Amoxil tablet

Abstract

The application belongs to the field of pharmaceutical preparations, and particularly relates to a kind of ambroxol anhydrous swallowing granules and a preparation method thereof.The ambroxol anhydrous swallowing granules comprise a drug-containing taste-masking granule and a flavoring component, and the drug-containing taste-masking granule comprises, from inside to outside, a core, a drug-containing layer, a separation layer and a taste-masking layer.The ambroxol anhydrous swallowing granules of the application can be conveniently and quickly swallowed without water, and have good taste, greatly improving the convenience and drug compliance of the user, and are particularly suitable for children and other people with swallowing difficulties.The preparation process of the application is simple and feasible, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to an anhydrous ambroxol granules for oral administration and a method for preparing the same. Background Technology

[0002] Ambroxol hydrochloride, chemical name: trans-4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol hydrochloride; molecular formula: C 13 H 18 Br₂N₂O·HCl; Molecular weight: 414.564; Chemical structural formula as follows:

[0003]

[0004] Clenbuterol hydrochloride, chemical name: 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride; molecular formula: C 12 H 18 Cl₂N₂O·HCl; Molecular weight: 313.65; Chemical structural formula as follows:

[0005]

[0006] Ambroxol hydrochloride is a mucolytic agent that can increase the secretion of serous glands in the respiratory mucosa, reduce mucus secretion, lower sputum viscosity, promote the secretion of pulmonary surfactant, increase bronchial ciliary movement, and make sputum easier to cough up.

[0007] Clenbuterol hydrochloride is a selective β-receptor agonist that relaxes bronchial smooth muscle, enhances ciliary movement, dissolves mucus, and promotes sputum expectoration.

[0008] Ambroxol oral solution is a compound preparation composed of ambroxol hydrochloride and clenbuterol hydrochloride. The two active ingredients have shown pharmacodynamic synergy in the treatment of obstructive respiratory diseases: ambroxol hydrochloride acts on secretions in the bronchial region, while clenbuterol hydrochloride treats bronchospasm. The two substances activate the bronchial mucus transport system in different ways, improve the opening of the bronchial system, and thus improve breathing.

[0009] Sanofi-Aventis developed ambroxol oral solution, which was launched in Germany in 1984 for the treatment of acute and chronic respiratory diseases, particularly spastic bronchitis, emphysematous bronchitis, and bronchial asthma.

[0010] Clinical trial results show that ambroxol can significantly relieve respiratory symptoms such as cough, sputum production, difficulty expectorating, and wheezing. Due to its good safety and efficacy, it has been widely used in the treatment of cough and sputum in recent years and holds a high position in pediatric clinical medication. Currently, ambroxol compound preparations are only available in two dosage forms: ambroxol tablets and ambroxol oral solution. Tablets pose risks of swallowing difficulties and choking for children. Furthermore, ambroxol hydrochloride has a very strong bitter taste, which is difficult to mask in solutions. Oral liquid preparations rely on measuring cups for carrying and administration, posing risks of contamination and inaccurate dosage, thus limiting their use in children. Additionally, repeated use of measuring cups during use may lead to microbial growth. To prevent microbial growth, a preservative (sodium benzoate) is added to ambroxol oral solution. Sodium benzoate is generally safe when used in appropriate amounts, but excessive intake or long-term use may pose potential risks to children's health.

[0011] For the production of syrups, chewable tablets, granules, and capsules suitable for children, masking the taste is a key technical challenge. Current technologies for masking taste involve adding large amounts of flavoring agents, sweeteners, and syrups to conceal the drug's inherent odor. However, this not only fails to completely mask the odor but also results in insufficient encapsulation of the drug's taste and bitterness, leaving a noticeable lingering taste in the mouth after ingestion and causing patient aversion.

[0012] Chinese invention patent application CN116327696A discloses an ambroxol oral solution and its manufacturing process, comprising ambroxol hydrochloride and clenbuterol hydrochloride, a stabilizer, an antibacterial agent, a sweetener, a solvent, and a pH adjuster. The stabilizer is an ammonia / ammonium compound and a carbonate or bicarbonate; the antibacterial agent is sodium benzoate; the sweetener is sorbitol; the solvent is propylene glycol, glycerin, and purified water; and the pH of the oral solution is 4.0-6.0. However, this product cannot completely mask the bitter taste of the drug and does not improve patient, especially child, medication adherence.

