WO2025118169A1 - Nicotine pouch absorbed by oral mucosa and preparation method therefor - Google Patents

Abstract

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

Description

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

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

Background Art

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 product. They are made by mixing nicotine base or nicotine salt or nicotine complex/adsorbent with fillers, dispersants, lubricants, sweeteners, flavors, acid-base regulators, adhesives and other materials to form particles, and then put them into small non-woven bags. When consumers use nicotine pouches, the saliva in the mouth will moisten the nicotine pouch in the non-woven bag, release nicotine from the composite particles, and absorb it into the human body through the oral mucosa. The flavor substances such as flavors and fragrances added to nicotine bags can not only enrich the flavor of the product, but also promote saliva secretion and increase the dissolution of effective ingredients in the product.

However, since nicotine produces spicy and irritating taste when released, it causes discomfort to the user. The aroma in the bag will also fade over time, resulting in a difference in taste. In order to solve the irritation problem of nicotine release, some people have improved the nicotine bag prescription. For example, patents with publication numbers CN1561214A and WO2003/026655 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 dissolution 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 CN101437496A and WO2007/104575 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, and is used 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.

In order to improve user compliance, patents with publication numbers CN102076362A and WO2009/134947 relate to a nicotine lozenge composition, which includes 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. In one embodiment, the average in vivo dissolution 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.

In order to achieve a nicotine bag with good taste and fast oral absorption, patents with publication numbers CN104169346A 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. It can provide a satisfactory tactile and/or flavor experience while also providing an extended release time of the additive. However, the mouth-stable polymer matrix in the nicotine bag includes polyurethane and a large amount of plasticizers, which will affect the rapid release of nicotine. The dissolution data of the nicotine bag is not mentioned in the patent description, so we cannot assume that the nicotine bag has the effect of rapidly releasing nicotine.

In order to solve the problem of nicotine rapid release, it can also be continuously released for a considerable time, and it is necessary to have a good taste. The patents of publication number CN104271137A and WO2013/147687 illustrate a powdered nicotine oral delivery product encapsulated in a water-insoluble bag, wherein the powder includes at least nicotine and a chewing gum composition, wherein the bag is permeable to saliva and dissolves part of the powder therein, releasing part of nicotine and other components, such as chewing the bag can further promote nicotine release, and continuing to chew will cause the chewing gum composition in the bag 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 bag 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 granules and nicotine slow-release granules, 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 WO2021/053078 describe oral delivery products encapsulated in non-woven bags 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 bag products. Similarly, none of the above patents describe whether the irritation of nicotine can be reduced.

In order to keep the aroma in the tobacco nicotine bag for a long time without weakening due to oxidation, etc., Publication No. CN111035047A provides a buccal tobacco product, including tobacco material and at least one popping bead, by encapsulating liquid substances and/or extract substances that easily induce the deterioration of tobacco material in the popping bead, thereby improving the stability of the buccal tobacco product and enriching the taste of the buccal tobacco. However, the invention encapsulates the popping bead and the tobacco material together in a non-woven bag. Although the problem of aroma retention is solved, traditional plant tobacco is still used, which is different from the modern popular nicotine bag mainly composed of synthetic nicotine.

The prior art has not provided a nicotine bag 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 invention

The prior art has not been able to provide a nicotine bag 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 bag for oral mucosal absorption and a preparation method thereof to solve the above problems.

To achieve the above-mentioned object, in a first aspect, the present invention provides a nicotine bag for oral mucosal absorption, the nicotine bag comprising nicotine particles, at least one bursting bead containing liquid and a non-woven bag, the nicotine particles and the bursting bead are encapsulated in the non-woven bag, and the number of the bursting beads contained in each non-woven bag is 1 to 3, wherein:

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

The nicotine particles are wet particles, the particle size of the wet particles is 1-1000 microns, and the moisture content ranges from 5% to 15% (W/W); or

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(2) Materials that can be dissolved in the oral cavity, made of one or more of sugar coating, starch, and hydroxypropyl methylcellulose;

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

In one implementation, the liquid substance includes one or more of a cooling agent, an acidity regulator, an anti-caking agent, an antioxidant, a colorant, a flavor enhancer, a humectant, a preservative, or a sweetener.

In a second aspect, the present invention further provides a method for preparing a nicotine bag, which is used to prepare the above-mentioned nicotine bag absorbed through the oral mucosa, and the specific steps include:

S1. Weighing the raw materials of the nicotine bag;

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

S3, placing the nicotine particles obtained by granulation into a drying oven or a fluidized bed for drying or coating;

S4, transferring the dried nicotine granules to a granule packaging machine, putting the popping beads and the non-woven fabric coil into the machine, and placing the nicotine granules and the popping beads into the non-woven fabric bag for packaging to obtain the nicotine bag.

