Buccal product and preparation method thereof

Abstract

The invention provides a buccal product and a preparation method thereof. In the application, the buccal product comprises the sustained-release agent, the sustained-release agent comprises at least one of a beta-cyclodextrin inclusion compound of the nicotine derivative and carboxylate of the nicotine derivative, and the sustained-release agent can enable the nicotine derivative to be uniformly, slowly and durably released in the oral cavity, so that the residence time of the nicotine derivative in the oral cavity is prolonged; therefore, the buccal product can keep stable strength for a long time, long-acting and mild physiological satisfaction is provided for consumers, and irritation to digestive tracts can be effectively reduced.

Description

Technical Field

[0001] The present application relates to the technical field of oral products, and in particular to an oral product and a preparation method thereof. Background Art

[0002] As the impact of cigarettes on health is increasingly valued and the comprehensive ban on smoking in public places is becoming more and more in-depth, new smoke-free oral products such as snus, nicotine lozenges, and nicotine gum are receiving more and more attention. Currently, nicotine derivatives or nicotine used in oral products are mostly added directly to the oral products in the form of liquid. The nicotine derivatives or nicotine in the oral products are released too quickly in the mouth, the initial strength is too strong and the strength is small in the later stage, and the smoke taste quickly fades during the entire oral process, affecting the consumer's experience. Summary of the invention

[0003] The embodiments of the present application provide an oral product and a preparation method thereof, which can improve technical problems such as the too fast release rate of nicotine derivatives or nicotine in the oral product in the oral cavity, too much strength in the early stage of oral administration and too little strength in the later stage, and rapid fading of tobacco flavor during the entire oral administration process, which affect consumers' usage experience.

[0004] In a first aspect, an embodiment of the present application provides an oral product, comprising a sustained-release agent, wherein the sustained-release agent comprises at least one of a β-cyclodextrin inclusion complex of a nicotine derivative and a carboxylate of a nicotine derivative.

[0005] In one embodiment, the carboxylate salt of the nicotine derivative comprises at least one of nicotine derivative ditartaric acid dihydrate and a resin carrier of a nicotine derivative.

[0006] In one embodiment, the nicotine derivative ditartaric acid dihydrate includes at least one of 2-methylnicotine ditartaric acid dihydrate, 6-methylnicotine ditartaric acid dihydrate, 2-ethylnicotine ditartaric acid dihydrate, 6-chloronicotine ditartaric acid dihydrate, and 4-trifluoromethylated nicotine ditartaric acid dihydrate; and / or

[0007] The resin carrier of the nicotine derivative includes at least one of a resin carrier of 2-methyl nicotine, a resin carrier of 6-methyl nicotine, a resin carrier of 2-ethyl nicotine, a resin carrier of 6-chloro nicotine, and a resin carrier of 4-trifluoromethylated nicotine; and / or

[0008] The nicotine derivative includes a pyridine ring substituted with a substituent, and the substituent includes at least one of a halogen, a C1-C2 alkyl group, and a trifluoromethyl group.

[0009] In one embodiment, the nicotine derivative includes at least one of 2-methyl nicotine, 6-methyl nicotine, 2-ethyl nicotine, 6-chloronicotine, and 4-trifluoromethylated nicotine.

[0010] In one embodiment, the oral product is a snus;

[0011] The sustained-release agent is a β-cyclodextrin inclusion complex of the nicotine derivative, the mass percentage of the β-cyclodextrin inclusion complex of the nicotine derivative in the oral product is 7.1%-14.9%, and in the β-cyclodextrin inclusion complex of the nicotine derivative, the molar ratio between the nicotine derivative and the β-cyclodextrin is (1-1.05):1; and / or

[0012] The sustained-release agent is the nicotine derivative ditartaric acid dihydrate, and the mass percentage of the nicotine derivative ditartaric acid dihydrate in the oral product is 2.9%-5.9%; and / or

[0013] The sustained-release agent is a resin carrier of the nicotine derivative, and the mass percentage of the resin carrier of the nicotine derivative in the oral product is 3.4%-5.7%; and / or

[0014] The oral preparation further comprises microcrystalline fiber, propylene glycol, water, food flavor, sodium chloride, sodium carbonate, acesulfame potassium, aspartame and vitamin E.

[0015] In one embodiment, the oral product is an oral tablet;

[0016] The sustained-release agent is a β-cyclodextrin inclusion complex of the nicotine derivative, the mass percentage of the β-cyclodextrin inclusion complex of the nicotine derivative in the oral product is 0.5%-2.2%, and in the β-cyclodextrin inclusion complex of the nicotine derivative, the molar ratio between the nicotine derivative and the β-cyclodextrin is (1-1.05):1; and / or

[0017] The sustained-release agent is the nicotine derivative ditartaric acid dihydrate, and the mass percentage of the nicotine derivative ditartaric acid dihydrate in the oral product is 0.2%-0.9%; and / or

[0018] The oral preparation further comprises mannitol, maltitol, xylitol, citric acid, magnesium stearate, anhydrous silica colloid, sodium bicarbonate, xanthan gum, food flavor, menthol and peppermint oil.

[0019] In one embodiment, the oral product is chewing gum;

[0020] The sustained-release agent is a β-cyclodextrin inclusion complex of the nicotine derivative, the mass percentage of the β-cyclodextrin inclusion complex of the nicotine derivative in the oral product is 0.8%-1.9%, and in the β-cyclodextrin inclusion complex of the nicotine derivative, the molar ratio between the nicotine derivative and the β-cyclodextrin is (1-1.05):1; and / or

[0021] The sustained-release agent is the nicotine derivative ditartaric acid dihydrate, and the mass percentage of the nicotine derivative ditartaric acid dihydrate in the oral product is 0.4%-0.8%; and / or

[0022] The sustained-release agent is a resin carrier of the nicotine derivative, and the mass percentage of the resin carrier of the nicotine derivative in the oral product is 0.3%-0.8%; and / or

[0023] The oral product further comprises chewing gum base, xylitol, food flavor, lecithin, carboxymethyl cellulose and vitamin E.

