Preparation method of nicotine oral soluble film based on nanofiber carrier

Abstract

The invention belongs to the technical field of preparation of oral soluble films, and relates to a preparation method of a nicotine oral soluble film based on a nanofiber carrier. The preparation method comprises the following steps: dissolving nicotine salt and a carrier material in a water / ethanol mixed solvent to form a drug-loaded solution, and preparing a nanofiber membrane for later use by electrostatic spinning; adding an instant polymer, a high-strength sweetening agent, a freshener and a plasticizer into purified water, stirring until the materials are uniformly mixed, and defoaming to obtain a functional isolation lower layer film-forming solution; the functional isolation lower layer film forming liquid is cast on the base material, the nanofiber film is immediately laid on the functional isolation lower layer, the two layers of composite wet films are placed in a drying oven at the temperature of 50-60 DEG C to be dried, the oral dissolving film of a double-layer composite structure is formed, and the film is uncovered and cut. According to the preparation method, an electrostatic spinning nanotechnology and a traditional tape casting process are innovatively combined, and the product has a double-layer structure of a functional isolation lower layer and a nanofiber drug-loading layer and has extremely high content uniformity, excellent taste activation, excellent stability and process expandability.

Description

Technical Field

[0001] This invention belongs to the field of oral dissolving film preparation technology, specifically relating to a method for preparing a nicotine oral dissolving film based on a nanofiber carrier. Background Technology

[0002] Oral dissolving film (ODF) is a novel dosage form that, when placed on the tongue or cheek, rapidly dissolves or disintegrates within tens of seconds, releasing the active ingredient. Most existing nicotine oral dissolving films are prepared using the traditional "cast-coat" process to create a single-layer film. This process has the following main drawbacks: Uniformity problem: Nicotine bases or salts are prone to migration and aggregation in the film-forming slurry, resulting in uneven distribution of nicotine in the membrane and large differences in drug loading per unit area, which affects the accuracy of dosage.

[0003] Taste vs. Stability: To mask the pungent and irritating sensation of nicotine, large amounts of flavoring agents and cooling agents are often added. This not only affects the mechanical properties of the membrane, but the high concentration of flavor substances themselves may also lead to unpleasant aftertastes. Furthermore, nicotine is prone to oxidative degradation during storage, affecting the product's shelf life.

[0004] Balancing strength and dissolution rate: A single film layer can hardly simultaneously achieve good mechanical strength (for easy handling and packaging) and extremely fast dissolution rate. The selection of plasticizer and polymer dosages often requires compromise.

[0005] Electrospinning technology was discovered by Rayleigh in the late 19th century, and in 1934, Formalas created a device for preparing polymer fibers using electrostatic forces. This device utilizes electricity to produce polymer fibers with diameters ranging from 2 nm to several micrometers. Electrospun fibers have smaller pores and higher specific surface areas than ordinary fibers and have been successfully applied in nanocatalysis, tissue engineering scaffolds, protective clothing, filtration, biomedicine, pharmaceuticals, optoelectronics, healthcare, biotechnology, defense and security, and environmental engineering.

[0006] The basic apparatus for electrospinning consists of three parts: a high-voltage power supply, a spinneret, and a grounded collecting plate. It utilizes the high-voltage power supply to inject a charge of a certain polarity into the polymer solution, which is then accelerated towards the collecting plate of the opposite polarity. When the applied electric field reaches a critical value, the repulsive force overcomes the surface tension, and a charged jet of solution is ejected from the spinneret. This jetting occurs rapidly and unstably in the space between the capillary tip and the collector, causing the solvent to evaporate. The polymer then deposits as fibers on the metal collecting plate.

[0007] Oral dissolving films prepared using traditional materials and processes have low drug loading capacity, and nicotine salts tend to precipitate out after the film dries, resulting in a whitening or white spot appearance on the film surface. Therefore, there is an urgent need in this field for an innovative preparation method to overcome these technical bottlenecks. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing a nicotine oral dissolving film based on a nanofiber carrier that features rapid release, high content uniformity, and excellent taste.