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

Beneficial effects: The nicotine bag for oral mucosal absorption provided by the present invention and the preparation method thereof, the nicotine particles and the popping beads are encapsulated by non-woven fabric, and the moisture content in the nicotine particles is controlled to ensure the long-term stability of the nicotine particles. At the same time, the popping beads added are rapidly disintegrated in saliva, and the disintegration time is basically the same as the time for the nicotine release in the nicotine particles to reach the mucosal irritation, which can effectively mask the irritation caused by nicotine and enhance the aroma in the nicotine particles; when multiple popping beads are used, in addition to the taste masking effect, the popping beads of different flavors will quickly mix to form a variety of flavors, improving the user's experience; the nicotine bag provided by the present invention has a shelf life of at least 24 months at room temperature, and has better stability. The present invention provides a nicotine bag for oral mucosal absorption that 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.

DETAILED DESCRIPTION

[Corrected 23.04.2024 in accordance with Article 91]
In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the description of the terms "one embodiment", "some embodiments", "example", "specific example", 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. In 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 bag for oral mucosal absorption, the nicotine bag comprising nicotine particles, at least one bursting bead containing liquid and a non-woven bag, the nicotine particles and the bursting bead are encapsulated in the non-woven bag, and the number of the bursting beads contained in each non-woven bag is 1 to 3, wherein:

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

The nicotine particles are wet particles, the particle size of the wet particles is 1-1000 microns, and the moisture content ranges from 5% to 15% (W/W); or

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

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

Among them, 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 particles are moist and have good fluidity; the characteristics of micro-pellets are that the particles are dry, in the form of small balls, and have good fluidity. Preferably, the particle size of the dry particles is 1-700 microns, and the moisture content ranges from 1% to 8% (W/W); the particle size of the wet particles is 1-700 microns, and the moisture content ranges from 6% to 15% (W/W); the particle size of the oily particles is 1-700 microns, and the moisture content ranges from 1% to 5% (W/W); the particle size of the micro-pellets is 30-2000 microns, and the moisture content ranges from 1% to 8% (W/W).

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

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

Specifically, the nicotine refers to any form of nicotine and nicotine derivatives, and the nicotine includes 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, and the non-covalently bound nicotine includes nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, and nicotine benzoate. One or more mixtures; the content of nicotine base in the nicotine is 1 mg/g-80 mg/g. Preferably, the nicotine comprises one or more combinations of nicotine base, nicotine tartrate dihydrate, nicotine cyclodextrin embedding complex, nicotine-resin complex and nicotine benzoate.

Specifically, the sugar alcohol is a polyol containing more than two hydroxyl groups used as a thickener, adhesive and/or sweetener or stabilizer, and the sugar alcohol includes one or more combinations of propylene glycol, xylitol, maltitol, mannitol, erythritol, isomalt and lactitol, and the content of the sugar alcohol is 3%-30% (W/W). Preferably, the sugar alcohol is 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, cocoa fiber, bran fiber, bamboo fiber, powdered cellulose and combinations thereof. The cellulose and cellulose derivatives include one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose, and the content of the cellulose and cellulose derivatives is 40%-85% (W/W). The cellulose and cellulose derivatives have a water binding capacity of at least 200%, and the cellulose and cellulose derivatives can be partially or completely dissolved in the nicotine bag. At the same time, the cellulose and cellulose derivatives are permeable to saliva.

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

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

Specifically, the oily substance refers to a pharmaceutically acceptable lipid substance or a substance with emulsifying ability. Specifically, the oily substance includes 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 various vegetable oils, and the content of the oily substance is 0%-25% (W/W). Preferably, the oily substance is one or more combinations of propylene glycol, glycerol, and medium-chain fatty acids (C6-C12).

Specifically, the sweetener refers to a sweet substance that is artificially synthesized and/or naturally extracted. The sweetener includes one or more combinations of aspartame, acesulfame potassium, sodium cyclamate, saccharin, saccharin sodium, sucralose, neotame, sodium cyclamate, asparagine phenylalanine methyl ester, stevioside, licorice, disodium glycyrrhizinate, tripotassium and trisodium glycyrrhizinate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar and lactose, sorbitol, maltitol, isomalt, palatinol, xylitol, lactitol, mannitol, erythritol and dextran, and the content of the sweetener is 0.2%-10% (W/W). Preferably, the sweetener is one or more combinations of mannitol, xylitol, maltitol, acesulfame potassium, neotame and sucralose.

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

Specifically, the hydrophilic sugar-based pellet core and/or the hydrophobic cellulose pellet core refer to the masterbatch necessary for preparing the skeleton-type micropellets, which is a spherical or quasi-spherical solid with a diameter of less than 1000 microns. Specifically, the hydrophilic sugar-based pellet core and/or the hydrophobic cellulose pellet core have a diameter of less than 1000 microns, the hydrophilic sugar-based pellet core is a sucrose blank pellet core or a starch blank pellet core, the hydrophobic cellulose pellet core is a microcrystalline cellulose blank pellet core, and the content of the hydrophilic sugar-based pellet core and/or the hydrophobic cellulose pellet core is 20%-90% (W/W). The preferred diameter is between 0.1mm-1.5mm. Preferably, the hydrophilic sugar-based pellet core and/or the hydrophobic cellulose pellet core is a hydrophilic sucrose pellet core or a hydrophobic microcrystalline cellulose.

