Directional release nicotine oral soluble film, preparation method thereof and buccal product

Abstract

The invention provides a directionally-released nicotine oral soluble film, a preparation method thereof and an oral product. The preparation method comprises the following steps: S1, respectively preparing a first-layer film, a second-layer coating liquid and a third-layer coating liquid; s2, coating the first layer of film with a second layer of coating liquid, and performing vacuum drying to obtain a double-layer composite film; and S3, coating the double-layer composite film with a third layer of coating liquid, and drying to obtain a three-layer composite film. According to the three-layer composite structure, the hydrophobic substrate layer is used as a physical barrier, and the release path of nicotine is strictly limited in the single direction facing the oral mucosa; due to the directional release mechanism, the medicine utilization efficiency is greatly improved, and nicotine can be quickly absorbed through oral mucosa capillaries to enter systemic circulation, so that the onset speed exceeding that of a traditional transdermal patch is realized; and aiming at the inherent strong bitter taste of nicotine, the flavoring system compounded in the nicotine release layer can effectively cover bad taste, so that the sensory experience of the nicotine in the first mouth is improved.

Description

Technical Field

[0001] This patent relates to the field of oral products technology, specifically to a directional release nicotine oral film, its preparation method, and oral products. Background Technology

[0002] Tobacco dependence is a significant public health problem worldwide. Nicotine replacement therapy, as an effective smoking cessation aid, focuses on delivering nicotine to users through non-combustion methods to alleviate withdrawal symptoms and improve the success rate of quitting smoking.

[0003] To achieve this goal, various dosage forms have been developed on the market, such as chewing gum, transdermal patches, lozenges, and nasal sprays. However, these traditional formulations still have significant limitations in terms of release control, ease of use, and user experience.

[0004] Nicotine chewing gum was one of the earliest and most widely used dosage forms. It requires users to chew to release nicotine from the base. However, frequent chewing can lead to fatigue of the jaw muscles, and the release of nicotine is highly dependent on saliva flow rate and swallowing frequency, resulting in a short effective duration and large fluctuations in blood drug concentration. Users need to switch gums frequently to maintain the effect, which challenges compliance.

[0005] More importantly, this release method cannot achieve targeted and sustained drug action on the oral mucosa. A large amount of nicotine enters the digestive tract with saliva, undergoes the first-pass effect of the liver and is metabolized, resulting in low bioavailability. It may also cause side effects such as gastrointestinal irritation.

[0006] Nicotine transdermal patches offer another route of continuous administration, allowing for systemic absorption of nicotine through skin penetration. While this formulation avoids gastrointestinal side effects, its onset of action is extremely slow, typically requiring several hours to reach an effective nicotine concentration in the plasma, thus failing to provide timely relief for sudden withdrawal symptoms.

[0007] In addition, factors such as the thickness of the stratum corneum, local blood circulation, and environmental temperature and humidity can significantly affect the drug penetration rate, resulting in huge differences in release rates between individuals and even within an individual. This makes it difficult to achieve precise dosage control and flexibly adapt to the personalized needs of users for nicotine dosage at different stages of smoking cessation.

[0008] To overcome the shortcomings of the aforementioned dosage forms, orally dissolving film technology has been introduced into the field of nicotine delivery. Orally dissolving films can be rapidly wetted, adhered to, and dissolved or eroded in the oral cavity, allowing the drug to be absorbed through the oral mucosa, thereby avoiding the first-pass effect and theoretically improving bioavailability and accelerating onset of action.

[0009] However, most existing nicotine oral dissolving films use a single-layer homogeneous structure. When placed in the mouth, the entire film comes into contact with saliva, and nicotine diffuses freely in all directions. This not only reduces the local drug concentration in the target mucosal area, affecting absorption efficiency, but also causes a large amount of drug to diffuse throughout the oral cavity and be swallowed, repeating the problems of low bioavailability and gastrointestinal irritation.

[0010] In addition, single-layer membranes may break into fragments after dissolution, posing a risk of accidental ingestion, and their mechanical strength is often insufficient to maintain structural integrity and positional stability in the dynamic oral environment.

[0011] In the pharmaceutical field, multilayer composite membrane structures have been used to solve the problem of targeted drug release. For example, the Yike Patch for treating oral ulcers adopts a composite design of drug-containing layer and protective layer, which realizes targeted adhesion and local sustained release of ulcer lesions in a moist oral environment.

[0012] This indicates that by designing a composite architecture with different functional layers, the direction and rate of drug release can be effectively controlled. However, applying this approach to nicotine delivery systems presents entirely new challenges: the physicochemical properties of nicotine, the required release kinetics, and the extreme ease of use and comfort required for consumer-grade health products are all fundamentally different from those of hormonal preparations used to treat oral ulcers.

[0013] Therefore, there is a need for an innovative, targeted-release nicotine oral film and its preparation method, as well as oral products, that can comprehensively address a series of issues such as rapid onset of action, long-lasting effect, targeted delivery, precise dosage, convenient use, and high comfort, in order to meet the diverse needs of modern smokers trying to quit. Summary of the Invention

[0014] This invention aims to solve the technical problems of existing nicotine replacement formulations, such as uncontrollable release, slow onset of action, low bioavailability, inconvenience of use, and poor comfort. This patent provides the following technical solution: In a first aspect, a method for preparing a directional release nicotine oral solution membrane is provided, the method comprising the following steps: Step S1: preparing a first layer membrane, a second layer coating liquid, and a third layer coating liquid respectively; Step S2: coating the second layer coating liquid onto the first layer membrane and vacuum drying to obtain a bilayer composite membrane; Step S3: coating the third layer coating liquid onto the bilayer composite membrane and drying to obtain a trilayer composite membrane.

[0015] Furthermore, in step S1, the preparation steps of the first layer membrane include: step A1: preparing the first matrix solution and the second matrix solution respectively and then mixing them to obtain a homogeneous matrix solution; step A2: adding plasticizer, compound flavoring agent and nicotine to the homogeneous matrix solution in sequence and stirring at a constant temperature to obtain the first layer coating liquid; step A3: coating the first layer coating liquid onto the carrier membrane and drying and demolding to obtain the first layer membrane.

