Nicotine pouch absorbed by oral mucosa and preparation method therefor

Abstract

The present invention relates to a nicotine pouch absorbed by oral mucosa and a preparation method therefor. The nicotine pouch comprises nicotine particles, at least one liquid-containing filter capsule and a non-woven bag. The nicotine particles and the filter capsule are packaged in the non-woven bag, and each non-woven bag contains 1-3 filter capsules. The nicotine particles have a particle size of 1-1000 μm and a moisture content ranging from 1-10% (W / W) for dry particles, a particle size of 1-1000 μm and a moisture content ranging from 5-15% (W / W) for wet particles, a particle size of 1-1000 μm and a moisture content ranging from 1-10% (W / W) for oil particles, and a particle size of 30-2500 μm and a moisture content ranging from 1-10% (W / W) for pellet particles. Provided in the present invention is a nicotine pouch absorbed by oral mucosa that can rapidly and continuously release nicotine and has a relatively long shelf life.

Description

Nicotine bag absorbed through oral mucosa and preparation method thereof Technical Field

[0001] The present invention relates to the technical field of nicotine, and in particular to a nicotine bag capable of being absorbed through the oral mucosa and a preparation method thereof. Background Art

[0002] Traditional cigarettes produce harmful smoke, and the aerosols produced by vaping e-cigarettes can also cause harm. Smokeless nicotine products are considered by the World Health Organization to be less harmful than regular cigarettes and are an ideal alternative. Since smokeless nicotine products absorb nicotine through the oral mucosa, gastrointestinal tract, respiratory tract, or skin, users can experience the physiological benefits of nicotine without the need for smoke. Nicotine pouches are a type of smokeless product. They are made by mixing nicotine base, nicotine salts, or nicotine complexes / adsorbents with fillers, dispersants, lubricants, sweeteners, flavorings, pH regulators, and adhesives to form granules. These granules are then packaged in a small non-woven fabric pouch. When a consumer uses a nicotine pouch, oral saliva moistens the pouch, releasing nicotine from the granules for absorption through the oral mucosa. The flavoring substances such as flavors and spices added to nicotine bags can not only enrich the flavor of the product, but also promote saliva secretion and increase the dissolution of effective ingredients in the product.

[0003] However, the spicy and irritating taste produced by nicotine release can cause discomfort to users. The aroma in the bag also fades over time, resulting in a different taste. To address the irritation caused by nicotine release, some have improved nicotine bag formulations. For example, patents with publication numbers CN1561214A and WO2003 / 026655 mention the use of emulsified cocoa powder for taste masking, which effectively conceals the nicotine odor and promotes rapid nicotine absorption. However, the patents do not describe the dissolution and stability of the improved nicotine.

[0004] For example, patent publication number CN114521668A claims that the addition of an emulsifier can slow the loss of flavoring substances during storage, increase the stability of flavoring substances in oral nicotine products, and improve the sensory quality of the product. However, the examples only provide the results of a six-week stability test on the effect of the addition of an emulsifier on the menthol and anethole content, without mentioning long-term stability results.

[0005] For example, patents with publication numbers CN101437496A and WO2007 / 104575 describe a nicotine-cellulose combination and one or more pharmaceutically acceptable excipients for use in preparing a lozenge composition to achieve rapid oral release of nicotine. These lozenge compositions are also described as having a shelf life exceeding 24 months. Furthermore, these patents explain that the lozenge composition is a chewing gum composition prepared from a nicotine-cellulose combination and a gum base, intended for chewing. However, these patents claim that the nicotine used is in base form, indicating that the irritation of nicotine is not effectively addressed in these lozenge compositions.

[0006] To improve user compliance, patents with publication numbers CN102076362A and WO2009 / 134947 relate to a nicotine lozenge composition that includes a lower buffer content than traditional nicotine lozenges and provides an optimal oral pH and rapid nicotine absorption in a smaller, more convenient dosage form. In one embodiment, the average in vivo dissolution time of the lozenge is approximately 10 times faster than that of traditional lozenges. However, the patents do not address the issue of improved taste.

[0007] To achieve a nicotine pouch with a pleasant taste and rapid oral absorption, patents CN104169346A and WO2013 / 109961 describe an oral nicotine product comprising a mouth-stable polymer and one or more additives. These products include a mouth-stable polymer matrix and nicotine or its derivatives dispersed within the matrix. The product utilizes an extrusion-spheronization tableting process. This product can provide a satisfying tactile and / or flavor experience while also offering a prolonged release of the additives. However, the mouth-stable polymer matrix in these nicotine pouches includes polyurethane and a large amount of plasticizer, which can affect the rapid release of nicotine. The patent descriptions do not mention dissolution data for these nicotine pouches, so we cannot assume that these nicotine pouches provide a rapid release of nicotine.

[0008] In order to solve the problem of rapid nicotine release, it is also possible to continuously release nicotine for a considerable period of time, and it is necessary to have a good taste. Patents such as publication numbers CN104271137A and WO2013 / 147687 describe a powdered nicotine oral delivery product encapsulated in a water-insoluble bag, wherein the powder includes at least nicotine and a chewing gum composition, wherein the bag is permeable to saliva and dissolves part of the powder therein, releasing part of the nicotine and part of other components, such as chewing the bag can further promote nicotine release, and continued chewing will cause the chewing gum composition in the bag to be converted into a chewing gum block, at which point the release of nicotine will be similar to a nicotine chewing gum product. Obviously, the nicotine bag is absorbed through the gastrointestinal tract in addition to being absorbed through the oral mucosa. Publication number CN112220756A discloses a nicotine granule composition, which is mainly composed of nicotine quick-release granules and nicotine sustained-release granules, to ensure the speed at which the human body obtains pleasure and the duration of nicotine concentration with therapeutic effects in the human body. Furthermore, patents CN114390922A and WO2021 / 053078 describe oral delivery products containing a nicotine benzoate / maleate-resin combination, at least one pH adjuster, and at least one filler, encapsulated in a non-woven bag. These products improve upon other commercially available nicotine pouches. Similarly, none of these patents address the question of whether nicotine irritation can be reduced.

[0009] To preserve the aroma of tobacco nicotine pouches over time without weakening due to oxidation, publication number CN111035047A provides a snus product comprising tobacco material and at least one popping bead. By encapsulating liquid substances and / or extracts that can easily cause tobacco deterioration within the popping bead, the product's stability is improved and the taste of the snus is enriched. However, this invention encapsulates the popping bead and tobacco material together within a non-woven fabric bag. While this solves the aroma retention issue, it still uses traditional plant-based tobacco, unlike modern nicotine pouches that primarily use synthetic nicotine.

[0010] The prior art has failed to provide a nicotine bag that can maintain aroma for a long time, effectively mask the irritating sensory effects of nicotine, release nicotine quickly and continuously, and has a long shelf life and can be absorbed through the oral mucosa.

[0011] Therefore, the existing technology needs to be improved. Summary of the Invention

[0012] The prior art fails to provide a nicotine pouch for oral delivery that maintains aroma for a long time, effectively masks the sensory irritation of nicotine, releases nicotine quickly and continuously, and has a long shelf life. Therefore, the present invention provides a nicotine pouch for oral mucosal absorption and a preparation method thereof to address the above-mentioned problems.

[0013] To achieve the above objectives, in a first aspect, the present invention provides a nicotine bag for oral mucosal absorption, the nicotine bag comprising nicotine particles, at least one popping bead containing liquid, and a non-woven bag, the nicotine particles and the popping bead being encapsulated in the non-woven bag, and each non-woven bag containing 1 to 3 popping beads, wherein:

[0014] The nicotine particles are dry particles, the particle size of the dry particles is 1-1000 microns, and the moisture content is in the range of 1%-10% (W / W); or

[0015] The nicotine particles are wet particles, the particle size of the wet particles is 1-1000 microns, and the moisture content is in the range of 5%-15% (W / W); or

[0016] The nicotine particles are oily particles, the particle size of the oily particles is 1-1000 microns, and the moisture content ranges from 1% to 10% (W / W); or

[0017] The nicotine particles are micro-pellet particles, the particle size of the micro-pellet particles is 30-2500 microns, and the moisture content ranges from 1% to 10% (W / W).

