SE2550706A1 - Nicotine pouch for oral mucosal absorption and preparation method thereof - Google Patents

Abstract

A nicotine pouch comprises particles of nicotine, bursting beads, at least one of which comprises liquid and non-woven pouches. The particles of nicotine and the bursting beads are encapsulated in the non-woven pouches, and each of the non-woven pouches comprises 1 to 3 bursting beads. When the particles of nicotine are dry particles, the dry particles comprise particle sizes of 1-1000 microns and moisture content ranging from 1% to 10% (W/W); when the particles of nicotine are wet particles, the wet particles comprise particle sizes of 1-1000 microns and moisture content ranging from 5% to 15% (W/W); when the particles of nicotine are oily particles, the oily particles comprise particle sizes of 1-1000 microns and moisture content ranging from 1% to 10% (W/W); and when the particles of nicotine are micropellet particles, the micro-pellet particles comprise particle sizes of 30-2500 microns and moisture content ranging from 1% to 10% (W/W).

Description

Nicotine pouch for oral mucosal absorption and preparation method thereof Technical Field The present invention relates to the technical field of nicotine, and in particular to a nicotine pouch for oral mucosal absorption and a preparation method thereof.

Background Technology Traditional cigarettes produce smoke that is harmful to the human body, and the aerosols produced by atomized electronic cigarettes can also cause harm to the human body. Smokeless nicotine products are considered by the World Health Organization to be less harmful than ordinary cigarettes and are an ideal substitute for cigarettes. Since smokeless nicotine products absorb nicotine through the oral mucosa, gastrointestinal tract, respiratory tract or skin, users can obtain the physiological satisfaction brought by nicotine without smoke. Nicotine pouches are a type of smokeless products, which are made by mixing nicotine base or nicotine salts or nicotine complex/adsorbent with fillers, dispersants, lubricants, sweeteners, flavors, acid-base regulators, adhesives and other materials to form particles, and then putting them into small non-woven pouches. When consumers use nicotine pouches, the saliva in oral cavities will moisten the nicotine pouch in the non-woven pouch, release nicotine from the composite particles, and absorb it into human bodies through the oral mucosa. The flavor substances such as flavors and fragrances added to nicotine pouches can not only enrich the flavor of the products, but also promote saliva secretion and increase the dissolution of effective ingredients in the products. However, since nicotine produces spicy and irritating taste when released, it causes discomfort to the user. The aroma in the pouch will also fade over time, resulting in a difference in taste. ln order to solve the irritation problem of nicotine release, some people have improved the nicotine pouch prescription. For example, patents with publication numbers CN15612l4A and WO2003/O26655 mention the use of emulsified cocoa powder for taste masking, which can effectively cover up the odor of nicotine and promote the rapid absorption of nicotine. However, the patents do not describe the dissolutíon and stability of the improved nicotine.

For example, the patent with publication number CN114521668A claims that the addition of an emulsifier can slow down the loss of flavor substances during storage, increase the stability of flavor substances in nicotine oral products, and improve the sensory quality of the product. However, in the examples, only the results of a 6-week stability experiment on the effect of the addition of an emulsifier on the content of menthol and anethole are mentioned, and the long-term stability results are not mentioned.

For example, patents with publication numbers CN 101437496A and WOZOO7/104575 mention that a nicotine-cellulose combination and one or more pharmaceutically acceptable excipients are used to prepare a lozenge composition to achieve rapid release of nicotine in the oral cavity, and also state that the lozenge composition can have a shelf life of more than 24 months. Furthermore, the patent states that the lozenge composition is a chewing gum composition prepared from a nicotine-cellulose combination and a gum base for chewing. However, the patent claims that the nicotine used is in the form of a base, and it is obvious that the irritation of nicotine is not effectively resolved in the lozenge composition. ln order to improve user compliance, patents with publication numbers CN 102076362A and WO2009/l34947 relate to a nicotine lozenge composition, which comprises a lower content of buffer than traditional nicotine lozenges and provides an optimal oral pH value and rapid nicotine absorption in a smaller and more convenient dosage form. ln one embodiment, the average in vivo dissolutíon time of the lozenge is about 10 times faster than that of traditional lozenges. However, the patent also does not explain the problem of taste improvement. ln order to achieve a nicotine pouch with good taste and fast oral absorption, patents with publication numbers CN 104169346A and WO2013/109961 describe an oral nicotine product of a mouth-stable polymer and one or more additives, including a mouth-stable polymer matrix and nicotine or its derivatives dispersed in the matrix. An extrusion and rounding tableting production process is adopted. lt can provide a satisfactory tactile and/or flavor experience while also providing an extended release time ofthe additíve. However, the mouth-stable polymer matrix in the nicotine pouch comprises polyurethane and a large amount of plasticizers, which will affect the rapid release of nicotine. The dissolution data of the nicotine pouch is not mentioned in the patent description, so we cannot assume that the nicotine pouch has the effect of rapidly releasing nicotine. ln order to solve the problem of nicotine rapid release, it can also be continuously released for a consíderable time, and it is necessary to have a good taste. The patents of publication number CN104271137A and WO20l3/147687 illustrate a powdered nicotine oral delivery product encapsulated in a water-insoluble pouch, wherein the powder comprises at least nicotine and a chewing gum composition, wherein the pouch is permeable to saliva and dissolves part of the powder therein, releasing part of nicotine and other components, such as chewing the pouch can further promote nicotine release, and continuing to chew will cause the chewing gum composition in the pouch to be converted into a chewing gum block, and the release of nicotine will be shown as a similar nicotine chewing gum product. Obviously, the nicotine pouch is also absorbed by the gastrointestinal tract in addition to being absorbed by the oral mucosa. Publication number CN112220756A discloses a nicotine granule composition, which is mainly composed of nicotine quick-release particles and nicotine slow-release particles, to ensure the speed at which the human body obtains pleasure and the duration of nicotine maintaining a concentration with a therapeutic effect in the human body. Furthermore, patents with publication numbers CN114390922A and WO2021/O53078 describe oral delivery products encapsulated in non-woven pouches with a composition formed by a nicotine benzoate/maleate-resin combination and at least one pH adjuster; and at least one filler, which are improved on the basis of other commercially available nicotine pouch products. Similarly, none of the above patents describe whether the irritation of nicotine can be reduced. ln order to keep the aroma in the tobacco nicotine pouch for a long time without weakening due to oxidation, etc., Publication No. CN1l1035047A provides a buccal tobacco product, including tobacco material and at least one bursting bead, by encapsulating liquid substances and/or extract substances that easily induce the deteríoration of tobacco material in the bursting bead, thereby improving the stability of the buccal tobacco product and enriching the taste of the buccal tobacco. However, the invention encapsulates the bursting bead and the tobacco material together in a non-woven pouch. Although the problem of aroma retention is solved, traditional plant tobacco is still used, which is different from the modern popular nicotine pouch mainly composed of synthetic nicotine.

The prior art has not provided a nicotine pouch that can maintain the aroma for a long time, effectively mask the irritating sensory effect of nicotine, release nicotine quickly and continuously, and has a long shelf life and can be absorbed through the oral mucosa.

Therefore, the existing technology needs to be improved.

Summary of the lnvention The prior art has not been able to provide a nicotine pouch for oral delivery that can maintain aroma for a long time, effectively mask the irritating sensory effects of nicotine, quickly release nicotine, continuously release nicotine, and have a long shelf life. Therefore, the present invention provides a nicotine pouch for oral mucosal absorption and a preparation method thereof to solve the above problems.

To achieve the above-mentioned purpose, on a first aspect, the present invention provides a nicotine pouch for oral mucosal absorption, comprising particles of nicotine, bursting beads wherein at least one of the bursting beads comprises liquid, and non- woven pouches, wherein the particles of nicotine and the bursting beads are encapsulated in the non-woven pouches, and each of the non-woven pouches comprises 1 to 3 bursting beads; wherein when the particles of nicotine are dry particles, the dry particles comprise particle sizes of 1-1000 microns and moisture content ranging from 1% to 10% (W/W); when the particles of nicotine are wet particles, the wet particles comprise particle sizes of 1-1000 microns and moisture content ranging from 5% to 15% (W/W); when the particles of nicotine are oily particles, the oily particles comprise particle sizes of 1-1000 microns and moisture content ranging from 1% to 10% (W/W), or when the partícles of nicotine are micro-pellet partícles, the micro-pellet partícles comprise particle sizes of 30-2500 microns and moisture content ranging from 1% to 10% (W/W). ln one implementation, the dry partícles comprise particle sizes of 1-700 microns and moisture content rangíng from 1% to 8% (W/W), the wet partícles comprise particle sizes of 1-700 microns and moisture content ranging from 6% to 15% (W/W), the oily partícles comprise particle sizes of 1-700 microns and moisture content ranging from 1% to 5% (W/W);or the micro-pellet partícles comprise particle sizes of 30-2000 microns and moisture content rangíng from 1% to 8% (W/W). ln one implementation, the partícles of nicotine comprise one or more combinations of nicotine, sugar alcohols, cellulose and cellulose derivatíves, pH regulators, adhesives, oily substances, sweeteners, flavors and fragrances, hydrophilic sugar-based pellet cores and/or hydrophobíc cellulose pellet cores, polymer coating materials and preservatives. ln one implementation, the nicotine comprises nicotine and nicotine derivatíves, 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 comprises nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloríde, nicotine benzoate or one or more mixtures thereof; and a content of nicotine base in the nicotine is 1 mg/g-80 mg/g. ln one implementation, the dry partícles do not comprise oily substances, hydrophilic sugar-based pellet cores and/or hydrophobíc cellulose pellet cores; the wet partícles may or may not comprise oily substances, and may not comprise hydrophilic sugar- based pellet cores and/or hydrophobíc cellulose pellet cores; the oily partícles comprise oily substances but do not comprise hydrophilic sugar-based pellet cores and/or hydrophobic cellulose pellet cores; and the micro-pellet partícles may or may not com prise oily su bstances, hyd rophilic sugar-based pellet cores and/or hyd rophobic cellulose pellet cores. ln one implementation, the sugar alcohols are polyols comprising two or more hydroxyl groups used as a thickener, an adhesive and/or a sweetener or a stabilizer, the sugar alcohols comprise one or more combinations of propylene glycol, xylitol, maltitol, mannítol, erythritol, isomalt and lactitol; and a content of the sugar alcohols is 3%-3o% (W/W). ln one implementation, the cellulose and cellulose derívatives comprise one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose, and a content of the cellulose and cellulose derivatives is 40%-85% (W/W). ln one implementation, the cellulose and cellulose derivatives comprise a water binding capacity of at least 200%, and the cellulose and cellulose derivatives are able to be partially or completely díssolved in the nicotine pouch. ln one implementation, the pH regulators comprise one or more combinations of monocarbonate, bicarbonate and carbonate, acetate, lactate, glycinate, gluconate, borate, sulfate, glycerophosphate and citrate, and a content of the pH regulators is O.5%-20% (W/W). ln one implementation, the adhesives comprise one or more combinations of povidone, cellulose derivatives, pregelatinized starch, syrup, gelatin, gum arabic, sodium alginate and polyethylene glycol, and a content of the adhesives is 0%-10% (W/Wl- ln one implementation, the oily substances are lipid substances or substances with emulsifying ability, including one or more combinations of glycerol, fatty acids with carbon ion numbers between 6 and 24 (C6-C24), monostearate, sucrose esters, soybean lecithin, egg yolk lecithin, glycocholic acid, Tween and one or more com binations of various vegeta ble oils, and a content of the oily su bstances is 0%-25% (W/Wi- ln one implementation, the sweeteners comprise one or more combinations of aspartame, acesulfame potassium, sodíum cyclamate, saccharin, saccharin sodíum, sucralose, neotame, sodíum cyclamate, stevioside, licorice, disodium glycyrrhizinate, trípotassium and trisodium glycyrrhizinate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar and lactose, sorbitol, maltitol, isomalt, palatinol, xylitol, lactitol, mannitol, erythritol and dextran, and a content of the sweeteners is 0.2%-10% (W/W). ln one implementation, flavors and fragrances comprise one or more com binations 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 a content of the flavors and fragrances is 2%-10% (W/W). ln one implementation, diameters of the hydrophilic sugar-based pellet cores and/or the hydrophobic cellulose pellet cores are less than 1000 microns, the hydrophilic sugar-based pellet cores are sucrose blank pellets or starch blank pellets, the hydrophobic cellulose pellet cores are microcrystalline cellulose blank pellets, and a content of the hydrophilic sugar-based pellet cores and/or the hydrophobic cellulose pellet cores is 20%-90% (W/W). ln one implementation, the polymer coating materials comprise sugar materials or polymer materials, the sugar materials comprise one or more combinations of syrup, colored syrup, glue, talcum powder or white Wax, the polymer materials comprise 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, cellulose acetate phthalate, and a content of the polymer coating materials is 5%-15% (W/W). ln one implementation, the preservatíves comprise one or more combinations of sorbic acid and salts thereof, dehydroacetic acid and sodíum salts thereof, parabens, sodíum diacetate, calcium propionate and sodíum/calcium lactate, and a content of the preservatíves is 0.1%-2% (W/W). ln one implementation, the bursting beads comprise encapsulating materials and liquid materials contained in the encapsulating materials, and diameters of the bursting beads are S 10 mm. ln one implementation, the encapsulating materials comprise one or more offollowing materials: I. edible materials made of one or more of alginate, carrageenan, sodium cellulose sulfate, chitosan, bovine gelatin, pectín and wax; ll. materials that can be dissolved in oral cavities made of one or more ofsugar coating, starch, hydroxypropyl methylcellulose; and |||. plastic materials made of one or more of PP, PET, PE, HDPE, LDPE, PC and PS. ln one implementation, the liquid materials comprise one or more of cooling agents, acidity regulators, anticaking agents, antioxídants, colorants, flavor enhancers, moisture retainers, preservatives or sweeteners. On a second aspect, the present invention provides a nicotine pouch preparation method used for preparing the nicotine pouch for oral mucosal absorption mentioned above, comprising following steps of: Sl-weighing raw materials of the nicotine pouch; S2-sequentially putting the raw materials into a wet granulator or a fluidized bed or a centrifugal granulator according to a prescription for granulation and/or coating; SS-putting the particles of nicotine obtained by granulation into a drying oven or a fluidized bed for drying or coating; and S4-transferring the particles of nicotine dríed to a particle packaging machine, and putting the bursting beads and non-woven fabric coils at a same time, and putting the particles of nicotine and the bursting beads into the non-woven fabric pouches for encapsulation to obtain the nicotine pouch. ln one implementation, particle sizes of granulated particles in S2 are 20-40 meshes, drying temperature in S3 is 40-60°C, and horizontal sealing temperature during packaging in S4 is 160-200°C and vertical sealing temperature is 200-360°C. Beneficial effects: in the nicotine pouch for oral mucosal absorption provided by the present invention and the preparation method thereof, the particles of nicotine and the bursting beads are encapsulated by non-woven fabric, and the moisture content in the particles of nicotine is controlled to ensure the long-term stability of the particles of nicotine. At the same time, the bursting beads added are rapidly disintegrated in salíva, and the disintegration time is basically the same as the time for the nicotine release in the particles of nicotine to reach the mucosal irritation, which can effectively mask the irritation caused by nicotine and enhance the aroma in the particles of nicotine; when multiple bursting beads are used, in addition to the taste masking effect, the bursting beads of different flavors will quickly mix to form a variety of flavors, improving the user's experience; the nicotine pouch 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 pouch for oral mucosal absorption that can maintain aroma for a long time, can effectively mask the irritating sense of nicotine, can quickly release nicotine, and can also continuously release nicotine, and can have a long shelf life.

