A gradient controlled release nicotine particle, a nicotine pouch and a method of preparing the same

Abstract

The application discloses a gradient-controlled nicotine particle, a nicotine bag and a preparation method thereof. The nicotine particle comprises a core layer and an outer layer, and the core layer and the outer layer contain a disintegrant, so that when the nicotine particle is eaten in the oral cavity, the disintegration rate of the components of the outer layer is 2-5 times that of the components of the core layer; or the outer layer contains a disintegrant, and the core layer does not contain a disintegrant, so that when the nicotine particle is eaten in the oral cavity, the disintegration rate of the components of the outer layer is 2-5 times that of the components of the core layer. The application upgrades the configuration of the disintegrant from "single-layer optimization" to "multi-layer gradient", gives the disintegrant a new function of structure regulation, and realizes segmented release through the synergistic effect of the disintegrants in different layers in the same particle. The application reduces equipment investment and process steps, and can meet the individualized needs of users with different sensitivities.

Description

Technical Field

[0001] This application belongs to the field of new tobacco product technology, specifically relating to a gradient controlled-release nicotine granule, a nicotine pouch, and a method for preparing the same. Background Technology

[0002] Nicotine pouches are a new type of smokeless nicotine delivery product that has gained widespread attention globally in recent years. These pouches deliver nicotine through the oral mucosa, providing users with an alternative to traditional tobacco. The core contents of the nicotine pouch are the filling granules, whose physicochemical properties directly determine the product's user experience and efficacy, including the nicotine release rate, taste comfort, storage stability, and product uniformity.

[0003] However, existing technologies face the following significant technical bottlenecks when applied to the preparation of nicotine bag filling granules: First, the release mode is singular and cannot meet the differentiated needs of different stages of smoking cessation. Most commercially available nicotine pouch products are either single-use rapid release (complete release within about 30 minutes) or a single slow-release structure, and cannot achieve the dual-phase release function of "rapid onset - sustained effect" in the same product.

[0004] II. The application of disintegrants is limited to single-system optimization and not used for structural gradients. Disintegrants are commonly used excipients in solid dosage forms to promote rapid drug release. In the prior art, the application of disintegrants is usually to uniformly mix them in tablets or granules to optimize overall disintegration and dissolution. For example, patent document CN121128953A discloses a nicotine orally disintegrating tablet with a multi-layered composite sustained-release structure and its preparation method. By adding disintegrants to both the middle and outer layers of the nicotine orally disintegrating tablet, rapid dissolution of nicotine is achieved when ingested in the mouth. However, nicotine orally disintegrating tablets are tablets, and after disintegration, part of them are absorbed through the oral mucosa, and part are swallowed into the gastrointestinal tract. Rapid disintegration of nicotine can easily cause gastrointestinal irritation.

[0005] Third, macroscopic mixing processes present quality control challenges. For example, patent document JP2012505878A discloses various oral dosage forms, at least one of which consists of rapidly disintegrating particles and at least one of which consists of slowly disintegrating particles, with the slowly disintegrating particles having a disintegration time 3-5 times longer than the rapidly disintegrating particles. While two-phase release can be achieved by physically mixing the rapidly and slowly disintegrating particles, this method requires preparing two types of particles with different disintegration characteristics separately before mixing, resulting in complex process steps and quality risks such as particle stratification, uneven filling, and large batch-to-batch variations.

[0006] Therefore, developing a method to prepare these particles using an integrated fluidized bed process, by gradient configuration of disintegrants in different layers of the same particle, to achieve a dual-phase release function of "rapid disintegration and release in the outer layer and slow release in the core layer" in bilayer nicotine-containing particles, and preparing nicotine bags, thus breaking through the bottlenecks of existing technologies such as single nicotine bag release mode, simple application of disintegrants, and complex processes, has significant market value and technical significance. Summary of the Invention

[0007] The purpose of this application is to provide a gradient-release nicotine granule, nicotine pouch, and its preparation method. By gradient configuration of disintegrants in different layers of the same granule, a bi-phase release function of "rapid disintegration and release in the outer layer and slow release in the core layer" is achieved in the preparation of a nicotine pouch. This method breaks through the bottlenecks of existing technologies, such as the single release mode of nicotine pouches, simple application of disintegrants, and complex processes. It has significant market value and technical significance.

[0008] To solve the above-mentioned technical problems, this application provides the following technical solution: This application provides a gradient controlled-release nicotine particle, which includes a core layer and an outer layer, and the core layer and the outer layer contain a disintegrant, such that when the nicotine particle is ingested in the mouth, the components of the outer layer disintegrate at a rate 2-5 times that of the components of the core layer.

[0009] The outer layer contains a disintegrant, while the core layer does not, so that when nicotine particles are ingested in the mouth, the components of the outer layer disintegrate at a rate 2-5 times faster than the components of the core layer.

[0010] Furthermore, based on the mass of the core layer as 100%, it includes 5-30% of a first nicotine source, 0-15% of a first disintegrant, 30-70% of a first filler, 0.5-3.0% of a first lubricant, and 2-10% of a first binder.

[0011] This can be understood as the amount of the first disintegrant added being 0. When the amount of the first disintegrant is 0, it means that there is no disintegrant in the core layer.

[0012] Furthermore, based on the outer layer by weight (100%), it includes 0-15% of a second nicotine source, 15-50% of a second disintegrant, 20-60% of a second filler, 0.5-3% of a lubricant, and 2-10% of a binder.

[0013] This can be understood as the amount of a second nicotine source added being zero. When the amount of a second nicotine source is zero, it means that the outer layer does not contain any nicotine source.

[0014] Furthermore, the first disintegrating force is a low-disintegrating-force disintegrating agent, so that the core layer disintegrates slowly and the core layer structure is stable.

[0015] Furthermore, the second disintegrant is a high-disintegrant disintegrant, which causes the outer layer to expand strongly and disintegrate rapidly.

[0016] Furthermore, the disintegration rate of the second disintegrant in the outer layer is 2-5 times that of the first disintegrant in the core layer.

[0017] Furthermore, the first disintegrant includes one or more combinations of low-substituted hydroxypropyl cellulose, croscarmellose sodium, or sodium carboxymethyl starch.

[0018] Furthermore, the second disintegrant includes one or a combination of two of crospovidone or sodium carboxymethyl starch.

[0019] Furthermore, the thickness of the outer layer is 50-100 μm, 10-200 μm, 200-300 μm, or 300-500 μm.

[0020] Furthermore, the particle size of nicotine particles is 100-200 μm, 200-300 μm, 300-500 μm, 500-700 μm or 700-1000 μm.