[0018] In one implementation, the dry particles have a particle size of 1-700 microns and a moisture content of 1%-8% (W / W); or

[0019] The wet granules have a particle size of 1-700 μm and a moisture content of 6%-15% (W / W); or

[0020] The oily particles have a particle size of 1-700 microns and a moisture content of 1%-5% (W / W); or

[0021] The particle size of the micro-pellets is 30-2000 microns, and the moisture content ranges from 1% to 8% (W / W).

[0022] In one implementation, the nicotine particles comprise one or more combinations of nicotine, sugar alcohols, cellulose and cellulose derivatives, pH regulators, binders, oily substances, sweeteners, flavors and fragrances, hydrophilic sugar-based cores and / or hydrophobic cellulose cores, polymer coating materials, and preservatives.

[0023] In one implementation, the nicotine includes nicotine and nicotine derivatives, including: free base nicotine, nicotine salts, nicotine in a matrix such as a sugar matrix or an organometallic complex, a nicotine-ion exchange resin combination, a nicotine inclusion complex, and non-covalently bound nicotine, wherein the non-covalently bound nicotine includes a mixture of one or more of nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, and nicotine benzoate; the content of nicotine base in the nicotine is 1 mg / g-80 mg / g.

[0024] In one implementation, the dry granule material does not contain oily substances, does not contain hydrophilic sugar-based pellet cores and / or hydrophobic cellulose pellet cores; the wet granule material contains or does not contain oily substances, does not contain hydrophilic sugar-based pellet cores and / or hydrophobic cellulose pellet cores; the oily granule material contains oily substances, does not contain hydrophilic sugar-based pellet cores and / or hydrophobic cellulose pellet cores; the micropellet material contains or does not contain oily substances, contains or does not contain hydrophilic sugar-based pellet cores and / or hydrophobic cellulose pellet cores.

[0025] In one implementation, the sugar alcohol is a polyol containing two or more hydroxyl groups used as a thickener, binder and / or sweetener or stabilizer, and the sugar alcohol includes one or more combinations of propylene glycol, xylitol, maltitol, mannitol, erythritol, isomalt and lactitol, and the content of the sugar alcohol is 3%-30% (W / W).

[0026] In one implementation, the cellulose and cellulose derivatives used as fillers, dispersants, and sustained-release materials include one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and ethyl cellulose, and the content of the cellulose and cellulose derivatives is 40%-85% (W / W).

[0027] In one implementation, the cellulose and cellulose derivatives have a water binding capacity of at least 200%, and the cellulose and cellulose derivatives can be partially or completely dissolved in the nicotine pouch.

[0028] In one embodiment, the pH adjuster includes one or more combinations of monocarbonate, bicarbonate and carbonate, acetate, lactate, glycinate, gluconate, borate, sulfate, glycerophosphate and citrate, and the content of the pH adjuster is 0.5%-20% (W / W).

[0029] In one implementation, the binder includes one or more combinations of povidone, cellulose derivatives, pregelatinized starch, syrup, gelatin, gum arabic, sodium alginate, and polyethylene glycol, and the content of the binder is 0%-10% (W / W).

[0030] In one implementation, the oily substance is a lipid substance or a substance with emulsifying ability, and the emulsifier, dispersant, and wetting agent used include one or more combinations of glycerol, fatty acids with carbon ion numbers of 6-24 (C6-C24), monostearate, sucrose esters, soybean lecithin, egg yolk lecithin, glycocholic acid, Tween, and various vegetable oils. The content of the oily substance is 0%-25% (W / W).

[0031] In one implementation, the sweetener includes one or more combinations of aspartame, acesulfame potassium, cyclamate, saccharin, saccharin sodium, sucralose, neotame, sodium cyclamate, stevia, licorice, disodium glycyrrhizate, tripotassium and trisodium glycyrrhizate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar and lactose, sorbitol, maltitol, isomalt, palatinitol, xylitol, lactitol, mannitol, erythritol and dextran, and the content of the sweetener is 0.2%-10% (W / W).

[0032] In one implementation, the flavors and fragrances include one or more combinations of bergamot flavor, eucalyptus flavor, citrus flavor, lemon flavor, peppermint flavor, mint flavor, menthol, licorice flavor, wintergreen flavor, tobacco flavor, coffee flavor, vanilla flavor, lime flavor, apple flavor, peach flavor, mango flavor, cherry flavor, blueberry flavor, strawberry flavor, cola flavor, cinnamon flavor and watermelon flavor, and the content of the flavors and fragrances is 2%-10% (W / W).

[0033] In one implementation, the diameter of the hydrophilic sugar-based pellet core and / or the hydrophobic cellulose pellet core is less than 1000 microns, the hydrophilic sugar-based pellet core is a sucrose blank pellet core or a starch blank pellet core, the hydrophobic cellulose pellet core is a microcrystalline cellulose blank pellet core, and the content of the hydrophilic sugar-based pellet core and / or the hydrophobic cellulose pellet core is 20%-90% (W / W).

[0034] In one implementation, the polymer coating material includes a sugar material or a polymer material, the sugar material includes one or more combinations of syrup, colored syrup, mucilage, talc or white wax, the polymer material includes one or more combinations of cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose and hydroxypropyl cellulose, ethyl cellulose, methacrylic acid copolymer, methacrylate copolymer, and cellulose acetate phthalate, and the content of the polymer coating material is 5%-15% (W / W).

[0035] In one implementation, the preservative includes one or more combinations of sorbic acid and its salts, dehydroacetic acid and its sodium salts, parabens, sodium diacetate, calcium propionate, and sodium / calcium lactate, and the content of the preservative is 0.1%-2% (W / W).

[0036] In one implementation, the bursting bead includes a packaging substance and a liquid substance contained in the packaging substance, and the diameter of the bursting bead is ≤10 mm.

[0037] In one implementation, the packaging material includes one or more of the following two materials:

[0038] (1) Edible materials made from one or more of alginate, carrageenan, sodium cellulose sulfate, chitosan, bovine gelatin, pectin, and wax;

[0039] (2) Materials that dissolve in the oral cavity, made from one or more of sugar coating, starch, and hydroxypropyl methylcellulose;

[0040] (3) Plastic materials made of one or more of PP, PET, PE, HDPE, LDPE, PC and PS.

[0041] In one implementation, the liquid substance includes one or more of a cooling agent, an acidity regulator, an anticaking agent, an antioxidant, a colorant, a flavor enhancer, a humectant, a preservative, or a sweetener.

[0042] In a second aspect, the present invention further provides a method for preparing a nicotine bag, which is used to prepare the above-mentioned nicotine bag for oral mucosal absorption, and the specific steps include:

[0043] S1. Weighing the raw materials of the nicotine bag;

[0044] S2. Put the materials into a wet granulator, fluidized bed granulator or centrifugal granulator in sequence according to the prescription for granulation and / or coating;

[0045] S3. placing the nicotine granules obtained by granulation into a drying oven or a fluidized bed for drying or coating;

[0046] S4. Transfer the dried nicotine granules to a granule packaging machine, add the popping beads and the non-woven fabric roll at the same time, put the nicotine granules and the popping beads into the non-woven fabric bag, and package them to obtain the nicotine bag.

[0047] In one implementation, the granulation particles in S2 have a particle size of 20-40 mesh, the drying temperature in S3 is 40-60°C, the transverse sealing temperature of the packaging in S4 is 160-200°C, and the longitudinal sealing temperature is 200-360°C.