Specific Embodiments ln order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. lt 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. ln addition, the description of the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" described below means 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. ln this specification, the schematic representation of the above terms is not necessarily for the same embodiment or example. Moreover, the technical features involved in each embodiment of the present invention can be combined with each other as long as they do not conflict with each other.

The present invention provides a nicotine pouch for oral mucosal absorption, comprising particles of nicotine, bursting beads wherein at least one of the bursting beads comprises liquid, and non-woven pouches, wherein the particles of nicotine and the bursting beads are encapsulated in the non-woven pouches, and each of the non- woven pouches comprises 1 to 3 bursting beads; wherein when the particles of nicotine are dry particles, the dry particles comprise particle sizes of 1-1000 microns and moísture content ranging from 1% to 10% (W/W); when the particles of nicotine are wet particles, the wet particles comprise particle sizes of 1-1000 microns and moísture content ranging from 5% to 15% (W/W), when the particles of nicotine are oily particles, the oily particles comprise particle sizes of 1-1000 microns and moísture content ranging from 1% to 10% (W/W), or when the particles of nicotine are micro-pellet particles, the micro-pellet particles comprise particle sizes of 30-2500 microns and moísture content ranging from 1% to 10% (w/w).

The characteristics of dry particles are that the particles are dry and have good fluidity; the characteristics of wet particles are that the particles are moist and have poor fluidity; the characteristics of oily particles are that the partícles are moist and have good fluidity; the characteristics of micro-pellet particles are that the particles are dry, in the form of small pills, and have good fluidity. Preferably, the dry particles comprise particle sizes of 1-700 microns and moisture content ranging from 1% to 8% (W/W); the wet particles comprise particle sizes of 1-700 microns and moisture content ranging from 6% to 15% (W/W); the oily particles comprise particle sizes of 1-700 microns and moísture content ranging from 1% to 5% (W/W);or the micro-pellet particles comprise particle sizes of 30-2000 microns and moísture content ranging from 1% to 8% (W/W).

That is to say, the nicotine pouch for oral mucosal absorption provided by the present invention comprises four modes, namely, bursting beads and nícotine dry particles, bursting beads and nicotine wet particles, bursting beads and nicotine oily particles, and bursting beads and nicotine micro-pellet particles. Among them, the dry particles do not comprise oily substances, hydrophilic sugar-based pellet cores and/or hydrophobíc cellulose pellet cores. The wet particles may comprise or may not comprise oily substances, hydrophilic sugar-based pellet cores and/or hydrophobic ll cellulose pellet cores. The oily partícles comprise oily substances, but do not comprise hydrophilic sugar-based pellet cores and/or hydrophobic cellulose pellet cores. The micro-pellet partícles may comprise or may not comprise oily su bstances, comprise or do not comprise hydrophilic sugar-based pellet cores and/or hydrophobic cellulose pellet cores. The micro-pellet partícles can have the effect of rapidly releasing nicotine or slowly releasing nicotine or both.

Further, the partícles of nicotine comprise one or more combinations of nicotine, sugar alcohols, cellulose and cellulose derivatives, pH regulators, adhesives, oily substances, sweeteners, flavors and fragrances, hydrophilic sugar-based pellet cores and/or hydrophobic cellulose pellet cores, polymer coating materials and preservatives. Specifically, the nicotine comprises 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 comprises nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrín inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, nicotine benzoate or one or more mixtures thereof; and a content of nicotine base in the nicotine is 1 mg/g-80 mg/g. Prefera bly, the nicotine comprises one or more com bínatíons of nicotine base, nicotine tartrate dihydrate, nicotine cyclodextrin embedding complex, nicotine-resin complex and nicotine benzoate.

Specifically, the sugar alcohols are polyols comprising two or more hydroxyl groups used as a thickener, an adhesive and/or a sweetener or a stabilizer, the sugar alcohols comprise one or more combinations of propylene glycol, xylitol, maltitol, mannitol, erythritol, isomalt and lactítol; and a content of the sugar alcohols is 3%-30% (W/W). Preferably, the sugar alcohols are one or more combinations of maltitol, xylitol, mannitol and propylene glycol.

Specifically, the cellulose and cellulose derivatives refer to insoluble fibers, mainly 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, 12 cocoa fiber, bran fiber, bamboo fiber, powdered cellulose and combinations thereof. the cellulose and cellulose derivatives comprise one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose, and a content ofthe cellulose and cellulose derivatives is 40%-85% (W/W). The cellulose and cellulose derivatives have a water binding capacity of at least 200%, the cellulose and cellulose derivatives can be partially or completely dissolved in the nicotine pouch, and at the same time, the cellulose and cellulose derivatives are permeable to saliva.

Specifically, the pH regulators comprise one or more combinations of monocarbonate, bicarbonate and carbonate, acetate, lactate, glycinate, gluconate, borate, sulfate, glycerophosphate and citrate, and a content of the pH regulators is 0.5%-20% (W/W). Preferably, the pH regulators comprise one or more com binations of monocarbonate, bicarbonate and carbonate, lactate, monohydrogen phosphate, and dihydrogen phosphate.

Specifically, the adhesives comprise one or more combinations of povidone, cellulose derivatives, pregelatinized starch, syrup, gelatin, gum arabic, sodium alginate and polyethylene glycol, and a content of the adhesives is O%-10% (W/W). Preferably, the adhesives comprise one or more combinations of sodium alginate, cellulose derivatives and povidone.

Specifically, the oily substances are lipid substances or substances with emulsifying ability, including one or more combinations of glycerol, fatty acids with carbon ion numbers between 6 and 24 (C6-C24), monostearate, sucrose esters, soybean lecithin, egg yolk lecithin, glycocholic acid, Tween and one or more combinations of various vegetable oils, and a content of the oily substances is O%-25% (W/W). Preferably, the oily substances comprise one or more com binations of propylene glycol, glycerol, and medium-chain fatty acids (C6-C12).

Specifically, the sweeteners are artificially synthesized and/or naturally extracted sweeteners. The sweeteners comprise one or more combinations of aspartame, acesulfame potassium, sodium cyclamate, saccharin, saccharin sodium, sucralose, neotame, sodium cyclamate, stevioside, licorice, disodium glycyrrhizinate, 13 trípotassium and trisodium glycyrrhizínate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar and lactose, sorbitol, maltitol, isomalt, palatinol, xylitol, lactitol, mannitol, erythritol and dextran, and a content of the sweeteners is 0.2%-10% (W/W). Preferably, the sweeteners are one or more combinations of mannitol, xylitol, maltitol, acesulfame potassium, neotame and sucralose.

Specifically, the flavors and fragrances refer to substances with certain aroma and fragrance composed of compounds such as hydrocarbons, alcohols, acids, esters, lactones, ethers, aldehydes, ketones, acetals, ketals, phenols, macrocycles, polycycles, heterocycles (comprisíng nitrogen, oxygen, and sulfur elements), halídes, nitriles, etc. The flavors and fragrances comprise 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 a content of the flavors and fragrances is 2%-10% (W/W).

Specifically, the hydrophilic sugar-based pellet cores and/or the hydrophobic cellulose pellet cores refer to the masterbatch necessary for preparing the skeleton-type pellets. Diameters of the hydrophilic sugar-based pellet cores and/or the hydrophobic cellulose pellet cores are less than 1000 mícrons, the hydrophilic sugar-based pellet cores are sucrose blank pellets or starch blank pellets, the hydrophobic cellulose pellet cores are microcrystalline cellulose blank pellets, and a content of the hydrophilic sugar-based pellet cores and/or the hydrophobic cellulose pellet cores is 20%-90% (W/W). The preferred diameters are between 0.1 mm and 1.5 mm; and preferably the hydrophilic sugar-based pellet cores and/or the hydrophobic cellulose pellet cores are hydrophilic sucrose pellets or hydrophobic microcrystalline cellulose pellets. Specifically, the polymer coating materials refer to sugar or hydrophilic/hydrophobic polymer materials coated on solid surfaces to form one or more multifunctional protective layers of different thicknesses and elasticities that are tightly adhered to the surfaces. The polymer coating materials comprise sugar materials or polymer materials, the sugar materials comprise one or more combinations of syrup, colored 14 syrup, glue, talcum powder or white wax, the polymer materials comprise one or more com binations of cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose and hydroxypropyl cellulose, ethyl cellulose, methacrylic acid copolymer, methacrylate copolymer, cellulose acetate phthalate, and a content of the polymer coating materials is 5%-15% (W/W). Preferably, the polymer coating materials are one or more combinations of polymer materials that can dissolve at a pH above 4.7, such as cellulose acetate, hydroxypropyl methylcellulose, polyvinyl alcohol ester, copolymer of methacrylic acid and methyl methacrylate, styrene maleic acid copolymer, etc. Specifically, the preservatives comprise one or more combinations of sorbic acid and salts thereof, dehydroacetic acid and sodium salts thereof, parabens, sodium diacetate, calcium propionate and sodium/calcium lactate, and a content of the preservatives is O.l%-2% (W/W). Preferably, the preservatives are one or more combinations of parabens, lactates, sorbic acid and their salts. Specifically, the bursting beads comprise encapsulating materials and liquid materials contained in the encapsulating materials, and diameters of the bursting beads are 5 10 mm. The encapsulating materials comprise one or more of following materials: l. edible materials made of one or more of alginate, carrageenan, sodium cellulose sulfate, chitosan, bovine gelatin, pectin and Wax; ll. materials that can be dissolved in oral cavities made of one or more ofsugar coating, starch, hydroxypropyl methylcellulose, and lll. plastic materials made of one or more of PP, PET, PE, HDPE, LDPE, PC and PS.

Preferably, the encapsulating materials are one or more combinations of alginate, carrageenan, sodium cellulose sulfate, chitosan, gelatin, pectin and Wax. The liquid materials comprise one or more of cooling agents, acidity regulators, anticaking agents, antioxidants, colorants, flavor enhancers, moisture retainers, preservatives or sweeteners.

The bursting beads can be one or more, and the bursting beads quickly disintegrate in saliva. The disintegration time is basically the same as the time when the nicotine release in the particles of nicotine reaches the mucosal irritation feeling, which can effectively mask the irritation caused by nicotine and enhance the aroma in the particles of nicotine. When multiple bursting beads are used, in addition to the above- mentioned masking effect, the bursting beads of different flavors will quickly mix to form a variety of flavors, thereby improving the user experience.

The present invention provides a nicotine pouch preparation method used for preparing the nicotine pouch for oral mucosal absorption as mentioned above, com prising following steps of: S1-weighing raw materials of the nicotine pouch; S2-sequentially putting the raw materials into a wet granulator or a fluidized bed or a centrifugal granulator according to a prescription for granulation and/or coating; SS-putting the particles of nicotine obtained by granulation into a drying oven or a fluidized bed for drying or coating; and S4-transferring the particles of nicotine dríed to a particle packaging machine, and putting the bursting beads and non-woven fabric coils at a same time, and putting the particles of nicotine and the bursting beads into the non-woven fabric pouches for encapsulation to obtain the nicotine pouch.

Particle sizes of granulated particles in S2 are 20-40 meshes, drying temperature in S3 is 40-60°C, and horizontal sealing temperature during packaging in S4 is l60-200°C and vertical sealing temperature is 200-250°C.

Specifically, the nicotine pouch for oral mucosal absorption provided by the present invention comprises four modes and production processes thereof are described as follows: Production process of compositíon 1: Sll-weighing materials; S12-putting the materials into a wet granulator in order according to a prescription for granulation, wherein a preferred process parameter is that granulated particles need to be screened through a 20-40 mesh screen; S13-drying process: putting granulated nicotine pa rticles into a drying oven or fluidized 16 bed for drying, wherein a preferred process parameter is drying at a temperature of 40-60°C; and S14-transferring dríed nicotine dry particles to a powder silo of a particle packaging machine, and at a same time putting weighed burst beads into a burst bead silo ofthe particle packaging machine according to a prescription amount, putting non-woven fabric roll coils into a roll film silo of the particle packaging machine, and starting the particle packaging machine for filling and packaging processes, wherein preferred process parameters are that the horizontal sealing temperature during packaging is 160-180°C and the vertical sealing temperature is 200-230°C.

Production process of composition 2: S21-weíghing materials; S22-putting the materials into a wet granulator in order according to a prescription for granulation, wherein a preferred process parameter is that granulated particles need to be screened through a 20-40 mesh screen; S23-transferring nicotine oily particles that meet the requirements to a powder silo of a granule packaging machine, and also putting weighed bursting beads into a bursting bead silo of a granule packaging machine according to a prescription amount, putting non-woven fabric roll coils into a roll film silo of a granule packaging machine, and starting the granule packaging machine for filling and packaging processes, wherein preferred process parameters are that the horizontal sealing temperature during packaging is 160-180°C and the vertical sealing temperature is 200-230°C.

Production process of composition 3: S31-weighing materials; S32-putting the materials into a wet granulator in order according to a prescription for granulation, wherein a preferred process parameter is that granulated particles need to be screened through a 20-40 mesh screen; S33-transferring nicotine wet particles that meet the requirements to the powder silo of the particle packaging machine, and also putting the weighed bursting beads into a bursting bead silo of a particle packaging machine according to a prescription amount, putting non-woven fabric roll coils into a roll film silo of the particle packaging machine, 17 and starting the particle packaging machine for filling and packaging processes, wherein preferred process parameters are that the horizontal sealing temperature during packaging is 160-180°C, and the vertical sealing temperature is 200-230°C. Production process of composition 4: S41-material weighing; S42- according to the sustained release function, dividing into: @ fluidized pelleting process: putting prepared polymer coating materials and the materials into a spray gun silo, putting weighed solid materials including pellet cores into a solid silo of a fluidized bed or centrifugal granulator in sequence according to a prescription, starting the machine to carry out fluidized bed granulation coating or centrifugal granulation coating process, and evenly wrapping the materials on the pellet cores to form one or more layers of material layers, wherein this process is suitable for producing nicotine microcapsules that achieve sustained release effects through functional coatings; ® extrusion and spheronization pelleting process: putting various materials into the granulator according to the prescription to make wet materials; then transferring to the extruder, passing wet materials through a hole or sieve with a certain diameter by screw propulsion or rolling, and squeezing into cylindrical strip-shaped extrusions; stacking the extrusions on the self-rotating friction plate of the spheronization machine, and dispersing the extrusions into smaller cylinders with a length equivalent to their diameter, and gradually rolling into spheres through continuous rolling friction; drying the formed spherical composition; then is coating and transferring the dried spherical composition to the next process or directly transferring to the next process without coating, wherein this process is suitable for producing nicotine particles that achieve sustained release effects in the form of skeletons.