[0021] Furthermore, the first and second nicotine sources refer to either form of nicotine that provides "nicotine that can be orally absorbed." The first and second nicotine sources may include one or more combinations of nicotine salts, free nicotine bases, or tobacco extracts. Nicotine salts include nicotine hydrochloride, nicotine dihydrochloride, nicotine phosphate, nicotine sulfate, nicotine hydrogen tartrate, nicotine hydrogen tartrate dihydrate, nicotine pyruvate, nicotine formate, nicotine oxalate, nicotine ascorbate, nicotine glycolate, nicotine acetate, nicotine isovalerate, nicotine valerate, nicotine propionate, nicotine caprylate, nicotine lactate, nicotine acetylpropionate, nicotine sorbate, nicotine malate, nicotine fumarate, nicotine salicylate, and nicotine... The first nicotine source may be the same as or different from the second nicotine source. The first nicotine source may be the same as or different from the second nicotine source.

[0022] Furthermore, the first and second fillers include one or more combinations of microcrystalline cellulose, mannitol, or lactose.

[0023] The first filler can be the same as or different from the second filler.

[0024] Furthermore, the first lubricant includes one or a combination of two of magnesium stearate or talc.

[0025] The first lubricant can be the same as or different from the second lubricant.

[0026] Furthermore, the first and second adhesives include one or more combinations of povidone, hydroxypropyl methylcellulose, carrageenan, gum arabic, xanthan gum, pectin, chitosan, or polyvinyl alcohol.

[0027] The first adhesive may be the same as or different from the second adhesive.

[0028] Furthermore, the mass concentration range of the first and second adhesives is 2-8% (w / w).

[0029] Alternatively, flavoring agents may be added to the core and / or outer layers. The amount of flavoring agent added is 2-6% of the total mass of the nicotine granules. Flavoring agents include one or more combinations of edible salt, aspartame, acesulfame potassium, cyclamate, saccharin, sodium saccharin, sucralose, neotame, sodium cyclohexylsulfamate, steviol glycosides, licorice, disodium glycyrrhizate, tripotassium and trisodium glycyrrhizate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar and lactose, sorbitol, maltitol, isomaltitol, palaginitol, xylitol, lactitol, mannitol, erythritol, or dextran.

[0030] Alternatively, a pH adjuster may be added to the core and / or outer layer, at an amount of 1-5% of the total mass of the nicotine granules. The pH adjuster may include one or more combinations of monocarbonates, bicarbonates, acetates, lactates, glycinates, gluconates, borates, sulfates, phosphates, and citrates.

[0031] Alternatively, flavorings may be added to the core and / or outer layer, with the amount of flavoring added being 1-5% of the total mass of the nicotine particles. Flavorings include one or more combinations of peppermint, fruit, herbal, or tobacco flavorings. Fruit flavorings are a non-exhaustive list, including coconut, green apple, blueberry, mango, grapefruit, orange, lime, bergamot, lemon, pineapple, strawberry, raspberry, cherry, watermelon, pear, peach, apricot, raspberry, lime, plum, etc. Herbal flavorings include cinnamon, cumin, pepper, deer hoof grass, eucalyptus, clove, bay leaf, fennel, thyme, cedar leaf oil, nutmeg, vanilla, licorice, etc.

[0032] Another aspect of this application provides a nicotine pouch, which includes a saliva-permeable pouch and nicotine particles; The materials for saliva-permeable pouches include one or more combinations of nonwoven fabric, cotton, linen, bamboo fiber, wood pulp fiber, lyocell, modal, or Tencel. Nonwoven fabrics are made of one or more of the following materials: polypropylene fiber, polyester fiber, polyamide fiber, polytetrafluoroethylene fiber, and glass fiber.

[0033] Furthermore, the amount of nicotine particles in the nicotine bag is 0.1-0.3 g, 0.3-0.4 g, or 0.4-0.5 g.

[0034] This application also provides a method for preparing a nicotine bag, comprising the following steps: Step A: The first nicotine source, the first disintegrant, the first filler, and the first lubricant are mixed for the first time to obtain a first mixture; the first adhesive is sprayed onto the surface of the first mixture to obtain a core layer; Step B: The second nicotine source, the second disintegrant, the second filler, and the second lubricant are mixed for a second time to obtain a second mixture; the second mixture and the second binder are sprayed onto the outer surface of the core layer, and after drying and sieving, nicotine particles are obtained. Step C: Fill saliva-permeable pouches with nicotine granules as the nicotine contents, and then heat-seal them to obtain nicotine pouches.

[0035] Furthermore, the heat-sealing temperature is 130-140℃, 140-145℃, or 145-150℃.

[0036] Furthermore, the heat sealing time is 0.5-0.7 s, 0.7-0.8 s, or 0.8-1.0 s.

[0037] Furthermore, the heat sealing pressure is 0.1-0.2 MPa or 0.2-0.3 MPa.

[0038] Compared with the prior art, this application has the following beneficial technical effects: (1) On-demand customization of release mode is achieved. Through the gradient configuration of disintegrants, a dual-phase release function of "rapid disintegration and release of the outer layer and slow release of the core layer" is realized for the first time in a single nicotine oral particle. Most commercially available products are either single-release rapid release or single-release sustained release, which cannot simultaneously meet the dual needs of "rapid relief of nicotine cravings" and "continuous maintenance of concentration" in the same product, so as to meet the personalized needs of users at different stages of smoking cessation or with different sensitivities.

[0039] (2) High process integration and strong quality control. The fluidized bed integrated process is adopted: after the core layer is granulated, it is not unloaded and the outer layer is directly laminated in the same equipment. There is no need to prepare two kinds of particles with different disintegration characteristics separately and then mix them. This reduces equipment investment and process steps, avoids stratification and filling quality accidents caused by uneven particle mixing, and realizes the precise distribution of disintegrant gradient in micro particles. The batch reproducibility is good.

[0040] (3) It breaks through the mindset that disintegrants are only used for single-system optimization. For the first time, the configuration of disintegrants is upgraded from "single-layer optimal" to "multi-layer gradient", which gives disintegrants a new function of structure regulation, so that disintegrants at different levels within the same particle work synergistically to achieve segmented release. This design concept can be extended to other oral or oral formulations that require biphasic release. Attached Figure Description

[0041] The above description of this application and the following detailed embodiments will be better understood when read in conjunction with the accompanying drawings. It should be noted that the drawings are merely examples of the claimed technical solutions.

[0042] Figure 1 This is a schematic diagram of the structure of the dynamic diaphragm controlled-release nicotine bag in a specific embodiment of this application; Figure 2 This is a process diagram illustrating the preparation of the dynamic diaphragm controlled-release nicotine bag in a specific embodiment of this application.

[0043] The reference numerals in the attached figures are explained as follows: Nicotine bags: 10; Nonwoven fabrics: 11; Nicotine contents: 12; Horizontal seam: 13; Longitudinal joint: 14; Equipment for manufacturing bagged products for oral use: 20; Packaging materials roll: 21; Packaging materials: 22; Feed port: 23; Management institutions: 24; First seam mechanism: 25; Second seam mechanism: 26. Detailed Implementation

[0044] 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.

