Levalbuterol hydrochloride oral fast-dissolving film based on taste masking technology and preparation method and application thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a salted hydrochloric acid levo-salbutamol oral fast-dissolving film based on taste masking by inclusion technology and a preparation method and application thereof. The film includes 1%-5% of salted hydrochloric acid levo-salbutamol, 50%-80% of film forming material, a plasticizer, a taste masking agent, 5%-15% of a disintegrating agent and 1%-5% of a saliva stimulant according to the weight of the dry film; the film forming material is a combination of hydroxypropyl methyl cellulose and polyvinyl alcohol, the taste masking agent is beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin and a pre-inclusion compound of the drug, the disintegrating agent is cross-linked polyvidone, and the saliva stimulant is citric acid. The preparation is prepared by using a low-temperature solvent casting method, and the drying temperature is 40-50 DEG C. The film can be quickly disintegrated in the oral cavity within 30 seconds, avoids the first pass effect through mucosal absorption, effectively masks the taste, ensures the stability of chiral drugs, has good mechanical properties, does not need water and equipment for administration, and is suitable for out-of-hospital first aid for bronchial asthma, acute attack of chronic obstructive pulmonary disease.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a taste-masking oral film of levosalbutanol hydrochloride based on inclusion technology, its preparation method, and its application. Background Technology

[0002] Bronchial asthma and chronic obstructive pulmonary disease are common respiratory illnesses that can cause severe breathing difficulties and even be life-threatening during acute exacerbations. Rapid relief of bronchospasm is crucial for treating acute exacerbations, thus requiring a fast-acting and easy-to-use drug formulation.

[0003] Levosalbutamol hydrochloride is the single R-enantiomer of salbutamol and a β2-adrenergic receptor agonist. Its bronchodilatory effect is 4-10 times that of racemic salbutamol, with a lower incidence of adverse reactions, making it a first-line drug for treating bronchospasm. Currently, levosalbutamol hydrochloride formulations used clinically are mainly nebulized inhalation solutions. This dosage form requires a dedicated nebulizer for administration, which is bulky, requires a power source, and is inconvenient to carry, making it unsuitable for immediate self-treatment by patients experiencing acute attacks outside of hospitals. Furthermore, multi-dose nebulized inhalation solutions pose a risk of microbial contamination during repeated use.

[0004] Existing technologies include research on orally disintegrating tablets. While this dosage form can be taken without drinking water, patients still need to swallow, posing a dosing obstacle for patients with severe respiratory distress or swallowing dysfunction. Furthermore, orally disintegrating tablets are typically several millimeters thick, causing a noticeable foreign body sensation in the mouth and resulting in poor patient compliance. In addition, the direct compression process requires high pressure, which may potentially affect the stereoconfigurational stability of chiral drugs like levosalbutamol hydrochloride.

[0005] Oral fast-dissolving films are a novel oral dosage form characterized by their thinness, minimal foreign body sensation, no need for swallowing, rapid disintegration in the oral cavity, and absorption through the mucosa, making them particularly suitable for emergency administration. However, there are currently no research reports on oral fast-dissolving films containing levosalbutamol hydrochloride. Developing this drug into an oral fast-dissolving film presents numerous technical challenges: levosalbutamol hydrochloride has an extremely bitter taste, and the large exposed area of ​​the drug in the oral cavity during film administration makes masking the taste significantly more difficult than with tablets; levosalbutamol hydrochloride is a chiral drug and thermally unstable; the high temperatures of conventional hot-melt extrusion film-forming processes easily lead to racemization and oxidative degradation of its R-configuration, reducing efficacy and increasing impurity content; furthermore, there is a lack of directly applicable technical data regarding the drug's stability in polymer film matrices and its compatibility with various excipients.

[0006] Therefore, there is an urgent need to develop a fast-dissolving oral film for levosalbutanol hydrochloride that can rapidly disintegrate in the oral cavity, effectively mask the bitter taste of the drug, ensure the stereochemical stability of the chiral drug, and at the same time have good mechanical properties and storage stability to meet the drug administration needs in out-of-hospital emergency scenarios. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a flavor-masking oral instant film of levosalbutanol hydrochloride based on inclusion technology, its preparation method, and its application.

[0008] The purpose of this invention is to provide a fast-acting oral film of levosalbutamol hydrochloride that is convenient to use, has good stability, and high patient compliance.