[0016] Further, in step A1, the first matrix solution is obtained by mixing polyvinyl alcohol and deionized water and stirring at a constant temperature; the first matrix solution is kept at a constant temperature in a water bath at a temperature of 75~85℃; the stirring time is 25~35min; and the stirring speed is 750~850r / min; the second matrix solution is obtained by mixing hydroxypropyl methylcellulose and deionized water and stirring at a constant temperature; the second matrix solution is kept at a constant temperature in a water bath at a temperature of 45~55℃; the stirring time is 25~35min; and the stirring speed is 750~850r / min.

[0017] Further, in step A2, the plasticizer includes polyethylene glycol 400; the compound flavoring agent includes aspartame and / or a cooling agent; the constant temperature stirring temperature is 45~55℃; the stirring time after adding the plasticizer is 12~18 min; the stirring time after adding the compound flavoring agent is 17~23 min; the stirring time after adding nicotine is 12~18 min; in step S3, the carrier film is a polytetrafluoroethylene carrier film; the drying temperature of the first coating liquid is 45~55℃; the drying time is 40~80 min; the coating thickness of the first coating liquid is 160~200 μm.

[0018] Furthermore, in step S1, the raw materials for the second membrane are mixed, stirred at a constant temperature, and filtered to obtain the second coating liquid; the raw materials for the second membrane include ethyl cellulose and anhydrous ethanol; after mixing the raw materials for the second membrane, they are kept at a constant temperature in a water bath, with the water bath temperature being 40~50℃; the stirring time is 25~35min; the stirring speed is 200~300r / min; and the filtration mesh size is 80~120 mesh.

[0019] Furthermore, in step S1, the raw materials for the third membrane are mixed, stirred at room temperature, and filtered to obtain the third coating solution; the raw materials for the third membrane include modified polyacrylate and ethyl acetate; the stirring speed is 250~350 r / min; the stirring time is 20~30 min; and the filtration mesh size is 100~140 mesh.

[0020] Furthermore, in step S2, the coating thickness of the second coating liquid on the first film is 450~550μm; after the second coating liquid is coated on the first film, it is sent into a vacuum drying oven for vacuum drying; the temperature of the vacuum drying oven is 35~45℃; the vacuum degree of the vacuum drying oven is -0.05~-0.11MPa; and the drying time of the vacuum drying oven is 13~23min.

[0021] Furthermore, in step S3, the coating thickness of the third coating liquid on the double-layer composite film is 25~35μm; the drying time is 8~16min; and the drying temperature is 30~40℃.

[0022] Secondly, a directional nicotine oral dissolving membrane is provided. The nicotine oral dissolving membrane is prepared by the above-described preparation method. The nicotine oral dissolving membrane comprises: a nicotine release layer that directly contacts and releases nicotine into the oral mucosa; a hydrophobic base layer for isolating saliva and directionally releasing nicotine; and an oleophilic adhesive layer for absorbing the nicotine oral dissolving membrane. The nicotine oral dissolving membrane is a three-layer composite membrane. In use, the nicotine release layer is located in the inner layer and contacts the oral mucosa, the oleophilic adhesive layer is located in the outer layer, and the hydrophobic base layer is located in the middle layer between the nicotine release layer and the oleophilic adhesive layer. The nicotine in the nicotine release layer is released in a direction away from the hydrophobic base layer.

[0023] Thirdly, an oral product containing a directionally released nicotine oral solution film, comprising the aforementioned nicotine oral solution film; the nicotine oral solution film is obtained by punching, screening, and packaging; the punching pressure is 0.3~0.7MPa; qualified products are retained after screening, with a defect rate of less than 3%; the packaging material is an aluminum-plastic blister pack, with the nicotine oral solution film single-layer encapsulation; the packaging temperature is 20~24℃; the relative humidity of the packaging is 45~55%; after packaging, a negative pressure method is used for sealing testing, with a leakage rate ≤0.1%; after packaging, the product is stored in a warehouse at a temperature of 15~25% and a humidity of ≤60%.

[0024] This patent has the following beneficial effects: 1. A directional release nicotine oral coating membrane and its preparation method and oral product are provided. The preparation method includes: step S1: preparing a first layer membrane, a second layer coating liquid and a third layer coating liquid respectively; step S2: coating the second layer coating liquid onto the first layer membrane and vacuum drying to obtain a bilayer composite membrane; step S3: coating the third layer coating liquid onto the bilayer composite membrane and drying to obtain a trilayer composite membrane.

[0025] 2. This patent, through its innovative three-layer composite structure design and precise manufacturing process, achieves a series of significant beneficial effects. Utilizing a hydrophobic base layer as a physical barrier, the release pathway of nicotine is strictly limited to a single direction towards the oral mucosa. This targeted release mechanism greatly improves drug utilization efficiency, allowing nicotine to be rapidly absorbed into the systemic circulation through the capillaries of the oral mucosa, thus achieving an onset speed exceeding that of traditional transdermal patches and promptly relieving cravings in smokers trying to quit. Simultaneously, by avoiding unnecessary diffusion of the drug into the oral cavity and subsequent swallowing, it significantly reduces metabolic losses caused by the liver, delivering more nicotine to the target site. This allows for a corresponding reduction in the drug load in the film while achieving the same physiological effect, reducing the risk of potential side effects and avoiding the potential irritation of the gastrointestinal tract by nicotine.

[0026] 3. By designing the material composition and microstructure of the nicotine release layer, a long-lasting and stable drug release is achieved. The nicotine release layer dissolves at a controllable rate in the saliva environment, maintaining an effective drug concentration in the oral mucosa for a longer period. The effective duration of action after a single use is significantly extended, reducing the need for frequent replacements and greatly improving ease of use and user compliance. More importantly, the hydrophobic base layer maintains its structural integrity throughout use and does not disintegrate. Together with the outermost lipophilic adhesive layer, it forms a support framework that can be easily and completely removed after release, reducing the risk of accidental ingestion of fragments that may exist with traditional orally dissolving films, and particularly improving safety.

[0027] 4. Addressing the inherently strong bitterness of nicotine, the flavor-enhancing system in the nicotine release layer effectively masks this unpleasant taste and provides a refreshing, cooling sensation. This significantly improves the initial sensory experience, and the cooling components can alleviate the common dry mouth symptoms during smoking cessation. The ingenious design of the oleophilic adhesive layer allows for easy and precise application even with wet fingers, solving the inconvenience of traditional film application methods. This greatly expands the product's applicability, making it convenient for use in various dynamic or hands-free environments such as sports, driving, and office work. Combined with individual, compact aluminum-plastic blister packaging, the product is easy to carry and store, ensuring hygiene and accurate dosage each time, while also protecting user privacy in public places. Attached Figure Description

[0028] To more clearly illustrate the technical solutions of the embodiments of this patent, the drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this patent and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained from these drawings without creative effort.