[0024] In a second aspect, an embodiment of the present application provides a method for preparing the oral product as described above, the method comprising the following steps:

[0025] Providing raw materials, wherein the raw materials include a sustained-release agent, wherein the sustained-release agent includes at least one of a β-cyclodextrin inclusion complex of a nicotine derivative and a carboxylate of a nicotine derivative;

[0026] The raw materials are mixed to obtain the oral product.

[0027] In one embodiment, the method for preparing the sustained-release agent comprises the following steps:

[0028] Adding a nicotine derivative into an aqueous solution of β-cyclodextrin so that the nicotine derivative enters the cavity of the β-cyclodextrin to obtain a first mixed solution containing a β-cyclodextrin inclusion complex of the nicotine derivative;

[0029] The first mixed solution is allowed to stand at low temperature, filtered, washed, and dried to obtain the sustained-release agent, wherein the sustained-release agent comprises the β-cyclodextrin inclusion complex of the nicotine derivative.

[0030] In one embodiment, the method for preparing the aqueous solution of β-cyclodextrin comprises the following steps: adding β-cyclodextrin to water, heating and stirring at 60° C.-80° C. until the β-cyclodextrin is completely dissolved, to obtain the aqueous solution of β-cyclodextrin; and / or

[0031] In the aqueous solution of β-cyclodextrin, the mass ratio of water to β-cyclodextrin is (8-10):1; and / or

[0032] In the step of adding the nicotine derivative to the aqueous solution of β-cyclodextrin, the molar ratio of the β-cyclodextrin to the nicotine derivative is 1:1.05, and / or the nicotine derivative and the aqueous solution of β-cyclodextrin are mixed by stirring, the stirring and mixing temperature is 60° C.-80° C., and the stirring and mixing time is 2 h-4 h; and / or

[0033] The low temperature standing temperature is 0°C-6°C, and / or the low temperature standing time is 20h-26h; and / or

[0034] The drying is vacuum drying, the temperature of the vacuum drying is 40° C.-50° C., and / or the vacuum degree of the vacuum drying is 0.05 MPa-0.2 MPa.

[0035] In one embodiment, the method for preparing the sustained-release agent comprises the following steps:

[0036] Providing a nicotine derivative and a tartaric acid solution, wherein the nicotine derivative has a pyridine ring substituted with a substituent, the substituent comprising at least one of a halogen, a C1-C2 alkyl group, and a trifluoromethyl group, and the tartaric acid solution comprises tartaric acid;

[0037] adding the nicotine derivative to the tartaric acid solution so that the nicotine derivative undergoes an acid-base neutralization reaction with the tartaric acid to obtain a second mixed solution containing nicotine derivative ditartaric acid dihydrate;

[0038] Refrigerating and crystallizing the second mixed solution, filtering, washing, and drying to obtain the sustained-release agent;

[0039] Wherein, the sustained-release agent includes the nicotine derivative ditartaric acid dihydrate.

[0040] In one embodiment, the preparation method of the tartaric acid solution comprises the following steps: dissolving the tartaric acid in ethanol to obtain the tartaric acid solution, wherein the weight ratio of the ethanol to the tartaric acid is (3-5):1, and / or the ethanol is 95% ethanol; and / or

[0041] In the step of adding the nicotine derivative to the tartaric acid solution, the nicotine derivative and the tartaric acid solution are mixed by stirring, the stirring and mixing temperature is 20° C.-30° C., and / or, the stirring and mixing time is 3 h-4 h, and / or, the molar ratio of the tartaric acid to the nicotine derivative is (2-2.05):1; and / or

[0042] The temperature of the refrigerated crystallization is 0-4°C, and / or the time of the refrigerated crystallization is 16h-20h.

[0043] In one embodiment, the method for preparing the sustained-release agent comprises the following steps:

[0044] A nicotine derivative and a resin suspension are provided, wherein the nicotine derivative has a pyridine ring substituted with a substituent, the substituent includes at least one of a halogen, a C1-C2 alkyl group, and a trifluoromethyl group, and the resin suspension includes a resin, and the resin has a carboxyl group;

[0045] adding the nicotine derivative to the resin suspension so that the nicotine derivative undergoes an acid-base neutralization reaction with the resin to obtain a third mixed solution of the resin carrier containing the nicotine derivative;

[0046] filtering, washing, and drying the third mixed solution to obtain the sustained-release agent;

[0047] Wherein, the sustained-release agent comprises a resin carrier of the nicotine derivative.

[0048] In one embodiment, the method for preparing the resin suspension comprises the following steps: adding the resin to water and stirring for 10h-14h to obtain the resin suspension, and / or the mass ratio of the water to the resin is (7-9):1; and / or

[0049] In the step of adding the nicotine derivative to the resin suspension, the mass ratio of the resin to the nicotine derivative is 1:(0.60-0.75), and / or the nicotine derivative and the resin suspension are mixed by stirring, and the stirring and mixing time is 10h-14h.