[0009] The first aspect of the present invention provides a flavor-masking oral film of levosalbutamol hydrochloride based on inclusion technology, comprising the following components by dry film weight: 1% to 5% levosalbutamol hydrochloride, 50% to 80% film-forming material, 10% to 25% plasticizer by mass of film-forming material, 2 to 5 times the mass of levosalbutamol hydrochloride, 5% to 15% disintegrant, and 1% to 5% saliva stimulant.

[0010] As a further improvement to the above-mentioned levosalbutanol hydrochloride oral instant film, the film-forming material is a combination of hydroxypropyl methylcellulose and polyvinyl alcohol in a mass ratio of 7:3 to 5:5; the flavor masking agent is β-cyclodextrin or hydroxypropyl-β-cyclodextrin, and levosalbutanol hydrochloride and the flavor masking agent form an inclusion complex beforehand; the disintegrant is crospovidone; and the salivary stimulant is citric acid.

[0011] As a further improvement to the above-mentioned levosalbutanol hydrochloride oral instant dissolving film, the content of levosalbutanol hydrochloride is 0.5~2.5mg per film.

[0012] As a further improvement to the above-mentioned levosalbutanol hydrochloride oral instant dissolving film, hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5 or hydroxypropyl methylcellulose E15, and polyvinyl alcohol is polyvinyl alcohol 1788.

[0013] As a further improvement to the above-mentioned levosalbutanol hydrochloride oral instant film, the plasticizer is glycerin or polyethylene glycol 400.

[0014] As a further improvement to the above-mentioned levosalbutanol hydrochloride oral instant film, it also includes a sweetener of 0.5% to 2%, wherein the sweetener is sucralose.

[0015] As a further improvement to the above-mentioned levosalbutanol hydrochloride oral instant film, it also includes the stabilizer disodium ethylenediaminetetraacetate, the concentration of which in the casting solution is 0.01%~0.05% (w / v).

[0016] A second aspect of this invention provides a method for preparing the above-mentioned flavor-masking oral instant film of levosalbutamol hydrochloride based on inclusion technology, comprising the following steps: S1. Preparation of inclusion complex: levosalbutanol hydrochloride and flavor masking agent are mixed in proportion, wetting agent is added and ground for 20-30 min, and dried at no more than 40℃ to obtain levosalbutanol hydrochloride inclusion complex; S2. Preparation of adhesive solution: Disperse the film-forming material in the solvent and stir for 1-2 hours at a temperature not exceeding 60°C to form a homogeneous polymer solution; S3. Adding and mixing: Add plasticizer, levosalbutanol hydrochloride inclusion complex, disintegrant, salivary stimulant and other optional components to the polymer solution in sequence, and stir until homogeneous; S4. Degassing: Degas the mixed adhesive solution under vacuum or allow it to stand for degassing; S5. Casting: Apply the degassed adhesive to the release substrate, controlling the wet film thickness to be 0.8~1.0mm; S6. Drying: Dry with hot air at 40~50℃ for 2~4 hours to form a film; S7. Cutting and Packaging: Peel and cut the dried film agent for single-dose packaging.

[0017] As a further improvement to the above preparation method, in step S1, the mass ratio of levosalbutanol hydrochloride to the masking agent is 1:2 to 1:3, and the wetting agent is a 50% ethanol solution.

[0018] As a further improvement to the above preparation method, the solvent in step S2 is purified water or a mixture of purified water and ethanol.

[0019] As a further improvement to the above preparation method, the vacuum degassing conditions in step S4 are -0.08 MPa and the degassing time is 10~15 min.

[0020] The third aspect of this invention provides the application of the above-mentioned levosalbutamol hydrochloride oral instant-dissolving film based on inclusion technology in the preparation of drugs for treating bronchospasm caused by bronchial asthma and chronic obstructive pulmonary disease.

[0021] Beneficial effects Compared with existing technologies, the oral levosalbutamol hydrochloride fast-dissolving film provided by this invention, based on inclusion technology for taste masking, achieves rapid disintegration and drug dissolution in the oral cavity while ensuring the mechanical properties and content uniformity of the film. This effectively masks the strong bitter taste of the drug and significantly improves the chemical and stereochemical stability of chiral drugs during preparation and storage. The film can be used without drinking water or medication equipment, is thin with minimal foreign body sensation, and allows for drug absorption through the oral mucosa, avoiding the first-pass effect of the liver. It also features rapid onset of action, good patient compliance, and convenient portability, making it particularly suitable for outpatient emergency administration of bronchial asthma and acute exacerbations of chronic obstructive pulmonary disease. Detailed Implementation

[0022] The present invention is further illustrated below with specific embodiments. These embodiments are exemplary and intended to illustrate the problem and explain the present invention, and are not intended to be limiting.