Specifically, the polymer coating material refers to a sugar material or a hydrophilic/hydrophobic polymer material coated on a solid surface, so that it becomes a multifunctional protective layer of one or more layers of different thicknesses and elasticities that are tightly adhered to the surface. The polymer coating material includes a sugar material or a polymer material, and the sugar material includes one or more combinations of syrup, colored syrup, glue, talcum powder or white wax. The polymer material includes one or more combinations of cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose and hydroxypropyl cellulose, ethyl cellulose, methacrylic acid copolymer, methacrylate copolymer, and cellulose acetate phthalate. The content of the polymer coating material is 5%-15% (W/W). Preferably, the polymer coating material is one or more combinations of polymer materials that can be dissolved above pH 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 preservative includes one or more combinations of sorbic acid and its salts, dehydroacetic acid and its sodium salts, parabens, sodium diacetate, calcium propionate and sodium/calcium lactate, and the content of the preservative is 0.1%-2% (W/W). Preferably, the preservative is one or more combinations of parabens, lactates, sorbic acid and its salts.

Specifically, the bursting bead includes a packaging material and a liquid material contained in the packaging material, and the diameter of the bursting bead is ≤10 mm.

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

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

(2) Materials that can be dissolved in the oral cavity, made of one or more of sugar coating, starch, and hydroxypropyl methylcellulose;

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

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

The liquid substance comprises one or more of a cooling agent, an acidity regulator, an anti-caking agent, an antioxidant, a colorant, a flavor enhancer, a moisture retainer, a preservative or a sweetener.

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

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

S1. Weighing the raw materials of the nicotine bag;

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

S3, placing the nicotine particles obtained by granulation into a drying oven or a fluidized bed for drying or coating;

S4, transferring the dried nicotine granules to a granule packaging machine, putting the popping beads and the non-woven fabric coil into the machine, and placing the nicotine granules and the popping beads into the non-woven fabric bag for packaging to obtain the nicotine bag.

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

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

Production process of combination 1:

S11, material weighing;

S12, putting the materials into the wet granulator in order according to the prescription for granulation. The preferred process parameter is that the granules after granulation need to be sieved through a 20-40 mesh screen;

S13, drying process: placing the granulated nicotine particles into a drying oven or fluidized bed for drying. The preferred process parameters are drying at a temperature of 40-60°C;

S14, the dried nicotine dry particles are transferred to the powder silo of the particle packaging machine, and the weighed popping beads are placed in the popping bead silo of the particle packaging machine according to the prescription amount, and the non-woven fabric roll is placed in the roll film silo of the particle packaging machine. The particle packaging machine is started to perform the filling and packaging process. The 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 combination 2:

S21, material weighing;

S22, putting the materials into the wet granulator in order according to the prescription for granulation. The preferred process parameter is that the granules after granulation need to be sieved through a 20-40 mesh screen;

S23, transfer the nicotine oily particles that meet the requirements to the powder silo of the granule packaging machine, and also put the weighed popping beads into the popping bead silo of the granule packaging machine according to the prescription amount, and put the non-woven fabric roll into the roll film silo of the granule packaging machine. Start the granule packaging machine to perform the filling and packaging process. The preferred process parameters are that the horizontal sealing temperature during packaging is 160-180℃ and the vertical sealing temperature is 200-230℃.

Production process of combination 3:

S31, material weighing;

S32, putting the materials into the wet granulator in order according to the prescription for granulation. The preferred process parameter is that the granules after granulation need to be sieved through a 20-40 mesh screen;

S33, transfer the nicotine wet granules that meet the requirements to the powder silo of the granule packaging machine, and also put the weighed popping beads into the popping bead silo of the granule packaging machine according to the prescription amount, and put the non-woven fabric roll into the roll film silo of the granule packaging machine. Start the granule packaging machine to perform the filling and packaging process. The 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, it is divided into ① fluidized pelletizing process: the polymer coating material and the prepared materials are put into the spray gun silo, and the weighed solid materials including the pill cores are put into the solid silo of the fluidized bed or centrifugal granulator in sequence according to the prescription, and the machine is turned on to carry out fluidized bed granulation coating or centrifugal granulation coating process, and the material is evenly wrapped on the pill core to form one or more material layers. This process is suitable for producing nicotine pellets that achieve sustained release effects through functional coatings;② Extrusion spheronization pelleting process: various materials are put into the granulator according to the prescription to make wet materials; then transferred to the extruder, the wet materials are extruded through holes or sieves with a certain diameter by screw propulsion or rolling, and squeezed into cylindrical strip extrudates; these extrudates are piled on the self-rotating friction plate of the spheronization machine, and the extrudates are dispersed into smaller cylinders with a length equivalent to their diameter, and gradually rolled into spheres through continuous rolling friction; the formed spherical composition is dried; then the dried spherical composition is coated and transferred to the next process or directly transferred to the next process without coating. This process is suitable for producing nicotine particles that achieve sustained release effects in the form of skeletons.