[0029] Figure 1 This is a flowchart of the preparation method in this patent. Detailed Implementation

[0030] The detailed features and advantages of this application are described below in the specific embodiments. The content of this description is sufficient to enable any person skilled in the art to understand the technical content of this application and implement it accordingly. Based on the specification, claims and drawings disclosed in this specification, a person skilled in the art can easily understand the related objectives and advantages of this application.

[0031] The invention will now be described with reference to the accompanying drawings, in which similar reference numerals denote similar elements. While specific structures and arrangements are discussed, it should be understood that this is done merely for illustrative purposes. Those skilled in the art will recognize that other structures and arrangements can be used without departing from the spirit and scope of the invention. It will be apparent to those skilled in the art that the invention can also be used in a variety of other applications.

[0032] In this specification and claims, several terms will be used, and unless otherwise indicated, these terms will be defined to have the following meanings: The singular forms “a” and “the” include their corresponding plural forms. “At least one” means one or more, and “more” means two or more. “At least one of the following” or similar expressions refer to any combination of these items, including any combination of single or plural items. For example, at least one of a, b, or c can be expressed as: a, b, c, ab, ac, bc, or abc, where a, b, and c can be single or multiple.

[0033] All figures used to represent component amounts, properties (e.g., molecular weight), reaction conditions, etc., should be considered to be modified in all cases by the terms "within the unavoidable margin of error" or "about". Therefore, the numerical values ​​set forth herein are approximate and may vary depending on the desired properties sought to be obtained by the present invention. The principles of equivalents, which are applied to a minimum and not intended to limit the scope of the claims, should be applied, for example, each value should be interpreted at least according to the reported significant digits and by applying conventional rounding techniques.

[0034] It should be understood that the term "and / or" in this article is merely a description of the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A existing alone, A and B existing simultaneously, or B existing alone. A and B can be singular or plural. Additionally, the character " / " in this article generally indicates an "or" relationship between the preceding and following related objects, but it can also represent an "and / or" relationship. Please refer to the context for a more accurate understanding.

[0035] In the description of this embodiment, it should be noted that the terms "upper", "lower", "inner", "bottom", etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, or the orientation or positional relationship in which the product is usually placed during use. They are only for the convenience of describing this application and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this application.

[0036] Unless otherwise indicated, the following abbreviations have the following meanings, and any other abbreviations used herein but not defined have their generally accepted standard meanings: All other terms used herein for special definition are intended to have the general meaning understood by one of ordinary skill in the art, and in particular, meaning that one of ordinary skill in the art, upon reading the claims, specification and drawings of this patent, can directly and without doubt determine how the technical solution of this patent can be implemented.

[0037] Even if there are incomplete descriptions, omissions, or ambiguities in the grammar, words, punctuation, graphics, symbols, etc. of the claims, specification, and drawings of this patent, a person skilled in the art can still arrive at the only correct understanding by reading the claims, specification, and drawings as a whole without extensive reasoning or experimentation, and effectively exclude various incorrect interpretations that are not aimed at achieving the purpose of this patent.

[0038] Those skilled in the art would first choose to read the claims, specification, and drawings of this patent to reasonably interpret the terms; secondly, they would choose to refer to the relevant definitions in other documents published by the applicant before the filing date to reasonably interpret the terms; thirdly, they would choose the references cited in this patent to reasonably interpret the terms; and finally, they would choose to combine the technical dictionaries, technical manuals, reference books, textbooks, national or industry technical standards, etc., commonly used by those skilled in the art to reasonably interpret the terms.

[0039] To make the objectives, technical solutions, and advantages of this application clearer, the following will describe in detail its implementation methods in conjunction with the specific structure and working process of the device of the present invention.

[0040] Please refer to Figure 1 A method for preparing a directional release nicotine oral coating, the method comprising the following steps: Step S1: Prepare the first film, the second coating solution, and the third coating solution respectively.

[0041] In step S1, the raw materials for the first membrane include a matrix, nicotine, plasticizer, and compound flavoring agent.

[0042] Specifically, the matrix includes polyvinyl alcohol (PVA) and hydroxypropyl methylcellulose (HPMC); the mass ratio of polyvinyl alcohol to hydroxypropyl methylcellulose is 1:5 to 3:10, preferably 1:4.

[0043] Among them, PVA provides excellent film-forming properties and biocompatibility, creating a stable matrix for nicotine loading; HPMC, with its excellent water solubility and thickening properties, precisely regulates the film dissolution rate and nicotine release rhythm.

[0044] The plasticizer includes polyethylene glycol 400 (PEG400), and the amount of plasticizer added accounts for 15~20% of the mass of the matrix. This can optimize the flexibility of the film to adapt to the dynamic oral environment, improve the extensibility of the film by reducing the intermolecular forces of the matrix, and achieve an elongation at break of ≥150%.

[0045] To address the inherent bitterness of nicotine, a compound flavoring system was developed: the compound flavoring agents include aspartame and a cooling agent.

[0046] Specifically, aspartame is added at a rate of 0.5-1% of the matrix. Aspartame is 180-200 times sweeter than sucrose and can effectively mask bitterness.

[0047] The amount of cooling agent added is 0.3~0.8% of the base mass. The cooling agent not only provides a fresh and cool taste, but also relieves the common symptoms of dry mouth and discomfort during smoking cessation.

[0048] The cooling agent includes WS-23 and WS-3, with the mass ratio of WS-23 to WS-3 being 4:5 to 6:5, preferably 1:1.

[0049] The preparation steps of the first membrane include: Step A1: Prepare the first matrix solution and the second matrix solution separately, and then mix them to obtain a homogeneous matrix solution.

[0050] Polyvinyl alcohol and deionized water are mixed and stirred at a constant temperature to obtain a homogeneous and transparent first matrix solution; the first matrix solution is kept at a constant temperature by a water bath, the temperature of which is 75~85℃, preferably 80℃.

[0051] The stirring time is 25-35 minutes, preferably 30 minutes.

[0052] The stirring speed is 750~850 r / min, preferably 800 r / min.