[0050] Beneficial effects of the embodiments of the present application:

[0051] In the present application, the oral preparation includes a sustained-release agent, and the sustained-release agent includes at least one of a β-cyclodextrin inclusion complex of a nicotine derivative and a carboxylate of a nicotine derivative. On the one hand, when the oral preparation includes a β-cyclodextrin inclusion complex of a nicotine derivative, the β-cyclodextrin inclusion complex of a nicotine derivative includes β-cyclodextrin and a nicotine derivative, and the β-cyclodextrin has a cavity, and the nicotine derivative molecules can enter the cavity of the β-cyclodextrin to form the β-cyclodextrin inclusion complex of the nicotine derivative. When the oral preparation is placed in the oral cavity, due to the presence of the inclusion complex, the nicotine derivative molecules are not immediately released from the inclusion complex, but as the inclusion complex is affected by the oral temperature, the thermal motion between the nicotine derivative molecules and the β-cyclodextrin molecules intensifies, and the cavity structure of the β-cyclodextrin molecules is formed. It tends to become larger after absorbing heat, and the enveloping ability of the cavity structure for nicotine derivative molecules is weakened. Nicotine derivative molecules will be slowly released after breaking free from the interaction with β-cyclodextrin molecules, thereby playing a sustained-release effect; on the other hand, when the oral preparation includes carboxylates of nicotine derivatives, oral saliva is weakly alkaline. When the oral preparation is placed in the mouth, the oral preparation will not immediately release a large amount of nicotine derivatives. Instead, as the carboxylates of nicotine derivatives come into contact with and infiltrate the oral saliva, the carboxylates of nicotine derivatives gradually undergo acid-base neutralization reaction with saliva to generate nicotine derivative molecules, thereby playing a sustained-release effect. In the present application, the oral preparation includes a sustained-release agent, which includes at least one of a β-cyclodextrin inclusion complex of a nicotine derivative and a carboxylate of a nicotine derivative. The sustained-release agent can release the nicotine derivative evenly, slowly and persistently in the oral cavity, prolonging the retention time of the nicotine derivative in the oral cavity, so that the oral preparation can maintain a stable effect over a long period of time, providing consumers with a long-lasting and peaceful physiological satisfaction, while effectively reducing irritation to the digestive tract. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] In order to more clearly illustrate the solutions in the present application or the prior art, a brief introduction is given below to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0053] Figure 1 A product diagram of the sustained-release agent prepared in Example 1 of the sustained-release agent of the present application;

[0054] Figure 2 A product diagram of the sustained-release agent prepared in Example 3 of the sustained-release agent of the present application;

[0055] Figure 3 A product diagram of the sustained-release agent prepared in Example 5 of the sustained-release agent of the present application;

[0056] Figure 4 A product diagram of the buccal cigarette prepared in Example 1 of the buccal cigarette of the present application;

[0057] Figure 5 A product picture of the buccal tablet prepared in Example 1 of the buccal tablet of the present application;

[0058] Figure 6 A product picture of the chewing gum prepared in chewing gum Example 1 of the present application;

[0059] Figure 7 The release curves of the buccal tablets of buccal tablet Example 1, buccal tablet Example 6, and buccal tablet comparative example 1 of the present application;

[0060] Figure 8 The release curves of the buccal cigarettes of buccal cigarette embodiment 1, buccal cigarette embodiment 6, buccal cigarette embodiment 11, buccal cigarette comparative example 1, buccal cigarette comparative example 2, and buccal cigarette comparative example 3 of the present application;

[0061] Fig. 9 This is a release curve diagram of the chewing gum of Gum Example 1, Chewing Gum Example 6, Chewing Gum Example 11, Chewing Gum Comparative Example 1, Chewing Gum Comparative Example 2, and Chewing Gum Comparative Example 3 of the present application. DETAILED DESCRIPTION

[0062] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present application. In addition, it should be understood that the specific implementation methods described herein are only used to illustrate and explain the present application, and are not used to limit the present application. In the present application, unless otherwise stated, the directional words such as "upper" and "lower" used generally refer to the upper and lower parts of the device in actual use or working state, specifically the drawing direction in the accompanying drawings; while "inside" and "outside" refer to the outline of the device.

[0063] In the related art, the release rate of nicotine derivatives or nicotine in oral products in the oral cavity is too fast, the initial strength of oral administration is too strong and the later strength is relatively small, and the smell of smoke fades rapidly during the entire oral administration process, which affects the consumer's experience and needs further improvement.

[0064] To solve the above problems, an embodiment of the present application provides an oral preparation, comprising a sustained-release agent, wherein the sustained-release agent comprises at least one of a β-cyclodextrin inclusion complex of a nicotine derivative and a carboxylate of a nicotine derivative.

[0065] In this embodiment, the oral product includes a sustained-release agent, and the sustained-release agent includes at least one of a β-cyclodextrin inclusion complex of a nicotine derivative and a carboxylate of a nicotine derivative. On the one hand, when the oral product includes a β-cyclodextrin inclusion complex of a nicotine derivative, the β-cyclodextrin inclusion complex of a nicotine derivative includes β-cyclodextrin and a nicotine derivative, and the β-cyclodextrin has a cavity, and the nicotine derivative molecules can enter the cavity of the β-cyclodextrin to form the β-cyclodextrin inclusion complex of the nicotine derivative. When the oral product is placed in the oral cavity, due to the presence of the inclusion complex, the nicotine derivative molecules are not immediately released from the inclusion complex, but as the inclusion complex is affected by the oral temperature, the thermal motion between the nicotine derivative molecules and the β-cyclodextrin molecules intensifies, and the cavity structure of the β-cyclodextrin molecules is formed. It tends to become larger after absorbing heat, and the enveloping ability of the cavity structure for nicotine derivative molecules is weakened. Nicotine derivative molecules will be slowly released after breaking free from the interaction with β-cyclodextrin molecules, thereby playing a sustained-release effect; on the other hand, when the oral preparation includes carboxylates of nicotine derivatives, oral saliva is weakly alkaline. When the oral preparation is placed in the mouth, the oral preparation will not immediately release a large amount of nicotine derivatives. Instead, as the carboxylates of nicotine derivatives come into contact with and infiltrate the oral saliva, the carboxylates of nicotine derivatives gradually undergo acid-base neutralization reaction with saliva to generate nicotine derivative molecules, thereby playing a sustained-release effect. The oral preparation includes a sustained-release agent, which includes at least one of a β-cyclodextrin inclusion compound of a nicotine derivative and a carboxylate of a nicotine derivative. The sustained-release agent can release the nicotine derivative evenly, slowly and persistently in the oral cavity, and prolong the retention time of the nicotine derivative in the oral cavity, so that the oral preparation can maintain a stable effect for a long time, providing consumers with a long-lasting and peaceful physiological satisfaction; in addition, the nicotine derivative is slowly released in the oral cavity and absorbed by the oral mucosa, thereby entering the blood and binding to the human body's nicotine receptors, which can effectively reduce the irritation to the digestive tract while playing a role in relieving addiction.