[0013] Chinese invention patent application CN117298070A discloses an ambroxol oral instant-dissolving film. The raw materials of this oral instant-dissolving film include: an active pharmaceutical ingredient, a film-forming material, and a plasticizer; the active pharmaceutical ingredient is ambroxol hydrochloride and clenbuterol hydrochloride, the film-forming material is polyvinyl alcohol, and the plasticizer is selected from glycerin, polyethylene glycol 400, propylene glycol, or triethyl citrate. The ambroxol oral instant-dissolving film provided in this document has good mechanical properties, disintegration properties, and taste, with very low levels of formulation-related substances and good stability. However, the production process requires specialized equipment, increasing the complexity of the process.

[0014] Ambroxol oral solution comes in multi-dose packaging, requiring the use of a measuring cup for dispensing, which is inconvenient and may lead to inaccurate dosage. Anhydrous swallowable granules, on the other hand, are single-dose packaging, making them easy to carry and significantly improving dosage accuracy and ease of administration.

[0015] Compared to ambroxol oral solution, anhydrous granules do not contain preservatives, thus avoiding potential health risks to children from excessive intake or prolonged use of oral solutions.

[0016] Anhydrous swallowable granules are prepared using multi-layer coating technology, which is simple to prepare and makes it easier to achieve large-scale production.

[0017] Therefore, developing an anhydrous ambroxol granule formulation that is easy to prepare and can significantly improve medication adherence in patients, especially children, is of great practical significance. Summary of the Invention

[0018] To address the shortcomings of existing technologies, the present invention aims to provide anhydrous ambroxol granules for oral administration. These granules are composed of drug-containing taste-masking granules and flavor-enhancing components. The drug-containing taste-masking granules, from the inside out, consist of a core, a drug-containing layer, an isolation layer, and a taste-masking layer. Drug-containing pellets are prepared by mixing the active pharmaceutical ingredients ambroxol hydrochloride and clenbuterol hydrochloride with a suitable binder (using a fluidized bed suspension method), followed by isolation and taste-masking coating. This process completely masks the bitterness and odor of the drug, achieving rapid drug release and fast onset of action. The anhydrous granules of this invention utilize multi-layer coating technology to prevent drug release in the oral cavity, effectively masking the bitterness of ambroxol hydrochloride. The anhydrous granule technology platform allows for direct swallowing without water. During oral administration, when the drug is placed on the tongue, it spontaneously generates additional saliva. The swallowed granules and appropriate additional saliva form a soft, smooth, and pleasantly palatable stable surface within seconds, facilitating swallowing. Furthermore, this invention contains sweeteners and flavorings suitable for children, making it easier for pediatric patients to accept the medication and thus improving their medication adherence.

[0019] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows:

[0020] An anhydrous ambroxol granule, comprising: a drug-containing and flavor-masking granule and a flavoring component; wherein the drug-containing and flavor-masking granule comprises, from the inside out: a core, a drug-containing layer, an isolation layer, and a flavor-masking layer.

[0021] That is, the ambroxol anhydrous granules are a mixture of drug-masked granules and flavoring components.

[0022] The core is selected from one or more of sucrose core and microcrystalline cellulose core; preferably, the core is sucrose core and the core diameter is 180-250 μm.

[0023] The drug-containing layer comprises: 5-15 parts by weight of ambroxol hydrochloride, 0.005-0.015 parts by weight of clenbuterol hydrochloride, and 5-20 parts by weight of the first binder.

[0024] The first adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone, preferably hydroxypropyl methylcellulose (e.g. hydroxypropyl methylcellulose E5).

[0025] The isolation layer comprises: 15-40 parts by weight of a second adhesive and 10-25 parts by weight of a first anti-adhesion agent.

[0026] The second adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone, preferably hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose E5).

[0027] The first anti-adhesion agent is selected from one or more of talc, titanium dioxide and magnesium stearate, preferably talc.

[0028] The odor-masking layer comprises: 20-60 parts by weight of acrylic resin polymer and 0.5-5 parts by weight of a second anti-sticking agent.

[0029] The acrylic resin polymer is selected from one or more of the following: Euteco E100, Euteco EPO, Euteco L30D, and Euteco L30D-55, with Euteco E100 being preferred.

[0030] The second anti-adhesion agent is selected from one or more of talc, titanium dioxide and magnesium stearate, preferably talc and magnesium stearate.

[0031] The flavoring components include: 100-450 parts by weight of flavoring agent, 1-5 parts by weight of sweetener and 1-5 parts by weight of flavoring.

[0032] The flavoring agent is selected from one or more of sorbitol, mannitol and maltodextrin, preferably sorbitol.