[0045] In this specification and claims, several terms will be used, and unless otherwise indicated, these terms will be defined to have the following meanings: In this application, the term "nicotine," also known as nicotine alkaloid, is an organic compound with the chemical formula C. 10 H 14 N2. Nicotine belongs to the alkaloid class of compounds. Alkaloids are a class of nitrogen-containing basic organic molecules that exhibit base-like chemical properties, forming salt solutes in water or reacting with acids. Nicotine's structure contains a pyridine ring and a pyrrolidine ring, and its nitrogen atom readily accepts protons (H). + Nicotine is alkaline and can neutralize acids to form salt compounds. Free nicotine has a high pH (approximately 8.0-10.0) and causes strong irritation to the mucous membranes of the mouth and throat. Nicotine salts significantly reduce irritation and provide a gentler user experience by lowering the pH (approximately 5.0-7.0).

[0046] In this application, the term "nonwoven fabric" refers to fibrous materials, fiber webs, mats, wadding, or sheets in which fibers are arranged in an indeterminate or random orientation. In one embodiment, the nonwoven fibers initially exist as continuous, unbonded fibers or filaments. The continuous fibers are arranged substantially parallel to each other in at least one direction. In some embodiments, a first plurality of continuous fibers are arranged substantially parallel to each other in a first direction, and a second plurality of continuous fibers are arranged substantially parallel to each other in the transverse direction relative to the first plurality of continuous fibers. Methods of manufacturing such nonwoven fabrics typically involve bonding various fibers or filaments together. The bonding method of the fibers or filaments can vary, including thermal, mechanical, and chemical techniques selected in part based on the desired properties of the final product. In some embodiments, oriented fibers undergo a heat treatment process (e.g., a lamination process) to bond them together. Due to the defined orientation of the continuous fibers, the overlap of the individual fibers is low, allowing for thin nonwoven fabrics. The surface of the nonwoven fabric can also be uniform and smooth.

[0047] Nonwoven fabrics can be manufactured in spunbond or melt-spun processes, including spunbond and melt-blown processes, where such processes are understood to typically involve melting, extruding, collecting, and bonding thermoplastic polymer materials to form a fibrous nonwoven web. Fibers can be spun and then directly dispersed into a web by deflectors. Spunbond typically involves melt spinning, where the polymer is melted into a liquid and forced through small orifices into cold air, causing the polymer strands to solidify according to the shape of the orifices. The resulting fiber bundles are then mechanically stretched to orient the fibers. A nonwoven fiber web is then formed by depositing the stretched fibers onto a moving belt.

[0048] Meltblowing is a method in which a polymer (or polymers) is melted into a liquid state and extruded through a linear die containing numerous small orifices. As the polymer is extruded, a stream of hot air is first blown toward the polymer, initially stretching and / or drawing the extruded polymer stream to form extremely fine filaments. The air stream typically causes the molten polymer to stretch or attenuate by many orders of magnitude. The stretched polymer fibers are collected as a randomly entangled, self-adhesive nonwoven fiber web.

[0049] Nonwoven fiber webs can be manufactured using a combination of orientation and spinning techniques. A nonwoven fiber web can be formed by spinning continuous filament fibers, aligning the fibers parallel to each other in at least one direction, and thermally bonding the fibers. In various embodiments, the nonwoven fiber web can be multilayered, with multiple layers laminated in more than one direction. In thermally bonded embodiments, the nonwoven fabric can be formed using thermoplastic polymers as bonding fibers. Thermoplastic polymers can exhibit relatively low melting points to facilitate heat sealing of bag materials. For example, thermoplastic polymer fibers typically have melting points of about 120-200°C. Exemplary thermoplastic polymers include various polyolefins and polyester materials.

[0050] In this application, the fibers used in the nonwoven fabric according to this disclosure can vary and include fibers having any type of cross-section, including but not limited to circular, rectangular, square, elliptical, triangular, and multi-lobed shapes. In some embodiments, the fibers may have one or more void spaces, wherein the void spaces may have, for example, circular, rectangular, square, elliptical, triangular, or multi-lobed cross-sections. The physical parameters of the fibers present in the nonwoven fabric can vary. For example, the fibers used in the nonwoven fabric may have different dimensions and crimp characteristics.

[0051] In this application, the methods for producing nonwoven fabrics can be varied, and the formation of the fiber web can be accomplished by any method known in the art. Nonwoven fiber webs can be produced by spunbonding and / or meltblown processes, and the nonwoven fiber webs can have varying thicknesses, porosities, and other parameters. Nonwoven fiber webs can be formed such that the fiber orientation and porosity of the bagged product formed therefrom can be maintained within the composition encapsulated in the bag in some embodiments, but also allow the consumer to enjoy the components of the composition.

[0052] All figures used to represent component amounts, properties (e.g., weight-average 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 in this application. The principle of equivalents, which is 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.

[0053] All other terms used herein for special definition are intended to have the general meaning understood by one of ordinary skill in the art, in particular, meaning that one of ordinary skill in the art can directly and without doubt determine how the technical solution of this application can be implemented after reading the claims, description and drawings of this application.

[0054] Even if there are incomplete descriptions, omissions, or ambiguities in the grammar, words, punctuation, graphics, symbols, etc. of the claims, description, and drawings of this application, those skilled in the art can still arrive at the only correct understanding by reading the claims, description, 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 application.

[0055] The "range" disclosed herein is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a specific parameter, it is expected that ranges of 60-110 and 80-120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5. In this application, unless otherwise stated, the numerical range "ab" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0-5" indicates that all real numbers between "0-5" have been listed in this article; "0-5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0056] Unless otherwise specified, all embodiments and preferred embodiments mentioned herein can be combined to form new technical solutions.

[0057] Unless otherwise specified, all the technical features and preferred features mentioned herein can be combined to form new technical solutions.

[0058] Unless otherwise specified, all steps mentioned herein may be performed sequentially or randomly, but are preferably performed sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the mention that the method may also include step (c) indicates that step (c) may be added to the method in any order; for example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0059] Unless otherwise specified, the terms "comprising" and "including" as used herein can be open-ended or closed-ended. For example, "comprising" and "including" may mean that other components not listed may also be included, or that only the listed components may be included.

[0060] In the description of this article, it should be noted that, unless otherwise stated, "above" and "below" include the number itself, and "several" in "one or more" means two or more.

[0061] In this description, unless otherwise stated, the term "or" is inclusive. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0062] Unless otherwise specified, percentages (%) in this document refer to percentages by mass relative to the composition.

[0063] Unless otherwise stated herein, the sum of the contents of the components in the composition is 100%.

[0064] In this document, unless otherwise stated, “combination of” means a multi-component mixture of the elements, such as two, three, four, and up to the maximum possible multi-component mixture.

[0065] Unless otherwise specified, the term "a" as used in this specification means "at least one".

[0066] The terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of this invention, "a plurality of" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0067] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0068] To make the objectives, technical solutions, and advantages of the present invention clearer, the embodiments of the present invention will be further described in detail below with reference to the accompanying drawings. Unless otherwise specified, the experimental methods described in the embodiments of the present invention are conventional methods, and the materials and reagents used in the following embodiments are commercially available unless otherwise specified.