S43- transferring the dried nicotine particles to a powder silo of a granule packaging machine, and placing the weighed bursting beads in the bursting bead silo of the granule packaging machine according to the prescription amount, placing the non- woven fabric roll coils in the roll film silo of the granule packaging machine, and starting the granule packaging machine to carry out the filling and packaging process, wherein preferred process parameters are that the horizontal sealing temperature 18 during packaging is 160-180°C and the vertical sealíng temperature is 200-230°C.

The present invention is tested through multiple em bodiments: Embodiment 1 The same dose (calculated as nicotine base) of nicotine tartrate dihydrate, nicotine-ß- cyclodextrin complex, nicotine benzoate, and nicotine base were mixed with the same dose of microcrystalline cellulose, povidone, xylitol, sodium carbonate, and sodium bicarbonate to prepare particles, and the headiness and irritation of different nicotine derivatives and nicotine were evaluated by artificial sensory evaluation. The results are shown in Table 1.

Dose Head Off» lrritancy (calculated Rush Flavor Evaluation Nlcotšne Name intensity as nicotine 'Tlrne Score {1~ Result (l-IO) basel (rnínutes) 10) Strong off» flavor, Nlcotlrle Base 6 mg 2.1 10 1G overly Spicy, not selected.

Gbvšous off-flavor, strong Nšcotine Benzoate 6 mg 4.2 8 8 spšcšrxess, HOT selected, Acceptable Nlcotšne Bitartrate 6 :ng Offl-llaliørl' FX) Ü: ~ll> U"l acceptabla splcšness, 19 selected.

Not obviotas Nicotine--ß- off-flavor, 5 mg fil 3 3 Cyciodextršri Conipiex xveak spicšness, selected, Note: The head rush time refers to the duration ofthe perceived effects of nicotine on the body, such as dizziness and relief from cravings. The time results are the average duration assessed by 8 evaluators.

The off-flavor score refers to the assessment of the odor of nicotine particles; a lighter smell receives a lower score, while a stronger smell receives a higher score.

The off-flavor score results are the average scores assessed by 8 evaluators. lrritancy intensity refers to the degree of spicy stimulation felt on the oral mucosa due to nicotine; the lower the irritancy, the lower the score, and the greater the irritancy, the higher the score. The irritancy intensity results are the average scores assessed by 8 evaluators.

Table 1: Sensory evaluation of different nicotine derivatives From the results in Table 1, it can be seen that the odor and irritation of nicotine dihydrate tartaric acid salt and nicotine-ß-cyclodextrin complex are better than nicotine base and nicotine benzoate salt in the sensory evaluation and the performance in the head feeling is also better than nicotine benzoate salt. ln addition, nicotine dihydrate tartaric acid salt and nicotine-ß-cyclodextrin complex are both solid and easier to store.

Embodiment 2 The fluidity of the composition is determined by comparing the bulk density (expressed as Carr's index) of nicotine pouches with different formulations. The fluidity is the key to determining whether the particles can be smoothly transferred into the non-woven pouch. The formulation composition and bulk density results are shown in Table 2.

Prescription Composition (W/W) Kadlndex (%) Nicotine Bštartrate 4.586, iviicrocrystašlirie Ceiiuiose 335%, Xyiitoi 6.596, Sodiurn Bicarboriate and Sodiurïi Czirbonate 4,596, Poiyviiwifipgfrroišdone 89-6, Moisture % I}.«1.3š3% Nicotine Bitartrate 4.596, Lactose 852%, Xylitoi 9%, Soditirri Bicarbonate and Sodiurn Carbonate 45496,.

Sodiurri Aiginate GLE/å, Moisture 1,13% l5.52% Nicotiiie Bitartrate 311%, iviicrocrystašline Celluiose 56.596, ii/iannitoi 11.396, Caiciuin Lactate 10%, Propylene Giycol 3.296, Giyceršn ïlïïá, Sodium Aiginate O.I1?6, Purified *vïfater 822% 16,36% Nicotiiie Bštartrate 3.496, iviicrocrystailine Celluiose 56.696, Mannitol 14.596, Soditzni Bicarbonate and Soditinfi Carbonate 1096, Giycerin 7.296, Sodiurn Alginate 9.196, Purified "iiifater 8.296 l7.lii3% Nicotšrie-ß-Cyclodextriii Cornplex ?.8?/à, Nišcrocrystalline Ceiiuiose 4596, iviaititoi 23.596, Calciuin Lactate 0.296, Sodium Carbonate O. 9-6, Propylene Giycol 5. 9-6, Giyceriii 1OJÜ96, iviedštsni Chain Fatty Acšds 7.196, Niošsture 1.396 14_98% Nicotšrieíš-Cgfcloitiextrin Cornpiex 'I.3*š6, Microcrystailirie Ceiiuiose 45%, Maititoi 23.596, Calciurn Lactate Gßfš/Lè, (šiycerín 19.696, Nioisture šíï/ä l5.l3% Table 2: Prescription composition of different nicotine pouches 21 Prescription A and Prescription B correspond to nicotine dry particles, Prescription C and Prescription D correspond to nicotine wet particles, and Prescription E and Prescription F correspond to nicotine oil particles. From Ta ble 2, it can be seen that the Carr index of Prescription A, Prescription C, and Prescription E is less than 15%, indicating that the fluidity of each prescription is very good.

Embodiment 3 Different sweeteners and flavors were added to the recipes A, C, and E in Table 2, and the palatability was evaluated by artificial sensory organs. The results are shown in Table 3.

Prescription Sweeterier (XNQ/'i/Xl) í-'iavorifig fiN/W) Score (ifïüfi Prescription A Neotame 9,21% EX/iint Flak/or 535% 8.2 Prescription B Acesuifaine i< 1.595» Lemon Fiavor 5.996 7.8 Vvaternieion Flavor Prescription C Sucralose 10.995 7.1 êíšïá Note: The scores indicate the average ratings from 8 evaluators based on olfactory (smell) and gustatory (taste) assessments. The lower the score, the worse the aroma and flavor; the higher the score, the better the aroma and flavor.

Table 3: Evaluation results of different sweeteners and flavors The evaluation results show that neotame and acesulfame potassium are better than sucralose and have higher sweetness. Embodiment 4 The in vitro release table of one of the nicotine micro-pellet particles of the present invention is shown in Table 4. "iirne Dissolutšon Rate 5 :nintstes 45% 1D rriinutes 656% 1.5 aninutes 85% 22 Table 4: In vitro dissolution data of nicotine micro-pellet particles Embodiment 5 2G rninutes 9096 30 anšafiutes 95% 45 minutes 98% An embodiment provided by the present invention: Comparison of the disintegration time of the bursting beads and the nicotine release time. Artificial saliva is placed in a 36-37°C water bath with a pH value of 6.8. At the same time, one bursting bead of each material is soaked in the artificial saliva, and the disintegration time of each bursting bead is recorded. ln the same way, two of the nicotine pouches described in the present invention are placed in the artificial saliva, and samples are taken every 1 minute to detect the nicotine release amount. The recorded results are shown in Ta ble Dissolution Time of Bursting Beads of Different Materials in Artificial Saliva Serial Average Dissoluticaiw Time (minutes) Ntlmber Bursting 5.11 Bead 1 Bursting 7.23 Bead 2 Nicotine Release Times from Different Particle Types in Artificial Saliva Niccatine Nicotine Nicotine Nicetine Nicotine Nicotine Release Release Release Release Release Release Particle fiercentage Percentage Eïlercerttage Wzrcentage Percerltage Percentage Type at 3 at 5 at 1G at 15 at 2G at 25 minutes minutes anšnutes näinutes minutes :nšntztes Nicotine 31% 42% 66% 81% 86% 90% Pouch 23 (Drv Particles) Nicotine Pouch 28% (Wet Particles) 43% 63% 83% 89% 93% Nicotine Pouch 34% (Oily Particles) 41% 65% 80% 88% 93% Nicotine Pouch (Micro- 21% pellet Particles) 29% 43% 48% 54% 60% Sensory Assessment of lrritation from Different Nicotine Pouches Particle Type Average Onset Time of Mucosal lrritation (minutes) Nicotine Pouch (Dry 4.7 minutes Particles) Nicotine Pouch (Wet 4.3 minutes Particles) Nicotine Pouch (Oily 5.2 minutes Particles) Nicotine Pouch (Micro-pellet 9.7 minutes Particles) Table 5: Comparison of the disintegration time of bursting beads and the nicotine release time The results in Ta ble 5 show that the irritation of nicotine depends on the concentration 24 of nicotine release. When the nicotine release reaches about 40%, people will obviously feel mucosal irritation. The time point when the particles of nicotine of the present inventíon reach the mucosal irritation is basically about 5 minutes (except for nicotine micro-pellet particles). Some materials of bursting beads also disintegrate in about 5 minutes, which can effectively cover up the irritation of nicotine. Different materials of bursting beads will cause them to disintegrate at different Time Point, indicating that placing more than one bursting bead in the same nicotine pouch will disintegrate and spill different flavors at different times during use, bringing different taste experiences. This is a design that was not available in previous products. Embodiment 6 The production process of nicotine pouches with nicotine dry particles and bursting beads, the prescription composition of one of the products, and in vitro dissolution and sensory evaluation thereof are as follows.

Production process description: processing of raw materials and auxiliary materials (weighing and screening) ä granulation (wet granulation) ä boiling drying ä whole particles ä granule packaging ä loading bursting beads ä edge sealing ä several particles packed in boxes.

Step 1: Weigh and screen the materials, pass the dihydrate nicotine tartaric acid salts and xylitol through a 60-mesh sieve respectívely, pass microcrystalline cellulose, sodium bicarbonate, sodium carbonate, and neotame through a 40-mesh sieve respectively.

Step 2: Granulation step. Add menthol to purified water and dissolve it, then add sodium alginate and stir to completely dissolve it; then add flavors, cooling agents, and ethyl para ben to the above solution and continue to stir evenly as a granulation binder. Then Q) add the sieved dihydrate nicotine tartaric acid salt, xylitol, microcrystalline cellulose, sodium bicarbonate, sodium carbonate, and neotame to the wet granulator; and ®mix the above materials for 10 minutes at a stirring speed of 100 rpm and shear off, add the granulation adhesive, set the stirring speed, the actual speed is 100 rpm, and the shear is off. Slowly and evenly add the granulation adhesive solution to the granulator for about 4-6 minutes. After adding the adhesive, stop the machine to scrape the material on the wall and the stirring paddle, set the stirríng speed to 100 rpm and shear off, continue stirring for about 2 minutes, start granulation, stirring speed 150 rpm, shear 1500 rpm, granulate for 2-3 minutes, discharge, and pass through a 20-mesh sieve to the next drying step.

Step 3: Drying step. The inlet air temperature is 50°C, the humidity is 55%, the material temperature is 45°C, the drying time is 30 minutes, and the material is sieved through 20 mesh and 100 mesh after discharge to obtain nicotine dry particles.

Step 4: Particle packaging step. Put the granulated material into a powder silo of a granule packaging machine, put the blasting beads into the blasting bead silo, and put the non-woven fabric into the roll film silo for granule packaging. Granule packaging machine parameters: speed setting 120 particles/minute, 1 granule/pouch, horizontal sealing temperature setting 170°C, vertical sealing temperature 210°C. Each pouch comprises nicotine dry particles and 1 bursting bead.

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

Serial Material Name Percentage (%} Number Nicotšrwe Salt Dšlfwdrate 1 531% Tartrate 2 lxñicrocrystalline Celluiose 753096 3 Xylitoi 900% 4 Socšiiim Aiginate 0.40% 5 Sodium Bicarbonate 3 00% 6 Sodšuin Carbonate 010945 'i Neotarïae ilüêššsš 26 8 ix/ienthoå 933% 9 (Iooimg Agent 16993 1G Ethyi Paraben 512% 11 Lemon Fiavor 5.00°/¿S 12 Purified Xfvater Acšetgtzate íüüïë/a Bursting Bead (Cinnamøri 3.3 l piece Fiavør) Table 6: Lemon-flavored nicotine dry particles + bursting beads nicotine pouch prescription composition The in vitro dissolution data of nicotine dry particles in the nicotine pouch and the results of the bursting beads disintegration time experiment are shown in Table 7.

Nicotine Dry Particles ln Vitro Dissolution Data Time Dissolution Rate 5 rnšnutes 43% 1G minutes 58% 15 nxinutes 83% 2G minutes 8794; 3G rninutes 93% 45 inšrautes 98% 5G minutes 161% Bursting bead disintegration time 27 Status Tlnwe Complete Ûšssolutlon .11 rninlites Table 7: ln vitro díssolution data of nícotine dry particles and disintegration time of As can be seen from Table 7, when 40% of nicotine is released, the human body will directly feel the strong stimulation of nicotine on the oral mucosa, and at this time the bursting beads are completely disintegrated, just covering up the strong stimulation of nicotine, and mixed with the flavor in the nicotine dry particles, a new flavor will be formed. Table 7 describes the evaluation of the irritation and taste changes of the nicotine pouch through artificial sensory evaluation. The method is to have 8 experienced assessors conduct 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 aroma change. bursting beads Table 8: Sensory evaluation of the nicotine pouch Flavor After Starting Ending Flavol' Evaluator lšlirstlng Bead irritation Flavor (39 rnânutes) Ruptllre Evaluator 1 Lemon Cšnnamon Cola lVšild Evaluator 2 Lemon Clnnamon Cola Mild Evaluator 3 Lernon Cšnnamon Cola Nššld Evaluator f-l Lernon Cinnanlon Cola Mild Evaluator 5 Lemon Clnnaanon Cola n/šild Evaluator 5 Lemon Cinnamon Cola Niild Evaluator 7 Lernon Clnalamolw Cola n/lšltl Evaluator 8 Lernon Cšnnamon Cola lvššlcl 28 The results of embodiment 6 show that the nicotine pouch is composed of nicotine dry particles and bursting beads comprising flavors, and has a good nicotine release effect. The bursting beads disintegrate and effectively cover the irritation of nicotine, and mix with the flavors in the nicotine dry particles to produce new flavors, allowing users to feel the changes in different flavors.