[0033] The sweetener is selected from one or more of aspartame, sucralose and acesulfame potassium, preferably sucralose.

[0034] The fragrance is selected from one or more of the following: vanilla extract, banana extract, sweet orange extract, and mixed fruit extract.

[0035] The weight gain of the drug-containing coating is 10-30%, preferably 15-25%, and more preferably 15-20% (e.g., about 18%), based on the weight of the pellet core.

[0036] The weight gain of the coating of the isolation layer is 5-50%, preferably 15-40%, and more preferably 25-35% (e.g., about 30%), based on the weight of the medicated pellet (including the pellet core and the medicated layer).

[0037] Based on the weight of the isolated pellet (including the pellet core, the drug-containing layer, and the isolation layer), the weight gain of the coating of the flavor-masking layer is 10-40%, preferably 15-30%, more preferably 20-30%, and even more preferably 23-28% (e.g., about 25%).

[0038] Preferably, the drug-containing layer comprises: 5-10 parts by weight of ambroxol hydrochloride, 0.005-0.01 parts by weight of clenbuterol hydrochloride, and 10-20 parts by weight of the first binder.

[0039] Preferably, the isolation layer comprises: 20-40 parts by weight of a second adhesive and 10-20 parts by weight of a first anti-adhesion agent.

[0040] Preferably, the odor-masking layer comprises: 30-50 parts by weight of an acrylic resin polymer and 1-4 parts by weight of a second anti-sticking agent.

[0041] Preferably, the flavoring component comprises: 150-250 parts by weight of flavoring agent, 2-4 parts by weight of sweetener and 2-4 parts by weight of flavoring.

[0042] More preferably, the drug-containing layer comprises: 6-8 parts by weight of ambroxol hydrochloride, 0.005-0.008 parts by weight of clenbuterol hydrochloride, and 13-17 parts by weight of the first binder; or,

[0043] More preferably, the isolation layer comprises: 25-35 parts by weight of a second adhesive and 13-17 parts by weight of a first anti-adhesive; or,

[0044] More preferably, the odor-masking layer comprises: 40-50 parts by weight of an acrylic resin polymer and 2-4 parts by weight of a second anti-adhesive agent; or,

[0045] More preferably, the flavoring component comprises: 180-230 parts by weight of flavoring agent (more preferably 190-220 parts by weight), 2-3 parts by weight of sweetener and 2-3 parts by weight of flavoring.

[0046] The anhydrous ambroxol granules have a dissolution rate of less than 4% in artificial saliva medium over 2 minutes, preferably less than 3%, and more preferably less than 2%.

[0047] The anhydrous ambroxol granules have a dissolution rate of greater than 90%, preferably greater than 95%, and more preferably greater than 98% in hydrochloric acid solution medium after 15 minutes.

[0048] In one specific embodiment, the components and their contents of the ambroxol anhydrous oral granules are as follows:

[0049]

[0050] The present invention also provides a method for preparing the ambroxol anhydrous oral granules. The preparation method is carried out by fluidized bed coating, in which a drug-containing layer, an isolation layer and a flavor-masking layer are sequentially coated on the outer surface of the granule core, and then the resulting flavor-masking granules are mixed with flavoring components.

[0051] Specifically, the preparation method of the anhydrous ambroxol granules includes the following steps:

[0052] (1) Preparation of drug-containing pellets:

[0053] Add the first binder to water (e.g., purified water). After the first binder is completely dissolved, dissolve clenbuterol hydrochloride in water and add it to the first binder solution. Then, add ambroxol hydrochloride while stirring to disperse the ambroxol hydrochloride evenly.

[0054] The pellet core is added to a fluidized bed, and the suspension is coated by bottom spraying of the fluidized bed. During the coating process, the material temperature is controlled at 35℃~60℃ (preferably, the material temperature is controlled at 40~50℃). After the coating is completed, the pellets are dried (for example, for no less than 10 minutes) to obtain drug-containing pellets.

[0055] (2) Preparation of isolation pellets:

[0056] Add the second adhesive to water, and after the second adhesive has completely dissolved, add the first anti-adhesion agent while stirring, and disperse it evenly.

[0057] Add drug-containing pellets to a fluidized bed and perform an isolation coating process by bottom spray coating of the fluidized bed. During the coating process, the material temperature is controlled at 35℃~60℃ (preferably, the material temperature is controlled at 40~50℃). After the isolation coating is completed, continue to dry the pellets (for example, for no less than 10 minutes) to obtain isolation pellets.