[0066] In one embodiment, the type of oral product is not limited, and the oral product may include at least one of oral cigarettes, oral tablets, chewing gum, etc.

[0067] In one embodiment, the carboxylate salt of the nicotine derivative comprises at least one of nicotine derivative ditartaric acid dihydrate and a resin carrier of the nicotine derivative.

[0068] In one embodiment, the nicotine derivative ditartaric acid dihydrate includes at least one of 2-methyl nicotine ditartaric acid dihydrate, 6-methyl nicotine ditartaric acid dihydrate, 2-ethyl nicotine ditartaric acid dihydrate, 6-chloronicotine ditartaric acid dihydrate, and 4-trifluoromethylated nicotine ditartaric acid dihydrate. In this embodiment, the nicotine derivative molecule is hydrogen bonded to two tartaric acid molecules and contains two crystal water molecules.

[0069] In one embodiment, the resin carrier of the nicotine derivative includes at least one of a resin carrier of 2-methylnicotine, a resin carrier of 6-methylnicotine, a resin carrier of 2-ethylnicotine, a resin carrier of 6-chloronicotine, and a resin carrier of 4-trifluoromethylated nicotine.

[0070] In one embodiment, the nicotine derivative includes a pyridine ring substituted with a substituent, and the substituent includes at least one of a halogen, a C1-C2 alkyl, and a trifluoromethyl group. Optionally, the nicotine derivative includes at least one of 2-methyl nicotine, 6-methyl nicotine, 2-ethyl nicotine, 6-chloronicotine, and 4-trifluoromethylated nicotine. In this embodiment, the above-mentioned nicotine derivative refers to a class of compounds formed after the hydrogen atom connected to the carbon atom in the pyrimidine ring of nicotine is replaced by a substituent, which has better lipophilicity than nicotine, and exhibits superior excitatory properties in response to nicotine receptors. The above-mentioned nicotine derivative is applied to oral products, which can enhance the addiction-relieving ability of the oral products, reduce the amount of nicotine used, and thus reduce the harm of nicotine to the human body.

[0071] In one embodiment, the oral product is a buccal cigarette. When the sustained-release agent is a β-cyclodextrin inclusion complex of a nicotine derivative, the mass percentage of the β-cyclodextrin inclusion complex of the nicotine derivative in the buccal cigarette is 7.1%-14.9%, and in the β-cyclodextrin inclusion complex of the nicotine derivative, the molar ratio between the nicotine derivative and the β-cyclodextrin is (1-1.05): 1; optionally, the mass percentage of the β-cyclodextrin inclusion complex of the nicotine derivative in the buccal cigarette can be any one of 7.1%, 8.1%, 10.1%, 12.1%, 14.9%, etc. or a range between any two. In this embodiment, setting the content of the sustained-release agent within the above range can further ensure that the amount of nicotine derivatives released by the sustained-release agent in the oral cavity has a suitable range, so that the buccal cigarette can bring sufficient addiction relief while reducing the irritation of the nicotine derivatives to the oral cavity.

[0072] When the sustained-release agent is nicotine derivative ditartaric acid dihydrate, the mass percentage of nicotine derivative ditartaric acid dihydrate in the oral smoke is 2.9%-5.9%; optionally, the mass percentage of nicotine derivative ditartaric acid dihydrate in the oral smoke can be any one of 2.9%, 3.9%, 4.9%, 5.9%, etc. or a range between any two. When the sustained-release agent is a resin carrier of a nicotine derivative, the mass percentage of the resin carrier of the nicotine derivative in the oral smoke is 3.4%-5.7%; optionally, the mass percentage of the resin carrier of the nicotine derivative in the oral smoke can be any one of 3.4%, 4.4%, 5.4%, 5.7%, etc. or a range between any two. In this embodiment, the content of the sustained-release agent is set within the above range, which can further ensure that the amount of nicotine derivatives released by the sustained-release agent in the oral cavity is within a suitable range, so that the snus can bring sufficient addiction relief while reducing the irritation of the nicotine derivatives to the oral cavity.

[0073] In one embodiment, the oral smoke further comprises microcrystalline fiber, propylene glycol, water, food flavor, sodium chloride, sodium carbonate, acesulfame potassium, aspartame and vitamin E.

[0074] In one embodiment, the mass percentage of the microcrystalline fiber in the snus is 55%-65%; optionally, the mass percentage of the microcrystalline fiber in the snus can be any one of 55%, 58%, 60%, 63%, 65%, etc. or a range between any two of them.

[0075] In one embodiment, the mass percentage of propylene glycol in the snus is 3%-5%; optionally, the mass percentage of propylene glycol in the snus can be any one of 3%, 3.5%, 4%, 4.5%, 5%, etc., or a range between any two of them.

[0076] In one embodiment, the mass percentage of water in the snus is 10%-20%; alternatively, the mass percentage of water in the snus can be any one of 10%, 12%, 16%, 18%, 20%, etc. or a range between any two.