S43, the dried nicotine granules are transferred to the powder silo of the granule packaging machine, and the weighed popping beads are placed in the popping bead silo of the granule packaging machine according to the prescription amount, and the non-woven fabric roll is placed in the roll film silo of the granule packaging machine. The granule packaging machine is started to perform the filling and packaging process. The preferred process parameters are that the transverse sealing temperature during packaging is 160-180°C and the longitudinal sealing temperature is 200-230°C.

The present invention is tested through multiple embodiments:

Example 1

The same dose (calculated as nicotine base) of nicotine tartrate dihydrate, nicotine-β-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 granules, and the headiness and irritation of different nicotine derivatives and nicotine were evaluated by artificial sensory evaluation. The results are shown in Table 1.

Table 1 Sensory evaluation of different nicotine derivatives

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

Example 2

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

Table 2 Prescription composition of different nicotine bags

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 Table 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.

Example 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.

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.

Example 4

The in vitro release of one of the nicotine pellets of the present invention is shown in Table 4.

Table 4 In vitro dissolution data of nicotine micropellets

Example 5

An embodiment provided by the present invention: Comparison of the disintegration time of the popping 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 popping bead of each material is soaked in the artificial saliva, and the disintegration time of each popping bead is recorded. In the same way, two of the nicotine bags 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 Table 5.

Table 5 Comparison of disintegration time of popping beads and nicotine release time

The results in Table 5 show that the irritation of nicotine depends on the concentration of nicotine release. When the nicotine release reaches about 40%, people will obviously feel mucosal irritation. The time point when the nicotine particles described in the present invention reach the mucosal irritation is basically about 5 minutes (except for nicotine micro-pellets). Some materials of bursting beads also disintegrate in about 5 minutes, which can just effectively cover up the irritation of nicotine. Different materials of bursting beads will cause them to disintegrate at different time points. This means that if more than one bursting bead is placed in the same nicotine bag, different flavors will be disintegrated at different times during use, giving different taste sensations. This is a design that was not available in previous products.

Example 6

The production process of nicotine bags composed of nicotine dry particles and bursting beads, the formula composition of one of the products, and its in vitro dissolution and sensory evaluation.

Description of production process: processing of raw materials and auxiliary materials (weighing and screening) → granulation (wet granulation) → boiling drying → granulation → granule packaging → loading of blasting beads → edge sealing → packing of several tablets into boxes.

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

Step 2: Granulation step. After menthol is dissolved in purified water, sodium alginate is added and stirred to completely dissolve; then flavors, cooling agents, and ethyl paraben are added to the above solution and continued to stir evenly as a granulation binder. Then ① add the sieved nicotine tartaric acid dihydrate salt, xylitol, microcrystalline cellulose, sodium bicarbonate, sodium carbonate, and neotame to the wet granulator. ② Mix the above materials for 10 minutes at a stirring speed of 100 rpm and shear off, add the granulation binder, set the stirring speed, the actual speed is 100 rpm, and the shear is off. Slowly and evenly add the granulation binder solution to the granulator for about 4-6 minutes. After the addition of the binder, stop the machine and scrape the material on the wall of the device and the stirring paddle, set the stirring 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, and the drying time is 30 minutes. After the material is discharged, it is sieved through 20 mesh and 100 mesh to obtain nicotine dry particles.

Step 4: Granule packaging step. Put the granulated material into the powder silo of the granule packaging machine, put the popping beads into the popping bead silo, put the non-woven fabric into the roll film silo, and pack the granules. Granule packaging machine parameters: speed setting 120 granules/minute, popping bead addition amount 1 granule/bag: horizontal sealing temperature setting 170℃, vertical sealing temperature 210℃. Each bag contains nicotine dry granules and 1 popping bead.

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

Table 6 Lemon-flavored nicotine dry particles + popping beads nicotine bag prescription composition

The in vitro dissolution data of the nicotine dry particles in the nicotine bag and the results of the bursting bead disintegration time experiment are shown in Table 7.

Table 7 In vitro dissolution data and disintegration time of nicotine dry particles

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 popping beads are completely disintegrated, just covering up the strong stimulation of nicotine, and mixed with the flavor in the nicotine dry particles, a new taste will be formed. Table 7 describes the evaluation of the irritation and taste changes of the nicotine bag through artificial sensory evaluation. The method is to have 8 experienced assessors conduct the evaluation, each assessor places a nicotine bag on the upper lip and gums of the mouth, and records the time and flavor of the nicotine bag aroma change.