[0058] (3) Preparation of flavor-masked pellets:

[0059] Dissolve the acrylic resin polymer in 95% ethanol. After it is completely dissolved, add the second anti-blocking agent while stirring and disperse it evenly.

[0060] Isolation pellets are added to a fluidized bed, and a deodorizing coating process is carried out by bottom spray coating of the fluidized bed. During the coating process, the material temperature is controlled at 20℃~40℃ (preferably, the material temperature is controlled at 20~30℃). After the deodorizing coating is completed, the pellets are dried (for example, for no less than 10 minutes) to obtain deodorizing pellets.

[0061] (4) Mixing of flavor-masking particles and flavoring components:

[0062] The above-mentioned flavor-masking pellets are mixed with the flavor-correcting components to obtain the ambroxol anhydrous swallowable granules.

[0063] The ambroxol anhydrous granules provided by this invention overcome the bitter taste defect of traditional oral ambroxol preparations by preparing a specific coating layer, isolation layer, and taste-masking layer on a blank pellet core. This makes it easier for patients to swallow. Furthermore, the taste is harmonized and balanced through flavor-correcting components, achieving the technical characteristic of anhydrous swallowing of the entire formulation, thus improving medication adherence, especially in children. This ambroxol anhydrous granule formulation fills a domestic gap, provides users with a better formulation option, expands the applicable population, changes the traditional dosage form, and makes it more convenient for patients to carry and take.

[0064] In summary, the anhydrous ambroxol granules of the present invention can be conveniently and rapidly swallowed without water, while maintaining a good taste throughout the process, greatly improving the convenience of medication and medication compliance for users, and are especially suitable for children and other people with swallowing difficulties. The preparation process of the present invention is simple and feasible, and suitable for large-scale production. Detailed Implementation

[0065] To better understand and illustrate the present invention, the following illustrative description is given of the ambroxol anhydrous swallowable granules provided by the present invention, but it should not be construed as a limitation on the content of the invention.

[0066] Currently, the only available dosage form of ambroxol for treating cough, thick sputum, difficulty expectorating, and wheezing caused by acute and chronic respiratory diseases in children (such as acute and chronic bronchitis, bronchial asthma, and emphysema) is oral solution. This single dosage form is inconvenient to carry, and the solution has a bitter taste, resulting in poor medication adherence in children. Therefore, developing an anhydrous ambroxol granule formulation that improves medication adherence in children and is easy to carry is of great practical significance.

[0067] The anhydrous swallowable granules of this invention utilize a multi-layer coating technology to prevent drug release into the oral cavity, effectively masking the bitter taste of ambroxol hydrochloride. The anhydrous swallowable granule technology platform also enables direct swallowing without water. During oral administration, when the anhydrous swallowable granules of this invention are placed on the tongue, additional saliva is spontaneously generated. The granules and appropriate additional saliva form a soft, smooth, and pleasantly palatable stable surface within seconds, facilitating swallowing. Furthermore, this invention contains sweeteners and flavorings suitable for children, making it more acceptable to pediatric patients and further improving medication adherence in children.

[0068] Existing ambroxol oral solutions are packaged in multiple doses, requiring the use of a measuring cup for dispensing, which is inconvenient and may lead to inaccurate dosages. The anhydrous swallowable granules of this invention are packaged in single-dose packaging, making them easy to carry and significantly improving the accuracy of dosage and convenience of administration.

[0069] The present invention provides anhydrous ambroxol granules that, compared to ambroxol oral solution, do not contain preservatives, thus avoiding potential health risks to children from excessive or prolonged use of oral solutions.

[0070] Pharmaceutical standards for masking taste: By screening different formulations and increasing the weight, the taste must be so good that no bitterness can be felt in the mouth, and the solubility in artificial saliva medium must be less than 5% for 2 minutes and more than 86% for 15 minutes in hydrochloric acid medium.

[0071] The inventors have discovered that excessive coating weight gain can mask the taste, but it slows down the product's dissolution in hydrochloric acid. Insufficient coating weight gain fails to mask the taste, and the dissolution rate in artificial saliva medium after 2 minutes does not meet requirements. Furthermore, simply adjusting the coating weight gain is insufficient to achieve the above objectives; extensive formulation screening is still necessary.