[0077] In one embodiment, the mass percentage of the food flavor in the snus is 5%-10%; optionally, the mass percentage of the food flavor in the snus can be any one of 5%, 6%, 8%, 9%, 10%, etc. or a range between any two.

[0078] In one embodiment, the mass percentage of sodium chloride in the snus is 1%-3%; optionally, the mass percentage of sodium chloride in the snus can be any one of 1%, 1.5%, 2%, 2.5%, 3%, etc., or a range between any two of them.

[0079] In one embodiment, the mass percentage of sodium carbonate in the snus is 1%-2%; alternatively, the mass percentage of sodium carbonate in the snus can be any one of 1%, 1.5%, 2%, etc. or a range between any two of them.

[0080] In one embodiment, the mass percentage of acesulfame potassium in the snus is 2%-4%; alternatively, the mass percentage of acesulfame potassium in the snus can be any one of 2%, 2.5%, 3%, 3.5%, 4%, etc., or a range between any two of them.

[0081] In one embodiment, the mass percentage of aspartame in the snus is 1%-2%; alternatively, the mass percentage of aspartame in the snus can be any one of 1%, 1.2%, 1.5%, 1.8%, 2%, etc., or a range between any two of them.

[0082] In one embodiment, the mass percentage of vitamin E in the snus is 1%-2%. Optionally, the mass percentage of vitamin E in the snus can be any one of 1%, 1.2%, 1.5%, 1.8%, 2%, etc., or a range between any two of them.

[0083] In one embodiment, the oral product is an oral tablet. When the sustained-release agent is a β-cyclodextrin inclusion complex of a nicotine derivative, the mass percentage of the β-cyclodextrin inclusion complex of a nicotine derivative in the oral tablet is 0.5%-2.2%, and in the β-cyclodextrin inclusion complex of a nicotine derivative, the molar ratio between the nicotine derivative and β-cyclodextrin is (1-1.05):1; optionally, the mass percentage of the β-cyclodextrin inclusion complex of a nicotine derivative in the oral tablet can be any one of 0.5%, 0.8%, 1.0%, 1.5%, 2.2%, etc., or a range between any two of them. When the sustained-release agent is nicotine derivative ditartaric acid dihydrate, the mass percentage of nicotine derivative ditartaric acid dihydrate in the lozenge is 0.2%-0.9%; optionally, the mass percentage of nicotine derivative ditartaric acid dihydrate in the lozenge can be any one of 0.2%, 0.4%, 0.6%, 0.8%, 0.9%, etc. or a range between any two of them.

[0084] In this embodiment, setting the content of the sustained-release agent within the above range can further ensure that the amount of nicotine derivatives released by the sustained-release agent in the oral cavity is within a suitable range, so that the lozenge can provide sufficient addiction relief while reducing the irritation of the nicotine derivatives to the oral cavity.

[0085] In one embodiment, the buccal tablet further comprises mannitol, maltitol, xylitol, citric acid, magnesium stearate, anhydrous colloidal silica, sodium bicarbonate, xanthan gum, food flavor, menthol and peppermint oil.

[0086] In one embodiment, the mass percentage of mannitol in the lozenge is 13%-15%; optionally, the mass percentage of mannitol in the lozenge can be any one of 13%, 13.5%, 14%, 14.5%, 15%, etc. or a range between any two of them.

[0087] In one embodiment, the mass percentage of maltitol in the lozenge is 30%-35%; optionally, the mass percentage of maltitol in the lozenge can be any one of 30%, 31%, 33%, 34%, 35%, etc. or a range between any two of them.

[0088] In one embodiment, the mass percentage of xylitol in the buccal tablet is 30%-35%; optionally, the mass percentage of xylitol in the buccal tablet can be any one of 30%, 31%, 33%, 34%, 35%, etc. or a range between any two of them.

[0089] In one embodiment, the mass percentage of citric acid in the lozenge is 2%-4%; optionally, the mass percentage of citric acid in the lozenge can be any one of 2%, 2.5%, 3%, 3.5%, 4%, etc. or a range between any two of them.

[0090] In one embodiment, the mass percentage of magnesium stearate in the buccal tablet is 2%-4%; optionally, the mass percentage of magnesium stearate in the buccal tablet can be any one of 2%, 2.5%, 3%, 3.5%, 4%, etc. or a range between any two of them.

[0091] In one embodiment, the mass percentage of anhydrous silica colloidal body in the lozenge is 1%-3%; optionally, the mass percentage of anhydrous silica colloidal body in the lozenge can be any one of 1%, 1.5%, 2%, 2.5%, 3%, etc. or a range between any two of them.

[0092] In one embodiment, the mass percentage of sodium bicarbonate in the lozenge is 1%-3%; optionally, the mass percentage of sodium bicarbonate in the lozenge can be any one of 1%, 1.5%, 2%, 2.5%, 3%, etc. or a range between any two of them.

[0093] In one embodiment, the mass percentage of xanthan gum in the lozenge is 4%-6%; optionally, the mass percentage of xanthan gum in the lozenge can be any one of 4%, 4.5%, 5%, 5.5%, 6%, etc. or a range between any two of them.

[0094] In one embodiment, the mass percentage of the food flavor in the lozenge is 1%-5%; optionally, the mass percentage of the food flavor in the lozenge can be any one of 1%, 2%, 3%, 4%, 5%, etc. or a range between any two.

[0095] In one embodiment, the mass percentage of menthol in the oral preparation is 0.5%-1.5%. Optionally, the mass percentage of menthol in the oral preparation can be any one of 0.5%, 0.8%, 1.0%, 1.2%, 1.5%, etc. or a range between any two.