[0048] Beneficial effects: The nicotine bag for oral mucosal absorption provided by the present invention and the preparation method thereof, encapsulates the nicotine particles and the popping beads by non-woven fabric, and controls the moisture content in the nicotine particles to ensure the long-term stability of the nicotine particles. At the same time, the popping beads added quickly disintegrate in saliva, and their disintegration time is basically the same as the time it takes for the nicotine in the nicotine particles to release nicotine and reach the mucosal irritation, which can effectively mask the irritation caused by nicotine and enhance the aroma in the nicotine particles; when multiple popping beads are used, in addition to the taste masking effect, the popping beads of different flavors will quickly mix to form a variety of flavors, improving the user experience; the nicotine bag provided by the present invention has a shelf life of at least 24 months at room temperature, and has better stability. The present invention provides a nicotine bag for oral mucosal absorption that maintains aroma for a long time, can effectively mask the irritating sense of nicotine, can quickly release nicotine, can also continuously release nicotine, and can have a long shelf life. DETAILED DESCRIPTION

[0049] [Corrected 23.04.2024 according to Rule 91] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention is further described in detail in conjunction with the following embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the descriptions of the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" described below mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0050] The present invention provides a nicotine bag for absorption through the oral mucosa, the nicotine bag comprising nicotine particles, at least one popping bead containing liquid and a non-woven bag, the nicotine particles and the popping bead being encapsulated in the non-woven bag, and each non-woven bag containing 1 to 3 popping beads, wherein:

[0051] The nicotine particles are dry particles, the particle size of the dry particles is 1-1000 microns, and the moisture content is in the range of 1%-10% (W / W); or

[0052] The nicotine particles are wet particles, the particle size of the wet particles is 1-1000 microns, and the moisture content is in the range of 5%-15% (W / W); or

[0053] The nicotine particles are oily particles, the particle size of the oily particles is 1-1000 microns, and the moisture content ranges from 1% to 10% (W / W); or

[0054] The nicotine particles are micro-pellet particles, the particle size of the micro-pellet particles is 30-2500 microns, and the moisture content ranges from 1% to 10% (W / W).

[0055] Among them, dry granules are characterized by dry particles and good fluidity; wet granules are characterized by damp particles and poor fluidity; oily granules are characterized by damp particles and good fluidity; and micropellet granules are characterized by dry particles, small balls, and good fluidity. Preferably, the dry granules have a particle size of 1-700 microns and a moisture content of 1%-8% (W / W); the wet granules have a particle size of 1-700 microns and a moisture content of 6%-15% (W / W); the oily granules have a particle size of 1-700 microns and a moisture content of 1%-5% (W / W); and the micropellet granules have a particle size of 30-2000 microns and a moisture content of 1%-8% (W / W).

[0056] That is to say, the nicotine bag for oral mucosal absorption provided by the present invention includes four modes, namely, bursting beads and nicotine dry particles, bursting beads and nicotine wet particles, bursting beads and nicotine oily particles, and bursting beads and nicotine micro-pellets. Among them, the material of the dry particles does not contain oily substances, does not contain hydrophilic sugar-based pellets and / or hydrophobic cellulose pellets. The material of the wet particles contains or does not contain oily substances, does not contain hydrophilic sugar-based pellets and / or hydrophobic cellulose pellets. The material of the oily particles contains oily substances, does not contain hydrophilic sugar-based pellets and / or hydrophobic cellulose pellets. The material of the micro-pellets contains or does not contain oily substances, contains or does not contain hydrophilic sugar-based pellets and / or hydrophobic cellulose pellets. The micro-pellets can have the effect of rapidly releasing nicotine or slowly releasing nicotine, or both.

[0057] Furthermore, the nicotine particles contain one or more combinations of nicotine, sugar alcohols, cellulose and cellulose derivatives, pH regulators, binders, oily substances, sweeteners, flavors and fragrances, hydrophilic sugar-based cores and / or hydrophobic cellulose cores, polymer coating materials, and preservatives.

[0058] Specifically, the nicotine refers to any form of nicotine and nicotine derivatives, including nicotine and nicotine derivatives, including: free base nicotine, nicotine salts, nicotine in a matrix such as a sugar matrix or an organic metal complex, a nicotine-ion exchange resin combination, a nicotine inclusion complex and non-covalently bound nicotine, the non-covalently bound nicotine includes nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, nicotine benzoate or one or more mixtures; the content of nicotine base in the nicotine is 1 mg / g-80 mg / g. Preferably, the nicotine comprises one or more combinations of nicotine base, nicotine tartrate dihydrate, nicotine cyclodextrin embedded complex, nicotine-resin complex and nicotine benzoate.

[0059] Specifically, the sugar alcohol is a polyol containing two or more hydroxyl groups and used as a thickener, binder, and / or sweetener or stabilizer. The sugar alcohol includes one or more combinations of propylene glycol, xylitol, maltitol, mannitol, erythritol, isomalt, and lactitol, and the content of the sugar alcohol is 3%-30% (W / W). Preferably, the sugar alcohol is one or more combinations of maltitol, xylitol, mannitol, and propylene glycol.

[0060] Specifically, the cellulose and cellulose derivatives are insoluble fibers primarily selected from wheat fiber, pea fiber, rice fiber, corn fiber, oat fiber, tomato fiber, barley fiber, rye fiber, beet fiber, buckwheat fiber, potato fiber, cellulose fiber, apple fiber, cocoa fiber, bran fiber, bamboo fiber, powdered cellulose, and combinations thereof. The cellulose and cellulose derivatives include one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and ethyl cellulose, with the cellulose and cellulose derivative content ranging from 40% to 85% (w / w). The cellulose and cellulose derivatives have a water binding capacity of at least 200%, are partially or fully soluble in the nicotine pouch, and are permeable to saliva.

[0061] Specifically, the pH adjuster includes one or more combinations of monocarbonate, bicarbonate and carbonate, acetate, lactate, glycinate, gluconate, borate, sulfate, glycerophosphate, and citrate, and the content of the pH adjuster is 0.5%-20% (W / W). Preferably, the pH adjuster component is one or more combinations of monocarbonate, bicarbonate and carbonate, lactate, monohydrogen phosphate, and dihydrogen phosphate.

[0062] Specifically, the binder includes one or more combinations of povidone, cellulose derivatives, pregelatinized starch, syrup, gelatin, gum arabic, sodium alginate, and polyethylene glycol, and the content of the binder is 0%-10% (W / W). Preferably, the binder is one or more combinations of sodium alginate, cellulose derivatives, and povidone.

[0063] Specifically, the oily substance refers to a pharmaceutically acceptable lipid or emulsifying substance. Specifically, the oily substance includes one or more combinations of glycerol, fatty acids with carbon ions between 6 and 24 (C6-C24), glyceryl monostearate, sucrose esters, soybean lecithin, egg yolk lecithin, glycocholic acid, Tween, and various vegetable oils, with the content of the oily substance ranging from 0% to 25% (W / W). Preferably, the oily substance is one or more combinations of propylene glycol, glycerol, and medium-chain fatty acids (C6-C12).

[0064] Specifically, the sweetener refers to a synthetic and / or naturally extracted sweetener. The sweetener includes one or more combinations of aspartame, acesulfame potassium, cyclamate, saccharin, saccharin sodium, sucralose, neotame, sodium cyclamate, aspartame, alitame, stevia, licorice, disodium glycyrrhizate, tripotassium and trisodium glycyrrhizate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar and lactose, sorbitol, maltitol, isomalt, palatinol, xylitol, lactitol, mannitol, erythritol, and dextran. The content of the sweetener is 0.2%-10% (w / w). Preferably, the sweetener is one or more combinations of mannitol, xylitol, maltitol, acesulfame potassium, neotame, and sucralose.

[0065] Specifically, the flavors and fragrances refer to substances with a certain aroma and fragrance composed of compounds such as hydrocarbons, alcohols, acids, esters, lactones, ethers, aldehydes, ketones, acetals, ketals, phenols, macrocyclic, polycyclic, heterocyclic (containing nitrogen, oxygen, and sulfur elements), halides, and nitriles. Specifically, the flavors and fragrances include one or more combinations of bergamot flavor, eucalyptus flavor, citrus flavor, lemon flavor, peppermint flavor, mint flavor, menthol, licorice flavor, wintergreen flavor, tobacco flavor, coffee flavor, vanilla flavor, lime flavor, apple flavor, peach flavor, mango flavor, cherry flavor, blueberry flavor, strawberry flavor, cola flavor, cinnamon flavor, and watermelon flavor. The content of the flavors and fragrances is 2%-10% (W / W).

