of each component as a percentage of the total mass of the composition; Formula 14: 16.17% ambroxol hydrochloride, 40.40% polycrylene potassium, 32.32% polyvinyl alcohol, 10.77% glycerol, 0.32% neotame and 0.02% lake, where the percentages refer to the mass percentage of each component to the total mass of the composition; Formula 15: 9.10% ambroxol hydrochloride, 45.45% sodium polystyrene sulfonate, 18.18% sodium alginate, 12.12% polyvinyl alcohol, 6.06% glycerin, 3.03% sucralose, 3.03% steviol glycoside and 3.03% fragrance, where the percentages refer to the mass of each component as a percentage of the total mass of the composition; Formula 16: 21.43% ambroxol hydrochloride, 21.43% sodium polystyrene sulfonate, 14.29% xanthan gum, 14.29% sucralose, 14.29% steviol glycoside and 14.27% fragrance, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.

[0055] According to an embodiment of the present invention, the mass percentage content of each component in the ambroxol oral solution composition (such as an ambroxol hydrochloride oral solution composition) is 100%. However, it should be understood that there may be a rounding error of ±0.2% due to the rounding of numerical values.

[0056] The present invention also provides a method for preparing the aforementioned ambroxol oral solution composition (such as an ambroxol hydrochloride oral solution composition), which includes the following steps: Step 1: Prepare an aqueous solution of the active drug; Step 2: Add a masking agent to the aqueous solution obtained in Step 1, stir, and obtain the sample; Step 3: Centrifuge the sample obtained in Step 2, discard part of the supernatant, and make the mass of the remaining lower layer material 10-15 times that of the active drug to obtain the drug-loaded resin. Step 4: Dissolve the film-forming material in water and mix it with one or more of the flavoring agent, plasticizer, colorant and filler (if present), stir well to obtain the adhesive solution; Step 5: Transfer the drug-loaded resin obtained in Step 3 to the adhesive solution obtained in Step 4 and stir thoroughly to obtain a homogeneous adhesive solution. After stirring, remove air bubbles from the adhesive solution under vacuum, coat, dry, and cut to obtain the ambroxol hydrochloride oral solution preparation.

[0057] According to an embodiment of the present invention, in step 1, the active drug solution is preferably prepared under light-protected conditions.

[0058] According to an embodiment of the present invention, the water mentioned in step 1 is preferably purified water.

[0059] According to an embodiment of the present invention, in step 2, the stirring is preferably carried out in the dark.

[0060] According to an embodiment of the present invention, the stirring time in step 2 is preferably 8 hours or more.

[0061] According to an embodiment of the present invention, in step 3, the centrifugation is preferably carried out in a centrifuge; the centrifuge can be a benchtop centrifuge or a low-speed centrifuge.

[0062] According to an embodiment of the present invention, in the ambroxol oral solution film composition (such as ambroxol hydrochloride oral solution film composition), the film thickness is 10 μm to 300 μm, for example 20 μm to 100 μm.

[0063] According to an embodiment of the present invention, the ambroxol oral soluble film composition (such as ambroxol hydrochloride oral soluble film composition) can completely disintegrate within 120 seconds in 900 ml of simulated saliva at 37±1°C, for example, within 80 seconds.

[0064] The present invention also provides the use of the aforementioned ambroxol oral solution composition (such as ambroxol hydrochloride oral solution composition) in the preparation of medicines for the treatment and / or prevention of the indications targeted by ambroxol or its pharmaceutically acceptable salts, such as allergies.

[0065] According to an embodiment of the present invention, the drug is an expectorant or a mucolytic.

[0066] According to embodiments of the present invention, the drug is used for the expectorant treatment of acute or chronic respiratory diseases accompanied by abnormal respiratory secretions, particularly chronic bronchitis, neonatal respiratory distress syndrome, and as an adjunct to lung surgery.

[0067] The present invention also provides a method for preventing and / or treating diseases or conditions, comprising administering the ambroxol oral solution composition (such as ambroxol hydrochloride oral solution composition) to a patient in need (e.g., a human or other mammal).