Embodiment 7 The present embodiment describes the production process of nicotine pouches composed of nicotine wet particles and bursting beads, the formulation composition of one of the products, and in vitro dissolution and sensory evaluation thereof. Description of production process: Processing of raw materials (weighing and screening) à granulation (wet granulation) à whole particles à granule packagíng 9 loading into bursting beads à edge sealing å packing of several particles into boxes. Step 1: Weigh and screen the materials. Pass the dihydrate nicotine tartrate salt and mannitol through a 60-mesh sieve respectively; pass microcrystalline cellulose, calcium lactate, sodium bicarbonate, sodium carbonate, and acesulfame potassium through a 40-mesh sieve respectively.

Step 2: Granulation step. Add propylene glycol and glycerol to purified water and dissolve them, then add sodium alginate and stir to completely dissolve; then add flavors and cooling agents to the above solution and continue to stir evenly as a water- phase binder. Then Q) add the sieved dihydrate nicotine tartrate salt, mannitol, microcrystalline cellulose, calcium lactate, sodium bicarbonate, sodium carbonate, and acesulfame potassium into the wet granulator. ® Mix the above materials for 10 minutes at a stirring speed of 150rpm and shear off, add water-phase binder, set the stirring speed, the actual speed is 150rpm, and the shear is off. Add the aqueous phase adhesive solution slowly and evenly to the granulator for about 4-6 minutes. After adding the aqueous phase adhesive, stop the machine and scrape the material on the wall and the stirring paddle, set the stirring speed to 150rpm and shear off, continue stirring for about 2 minutes, start granulation, stir at 200rpm and shear at 1500rpm. After granulation for 2-3 minutes, discharge the material and pass through a 20-mesh sieve to obtain nicotine wet particles. 29 Step 3: Granule packaging step. Put the granulated material into a powder silo of a granule packaging machine, put the bursting beads into the bursting bead silo, put the non-woven fabric into the roll film silo, and package the particles. Granule packaging machine parameters: speed setting 120 particles/minute, bursting bead addition amount 2 particles/pouch: horizontal sealing temperature setting 170 °C, vertical sealing temperature 210°C. Each pouch comprises nicotine wet particles and at least 1 bursting bead.

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

Serial Material Name Percentage (fl/é) Number Nšcotšne Salt Dšhydrate 1 33-6910 Tartrate 2 íviicrocrystalline Celiuiose EšíHÉW/é 3 Niannítol 10113096 4 Acesulfarne 159% 5 Sodšurta Bicarbonate 350% 6 Sodium Carbonate 15995 7 Caícitsnï Lactate 2.ÜG% 8 Cooling Agent 030%» 9 Socåšurn Algšnate Oßflšfá 1G Propyierte Glycol 3.ü0*?/¿ Giyceršn 313993 12 Vvhšte Lerncm Fiavda' ÅOOÜ-á 13 iffurâfied Water öjüífi/e 169% Bursting Ešead (Cirmarnoiw 14 l piece Fiavor) Burstšng Bead (Soda kiiiater' 15 l piece Fiavor) Table 9: White lemon-flavored nicotine wet particles + cinnamon-flavored bursting beads + soda water-flavored bursting beads nicotine pouch prescription composition The in vitro dissolution data of nicotine wet particles in the nicotine pouch and the results of the bursting beads disintegration time experiment are shown in Table 10.

Nicotine Wet Particles ln Vitro Dissolution Data Time Dissfliutâdst Rate minutes 110% 1G rninzjtes 5194,- aninutes 89% 2G minutes 88% næirztates 92% 135 :minutes âïïá 6G minutes 10 36 Burstíng bead Dissolution Times Status Time 31 Complete Dissolution of Bursting 4.9 minutes bead 1 Complete Dissolution of Bursting X2 minutes bead 2 Table 10: ln vitro dissolution data of nicotine wet particles and disintegration time of burst beads lt can be seen from Table 10 that when 40% of nicotine is released, the human body will directly feel the strong stímulation of nicotine on the oral mucosa, and at this time, burst bead 1 completely disintegrates, just covering up the strong stimulation of nicotine, and mixing with the flavor in the nicotine wet particles, a new taste will be formed; then burst bead 2 will also disintegrate, and mix with other flavors in burst bead 1 and nicotine wet particles to form a new taste. Table 11 describes the evaluation of the irritation and taste changes of the nicotine pouch through artificial sensory evaluation. The method is to be evaluated by 8 experienced assessors, each of whom places a nicotine pouch on the upper lip and gums ofthe mouth and records the time and flavor of the nicotine pouch aroma change.

Flavor After Fiavor After Starting Bursting Ending Flavoa' iivaiuator Bursting Bead irritation Flavoa' Bead 2 (36 rninutes) 1 Rupture Rupture White Evaiuator 1 Cinnarraori Soda 'vkfater Cola iviild Lermon White Evaiuatoz' 2 Cinriarrlori Soda 'vVater Cola iviild Lermon White Evaiuator' 3 Cirinamon Soda Water Cola Mild Lemon Evaiuator 4 Wš . _ Cinnarrion Soda Water Cola iviild nte 32 Lemon Vi/hite Etaluator 5 Cinnamon Soda Water Cola Mild Lemon "tA/hite Evfaltsator 6 Cinnamozw Soda Water Cola Evlilcl Lernon Viihite Evaluator 7 Cinnamon Soda Water Cola Mild Lernon Vvhite Evaluater 8 Cinnanwoit Soda Water Cola EX/Ešlcl Lemon Table 11: Sensory evaluation of the nicotine pouch The results of Embodiment 7 show that the nicotine pouch is composed of nicotine wet particles and at least one bursting bead comprising flavors, and has a good nicotine release effect. The disintegration of the bursting bead can not only effectively cover up the irritation of nicotine, but also mix with the flavors in the nicotine wet particles to produce new flavors, and the disintegration of different bursting beads makes the flavors more varied. Let the user feel the changes in different flavors. Embodiment 8 The production process of nicotine pouches with nicotine oily particles and bursting beads, the prescription composition of one of the products, and in vitro dissolution and sensory evaluation thereof are shown in present embodiment.

Production process description: processing of raw materials and auxiliary materials (weighing and screening) 9 granulation (wet granulation) 9 whole particles 9 granule packaging 9 loading bursting beads 9 edge sealing 9 packing several particles into boxes.

Step 1: Weigh and screen the materials. Pass the nicotine-ß-cyclodextrin complex and maltitol through a 60-mesh sieve respectively; pass microcrystalline cellulose, calcium lactate, sodium carbonate, and acesulfame potassium through a 40-mesh sieve 33 respectively.

Step 2: Granulation step. Add medium-chain triglycerides, propylene glycol, and glycerol to purified water to dissolve, then add flavors, continue to stír evenly, and make an oil phase solution. Then ® add the sieved nicotine-ß-cyclodextrin complex, maltitol, microcrystalline cellulose, calcium lactate, sodium carbonate, and acesulfame potassium into the wet granulator. ®Mix the above materials at a stirring speed of 150 rpm and shear off for 10 minutes, add the oil phase solution, set the stirring speed, the actual speed is 150 rpm, and the shear is off. Slowly and evenly add the oil phase solution to the granulator for about 4-6 minutes. After adding the oil phase solution, stop the machine to scrape the material on the wall and the stirring paddle, set the stirring speed to 100rpm and shear off, continue stirring for about 2 minutes, and then start granulation. The stirring speed is 150rpm and the shear is 2000 rpm. After granulation for 2-3 minutes, the material is discharged and nicotine oily particles are obtained after passing through a 20-mesh sieve.

Step 3: Particle packaging step. Put the granulated material into a powder silo of a granule packaging machine, put the bursting beads into the bursting bead silo, put the non-woven fabric into the roll film silo, and carry out granule packaging. Granule packaging machine parameters: speed setting 120 grains/minute, bursting bead addition amount 1 grain/pouch: horizontal sealing temperature setting 170°C, vertical sealing temperature 210°C. Each pouch comprises nicotine oily particles and at least 1 bursting bead.

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

Serial Åfiaterial Name Percentage få) Nairnber Nicotine-ß-Cyclodextrân 1 759% Cornpiex 2 lviicrocrystallšswe Celiuiose 5282913 34 3 Xyištoi 219696 å Caiciuira Lactate lfiüíiá 5 Acesuäfante .LÜEFF/è 6 Sodium Carbenate ÜI/'Gäé Y Cocemat Oši 6,89% S Prczpyieiie Giycoš 190% 9 (šiycerin 2.28"š~6 10 Greene Fiaver 536% 159% Burstiaïg Bead (Choceiate 11 l piece Fiavørå Table 12: Grape-flavored nicotine oily particles + chocolate-flavored bursting beads nicotine pouch formula composition The in vitro díssolution data ofthe nicotine oily particles in the nicotine pouch and the results of the bursting beads disintegration time experiment are shown in Table 13.

Nicotine Oily Particles ln Vitro Dissolution Data Time Üšssoiutiøn Rate 5 rrainutes 44% 1G minutes 67% ilš rniniites 82941 2G aninutes 89% sninutes 45 :minutes 6G rnlnijtes 199% Bursting Bead Dissolution Time Status Time Coinplete Üissolution of bursting beads 13.5 rninutes Table 13: ln vitro dissolution data of nicotine oily particles and disintegration time of lt can be seen from Table 13 that when 40% of nicotine is released, the human body will directly feel the strong stímulation of nicotine on the oral mucosa, and at this time the bursting beads are completely disintegrated, just covering up the strong stímulation of nicotine, and mixed with the flavor in the nicotine oily particles, a new flavor will be formed. Table 14 describes the evaluation of the irritation and taste changes of the nicotine pouch through artificial sensory evaluation. The method is to evaluate by 8 experienced assessors, each assessor places a nicotine pouch on the upper lip and gums of the mouth, and records the time and flavor of the nicotine bursting beads pouch aroma change. :flavor After Starting Ending Flavor iívaluator Btsrstíawg irritation flavor (30 minutes) Bead Rupture Evaiuator l Greene Chocolate Durian Mild livaiuator 2 (irape Chocolate Durian lvliid Evaluator 3 Grape Chocolate Durian Mild Evaluator 4 Grape Chocolate Ekman lvlild 36 Eufaiuatoz' 5 Grape Chocolate Ûuršan Mild išvaiuator 5 Grape Chocolate Durian kflild Evaluator ? Grape Chocolate Durian Mild Evaiuator 8 Gra pe Chocolate Durian Nliid Table 14: Sensory evaluation of the nicotine pouch The results of embodíment 8 show that the nicotine pouch is com posed of nicotine oil particles and bursting beads comprising flavors, and has a good nicotine release effect. The bursting beads can effectively cover up the irritation of nicotine and mix with the flavors in the nicotine oil particles to produce new flavors, allowing users to feel the changes in different flavors.

Embodiment 9 Test the production process of nicotine pouches with nicotine pellets and bursting beads, the prescription composition of one of the products, and in vitro dissolution and sensory evaluation thereof.

Production process description: processing of raw materials (weighing and screening) à pelleting à granule packaging à loading bursting beads à edge sealing à packing several pellets into boxes.

Step 1: Weigh and screen the materials. Pass the dihydrate nicotine tartaric acid salt, ethyl cellulose, and talcum powder through a 40-mesh sieve respectively.

Step 2: Fluidized pelleting process: Q) Mix ethyl cellulose, magnesium stearate and methanol in a fluidized bed to coat the sugar pills with an isolation coat to obtain isolation layer pellets; ® then use methanol to dissolve nicotine tartrate dihydrate, mix with povidone and polysorbate 80, and then coat the isolation layer pellets in a fluidized bed to obtain drug-comprising layer pellets 1; ® use methanol to dissolve nicotine tartrate dihydrate, mix with povidone and magnesium stearate, and then coat the drug-comprising layer sustained-release pellets 1 to obtain drug-comprising layer pellets 2; and Qi) use methacrylic acid/ethyl acrylate copolymer, triethyl citrate and 37 purified water to make a coating solution, and coat the drug-comprising layer pellets 2 with a functional film coat on a fluidized bed to obtain nicotine pellet particles. Step 3: Granule packaging step. Put the granulated material into a powder silo of a granule packaging machine, put the blasting beads into the blasting bead silo, and put the non-woven fabric into the film roll silo for granule packaging. Granule packaging machine parameters: speed setting: 120 particles/minute, 1 granule/pouch, horizontal sealing temperature setting: 170°C, and vertical sealing temperature: 210°C. Each pouch comprises nicotine oily particles and at least 1 granule.

The prescription composition of the nicotine pouch is shown in Table 15.

Serial iviaterial Narne Percentage (9-(1) Number 11. Dihydrated Tartrate Nicotine Salt 2727426 2 Ethyl Ceilulose 136% 3 Talc 1l.9S% 4 Sugars (Sugar Balls) šššflffšíié 5 Povidorie üfišíié Methyl MethacrylatelAcrylšc Acid (5 119296 Copolyrïaer 3' Triethyl Cítrate 111.794» 8 lviagnesâtim Stearate Lïfišïí» E? šwlysorbate 80 931% 10 Nlertthoi 913395 ll Fiavoršrig Agent öíšíšäïé 38 33996 12 Burstiiig Bead 1 piece Table 15: Grape-flavored nicotine micro-pellet particles + mint-flavored bursting beads nicotine pouch prescription composition The in vitro dissolution data ofthe nicotine micro-pellet particles in the nicotine pouch and the results of the bursting beads disintegration time experiment are shown in Table 16. Nicotine Oily Particles ln Vitro Dissolution Data Table 16: ln vitro Time Dissolution Rate dissolution 5 rninutes 42% data Of nicotine 1G rnirsutes 59% _ micro- 15 rrainutes 55% penet particles 20 minutes 51% and :iainutes 63% 4.5 minutes 7296 5G niinutes 8?% 90 rrainutes 98% Bursting Bead Dissolution Time Status Time Compiete Dissolution of Bustíng Bead 4.9 rninutes disintegration time of bursting beads lt can be seen from Table 16 that when 20% of nicotine is released, the bursting beads 39 will disintegrate, and the flavor in the bursting beads will infiltrate the nicotine micro- pellet particles and mix with the flavor in the nicotine micro-pellet particles, effectively masking the strong stimulatíon of nicotine on the oral mucosa, while strengthening the aroma in the nicotine micro-pellet particles and keeping the aroma lasting. Table 17 describes the evaluation of the irritation and taste changes of the nicotine pouch through artificial sensory evaluation. The method is to be evaluated by 8 experienced assessors, each of whom places a nicotine pouch on the upper lip and gums of the mouth and records the time and aroma of the nicotine pouch.