[0096] In one embodiment, the mass percentage of peppermint oil in the buccal tablet is 0.5%-1.5%. Optionally, the mass percentage of peppermint oil in the buccal product can be any one of 0.5%, 0.8%, 1.0%, 1.2%, 1.5%, etc. or a range between any two.

[0097] In one embodiment, the oral product is chewing gum. When the sustained-release agent is a β-cyclodextrin inclusion complex of a nicotine derivative, the mass percentage of the β-cyclodextrin inclusion complex of a nicotine derivative in the chewing gum is 0.8%-1.9%, and in the β-cyclodextrin inclusion complex of a nicotine derivative, the molar ratio between the nicotine derivative and β-cyclodextrin is (1-1.05):1; optionally, the mass percentage of the β-cyclodextrin inclusion complex of a nicotine derivative in the chewing gum may be any one of 0.8%, 1.0%, 1.3%, 1.6%, 1.9%, etc., or a range between any two of them. When the sustained-release agent is nicotine derivative ditartaric acid dihydrate, the mass percentage of nicotine derivative ditartaric acid dihydrate in chewing gum is 0.4%-0.8%; optionally, the mass percentage of nicotine derivative ditartaric acid dihydrate in chewing gum can be any one of 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, etc. or a range between any two. When the sustained-release agent is a resin carrier of nicotine derivatives, the mass percentage of the resin carrier of nicotine derivatives in chewing gum is 0.3%-0.8%; optionally, the mass percentage of the resin carrier of nicotine derivatives in chewing gum can be any one of 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, etc. or a range between any two.

[0098] In this embodiment, setting the content of the sustained-release agent within the above range can further ensure that the amount of nicotine derivatives released by the sustained-release agent in the oral cavity is within a suitable range, so that the chewing gum can provide sufficient addiction relief while reducing the irritation of the nicotine derivatives to the oral cavity.

[0099] In one embodiment, the chewing gum further comprises chewing gum base, xylitol, food flavor, lecithin, carboxymethyl cellulose and vitamin E.

[0100] In one embodiment, the mass percentage of the chewing gum base in the chewing gum is 23.4%-38%; optionally, the mass percentage of the chewing gum base in the chewing gum can be any one of 23.4%, 30%, 34%, 36%, 38%, etc. or a range between any two of them.

[0101] In one embodiment, the mass percentage of xylitol in the chewing gum is 49%-65%; optionally, the mass percentage of xylitol in the chewing gum can be any one of 49%, 53%, 57%, 60%, 65%, etc. or a range between any two.

[0102] In one embodiment, the mass percentage of the food flavor in the chewing gum is 1-3%; optionally, the mass percentage of the food flavor in the chewing gum can be any one of 1%, 1.5%, 2%, 2.5%, 3%, etc. or a range between any two.

[0103] In one embodiment, the mass percentage of lecithin in the chewing gum is 0.1%-5%; optionally, the mass percentage of lecithin in the chewing gum can be any one of 0.1%, 1%, 2%, 3%, 5%, etc. or a range between any two.

[0104] In one embodiment, the mass percentage of carboxymethyl cellulose in the chewing gum is 0.1%-3%; alternatively, the mass percentage of carboxymethyl cellulose in the chewing gum can be any one of 0.1%, 1%, 2%, 3%, etc. or a range between any two.

[0105] In one embodiment, the mass percentage of vitamin E in the chewing gum is 0.1%-5%. Optionally, the mass percentage of vitamin E in the chewing gum can be any one of 0.1%, 1%, 2%, 3%, 5%, etc. or a range between any two.

[0106] The present application also provides a method for preparing the oral product as described above, comprising the following steps:

[0107] S11, mixing the sustained-release agent, microcrystalline cellulose, propylene glycol, water, food flavor, sodium chloride, sodium carbonate, acesulfame potassium, aspartame and vitamin E to obtain a first mixture;

[0108] S12, sterilizing the first mixture, sealing and refrigerating, and sieving to obtain an oral product. In this embodiment, the oral product is a buccal cigarette.

[0109] The present application also provides another method for preparing the oral product as described above, comprising the following steps:

[0110] S21. Mix the sustained-release agent, mannitol, maltitol, xylitol, citric acid, magnesium stearate, anhydrous silica colloid, sodium bicarbonate and xanthan gum, and granulate to obtain mixture granules.

[0111] S22, mixing food flavor, menthol, peppermint oil and the mixture particles, and pressing into tablets to obtain an oral product. In this embodiment, the oral product is an oral tablet.

[0112] The present application also provides another method for preparing the oral product as described above, comprising the following steps:

[0113] S31, providing a softened chewing gum base and an aqueous solution of carboxymethyl cellulose;

[0114] S32, adding xylitol, an emulsifier, a food flavor, a sustained-release agent and an antioxidant to an aqueous solution of carboxymethyl cellulose, and heating to obtain a paste;

[0115] S33, adding the paste to the softened chewing gum base and mixing to obtain a second mixture;

[0116] S34, cutting and shaping the second mixture to obtain embryos;

[0117] S35, aging the embryo, coating, and polishing to obtain an oral product. In this embodiment, the oral product is chewing gum.

[0118] In one embodiment, the method for preparing the softened chewing gum base comprises the following steps: heating the chewing gum base in an oven at 50° C.-60° C. for 4 h-5 h to obtain the softened chewing gum base.

[0119] In one embodiment, the method for preparing an aqueous solution of carboxymethyl cellulose comprises the following steps: adding carboxymethyl cellulose to water at 45° C.-55° C. to obtain an aqueous solution of carboxymethyl cellulose.

[0120] In one embodiment, in step S32, the heating temperature is 80°C-90°C.

[0121] In one embodiment, in step S35, the aging temperature is 15°C-25°C, the aging time is 14h-18h, and the aging relative humidity is 50%-60%.