[0072] Preparation Example 1: Preparation of anhydrous ambroxol granules

[0073] The prescriptions are shown in Table 1:

[0074] Table 1. Prescription for Ambroxol Anhydrous Granules

[0075]

[0076]

[0077] Preparation process description:

[0078] A fluidized bed coating process was used to coat the sucrose pellet core, creating a drug-containing layer, an isolation layer, and a flavor-masking layer, followed by mixing with flavoring components. Details are as follows:

[0079] (1) Preparation of drug-containing pellets:

[0080] Dissolve hydroxypropyl methylcellulose E5 in purified water. After the hydroxypropyl methylcellulose E5 is completely dissolved, add clenbuterol hydrochloride solution to the hydroxypropyl methylcellulose E5 solution. Finally, add ambroxol hydrochloride while stirring to ensure that the ambroxol hydrochloride is evenly dispersed.

[0081] Add sucrose pellet cores to a fluidized bed and use bottom spray coating of the fluidized bed to carry out the drug loading process of the suspension. During the drug loading process, control the material temperature at 40-50℃. After the drug loading is completed, continue to dry the pellets for no less than 10 minutes to obtain drug-containing pellets.

[0082] (2) Preparation of isolation pellets:

[0083] Dissolve hydroxypropyl methylcellulose E5 in purified water. After the hydroxypropyl methylcellulose E5 is completely dissolved, add talc powder while stirring and disperse evenly.

[0084] Add drug-containing pellets to a fluidized bed and perform a separation coating process by bottom spray coating of the fluidized bed. During the coating process, control the material temperature at 40-50℃. After the separation coating is completed, continue to dry the pellets for no less than 10 minutes to obtain the separation pellets.

[0085] (3) Preparation of flavor-masked pellets:

[0086] Dissolve E100 in 95% ethanol. After E100 is completely dissolved, add magnesium stearate and talc in sequence while stirring, and disperse evenly.

[0087] Isolation pellets are added to a fluidized bed, and a deodorizing coating process is carried out by bottom spray coating of the fluidized bed. During the coating process, the material temperature is controlled at 20-30℃. After the deodorizing coating is completed, the pellets are dried for no less than 10 minutes to obtain deodorizing pellets.

[0088] (4) Mixing of flavor-masking particles and flavoring components:

[0089] The above-mentioned flavor-masked pellets were mixed with flavor-correcting components to prepare the anhydrous ambroxol granules. Experimental Example 1: Evaluation of Formulation Efficacy: Dissolution, Taste, and Anhydrous Swallowing Efficacy.

[0090] Dissolution: Determined according to the Dissolution and Release Test Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Using 900 ml of hydrochloric acid solution (9→1000) as the dissolution medium, the rotation speed was 50 rpm. The procedure was followed, and samples were taken after 15 minutes. An appropriate amount of the dissolution solution was taken, filtered, and the filtrate was used as the test solution. Appropriate amounts of ambroxol hydrochloride and clenbuterol hydrochloride reference standards were accurately weighed, dissolved in the dissolution medium, and quantitatively diluted to prepare a solution containing approximately 7.5 μg of ambroxol hydrochloride and 0.1 μg of clenbuterol hydrochloride per ml, which was used as the reference solution. Dissolution was determined using high-performance liquid chromatography (HPLC). Specific results are shown in Table 2.

[0091] Dissolution in artificial saliva: Determined according to the method for determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Dissolution conditions: Using 500 ml of artificial saliva (containing enzymes) [0.795 g calcium chloride, 0.78 g sodium dihydrogen phosphate dihydrate, 5 mg sodium sulfide dihydrate, 0.4 g potassium chloride, 1 g urea, 0.4 g sodium chloride, 1 g α-amylase, dissolved in water and diluted to 1000 ml, pH adjusted to 6.8 with sodium hydroxide test solution (a small amount of precipitate will be generated in the solution during pH adjustment)] as the dissolution medium, the rotation speed is 50 rpm, and the procedure is followed. Samples are taken after 2 minutes. An appropriate amount of the dissolution solution is taken, filtered, and the filtrate is used as the test solution. Accurately weigh appropriate amounts of ambroxol hydrochloride and clenbuterol hydrochloride reference standards, dissolve them in dissolution medium, and quantitatively dilute to prepare a solution containing approximately 7.5 μg of ambroxol hydrochloride and 0.1 μg of clenbuterol hydrochloride per 1 ml. This solution is used as the reference solution. Dissolution was determined using high-performance liquid chromatography (HPLC), and the specific results are shown in Table 2.

[0092] Table 2 Dissolution test results

[0093] # Dissolution rate (%) in hydrochloric acid solution medium after 15 minutes Dissolution rate (%) of artificial saliva medium after 2 minutes Prescription 1 99.5 / 99.6 1.3 / 1.4 Prescription 2 98.6 / 100.1 1.6 / 0.9 Prescription 3 99.1 / 98.5 1.5 / 0.8

[0094] Note: / before: content of ambroxol hydrochloride, / after: content of clenbuterol hydrochloride.