[0068] According to an embodiment of the present invention, the disease or symptom is selected from acute or chronic respiratory diseases such as allergies, excessive phlegm, and abnormal respiratory secretions, especially chronic bronchitis, neonatal respiratory distress syndrome, and symptoms after lung surgery.

[0069] The ambroxol oral dissolving film composition of the present invention, particularly the ambroxol hydrochloride oral dissolving film composition, exhibits a good dissolution rate, rapidly disintegrates in the oral cavity, and dissolves without a gritty sensation, improving the taste of the medication and increasing patient compliance. Furthermore, the ambroxol oral dissolving film composition of the present invention, particularly the ambroxol hydrochloride oral dissolving film composition, produces a film with uniform appearance and good flexibility. No sedimentation occurs during the preparation of the film solution, and the content uniformity meets requirements.

[0070] The reagents and raw materials used in this invention are all commercially available.

[0071] Beneficial effects The ambroxol oral dissolving film composition (such as ambroxol hydrochloride oral dissolving film composition) provided by the present invention has the advantages of thin thickness, good taste, improved stability, and can be dissolved in the mouth without drinking water and has a fast oral absorption rate, and has good market prospects.

[0072] Furthermore, the ambroxol oral soluble film composition of the present invention (such as ambroxol hydrochloride oral soluble film composition) has readily available raw materials, simple process, easy operation, high drug loading capacity, and good drug content uniformity, making it suitable for industrial production. Detailed Implementation

[0073] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0074] Examples 1-12 The percentage content of each component in Examples 1-12 in Table 1 below is the mass percentage of the component in the dried (water-free) formulation, calculated based on the mass of each component: Table 1

[0075]

[0076] "*" indicates that the substance is removed during the process; " / " indicates that it is not contained.

[0077] The preparation methods of the formulations in the above embodiments include: 1) Weighing and mixing ingredients Weigh out the raw and auxiliary materials according to the prescription amount and set aside.

[0078] 2) Resin-loaded drug A: Dissolve the active drug completely in a certain amount of purified water under light-protected conditions.

[0079] B: Add a masking agent to the above solution and continue stirring in the dark for at least 8 hours.

[0080] C: Centrifuge the above samples in a low-speed benchtop large-capacity centrifuge. After centrifugation, discard part of the supernatant, so that the mass of the remaining lower layer material is 10-15 times that of the active drug.

[0081] 3) Preparation of adhesive solution D: Dissolve the film-forming material in a certain amount of purified water, add flavoring agent, plasticizer and colorant (if any), and stir well.

[0082] E: Transfer the lower layer material from step 2) to the solution prepared in step 3) and stir thoroughly to obtain a homogeneous adhesive solution. After stirring, remove air bubbles from the adhesive solution in a vacuum environment.

[0083] 4) Coating, drying, and cutting G: Apply the above adhesive solution using a coating machine, dry it, and cut it into appropriate sizes to obtain an ambroxol hydrochloride oral solution film preparation.

[0084] Comparative Examples 1-3 Comparative Examples 1-3 were prepared according to the methods described in Examples 3-5 of CN 102846581 A: Table 2

[0085] "*" indicates that the substance was removed during the process.

[0086] Performance testing The mechanical strength, disintegration time and related substances of the above comparative examples 1-3 and the ambroxol hydrochloride oral soluble films prepared according to examples 3-8 were investigated respectively.

[0087] Test Example 1 Methods for testing the mechanical strength of molten film The oral film of ambroxol hydrochloride was tested using a texture analyzer, and its tensile strength, elongation at a percentage, and flexural endurance were calculated. The results are shown in Table 3 below (6 samples were tested for each example): Table 3

[0088]

[0089] Note: In the table above, "cross-sectional area" refers to the surface area of ​​the oral dissolution membrane.

[0090] The maximum force (gf) is the maximum force that the oral membrane can resist after the yielding stage.

[0091] Tensile strength (MPa) = Maximum force (gf) ÷ 10² ÷ Cross-sectional area (mm²) 2 Percentage elongation = maximum force distance (mm) ÷ sample height (mm) × 100%.

[0092] The average tensile strength is the average of the 6 sets of data.

[0093] The maximum force distance is the distance the effluent membrane elongates under the maximum force.