[0069] This application provides a gradient-release nicotine granule, a nicotine bag, and a method for preparing the same, comprising the following steps: S1. Preparation of nicotine granules, the specific steps are as follows: (1) The first nicotine source, the first disintegrant, the first filler, and the first lubricant are placed together in a three-dimensional motion mixer (commercially available) at a mass ratio of (5-30):(0-15):(30-70):(0.5-3.0) for the first mixing treatment. The rotation speed of the first mixing treatment is 15-25 r / min, and the mixing time is 15-25 min, to ensure that the components can be evenly dispersed, thus obtaining the first mixture. It can be understood that when the addition ratio of the first disintegrant is 0, it means that no first disintegrant is added.

[0070] The term "primary nicotine source" refers to any form of nicotine that provides "orally absorbed nicotine." Primary nicotine sources include one or more combinations of nicotine salts, free nicotine bases, or tobacco extracts. Nicotine salts include nicotine hydrochloride, nicotine dihydrochloride, nicotine phosphate, nicotine sulfate, nicotine hydrogen tartrate, nicotine hydrogen tartrate dihydrate, nicotine pyruvate, nicotine formate, nicotine oxalate, nicotine ascorbate, nicotine glycolate, nicotine acetate, nicotine isovalerate, nicotine valerate, nicotine propionate, nicotine caprylate, nicotine lactate, nicotine levulinate, nicotine sorbate, nicotine malate, nicotine fumarate, nicotine salicylate, and so on. Nicotine glycinate, nicotine tartrate, nicotine succinate, nicotine citrate, nicotine benzoate, nicotine resinate, nicotine oleate, nicotine aconitate, nicotine butyrate, nicotine cinnamate, nicotine caprate, nicotine 3,7-dimethyl-6-octenate, nicotine 1-glutamate, nicotine heptarate, nicotine hexanoate, nicotine 3-hexenoate, nicotine trans-2-hexenoate, nicotine isobutyrate, nicotine laurate, nicotine 2-methylbutyrate, nicotine 2-methylvalerate, nicotine myristate, nicotine nonanoate, nicotine palmitate, nicotine 4-pentenoate, nicotine phenylacetate, or nicotine 3-phenylpropionate, or one or more combinations thereof.

[0071] The primary disintegrant includes one or more combinations of low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium (CCS), and sodium carboxymethyl starch (SSG). The primary disintegrant is a low-disintegrant to ensure slow disintegration of the core layer and stability of the core layer structure.

[0072] The first filler includes one or more combinations of microcrystalline cellulose, mannitol, or lactose.

[0073] The first lubricant includes one or a combination of magnesium stearate or talc.

[0074] (2) Weigh a certain amount of the first adhesive and place it in hot water to swell, and prepare a first adhesive solution with a concentration of 2-8% (w / w).

[0075] The first adhesive includes one or more combinations of polyvinylpyrrolidone, hydroxypropyl methylcellulose, carrageenan, gum arabic, xanthan gum, pectin, chitosan, or polyvinyl alcohol.

[0076] (3) Place the first mixture obtained in step (1) and the first binder solution obtained in step (2) into a fluidized bed granulation and coating machine, respectively, and set the inlet air temperature to 40-80℃ and the air volume to 100-200 m³ / h. 3 The atomization pressure is 1.0-3.0 bar, the spray rate is 10-50 mL / min, and after the fluidization is stable and the bed temperature reaches 42℃, the first binder solution is sprayed onto the powder material for granulation. The powder is dried until the moisture content is ≤3%, and then the particles of 100-200 μm, 200-300 μm, 300-400 μm, 400-500 μm or 500-800 μm are collected by sieving to obtain the core layer particles (also known as the core layer).

[0077] Based on the mass of the core layer (100%), it includes 5-30% of a first nicotine source, 0-15% of a first disintegrant, 30-70% of a first filler, 0.5-3.0% of a first lubricant, and 2-10% of a first binder.

[0078] (4) The second nicotine source, the second disintegrant, the second filler, and the second lubricant are placed together in a three-dimensional motion mixer (commercially available) at a mass ratio of (0-15):(15-50):(20-60):(0.5-3.0) for a second mixing treatment. The rotation speed of the second mixing treatment is 15-25 r / min, and the mixing time is 15-25 min, to ensure that the components are evenly dispersed, thus obtaining the second mixture. It can be understood that when the addition ratio of the second nicotine source is 0, it means that no second nicotine source is added.

[0079] The term "secondary nicotine source" refers to any form of nicotine that provides "orally absorbed nicotine." Secondary nicotine sources include two or more combinations of nicotine salts, free nicotine bases, or tobacco extracts. Nicotine salts include nicotine hydrochloride, nicotine dihydrochloride, nicotine phosphate, nicotine sulfate, nicotine hydrogen tartrate, nicotine hydrogen tartrate dihydrate, nicotine pyruvate, nicotine formate, nicotine oxalate, nicotine ascorbate, nicotine glycolate, nicotine acetate, nicotine isovalerate, nicotine valerate, nicotine propionate, nicotine caprylate, nicotine lactate, nicotine acetylpropionate, nicotine sorbate, nicotine malate, nicotine fumarate, nicotine salicylate, and so on. Nicotine glycinate, nicotine tartrate, nicotine succinate, nicotine citrate, nicotine benzoate, nicotine resinate, nicotine oleate, nicotine aconitate, nicotine butyrate, nicotine cinnamate, nicotine caprate, nicotine 3,7-dimethyl-6-octenate, nicotine 1-glutamate, nicotine heptarate, nicotine hexanoate, nicotine 3-hexenoate, nicotine trans-2-hexenoate, nicotine isobutyrate, nicotine laurate, nicotine 2-methylbutyrate, nicotine 2-methylvalerate, nicotine myristate, nicotine nonanoate, nicotine palmitate, nicotine 4-pentenoate, nicotine phenylacetate, or nicotine 3-phenylpropionate, or one or more combinations thereof.

[0080] The second disintegrant includes one or a combination of two of crospovidone (PVPP) or sodium carboxymethyl starch (SSG), which are high-disintegrant disintegrants that cause strong expansion and rapid disintegration of the outer layer.

[0081] The second filler includes one or more combinations of microcrystalline cellulose, mannitol, or lactose.

[0082] The second lubricant includes one or a combination of magnesium stearate or talc.

[0083] (5) Weigh out two quantities of the second adhesive and place it in hot water to swell, and prepare a second adhesive solution with a concentration of 2-8% (w / w).

[0084] The second adhesive includes one or more combinations of polyvinylpyrrolidone, hydroxypropyl methylcellulose, carrageenan, gum arabic, xanthan gum, pectin, chitosan, or polyvinyl alcohol.

[0085] (6) The core layer particles prepared in step (3) are retained in the fluidized bed without unloading. The fluidized bed is switched to bottom spray mode. The second mixture prepared in step (4) is sprayed into the fluidized bed in solid form. The second binder solution prepared in step (5) and the second mixture are sprayed into the fluidized bed simultaneously or alternately. The inlet air temperature of the bottom spray mode is 30-60℃, the material temperature of the second mixture and the second binder solution is 25-45℃, the spray rate is 3-15 mL / min, and the atomization pressure is 1.0-2.5. bar; thereby causing the solid powder of the second mixture to adhere to the outer surface of the core layer particles prepared in step (3) above, so as to form an outer layer on the outer surface of the core layer particles. The outer layer, by mass of 100%, includes 0-15% nicotine source, 15-50% second disintegrant, 20-60% second filler, 0.5-3% lubricant and 2-10% binder. After drying and sieving, the core layer particles and the outer layer are combined to obtain nicotine particles.