[0053] Hydroxypropyl methylcellulose is mixed with deionized water and stirred at a constant temperature to obtain a homogeneous and transparent second matrix solution; the second matrix solution is kept at a constant temperature by a water bath, the temperature of which is 45~55℃, preferably 50℃.

[0054] The stirring time is 25-35 minutes, preferably 30 minutes.

[0055] The stirring speed is 750~850 r / min, preferably 800 r / min.

[0056] Mix the first matrix solution and the second matrix solution for later use.

[0057] Step A2: Plasticizer, compound flavoring agent and nicotine are added sequentially to the homogeneous matrix solution and stirred at a constant temperature to obtain the first coating layer.

[0058] After adding plasticizer to the matrix solution, stir for 12-18 minutes, then add compound flavoring agent and stir for 17-23 minutes, and finally add nicotine and stir for 12-18 minutes to prepare the first coating liquid.

[0059] The entire process is kept at a constant temperature of 45~55℃. The first layer of coating liquid is evenly coated onto the polytetrafluoroethylene carrier film using a doctor blade coater. The coating thickness is 160~200μm, preferably 180μm.

[0060] Step A3: Apply the first coating liquid onto the carrier film, and after drying and demolding, the first film is obtained.

[0061] The carrier film coated with the first layer of coating liquid is placed on a heating plate at 45~55℃ and dried for 40~80 minutes. After demolding, the first layer of film is obtained for later use.

[0062] The second membrane is made of ethyl cellulose with a purity of ≥99%. The large number of ethyl groups in the molecular structure of ethyl cellulose endow it with strong hydrophobicity, making the water contact angle of the hydrophobic substrate layer ≥90°, thereby constructing a hydrophobic support framework that is insoluble in water and saliva.

[0063] Ethyl cellulose was added to anhydrous ethanol and placed in a constant temperature water bath at 40-50°C. The mixture was stirred at 200-300 rpm for 25-35 minutes until completely dissolved. The mixture was then filtered through an 80-120 mesh filter cloth to remove impurities, and the second coating solution was obtained for later use.

[0064] The raw materials for the third membrane are mixed, stirred at room temperature, and filtered to obtain the third coating solution. The raw materials for the third membrane include modified polyacrylate and ethyl acetate. The stirring speed is 250~350 r / min. The stirring time is 20~30 min. The filtration mesh size is 100~140 mesh.

[0065] Step S2: The second coating liquid is coated onto the first membrane and then vacuum dried to obtain a double-layer composite membrane.

[0066] The first layer of film is fixed on the worktable of the coating machine. The second layer of coating liquid is taken and evenly coated on the surface of the first layer of film with a coating thickness of 450~550μm, preferably 400μm.

[0067] It is then placed in a vacuum drying oven at 35~45℃ with a vacuum degree of -0.05~-0.11MPa, preferably -0.08MPa.

[0068] The vacuum drying time is 13~23 minutes, preferably 18 minutes, to ensure that the ethanol evaporates completely and forms a double-layer composite membrane of the first layer membrane and the second layer membrane, which is then ready for use.

[0069] Step S3: Apply the third coating solution onto the double-layer composite membrane and dry to obtain a three-layer composite membrane. The double-layer composite membrane is fixed with the top facing up. The third coating liquid is applied to the surface of the double-layer composite membrane with a coating thickness of 25~35μm, preferably 30μm. It is then placed in a ventilated drying room at 30~40℃ and dried for 8~16min to allow the ethyl acetate to fully evaporate, thus obtaining a three-layer composite membrane preform consisting of a first-layer membrane, a second-layer membrane, and a third-layer membrane.

[0070] A directional nicotine oral solvent membrane is prepared by the above-described method. The nicotine oral solvent membrane comprises a nicotine release layer, a hydrophobic base layer, and an oleophilic adhesive layer, corresponding to a three-layer composite membrane structure. The first membrane is the nicotine release layer, the second membrane is the hydrophobic base layer, and the third membrane is the oleophilic adhesive layer.

[0071] The nicotine release layer directly contacts and releases nicotine into the oral mucosa; the hydrophobic base layer isolates saliva and directs the release of nicotine; and the oleophilic adhesive layer is used to absorb the nicotine oral solution membrane.

[0072] In use, the nicotine release layer is located in the inner layer, the oleophilic adhesive layer is located in the outer layer, and the hydrophobic base layer is located in the middle layer between the nicotine release layer and the oleophilic adhesive layer. Nicotine in the nicotine release layer is released in the direction away from the hydrophobic base layer. The thickness of the nicotine oral film is 0.13~0.18mm.

[0073] The thickness of the nicotine release layer is 0.05~0.07mm. At this thickness, the matrix can form a uniform porous network through intermolecular hydrogen bonds, with a pore size distribution of 50~200nm, providing directional diffusion channels for the controlled release of nicotine. The nicotine loading is controlled at 0.5~1.0mg per tablet.

[0074] The thickness of the hydrophobic substrate is 0.06~0.08mm, and the tensile strength of the hydrophobic substrate is ≥15N / cm², which can withstand dynamic external forces such as oral chewing and swallowing without damage.

[0075] The thickness of the oleophilic adhesive layer is 0.02~0.03mm. This thickness ensures the flexibility and ease of peeling of the oleophilic adhesive layer, which can not only meet the packaging folding requirements, but also be easily removed together with the nicotine release layer after use, avoiding secondary contamination.

[0076] An oral product containing a directionally releasing nicotine oral dissolving film, the oral product comprising the aforementioned nicotine oral dissolving film; the oral product is obtained by punching, screening and packaging the nicotine oral dissolving film.

[0077] The dried three-layer composite film blank is peeled off from the carrier film and cut into a circular film with a radius of 0.5 cm using a circular die. The cutting pressure is 0.3~0.7MPa, preferably 0.5MPa, to ensure that the edges are flat and burr-free.

[0078] After punching, each piece is inspected with a thickness tester to select qualified products with a total thickness of 0.15±0.02mm, and the defective product rate is controlled within 3%.

[0079] The qualified film agent is packaged in aluminum-plastic blister packs, with each film individually sealed.

[0080] The packaging environment is controlled to a cleanliness level of Class 10000, the packaging temperature is 20~24℃, preferably 22℃, and the relative humidity is 45~55%, preferably 50%. After sealing, the sealing performance is tested using the negative pressure method, and the leakage rate is ≤0.1%.

[0081] After packaging, the product is stored in a cool, dry place at a temperature of 15-25% and a humidity of ≤60%, thus obtaining the oral product.