[0094] The average percentage elongation is the average of the six data sets.

[0095] The folding endurance is the ability of the oral thaw film to withstand being folded 180°.

[0096] The above results indicate that the tensile strength and folding endurance of the ambroxol hydrochloride oral soluble film prepared according to Examples 3-8 are higher than those of Comparative Examples 1-3, making it more suitable for commercial production, transportation, storage, and patient administration.

[0097] Test Example 2 Six orally disintegrating films prepared in Examples 1-12 and Comparative Examples 1-3 were taken respectively, and the disintegration time of the orally disintegrating films was determined. The test method is as follows: 900 ml of pH 6.8 phosphate buffer medium (preparation method refers to the Chinese Pharmacopoeia 2020 edition 8004 Buffer Section) was added to a 1000 ml beaker and heated to 37±0.5℃. Six orally disintegrating films were placed simultaneously in the beaker of the disintegration apparatus, and the time for complete disintegration of all six orally disintegrating films in each example and comparative example was recorded. The results are summarized in Table 4 below.

[0098] Table 4

[0099] The results showed that the ambroxol hydrochloride oral soluble film prepared according to Examples 1-12 could completely disintegrate within 120 s.

[0100] Test Example 3 Oral dissolution membrane related substances test The compatibility test of raw materials and excipients was designed according to the mass ratio of ambroxol hydrochloride to citric acid in Comparative Examples 1-3. The materials were placed at a high temperature of 60°C for 30 days, and the compatibility of raw materials and excipients, as well as the levels of related substances in Comparative Examples 1-3 and Examples 3-8, were tested.

[0101] The relevant substances were determined according to the high performance liquid chromatography method (General Chapter 0512, Part IV, Chinese Pharmacopoeia 2020).

[0102] Solvent Methanol Take two tablets (7.5 mg) or one tablet (15 mg) of this product (as prepared in the above examples or comparative examples) and place them in a 20 mL volumetric flask. Add an appropriate amount of methanol and sonicate for 15 minutes to dissolve the ambroxol hydrochloride. Cool the solution and prepare a solution containing approximately 0.75 mg of ambroxol hydrochloride per mL with methanol. Take the supernatant as the test solution.

[0103] Accurately measure an appropriate amount of the test solution and dilute it with methanol to prepare a solution containing approximately 1.5 μg per mL.

[0104] Chromatographic conditions: Octylsilane-bonded silica gel was used as the stationary phase (Agient ZORBAX SB-C8 4.6mm*150mm, 3.5μm); the mobile phase was 10mmol / L diammonium hydrogen phosphate solution (pH adjusted to 7.0 with phosphoric acid)-acetonitrile (50:50); the detection wavelength was 248nm; the flow rate was 0.8mL / min; the column temperature was 30℃; the injection plate temperature was 4℃; the injection volume was 10μL; and the run time was 30 minutes.

[0105] The system suitability requirement is that the resolution between the main peak and adjacent chromatographic peaks in the chromatogram of the test sample solution should meet the requirements.

[0106] For the assay, accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms for up to 30 minutes.

[0107] Table 5 Impurity Correction Factors and Limits

[0108] Table 6 Results of Related Substance Detection

[0109] Note: * indicates that the proportions in the guidelines are followed and no other auxiliary materials are used.

[0110] The results show that the oral dissolving films prepared in Examples 3-6 of this invention have good stability, while the contents of unknown impurities in Comparative Examples 1-3 are relatively high. The oral dissolving film of this application has better stability than that of Comparative Examples 1-3.

[0111] Test Example 4 Oral dissolution film dissolution curve test The ambroxol hydrochloride oral dissolution films prepared in Examples 1, 3, and 6-8 were subjected to dissolution curve testing according to Method 4 (paddle disc method) of Dissolution and Release Determination, Section IV, 0931, Part IV of the 2020 Chinese Pharmacopoeia, using Method 1 (stirring paddle and dissolution vessel) and Method 2. The ambroxol hydrochloride oral dissolution films were placed in a stainless steel mesh dish under the following test conditions: Experimental apparatus: Tianda Tianfa dissolution apparatus.