[0066] Specifically, the hydrophilic sugar-based core and / or hydrophobic cellulose core refer to the masterbatch necessary for the production of skeleton-type micropellets. These cores are spherical or quasi-spherical solids with a diameter of less than 1000 microns. Specifically, the hydrophilic sugar-based core and / or hydrophobic cellulose core have a diameter of less than 1000 microns. The hydrophilic sugar-based core is a sucrose blank core or a starch blank core, while the hydrophobic cellulose core is a microcrystalline cellulose blank core. The hydrophilic sugar-based core and / or hydrophobic cellulose core content is 20%-90% (w / w). The preferred diameter is between 0.1 mm and 1.5 mm. Preferably, the hydrophilic sugar-based core and / or hydrophobic cellulose core are either hydrophilic sucrose core or hydrophobic microcrystalline cellulose.

[0067] Specifically, the polymer coating material refers to a sugar or hydrophilic / hydrophobic polymer material coated on a solid surface, forming one or more layers of a multifunctional protective layer of varying thickness and elasticity that adheres tightly to the surface. The polymer coating material includes a sugar material or a polymer material. The sugar material includes one or more combinations of syrup, colored syrup, mucilage, talc, or white wax. The polymer material includes one or more combinations of cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and ethyl cellulose, methacrylic acid copolymers, methacrylate copolymers, and cellulose acetate phthalate. The polymer coating material content is 5%-15% (w / w). Preferably, the polymer coating material is one or more combinations of polymer materials soluble above pH 4.7, such as cellulose acetate, hydroxypropyl methylcellulose, polyvinyl alcohol ester, copolymers of methacrylic acid and methyl methacrylate, and styrene-maleic acid copolymers.

[0068] Specifically, the preservative includes one or more combinations of sorbic acid and its salts, dehydroacetic acid and its sodium salt, parabens, sodium diacetate, calcium propionate, and sodium / calcium lactate, with the content of the preservative being 0.1%-2% (W / W). Preferably, the preservative is one or more combinations of parabens, lactates, and sorbic acid and its salts.

[0069] Specifically, the popping bead includes a packaging material and a liquid material contained in the packaging material, and the diameter of the popping bead is ≤10 mm.

[0070] The packaging material includes one or more of the following two materials:

[0071] (1) Edible materials made from one or more of alginate, carrageenan, sodium cellulose sulfate, chitosan, bovine gelatin, pectin, and wax;

[0072] (2) Materials that dissolve in the oral cavity, made from one or more of sugar coating, starch, and hydroxypropyl methylcellulose;

[0073] (3) Plastic materials made of one or more of PP, PET, PE, HDPE, LDPE, PC and PS.

[0074] Preferably, the encapsulating material is one or more combinations of alginate, carrageenan, sodium cellulose sulfate, chitosan, gelatin, pectin and wax.

[0075] The liquid substance comprises one or more of a cooling agent, an acidity regulator, an anticaking agent, an antioxidant, a colorant, a flavor enhancer, a moisture retainer, a preservative or a sweetener.

[0076] Among them, the popping beads can be one or more, and the popping beads quickly disintegrate in saliva. The disintegration time is basically the same as the time when nicotine in the nicotine particles is released to reach the mucosal irritation, which can effectively mask the irritation caused by nicotine and enhance the aroma in the nicotine particles. When multiple popping beads are used, in addition to the above-mentioned taste-masking effect, popping beads of different flavors will quickly mix to form multiple flavors, thereby improving the user experience.

[0077] The present invention also provides a method for preparing a nicotine bag, which is used to prepare the above-mentioned nicotine bag absorbed through the oral mucosa, and the specific steps include:

[0078] S1. Weighing the raw materials of the nicotine bag;

[0079] S2. Put the materials into a wet granulator, fluidized bed granulator or centrifugal granulator in sequence according to the prescription for granulation and / or coating;

[0080] S3. placing the nicotine granules obtained by granulation into a drying oven or a fluidized bed for drying or coating;

[0081] S4. Transfer the dried nicotine granules to a granule packaging machine, add the popping beads and the non-woven fabric roll at the same time, put the nicotine granules and the popping beads into the non-woven fabric bag, and package them to obtain the nicotine bag.

[0082] Among them, the particle size of the granulated particles in S2 is 20-40 mesh, the drying temperature in S3 is 40-60℃, the horizontal sealing temperature of the packaging in S4 is 160-200℃, and the vertical sealing temperature is 200-250℃.

[0083] Specifically, the four production processes of the nicotine pouch for oral mucosal absorption provided by the present invention are described as follows:

[0084] Production process of combination 1:

[0085] S11, material weighing;

[0086] S12. The materials are sequentially placed into a wet granulator according to the recipe for granulation. The preferred process parameter is that the granules after granulation need to be sieved through a 20-40 mesh screen;

[0087] S13, Drying process: Place the granulated nicotine granules into a drying oven or fluidized bed for drying. The preferred process parameters are drying at a temperature of 40-60°C;

[0088] In step S14, the dried nicotine granules are transferred to the powder hopper of the granule packaging machine. The weighed popping beads according to the prescribed amount are also placed into the popping bead hopper of the granule packaging machine, and the non-woven fabric roll is placed into the film roll hopper of the granule packaging machine. The granule packaging machine is then started to perform the filling and packaging processes. The preferred process parameters for packaging are a horizontal sealing temperature of 160-180°C and a vertical sealing temperature of 200-230°C.

[0089] Production process of combination 2:

[0090] S21, material weighing;

[0091] S22. The materials are sequentially placed into a wet granulator according to the recipe for granulation. The preferred process parameter is that the granules after granulation need to be sieved through a 20-40 mesh screen;

[0092] S23. Transfer the nicotine oily granules that meet the requirements into the powder hopper of the granule packaging machine. Also, place the weighed popping beads according to the prescribed amount into the popping bead hopper of the granule packaging machine, and place the non-woven fabric roll into the film roll hopper of the granule packaging machine. Start the granule packaging machine to begin the filling and packaging process. The preferred process parameters are a horizontal sealing temperature of 160-180°C and a vertical sealing temperature of 200-230°C during packaging.

[0093] Production process of combination 3:

[0094] S31, material weighing;

[0095] S32. The materials are sequentially placed into a wet granulator according to the recipe for granulation. The preferred process parameter is that the granules after granulation need to be sieved through a 20-40 mesh screen;

[0096] S33. Transfer the nicotine wet granules that meet the requirements into the powder hopper of the granule packaging machine. Also, place the weighed popping beads according to the prescribed amount into the popping bead hopper of the granule packaging machine, and place the non-woven fabric roll into the film roll hopper of the granule packaging machine. Start the granule packaging machine to begin the filling and packaging process. The preferred process parameters are a horizontal sealing temperature of 160-180°C and a vertical sealing temperature of 200-230°C during packaging.

[0097] Production process of composition 4:

[0098] S41, material weighing;

[0099] S42. According to the sustained-release function, it is divided into ① fluidized pelletizing process: the polymer coating material and the materials are prepared and put into the spray gun hopper, and the weighed solid materials including the pill cores are put into the solid hopper of the fluidized bed or centrifugal granulator in sequence according to the prescription, and the machine is turned on to perform fluidized bed granulation coating or centrifugal granulation coating process, and the material is evenly wrapped on the pill core to form one or more layers of material layer. This process is suitable for producing nicotine pellets that achieve sustained-release effects through functional coatings. Secondly, the extrusion and spheronization process involves feeding various materials into a granulator according to the recipe to create a wet material. This material is then transferred to an extruder, where it is forced through holes or sieves of a certain diameter through screw propulsion or rolling, resulting in a cylindrical extrudate. This extrudate is then deposited onto the spheronizer's rotating friction plate, where it is dispersed into smaller cylinders of a length equivalent to its diameter. These cylinders are then gradually rolled into spheres through continuous rolling friction. The resulting spherical composition is then dried. The dried spherical composition can then be coated and transferred to the next process, or it can be transferred directly to the next process without coating. This process is suitable for producing nicotine particles that achieve sustained-release effects in a skeleton form.