[0023] Example 1 This embodiment provides a flavor-masking oral instant film of levosalbutanol hydrochloride based on inclusion technology. The formulation is based on a 2×3cm size per film, and consists of: levosalbutanol hydrochloride-β-cyclodextrin inclusion complex (1:2) 3.0mg (containing levosalbutanol hydrochloride 1.0mg), hydroxypropyl methylcellulose E5 35mg, polyvinyl alcohol 1788 15mg, glycerin 7.5mg, crospovidone 5mg, citric acid 3mg, sucralose 1mg, and disodium EDTA 0.016mg.

[0024] The preparation method is as follows: Take 100 mg of levosalbutanol hydrochloride and 200 mg of β-cyclodextrin, add 0.3 mL of 50% ethanol solution, grind for 25 min, dry under reduced pressure at 40℃ for 4 h, and pass through an 80-mesh sieve to obtain the levosalbutanol hydrochloride-β-cyclodextrin inclusion complex. Take 3.5 g of hydroxypropyl methylcellulose E5 and 1.5 g of polyvinyl alcohol 1788, disperse in 80 mL of purified water, and stir in a water bath at 60℃ for 1.5 h to form a uniform polymer solution. Add 0.75 g of glycerol to the solution, stir for 30 min, and then add disodium ethylenediaminetetraacetate solution to make the concentration reach 0.02% (w / v). Add the above inclusion complex powder, 0.5 g of crospovidone, 0.3 g of citric acid, and 0.1 g of sucralose in sequence, and continue stirring for 30 min to ensure uniform dispersion of all components. Place the solution under vacuum at -0.08 MPa for 12 min to degas. The degassed adhesive was cast onto a glass plate, and the wet film thickness was controlled to be 0.9 mm using a film scraper. The film was then dried in a 45℃ hot air drying oven for 3.5 hours. The dried film was then peeled off the glass plate, cut into 2×3 cm sheets, and sealed in nitrogen-filled aluminum foil bags to obtain the final product.

[0025] Example 2 This embodiment provides a flavor-masking oral film of levosalbutanol hydrochloride based on inclusion technology. The difference from Example 1 is that the film-forming material is adjusted to 50 mg of hydroxypropyl methylcellulose E5, and polyvinyl alcohol 1788 is not added; the amount of glycerin is adjusted to 10 mg. The remaining formulation and preparation method are the same as in Example 1.

[0026] Example 3 This embodiment provides a flavor-masking oral film of levosalbutamol hydrochloride based on inclusion technology. The difference from Example 1 is that the plasticizer is replaced with polyethylene glycol 400 at a dosage of 7.5 mg, and no glycerin is added. The remaining formulation and preparation method are the same as in Example 1.

[0027] Comparative Example 1 This comparative example provides a levosalbutamol hydrochloride oral instant dissolving film, which differs from Example 1 in that: no inclusion complex is prepared in advance, and 1.0 mg of levosalbutamol hydrochloride active pharmaceutical ingredient is directly added to the gel solution, without the addition of β-cyclodextrin. The remaining formulation and preparation method are the same as in Example 1.

[0028] Comparative Example 2 This comparative example provides a levosalbutanol hydrochloride oral instant-dissolving film, which differs from Example 1 in that cross-linked povidone is removed from the formulation and replaced with an equal amount of mannitol. The remaining formulation composition and preparation method are the same as in Example 1.

[0029] Comparative Example 3 This comparative example provides a levosalbutanol hydrochloride oral instant-dissolving film, which differs from Example 1 in that the drying process parameters are adjusted to 80℃ for 1.5h. The remaining formulation and preparation method are the same as in Example 1.

[0030] Comparative Example 4 This comparative example provides a levosalbutamol hydrochloride oral instant-dissolving film, which differs from Example 1 in that: the film-forming material is adjusted to hydroxypropyl methylcellulose E5 50mg, and polyvinyl alcohol 1788 is not added; the amount of glycerin is adjusted to 5mg. The remaining formulation and preparation method are the same as in Example 1.