[0009] The technical solution adopted by this invention to solve its technical problem is: a method for preparing a nicotine oral solution membrane based on a nanofiber carrier, comprising the following steps: (1) Preparation of nanofiber carrier layer: Nicotine salt and carrier material are dissolved in a water / ethanol mixed solvent to form a drug loading solution, and nanofiber membranes are prepared by electrospinning for later use. (2) Preparation of functional isolation lower film-forming solution: Add the fast-dissolving polymer, high-intensity sweetener, cooling agent and plasticizer to purified water, stir until evenly mixed, degas to obtain the functional isolation lower film-forming solution; (3) Compounding and drying: The film-forming liquid for the functional isolation layer is cast onto the substrate, with a wet film thickness of 300 μm. The nanofiber membrane is then immediately laid on the functional isolation layer. The two composite wet films are dried in an oven at 50~60℃ to form a bilayer composite oral dissolution film. The film is then peeled off and cut.

[0010] Furthermore, the nicotine salt in step (1) is one of nicotine malate, nicotine tartrate, or nicotine lactobionate.

[0011] Furthermore, the carrier material in step (1) is one or more of hydroxypropyl-β-cyclodextrin, sodium alginate, gelatin, and polyethylene glycol.

[0012] Furthermore, in step (1), the mass concentration of ethanol in the water / ethanol mixed solvent is 50-60%.

[0013] Furthermore, the mass-to-volume ratio of the nicotine salt, carrier material, and mixed solvent is 80-120 mg: 0.9-1.1 g: 10-11 mL.

[0014] Furthermore, the electrospinning voltage is 13-15kV and the feed rate is 0.7-0.8 mL / h.

[0015] Furthermore, in step (2), the weight ratio of the instant polymer, high-strength sweetener, cooling agent, plasticizer and purified water is 15-25:1.5-5:0.08-0.15:3-6:50-65.

[0016] Furthermore, the instant polymer is one or more of hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, and carboxymethyl cellulose; the high-intensity sweetener is one or more of sucralose, mannitol, and erythritol; the cooling agent is one or more of menthol, WS-3 (N-ethyl-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) or WS-23 (N,2,3-trimethyl-2-isopropylbutyramide); and the plasticizer is glycerol or propylene glycol.

[0017] Furthermore, the oral dissolution membrane with a double-layer composite structure prepared in step (3) is cut into square pieces containing 2 mg of nicotine per piece, with a complete dissolution time in the oral cavity of less than 30 seconds and a content uniformity AV value of less than 1.

[0018] The present invention has the following beneficial effects: 1. Extremely high content uniformity: This invention uses electrospinning technology to fix nicotine in nanofibers. In this process, nicotine molecules are effectively encapsulated or adsorbed in the huge network structure of nanofibers, achieving molecular-level immobilization and highly uniform dispersion. This fundamentally eliminates the migration and aggregation of active ingredients during the preparation process, ensuring that the nicotine content of each unit dose membrane is highly accurate, which is superior to the content uniformity requirements of the Chinese Pharmacopoeia.

[0019] 2. Excellent taste-enhancing activity: This invention achieves effective masking of high concentrations of nicotine without the need to add a large amount of flavoring agent to the core layer, thus ensuring the mechanical properties of the membrane.

[0020] 3. Excellent stability: The nanofiber carrier in this invention has an encapsulating effect on nicotine, effectively isolating moisture and oxygen, significantly slowing down the oxidative degradation of nicotine, and extending the product shelf life.

[0021] 4. Process scalability: This invention innovatively combines electrospinning nanotechnology with traditional casting process. The functional isolation lower layer does not contain nicotine. The product has a double-layer structure of "functional isolation lower layer - nanofiber drug-carrying layer". The process flow is clear, fundamentally solving the problems of nicotine distribution uniformity, taste masking and release stability, and is easy to achieve large-scale continuous production. Attached Figure Description

[0022] Figure 1 This is a schematic flowchart of the preparation process of the present invention.

[0023] Figure 2 This is a schematic diagram comparing the conventional single-layer oral fusion membrane (left) of Comparative Example 1 with the nanofiber oral fusion membrane prepared in Example 1 of the present invention (right). Detailed Implementation

[0024] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention. Example 1

[0025] The preparation process of the nicotine oral solution membrane based on nanofiber carrier of this invention is as follows: Figure 1 As shown.

[0026] (1) Preparation of nanofiber carrier layer: 100 mg of nicotine tartrate and 1 g of hydroxypropyl-β-cyclodextrin were dissolved in 10 mL of 50 wt% ethanol solution to form a drug loading solution. Nanofiber membranes were prepared by electrospinning (voltage 15 kV, feed rate 0.8 mL / h) for later use.