[0095] As can be seen from the data in Table 2, the dissolution rate of the anhydrous ambroxol granules of the present invention in artificial saliva medium is less than 5% after 2 minutes.

[0096] Taste: A trial was conducted on 12 healthy volunteers. The results showed that the drug did not taste bitter or unpleasant for 2 minutes in the mouth. After taking the drug, all volunteers reported a cool and refreshing feeling in their mouths, indicating that the drug effectively masked any unpleasant taste.

[0097] Anhydrous swallowing effect: After oral administration of the anhydrous ambroxol granules prepared according to Formula 1 of Example 1 to 12 volunteers, all of them could be swallowed smoothly within 1 minute under the condition of no water in the throat. This shows that the drug meets the quality requirements in terms of taste masking and swallowing effect after contact with saliva.

[0098] The results show that the anhydrous ambroxol granules of this invention have good taste masking and swallowing effect, and produce a pleasant refreshing feeling after oral administration. The drug formulation satisfies the requirements of taste masking and rapid drug release in acid, and also meets the requirements of rapid drug release in the stomach, thus achieving rapid onset of action.

[0099] Preparation Example 2: Preparation of anhydrous ambroxol granules

[0100] The prescriptions are shown in Table 3:

[0101] Table 3 Prescription for Ambroxol Anhydrous Granules

[0102]

[0103] The preparation process was the same as in Preparation Example 1. The effects of the weight gain of the masking layer coating (approximately 15%, 25%, and 30% respectively) on drug release and masking effect were investigated.

[0104] Experimental Example 2: Evaluation of Formulation Efficacy: Dissolution, Taste, and Anhydrous Swallowing Effect

[0105] Dissolution: Determined according to the Dissolution and Release Test Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Using 900 ml of hydrochloric acid solution (9→1000) as the dissolution medium, the rotation speed was 50 rpm. The procedure was followed, and samples were taken after 15 minutes. An appropriate amount of the dissolution solution was taken, filtered, and the filtrate was used as the test solution. Appropriate amounts of ambroxol hydrochloride and clenbuterol hydrochloride reference standards were accurately weighed, dissolved in the dissolution medium, and quantitatively diluted to prepare a solution containing approximately 7.5 μg of ambroxol hydrochloride and 0.1 μg of clenbuterol hydrochloride per ml, which was used as the reference solution. Dissolution was determined using high-performance liquid chromatography (HPLC). Specific results are shown in Table 4.

[0106] Dissolution in artificial saliva: Determined according to the method for determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Dissolution conditions: Using 500 ml of artificial saliva (containing enzymes) [0.795 g calcium chloride, 0.78 g sodium dihydrogen phosphate dihydrate, 5 mg sodium sulfide dihydrate, 0.4 g potassium chloride, 1 g urea, 0.4 g sodium chloride, 1 g α-amylase, dissolved in water and diluted to 1000 ml, pH adjusted to 6.8 with sodium hydroxide test solution (a small amount of precipitate will be generated in the solution during pH adjustment)] as the dissolution medium, the rotation speed is 50 rpm, and the procedure is followed. Samples are taken after 2 minutes. An appropriate amount of the dissolution solution is taken, filtered, and the filtrate is used as the test solution. Accurately weigh appropriate amounts of ambroxol hydrochloride and clenbuterol hydrochloride reference standards, dissolve them in dissolution medium, and quantitatively dilute to prepare a solution containing approximately 7.5 μg of ambroxol hydrochloride and 0.1 μg of clenbuterol hydrochloride per ml. This solution is used as the reference solution. Dissolution was determined using high-performance liquid chromatography (HPLC), and the specific results are shown in Table 4.

[0107] Table 4 Dissolution test results

[0108]

[0109] Note: / before: content of ambroxol hydrochloride, / after: content of clenbuterol hydrochloride.

[0110] As can be seen from the data in Table 4, the release rate of the anhydrous ambroxol granules of the present invention, with a masking layer weight gain of about 15% to about 30%, meets the limit requirement of 85% release within 15 minutes.

[0111] Anhydrous swallowing efficacy: After oral administration of the anhydrous ambroxol granules prepared according to prescriptions 1, 4 and 5 to 12 volunteers, all of them could be swallowed smoothly within 1 minute under anhydrous swallowing conditions. This indicates that the drug meets the quality requirements in terms of taste masking and swallowing efficacy after contact with saliva.