[0112] Test media: pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer.

[0113] Experimental conditions: medium volume was 900 ml, temperature was 37 ± 0.5 ℃, stirring speed was 50 rpm, and sampling time was 5 min, 10 min, 15 min, and 30 min.

[0114] The dissolution results and dissolution curves of two batches of ambroxol hydrochloride are shown in the table below: Table 7

[0115] The results showed that the ambroxol hydrochloride oral dissolution membrane of the present invention had a cumulative dissolution rate of over 85% in pH 1.2 hydrochloric acid solution and pH 6.8 phosphate buffer solution after 15 min; in pH 4.5 acetate buffer solution, the cumulative dissolution rate of batches 3, 6-8 of the formulations in Examples 3 and 6-8 was over 85% in 15 min, and the cumulative dissolution rate of batch 1 of the formulation in Example 1 was over 85% in 30 min.

[0116] Test Example 4 Oral dissolving film palatability evaluation According to Example 3, a batch of ambroxol hydrochloride oral dissolving film was prepared. Referring to the "Technical Guidelines for the Design and Evaluation of Taste of Pediatric Drugs (Draft for Public Comment)" and the literature "Li Pan et al. Application and Development Research of Volunteer Sensory Testing in Drug Taste Evaluation [J]. Chinese Pharmaceutical Journal, 2017, 52(22): 1971-1975", six volunteers were randomly selected to evaluate the palatability of this batch of ambroxol hydrochloride oral dissolving film by comprehensively using the bitterness value grading method and the multi-factor survey evaluation method.

[0117] Based on the quality attributes of the oral dissolving film, palatability was evaluated from aspects such as appearance, bitterness, sweetness, numbing sensation, and oral foreign body sensation. Bitterness, numbing sensation, and oral foreign body sensation were the primary scoring items, while appearance and sweetness were bonus items. The grading and scoring rules are as follows: Table 8. Palatability Evaluation Table for Oral Dissolution Film

[0118] The results showed that the final palatability scores of the six volunteers were all in the range of 24-30, indicating that the ambroxol hydrochloride oral film prepared in this invention had a good taste and good acceptability.

[0119] As can be seen from the above experimental data, the ambroxol hydrochloride oral dissolving film provided by the present invention has the advantages of being thin, having a good taste, being stable in properties, and being able to dissolve instantly in the oral cavity without drinking water and being absorbed quickly by oral administration.

[0120] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. An oral solution composition for ambroxol, characterized in that: The composition comprises an active pharmaceutical ingredient, a film-forming material, and a flavor masking agent, wherein the active pharmaceutical ingredient contains 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzylamine or a pharmaceutically acceptable salt thereof, such as the hydrochloride salt of 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzylamine as shown in Formula I below: I Preferably, the ambroxol oral solution composition is an ambroxol hydrochloride oral solution composition; Preferably, the ambroxol oral solution composition (such as an ambroxol hydrochloride oral solution composition) does not contain a pH adjuster; for example, the pH adjuster includes, but is not limited to, pharmaceutically acceptable acids used to adjust pH values.

2. The composition according to claim 1, characterized in that: The active pharmaceutical ingredient has a mass percentage content of 1.00% to 40.00%, preferably 5.00% to 30.00%, where the mass percentage content refers to the percentage of the mass of the active pharmaceutical ingredient to the total mass of the composition.

3. The composition according to claim 1 or 2, characterized in that: The odor masking agent is a cation exchange resin; the cation exchange resin is preferably selected from one, two or three of sodium polystyrene sulfonate, potassium polykrylene and polacrine resin; preferably, the particle size D90 of the cation exchange resin is less than 200 μm; And / or, The mass percentage of the masking agent is 10.00% to 70.00%, preferably 15.00% to 60.00%, where the mass percentage refers to the percentage of the mass of the masking agent to the total mass of the composition.

4. The composition according to any one of claims 1-3, characterized in that: The film-forming material is selected from one or more of the following: xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hydroxypropyl methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, pullulan, polyvinylpyrrolidone, sodium alginate, polyethylene glycol, polyoxyethylene, acrylic acid copolymer, polylactic acid, and silicone rubber. And / or, The mass percentage of the film-forming material is 10.00% to 70.00%, preferably 15.00% to 60.00%, where the mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the composition.