[0086] The outer layer has a thickness of 50-100 μm, 10-200 μm, 200-300 μm, or 300-500 μm, resulting in nicotine particles with particle sizes of 100-200 μm, 200-300 μm, 300-500 μm, 500-700 μm, or 700-1000 μm. The drying temperature is 60-65℃, 65-75℃, or 75-85℃.

[0087] When nicotine granules are ingested in the mouth, the outer layer of components disintegrates at a rate 2-5 times faster than the core layer. The disintegration rate of the outer layer mainly depends on the disintegration rate of the second disintegrant in the outer layer, which drives the rapid disintegration of other outer layer components. The disintegration rate of the core layer mainly depends on the disintegration rate of the first disintegrant in the core layer, which drives the slow disintegration of other core layer components. If there is no first disintegrant in the core layer, the disintegration rate of the core layer mainly depends on the disintegration rate of all components.

[0088] In some other embodiments, flavoring agents may also be added to the core layer and / or outer layer. The amount of flavoring agent added is 2-6% of the total mass of the nicotine particles. Flavoring agents include one or more combinations of edible salt, aspartame, acesulfame potassium, cyclamate, saccharin, sodium saccharin, sucralose, neotame, sodium cyclohexylsulfamate, steviol glycosides, licorice, disodium glycyrrhizate, tripotassium and trisodium glycyrrhizate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar and lactose, sorbitol, maltitol, isomaltitol, palaginitol, xylitol, lactitol, mannitol, erythritol or dextran.

[0089] In some other specific embodiments, a pH adjuster may also be added to the core layer and / or outer layer, the amount of which is 1-5% of the total mass of the nicotine particles. The pH adjuster includes one or more combinations of monocarbonates, bicarbonates, acetates, lactates, glycines, gluconates, borates, sulfates, phosphates, and citrates.

[0090] In some other specific embodiments, flavorings may also be added to the core layer and / or outer layer, with the amount of flavoring added being 1-5% of the total mass of the nicotine particles. The flavorings include one or more combinations of peppermint flavoring, fruit flavoring, herbal flavoring, or tobacco flavoring. Fruit flavorings are non-exhaustive examples, including coconut, green apple, blueberry, mango, grapefruit, orange, lime, bergamot, lemon, pineapple, strawberry, raspberry, cherry, watermelon, pear, peach, apricot, raspberry, lime, plum, etc. Herbal flavorings include cinnamon, cumin, pepper, deer hoof grass, eucalyptus, clove, bay leaf, fennel, thyme, cedar leaf oil, nutmeg, vanilla, licorice, etc.

[0091] S2. Prepare the nicotine pouch, the specific steps of which are as follows: (1) A saliva-permeable material is selected as the base material for the nicotine bag. The saliva-permeable material includes one or more combinations of non-woven fabric, cotton, linen, bamboo fiber, wood pulp fiber, lyocell, modal, or Tencel. The non-woven fabric material includes one or more combinations of polypropylene fiber, polyester fiber, polyamide fiber, polytetrafluoroethylene fiber, and glass fiber.

[0092] (2) Using existing fully automated nicotine bag production equipment, the nicotine contents obtained in step (2) above are filled into saliva-permeable bags. The saliva-permeable bags include food-grade non-woven fabric. After heat sealing and ultraviolet sterilization, the nicotine bags are obtained.

[0093] The structure of nicotine bag 10 is as follows Figure 1 As shown, the nicotine bag 10 is typically made of non-woven fabric 11 or other non-woven materials, and the nicotine contents 12 prepared above are wrapped in it using specialized equipment. The nicotine bag 10 has serrated transverse seams 13 on both sides and a longitudinal seam 14 in the middle.

[0094] The manufacturing process of nicotine pouch 10 is as follows: Figure 2As shown, nicotine pouches 10 are manufactured using a bag-making equipment 20, which combines packaging materials and nicotine contents 12. A roll 21 of packaging material is unrolled into a strip 22 and fed into a tube-forming mechanism 24, gradually forming a non-woven tube with a tubular structure. A longitudinal seam 14 is formed by high-temperature rollers on a first seam mechanism 25, thus shaping the pouch into a saliva-permeable bag. A measured amount of nicotine contents 12 is periodically fed into the saliva-permeable pouch through a feeding port 23. Then, a second seam mechanism 26 is activated, using its high-temperature clamps to form a new transverse seam at the upper end of the saliva-permeable pouch. The pouch is then serrated, with the lower half forming the transverse seam 13 at the upper end of the nicotine pouch 10, and the upper half forming the longitudinal seam 14 at the lower end of a new nicotine pouch 10. The nicotine contents 12 are fed in again, and this process is repeated continuously to manufacture nicotine pouches 10.

[0095] The nicotine content is 0.1-0.3 g, 0.3-0.4 g, or 0.4-0.5 g, the heat-sealing temperature is 130-140℃, 140-145℃, or 145-150℃, and the heat-sealing time is 0.5-0.7 s, 0.7-0.8 s, or 0.8-1.0 s.

[0096] Example 1

[0097] (1) Nicotine tartrate, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate were placed together in a three-dimensional motion mixer (commercially available) in a mass ratio of 15:5:70:3.0 for the first mixing treatment. The rotation speed of the first mixing treatment was 15 r / min and the time of the first mixing treatment was 25 min to ensure that each component could be evenly dispersed, thus obtaining the first mixture.

[0098] (2) Weigh 5 g of polyvinyl chloride and place it in 95 mL of hot water to swell, and prepare a polyvinyl chloride solution with a concentration of 5% (w / v), which is the first adhesive solution.

[0099] (3) The first mixture obtained in step (1) and the first binder solution obtained in step (2) are placed in a fluidized bed granulation and coating machine, with the inlet air temperature set at 40°C and the air volume at 200 m³ / h. 3 The atomization pressure is 1.0 bar, the spray rate is 50 mL / min, and after the fluidization is stable and the bed temperature reaches 42℃, the first binder solution is sprayed onto the powder material for granulation. The powder is dried until the moisture content is ≤3%, and then the 100-200 μm particles are collected by sieving to obtain the core layer particles (also known as the core layer).

[0100] Based on the mass of the core layer (100%), it includes 15% nicotine tartrate, 5% low-substituted hydroxypropyl cellulose, 70% microcrystalline cellulose, 3.0% magnesium stearate, and 7% povidone.

[0101] (4) Nicotine tartrate, crospovidone, microcrystalline cellulose and magnesium stearate are placed together in a three-dimensional motion mixer (commercially available) in a mass ratio of 15:35:40:3 for a second mixing process. The rotation speed of the second mixing process is 15 r / min and the time of the second mixing process is 25 min to ensure that each component can be evenly dispersed, thus obtaining the second mixture.