[0112] The results show that the anhydrous ambroxol granules of this invention have good taste masking and swallowing effect. The drug formulation satisfies the requirements of rapid drug release in acid and also meets the requirements of rapid drug release in the stomach, thus achieving rapid onset of action.

[0113] Comparative Example 1: Preparation of Ambroxol Granules

[0114] The prescriptions are shown in Table 5:

[0115] Table 5. Prescription for Ambroxol Granules

[0116]

[0117] Preparation process description:

[0118] The drug-containing granule component is granulated using a fluidized bed to obtain dry granules, which are then mixed with flavoring components. Details are as follows:

[0119] (1) Preparation of drug-containing granules:

[0120] Dissolve hydroxypropyl methylcellulose E5 in purified water. After the hydroxypropyl methylcellulose E5 is completely dissolved, add clenbuterol hydrochloride solution to the hydroxypropyl methylcellulose E5 solution for later use.

[0121] Sorbitol and xanthan gum were added to a fluidized bed, and fluidized bed granulation was performed using a top-spray method. The material temperature was controlled at 40–50°C during granulation. After granulation, the granules were dried for at least 10 minutes. Finally, the dried granules were sieved through a 20-mesh sieve to obtain drug-containing granules.

[0122] (2) Mixing of medicated granules and flavoring components:

[0123] The above-mentioned drug-containing granules are mixed with flavoring components to obtain the ambroxol granules.

[0124] Experimental Example 3: Evaluation of Formulation Efficacy: Taste Evaluation

[0125] Taste evaluation: The palatability of prescriptions 1, 4, 5 and 6 was compared with that of prescriptions 6 in accordance with the "Technical Guidelines for Taste Design and Evaluation of Pediatric Medication (Trial)". The taste evaluation results are shown in Table 6 and the taste scoring criteria are shown in Table 7.

[0126] Table 6: Adult Tasting Evaluation Results

[0127]

[0128]

[0129] Table 7 Evaluation Scoring Criteria for Adult Tasting Test

[0130]

[0131] Taste evaluation: After oral administration of the pharmaceutical preparations prepared by prescriptions 1, 4, 5 and 6 to 10 volunteers, prescriptions 1, 4 and 5 were superior to prescription 6 in terms of odor, sweetness, taste and aftertaste. This indicates that the ambroxol anhydrous granules provided by this invention can ensure a good taste, making them easier for pediatric patients to accept, thereby improving medication adherence in pediatric patients.

[0132] Based on the above description of the invention, those skilled in the art can fully apply the present invention, and all modifications based on the same principles or similar modifications should be considered to be included within the scope of the present invention.

Claims

1. An anhydrous ambroxol granules, comprising: drug-containing and flavor-masking granules and flavoring components; wherein the drug-containing and flavor-masking granules, from the inside out, are: a core, a drug-containing layer, an isolation layer, and a flavor-masking layer.

2. The ambroxol anhydrous oral granules according to claim 1, wherein: The drug-containing layer comprises: 5-15 parts by weight of ambroxol hydrochloride, 0.005-0.015 parts by weight of clenbuterol hydrochloride, and 5-20 parts by weight of the first binder; The isolation layer comprises: 15-40 parts by weight of a second adhesive and 10-25 parts by weight of a first anti-adhesion agent; The odor-masking layer comprises: 20-60 parts by weight of acrylic resin polymer and 0.5-5 parts by weight of a second anti-sticking agent.

3. The ambroxol anhydrous granules according to claim 2, wherein: The core is selected from one or more of sucrose core and microcrystalline cellulose core; preferably, the core is sucrose core and the core diameter is 180-250 μm. The first adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone, preferably hydroxypropyl methylcellulose; The second adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone, preferably hydroxypropyl methylcellulose; The first anti-adhesion agent is selected from one or more of talc, titanium dioxide and magnesium stearate, preferably talc; The acrylic resin polymer is selected from one or more of the following: Eutech E100, Eutech EPO, Eutech L30D, and Eutech L30D-55, preferably Eutech E100; The second anti-adhesion agent is selected from one or more of talc, titanium dioxide and magnesium stearate, preferably talc and magnesium stearate.

4. The ambroxol anhydrous oral granules according to claim 1, wherein: The flavoring component comprises: 100-450 parts by weight of flavoring agent, 1-5 parts by weight of sweetener and 1-5 parts by weight of flavoring; The flavoring agent is selected from one or more of sorbitol, mannitol and maltodextrin, preferably sorbitol; The sweetener is selected from one or more of aspartame, sucralose and acesulfame potassium, preferably sucralose; The fragrance is selected from one or more of the following: vanilla extract, banana extract, sweet orange extract, and mixed fruit extract.