[0122] The present application also provides a method for preparing the sustained-release agent as described above, comprising the following steps:

[0123] S41, adding the nicotine derivative to the aqueous solution of β-cyclodextrin, so that the nicotine derivative enters the cavity of the β-cyclodextrin, to obtain a first mixed solution containing the β-cyclodextrin inclusion complex of the nicotine derivative;

[0124] S42, allowing the first mixed solution to stand at low temperature, filtering, washing, and drying to obtain a sustained-release agent, wherein the sustained-release agent comprises a β-cyclodextrin inclusion complex of a nicotine derivative.

[0125] In one embodiment, the method for preparing an aqueous solution of β-cyclodextrin comprises the following steps: adding β-cyclodextrin to water, heating and stirring at 60° C.-80° C. until the β-cyclodextrin is completely dissolved, to obtain an aqueous solution of β-cyclodextrin.

[0126] In one embodiment, in the aqueous solution of β-cyclodextrin, the mass ratio of water to β-cyclodextrin is (8-10): 1. Optionally, the mass ratio of water to β-cyclodextrin can be any one of 8:1, 8.5:1, 9:1, 9.5:1, 10:1, etc., or a range between any two of them.

[0127] In one embodiment, in step S41, the molar ratio of β-cyclodextrin to nicotine derivative is 1:1.05. In this embodiment, β-cyclodextrin usually has only one cavity, and one β-cyclodextrin can only include one nicotine derivative molecule. The molar ratio of β-cyclodextrin to nicotine derivative is 1:1.05, which can ensure the inclusion effect of β-cyclodextrin and reduce resource waste.

[0128] In one embodiment, in step S41, the aqueous solution of nicotine derivatives and β-cyclodextrin are stirred and mixed, and the stirring and mixing temperature is 60° C.-80° C., and the stirring and mixing time is 2 h-4 h. In this embodiment, the stirring and mixing temperature is 60° C.-80° C., and the stirring and mixing time is 2 h-4 h, which can further ensure the mixing uniformity of nicotine derivatives and β-cyclodextrin, accelerate the movement and collision between molecules, and improve the inclusion effect of β-cyclodextrin on nicotine derivatives.

[0129] In one embodiment, in step S42, the low temperature standing temperature is 0°C-6°C, and the low temperature standing time is 20h-26h. In this embodiment, the low temperature standing temperature is 0°C-6°C, and the low temperature standing time is 20h-26h, which can further promote the precipitation of the β-cyclodextrin inclusion complex of the nicotine derivative, so that the β-cyclodextrin inclusion complex of the nicotine derivative in the solution is more likely to precipitate out in the form of a solid, which is convenient for subsequent filtration and collection of the β-cyclodextrin inclusion complex of the nicotine derivative.

[0130] In one embodiment, washing comprises washing the filtrate with ethanol 2-3 times.

[0131] In one embodiment, in step S42, the drying is vacuum drying, the temperature of the vacuum drying is 40°C-50°C, and the vacuum degree of the vacuum drying is 0.05MPa-0.2MPa.

[0132] The present application also provides another method for preparing the sustained-release agent as described above, comprising the following steps:

[0133] S51, providing a nicotine derivative and a tartaric acid solution, wherein the nicotine derivative has a pyridine ring substituted with a substituent, the substituent comprises at least one of a halogen, a C1-C2 alkyl, and a trifluoromethyl group, and the tartaric acid solution comprises tartaric acid;

[0134] S52, adding the nicotine derivative to the tartaric acid solution to cause an acid-base neutralization reaction between the nicotine derivative and the tartaric acid to obtain a second mixed solution containing nicotine derivative ditartaric acid dihydrate;

[0135] S53, refrigerating and crystallizing the second mixed solution, filtering, washing, and drying to obtain a sustained-release agent; wherein the sustained-release agent includes nicotine derivative ditartaric acid dihydrate.

[0136] In this embodiment, the nicotine derivative has a pyridine ring substituted with a substituent, the nitrogen atom on the pyridine ring in the nicotine derivative can accept a proton and become alkaline, and the carboxyl group of tartaric acid can release a proton, making the tartaric acid acidic, and the nicotine derivative can undergo an acid-base reaction with tartaric acid to generate nicotine derivative ditartaric acid dihydrate.

[0137] In one embodiment, the method for preparing the tartaric acid solution comprises the following steps:

[0138] Tartaric acid is dissolved in ethanol to obtain a tartaric acid solution, wherein the weight ratio of ethanol to the tartaric acid is (3-5):1, and the ethanol is 95% ethanol.

[0139] In one embodiment, in step S52, the molar ratio of tartaric acid to nicotine derivative is (2-2.05):1, which can ensure that the tartaric acid and nicotine derivative react relatively completely, reduce reactant residues, and improve product purity and yield.

[0140] In one embodiment, in step S52, the nicotine derivative and the tartaric acid solution are mixed by stirring, the stirring temperature is 20°C-30°C, and the stirring time is 3h-4h.

[0141] In one embodiment, in step S52, the temperature of the cold storage crystallization is 0-4°C, and the cold storage crystallization time is 16h-20h. In this embodiment, the temperature of the cold storage crystallization is 0-4°C, and the cold storage crystallization time is 16h-20h, which can further promote the crystallization of the nicotine derivative ditartaric acid dihydrate, making it easier for the nicotine derivative ditartaric acid dihydrate in the solution to precipitate out in the form of a solid, and facilitating the subsequent filtration and collection of the nicotine derivative ditartaric acid dihydrate.

[0142] In one embodiment, washing is washing the filtrate with water 2-3 times.