[0082] Table 1 lists the names of the raw materials and their suppliers used in the following examples, comparative examples, and experimental cases.

[0083] Table 1. Names of Raw Materials and Suppliers

[0084] Example 1

[0085] 1. Preparation of nicotine release layer

[0086] Weigh the following raw materials for the nicotine release layer according to the following mass percentages: PVA 15 parts, HPMC 60 parts, PEG400 20 parts, aspartame 0.4 parts, WS-23 0.2 parts, WS-3 0.2 parts, nicotine 1 part, and deionized water 500 parts.

[0087] PVA was added to deionized water and placed in an 80°C constant temperature water bath. The mixture was stirred at 800 rpm for 30 minutes until it was completely dissolved to form a homogeneous and transparent first matrix solution.

[0088] HPMC is added to deionized water and placed in a 50°C constant temperature water bath. It is stirred at 800 rpm for 30 minutes until it is completely dissolved to form a homogeneous and transparent second matrix solution. The PVA and HPMC solutions are then mixed to obtain a homogeneous matrix solution.

[0089] PEG400 (stir for 15 min), aspartame and cooling agent (stir for 20 min), and nicotine (stir for 15 min) were added sequentially to a homogeneous matrix solution. The temperature was kept constant at 50°C throughout the process to prepare a uniform nicotine coating solution.

[0090] The coating liquid was evenly coated onto the polytetrafluoroethylene carrier film using a doctor blade coater, with a coating thickness of 180 μm. After drying on a 50°C heating plate for 1 hour, a 70 μm nicotine layer pre-film was obtained after demolding and set aside for later use.

[0091] 2. Preparation of hydrophobic substrate layer

[0092] Weigh 80 parts of ethyl cellulose and 400 parts of anhydrous ethanol. Add the ethyl cellulose to the anhydrous ethanol and place it in a constant temperature water bath at 45°C. Stir at 250 r / min for 30 min until completely dissolved. Filter the solution through a 100-mesh filter cloth to remove impurities and obtain the hydrophobic substrate coating solution.

[0093] The nicotine release layer pre-film is fixed on the worktable of the coating machine, and the hydrophobic substrate coating liquid is evenly coated on the surface of the nicotine release layer with a coating thickness of 400μm. Then it is sent into a 40℃ vacuum drying oven with a vacuum degree of -0.08MPa and dried for 18min to ensure that the ethanol is completely evaporated, forming a bilayer composite film of nicotine release layer-hydrophobic substrate layer, which is ready for use.

[0094] 3. Preparation of oleophilic adhesive layers

[0095] Weigh 30 parts of modified polyacrylate and 300 parts of ethyl acetate, stir at 300 r / min for 25 min at room temperature (25℃) until the materials are completely dissolved, and then filter through a 120 mesh filter cloth to obtain an oleophilic and adhesive coating solution.

[0096] The hydrophobic substrate layer of the bilayer composite membrane of nicotine release layer-hydrophobic substrate layer is fixed with the hydrophobic substrate layer facing upward. The oleophilic adhesive coating liquid is coated on the surface of the hydrophobic substrate layer with a coating thickness of 30 μm. The membrane is then dried in a ventilated drying room at 35℃ for 12 min to allow the ethyl acetate to fully evaporate, resulting in a three-layer composite membrane blank of nicotine release layer-hydrophobic substrate layer-oleophilic adhesive layer. This three-layer composite membrane is a nicotine oral solution membrane.

[0097] Example 2

[0098] 1. Preparation of nicotine release layer

[0099] Weigh the following raw materials for the nicotine release layer according to the following mass percentages: PVA 20 parts, HPMC 55 parts, PEG400 20 parts, aspartame 0.4 parts, WS-23 0.2 parts, WS-3 0.2 parts, nicotine 1 part, and deionized water 500 parts.

[0100] PVA was added to deionized water and placed in an 80°C constant temperature water bath. The mixture was stirred at 800 rpm for 30 minutes until it was completely dissolved to form a homogeneous and transparent first matrix solution.

[0101] HPMC is added to deionized water and placed in a 50°C constant temperature water bath. It is stirred at 800 rpm for 30 minutes until it is completely dissolved to form a homogeneous and transparent second matrix solution. The PVA and HPMC solutions are then mixed to obtain a homogeneous matrix solution.

[0102] PEG400 (stir for 15 min), aspartame and cooling agent (stir for 20 min), and nicotine (stir for 15 min) were added sequentially to a homogeneous matrix solution. The temperature was kept constant at 50°C throughout the process to prepare a uniform nicotine coating solution.

[0103] The coating liquid was evenly coated onto the polytetrafluoroethylene carrier film using a doctor blade coater, with a coating thickness of 180 μm. After drying on a 50°C heating plate for 1 hour, a 70 μm nicotine layer pre-film was obtained after demolding and set aside for later use.

[0104] 2. Preparation of hydrophobic substrate layer

[0105] Weigh 80 parts of ethyl cellulose and 400 parts of anhydrous ethanol. Add the ethyl cellulose to the anhydrous ethanol and place it in a constant temperature water bath at 45°C. Stir at 250 r / min for 30 min until completely dissolved. Filter the solution through a 100-mesh filter cloth to remove impurities and obtain the hydrophobic substrate coating solution.

[0106] The nicotine release layer pre-film is fixed on the worktable of the coating machine, and the hydrophobic substrate coating liquid is evenly coated on the surface of the nicotine release layer with a coating thickness of 400μm. Then it is sent into a 40℃ vacuum drying oven with a vacuum degree of -0.08MPa and dried for 18min to ensure that the ethanol is completely evaporated, forming a bilayer composite film of nicotine release layer-hydrophobic substrate layer, which is ready for use.

[0107] 3. Preparation of oleophilic adhesive layers

[0108] Weigh 30 parts of modified polyacrylate and 300 parts of ethyl acetate, stir at 300 r / min for 25 min at room temperature (25℃) until the materials are completely dissolved, and then filter through a 120 mesh filter cloth to obtain an oleophilic and adhesive coating solution.

[0109] The hydrophobic substrate layer of the bilayer composite membrane of nicotine release layer-hydrophobic substrate layer is fixed with the hydrophobic substrate layer facing upward. The oleophilic adhesive coating liquid is coated on the surface of the hydrophobic substrate layer with a coating thickness of 30 μm. The membrane is then dried in a ventilated drying room at 35℃ for 12 min to allow the ethyl acetate to fully evaporate, resulting in a three-layer composite membrane blank of nicotine release layer-hydrophobic substrate layer-oleophilic adhesive layer. This three-layer composite membrane is a nicotine oral solution membrane.