Flavor Alter Starting Enclšrtg lïlavor Evaluator Burstlng Bead irritation Flavor (96 mšsiutes) Rupture Evaluatori Grape Mint Cool Grape ivlíld Evaluator 2 Grape lvlšnt Cool Grape ivlšlcl Evaluator 3 Grape Mint Cool Grape Mšlcl Evaluator ll Grape lvlšnt Cool Grape lvläld Exfaluator 5 Grape Mint Cool Grape Mild Evaluator 6 Grape lvlint Cool Grape ivlšlcl Evaluator 7 Grape lvlint Cool Grape Nlild Evaluator 8 Grape lvlint Cool Grape Milcl Table 17: Sensory evaluation of the nicotine pouch The results of embodiment 9 show that the nicotine pouch is composed of nicotine micro-pellet particles and bursting beads comprising flavors, and has a good nicotine release effect. The bursting beads can effectively cover up the irritation of nicotine and maintain the aroma in the nicotine micro-pellet particles.

The present invention provides an implementation scheme: ln order to investigate the law of changes in the relevant substances, properties and contents of the nicotine pouch over time under the influence of environmental factors (such as temperature and humídíty), the storage conditions and shelf life of the product are determined based on the data of the stability study.

Embodiment 10 The results of the long-term stability experiment of several combinations of nicotine pouches were tested. The storage conditions were: 25°C / 60% RH i 5% RH. Three batches of four types of nicotine pouches were tested, namely: nicotine dry particles + burst beads (batch numbers: 21081002, 21081003, 21081004), nicotine wet particles + burst beads (batch numbers: 21082301, 21082302, 21082303), nicotine oily particles + burst beads (batch numbers: 21090202, 21090203, 21090204), nicotine micro-pellet particles + burst beads (batch numbers: 21092501, 21092801, 21093001), and the observation time was 24 months. The long-term stability experiment data is summarized in Tables 18-29.

Through the trend analysis of the content data of the long-term stability test, the content values ofthe nicotine pouches of each batch number of the four combinations were within the qualified range under the long-term test conditions, and the changes in moisture and microorganisms were not obvious. The results met the stability quality standards of nicotine pouches. During the stability test, the results were relatively stable, with no obvious trend of change.