[0031] Performance testing The following performance tests were performed on the levosalbutamol hydrochloride oral instant-dissolving films prepared in Examples 1-3 and Comparative Examples 1-4. Disintegration time was determined using a modified basket method, where the film was placed in 2 mL of purified water at 37±0.5℃, and the time for complete disintegration was recorded. Content and related substances were determined using ultra-high performance liquid chromatography (UHPLC) with a C18 column, using 0.1% phosphoric acid aqueous solution as mobile phase A and methanol-acetonitrile-water-phosphoric acid as mobile phase B for gradient elution. The detection wavelength was 220 nm, and the levosalbutamol hydrochloride content and total impurity content were calculated using the external standard method. Content uniformity was determined according to the Chinese Pharmacopoeia content uniformity test method, measuring the content of 10 films and calculating the A+2.2S value. Surface pH was measured by immersing the film in 2 mL of purified water for 5 min and measuring the pH value of the extract. Taste evaluation was conducted by 5 healthy volunteers using a 5-point scoring system, with 1 point indicating no bitterness and 5 points indicating extreme bitterness. The flexibility test involves repeatedly bending the film at 180° three times and observing whether it breaks or crumbles. The performance test results of each embodiment and comparative example are shown in Table 1.

[0032] Table 1 Performance test results of levosalbutanol hydrochloride oral instant film The test results show that Example 1, using a composite film-forming material of hydroxypropyl methylcellulose and polyvinyl alcohol, β-cyclodextrin for taste masking, and crospovidone as a disintegrant, and employing a low-temperature drying process, exhibits the best overall performance. Its disintegration time is 24 seconds, allowing for rapid disintegration in the oral cavity; the levosalbutanol hydrochloride content is 99.2%, with content uniformity meeting requirements; the total impurities are only 0.28%, indicating good drug stability; the taste score is 1.4, with virtually no bitterness; the film exhibits good flexibility, resisting repeated bending without cracking, meeting the requirements for production, transportation, and use. Example 2, using hydroxypropyl methylcellulose as the film-forming material, although increasing the amount of plasticizer, resulted in a prolonged disintegration time of 38 seconds, and a slight decrease in film flexibility with minor flaking, indicating that the addition of polyvinyl alcohol has a positive effect on improving the mechanical and disintegration properties of the film. Example 3, using polyethylene glycol 400 instead of glycerin as a plasticizer, shows similar performance indicators to Example 1, indicating that polyethylene glycol 400 can be an effective alternative plasticizer to glycerin.

[0033] Comparative Example 1, without pre-prepared drug inclusion complexes, directly added the active pharmaceutical ingredient (API) to the gel, relying solely on sweeteners to improve taste. Its taste score was as high as 4.7, indicating that the bitterness of the drug was not effectively masked. This demonstrates that in high specific surface area film systems, simply adding sweeteners cannot overcome the strong bitterness of levosalbutanol hydrochloride; cyclodextrin inclusion complexes are needed to form a host-guest structure, establishing a physical barrier between the drug and taste buds to achieve effective taste masking. Comparative Example 2, after removing cross-linked povidone, relied solely on the solubilizing effect of citric acid, resulting in a significantly prolonged film disintegration time of 82 seconds, failing to meet the requirements for rapid disintegration. This indicates that in high-viscosity hydroxypropyl methylcellulose and polyvinyl alcohol composite film matrices, the capillary channels provided by cross-linked povidone are needed to rapidly introduce saliva, while citric acid stimulates saliva secretion to create a chemically solubilizing environment; both factors work together to achieve rapid film disintegration. Comparative Example 3, using an 80℃ high-temperature drying process, while accelerating the drying speed, significantly increased the total impurity content, decreased the drug content, and exceeded the acceptable range for content uniformity. This indicates that high-temperature conditions adversely affect the chemical and stereochemical stability of chiral drugs. Strict control of the drying temperature, combined with the use of metal ion chelating agents, is necessary to ensure drug stability from both process and formulation perspectives. Comparative Example 4, using a single film-forming material and insufficient plasticizer, showed a significant increase in film brittleness, making it prone to cracking. Simultaneously, disintegration time and content uniformity were also affected. This demonstrates that appropriate film-forming material ratios and plasticizer dosages are fundamental to obtaining good mechanical properties and formulation quality.