Table 8 Sensory evaluation of the nicotine pouch

The results of Example 6 show that the nicotine bag is composed of nicotine dry particles and bursting beads containing flavors, and has a good nicotine release effect. The bursting beads disintegrate and effectively mask the irritation of nicotine, and mix with the flavors in the nicotine dry particles to produce new flavors, allowing users to experience changes in different flavors.

Implementation 7

The article describes the production process of nicotine bags that are a combination of nicotine wet particles and bursting beads, the formulation composition of one of the products, and its in vitro dissolution and sensory evaluation.

Description of production process: processing of raw materials and auxiliary materials (weighing and screening) → granulation (wet granulation) → granulation → granule packaging → loading of blasting beads → edge sealing → several tablets packed in boxes.

Step 1: Weigh and sieve the materials. Nicotine tartrate dihydrate and mannitol are sieved through a 60-mesh sieve respectively; microcrystalline cellulose, calcium lactate, sodium bicarbonate, sodium carbonate, and acesulfame potassium are sieved 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 until completely dissolved; then add flavors and cooling agents to the above solution, continue to stir evenly, as a water-phase adhesive. Then ① add the sieved dihydrate nicotine tartaric acid salt, mannitol, microcrystalline cellulose, calcium lactate, sodium bicarbonate, sodium carbonate, and acesulfame potassium to the wet granulator. ② Mix the above materials for 10 minutes at a stirring speed of 150rpm and shear off, add the water-phase adhesive, set the stirring speed, the actual speed is 150rpm, and the shear is off. Slowly and evenly add the water-phase adhesive solution to the granulator for about 4-6 minutes. After the water-phase adhesive is added, stop the machine and scrape the materials on the wall and the stirring paddle, set the stirring speed to 150rpm and shear off, continue stirring for about 2 minutes, start granulation, stirring speed 200rpm, shear 1500rpm, granulate for 2-3 minutes, discharge, pass through a 20-mesh sieve, and obtain nicotine wet granules.

Step 3: Granule packaging step. Put the granulated material into the powder silo of the granule packaging machine, put the popping beads into the popping bead silo, put the non-woven fabric into the roll film silo, and pack the granules. Granule packaging machine parameters: speed setting 120 granules/minute, popping bead addition amount 2 granules/bag: horizontal sealing temperature setting 170℃, vertical sealing temperature 210℃. Each bag contains nicotine wet granules and at least 1 popping bead.

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

Table 9 Composition of white lemon flavored nicotine wet granules + cinnamon flavored popping beads + soda water flavored popping beads nicotine bag prescription

The in vitro dissolution data of the nicotine wet particles in the nicotine bag and the results of the bursting bead disintegration time experiment are shown in Table 10.

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

As can be seen from Table 10, 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 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 the bursting bead 2 will also disintegrate, and mix with the other flavors in the bursting bead 1 and the nicotine wet particles to form a new taste. Table 11 describes the evaluation of the irritation and taste changes of the nicotine bag through artificial sensory evaluation. The method is to have 8 experienced assessors conduct the evaluation, each assessor places a nicotine bag on the upper lip and gums of the mouth, and records the time and flavor of the nicotine bag aroma change.

Table 11 Sensory evaluation of the nicotine pouch

The results of Example 7 show that the nicotine bag is composed of nicotine wet particles and at least one popping bead containing flavors, and has a good nicotine release effect. The disintegration of the popping 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 flavors are more varied with the disintegration of different popping beads, so that users can feel the changes in different flavors.

Example 8

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

Description of production process: processing of raw materials and auxiliary materials (weighing and screening) → granulation (wet granulation) → granulation → granule packaging → loading of blasting beads → edge sealing → several tablets packed in boxes.

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

Step 2: Granulation step. Add medium-chain triglycerides, propylene glycol, and glycerol to purified water to dissolve, then add flavors, continue to stir evenly, and make an oil phase solution. Then ① add the sieved nicotine-β-cyclodextrin complex, maltitol, microcrystalline cellulose, calcium lactate, sodium carbonate, and acesulfame potassium to the wet granulator. ② Mix the above materials for 10 minutes at a stirring speed of 150rpm and shear off, add the oil phase solution, set the stirring speed, the actual speed is 150rpm, and the shear is turned 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 off the materials 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 2000rpm. After granulation for 2-3 minutes, discharge the material and pass through a 20-mesh sieve to obtain nicotine oily particles.

Step 3: Granule packaging step. Put the granulated material into the powder silo of the granule packaging machine, put the popping beads into the popping bead silo, put the non-woven fabric into the roll film silo, and pack the granules. Granule packaging machine parameters: speed setting 120 granules/minute, popping bead addition amount 1 granule/bag: horizontal sealing temperature setting 170℃, vertical sealing temperature 210℃. Each bag contains nicotine oily granules and at least 1 popping bead.