The results of embodiment 10 show that the properties of the four combinations of nicotine pouches did not change under the conditions of 25°C/60i5%RH (0-24M), and the contents were all within the qualified range. There were no significant changes in other inspection items. Based on the data in Tables 18 to 29, it can be determined that the shelf life of the nicotine pouches at room temperature is at least 24 months. 41 Product Name: Nicotirie Pouch Batch Num ber: 2110821002 Storage Conditions: 25i2°C _/ 501826 RH Active Ingredient: Nšcotine Formulation Type: Dry Partšcies Sampling Date: August 12, 2021 Specification: 4 mgjpouch (Mango Fåavor) Batch Size: 6000 pieces Packaging Description: pieces/box Production Address: Production Date: fäugust 10, Type: Long-terrn Stabiiity 2021 Study Time Point 0 Ni 3 M 6 ivi Ef: ivi 12 M 18 ivi 24 ivi 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Sarnpiing "time Study Date 2021 2021 2022 2022. 2023 2023 Testing Start 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Date 2021 2021 2022 2022 2022 2023 2023 Acceptabie Test item Resuit Standard kftlhíte to šight tfvhite White "vkfhite Vïjhšte kfiihite Vvhite Xftíhite Appearaiïce yeiiow partici partici partici partici partici partici partici particies es es es es es es es Retention time of the main identification peak in the: Comp! Compå Coinpi Compi Comp! Cox/dpi Compi HPLC ies šes ies ies ies ies ies sampie soiutšoai is consists-nt xwith 42 Product Name: Nšcotšrle Storage Conditions: Batch Number: 2110821002 Pouch 25i2°C _/ 5018126 RH Sampling Date: August Active Ingredient: Nšcotine Formulation Type: Dry' Partšties 12, 2021 Specification: 4 rngjpouch Packaging Description: Batch Size: 6000 pšeces (Mango Fåavor) 20 pieces/box Production Date: fäugust 10, Type: Long-terrn Stabiiity Production Address: Study Tšnïe Point Û M 3 M 6 EVE S? EVE 12 M 18 EVE 24 EVE 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Sanfipiing Tirne Study Date 2021 2021 2022 2022 2023 Tastingštart 12-08- 12-11- 12-02 12-05- 12-08- 12-02- 12-08- Date 2021 2021 2022 2022 2022 2023 that in the standard soEution; caicuiated based on puršty gfilgç-gfilltïgfyg 4.12m 412m 4.07m 4.28m 4.19m 4.20m 4.09m h hf! bi d s/pou you s/pou g/pou s/pou g/pou g/pou content t. aiee ch šPh ch ch ch ch Ch c amount 104.2 103% 101.8 107.1 104.8 105.0 102.2 % % % % % % Niošsture 380% 39% 4.4% 4.4% 4.2% 4.1% 43% 4.5% 43 Product Name: Nšcotirie Pouch Batch Num ber: 2110821002 Storage Conditions: 25i2°C _/ 501826 RH Active Ingredient: Nšcotine Formulation Type: Dry Partšcies Sampling Date: August 12, 2021 Specification: 4 rngipouch (Mango Fåavor) Batch Size: 6000 pšeces Packaging Description: pieces/bcsx Production Address: Production Date: fäugust 10, Type: íong-terrn Stabiiity 2021 Study Time Point 0 M 3 M 6 EVE Så FV! 12 M 18 EVE 24 FV! 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Sanfipiing Tirne Study Date 2021 2021 2022 202,2 2023 2023 Testing Start 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Date 2021 2021 2022 2022 2022 2023 2023 p" 3929-13 8.6 8.8 8.6 8.6 8.6 8.7 8.7 Tefitai aerobic bacteria; 1000 Cqmpl NA NA NA Compl NA Cqmpl _ |es |es |es ctujg Äiïšgmbíaå Tmtaš møids . . _ Comp! Clornpi Compi Limiß :md yeasts: NA NA NA NA ies ies ies 100 cftajg Controi bacteria: E. coh Comp! Comp: Comp: not detectabåe _ NA NA NA _ NA _ :es ses :es in lg Remarks: 44 Table 18: Summary of long-term stability experimental data of nicotine pouches (comprising nícotine dry particles with bursting beads) Batch number: 21081002 Product Name: Nícotine Pouch Batch Number: 21081003 Storage Conditions: 25i2°C f íšüišïé RH Active Ingredient: Nicetine Formulation Type: Dry Partšcies Sampling Date: August 12, 2021 Specification: 4 rnglpotactï (Ntango Fiat/or) Batch Size: 6000 pšeces pšecesjbox Packaging Description: 20 Production Address: Production Date: Ategtist 10, Type: Lang-term Stabiišty 2021 Stuciy 'Tïnte Point 0 ivi 3 tvi 6 M S? M 12 M 18 M 24 fvt 12-08- 12-11- 12-02- 12-05- 112-08- 12-02- 1.208- Sarttpiing Time Study Date 2021 2021 2022 2022 2022 2023 2023 Testing Sta rt 112-08- 12-11- 12-02- 12-05- 112-08- 12-02- 12-08- Date 2021. 2021: 2022 2022 2023 Aceeptabie "Test item Resuåt Standard Vïjhšte Vtihite White Xfvhite White White Vïfhite *tflihšte to Eight Appearence partšci partšci pertšci partici partšci partšci partšc! yeiionv partícåes es es es. es es es es identificatio Remntšon time Cornpi Cornpi Cernpi Compi Compi Comp! Cornpš n HPLC of the "min ies ies ies ies tes ies šes peak än the Product Name: Nicotisie Storage Conditions: 25i2°Cf Batch Number: 21681663 Poucifi öüiššá E-i Formulation Type: Dry Sampling Date: August 12, Active Ingredient: Nicotiaïe Particies 2021 Specification: 4 frag/'poucti Packaging Description: 2G Batch Size: šüüfi pieces (Marigo Fiavot) pieces/box Production Date: :Xugust 10, Type: Long-term Stabiiity Production Address: 2621 Study Time Point 0 Ni 3 M GM ååh/i 12 M 18 EVE 241V! 12438- 12-11- 12-9" 12-05- 12~O8~ 12112- 12-(18- Sampiing 'íime Study Date 2921 2621 2622 21322 2623 Tefitiiïgštart 12-118- 12-11- 1" 02- 12-05- 12-138- 12-122- 12-98- Date 2021 2021 2Ü22 2Ü22 2022 2023 2623 sanipie soiutšor: is consistent uvitifi that in the standard soiution; caicuiated based on purity gggtyylígmggg 4.11m 4.13m 4.08m 4.18m 4.19m 4.21m 4.08m n H b i d g/pou g/pou g/pou g/pou g/pou g/pou g/pou "ontem Û a aa ch ch ch ch ch ch ch ämmmï 102.8 103.3 102.0 104.5 104.8 105.3 102.0 % % % % % % % Moisture 3811910 21% 33% 3.294: 4.296 43% 531% Sååå 46 Product Name: Nšcotiswe Pouch Batch Number: 21681663 öÛÉSW/á E-i Storage Conditions: 25132121' Active Ingredient: Nicotšaïe Formulation Type: Dry Partâcies 2Û21 Sampling Date: August 12, Specification: 4 frag/'poucia (Marsgo Fiavor) Batch Size: šüüfi pieces pEeces/box Packaging Description: 2G Production Address: Production Date: :Xugust 10, Type: Long-term Stabiiity 2621 Study Time Point Û M 3 M 6 EVE E? EVE 12 M 18 EVE 24 EVE 12-98- 12-11- 12-92- 12-05- 12~Û8- 12-112- 12-(18- Sarnpiíng 'iâme Study Date 2921 2621 ZGZZ 2022 2623 2623 ïesting Start 12-58- 12-11- 12-02- 12-05- 12-138- 12422- 12-98- Date 2021 2021 2622 2Ü22 2022 2023 2023 pi-š 8.0 ~- 10,11 'ÅS 3.6 8.4 8.6 8,6 817 8.9 TotaE aerobic bactëna; :Gao Cqfflpi NA NA NA Compl NA Compl :es |es |es cfulg Nficïübšaí 'EotaE rnoEcEs and Ufiïiïß yfeasts; :om Compl NA NA NA Cqmpl NA Cgmpl _ |es |es |es cite/g Controi bacteria: E. coh Cqmpl NA NA NA Cémpl NA Cémpl not detecta bie |es |es |es in lg 47 Product Name: Nšcotiswe Pouch Batch Number: 21081003 öÛÉSW/á E-i Storage Conditions: 25132121' Active Ingredient: Nicotšaïe Formulation Type: Dry Partâcies 2021 Sampling Date: August 12, Specification: 4 ftag/'poucta (Marsgo Fiavor) Batch Size: 6000 pieces pEeces/box Packaging Description: 20 Production Address: Production Date: :Xugust 10, Type: Long-term Stabiiity 2021 Study Time Point 0 M 3 M 6 EVE Så EVE 12 M 18 EVE 24 EVE 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Sarnpiíng 'Eâme Study Date 2021 2021 2022 2022 2023 2023 Testing Start 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Date 2021 2021 2022 2022 2022 2023 2023 Remarks: Table 19: Summary of long-term stability experimental data of nicotine pouches (comprising nicotine dry particles with bursting beads) Batch number: 21081003 48 Product Name: Nšcotine Pouch Batch Number: 2108110011 Storage Conditions: 25ï2° 501-596 Rå-i Active Ingredient: Nšcotine Formulation Type: Dry Particåes Sampling Date: August 1,2, 2021 Specification: 4 rngfpoucit (it/tango Fšavor) Batch Size: 5000 pieces Packaging Description: 20 piecesfbox Production Date: August 110, Production Address: Type: Long-term Stabšiity Study 2021 Time Point 0 iVi 3 Ni 6 šVi 9 M 12 iVi 18 tvi 24 Ni 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Sarnpišrig Tinfie Study Date 2021. 2021. 2022 2023 2023 Testšngåtart 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Date 2021 2021 2022 2022 2022 2023 2023 Acceptabåe Test item Resuit Standard Whitßtßiigifit White vvhite White Appeai-ange www: amd artig; partšci partici particå partâci yeiåotftfparticies i L' p " p " gig ef, 9; es es es es Retentíon time of the main identification peak in tm Sampiesüiutšün Compl Compl Compl Compl Compl Compl Compl HPicC _ _ ies ies ies ies ies ies ies as con-existerat »with that in the standard 49 Product Name: Nšcotšne Pouch Batch Number: 2108110011 Storage Conditions: 25t2° 601-596 RH Active Ingredient: Nicfitine Formulation Type: Bry Particåes Sampling Date: August 1.2, 2021 Specification: 4 mgfpøucåï (Ft/tango Fiavor) Batch Size: 5000 pieces Packaging Description: 20 piecesfbox Production Address: Production Date: .Lïxfigusï 13.0, Type: Long-term Stabšiity Study 2021 Time Point 0 EVE 3 Ni 5 Ni 9 M 12 iVi 11.8 M 24 M 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Sarnpiirig Tinfie Study Date 20211. 2021. 2022 2023 2023 Testing Start 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Date 2021 2021 2022 2022 2022 2023 2023 soiution; caicušated hasaci on puršty gg, 9.5 _. 119 9.5 4.03m 4.06m 4.01m 4.11m 4.07m 4.18m 4.14m ß _ H b i á g/pou g/pou g/pou g/pou g/pou g/pou g/POU "Ûntenï Û a E Q ch ch ch ch ch ch ch ammmt 100.8 101.5 102.0 100.3 101.8 104.5 103.5 % % % % % % % Müšsïuïe Smfyé 3.7% 4.4% 47% 4.9% 5.1% 4.9% 5.3% pH 35 _ mg 8.3 8.8 8.5 8.9 8.2 8.7 8.4 Totai aerobic pvficrobiai Compl NA NA NA Compl NA Compl bacteria: 1000 ies ies ies Product Name: Nšcotšne Pouch Batch Number: 2108110011 Storage Conditions: 25ï2° 501-596 RH Active Ingredient: Nšcotine Formulation Type: Dry Particåes Sampling Date: August 1,2, 2021 Specification: 4 rngfïïwoucit (Et/Eango Fšavor) Batch Size: 5000 pieces Packaging Description: 20 piecesfbox Production Address: Production Date: August 13.0, Type: Long-term Stabšiity Study 2021 Time Point 0 EVE 3 EVE 6 EVE 9 M 12 EVE 11.8 M 24 M 12-08- 12-11- 12-02- 12-05- 12-03- 12-02- 12-08- Sarnpišrig Tinfie Study Date 20211. 20211. 2022 2023 2023 Testing Start 12-08- 12-11- 12-02- 12-05- 12-08- 12-02- 12-08- Date 2021 2021 2022 2022 2022 2023 2023 Limits cfu/g Totai rnoicäs and ygagïg; 103 Compl Compl Compl NA NA NA NA gfujg ies ies ies Controi bacteria: E. coii Compl Compl Compl not detectabie NÅ NÅ NÅ NÅ ies ies ies En lg Remarks: Tabie 20: Sumfnary of Fong-term stabišity experimentai data of raicotirie pouciäes (conwprâsšng nicotirae dry particies with bursting beadsf! Batch n u m ber: 2 Iiíšåftßüá Prociuct Name: Nšcotšite Pouch Batch Naim ber: 23282391 Storage Conditions: 25:2°C ftšfictšäéRH Active ingredient: Nicotine Formuiatšort Type: VVet Particies Sa rnpširtg Date: 23-98-2621 fliiingpoucta, Lemon Batch Size: 6909 pieces Packaging Description: 2G piecesfbox Production Address: Production Date: 23-03-2621 Type: Long-term Sta bšišty Tirne Point Ü M 3 Ni S IV! 9 Ni 12 Ni 13 iVi 24 Ni 23-98- 23-112- ZS-OZ- 23-65- 23-68- 23-52- 23-98- Sampåing Date Study Date 2021 2921 2922 2922 2622 2623 2023 Testing Start 23-98- 23-1 i- 23-02- 23-95- 23-68- 23-92- 23-98- Date 2021 2922 2922 2622 2023 292% Acceptaiaie 'test Etenfi Rtëstiit Standard White to Eight Mkfhšte *Jx/hite White "Afnite White käfhite White Appearaitce yešiow partici partici partšci particš partic! partšcí partici partšcies es es es es es es es Retention time ot the main icšentificatioit pêak in the Cornpi Coinpi Comp! Compi Compi Cornpi Cornpi HPLC Sanmie ies tes ias Ees šes. tes ies soiutíon Es consístent *iivith Product Narne: Nšcotšrxe Paxach Batch Nurn ber: Zilüååšišülí Storage Concäštiüns: 25iZ°C /êüišïéíši-i Active ârxgredšaswt: Nšcotšswa Førrnuiatiøn 'Yypez *vä/et Partšcies Sampiíng Daïe: 23-68-2021 àmg/pouch, Lemon Batch Size: 6996 gaieces Packaging Description: 28 pšecesfbox Pmduction .f-Xddress: Production Date: 23-98-2621 Type: Lang-term Sta bšišïy Tirne Point GM SM êšívi Qivi íZM 18 M 24 iv! 23-08- 23-11- 23-02- 23-125- 23-98- 22-02- 23-08- Searnpišrag Date Studg/Date 202l 2G21 2022 2022 2022 2923 2023 Testšngštart 23-08- 23-11- 23-02- 23-65- 23-98- 23-02- 23-08- Date 2921 2Ü2l 2022 2022 2622 2923 2G23 thatin tha standard soiutifin; caicuäaxïeci based on puríïy 405m fšßišnw êíšïnfi 496m 410m 4_O9m 412m 9G.Ü°/"- _ s/pfiu sfp-mf s/sfifiu g/mu g/afløu sfpßu gipßu líüiYš/.w of KlIc-aïtent ch ch ch ch ch ch ch iabeied 161.3 ÉGGB lüilšš 331.5 102.5 103.9 aanount 9-6 'šá % % % 91% 96 Nïfiisture 6°/ø-15.0"}í= 82996 8.896 âššäá 822% 813% 713% 721% Product Narne: Nšcotirxe Pauch Batch Nurn ber: 2Ii_08230li_ Storage Concištšens: 25i2°C /êüišïéíši-i Active ingredient: Nicotšsie Particies Førrnuiatian 'Yypez *tå/et Saitipiíng Date: 23-08-2021 Limg/pouch, Lemon Batch Size: 6000 gaieces Packaging Description: 20 piecesfbox Prnduction .f-Xddress: Production Date: 23-08-2021 Type: Lang-term Sta bâišty Tirne Point 0 EVE 3 Evi 6 Ni 9 ívi 12 EVE 18 Ni 24 ivi 23-08- 23-11- 23-02- 23-05- 23-08- 22-02- 23-08- Searnpiing Date Study Date 2021 2021 2022 2022 2022 2023 2.023 Testing Start 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Date 2021 2021 2022 2022 2022 2023 2023 pH 3.010,0 8.9 8.8 8,4 3:3 8.2 8.1 8.2 "iotai aerobšc Compi Compi Camp! bacteria: 1000 NA NA NA NA ies šes ies cfu/g Tata! rnoids Cnmpi Camp! Cempi and g/easts: 100 NA NA NA NA Mšcrobiai Limits _ ies ies ies cfuig Cantrai bacteria: E, ccviš Cørripi Compi Cornpi NA NA NA NA nat detectabie ies ies šes in íg Product Narne: Nšcotiixe Storage Concištšens: 25i2°C Batch Nurn ber: 2Ii_0823üli_ Petich /SÜiSÉ/QRE-i Førrnuiatian 'Yypez *tå/et Active ingredient: Nicotšswe Saitipiíng Date: 23-08-2021 Particies Packaging Description: 20 Limg/pouch, Lemon Batch Size: 6000 gaieces piecesfbox Preduction .f-Xddress: Production Date: 23-08-2021 Type: Lang-term Sta bäišty Time Point 0 EVE 3 EVE 6 Ni 9 M 12 EVE 18 Ni 24 M 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Searnpiing Date Study Date 2021 2021 2022 2022 2022 2023 2023 Testíngšïart 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Date 2021 2021 2022 2022 2022 2023 2023 Rerrtarks: 'iàhie 21: Surnrnargf of Ecmg-terrn stabiiity experirrierita! data ef riicotiree peuches (ceanprisšrig aiicetine wet gz-articies with bursting beads) Batch mim ber: 21082301 Woduct Narne: Nšcotšræe Peach Baïch Number: 21082302 Storage Conditions: 25i2°C föütšïéRH Acïšve ângredšeafit: Nšcotšswe Forrnuiatiflra 'ïypez Wei Partšcies Sampišng Date: 235-082021 Specšficatšon: lä-rwagfpcsuch, Lerner: Batch Size: 5000 pieces íäckagirsg Descriptâofæ: 20 pšecesfhcsx Pmcš uctšfin Acšcš ress: Production Date: 23-08- Type: Lang-term Sia bšišty 2021 Tšmeflæinï ÜêVE BM SM QEVE "tššßfl íåšêvi ZÅM Sampišawg 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Daïe 2021 2021 2022 2022 2022 2023 2023 Eštxjdyílate T . 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- estmg _ 2021 2021 2022 2022 2022 2023 2023 Btarïüate Acceptahi Test item Resuit eíštandard Whâteto Eight Whšïe Vïjhite White üvhíte XÅ/hite Vvhšïe Vvhšte Åüšíïëäfafïfië partici partšc! partici parïäci partici partšci partšci yeiåøw es es es es es es es partšcies Retentíon timeof |def1tifi<ïati0n COYWPÉ Cfimifiš Compå Cømpi Cornpš Cornpåi Compi themain HPLC E95' ses ies ies šes es ie: peakin " " ' " " the Woduct Narne: Nšcotšræe Pøuch Baïch Number: 21082302 Storage Conditions: 25i2°C föütšïéRH Acïšve ângredšaafit: Nšcotšswa Formuiatiflra 'ïypez Wei Partšcies Sampišng Date: 235438-2021 Specšficatšon: lä-rwagfpcsuch, Lermon Batch Size: 5000 pieces íäckagirsg Descriptâofæ: 20 pšacesfhcsx Pmd uctšfin Add mass: Production Date: 23-08- Type: Lang-term Sia hšišty 2021 Time Qzßinï 0 M 3 M 6 M 9 EVE 1,2. M 18 M 24 EVE Sampišawg 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Study Datæ Daïe 2021 2021 2022 2022 2022 2023 2023 Tastmg 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Staflüate 2021 2021 2022 2022 2022 2023 2023 sample solution is consístent withthat inthe standard solution; calculated basedon purüy 4.08m 4.11m 4.09m 4.l2m 4.05m 4.07m 4.08m C<>*ffef" gym/sv g/pou g/pou g/pou g/pou g/pou g/pou g/POU llüggá m: ch ch ch ch ch ch ch Woduct Narne: Nšcotirie Pøuch Batch Number: 21082302 Storage Conditions: 25i2°C /êI-Ütšïéiši-i Active ângrediaafit: Nicotšswa Forrnuiatiflra 'ïypez hVet Partšcies Sampišng Date: 235-082021 Specificatšon: limgfpcsuch, Lermon Batch Size: 5000 gaieces iäckagirsg Description: 20 pšecesfhcsx Pmcš uctštsn Acšci mass: Production Date: 23-08- Type: Lang-term Sta bšiity 2021 Time 905m 0 iVi 3 Ni 6 M 9 EVE 1.2. Ni 18 iVi 24 EVE Sampiiawg 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Date 2021 2021 2022 2022 2022 2023 2023 Study Data T . 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- astmg _ 2021 2021 2022 2022 2022 2023 2023 Btart Date Eabeâed 102.0 102.8 102.3 103.0 101.3 101.8 102.0 ammmt % % % % % % % iviflfßtufe 6%-15.0% 9.6% 9.3% 9.2% 37% 35% 7.9% 7.3% pH 8.0-10.0 9.1 8.9 8.7 8.4 8.3 8.3 8.1 Total aerobic Compl Compl Compl NA NA NA NA bacteria: ies ies ies Microbial Limits 1000 cfu/g Total Compl Compl Compl molds and NA NA NA NA ies ies ies yeasts: Woduct Narne: Nšcotirie Potacit Batch Number: 21082302 Storage Conditions: 25i2°C /êI-Ütšïéíšl-l Active âragredieafit: Nšcotšswe Particies Forrnuiatiora 'ïypez hliiet Sampišng Date: 235-082021 Specificatšon: lä-rwtgfpouch, Lerin-on Batch Size: 5000 gaieces iäckagirsg Description: 20 pšecesfhox Procš tsctšon Acšcl ress: Production Date: 23-08- Type: Long-term Sta bšlity 2021 TimePoint ülvi Sån/i SM Qivi .tšiivi íåšivi ZAR/E Sampimg 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Date 2021 2021 2022 2022 2022 2023 2023 Ešttidyilate T . 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- estmg 1 2021 2021 2022 2022 2022 2023 2023 Btartüate 100cfu/g Control bacteria: Compl Compl Compl E. coli not NA NA NA NA ies ies ies detectable in lg Remarks: Table 22 Summary of long-term stability experimental data of nicotine pouches (comprising nicotine wet particles with bursting beads) Batch number: 21082302 Product Name: Nicotine Pouch Batch Number: 21082303 Storage Conditions: 25i2°=lI /60i5%RH Active Ingredient: Nicotine Formulation Type: Wet Particles Sampling Date: 23-08-2021 Specification: 4mg/pouch, Lemon Batch Size: 6000 pieces Packaging Description: 20 pieces/box Production Address: Production Date: 23- Type: Long-term Stabilíty 08-2021 TimePoint OM 3M 6M 9M 12M 18M 24M 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Study Sampling Date 2021 2021 2022 2022 2022 2023 2023 Date TestingStart 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Date 2021 2021 2022 2022 2022 2023 2023 Acceptable Test Item Result Standard White White White White White White White Appeara White to light particl particl particl particl particl particl particl nce yellow particles es es es es es es es Retention time of the main peak in thesample solution is ldentific consistentwith Compl Compl Compl Compl Compl Compl Compl ation that in the ies ies ies ies ies ies ies HPLC standard solution; calculated based on purity 90.0%-110.0% 4.14m 4.13m 4.12m 4.14m 4.09m 4.11m 4.08m Content oflabeled g/pou g/pou g/pou g/pou g/pou g/pou g/pou amount ch ch ch ch ch ch ch Product Name: Nicotine Batch Storage Conditions: 25i2°=lI Pouch Number: 21082303 /60i5%RH Formulation Type: Wet Active Ingredient: Nicotine Sampling Date: 23-08-2021 Particles Specificatíon: 4mg/pouch, Packaging Description: 20 Batch Size: 6000 pieces Lemon pieces/box Production Date: 23- Production Address: Type: Long-term Stabilíty 08-2021 Time Point 0 M 3 M 6 M 9 M 12 M 18 M 24 M 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Study Sampling Date 2021 2021 2022 2022 2022 2023 2023 Date Testing Start 23-08- 23-11- 23-02- 23-05- 23-08- 23-02- 23-08- Date 2021 2021 2022 2022 2022 2023 2023 103.5 103.5 103.0 103.5 102.3 102.8 102.0 % % % % % % % Moisture 6%-15.0% 9.9% 9.6% 9.5% 9.1% 8.8% 8.4% 7.9% pH 8.0-10.0 9.0 8.8 8.9 8.7 8.4 8.5 8.3 Total aerobic Compl Compl Compl bacteria: 1000 NA NA NA NA ies ies ies cfu/g Microbia Total molds and Compl Compl Compl NA NA NA NA I Limits yeasts: 100 cfu/g ies ies ies Control bacteria: Compl Compl Compl E. coli not NA NA NA NA ies ies ies detectable in 1g Remarks: Table 23: Summary of long-term stability experimental data of nicotine pouches (comprising nicotine wet particles with bursting beads) Batch number: 21082303 61 Product Name: Nicotine Pouch Batch Number: 21090202 Storage Conditionsz25i2°flï /60i5%RH Active Ingredient: Nicotine Formulation Type: Wet Particles Sampling Date:02-09-2021 Specifícation: 4mg/pouch mint Batch Size: 6000 pieces Packaging Description: 20 pieces/box Production Address: Production Date: 02- Type: Long-term Sta bility 09-2021 Time Point OM 3M 6M 9M 12M 18M 24M 02-09- 02-12- 02-03- 02-06- 02-09- 02-03- 02-09- Study Sampling Date 2021 2021 2022 2022 2022 2023 2023 Date TestingStart 02-09- 02-12- 02-03- 02-06- 02-09- 02-03- 02-09- Date 2021 2021 2022 2022 2022 2023 2023 Acceptable Test Item Result Standard White White White White White White White Appeara White to light particl particl particl particl particl particl particl nce yellow particles es es es es es es es Retention time ofthemain peak in the sample solution ldentifica isconsistent Compl Compl Compl Compl Compl Compl Compl tion HPLC withthatínthe ies ies ies ies ies ies ies standard solution; calculated based on purity 90,0%~110,G% 416m ßníšnw 415m 415m 411m 414m 409m Content _ oflabelecl g/pou gigant: gjpot: gjpou gfpou g/pou g/pou 62 Product Name: Nicotine Batch Storage Conditionsz25i2°flï Pouch Number: 21090202 /60i5%RH Formulation Type: Wet Active Ingredient: Nicotine Sampling Date:02-09-2021 Particles Specifícation: 4mg/pouch Packaging Description: 20 Batch Size: 6000 pieces mint pieces/box Production Address: Production Date: 02- TVPGI LOHE-ïefm Sta bÜiïV 09-2021 Time Point 0 M 3 M 6 M 9 M 12 M 18 M 24 M 02-09- 02-12- 02-03- 02-06- 02-09- 02-03- 02-09- Study Sampling Date 2021 2021 2022 2022 2022 2023 2023 Date Testing Start 02-09- 02-12- 02-03- 02-06- 02-09- 02-03- 02-09- Date 2021 2021 2022 2022 2022 2023 2023 arnount ch ch ch ch ch ch ch 104.0 103.8 103.8 104.0 102.8 103.5 102.3 9% % 96 % % % "få Pifioisture 53% 21% 2.396 21% 259/:3 Zjïšá 3.193 3.596 pH 80-100 8.1 8.3 8.2 8.5 8.7' 8.9 otaš aerobšc Compi Comp! Compi bacteria: 1000 NA NÅ NA NA ies ies ies cfufg Totai moicis and Cornpi Cornpi Cornpi Pviicrobšai gfeasts: 100 NA NA NA NÅ šes ies šes Limits stilig Controi bacteria: E. coii Compi Comp! Conwpi NA NA NA NA not detectabie šes ies šes in ïg Remarks: Table 24 Summary of long-term stability experimental data of nícotine pouches 63 (comprising nicotine oily particles with bursting beads) Batch number: 21090202 Product Name: Nicetizwe Pouch Batch Number: 21082303 Storage Cczswditšoaws: 25i2°C Active ihgretišent: Nicatšne Formulation Type: Oily particies Sampling Date: 02-09-2021 Specifícation: limg/poucn, mi Fit Batch Size: 6000 pieces Packaging Descršptim: 20 piecesfbex Procitiction Aciciress: Production Date: 02- Tyiae: Long-term äta biiity 00-2021 Time Point 0 iVi 3 EVE 6 iVi 9 iVi 12 EVE 18 EVE 24 iVi Sainpiing 02-00-- 02--12- 02-03- 02--05- 02-09- 02-03- 02-09-- Stiidy Date Date 2021 2021 2022 2022 2023 2023 TestingStart 02-09- 02-12- 02-03- 02-05- 02-09- 02-03- 02-09- Date 2021 2021 2022 2022 2022 2023» 2023 Acceptabie Test item Resuit Standard Vilhitetniigiït i-Jilnite White White i/iihite tNhiïe White iliinšte Appezerance yeiiow partici partici partšci partici partici partici partici particies es es es es es es es Retention tinie oithe main peakin the sainpie soiutionis identification g Cømpi Coinpi Campi Compi Cempi Cnrnpi Cornpi cørisisteht i-EPLC ies ies ies ies ies ies ies *with that in the standard saiuticfn; caicuiated based on 64 Prnduct Name: Nicotšne Pouch Batsh Number: 21082303 Storage Cnndštioafis: 251232 Actšve ingredšent: Nšcntšne Formulation Type: Üšiy partšcies.