[0034] The above results demonstrate that this invention achieves multiple technical benefits, including rapid disintegration, effective taste masking, drug stability, and good mechanical properties, through the organic combination of hydroxypropyl methylcellulose and polyvinyl alcohol composite film-forming material, cyclodextrin inclusion masking, cross-linked povidone and citric acid synergistic disintegration, and low-temperature drying and antioxidant stabilization system. It solves the technical problems encountered in preparing levosalbutanol hydrochloride as an oral fast-dissolving film, such as difficulty in masking taste, poor thermal stability, and the difficulty in balancing film-forming performance and disintegration rate. This provides an effective dosage form for outpatient emergency treatment of acute bronchospasm.

[0035] The above embodiments are exemplary and are intended to illustrate the technical concept and features of the present invention, so that those skilled in the art can understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A flavor-masking oral film of levosalbutanol hydrochloride based on inclusion technology, characterized in that, Based on the weight of dry film, it includes the following components: Levosalbutamol hydrochloride 1%~5%, Film-forming material 50%~80%, The plasticizer accounts for 10% to 25% of the mass of the film-forming material. The masking agent is 2 to 5 times the mass of levosalbutanol hydrochloride. Disintegrant 5%~15%, Saliva stimulants 1%~5%.

2. The levosalbutanol hydrochloride oral instant-dissolving film based on inclusion technology according to claim 1, characterized in that, The film-forming material is a combination of hydroxypropyl methylcellulose and polyvinyl alcohol in a mass ratio of 7:3 to 5:5; the flavor masking agent is β-cyclodextrin or hydroxypropyl-β-cyclodextrin, and levosalbutanol hydrochloride forms an inclusion complex with the flavor masking agent beforehand; the disintegrant is crospovidone; and the salivary stimulant is citric acid.

3. The levosalbutanol hydrochloride oral instant-dissolving film based on inclusion technology according to claim 1, characterized in that, The content of levosalbutanol hydrochloride is 0.5~2.5 mg per film tablet.

4. The levosalbutanol hydrochloride oral instant-dissolving film based on inclusion technology according to claim 1, characterized in that, The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5 or hydroxypropyl methylcellulose E15, the polyvinyl alcohol is polyvinyl alcohol 1788, and the plasticizer is glycerol or polyethylene glycol 400.

5. The levosalbutanol hydrochloride oral instant-dissolving film based on inclusion technology according to claim 1, characterized in that, It also includes 0.5% to 2% sweetener, wherein the sweetener is sucralose.

6. The levosalbutanol hydrochloride oral instant-dissolving film based on inclusion technology according to claim 1, characterized in that, It also includes the stabilizer disodium ethylenediaminetetraacetate, wherein the concentration of disodium ethylenediaminetetraacetate in the casting solution is 0.01%~0.05% (w / v).

7. A method for preparing a taste-masking oral instant film of levosalbutanol hydrochloride based on inclusion technology as described in any one of claims 1 to 6, characterized in that, Includes the following steps: S1. Preparation of inclusion complex: levosalbutanol hydrochloride and flavor masking agent are mixed in proportion, wetting agent is added and ground for 20-30 min, and dried at no more than 40℃ to obtain levosalbutanol hydrochloride inclusion complex; S2. Preparation of adhesive solution: Disperse the film-forming material in the solvent and stir for 1-2 hours at a temperature not exceeding 60°C to form a homogeneous polymer solution; S3. Adding and mixing: Add plasticizer, levosalbutanol hydrochloride inclusion complex, disintegrant, salivary stimulant and other optional components to the polymer solution in sequence, and stir until homogeneous; S4. Degassing: Degas the mixed adhesive solution under vacuum or allow it to stand for degassing; S5. Casting: Apply the degassed adhesive to the release substrate, controlling the wet film thickness to be 0.8~1.0mm; S6. Drying: Dry with hot air at 40~50℃ for 2~4 hours to form a film; S7. Cutting and Packaging: Peel and cut the dried film agent for single-dose packaging.

8. The preparation method according to claim 7, characterized in that, In step S1, the mass ratio of levosalbutanol hydrochloride to the masking agent is 1:2 to 1:3, and the wetting agent is a 50% ethanol solution; in step S2, the solvent is purified water or a mixture of purified water and ethanol.

9. The preparation method according to claim 7, characterized in that, In step S4, the vacuum degassing conditions are -0.08 MPa and the degassing time is 10~15 min.

10. An application of a taste-masking oral instant-dissolving film of levosalbutanol hydrochloride based on inclusion technology, characterized in that, The oral instant film of levosalbutanol hydrochloride according to any one of claims 1 to 6 is used to treat bronchial asthma and bronchospasm caused by chronic obstructive pulmonary disease.

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