[0110] Example 3

[0111] 1. Preparation of nicotine release layer

[0112] Weigh the following raw materials for the nicotine release layer according to the following mass percentages: PVA 15 parts, HPMC 60 parts, PEG400 15 parts, glycerin 5 parts, aspartame 0.4 parts, WS-23 0.2 parts, WS-3 0.2 parts, nicotine 1 part, and deionized water 500 parts.

[0113] PVA was added to deionized water and placed in an 80°C constant temperature water bath. The mixture was stirred at 800 rpm for 30 minutes until it was completely dissolved to form a homogeneous and transparent first matrix solution.

[0114] HPMC is added to deionized water and placed in a 50°C constant temperature water bath. It is stirred at 800 rpm for 30 minutes until it is completely dissolved to form a homogeneous and transparent second matrix solution. The PVA and HPMC solutions are then mixed to obtain a homogeneous matrix solution.

[0115] PEG400 (stir for 15 min), aspartame and cooling agent (stir for 20 min), and nicotine (stir for 15 min) were added sequentially to a homogeneous matrix solution. The temperature was kept constant at 50°C throughout the process to prepare a uniform nicotine coating solution.

[0116] The coating liquid was evenly coated onto the polytetrafluoroethylene carrier film using a doctor blade coater, with a coating thickness of 180 μm. After drying on a 50°C heating plate for 1 hour, a 70 μm nicotine layer pre-film was obtained after demolding and set aside for later use.

[0117] 2. Preparation of hydrophobic substrate layer

[0118] Weigh 80 parts of ethyl cellulose and 400 parts of anhydrous ethanol. Add the ethyl cellulose to the anhydrous ethanol and place it in a constant temperature water bath at 45°C. Stir at 250 r / min for 30 min until completely dissolved. Filter the solution through a 100-mesh filter cloth to remove impurities and obtain the hydrophobic substrate coating solution.

[0119] The nicotine release layer pre-film is fixed on the worktable of the coating machine, and the hydrophobic substrate coating liquid is evenly coated on the surface of the nicotine release layer with a coating thickness of 400μm. Then it is sent into a 40℃ vacuum drying oven with a vacuum degree of -0.08MPa and dried for 18min to ensure that the ethanol is completely evaporated, forming a bilayer composite film of nicotine release layer-hydrophobic substrate layer, which is ready for use.

[0120] 3. Preparation of oleophilic adhesive layers

[0121] Weigh 30 parts of modified polyacrylate and 300 parts of ethyl acetate, stir at 300 r / min for 25 min at room temperature (25℃) until the materials are completely dissolved, and then filter through a 120 mesh filter cloth to obtain an oleophilic and adhesive coating solution.

[0122] The hydrophobic substrate layer of the bilayer composite membrane of nicotine release layer-hydrophobic substrate layer is fixed with the hydrophobic substrate layer facing upward. The oleophilic adhesive coating liquid is coated on the surface of the hydrophobic substrate layer with a coating thickness of 30 μm. The membrane is then dried in a ventilated drying room at 35℃ for 12 min to allow the ethyl acetate to fully evaporate, resulting in a three-layer composite membrane blank of nicotine release layer-hydrophobic substrate layer-oleophilic adhesive layer. This three-layer composite membrane is a nicotine oral solution membrane.

[0123] Example 4

[0124] Weigh the following raw materials for the nicotine release layer according to the following mass percentages: PVA 15 parts, HPMC 60 parts, PEG400 10 parts, glycerin 10 parts, aspartame 0.4 parts, WS-23 0.1 parts, WS-3 0.3 parts, nicotine 1 part, and deionized water 500 parts.

[0125] PVA was added to deionized water and placed in an 80°C constant temperature water bath. The mixture was stirred at 800 rpm for 30 minutes until it was completely dissolved to form a homogeneous and transparent first matrix solution.

[0126] HPMC is added to deionized water and placed in a 50°C constant temperature water bath. It is stirred at 800 rpm for 30 minutes until it is completely dissolved to form a homogeneous and transparent second matrix solution. The PVA and HPMC solutions are then mixed to obtain a homogeneous matrix solution.

[0127] PEG400 (stirred for 15 min), aspartame and cooling agent (stirred for 20 min), and nicotine (stirred for 15 min) were added sequentially to a homogeneous matrix solution. The temperature was kept constant at 50°C throughout the process to prepare a uniform coating solution. The coating solution was then uniformly coated onto a polytetrafluoroethylene carrier film using a doctor blade coater to a coating thickness of 700 μm. The film was then dried on a 50°C heating plate for 1 h to obtain a nicotine oral solution film.

[0128] Experimental Example 1

[0129] The nicotine oral dissolving film A1 prepared in Example 1 was made into a lozenge D1, and the specific process is as follows.

[0130] The dried three-layer composite film blank is peeled off from the carrier film and cut into circular film blanks with a radius of 0.5 cm using a circular die. The cutting pressure is 0.5 MPa to ensure that the edges are smooth and burr-free. After cutting, each blank is inspected with a thickness tester, and qualified products with a total thickness of 0.15 mm are selected. The defective product rate is controlled within 3%.

[0131] The qualified film agent is packaged in aluminum-plastic blister packs, with each blister individually sealed. The packaging environment is controlled to a cleanliness level of Class 10000, a temperature of 22℃, and a relative humidity of 50%. After sealing, a negative pressure method is used to test the seal, with a leakage rate of ≤0.1%. After packaging, the product is stored in a cool, dry place at a temperature of 15-25℃ and a relative humidity of ≤60%, thus obtaining oral product D1.

[0132] Experiment Example 2

[0133] The nicotine oral dissolving film prepared in Example 2 was made into oral product D2, and the specific process is as follows.

[0134] The dried three-layer composite film blank is peeled off from the carrier film and cut into circular film blanks with a radius of 0.5 cm using a circular die. The cutting pressure is 0.5 MPa to ensure that the edges are smooth and burr-free. After cutting, each blank is inspected with a thickness tester, and qualified products with a total thickness of 0.15 mm are selected. The defective product rate is controlled within 3%.