[0100] S43. Transfer the dried nicotine granules to the powder hopper of the granule packaging machine. Also, place the weighed popping beads according to the prescribed amount into the popping bead hopper of the granule packaging machine, and place the non-woven fabric roll into the film roll hopper of the granule packaging machine. Start the granule packaging machine to begin the filling and packaging process. The preferred process parameters are a horizontal sealing temperature of 160-180°C and a vertical sealing temperature of 200-230°C during packaging.

[0101] The present invention is evaluated through multiple embodiments:

[0102] Example 1

[0103] Equal doses (calculated as nicotine base) of nicotine tartrate dihydrate, nicotine-β-cyclodextrin complex, nicotine benzoate, and nicotine base were mixed with equal doses of microcrystalline cellulose, povidone, xylitol, sodium carbonate, and sodium bicarbonate to form granules. Sensory evaluation of the various nicotine derivatives and nicotine was conducted to assess their headiness and irritation. The results are shown in Table 1.

[0104]

[0105] Table 1 Sensory evaluation of different nicotine derivatives

[0106] From the results in Table 1, it can be seen that nicotine tartrate dihydrate and nicotine-β-cyclodextrin complex are superior to nicotine base and nicotine benzoate in terms of odor and irritation in the sensory evaluation. They also perform better than nicotine benzoate in terms of the feeling of being drunk. In addition, nicotine tartrate dihydrate and nicotine-β-cyclodextrin complex are both solid and easier to preserve.

[0107] Example 2

[0108] Comparing the bulk density (expressed as Carr's index) of nicotine pouches with different formulations was used to determine the flowability of the composition. Flowability is crucial for determining whether the granules can be smoothly transferred into the non-woven bag. The formulation composition and bulk density results are shown in Table 2.

[0109]

[0110] Table 2 Prescription composition of different nicotine pouches

[0111] Prescriptions A and B correspond to dry nicotine granules, Prescriptions C and D correspond to wet nicotine granules, and Prescriptions E and F correspond to oily nicotine granules. Table 2 shows that the Carr Index for Prescriptions A, C, and E is less than 15%, indicating that each formulation has excellent flowability.

[0112] Example 3

[0113] Different sweeteners and flavors were added to Recipes A, C, and E in Table 2, and their palatability was evaluated using artificial sensory testing. The results are shown in Table 3.

[0114]

[0115] Table 3 Evaluation results of different sweeteners and flavors

[0116] The evaluation results show that neotame and acesulfame potassium are better than sucralose and have higher sweetness.

[0117] Example 4

[0118] A graph showing the in vitro release of one of the nicotine pellets of the present invention is shown in Table 4.

[0119]

[0120] Table 4 In vitro dissolution data of nicotine micropellets

[0121] Example 5

[0122] One embodiment provided by the present invention compares the disintegration time of popping beads with the nicotine release time. Artificial saliva was placed in a 36-37°C water bath with a pH of 6.8. One popping bead of each material was immersed in the artificial saliva, and the disintegration time of each bead was recorded. Similarly, two nicotine bags described in the present invention were placed in the artificial saliva, and samples were taken every minute to measure the nicotine release. The results are shown in Table 5.

[0123]

[0124] Table 5 Comparison of disintegration time of popping beads and nicotine release time

[0125] The results in Table 5 show that the irritation of nicotine depends on the concentration of nicotine release. When the nicotine release reaches about 40%, people will feel obvious mucosal irritation. The time point when the nicotine particles described in the present invention reach mucosal irritation is basically about 5 minutes (except for nicotine micropellets). Some materials of popping beads also disintegrate in about 5 minutes, which is just enough to effectively mask the irritation of nicotine. Different materials of popping beads will cause them to disintegrate at different times. This means that if more than one popping bead is placed in the same nicotine bag, they will disintegrate at different times during use and release different flavors, bringing different taste sensations. This is a design that has not been seen in previous products.

[0126] Example 6

[0127] The production process of nicotine bags combining dry nicotine particles and popping beads, the formula composition of one of the products, and its in vitro dissolution and sensory evaluation.

[0128] Production process description: processing of raw materials and auxiliary materials (weighing and screening) → granulation (wet granulation) → boiling drying → granulation → granule packaging → filling with popping beads → edge sealing → several tablets packed in boxes.

[0129] Step 1: Weigh and sieve the materials. Pass nicotine tartrate dihydrate and xylitol through a 60-mesh sieve; pass microcrystalline cellulose, sodium bicarbonate, sodium carbonate, and neotame through a 40-mesh sieve.

[0130] Step 2: Granulation. Dissolve menthol in purified water, then add sodium alginate and stir until completely dissolved. Then, add flavoring, cooling agent, and ethyl paraben to the solution and continue stirring until uniformly dissolved. This will serve as the granulation binder. ① Add the sieved nicotine tartrate dihydrate, xylitol, microcrystalline cellulose, sodium bicarbonate, sodium carbonate, and neotame to the wet granulator. ② Mix these materials at a stirring speed of 100 rpm and shear off for 10 minutes. Add the granulation binder and set the stirring speed to 100 rpm with shear off. Slowly and evenly add the granulation binder solution to the granulator over approximately 4-6 minutes. After the binder is added, stop the granulator and scrape off the walls and impellers. Set the stirring speed to 100 rpm and shear off. Continue stirring for approximately 2 minutes. Then begin granulation at a stirring speed of 150 rpm and shear of 1500 rpm. Granulate for 2-3 minutes before discharging. Pass through a 20-mesh sieve and proceed to the next drying step.

[0131] Step 3: Drying: The inlet air temperature is 50°C, the humidity is 55%, the material temperature is 45°C, and the drying time is 30 minutes. After the material is discharged, it is sieved through 20 mesh and 100 mesh to obtain dry nicotine particles.

[0132] Step 4: Granule Packaging. Add the granulated material to the powder hopper of the granule packaging machine, place the popping beads into the popping bead hopper, and place the non-woven fabric into the film roll hopper for granule packaging. Granule packaging machine parameters: Speed ​​set to 120 pellets / minute, 1 popping bead per bag, horizontal sealing temperature set to 170°C, vertical sealing temperature set to 210°C. Each bag contains dry nicotine granules and one popping bead.

[0133] The prescription of the nicotine pouch is shown in Table 6.

[0134]

[0135] Table 6 Lemon-flavored nicotine dry granules + popping beads nicotine bag formula composition

[0136] The in vitro dissolution data of the nicotine dry particles in the nicotine pouch and the results of the burst bead disintegration time experiment are shown in Table 7.

[0137]

[0138] Table 7 In vitro dissolution data and disintegration time of nicotine dry granules

[0139] As can be seen in Table 7, when 40% of the nicotine is released, the body directly experiences a strong irritation of the oral mucosa. At this point, the popping beads completely disintegrate, masking the intense nicotine irritation. This irritation, combined with the flavoring in the dry nicotine granules, creates a new flavor. Table 7 describes the sensory evaluation of the irritation and flavor changes of the nicotine pouches. The evaluation was conducted by eight experienced assessors, each of whom placed a nicotine pouch on the upper lip and gums of the mouth and recorded the time and flavor of the aroma changes.

[0140]

[0141] Table 8 Sensory evaluation of the nicotine pouch

[0142] The results of Example 6 show that the nicotine pouch, which is composed of dry nicotine particles and popping beads containing flavors, has a good nicotine release effect. The popping beads disintegrate and effectively mask the irritation of nicotine. They also mix with the flavors in the dry nicotine particles to produce new flavors, allowing users to experience different flavor changes.

[0143] Implementation 7

[0144] This paper describes the production process of nicotine bags composed of nicotine wet granules and explosive beads, the formulation composition of one of the products, and its in vitro dissolution and sensory evaluation.