Sampling Date: 02-09-2021 Specifícation: Amgjpouch, rnš Mi Batch Size: 6000 pšaces Packaging Descršptinn: 20 pšeces/iacax Production Address: Prøductšøn Date: 02- "ï'ype: Long-term Sïa bšiity 09-2021 Time Point 0 Nä 3 EVE 6 Ni 9 M 12 EVE 18 Ni 24 :Vi Sainpåšng 02-09-- 02--12- 02-03- 02--06 02-09- 02-03- 02-09-- Stzjdy Date Date 20221 20211 202? 2023 2023 Testing Start 02-09- 02-12- 02-03- 02-05- 02-03- 02-09- Date 2021 2021 2022 2022 20222 2023» 2023 puršty 1118:11 4317:11 f-"Llšárn átllïm 412m 410m 1108:11 900% -- gjpou g/pou gfpou gipou g/ganu gfpfixs g/pau 1101396 of Cønïenï ch ch ch ch ch ch ch iabeied 104,5 104.3 104.3 104.0 103.0 102.5 102,0 arnount % % 9:3 % % % % tvioisture 55% 2.391 26% 2.996 3.296 Zfàfå/c 33% 559.3 pH 811-100 8.4 8.5 8.1 8.3 8.6 8.0 8.8 Tøtaš aernbšc (Ionapš Cønwpš Cørïapå bacteria: 100 NA NA NA NA ies Ees âes 0 cfu/g Toïai moids Cornpi Corrspš Cornpi iviicrobšai and yeasts: NA NA NA NA šes ies šes Limits 100 cfuig Cøntraš bacteria: E. Cornpi Compš Conmå NA NA NA NA cošš not šes šes šes deïectabše En Prnduct Name: Nicotšne Pouch Batch Number: 21082303 Storage Cnndštioafis: 252232 Actšve ingredšent: Nšcfitšne Formulation Type: Üšiy partšcies.

Sampling Date: 02-09-2021 Specifícation: LE-mgjpouch, mi Mi Batch Size: 6000 pšeces Packaging Descršptifin: 20 pšeces/bcax Production Address: Prøductšøn Date: 02- Type: Long-term Sia bšiity 09-2021 Time Pom: 0223 sm sm ewa 12221 10221 2421: sampsang 02-00-- 02--12- 02-02.-- 02--00 02-09- 02-03- 02-00-- 5221000222 02:e 2021 2021 2022 202:-: Tesxsngsrar: 02-00- 02-12- 02-03- 02-00- 02-00- 02-03- 02-09- Daxe 2021 2021 2022 2022 2022 2022 2022 12 Rerïaarks: Table 25: Summary of long-term stability experimental data of nicotine pouches (comprising nicotine oily particles with bursting beads) Batch number: 21090203 66 Prcrcšuct Name: Nšcotiafie Pøuch Batch Number: 21.090204 Storage Conáitšons: 25i2°C ffíüiïflšéRH Active Engredient: Nicutšne Formulation Type: Ûiiy particšas Sampling Date: 02-00-2021 Specification: flnwgfpoucifi, rninï Batch Siza: 5000 pšecas Packaging Descrâptšosw: 20 pieces/'bøx Production Address: Production Date: 02-09- 'ïypez Lørsg-ïerrïx Stabššâïy 2021 Tirne Püint OM EM 6EVE QFVE 125V? íâ-ÉM 24NE Sampiâiïg 02-09-- 02-»12- 02-03- 02-06- 0200-- 02-03-- 02-09-- Stlšdy Daïe Daïe 20211. 2021, 2.022 2022 2022 2023 2023 ïestšngStart 02-09- 02-12- 02-09- 02-06- 02-00- 02-03- 02-09- Elêate 2021 2021 2022 20212 2022 2023 2023 Accepmbie Test Emm Resuit Standard Vxihšteto "vvhíte kfiihite White Xfxíhite Whšte Whita Vvhšte Appearance išgšïtyeåiowv partšcš partšci partšci partici particš partšci partšcš parïícies es es es es es es es Retantäon time ofthe anašn peak in ïiwe sarnpie saiutiorïís ídentificatšan cømaistent Camp! Cornpi Conapå Cømpi Compi Comp! Cømpš HPLC uvíth that in šes šes ies has íes Ees šes the standard soiution; caicuiated based an purity Cfiment 900%- 4.12m 411m 415m lšflëårn 412m 409m 418m 67 Prcrcšuct Name: Nšcotiafie Pøuch Batch Number: 21990204 Storage Conüitšons: 25i2°C fííüiïflšéRH Active Engredieht: Nicutšne Formulation Type: Ûiiy particšas Sampling Date: 02-69-241321 Specification: flnwgfpoucifi, rninï Batch Siza: 5900 pšecas Packaging Descrâptšosw: 2O pieces/'bøx Productšøn Address: Production Date: 132-99- 'ïypez Lørsg-ïerrïx Stabššâïy 2021 Time Püint O NE 3 M 6 EVE 9 FV! 12 M 18 EVE 24 NE Sampišiïg 02-119-- 4312-12- 92-93- 02-66- 02-02- 02-433- (BE-GQ- Stlšdy Daïe Daïe 2Ü2I1. 25321, 2.022 2622 2022 21323 2623 Testing Start 02-59- 02-1 2- 62-0?- 02-66- GZ-OQ- 02-(33- 92-69- Elëzete 2621 2021 2022 29212 2022 2023 2023 1102096 of g/pou gipou g/pou g/pßu gfpcfu g/pou gjpou iabeiecš ch ch ch ch ch ch ch arnount 163.0 332.8 103 8 102.6 lÜ/Lš 152.3 1013-.5 9/6 "få % 96 94,- % % fvïnšsture 35% 19% 24% 2.894, 3.196 23% 3,495 3.996 pH 83-1110 8.5 8.5 3.2 8.7 8.5 814 8.9 Totaâ aembšc Compi Cornpå Compi bacteria: 106 NA NA NA NA _ šes ies has Ü :fu/g Tata! mošds and Camp! Cohfipi Cømpi NA NA NA NA Nïšcrobíai yæasts: lfiü šes Ses has Limits chi/g Cnntm! bacteria: E. Compi Compi Compi wii mi: NA NA NA. NA ies šes šes cietaëcïabie in ïêš 68 Product Name: Nicotine Storage Conditions: 251:2°C Batch Number: 21090204 Pouch /fiüi-Säí-.RH Formulation Type: Ûiiy Active ingredient: Nicotine Sampling Date: 02-09-2021 particies Specifícatíon: llnwgfpouch, Packaging Description: 20 Batch Size: 5000 pieces rnint pieces/'box Production Date: 02-09- Prodtectšon Address: Type: Lorsg-ternz Stabšiity 2021 Time Point 0 Ni 3 iVi 5 EVE 9 h!! 12 iVi 18 EVE 24 fvi Sampišiïg 02-09-- 02-»12- 02-03- 02-06- 02-09-- 02--03- 02-09-- Sttfidy Date Date 20211. 2021 2022 2022 2022 2023 2023 Testingštart 02-09- 02-12- 02-03- 02-06- 02-03- 02-03- 02-09- Date 2021 2021 2022 2022 2022 2023 2023 Reanarks: Table 26: Summary of long-term stability experimental data of nicotine pouches (comprising nicotine oily particles with bursting beads) Batch number: 21090204 Product Name: Nicotine Batch Storage Conditions: 25i-2°C Pouch Number:21092501 /60i5%RH Formulation Type: Micro- Active Ingredient: Nicotine Sampling Date: 2021.09.25 pellet particles Specifícatíon: 4mg/pouch, Packaging Description: 20 Batch Size: 6000 pieces vanilla pieces/box Production Address: Production Date: 2021.09.25 Type: Long-term Stability TimePoínt OM 3M 6I\/I 9M 12M 18M 24M 2021. 2021. 2022. 2022. 2022. 2023. 2023. Study Sampling Date: 09.25 12.25 03.25 06.25 09.25 03.25 09.25 Date 2021. 2021. 2022. 2022. 2022. 2023. 2023.