[0135] The qualified film agent is packaged in aluminum-plastic blister packs, with each blister individually sealed. The packaging environment is controlled at a cleanliness level of Class 10000, a temperature of 22℃, and a relative humidity of 50%. After sealing, a negative pressure method is used to test the seal, with a leakage rate of ≤0.1%. After packaging, the product is stored in a cool, dry place at a temperature of 15-25℃ and a relative humidity of ≤60%, thus obtaining oral product D2.

[0136] Experimental Example 3

[0137] The nicotine oral dissolving film prepared in Example 3 was used to make oral product D3. The specific process is as follows.

[0138] The dried three-layer composite film blank is peeled off from the carrier film and cut into circular film blanks with a radius of 0.5 cm using a circular die. The cutting pressure is 0.5 MPa to ensure that the edges are smooth and burr-free. After cutting, each blank is inspected with a thickness tester, and qualified products with a total thickness of 0.15 mm are selected. The defective product rate is controlled within 3%.

[0139] The qualified film agent is packaged in aluminum-plastic blister packs, with each blister individually sealed. The packaging environment is controlled to a cleanliness level of Class 10000, a temperature of 22℃, and a relative humidity of 50%. After sealing, a negative pressure method is used to test the seal, with a leakage rate of ≤0.1%. After packaging, the product is stored in a cool, dry place at a temperature of 15-25℃ and a relative humidity of ≤60%, thus obtaining oral product D3.

[0140] Comparative Example

[0141] The nicotine oral dissolving film prepared in Example 4 was made into a lozenge Z1, and the specific process is as follows.

[0142] After drying, the nicotine oral solution membrane was demolded to obtain a 290μm nicotine membrane, which was then cut into 2 pieces. Prepare a 2.5cm film sample for later use.

[0143] Roll feeding: The aluminum-plastic composite aluminum foil roll is fed into the fully automatic strip bag packaging machine, where it is folded into a bag shape by the forming device; Film filling and nitrogen filling: After the single-dose oral soluble film falls into the bag, the equipment automatically fills it with high-purity nitrogen (residual oxygen content ≤2%) to replace the air in the bag and inhibit nicotine oxidation; Heat sealing and cutting: The bag opening is sealed by longitudinal sealing (temperature 130-150℃) and transverse sealing (temperature 140-160℃), and then cut into individual strip bags. The heat sealing width of the bag opening is ≥8mm to ensure sealing strength.

[0144] Sublingual administration experiment

[0145] Forty participants were selected and divided into four groups of ten. Each group administered oral samples (Examples 1-3 and the comparative sample) after dispensing. Sensory evaluations were conducted using a 100-point scale. Evaluation indicators included irritation, euphoria, stickiness, residue, and disintegration time, with maximum scores of 20 for each indicator and a total score of 100. Higher scores indicated better vaping experience. Three batches of samples were randomly selected for each evaluation, and ten judges administered the samples and scored them. The average score was then calculated. The sensory quality evaluation results are shown in Table 2 below.

[0146] Table 2. Results of sublingual administration experiments for Examples 1-3 and the comparative example.

[0147] in conclusion: According to the sensory evaluation results, the nicotine oral dissolving film prepared using the three-layer composite structure of the present invention (corresponding to experimental examples D1, D2, and D3) is significantly superior to the traditional single-layer oral dissolving film (corresponding to experimental example Z1) in terms of overall oral dissolving experience.

[0148] Specifically, the membrane formulation of this invention exhibits superior performance in terms of disintegration time, a key indicator, providing a continuous and stable release sensation. In contrast, the comparative monolayer membrane disintegrates too quickly, resulting in a short duration of action and an abrupt experience. Regarding irritation and euphoria, thanks to the efficient absorption and dosage optimization resulting from targeted release, the membrane formulation of this invention exhibits a relatively gentle and controllable physiological sensation.

[0149] Regarding adhesion, the three-layer structure provides excellent mechanical support and shape retention, resulting in a more stable and comfortable fit in the oral cavity. As for residue, all films perform well, but the product of this invention is easier to remove due to its intact structure.

[0150] Ultimately, in terms of overall score, the inhalation scores (D1 and D3) of the representative product of this invention were far higher than those of the comparative product, fully demonstrating the improvement brought about by the three-layer directional release structure in terms of overall sensory experience, effective duration of action, and user satisfaction.

[0151] In the several embodiments provided in this application, it should be understood that the disclosed devices, apparatus and methods can be implemented in other ways.

[0152] For example, the device embodiments described above are merely illustrative. For instance, the division of units is only a logical functional division. In actual implementation, there may be other division methods. For example, multiple units or components may be combined or integrated into another device, or some features may be ignored or not executed.

[0153] The units described as separate components may or may not be physically separate. The components shown as units may or may not be physical units; that is, they may be located in one place or distributed across multiple network units. Some or all of the units can be selected to achieve the purpose of this embodiment according to actual needs.

[0154] In addition, the functional units in the various embodiments of this application can be integrated into one processing unit, or each unit can exist physically separately, or two or more units can be integrated into one unit.

[0155] In this specification, references to "an embodiment" or "a specific implementation" mean that a particular feature, structure, or characteristic described in connection with that embodiment / specific implementation is included in at least one embodiment / specific implementation of the invention. Therefore, the phrase "in one embodiment / specific implementation" appearing in various places in this specification does not necessarily refer to the same embodiment / setting, but rather to potentially different embodiments. Furthermore, specific features, structures, or characteristics may be combined in one or more embodiments / settings in any suitable manner, as will be apparent to those skilled in the art from this disclosure.

[0156] Similarly, it should be understood that in the above description of exemplary embodiments / specific implementations of the invention, various features of the invention are sometimes combined in a single embodiment / specific implementation or its figures and description, with the aim of simplifying the disclosure and aiding in the understanding of one or more of the various aspects of the invention. However, except for expressly stated instructions to the contrary or obvious technical contradictions or exclusions, the method of description in this patent should not be construed as reflecting an intention that the claimed features of the invention are more than those expressly stated in each claim.

[0157] Conversely, the inventive aspect reflected in the claims lies in not all the features of a single foregoing disclosed embodiment / specification. Therefore, the claims following the detailed description are expressly incorporated herein, each claim existing independently as a separate embodiment / specification of the invention.