[0145] Production process description: processing of raw materials and auxiliary materials (weighing and screening) → granulation (wet granulation) → granulation → granule packaging → filling with popping beads → edge sealing → several tablets packed in boxes.

[0146] Step 1: Weigh and sieve the materials. Pass nicotine tartrate dihydrate and mannitol through a 60-mesh sieve; pass microcrystalline cellulose, calcium lactate, sodium bicarbonate, sodium carbonate, and acesulfame potassium through a 40-mesh sieve.

[0147] Step 2: Granulation. Dissolve propylene glycol and glycerin in purified water, then add sodium alginate and stir until completely dissolved. Add flavoring and cooling agents to the solution and continue stirring to form the aqueous binder. Then, ① add the sieved nicotine tartrate dihydrate, mannitol, microcrystalline cellulose, calcium lactate, sodium bicarbonate, sodium carbonate, and acesulfame potassium to a wet granulator. ② Mix the above materials at a stirring speed of 150 rpm and shear off for 10 minutes. Add the aqueous binder and set the stirring speed to 150 rpm with shear off. Slowly and evenly add the aqueous binder solution to the granulator over approximately 4-6 minutes. After the aqueous binder is added, stop the granulator, scrape the material off the walls and impeller, set the stirring speed to 150 rpm and shear off, continue stirring for approximately 2 minutes, and begin granulation. Granulate at a stirring speed of 200 rpm and shear of 1500 rpm for 2-3 minutes. Discharge the granules and pass through a 20-mesh sieve to obtain nicotine wet granules.

[0148] Step 3: Granule Packaging. Add the granulated material to the powder hopper of the granule packaging machine, place the popping beads in the popping bead hopper, and place the non-woven fabric in the film roll hopper to begin granule packaging. Granule packaging machine parameters: Speed ​​set to 120 pellets / minute, 2 popping beads per bag, horizontal sealing temperature set to 170°C, vertical sealing temperature set to 210°C. Each bag contains wet nicotine granules and at least one popping bead.

[0149] The prescription of the nicotine pouch is shown in Table 9.

[0150]

[0151] Table 9 Composition of white lemon flavored nicotine wet granules + cinnamon flavored popping beads + soda water flavored popping beads nicotine bag formula

[0152] The in vitro dissolution data of the nicotine wet granules in the nicotine pouch and the results of the burst bead disintegration time experiment are shown in Table 10.

[0153]

[0154] Table 10 In vitro dissolution data and disintegration time of nicotine wet granules

[0155] As can be seen from Table 10, when 40% of the nicotine is released, the human body will directly feel the strong stimulation of nicotine on the oral mucosa. At this time, the popping bead 1 completely disintegrates, just covering up the strong stimulation of nicotine and mixing with the flavor in the nicotine wet granules to form a new flavor. Immediately afterwards, the popping bead 2 also disintegrates, mixing with the other flavors in the popping bead 1 and the nicotine wet granules to form a new flavor. Table 11 describes the evaluation of the irritation and taste changes of the nicotine pouches through manual sensory evaluation. The method is to have 8 experienced assessors perform the evaluation. Each assessor places a nicotine pouch on the upper lip and gums of the mouth and records the time and flavor of the nicotine pouch's aroma changes.

[0156]

[0157] Table 11 Sensory evaluation of the nicotine pouch

[0158] The results of Example 7 demonstrate that the nicotine pouch, composed of moist nicotine granules and at least one popping bead containing a flavoring, exhibits excellent nicotine release. The disintegration of the popping bead not only effectively masks the irritation of nicotine but also blends with the flavoring in the moist nicotine granules to produce new flavors. Furthermore, the flavors vary as different popping beads disintegrate, allowing users to experience a variety of flavors.

[0159] Example 8

[0160] The production process of nicotine bags that combine nicotine oily particles and explosive beads, the formula composition of one of the products, and its in vitro dissolution and sensory evaluation.

[0161] Production process description: processing of raw materials and auxiliary materials (weighing and screening) → granulation (wet granulation) → granulation → granule packaging → filling with popping beads → edge sealing → several tablets packed in boxes.

[0162] Step 1: Weigh and sieve the materials. Pass the nicotine-β-cyclodextrin complex and maltitol through a 60-mesh sieve; pass the microcrystalline cellulose, calcium lactate, sodium carbonate, and acesulfame potassium through a 40-mesh sieve.

[0163] Step 2: Granulation. Dissolve medium-chain triglycerides, propylene glycol, and glycerin in purified water, then add the flavoring and continue stirring to form an oil phase solution. Then, ① add the screened nicotine-β-cyclodextrin complex, maltitol, microcrystalline cellulose, calcium lactate, sodium carbonate, and acesulfame potassium to a wet granulator. ② Mix these materials at a stirring speed of 150 rpm and shear off for 10 minutes. Add the oil phase solution, set the stirring speed to an actual speed of 150 rpm, and turn off the shear. Slowly and evenly add the oil phase solution to the granulator over approximately 4-6 minutes. After the oil phase solution is added, stop the machine and scrape off the material on the walls and impellers. Set the stirring speed to 100 rpm and shear off. Continue stirring for approximately 2 minutes, then begin granulation. Stir at a stirring speed of 150 rpm and shear off at 2000 rpm. Granulate for 2-3 minutes before discharging. Pass the granules through a 20-mesh sieve to obtain nicotine oily granules.

[0164] Step 3: Granule Packaging. Add the granulated material to the powder hopper of the granule packaging machine, place the popping beads in the popping bead hopper, and place the non-woven fabric in the film roll hopper to begin granule packaging. Granule packaging machine parameters: Speed ​​set to 120 pellets / minute, 1 popping bead per bag, horizontal sealing temperature set to 170°C, vertical sealing temperature set to 210°C. Each bag contains nicotine oily granules and at least one popping bead.

[0165] The prescription of the nicotine pouch is shown in Table 12.

[0166]

[0167] Table 12: Composition of grape-flavored nicotine oily particles + chocolate-flavored popping beads nicotine bag formula

[0168] The in vitro dissolution data of the nicotine oily particles in the nicotine pouch and the results of the burst bead disintegration time experiment are shown in Table 13.

[0169]

[0170] Table 13 In vitro dissolution data and disintegration time of nicotine oily particles

[0171] As can be seen in Table 13, when 40% of the nicotine is released, the human body directly experiences a strong irritation of the oral mucosa. At this point, the popping beads completely disintegrate, masking the intense nicotine irritation. This, combined with the flavoring in the nicotine oil particles, creates a new flavor. Table 14 describes the evaluation of the irritation and flavor changes of the nicotine pouches through manual sensory testing. The evaluation was conducted by eight experienced assessors, each of whom placed a nicotine pouch on the upper lip and gums of the mouth and recorded the time and flavor of the nicotine pouch's aroma changes.

[0172]

[0173] Table 14 Sensory evaluation of the nicotine pouch

[0174] The results of Example 8 show that the nicotine pouch is composed of nicotine oil particles and popping beads containing flavors, and has a good nicotine release effect. The popping beads can effectively mask the irritation of nicotine after disintegration, and can also mix with the flavors in the nicotine oil particles to produce new flavors, allowing users to experience different flavor changes.

[0175] Example 9

[0176] The production process of nicotine bags containing nicotine micropellets and explosive beads, the formulation composition of one of the products, and its in vitro dissolution and sensory evaluation were tested.

[0177] Production process description: processing of raw materials and auxiliary materials (weighing and screening) → pelleting → granule packaging → loading of blasting beads → edge sealing → packing of several pellets into boxes.

[0178] Step 1: Weigh and sieve the materials. Pass nicotine tartrate dihydrate, ethyl cellulose, and talc through a 40-mesh sieve separately.