5. The composition according to any one of claims 1-4, characterized in that: The composition further includes one or more of plasticizers, flavoring agents, colorants, and fillers.

6. The composition according to claim 5, characterized in that: The plasticizer is selected from one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil, polypropylene glycol, and hexanediol; And / or, The flavoring agent is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycoside, neotame, glycyrrhizin, flavoring, fragrance, saccharin and sodium saccharin; And / or, The colorant is selected from one or more of titanium dioxide, pigments, and lakes; And / or, The filler is selected from one or more of sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose.

7. The composition according to claim 6, characterized in that: The plasticizer has a mass percentage content of 0-30.00%, preferably 0-25.00%, where the mass percentage content refers to the percentage of the mass of the plasticizer to the total mass of the composition; And / or, The flavoring agent has a mass percentage content of 0-50.00%, preferably 0-45.00%, where the mass percentage content refers to the percentage of the flavoring agent's mass to the total mass of the composition; And / or, The colorant has a mass percentage content of 0-2.00%, where the mass percentage content refers to the percentage of the mass of the colorant to the total mass of the composition; And / or, The filler has a mass percentage content of 0 to 20.00%, where mass percentage refers to the percentage of the filler's mass to the total mass of the composition.

8. The composition according to any one of claims 1-7, characterized in that: The composition is selected from any of the following formulations: Formulas 1-4 contain: 9-13% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 22-48% sodium polystyrene sulfonate, 30-40% film-forming material, 5-25% plasticizer, and 0.2-10% flavoring agent and / or coloring agent; Formulation 2-10: 7-11% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 44-48% sodium polystyrene sulfonate, 26-34% film-forming material, 4-8% plasticizer, 1-15% flavoring agent and / or colorant, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulation 2-11: 10-14% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 21-25% sodium polystyrene sulfonate, 35-39% film-forming material, 23-27% plasticizer and 0-0.5% flavoring agent and / or coloring agent, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formula 3-10: 7-11% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 44-48% sodium polystyrene sulfonate, 16-20% sodium alginate, 10-14% polyvinyl alcohol, 4-8% glycerin, 1-5% sucralose, 1-5% steviol glycoside and 1-5% fragrance, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formulation 3-11: 10-14% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 21-25% sodium polystyrene sulfonate, 35-39% hydroxypropyl methylcellulose, 23-27% glycerol and 0-0.5% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition; Formula 10: 9.09% ambroxol hydrochloride, 45.45% sodium polystyrene sulfonate, 18.18% sodium alginate, 12.12% polyvinyl alcohol, 6.06% glycerin, 3.03% sucralose, 3.03% steviol glycoside and 3.03% fragrance, where the percentages refer to the mass of each component as a percentage of the total mass of the composition; Formula 11: 12.45% ambroxol hydrochloride, 24.90% sodium polystyrene sulfonate, 37.34% hydroxypropyl methylcellulose, 24.90% glycerin and 0.41% lake, where the percentages refer to the mass of each component as a percentage of the total mass of the composition; Formula 15: 9.10% ambroxol hydrochloride, 45.45% sodium polystyrene sulfonate, 18.18% sodium alginate, 12.12% polyvinyl alcohol, 6.06% glycerin, 3.03% sucralose, 3.03% steviol glycoside and 3.03% fragrance, where the percentages refer to the mass of each component as a percentage of the total mass of the composition.

9. The composition according to any one of claims 1-8, characterized in that, The thickness of the composition is 10μm-300μm; And / or, The composition completely disintegrated within 120 seconds in 900 ml of simulated saliva at 37±0.5°C.

10. The use of the composition according to any one of claims 1-9 in the preparation of a medicament for treating and / or preventing allergies; Preferably, the drug is an expectorant or a mucolytic; Preferably, the drug is used for acute or chronic respiratory diseases accompanied by abnormal respiratory secretions, especially for expectorant treatment of chronic bronchitis, neonatal respiratory distress syndrome, and as an adjunct to lung surgery.

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