[0027] (2) Preparation of functional isolation lower film-forming solution: Dissolve 6g polyethylene glycol, 10g hydroxypropyl methylcellulose, 5g glycerin, 1.5g mannitol, 1.5g sucralose, 0.05g menthol, and 0.05g WS-23 cooling agent in 60g purified water, stir until well mixed, and defoam to obtain the functional isolation lower film-forming solution.

[0028] (3) Compounding and drying: The film-forming solution for the functional isolation layer is cast onto the substrate, with a wet film thickness of 300 μm. Immediately afterward, the cut nanofiber membrane (core layer) is laid on the functional isolation layer. The two composite wet films are dried in an oven at 55°C to form a bilayer composite oral dissolution film. The film is then peeled off and cut into square tablets, each containing 2 mg of nicotine. Example 2

[0029] (1) Preparation of nanofiber carrier layer: 80 mg of nicotine malate and 1.05 g of polyethylene glycol were dissolved in 10 mL of 60 wt% ethanol solution to form a drug loading solution. Nanofiber membranes were prepared by electrospinning (voltage 15 kV, feed rate 0.7 mL / h) for later use.

[0030] (2) Preparation of functional isolation lower film-forming solution: Dissolve 25g polyvinyl alcohol, 6g propylene glycol, 2.5g sucralose, and 0.13g WS-23 cooling agent in 65g purified water, stir until well mixed, and degas to obtain the functional isolation lower film-forming solution.

[0031] (3) Compounding and drying: The film-forming solution for the functional isolation layer is cast onto the substrate, with a wet film thickness of 300 μm. Immediately afterward, the cut nanofiber membrane (core layer) is laid on the functional isolation layer. The two composite wet films are dried in an oven at 60°C to form a bilayer composite oral dissolution film. The film is then peeled off and cut into square tablets, each containing 2 mg of nicotine. Example 3

[0032] (1) Preparation of nanofiber carrier layer: 90 mg of nicotine lactobionate, 0.3 g of gelatin, and 0.6 g of polyethylene glycol were dissolved in 10.5 mL of 60 wt% ethanol solution to form a drug-loaded solution. Nanofiber membranes were prepared by electrospinning (voltage 13 kV, feed rate 0.7 mL / h) for later use.

[0033] (2) Preparation of functional isolation lower film-forming solution: Dissolve 10g polyvinyl alcohol, 5g carboxymethyl cellulose, 3g propylene glycol, 1.0g mannitol, 0.5g erythritol, and 0.08g WS-3 cooling agent in 50g purified water, stir until well mixed, and degas to obtain the functional isolation lower film-forming solution.

[0034] (3) Compounding and drying: The film-forming solution for the functional isolation layer is cast onto the substrate, with a wet film thickness of 300 μm. Immediately afterward, the cut nanofiber membrane (core layer) is laid on the functional isolation layer. The two composite wet films are dried in an oven at 50°C to form a bilayer composite oral dissolution film. The film is then peeled off and cut into square tablets, each containing 2 mg of nicotine. Example 4

[0035] (1) Preparation of nanofiber carrier layer: 120 mg of nicotine tartrate, 0.7 g of hydroxypropyl-β-cyclodextrin, and 0.3 g of sodium alginate were dissolved in 11 mL of 55 wt% ethanol solution to form a drug loading solution. Nanofiber membranes were prepared by electrospinning (voltage 14 kV, feed rate 0.8 mL / h) for later use.

[0036] (2) Preparation of functional isolation lower film-forming solution: Dissolve 20g hydroxypropyl methylcellulose, 4g glycerin, 2g mannitol, 0.1g menthol, and 0.05g WS-3 cooling agent in 55g purified water, stir until well mixed, and defoam to obtain the functional isolation lower film-forming solution.

[0037] (3) Compounding and drying: The film-forming solution for the functional isolation layer is cast onto the substrate, with a wet film thickness of 300 μm. Immediately afterward, the cut nanofiber membrane (core layer) is laid on the functional isolation layer. The two composite wet films are dried in an oven at 60°C to form a bilayer composite oral dissolution film. The film is then peeled off and cut into square tablets, each containing 2 mg of nicotine.