[0102] (5) Weigh 5 g of hydroxypropyl methylcellulose and place it in 95 mL of hot water to swell, and prepare a 5% (w / v) hydroxypropyl methylcellulose solution, which is the second adhesive solution.

[0103] (6) The core layer particles prepared in step (3) are kept in the fluidized bed without unloading. The fluidized bed is switched to bottom spray mode. The second mixture prepared in step (4) is sprayed into the fluidized bed in solid form. The second binder solution prepared in step (5) and the second mixture prepared in step (4) are sprayed into the fluidized bed at the same time. The inlet air temperature of the bottom spray mode is 30°C, the material temperature of the second mixture and the second binder solution is 25°C, the spray rate is 3 mL / min, and the atomization pressure is 1.0 bar. Thus, the solid powder of the second mixture adheres to the outer surface of the core layer particles prepared in step (3) to form an outer layer on the outer surface of the core layer particles. The outer layer, by mass 100%, includes 15% nicotine tartrate, 35% crospovidone, 40% microcrystalline cellulose, 3% magnesium stearate, and 7% hydroxypropyl methylcellulose. The thickness of the outer layer is 50 mm. After drying and sieving, the core layer particles and the outer layer particles are combined to obtain nicotine particles with a particle size of 200 μm.

[0104] (7) The nicotine granules prepared in step (6) above are used as the contents and filled into the saliva-permeable pouch using the existing fully automatic nicotine pouch production equipment. The filling amount of nicotine granules is 0.5 g. The saliva-permeable pouch is made of food-grade non-woven fabric. After heat sealing and ultraviolet sterilization, the nicotine pouch is obtained.

[0105] Example 2

[0106] (1) Nicotine citrate, microcrystalline cellulose and talc are placed together in a three-dimensional motion mixer (commercially available) in a mass ratio of 20:70:1 for the first mixing treatment. The rotation speed of the first mixing treatment is 15 r / min and the time of the first mixing treatment is 25 min to ensure that each component can be evenly dispersed, thus obtaining the first mixture.

[0107] (2) Weigh 8 g of polyvinyl acetate and place it in 92 mL of hot water to swell, and prepare a polyvinyl acetate solution with a concentration of 8% (w / v), which is the first adhesive solution.

[0108] (3) The first mixture obtained in step (1) and the first binder solution obtained in step (2) are placed in a fluidized bed granulation and coating machine, with the inlet air temperature set at 80°C and the air volume at 100 m³ / h. 3 The atomization pressure is 3.0 bar, the spray rate is 10 mL / min, and after the fluidization is stable and the bed temperature reaches 42℃, the first binder solution is sprayed onto the powder material for granulation. The powder is dried until the moisture content is ≤3%, and then the 100-200 μm particles are collected by sieving to obtain the core layer particles (also known as the core layer).

[0109] Based on the mass of the core layer (100%), it includes 20% nicotine citrate, 70% microcrystalline cellulose, 1% talc, and 9% povidone.

[0110] (4) Nicotine citrate, sodium carboxymethyl starch, microcrystalline cellulose and talc are placed together in a three-dimensional motion mixer (commercially available) in a mass ratio of 5:35:50:2 for a second mixing process. The rotation speed of the second mixing process is 25 r / min and the time of the second mixing process is 15 min to ensure that each component can be evenly dispersed, thus obtaining the second mixture.

[0111] (5) Weigh 2 g of hydroxypropyl methylcellulose and place it in 95 mL of hot water to swell, and prepare a 2% (w / v) hydroxypropyl methylcellulose solution, which is the second adhesive solution.

[0112] (6) The core layer particles prepared in step (3) are kept in the fluidized bed without unloading. The fluidized bed is switched to bottom spray mode. The second mixture prepared in step (4) is sprayed into the fluidized bed in solid form. The second binder solution prepared in step (5) and the second mixture prepared in step (4) are sprayed into the fluidized bed simultaneously. The inlet air temperature of the bottom spray mode is 40°C, the material temperature of the second mixture and the second binder solution is 30°C, the spray rate is 8 mL / min, and the atomization pressure is 1.5 bar. This allows the solid powder of the second mixture to adhere to the outer surface of the core layer particles prepared in step (3) to form an outer layer on the outer surface of the core layer particles. The outer layer, by mass 100%, includes 5% nicotine citrate, 35% sodium carboxymethyl starch, 50% microcrystalline cellulose, 2% talc, and 8% hydroxypropyl methylcellulose. The thickness of the outer layer is 50 mm. After drying and sieving, the core layer particles and the outer layer particles are combined to obtain nicotine particles with a particle size of 200 μm.

[0113] (7) The nicotine granules prepared in step (6) above are used as the contents and filled into the saliva-permeable pouch using the existing fully automatic nicotine pouch production equipment. The filling amount of nicotine granules is 0.5 g. The saliva-permeable pouch is made of food-grade non-woven fabric. After heat sealing and ultraviolet sterilization, the nicotine pouch is obtained.

[0114] Example 3

[0115] (1) Nicotine hydrochloride, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and talc are placed together in a three-dimensional motion mixer (commercially available) in a mass ratio of 15:5:70:1 for the first mixing treatment. The rotation speed of the first mixing treatment is 15 r / min and the time of the first mixing treatment is 25 min to ensure that each component can be evenly dispersed, thus obtaining the first mixture.

[0116] (2) Weigh 2 g of polyvinyl acetate and place it in 98 mL of hot water to swell, and prepare a polyvinyl acetate solution with a concentration of 2% (w / v), which is the first adhesive solution.

[0117] (3) The first mixture obtained in step (1) and the first binder solution obtained in step (2) are placed in a fluidized bed granulation and coating machine, with the inlet air temperature set at 40°C and the air volume at 200 m³ / h. 3 The atomization pressure is 1.0 bar, the spray rate is 50 mL / min, and after the fluidization is stable and the bed temperature reaches 42℃, the first binder solution is sprayed onto the powder material for granulation. The powder is dried until the moisture content is ≤3%, and then the 100-200 μm particles are collected by sieving to obtain the core layer particles (also known as the core layer).

[0118] Based on the mass of the core layer (100%), it includes 15% nicotine hydrochloride, 5% croscarmellose sodium, 70% microcrystalline cellulose, 1% talc, and 9% povidone.

[0119] (4) Nicotine citrate, sodium carboxymethyl starch, microcrystalline cellulose and talc are placed together in a three-dimensional motion mixer (commercially available) in a mass ratio of 8:25:60:3 for a second mixing process. The rotation speed of the second mixing process is 15 r / min and the time of the second mixing process is 25 min to ensure that each component can be evenly dispersed, thus obtaining the second mixture.

[0120] (5) Weigh 2 g of hydroxypropyl methylcellulose and place it in 95 mL of hot water to swell, and prepare a 2% (w / v) hydroxypropyl methylcellulose solution, which is the second adhesive solution.