[0179] Step 2: Fluidized pelletizing process: ① Ethyl cellulose, magnesium stearate and methanol are mixed in a fluidized bed and the sugar pills are coated with an isolation coat to obtain isolation layer micropills; ② Nicotine tartrate dihydrate is then dissolved in methanol, mixed with povidone and polysorbate 80, and then coated with the isolation layer micropills in a fluidized bed to obtain drug-containing layer micropills 1; ③ Nicotine tartrate dihydrate is dissolved in methanol, mixed with povidone and magnesium stearate, and then coated on the drug-containing layer sustained-release micropills 1 to obtain drug-containing layer micropills 2; ④ Methacrylic acid / ethyl acrylate copolymer, triethyl citrate and purified water are prepared into a coating solution, and the drug-containing layer micropills 2 are coated with a functional film coat on the fluidized bed to obtain nicotine micropill particles.

[0180] Step 3: Granule Packaging. Add the granulated material to the powder hopper of the granule packaging machine, place the popping beads in the popping bead hopper, and place the non-woven fabric in the film roll hopper to begin granule packaging. Granule packaging machine parameters: Speed ​​set to 120 pellets / minute, 1 popping bead per bag, horizontal sealing temperature set to 170°C, vertical sealing temperature set to 210°C. Each bag contains nicotine oily granules and at least one popping bead.

[0181] The prescription composition of the nicotine bag is shown in Table 15.

[0182]

[0183] Table 15 Grape-flavored nicotine pellets + mint-flavored nicotine pouch formula composition

[0184] The in vitro dissolution data of the nicotine pellets in the nicotine pouch and the results of the bursting bead disintegration time experiment are shown in Table 16.

[0185]

[0186] Table 16 In vitro dissolution data and disintegration time of nicotine micropellets

[0187] As can be seen from Table 16, when 20% of the nicotine is released, the popping beads will disintegrate, and the flavor inside the popping beads will infiltrate the nicotine micropellets and mix with the flavor inside the nicotine micropellets, effectively masking the strong irritation of nicotine on the oral mucosa, while strengthening the aroma in the nicotine micropellets and maintaining the aroma for a long time. Table 17 describes the evaluation of the irritation and taste changes of the nicotine pouches through manual sensory evaluation. The method is to have 8 experienced assessors perform the evaluation. Each assessor places a nicotine pouch on the upper lip and gums of the mouth and records the time and aroma of the nicotine pouch.

[0188]

[0189] Table 17 Sensory evaluation of the nicotine pouch

[0190] The results of Example 9 show that the nicotine pouch is composed of nicotine micro-pellets and popping beads containing flavors, and has a good nicotine release effect. The collapse of the popping beads can effectively mask the irritation of nicotine and maintain the aroma of the nicotine micro-pellets.

[0191] The present invention provides an embodiment: in order to investigate how the relevant substances, properties, and content of nicotine pouches change over time under the influence of environmental factors (e.g., temperature and humidity), the storage conditions and shelf life of the product are determined based on data from stability studies.

[0192] Example 10

[0193] Long-term stability tests were conducted on several nicotine pouch combinations at 25°C / 60% ± 5% RH. Three batches of each of four nicotine pouches were tested: dry nicotine granules with popping beads (Batches 21081002, 21081003, and 21081004); wet nicotine granules with popping beads (Batches 21082301, 21082302, and 21082303); oily nicotine granules with popping beads (Batches 21090202, 21090203, and 21090204); and micro-granules with popping beads (Batches 21092501, 21092801, and 21093001). The long-term stability data are summarized in Tables 18-29.

[0194] Analysis of content trends from long-term stability studies revealed that the content values ​​for all four batches of nicotine pouches remained within acceptable limits under the long-term testing conditions, with no significant changes in moisture or microbial content. These results met the stability quality standards for nicotine pouches. During the stability testing period, the results remained relatively stable, with no significant trend.

[0195] The results of Example 10 show that the properties of the four nicotine pouch combinations remained unchanged under the conditions of 25°C / 60±5% RH (0-24M), and the contents were all within the acceptable range. No significant changes were observed in other test items. Based on the data in Tables 18-29, it can be determined that the shelf life of the nicotine pouches at room temperature is at least 24 months.

[0196]

[0197] Table 18 Summary of long-term stability experimental data of nicotine pouches (containing explosive nicotine dry granules)

[0198] Batch number: 21081002

[0199]

[0200] Table 19 Summary of long-term stability experimental data of nicotine pouches (containing explosive nicotine dry granules)

[0201] Batch number: 21081003

[0202]

[0203] Table 20 Summary of long-term stability experimental data of nicotine pouches (containing explosive nicotine dry granules)

[0204] Batch number: 21081004

[0205]

[0206] Table 21 Summary of long-term stability experimental data of nicotine pouches (containing explosive nicotine wet granules)

[0207] Batch number: 21082301

[0208]

[0209] Table 22 Summary of long-term stability experimental data of nicotine pouches (containing explosive nicotine wet granules)

[0210] Batch number: 21082302

[0211]

[0212] Table 23 Summary of long-term stability experimental data of nicotine pouches (containing explosive nicotine wet granules)

[0213] Batch number: 21082303

[0214]

[0215] Table 24 Summary of long-term stability experimental data of nicotine pouches (containing explosive nicotine oily granules)

[0216] Batch number: 21090202

[0217]

[0218] Table 25 Summary of long-term stability experimental data of nicotine pouches (containing explosive nicotine oily granules)

[0219] Batch number: 21090203

[0220]

[0221] Table 26 Summary of long-term stability experimental data of nicotine pouches (containing explosive nicotine oily granules)

[0222] Batch number: 21090204

[0223]

[0224] Table 27 Summary of long-term stability experimental data of nicotine pouches (containing popping nicotine pellets)

[0225] Batch number: 21092501

[0226]

[0227] Table 28 Summary of long-term stability experimental data of nicotine pouches (containing popping nicotine pellets)

[0228] Batch number: 21092801

[0229]

[0230] Table 29 Summary of long-term stability experimental data of nicotine pouches (containing popping nicotine pellets)

[0231] Batch number: 21093001

[0232] In summary, a preferred solution provided by the present invention is: nicotine dihydrate tartaric acid salt and nicotine-β-cyclodextrin complex are selected as nicotine; and neotame or acesulfame potassium is selected as sweetener. The nicotine bag for oral mucosal absorption provided by the present invention and its preparation method are encapsulated by non-woven fabric, and the moisture content in the nicotine particles is controlled to ensure the long-term stability of the nicotine particles. At the same time, the added popping beads quickly disintegrate in saliva, and the disintegration time is basically the same as the time when the nicotine release in the nicotine particles reaches the mucosal irritation. It can effectively mask the irritation caused by nicotine and enhance the aroma in the nicotine particles. When multiple popping beads are used, in addition to the taste masking effect, the popping beads of different flavors will quickly mix to form a variety of flavors, thereby improving the user's experience. The stability test results of the nicotine bag provided by the present invention show that the shelf life of the nicotine bag at room temperature is at least 24 months, which has better stability. The present invention provides a nicotine bag that can maintain aroma for a long time, effectively mask the irritating sensory effects of nicotine, release nicotine quickly and continuously, and has a long shelf life and can be absorbed through the oral mucosa.

[0233] [Corrected on 23.04.2024 according to Rule 91] The above description is only a preferred embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made by using the description of the present invention, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A nicotine pouch for oral mucosal absorption, characterized in that, the nicotine pouch comprises nicotine particles, at least one liquid-containing bursting bead and a non-woven fabric bag, the nicotine particles and the bursting beads are encapsulated in the non-woven fabric bag, and the number of bursting beads contained in each non-woven fabric bag is 1 to 3, wherein, the nicotine particles are dry particles, the dry particles have a particle size of 1-1000 microns and a moisture content range of 1%-10% (W / W); or the nicotine particles are wet particles, the wet particles have a particle size of 1-1000 microns and a moisture content range of 5%-15% (W / W); or the nicotine particles are oily particles, the oily particles have a particle size of 1-1000 microns and a moisture content range of 1%-10% (W / W); or the nicotine particles are pellet particles, the pellet particles have a particle size of 30-2500 microns and a moisture content range of 1%-10% (W / W).