[0038] Comparative Example 1 (Traditional Single-Layer Membrane): 2.6g of nicotine bitartrate, 6g of polyethylene glycol, 10g of hydroxypropyl methylcellulose, 5g of glycerin, 5g of mannitol, 0.05g of sucralose, and 0.05g of menthol flavoring were dissolved in 60mL of purified water, cast into a film, and dried at 50-60℃. The resulting film had poor nicotine distribution, obvious white spots, and a distinctly spicy aftertaste.

[0039] Effect verification: Comparative Example 1: A conventional monolayer oral dissolution membrane (left) versus the nanofiber oral dissolution membrane prepared in Example 1 of this invention (right). Figure 2 As shown, traditional single-layer orthosol film exhibits uneven distribution, with obvious white spots and color inconsistencies; while the product of Example 1 of this invention has a uniform and fine distribution.

[0040] HPLC analysis showed that the uniformity of content (AV value) of the products in Examples 1-4 was <1, which was far superior to that of the comparative example (AV value >15). Sensory evaluation by volunteers indicated that the products in Examples 1-4 had a strong sweet and cool taste upon entry, without any spiciness or irritation, and the taste acceptance rate was over 95%; while the comparative example, although artificially flavored, still had a noticeable unpleasant irritation, and the acceptance rate was only 60%.

[0041] This invention is not limited to the above-described embodiments. Anyone should know that any structural changes made under the guidance of this invention, and any technical solutions that are the same as or similar to this invention, fall within the protection scope of this invention.

[0042] The technologies, shapes, and structures not described in detail in this invention are all known technologies.

Claims

1. A method for preparing a nicotine oral solution membrane based on a nanofiber carrier, characterized in that, Includes the following steps: (1) Preparation of nanofiber carrier layer: Nicotine salt and carrier material are dissolved in a water / ethanol mixed solvent to form a drug loading solution, and nanofiber membranes are prepared by electrospinning for later use. (2) Preparation of functional isolation lower film-forming solution: Instant polymer, high-intensity sweetener, cooling agent and plasticizer are added to purified water, stirred until uniformly mixed, and defoamed to obtain functional isolation lower film-forming liquid; (3) Compounding and drying: The film-forming liquid for the functional isolation layer is cast onto the substrate, with a wet film thickness of 300 μm. The nanofiber membrane is then immediately laid on the functional isolation layer. The two composite wet films are dried in an oven at 50~60℃ to form a bilayer composite oral dissolution film. The film is then peeled off and cut.

2. The method for preparing a nicotine oral solution membrane based on a nanofiber carrier as described in claim 1, characterized in that, The nicotine salt in step (1) is one of nicotine malate, nicotine tartrate, or nicotine lactobionate.

3. The method for preparing a nicotine oral solution membrane based on a nanofiber carrier as described in claim 1, characterized in that, The carrier material in step (1) is one or more of hydroxypropyl-β-cyclodextrin, sodium alginate, gelatin, and polyethylene glycol.

4. The method for preparing a nicotine oral solution membrane based on a nanofiber carrier as described in claim 1, characterized in that, In step (1), the mass concentration of ethanol in the water / ethanol mixed solvent is 50-60%.

5. The method for preparing a nicotine oral solution membrane based on a nanofiber carrier as described in claim 1, characterized in that, The mass-to-volume ratio of the nicotine salt, carrier material, and mixed solvent is 80-120 mg: 0.9-1.1 g: 10-11 mL.

6. The method for preparing a nicotine oral solution membrane based on a nanofiber carrier as described in claim 1, characterized in that, The electrospinning voltage is 13-15kV, and the feed rate is 0.7-0.8 mL / h.

7. The method for preparing a nicotine oral solution membrane based on a nanofiber carrier as described in claim 1, characterized in that, In step (2), the weight ratio of the instant polymer, high-strength sweetener, cooling agent, plasticizer and purified water is 15-25:1.5-5:0.08-0.15:3-6:50-65.

8. The method for preparing a nicotine oral solution membrane based on a nanofiber carrier as described in claim 1 or 7, characterized in that, The fast-dissolving polymer is one or more of hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, and carboxymethyl cellulose.

9. The method for preparing a nicotine oral solution membrane based on a nanofiber carrier as described in claim 1, characterized in that, The oral dissolution membrane with a double-layer composite structure prepared in step (3) is cut into square pieces containing 2 mg of nicotine per piece. The complete dissolution time in the oral cavity is less than 30 seconds, and the content uniformity AV value is less than 1.

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