[0121] (6) The core layer particles prepared in step (3) are kept in the fluidized bed without unloading. The fluidized bed is switched to bottom spray mode. The second mixture prepared in step (4) is sprayed into the fluidized bed in solid form. The second binder solution prepared in step (5) and the second mixture prepared in step (4) are sprayed into the fluidized bed simultaneously. The inlet air temperature of the bottom spray mode is 60°C, the material temperature of the second mixture and the second binder solution is 45°C, the spray rate is 15 mL / min, and the atomization pressure is 2.5 bar. This allows the solid powder of the second mixture to adhere to the outer surface of the core layer particles prepared in step (3) to form an outer layer on the outer surface of the core layer particles. The outer layer, by mass 100%, includes 8% nicotine citrate, 25% sodium carboxymethyl starch, 60% microcrystalline cellulose, 3% talc, and 4% hydroxypropyl methylcellulose. The thickness of the outer layer is 50 mm. After drying and sieving, the core layer particles and the outer layer are combined to obtain nicotine particles with a particle size of 200 μm.

[0122] (7) The nicotine granules prepared in step (6) above are used as the contents and filled into the saliva-permeable pouch using the existing fully automatic nicotine pouch production equipment. The filling amount of nicotine granules is 0.5 g. The saliva-permeable pouch is made of food-grade non-woven fabric. After heat sealing and ultraviolet sterilization, the nicotine pouch is obtained.

[0123] Comparative Example 1

[0124] Compared with Example 1, the difference is that this comparative example uses the method described in the patent document with publication number CN121128953A to prepare nicotine orally disintegrating tablets.

[0125] Comparative Example 2

[0126] Compared with Example 1, the difference is that the nicotine particles in the nicotine bag of this comparative example are single-layer particles, that is, the core layer and the outer layer components are mixed, so that the disintegrant is uniformly mixed in the nicotine particles, and the nicotine bag is prepared.

[0127] Comparative Example 3

[0128] Compared with Example 1, the difference is that the nicotine particles in the nicotine bag of this comparative example include a core layer and an outer layer. The content of disintegrant in the core layer and the outer layer is the same, and both are made of low-substituted hydroxypropyl cellulose. The filling amount of low-substituted hydroxypropyl cellulose in the core layer and the outer layer is 8%, and nicotine particles are obtained. These particles are then used as nicotine contents to prepare the nicotine bag.

[0129] Comparative Example 4

[0130] Compared with Example 1, the difference is that the disintegrant configuration gradients in the core layer and outer layer of the nicotine particles in this comparative example are opposite. That is, the amount of low-substituted hydroxypropyl cellulose in the core layer is 35%, and the amount of low-substituted hydroxypropyl cellulose in the outer layer is 5%, thus obtaining nicotine particles, which are then used as nicotine contents to prepare the nicotine bag.

[0131] Test Example 1: In Vitro Nicotine Test

[0132] To further illustrate the advantages of the preparation method described in the embodiments of this application, the nicotine dissolution of the nicotine products prepared in Examples 1-3 and Comparative Examples 1-4 was tested using a dissolution apparatus-paddle method. Simulated artificial saliva was used as the dissolution medium, with a pH of 6.8. The dissolution of nicotine in the nicotine bag was detected within 2-60 minutes at a temperature of 37±0.5℃ and a rotation speed of 50 r / min.

[0133] The results are shown in Table 1. The in vitro nicotine release from the nicotine bags in Examples 1-3 showed a significant gradient release compared to the in vitro nicotine release from the nicotine bags in the comparative examples.

[0134] In Example 1, the outer layer of the nicotine particles in the nicotine bag contains a high-disintegration-force disintegrant (PVPP 35%) that rapidly absorbs water and swells. It releases a cumulative 18% in 2 minutes, 28% in 5 minutes, 45% in 10 minutes, 58% in 15 minutes, 90% in 30 minutes, 94% in 40 minutes, and 96% in 60 minutes, exhibiting a typical "fast-slow" biphasic characteristic, with the release essentially completed within 30 minutes.

[0135] The initial release rate of nicotine particles in the nicotine bag of Example 2 was slightly higher than that of Example 1 (20% vs 18% at 2 minutes), but the later release was more gradual, with a cumulative release of 85% at 30 minutes and 90% at 60 minutes. The core layer of Example 2 does not contain a disintegrant, and drug release mainly relies on diffusion through the pores of the filler to achieve relatively continuous drug delivery.

[0136] In Example 3, the outer layer disintegrant of the nicotine particles in the nicotine bag was changed from PVPP to SSG (which has weaker disintegrant power), resulting in a lower initial release rate (12% at 2 minutes and 35% at 10 minutes), but retaining the biphasic release characteristics; the complete release time was extended to about 60 minutes (88% at 60 minutes), which is suitable for users who need a more stable absorption curve.

[0137] The nicotine orally disintegrating tablets of Comparative Example 1 exhibited rapid disintegration and release characteristics in simulated artificial saliva. Within 5 minutes, the cumulative release of nicotine reached 40%, within 30 minutes it exceeded 78%, within 40 minutes it reached 90%, and within 60 minutes it was almost completely released (98%), showing a certain gradient release trend. However, it still could not achieve the biphasic or sustained controlled-release effect of nicotine in the embodiments of this application, and there was a significant difference from the gradient release performance of Examples 1-3.

[0138] In Comparative Example 2, all the disintegrants in the nicotine product were uniformly distributed inside the nicotine particles. After absorbing water, the particles swelled as a whole, exhibiting a rapid first-stage release: 30% within 2 minutes, 95% within 30 minutes, and 98% within 60 minutes. It lacked segmented control capabilities and could not achieve a two-phase release of "fast outer layer and slow core layer".

[0139] In Comparative Example 3, the nicotine product used a low-disintegrant disintegrant L-HPC (8% concentration) for both the core and outer layers of the nicotine particles. The release curve was generally flat, with only 5% release at 2 minutes, 65% at 30 minutes, and 78% at 60 minutes. The initial release was too slow (5% at 2 minutes), failing to take effect quickly and lacking obvious biphasic release characteristics.

[0140] In Comparative Example 4, the outer layer of the nicotine particles in the nicotine product exhibited weak disintegration power (L-HPC 5%), resulting in slow disintegration: only 6% at 2 minutes, 18% at 10 minutes, 55% at 30 minutes, and 70% at 60 minutes. Although the core layer contained 35% of the high-disintegration-power disintegrant PVPP, moisture required a longer time to penetrate to the core layer, and the high-disintegration-power disintegrant swelled upon absorbing water in the core layer, potentially blocking the drug release channels, leading to an even slower overall release. Therefore, it failed to achieve rapid onset of action.

[0141] Table 1. Statistical table of nicotine release rates in nicotine bags from different embodiments and comparative examples.