Testing Start Date 09.25 12.25 03.25 06.25 09.25 03.25 09.25 Testing Acceptable Standard Result Item 69 Product Name: Nicotine Pouch Batch Number:21092501 Storage Conditions: 25i2°=lI /60i5%RH Active Ingredient: Nicotine pellet particles Formulation Type: Micro- Sampling Date: 2021.09.25 Specification: 4mg/pouch, vanilla Batch Size: 6000 pieces Packaging Description: 20 pieces/box Production Address: Production Date: 2021.09.25 Type: Long-term Sta bílity Time Point 0 M 3 M 6 M 9 M 12 M 18 M 24 M 2021. 2021. 2022. 2022. 2022. 2023. 2023. Study Sampling Date: 09.25 12.25 03.25 06.25 09.25 03.25 09.25 Date 2021. 2021. 2022. 2022. 2022. 2023. 2023. Testing Start Date 09.25 12.25 03.25 06.25 09.25 03.25 09.25 White White White White White White White Appeara White to light yellow particl particl particl particl particl particl particl nce particles es es es es es es es ldentifica Retention time of tion the main peak in the HPLC sample solution is Compl Compl Compl Compl Compl Compl Compl consistent with that ies ies ies ies ies ies ies in the standard solution; calculated based on purity 4.20m 4.22m 4.18m 4.22m 4.16m 4.20m 4.21m 90.0% - 110.0% of g/pou g/pou g/pou g/pou g/pou g/pou g/pou Content labeled amount ch105 ch105 ch104 ch105 ch104 ch105 ch105 .0% .5% .5% .5% .0% .0% .3% Moisture 38% 4.8% 4.9% 5.2% 5.4% 5.3% 5.7% 6.3% pH 8.0-10.0 8.2 8.3 8.4 8.7 8.5 8.8 8.9 Total aerobic Compl Compl Compl Microbial NA NA NA NA bacteria:1000 cfu/g ies ies ies Limits Total molds and Compl NA NA NA Compl NA Compl Product Name: Nicotine Pouch Batch Number:21092501 Storage Conditions: 25i2°=lI /60i5%RH Active Ingredient: Nicotine Formulation Type: Micro- pellet particles Sampling Date: 2021.09.25 Specification: 4mg/pouch, vanilla Batch Size: 6000 pieces Packaging Description: 20 pieces/box Production Address: Production Date: 2021.09.25 Type: Long-term Sta bility Time Point 0 M 3 M 6 M 9 M 12 M 18 M 24 M 2021. 2021. 2022. 2022. 2022. 2023. 2023. Study Sampling Date: 09.25 12.25 03.25 06.25 09.25 03.25 09.25 Date 2021. 2021. 2022. 2022. 2022. 2023. 2023. Testing Start Date 09.25 12.25 03.25 06.25 09.25 03.25 09.25 yeasts:100 cfu/g ies ies ies Control bacteria: E. Compl Compl Compl coli not detectable NA NA NA NA ies ies ies in lg Remarks Table 27: Summary of long-term stability experimental data of nicotine pouches (comprising nicotine micro-pellet particles with bursting beads) Batch number: 21092501 71 Product Name: Nicotine Pouch Batch Number:21092801 Storage Conditions: 251-231". /60i5%RH Active Ingredient: Nicotine Formulation Type: Micro- pellet particles Sampling Date: 2021.09.28 Specification: 4mg/pouch ,vani||a Batch Size: 6000 pieces Packaging Description: 20 pieces/box Production Address: Production Date: Type: Long-term Stability 2021.09.28 TimePoint OM 3M 6M 9M 12M 18M 24M 2021. 2021. 2022. 2022. 2022. 2023. 2023. Sampling Date: StudyDate 09.28 12.28 03.28 06.28 09.28 03.28 09.28 2021. 2021. 2022. 2022. 2022. 2023. 2023. Testing Start Date 09.28 12.28 03.28 06.28 09.28 03.28 09.28 Acceptable Testing Item Result Standard White White White White White White White White to light Appearance particl particl particl particl particl particl particl yellow pa rticles es es es es es es es Retention time of the main peak in thesample solution is ldentificatio Compl Compl Compl Compl Compl Compl Compl consistent with n HPLC ies ies ies ies ies ies ies thatinthe standard solution; calculated based on purity 4.28m 4.26m 430m 4.29m 4.18m 4.24m 4.19m 90.0%-110.0%of g/pou g/pou g/pou g/pou g/pou g/pou g/pou Content labeledamount ch107 ch106 ch107 ch107 ch104 ch106 ch104 .0% .5% .5% .3% .5% .0% .8% 72 Product Name: Nicotine Pouch Batch Num ber:2109 2801 Storage Conditions: 251-231". /60i5%RH Active Ingredient: Nicotine Formulation Type: Micro- pellet particles Sampling Date: 2021.09.28 Specification: 4mg/pouch ,vani||a Batch Size: 6000 pieces Packaging Description: 20 pieces/box Production Address: Production Date: Type: Long-term Stability 2021.09.28 Time Point 0 M 3 M 6 M 9 M 12 M 18 M 24 M 2021. 2021. 2022. 2022. 2022. 2023. 2023. Sampling Date: Study Date 09.28 12.28 03.28 06.28 09.28 03.28 09.28 2021. 2021. 2022. 2022. 2022. 2023. 2023. Testing Start Date 09.28 12.28 03.28 06.28 09.28 03.28 09.28 Moisture 58% 5.4% 5.9% 6.3% 6.8% 6.8% 7.2% 7.4% pH 8.0-10.0 8.3 8.2 8.5 8.8 8.9 9.2 9.1 Total aerobic Compl Compl Compl bacteria:1000 NA NA NA NA ies ies ies cfu/g Microbial Total molds and Compl Compl Compl NA NA NA NA Limits yeasts:100 cfu/g ies ies ies Control bacteria: E. Compl Compl Compl coli not detectable NA NA NA NA ies ies ies in lg Remarks Table 28: Summary of long-term stability experimental data of nicotine pouches (comprising nicotine micro-pellet particles with bursting beads) Batch number: 21092801 73 Product Name: Nicotine Pouch Batch Number:21093001 Storage Conditions: 25i2°C /60i'5%RH Active Ingredient: Nicotine Formulation Type: Micro- pellet particles Sampling Date: 30-09-2021 Specification: 4mg/pouch ,vani||a Batch Size: 6000 pieces Packaging Description: 20 pieces/box Production Address: Production Date: 30-09- Type: Long-term Stability 2021 TimePoint OM 3M 6M 9M 12M 18M 24M 30-09- 30-12- 30-03- 30-06- 08-10- 30-03- 07-10- Study Sampling Date: 2021 2021 2022 2022 2022 2023 2023 Date 30-09- 30-12- 30-03- 30-06- 08-10- 30-03- 07-10- Testing Start Date 2021 2021 2022 2022 2022 2023 2023 Testing Acceptable Result Item Standard White White White White White White White Appea ra White to light particl particl particl particl particl particl particl nce yellow particles es es es es es es es Retention time of the main peak in ldentifíc the sample solution Compl Compl Compl Compl Compl Compl Compl ation is consistent with ies ies ies ies ies ies ies HPLC that in the standard solution; calculated based on purity 4.12m 4.16m 4.17m 4.21m 4.23m 4.10m 4.11m 90.0%-110.0%of g/pou g/pou g/pou g/pou g/pou g/pou g/pou Content labeledamount ch103 ch104 ch104 ch105 ch105 ch102. ch102. .0% .0% .3% .3% .8% 5% 8% Moistur 58% 5.0% 4.9% 5.9% 5.5% 5.9% 6.7% 7.0% e 74 Product Name: Nicotine Pouch Batch Number:21093001 Storage Conditions: 25i2°C /60i-5%RH Active Ingredient: Nicotine Formulation Type: Micro- pellet particles Sampling Date: 30-09-2021 Specification: 4mg/pouch ,vani||a Batch Size: 6000 pieces Packaging Description: 20 pieces/box Production Address: Production Date: 30-09- Type: Long-term Stability 2021 Time Point 0 M 3 M 6 M 9 M 12 M 18 M 24 M 30-09- 30-12- 30-03- 30-06- 08-10- 30-03- 07-10- Study Sampling Date: 2021 2021 2022 2022 2022 2023 2023 Date 30-09- 30-12- 30-03- 30-06- 08-10- 30-03- 07-10- Testing Start Date 2021 2021 2022 2022 2022 2023 2023 pH 8.0-10.0 8.3 8.2 8.5 8.8 8.9 9.2 9.1 Total aerobic Compl Compl Compl NA NA NA NA bacteria:1000 cfu/g ies ies ies Total molds and Compl Compl Compl Microbi NA NA NA NA yeasts:100 cfu/g ies ies ies al Limits Control bacteria: E. Compl Compl Compl coli not detectable NA NA NA NA ies ies ies in lg Remarks Table 29: Summary of long-term stability experimental data of nicotine pouches (comprising nicotine micro-pellet particles with bursting beads) Batch number: 21093001 ln summary, a preferred solution provided by the present invention is: nicotine dihydrate tartaric acid nicotine salt and nicotine-ß-cyclodextrin complex are selected for nicotine; and neotame or acesulfame potassium is selected for sweetener. The nicotine pouch absorbed by the oral mucosa provided by the present invention and the preparation method thereof, the particles of nicotine and the bursting beads are encapsulated by non-woven fabric, and the moisture content in the particles of nkoflneisconvofledtoenmuethelongterniflabflüyoftheparfldesofnKoüne,and the bursting beads added are rapidly disintegrated in saliva, and the disintegration time is basically the same as the time when the nicotine release in the particles of nicotine reaches the mucosal irritation, which can effectively cover up the irritation caused by nicotine and enhance the aroma in the particles of nicotine; when multiple bursting beads are used, in addition to the taste masking effect, the bursting beads of different flavors will quickly mix to form a variety of flavors, improving the user's experience; the stability test results of the nicotine pouch provided by the present invention show that the shelf life of the nicotine pouch at room temperature is at least 24 months, with better stability. The present invention provides a nicotine pouch which can maintain fragrance for a long time, effectively mask the irritating sense of nkoünqreæasenkofinequkfiyandconflnuouflyandhasalongshefilfieandcanbe absorbed through the oral mucosa.

The above descriptions are some preferred embodiment ofthe present invention, and do not limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made by using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims (9)

Claims

1. A nicotine pouch for oral mucosal absorption, comprising particles of nicotine, bursting beads wherein at least one of the bursting beads compríses liquid, and non-woven pouches, wherein the particles of nicotine and the bursting beads are encapsulated in the non-woven pouches, and each of the non-woven pouches compríses 1 to 3 bursting beads; wherein when the particles of nicotine are dry particles, the dry particles comprise particle sizes of 1-1000 microns and moisture content ranging from 1% to 10% (W/W); when the particles of nicotine are wet particles, the wet particles comprise particle sizes of 1-1000 microns and moisture content ranging from 5% to 15% (W/W); when the particles of nicotine are oily particles, the oily particles comprise particle sizes of 1-1000 microns and moisture content ranging from 1% to 10% (W/W); or when the particles of nicotine are micro-pellet particles, the micro-pellet particles comprise particle sizes of 30-2500 microns and moisture content ranging from 1% to 10% (W/W).

2. The nicotine pouch for oral mucosal absorption according to claim 1, wherein the dry pa rticles comprise particle sizes of 1-700 microns and moisture content ranging from 1% to 8% (W/W); the wet particles comprise particle sizes of 1-700 microns and moisture content ranging from 6% to 15% (W/W); the oily particles comprise particle sizes of 1-700 microns and moisture content ranging from 1% to 5% (W/W);or the micro-pellet particles comprise particle sizes of 30-2000 microns and moisture content ranging from 1% to 8% (W/W).

3. The nicotine pouch for oral mucosal absorption according to claim 1, wherein the particles of nicotine comprise one or more combinations of nicotine, sugar alcohols, cellulose and cellulose derivatives, pH regulators, adhesives, oily su bstances, sweeteners, flavors and fragrances, hydrophilic sugar-based pellet cores and/or hydrophobic cellulose pellet cores, polymer coating materials and preservatives.

4. The nicotine pouch for oral mucosal absorption according to claim 3, wherein the nicotine comprises 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 comprises 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 thereof; and a content of nicotine base in the nicotine is 1 mg/g-80 mg/g.

5. The nicotine pouch for oral mucosal absorption according to claim 3, wherein the dry particles do not comprise oily substances, hydrophilic sugar-based pellet cores and/or hydrophobic cellulose pellet cores; the wet particles may or may not comprise oily substances, and may not comprise hydrophilic sugar-based pellet cores and/or hydrophobic cellulose pellet cores; the oily particles comprise oily substances but do not comprise hydrophilic sugar-based pellet cores and/or hydrophobic cellulose pellet cores; and the micro-pellet particles may or may not comprise oily substances, hydrophilic sugar-based pellet cores and/or hydrophobic cellulose pellet cores.

6. The nicotine pouch for oral mucosal absorption according to claim 3, wherein the sugar alcohols are polyols comprising two or more hydroxyl groups used as a thickener, an adhesive and/or a sweetener or a stabilizer, the sugar alcohols comprise one or more combinations of propylene glycol, xylitol, maltítol, mannitol, erythritol, isomalt and lactitol; and a content of the sugar alcohols is 3%-30% (W/Wl-

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

8. The nicotine pouch for oral mucosal absorption according to claim 7, wherein the cellulose and cellulose derivatives comprise a water binding capacity of at least 200%, and the cellulose and cellulose derivatives are able to be partially or completely dissolved in the nicotine pouch.

9. The nicotine pouch for oral mucosal absorption according to claim 3, wherein the pH regulators com prise one or more com binations of monocarbonate, bicarbonate and carbonate, acetate, lactate, glycinate, gluconate, borate, sulfate, glycerophosphate and citrate, and a content of the pH regulators is 0.5%-20% (W/Wl- The nicotine pouch for oral mucosal absorption according to claim 3, wherein the adhesives comprise one or more combinations of povidone, cellulose derivatives, pregelatinized starch, syrup, gelatin, gum ara bic, sodium alginate and polyethylene glycol, and a content of the adhesives is 0%-10% (W/W). The nicotine pouch for oral mucosal absorption according to claim 3, wherein the oily substances are lipid substances or substances with emulsifying ability, including one or more combinations of glycerol, fatty acids with carbon ion numbers between 6 and 24 (C6-C24), monostearate, sucrose esters, soybean lecithin, egg yolk lecithin, glycocholic acid, Tween and one or more combinations of various vegetable oils, and a content of the oily su bstances is 0%-25% (W/W). The nicotine pouch for oral mucosal absorption according to claim 3, wherein the sweeteners comprise one or more combinations of aspartame, acesulfame potassium, sodium cyclamate, saccharin, saccharin sodium, sucralose, neotame, sodium cyclamate, stevioside, licorice, disodium glycyrrhízinate, tripotassium and trisodium glycyrrhízinate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar and lactose, sorbitol, maltitol, isomalt, palatinol, xylitol, lactitol, mannitol, erythritol and dextran, and a content of the sweeteners is 0.2%-10% (W/W). The nicotine pouch for oral mucosal absorption according to claim 3, wherein flavors and fragrances comprise 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, vanillaflavor, lime flavor, apple flavor, peach flavor, mango flavor, cherry flavor, blueberry flavor, strawberry flavor, cola flavor, cinnamon flavor and watermelon flavor, and a content of the flavors and fragrances is 2%-10% (W/W). The nicotine pouch for oral mucosal absorption according to claim 3, wherein diameters of the hydrophilic sugar-based pellet cores and/or the hydrophobic cellulose pellet cores are less than 1000 microns, the hydrophilic sugar-based pellet cores are sucrose blank pellets or starch blank pellets, the hydrophobic cellulose pellet cores are microcrystalline cellulose blank pellets, and a content of the hydrophilic sugar-based pellet cores and/or the hydrophobic cellulose pellet cores is 20%-90% (W/W). .The nicotine pouch for oral mucosal absorption according to claim 3, wherein the polymer coating materials comprise sugar materials or polymer materials, the sugar materials comprise one or more com binations of syrup, colored syrup, glue, talcum powder or white wax, the polymer materials comprise 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, cellulose acetate phthalate, and a content of the polymer coating materials is 5%-15% (W/W). The nicotine pouch for oral mucosal absorption according to claim 3, wherein the preservatives comprise one or more com binations of sorbic acid and salts thereof, dehydroacetic acid and sodium salts thereof, parabens, sodium diacetate, calcium propionate and sodium/calcium lactate, and a content of the preservatives is 0.1%- 2% (W/W). The nicotine pouch for oral mucosal absorption according to claim 1, wherein the bursting beads comprise encapsulating materials and liquid materials contained in the encapsulating materials, and diameters ofthe bursting beads are S 10 mm. .The nicotine pouch for oral mucosal absorption according to claim 17, wherein the encapsulating materials comprise one or more of following materials: I. edible materials made of one or more of alginate, carrageenan, sodium cellulose sulfate, chitosan, bovine gelatin, pectin and Wax;ll. materials that can be dissolved in oral cavíties made of one or more ofsugar coating, starch, hydroxypropyl methylcellulose; and |||. plastic materials made of one or more of PP, PET, PE, HDPE, LDPE, PC and PS. .The nicotine pouch for oral mucosal absorption according to claim 17, wherein the liquid materials comprise one or more of cooling agents, acidity regulators, anticaking agents, antioxidants, colorants, flavor enhancers, moisture retainers, preservatives or sweeteners. A nicotine pouch preparation method used for preparing the nicotine pouch for oral mucosal absorption according to claim 1, comprising: Sl-weighing raw materials of the nicotine pouch; S2-sequentíally putting the raw materials into a wet granulator or a fluidized bed or a centrifugal granulator according to a prescription for granulation and/or coating; S3-putting the particles of nicotine obtained by granulation into a drying oven or a fluidized bed for drying or coating; and S4-transferring the particles of nicotine dried to a particle packaging machine, and putting the bursting beads and non-woven fabric coils at a same time, and putting the particles of nicotine and the bursting beads into the non-woven fabric pouches for encapsulation to obtain the nicotine pouch. . The nicotine pouch preparation method according to claim 19, wherein particle sizes of granulated particles in S2 are 20-40 meshes, drying temperature in S3 is 40- 60°C, and horizontal sealing temperature during packaging in S4 is l60-200°C and vertical sealing temperature is 200-360°C.