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

Table 12 Formula composition of grape-flavored nicotine oily particles + chocolate-flavored popping beads nicotine bag

The in vitro dissolution data of the nicotine oily particles in the nicotine bag and the results of the bursting bead disintegration time experiment are shown in Table 13.

Table 13 In vitro dissolution data of nicotine oily particles and disintegration time of beads

As can be seen from Table 13, 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 popping beads are completely disintegrated, just covering up the strong stimulation of nicotine, and mixed with the flavor in the nicotine oil particles, a new taste will be formed. Table 14 describes the evaluation of the irritation and taste changes of the nicotine bag through artificial sensory evaluation. The method is to have 8 experienced assessors conduct the evaluation, each assessor places a nicotine bag on the upper lip and gums of the mouth, and records the time and flavor of the nicotine bag aroma change.

Table 14 Sensory evaluation of the nicotine pouch

The results of Example 8 show that the nicotine bag is composed of nicotine oily particles and bursting beads containing 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 oily particles to produce new flavors, allowing users to experience changes in different flavors.

Example 9

To test the production process of nicotine bags that are a combination of nicotine micropellets and explosive beads, the formula composition of one of the products, and its in vitro dissolution and sensory evaluation.

Description of production process: processing of raw materials and auxiliary materials (weighing and screening) → pelleting → granule packaging → loading of blasting beads → edge sealing → several pellets packed in boxes.

Step 1: Weigh and sieve the materials. Nicotine tartrate dihydrate, ethyl cellulose and talcum powder are sieved through a 40-mesh sieve respectively.

Step 2: Fluidized pelleting process: ① Mix ethyl cellulose, magnesium stearate and methanol in a fluidized bed and coat the sugar pills with an isolation coat to obtain isolation layer pellets; ② 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-containing layer pellets 1; ③ Use methanol to dissolve nicotine tartrate dihydrate, mix with povidone and magnesium stearate, and then coat the drug-containing layer sustained-release pellets 1 to obtain drug-containing layer pellets 2; ④ Use methacrylic acid/ethyl acrylate copolymer, triethyl citrate and purified water to make a coating solution, and coat the drug-containing 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 the powder silo of the granule packaging machine, put the popping beads into the popping bead silo, put the non-woven fabric into the roll film silo, and pack the granules. Granule packaging machine parameters: speed setting 120 granules/minute, popping bead addition amount 1 granule/bag: horizontal sealing temperature setting 170℃, vertical sealing temperature 210℃. Each bag contains nicotine oily granules and at least 1 popping bead.

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

Table 15 Grape-flavored nicotine pellets + mint-flavored nicotine bag formula composition

The in vitro dissolution data of the nicotine pellet particles in the nicotine bag and the results of the bursting bead disintegration time experiment are shown in Table 16.

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

As can be seen from Table 16, when 20% of nicotine is released, the popping beads will disintegrate, and the flavors in the popping beads will infiltrate the nicotine micro-pellets and mix with the flavors in the nicotine micro-pellets, effectively masking the strong stimulation of nicotine to the oral mucosa, while strengthening the aroma in the nicotine micro-pellets and keeping the aroma lasting. Table 17 describes the evaluation of the irritation and taste changes of the nicotine bag through artificial sensory evaluation. The method is to have 8 experienced assessors conduct the evaluation, each assessor places a nicotine bag on the upper lip and gums of the mouth, and records the time and flavor of the aroma change of the nicotine bag.

Table 17 Sensory evaluation of the nicotine pouch

The results of Example 9 show that the nicotine bag is composed of nicotine micro-pellets and bursting beads containing 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-pellets.

The present invention provides an embodiment: in order to investigate the change rules of the related substances, properties and contents of nicotine bags over time under the influence of environmental factors (such as temperature and humidity), the storage conditions and shelf life of the product are determined based on the data of stability research.

Example 10

The results of the long-term stability experiment of several combinations of nicotine bags were tested. The storage conditions were: 25℃/ 60% RH ± 5% RH. Three batches of four kinds of nicotine bags 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-pellets + burst beads (batch numbers: 21092501, 21092801, 21093001), and the observation time was 24 months. The long-term stability experiment data are summarized in Tables 18-29.

Through the trend analysis of the content data of the long-term stability test, the content values of the nicotine bags 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 bags. During the stability test, the results were relatively stable, with no obvious trend of change.

The results of Example 10 show that the properties of the four combinations of nicotine bags did not change under the conditions of 25°C/60±5%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 bags at room temperature is at least 24 months.