[0142] Therefore, it can be concluded that this application provides a gradient-release nicotine granule, a nicotine bag, and a method for preparing the same, which has the following beneficial technical effects: (1) On-demand customization of release mode is achieved. Through the gradient configuration of disintegrants, a dual-phase release function of "rapid disintegration and release of the outer layer and slow release of the core layer" is realized for the first time in a single nicotine oral particle. Most commercially available products are either single-release rapid release or single-release sustained release, which cannot simultaneously meet the dual needs of "rapid relief of nicotine cravings" and "continuous maintenance of concentration" in the same product, so as to meet the personalized needs of users at different stages of smoking cessation or with different sensitivities.

[0143] (2) High process integration and strong quality control. The fluidized bed integrated process is adopted: after the core layer is granulated, it is not unloaded and the outer layer is directly laminated in the same equipment. There is no need to prepare two kinds of particles with different disintegration characteristics separately and then mix them. This reduces equipment investment and process steps, avoids stratification and filling quality accidents caused by uneven particle mixing, and realizes the precise distribution of disintegrant gradient in micro particles. The batch reproducibility is good.

[0144] (3) It breaks through the mindset that disintegrants are only used for single-system optimization. For the first time, the configuration of disintegrants is upgraded from "single-layer optimal" to "multi-layer gradient", which gives disintegrants a new function of structure regulation, so that disintegrants at different levels within the same particle work synergistically to achieve segmented release. This design concept can be extended to other oral or oral formulations that require biphasic release.

[0145] In the foregoing description of exemplary embodiments / specific implementations of this application, various features of this application are sometimes combined in a single embodiment / specification or its figures and description, with the aim of simplifying the disclosure and aiding in the understanding of one or more of the various inventive aspects. However, the descriptive approach of this application should not be construed as reflecting an intention that the claimed features are more than expressly stated in each claim, except where expressly stated otherwise or in obvious technical contradictions or exclusions are found. Rather, the inventive aspects reflected in the claims lie in not all features of a single foregoing disclosed embodiment / specification. Therefore, the claims following the detailed description are hereby expressly incorporated into this detailed description, each claim existing independently as a separate embodiment / specification of this application.

[0146] The terms and expressions used in this specification are illustrative and not limiting. Their use is not intended to exclude any equivalents of the shown and described features or portions thereof, but rather to facilitate the understanding that various modifications may be possible within the scope of the claims. Therefore, it should be understood that while this application has been specifically disclosed through preferred embodiments, exemplary embodiments, and optional features, variations or modifications of the concepts disclosed herein may be adopted by those skilled in the art, and such variations and modifications are therefore considered to be within the scope of this application as defined by the appended claims. The specific embodiments given in this specification are examples of useful embodiments of this application, and it will be apparent to those skilled in the art that this application can be implemented using many variations of the devices, device components, and method steps disclosed herein.

[0147] The foregoing description of specific embodiments has fully disclosed the general features of this application, enabling others to easily modify and / or adapt such embodiments for various applications by applying knowledge within the scope of the art, without excessive experimentation or deviation from the general concept of this application. Therefore, based on the teachings and guidance provided herein, it is intended that such modifications and alterations be included within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that the wording or terminology used herein is for descriptive purposes and is not intended to be limiting; thus, the wording or terminology in this specification will be interpreted by those skilled in the art based on the foregoing teachings and guidance.

[0148] Furthermore, the scope of this application should not be limited to any of the exemplary embodiments described above, but only to the appended claims and their equivalents.

Claims

1. A gradient-release nicotine particle, characterized in that, The nicotine particle includes a core layer and an outer layer, wherein the core layer and the outer layer contain a disintegrant, such that when the nicotine particle is ingested in the mouth, the components of the outer layer disintegrate at a rate 2-5 times faster than the components of the core layer. Alternatively, the outer layer contains a disintegrant while the core layer does not, such that when the nicotine granules are ingested in the mouth, the components of the outer layer disintegrate at a rate 2-5 times faster than the components of the core layer.

2. The nicotine granules according to claim 1, characterized in that, Based on the mass of the core layer as 100%, it includes 5-30% of a first nicotine source, 0-15% of a first disintegrant, 30-70% of a first filler, 0.5-3.0% of a first lubricant, and 2-10% of a first binder; When the first disintegrant is 0, that is, the core layer does not contain a disintegrant.

3. The nicotine granules according to claim 2, characterized in that, The outer layer comprises, by weight 100%, 0-15% of a second nicotine source, 15-50% of a second disintegrant, 20-60% of a second filler, 0.5-3% of a lubricant, and 2-10% of an adhesive. When the second nicotine source is 0, that is, the outer layer does not contain a nicotine source.

4. The nicotine granules according to claim 3, characterized in that, The first disintegration force is a low-disintegration-force disintegrating agent, so that the core layer disintegrates slowly and the core layer structure is stable; The second disintegrant is a high-disintegrant disintegrant, so that the outer layer expands strongly and disintegrates rapidly; The disintegration rate of the second disintegrant in the outer layer is 2-5 times that of the first disintegrant in the core layer.

5. The nicotine granules according to claim 4, characterized in that, The first disintegrant includes one or more combinations of low-substituted hydroxypropyl cellulose, croscarmellose sodium, or sodium carboxymethyl starch; The second disintegrant includes one or a combination of two of crospovidone or sodium carboxymethyl starch.

6. The nicotine granules according to claim 5, characterized in that, The thickness of the outer layer is 50-100 μm, 10-200 μm, 200-300 μm, or 300-500 μm; The nicotine particles have a particle size of 100-200 μm, 200-300 μm, 300-500 μm, 500-700 μm or 700-1000 μm.

7. A nicotine bag, characterized in that, The nicotine pouch comprises a saliva-permeable pouch and nicotine particles as described in any one of claims 1-6; The material of the saliva-permeable pouch includes one or more combinations of non-woven fabric, cotton, linen, bamboo fiber, wood pulp fiber, lyocell, modal, or Tencel. The nonwoven fabric is made of one or more of the following materials: polypropylene fiber, polyester fiber, polyamide fiber, polytetrafluoroethylene fiber, and glass fiber.

8. The nicotine bag according to claim 7, characterized in that, The amount of nicotine particles in the nicotine bag is 0.1-0.3 g, 0.3-0.4 g, or 0.4-0.5 g.

9. A method for preparing a nicotine bag as described in claim 8, characterized in that, Includes the following steps: Step A: The first nicotine source, the first disintegrant, the first filler, and the first lubricant are mixed for the first time to obtain a first mixture; the first adhesive is sprayed onto the surface of the first mixture to obtain a core layer; Step B: The second nicotine source, the second disintegrant, the second filler, and the second lubricant are mixed for a second time to obtain a second mixture; the second mixture and the second binder are sprayed onto the outer surface of the core layer, and after drying and sieving, nicotine particles are obtained. Step C: The nicotine particles are filled into the saliva-permeable pouch as nicotine contents, and then heat-sealed to obtain the nicotine pouch.

10. The preparation method according to claim 9, characterized in that, The heat sealing temperature is 130-140℃, 140-145℃, or 145-150℃. The heat sealing time is 0.5-0.7 s, 0.7-0.8 s, or 0.8-1.0 s. The heat sealing pressure is 0.1-0.2 MPa or 0.2-0.3 MPa.

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