5. The ambroxol anhydrous oral granules according to claim 1, wherein: Based on the weight of the pellet core, the weight gain of the drug-containing coating is 10-30%, preferably 15-25%, and more preferably 15-20%. The weight gain of the coating of the isolation layer is 5-50% based on the weight of the medicated pellets, preferably 15-40%, and more preferably 25-35%. Based on the weight of the isolating pellets, the coating weight gain of the flavor-masking layer is 10-40%, preferably 15-30%, more preferably 20-30%, and even more preferably 23-28%.

6. The ambroxol anhydrous granules according to claim 1, wherein: The drug-containing layer comprises: 5-10 parts by weight of ambroxol hydrochloride, 0.005-0.01 parts by weight of clenbuterol hydrochloride, and 10-20 parts by weight of the first binder; The isolation layer comprises: 20-40 parts by weight of a second adhesive and 10-20 parts by weight of a first anti-adhesion agent; The flavor-masking layer comprises: 30-50 parts by weight of acrylic resin polymer and 1-4 parts by weight of second anti-adhesion agent; The flavoring components include: 150-250 parts by weight of flavoring agent, 2-4 parts by weight of sweetener and 2-4 parts by weight of flavoring.

7. The ambroxol anhydrous granules according to claim 1, wherein: The drug-containing layer comprises: 6-8 parts by weight of ambroxol hydrochloride, 0.005-0.008 parts by weight of clenbuterol hydrochloride, and 13-17 parts by weight of the first binder; The isolation layer comprises: 25-35 parts by weight of a second adhesive and 13-17 parts by weight of a first anti-adhesion agent; The flavor-masking layer comprises: 40-50 parts by weight of an acrylic resin polymer and 2-4 parts by weight of a second anti-adhesive agent; The flavoring components include: 180-230 parts by weight of flavoring agent, 2-3 parts by weight of sweetener and 2-3 parts by weight of flavoring.

8. The ambroxol anhydrous oral granules according to claim 1, wherein: The anhydrous ambroxol granules have a dissolution rate of less than 4% in artificial saliva medium over 2 minutes, preferably less than 3%, more preferably less than 2%; and / or The anhydrous ambroxol granules have a dissolution rate of greater than 90%, preferably greater than 95%, and more preferably greater than 98% in hydrochloric acid solution medium after 15 minutes.

9. The ambroxol anhydrous granules according to claim 1, wherein, The components and their contents of the anhydrous swallowable granules are as follows:

10. A method for preparing the anhydrous ambroxol granules of claim 1, comprising the following steps: (1) Preparation of drug-containing pellets: Add the first adhesive to water. After the first adhesive is completely dissolved, dissolve clenbuterol hydrochloride in water and add it to the first adhesive solution. Then, add ambroxol hydrochloride while stirring to disperse the ambroxol hydrochloride evenly. The pellet core is added to a fluidized bed, and the suspension is coated by bottom spraying of the fluidized bed. During the coating process, the material temperature is controlled at 35℃~60℃ (preferably, the material temperature is controlled at 40~50℃). After the coating is completed, the pellets are dried to obtain drug-containing pellets. (2) Preparation of isolation pellets: Add the second adhesive to water, and after the second adhesive has completely dissolved, add the first anti-adhesion agent while stirring, and disperse it evenly. Drug-containing pellets are added to a fluidized bed, and a bottom spray coating process is used for isolation coating. During the coating process, the material temperature is controlled at 35℃~60℃ (preferably, the material temperature is controlled at 40~50℃). After the isolation coating is completed, the pellets are dried to obtain isolation pellets. (3) Preparation of flavor-masked pellets: Dissolve the acrylic resin polymer in 95% ethanol. After it is completely dissolved, add the second anti-blocking agent while stirring and disperse it evenly. Isolation pellets are added to a fluidized bed, and a deodorizing coating process is carried out by bottom spray coating of the fluidized bed. During the coating process, the material temperature is controlled at 20℃~40℃ (preferably, the material temperature is controlled at 20~30℃). After the deodorizing coating is completed, the pellets are dried to obtain deodorizing pellets. (4) Mixing of flavor-masking particles and flavoring components: The above-mentioned flavor-masking pellets are mixed with the flavor-correcting components to obtain the ambroxol anhydrous swallowable granules.

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