Table 18 Summary of long-term stability experimental data of nicotine bags (containing explosive nicotine dry granules)

Batch number: 21081002

Table 19 Summary of long-term stability experimental data of nicotine bags (containing explosive nicotine dry granules)

Batch number: 21081003

Table 20 Summary of long-term stability experimental data of nicotine bags (containing explosive nicotine dry granules)

Batch number: 21081004

Table 21 Summary of long-term stability experimental data of nicotine bags (containing explosive nicotine wet granules)

Batch number: 21082301

Table 22 Summary of long-term stability experimental data of nicotine bags (containing explosive nicotine wet granules)

Batch number: 21082302

Table 23 Summary of long-term stability experimental data of nicotine bags (containing explosive nicotine wet granules)

Batch number: 21082303

Table 24 Summary of long-term stability experimental data of nicotine bags (containing nicotine oily granules)

Batch number: 21090202

Table 25 Summary of long-term stability experimental data of nicotine bags (containing nicotine oily granules)

Batch number: 21090203

Table 26 Summary of long-term stability experimental data of nicotine bags (containing nicotine oily granules)

Batch number: 21090204

Table 27 Summary of long-term stability experimental data of nicotine bags (containing nicotine pellets)

Batch number: 21092501

Table 28 Summary of long-term stability experimental data of nicotine bags (containing nicotine pellets)

Batch number: 21092801

Table 29 Summary of long-term stability experimental data of nicotine bags (containing nicotine pellets)

Batch number: 21093001

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

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

Claims (21)