2. The nicotine pouch for oral mucosal absorption according to claim 1, characterized in that, the dry particles have a particle size of 1-700 microns and a moisture content range of 1%-8% (W / W); or the wet particles have a particle size of 1-700 microns and a moisture content range of 6%-15% (W / W); or the oily particles have a particle size of 1-700 microns and a moisture content range of 1%-5% (W / W); or the pellet particles have a particle size of 30-2000 microns and a moisture content range of 1%-8% (W / W).

3. The nicotine pouch for oral mucosal absorption according to claim 1, characterized in that, the nicotine particles contain one or more combinations of nicotine, sugar alcohol, cellulose and cellulose derivatives, pH regulator, binder, oily substance, sweetener, flavor, hydrophilic sugar-based core and / or hydrophobic cellulose core, polymer coating material and preservative.

4. The nicotine pouch for oral mucosal absorption according to claim 3, characterized in that, the nicotine includes nicotine and nicotine derivatives, including: free base nicotine, nicotine salts, nicotine in matrices such as sugar matrices or organometallic complexes, nicotine-ion exchange resin combinations, nicotine inclusion complexes and non-covalently bound nicotine, the non-covalently bound nicotine includes one or more mixtures of nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, nicotine benzoate; the content of nicotine alkaloid in the nicotine is 1mg / g - 80mg / g.

5. The nicotine pouch for oral mucosal absorption according to claim 3, characterized in that, The material of the dry granules does not contain oily substances, hydrophilic sugar-based cores and / or hydrophobic cellulose cores; the material of the wet granules may or may not contain oily substances, and does not contain hydrophilic sugar-based cores and / or hydrophobic cellulose cores; the material of the oily granules contains oily substances and does not contain hydrophilic sugar-based cores and / or hydrophobic cellulose cores; the material of the pellets may or may not contain oily substances, and may or may not contain hydrophilic sugar-based cores and / or hydrophobic cellulose cores.

6. The nicotine pouch for transmucosal absorption according to claim 3, wherein, the sugar alcohol is a polyol having two or more hydroxyl groups used as a thickening agent, binder and / or sweetening agent or stabilizer, and the sugar alcohol includes one or more combinations of propylene glycol, xylitol, maltitol, mannitol, erythritol, isomaltulose and lactitol, and the content of the sugar alcohol is 3%-30% (W / W).

7. The nicotine pouch for transmucosal absorption according to claim 3, wherein, the cellulose and cellulose derivatives include one or more of microcrystalline cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose, and the content of the cellulose and cellulose derivatives is 40%-85% (W / W).

8. The nicotine pouch for transmucosal absorption according to claim 7, wherein, the cellulose and cellulose derivatives have a water-binding capacity of at least 200%, and the cellulose and cellulose derivatives can be partially or completely dissolved in the nicotine pouch.

9. The nicotine pouch for transmucosal absorption according to claim 3, wherein, the pH regulator includes one or more combinations of monocarbonates, bicarbonates and carbonates, acetates, lactates, glycine salts, gluconates, borates, sulfates, glycerophosphates and citrates, and the content of the pH regulator is 0.5%-20% (W / W).

10. The nicotine pouch for transmucosal absorption according to claim 3, wherein, the binder includes one or more combinations of polyvinylpyrrolidone, cellulose derivatives, pregelatinized starch, syrup, gelatin, gum arabic, sodium alginate and polyethylene glycol, and the content of the binder is 0%-10% (W / W).

11. The nicotine pouch for transmucosal absorption according to claim 3, wherein, the oily substance is a lipid substance or a substance having emulsifying ability, including one or more combinations of glycerol, fatty acids with 6-24 carbon atoms (C6-C24), glyceryl monostearate, sucrose esters, soy lecithin, egg yolk lecithin, glycocholic acid, tween and various vegetable oils, and the content of the oily substance is 0%-25% (W / W).

12. The nicotine pouch for transmucosal absorption according to claim 3, wherein, The sweetener includes one or a combination of more than one of aspartame, acesulfame potassium, sodium cyclamate, saccharin, sodium saccharin, sucralose, neotame, sodium cyclohexylsulfamate, stevioside, licorice, disodium glycyrrhizinate, tripotassium and trisodium glycyrrhizinate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar, and lactose, sorbitol, maltitol, isomaltitol, palatinose, xylitol, lactitol, mannitol, erythritol, and dextran. The content of the sweetener is 0.2% - 10% (W / W).

13. The nicotine pouch for oral mucosal absorption according to claim 3, wherein, the flavoring includes one or a combination of more than one of bergamot essence, eucalyptus essence, citrus essence, lemon essence, peppermint essence, mint essence, menthol, licorice essence, wintergreen essence, tobacco essence, coffee essence, vanilla essence, lime essence, apple essence, peach essence, mango essence, cherry essence, blueberry essence, strawberry essence, cola essence, cinnamon essence, and watermelon essence. The content of the flavoring is 2% - 10% (W / W).

14. The nicotine pouch for oral mucosal absorption according to claim 3, wherein, the diameter of the hydrophilic sugar-based core and / or the hydrophobic cellulose core is less than 1000 microns. The hydrophilic sugar-based core is a sucrose blank core or a starch blank core, and the hydrophobic cellulose core is a microcrystalline cellulose blank core. The content of the hydrophilic sugar-based core and / or the hydrophobic cellulose core is 20% - 90% (W / W).

15. The nicotine pouch for oral mucosal absorption according to claim 3, wherein, the polymer coating material includes a sugar material or a polymer material. The sugar material includes one or a combination of more than one of syrup, colored syrup, mucilage, talcum powder, or white wax. The polymer material includes one or a combination of more than one of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, ethyl cellulose and other cellulose derivatives, methacrylic acid copolymer, methacrylate copolymer, and cellulose acetate phthalate. The content of the polymer coating material is 5% - 15% (W / W).

16. The nicotine pouch for oral mucosal absorption according to claim 3, wherein, the preservative includes one or a combination of more than one of sorbic acid and its salts, dehydroacetic acid and its sodium salts, parabens, sodium diacetate, calcium propionate, and sodium / calcium lactate. The content of the preservative is 0.1% - 2% (W / W).

17. The nicotine pouch for oral mucosal absorption according to claim 1, wherein, the bursting bead includes an encapsulating substance and a liquid substance contained in the encapsulating substance. The diameter of the bursting bead is ≤10 mm.

18. The nicotine pouch for oral mucosal absorption according to claim 17, wherein, the encapsulating substance includes one or several of the following two materials: (1) An edible material made of one or a combination of more than one of alginate, carrageenan, sodium carboxymethyl cellulose, chitosan, bovine gelatin, pectin, and wax; (2)A material that can be dissolved in the mouth and is made of one or more of sugar coating, starch, and hydroxypropyl methylcellulose; (3)A plastic material made of one or more of PP, PET, PE, HDPE, LDPE, PC, and PS.

19. The nicotine pouch for transmucosal absorption according to claim 17, characterized in that the liquid substance includes one or more of a cooling agent, an acidity regulator, an anti-caking agent, an antioxidant, a colorant, a flavor enhancer, a moisture retainer, a preservative, or a sweetener.

20. A method for preparing a nicotine pouch, characterized in that it is used to prepare the nicotine pouch for transmucosal absorption according to any one of claims 1 to 19, and the specific steps include: S1. Weigh the raw materials of the nicotine pouch; S2. Sequentially put the materials into a wet granulator, a fluidized bed, or a centrifugal granulator according to the prescription for granulation and / or coating; S3. Put the nicotine granules obtained by granulation into a drying oven or a fluidized bed for drying or coating; S4. Transfer the dried nicotine granules to a granule packaging machine, and at the same time put the bursting beads and the non-woven fabric roll, and put the nicotine granules and the bursting beads into the non-woven fabric bag for encapsulation to obtain the nicotine pouch.

21. The method for preparing a nicotine pouch according to claim 19, characterized in that the particle size of the granulated particles in S2 is 20 - 40 mesh, the drying temperature in S3 is 40 - 60 °C for drying, the transverse sealing temperature during encapsulation in S4 is 160 - 200 °C, and the longitudinal sealing temperature is 200 - 360 °C.

Images