[0158] Furthermore, while some embodiments / specific implementations described herein include, but are not limited to, other features included in other embodiments / specific implementations, combinations of features from different embodiments / specific implementations are intended to be within the scope of the invention and form different embodiments / specific implementations, as will be understood by those skilled in the art. For example, in the following claims, embodiments / specific implementations of any claim can be used in any combination.

[0159] The terms and expressions used in this specification are for illustrative purposes and not for limitation. In using these terms and expressions, it is not intended to exclude any equivalents of the features or portions thereof shown and described, but rather to recognize that various modifications may be possible within the scope of the invention.

[0160] Therefore, it should be understood that although the invention has been specifically disclosed through preferred embodiments, exemplary embodiments and optional features, those skilled in the art may take variations or modifications of the concepts disclosed herein, and such variations and modifications are therefore considered to be within the scope of the invention as defined by the appended claims.

[0161] The specific embodiments given in this specification are examples of useful implementations of the present invention. It will be apparent to those skilled in the art that the present invention can be implemented using many variations of the devices, device components, and method steps disclosed in this specification.

[0162] The foregoing description of specific embodiments fully discloses the general features of the present invention, enabling others to easily modify and / or adapt such specific embodiments for various applications by applying knowledge within the scope of the art, without conducting excessive experimentation and without departing from the general concept of the present invention.

Claims

1. A method for preparing a targeted-release nicotine oral coating, characterized in that, The preparation method includes the following steps: Step S1: Prepare the first film layer, the second coating solution, and the third coating solution respectively; Step S2: The second coating liquid is coated onto the first membrane and then vacuum dried to obtain a double-layer composite membrane; Step S3: The third coating liquid is applied to the double-layer composite film and dried to obtain a three-layer composite film.

2. The preparation method according to claim 1, characterized in that, In step S1, the preparation step of the first film includes: Step A1: Prepare the first matrix solution and the second matrix solution separately, then mix them to obtain a homogeneous matrix solution; Step A2: Plasticizer, compound flavoring agent and nicotine are added sequentially to the homogeneous matrix solution and stirred at a constant temperature to obtain the first coating liquid; Step A3: Apply the first layer of coating liquid onto the carrier film, and after drying and demolding, obtain the first layer of film.

3. The preparation method according to claim 2, characterized in that, In step A1, the first matrix solution is obtained by mixing polyvinyl alcohol and deionized water and stirring at a constant temperature. The first matrix solution is kept at a constant temperature by a water bath, the temperature of which is 75~85℃; The stirring time is 25-35 minutes; The stirring speed is 750~850 r / min; The second matrix solution is obtained by mixing hydroxypropyl methylcellulose with the deionized water and stirring at a constant temperature; The second matrix solution is kept at a constant temperature by a water bath, the temperature of which is 45~55℃; The stirring time is 25-35 minutes; The stirring speed is 750~850 r / min.

4. The preparation method according to claim 3, characterized in that, In step A2, the plasticizer includes polyethylene glycol 400; The compound flavoring agent includes aspartame and / or a cooling agent; The temperature of the constant-temperature stirring is 45~55℃; The stirring time after adding the plasticizer is 12-18 minutes; The stirring time after adding the compound flavoring agent is 17-23 minutes; The stirring time after adding the nicotine is 12-18 minutes; In step S3, the carrier film is a polytetrafluoroethylene carrier film; The drying temperature of the first coating liquid is 45~55℃; The drying time is 40-80 minutes; The coating thickness of the first coating liquid is 160~200μm.

5. The preparation method according to claim 1, characterized in that, In step S1, the raw materials for the second layer membrane are mixed, stirred at a constant temperature, and filtered to obtain the second coating liquid. The raw materials for the second membrane include ethyl cellulose and anhydrous ethanol; The raw materials for the second membrane are mixed and then kept at a constant temperature in a water bath, with the water bath temperature being 40~50℃. The stirring time is 25-35 minutes; The stirring speed is 200~300 r / min; The mesh size of the filter is 80-120 mesh.

6. The preparation method according to claim 1, characterized in that, In step S1, the raw materials for the third layer membrane are mixed, stirred at room temperature, and filtered to obtain the third layer coating liquid; The raw materials for the third membrane include modified polyacrylate and ethyl acetate; The stirring speed is 250~350 r / min; The stirring time is 20-30 minutes; The mesh size of the filter is 100-140 mesh.

7. The preparation method according to claim 1, characterized in that, In step S2, the coating thickness of the second coating liquid on the first film is 450~550μm; The second coating liquid is applied to the first film and then sent to a vacuum drying oven for vacuum drying. The temperature of the vacuum drying oven is 35~45℃; The vacuum degree of the vacuum drying oven is -0.05 to -0.11 MPa; The drying time in the vacuum drying oven is 13-23 minutes.

8. The preparation method according to claim 1, characterized in that, In step S3, the coating thickness of the third coating liquid on the double-layer composite film is 25~35μm; The drying time is 8-16 minutes; The drying temperature is 30~40℃.

9. A directional release nicotine oral coating, characterized in that, The nicotine oral solution film is prepared by the preparation method according to any one of claims 1 to 8, and the nicotine oral solution film comprises: The nicotine release layer directly contacts the oral mucosa and releases nicotine into the oral mucosa. A hydrophobic base layer is used to isolate saliva and direct the release of the nicotine; An oleophilic adhesive layer is used for retrieving the nicotine oral solution membrane; The nicotine oral dissolving membrane is a three-layer composite membrane. In use, the nicotine release layer is located in the inner layer and contacts the oral mucosa, the oleophilic adhesive layer is located in the outer layer, and the hydrophobic base layer is located in the middle layer between the nicotine release layer and the oleophilic adhesive layer. The nicotine in the nicotine release layer is released in a direction away from the hydrophobic base layer.

10. A lozenge containing a targeted-release nicotine oral film, characterized in that, The oral product includes the nicotine dissolving film as described in claim 9; The nicotine oral dissolving film is cut, screened and packaged to obtain the oral product; The punching pressure is 0.3~0.7MPa; After the screening process, qualified products are retained, and the defective product rate is less than 3%. The packaging material is an aluminum-plastic blister pack, and the nicotine oral solution film is used for single-layer encapsulation. The temperature of the packaging is 20~24℃; The relative humidity of the packaging is 45-55%; The packaging was then subjected to a negative pressure test for airtightness, with a leakage rate ≤0.1%. After packaging, the product is stored in a warehouse at a temperature of 15-25%. The humidity of the stored material is ≤60%.

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