A nicotine bag for oral mucosal absorption, characterized in that the nicotine bag comprises nicotine particles, at least one bursting bead containing liquid and a non-woven bag, the nicotine particles and the bursting bead are encapsulated in the non-woven bag, and the number of the bursting beads contained in each non-woven bag is 1 to 3, wherein: The nicotine particles are dry particles, the particle size of the dry particles is 1-1000 microns, and the moisture content ranges from 1% to 10% (W/W); or The nicotine particles are wet particles, the particle size of the wet particles is 1-1000 microns, and the moisture content ranges from 5% to 15% (W/W); or The nicotine particles are oily particles, the particle size of the oily particles is 1-1000 microns, and the water content ranges from 1% to 10% (W/W); or The nicotine particles are micro-pellet particles, the particle size of the micro-pellet particles is 30-2500 microns, and the moisture content ranges from 1% to 10% (W/W). The nicotine bag for oral mucosal absorption according to claim 1, characterized in that the particle size of the dry particles is 1-700 microns and the moisture content ranges from 1% to 8% (W/W); or The wet granules have a particle size of 1-700 microns and a moisture content of 6%-15% (W/W); or The oily particles have a particle size of 1-700 microns and a water content of 1%-5% (W/W); or The particle size of the micro-pellets is 30-2000 microns, and the moisture content ranges from 1% to 8% (W/W). The nicotine bag for oral mucosal absorption according to claim 1, characterized in that the nicotine particles contain one or more combinations of nicotine, sugar alcohols, cellulose and cellulose derivatives, pH adjusters, adhesives, oily substances, sweeteners, flavors and fragrances, hydrophilic sugar-based pellets and/or hydrophobic cellulose pellets, polymer coating materials and preservatives. The nicotine bag for oral mucosal absorption according to claim 3, characterized in that the nicotine includes nicotine and nicotine derivatives, including: free base nicotine, nicotine salts, nicotine in 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, wherein the non-covalently bound nicotine includes nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin embedding complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, and nicotine benzoate. One or more mixtures; the content of nicotine base in the nicotine is 1 mg/g-80 mg/g. The nicotine bag for oral mucosal absorption according to claim 3 is characterized in that the material of the dry particles does not contain oily substances, does not contain hydrophilic sugar-based pellets and/or hydrophobic cellulose pellets; the material of the wet particles contains or does not contain oily substances, does not contain hydrophilic sugar-based pellets and/or hydrophobic cellulose pellets; the material of the oily particles contains oily substances, does not contain hydrophilic sugar-based pellets and/or hydrophobic cellulose pellets; the material of the micro-pellet particles contains or does not contain oily substances, contains or does not contain hydrophilic sugar-based pellets and/or hydrophobic cellulose pellets. The nicotine bag for oral mucosal absorption according to claim 3 is characterized in that the sugar alcohol is a polyol containing two or more hydroxyl groups used as a thickener, adhesive and/or sweetener or stabilizer, and the sugar alcohol includes one or more combinations of propylene glycol, xylitol, maltitol, mannitol, erythritol, isomalt and lactitol, and the content of the sugar alcohol is 3%-30% (W/W). The nicotine bag for oral mucosal absorption according to claim 3, characterized in that the cellulose and cellulose derivatives include one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose, and the content of the cellulose and cellulose derivatives is 40%-85% (W/W). The nicotine bag for oral mucosal absorption according to claim 7, characterized in that the cellulose and cellulose derivatives have a water binding capacity of at least 200%, and the cellulose and cellulose derivatives can be partially or completely dissolved in the nicotine bag. The nicotine bag for oral mucosal absorption according to claim 3, characterized in that the pH adjuster includes one or more combinations of monocarbonate, bicarbonate and carbonate, acetate, lactate, glycinate, gluconate, borate, sulfate, glycerophosphate and citrate, and the content of the pH adjuster is 0.5%-20% (W/W). The nicotine bag for oral mucosal absorption according to claim 3, characterized in that the adhesive comprises one or more combinations of povidone, cellulose derivatives, pregelatinized starch, syrup, gelatin, gum arabic, sodium alginate and polyethylene glycol, and the content of the adhesive is 0%-10% (W/W). The nicotine bag for oral mucosal absorption according to claim 3 is characterized in that the oily substance is a lipid substance or a substance with emulsification ability, including 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 the content of the oily substance is 0%-25% (W/W). The nicotine bag for oral mucosal absorption according to claim 3 is characterized in that the sweetener includes one or more combinations of aspartame, acesulfame potassium, sodium cyclamate, saccharin, saccharin sodium, sucralose, neotame, sodium cyclamate, stevioside, licorice, disodium glycyrrhizinate, tripotassium and trisodium glycyrrhizinate, glucose, fructose, sucrose, maltose, corn syrup, starch sugar and lactose, sorbitol, maltitol, isomalt, palatinol, xylitol, lactitol, mannitol, erythritol and dextran, and the content of the sweetener is 0.2%-10% (W/W). The nicotine bag for oral mucosal absorption according to claim 3 is characterized in that the flavors and fragrances include one or more combinations of bergamot flavor, eucalyptus flavor, citrus flavor, lemon flavor, peppermint flavor, mint flavor, menthol, licorice flavor, wintergreen flavor, tobacco flavor, coffee flavor, vanilla flavor, lime flavor, apple flavor, peach flavor, mango flavor, cherry flavor, blueberry flavor, strawberry flavor, cola flavor, cinnamon flavor and watermelon flavor, and the content of the flavors and fragrances is 2%-10% (W/W). The nicotine bag for oral mucosal absorption according to claim 3, characterized in that the diameter of the hydrophilic sugar-based pellet core and/or the hydrophobic cellulose pellet core is less than 1000 microns, the hydrophilic sugar-based pellet core is a sucrose blank pellet core or a starch blank pellet core, the hydrophobic cellulose pellet core is a microcrystalline cellulose blank pellet core, and the content of the hydrophilic sugar-based pellet core and/or the hydrophobic cellulose pellet core is 20%-90% (W/W). The nicotine bag for oral mucosal absorption according to claim 3 is characterized in that the polymer coating material comprises a sugar material or a polymer material, the sugar material comprises one or more combinations of syrup, colored syrup, glue, talcum powder or white wax, the polymer material comprises one or more combinations of cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose and hydroxypropyl cellulose, ethyl cellulose, methacrylic acid copolymer, methacrylate copolymer, and cellulose acetate phthalate, and the content of the polymer coating material is 5%-15% (W/W). The nicotine bag for oral mucosal absorption according to claim 3, characterized in that the preservative includes one or more combinations of sorbic acid and its salts, dehydroacetic acid and sodium salts, parabens, sodium diacetate, calcium propionate and sodium/calcium lactate, and the content of the preservative is 0.1%-2% (W/W). The nicotine bag for oral mucosal absorption according to claim 1 is characterized in that the bursting bead comprises a packaging material and a liquid substance contained in the packaging material, and the diameter of the bursting bead is ≤10 mm. The nicotine bag for oral mucosal absorption according to claim 17, characterized in that the packaging material comprises one or more of the following two materials: (1) Edible materials made from one or more of alginate, carrageenan, sodium cellulose sulfate, chitosan, bovine gelatin, pectin and wax; (2) Materials that can be dissolved in the mouth, made of one or more of sugar coating, starch, and hydroxypropyl methylcellulose; (3) Plastic materials made of one or more of PP, PET, PE, HDPE, LDPE, PC and PS. The nicotine bag for oral mucosal absorption according to claim 17, characterized in that the liquid substance includes one or more of a cooling agent, an acidity regulator, an anticaking agent, an antioxidant, a colorant, a flavor enhancer, a humectant, a preservative or a sweetener. A method for preparing a nicotine bag, characterized in that it is used to prepare the nicotine bag for oral mucosal absorption according to any one of claims 1 to 19, and the specific steps include: S1. Weighing the raw materials of the nicotine bag; S2. Put the materials into a wet granulator, fluidized bed or centrifugal granulator in sequence according to the prescription for granulation and/or coating; S3, placing the nicotine particles obtained by granulation into a drying oven or a fluidized bed for drying or coating; S4, transferring the dried nicotine granules to a granule packaging machine, putting the popping beads and the non-woven fabric coil into the machine, and placing the nicotine granules and the popping beads into the non-woven fabric bag for packaging to obtain the nicotine bag. The method for preparing a nicotine bag according to claim 19, characterized in that the granulated particles in S2 have a particle size of 20-40 mesh, the drying temperature in S3 is 40-60° C., and the transverse sealing temperature during packaging in S4 is 160-200° C. and the longitudinal sealing temperature is 200-360° C.