[0143] The present application also provides another method for preparing the sustained-release agent as described above, comprising the following steps:

[0144] S51, providing a nicotine derivative and a resin suspension, wherein the nicotine derivative has a pyridine ring substituted with a substituent, the substituent includes at least one of a halogen, a C1-C2 alkyl, and a trifluoromethyl group, and the resin suspension includes a resin, and the resin has a carboxyl group;

[0145] S52, adding the nicotine derivative to the resin suspension to cause an acid-base neutralization reaction between the nicotine derivative and the resin, thereby obtaining a third mixed solution of the resin carrier containing the nicotine derivative;

[0146] S53, filtering, washing, and drying the third mixed solution to obtain a sustained-release agent;

[0147] Among them, the sustained-release agent includes a resin carrier of a nicotine derivative.

[0148] In this embodiment, the nicotine derivative has a pyridine ring substituted with a substituent, the nitrogen atom on the pyridine ring in the nicotine derivative can accept a proton and become alkaline, and the carboxyl group of the resin can release a proton, making the resin acidic, and the nicotine derivative can undergo an acid-base reaction with the resin to generate a resin carrier of the nicotine derivative.

[0149] In a preferred embodiment, the resin can be commercially available food ion exchange resins such as Amberlite IRP64 ion exchange resin (trade name LPF-851), Purolite C104EPlus macroporous weakly acidic food grade resin, Purolite C-107E resin, etc.

[0150] In one embodiment, the method for preparing a resin suspension comprises the following steps: adding the resin to water and stirring for 10 hours to 14 hours to obtain a resin suspension, wherein the mass ratio of water to resin is (7-9): 1. In this embodiment, the resin is added to water and stirred for 10 hours to 14 hours, and the mass ratio of water to resin is (7-9): 1, which can further ensure that the resin is fully swollen in water. After the resin is fully swollen, the ion channels and exchange sites inside it will be more fully exposed, which is conducive to sufficient contact and ion exchange between the resin and the nicotine derivative in the third mixed solution, thereby improving the efficiency of the acid-base reaction between the resin and the nicotine derivative.

[0151] In one embodiment, in step S52, the mass ratio of the resin to the nicotine derivative is 1:(0.60-0.75). Optionally, the mass ratio of the resin to the nicotine derivative can be any one of 1:0.60, 1:0.64, 1:0.68, 1:0.70, 1:0.73, 1:0.75, etc., or a range between any two of them. In this embodiment, the mass ratio of the resin to the nicotine derivative is 1:(0.60-0.75), which can ensure that the resin and the nicotine derivative react more completely, reduce the reactant residue, and improve the purity and yield of the product.

[0152] In one embodiment, in step S52, the nicotine derivative and the resin suspension are mixed by stirring, and the stirring time is 10 hours to 14 hours.

[0153] In one embodiment, in step S53, the filtrate is washed 2-3 times with water, and the weight of water used for each washing is 4-6 times the weight of the filtrate, which can ensure the washing effect while saving water resources.

[0154] The above scheme is further described below in conjunction with specific implementation examples. The preferred embodiments of the present application are described in detail as follows:

[0155] Sustained Release Agent Example 1

[0156] This embodiment provides a method for preparing a sustained-release agent, comprising the following steps:

[0157] 1. Stir 30.8 g of L-tartaric acid and 92.4 g of 95% ethanol at room temperature until dissolved to obtain a tartaric acid solution;

[0158] 2. Add 2-methyl nicotine dropwise to the tartaric acid solution and stir for 4 hours to obtain a mixed solution, wherein the molar ratio of L-tartaric acid to 2-methyl nicotine is 2.05:1;

[0159] 3. The mixed solution was crystallized at 2°C for 16 hours, filtered, and the filtrate was washed with 100 g of ethanol three times to obtain a washed filtrate, and the washed filtrate was vacuum dried at 45°C to obtain Figure 1 The sustained-release agent shown is 2-methylnicotine ditartaric acid dihydrate, and the structure of 2-methylnicotine ditartaric acid dihydrate is shown in formula (I). The mass percentage of 2-methylnicotine in 2-methylnicotine ditartaric acid dihydrate is 33.9%, that is, each gram of 2-methylnicotine ditartaric acid dihydrate can release 0.339 grams of 2-methylnicotine in the oral cavity.

[0160]

[0161] Sustained Release Agent Example 2

[0162] This embodiment provides a method for preparing a sustained-release agent, comprising the following steps:

[0163] 1. Stir 30.3 g of L-tartaric acid and 90.9 g of 95% ethanol at room temperature until dissolved to obtain a tartaric acid solution;

[0164] 2. Add 6-chloronicotine dropwise to the tartaric acid solution and stir for 4 hours to obtain a mixed solution, wherein the molar ratio of L-tartaric acid to 6-chloronicotine is 2.02:1;

[0165] 3. The mixed solution is crystallized at low temperature at 2° C. for 16 hours, filtered, and the filtrate is washed with 100 g of ethanol three times to obtain a washed filtrate, and the washed filtrate is vacuum dried at 45° C. to obtain a sustained-release agent, which is 6-chloronicotine ditartaric acid dihydrate, wherein the mass percentage of 6-chloronicotine in 6-chloronicotine ditartaric acid dihydrate is 36.5%, that is, each gram of 6-chloronicotine ditartaric acid dihydrate can release 0.365 g of 6-chloronicotine in the oral cavity.

[0166] Sustained Release Example 3

[0167] This embodiment provides a method for preparing a sustained-release agent, comprising the following steps:

[0168] 1. Add 10 g of Amberlite IRP64 ion exchange resin into 80 mL of water and stir for 12 hours to fully swell the ion exchange resin to obtain a resin suspension;

[0169] 2. Add 6 g of 6-methylnicotine dropwise to the resin suspension and stir for 12 hours to obtain a mixed solution;

[0170] 3. Filter the mixed solution, wash the filtrate with 100 mL of water twice to obtain a washed filtrate, and dry the washed filtrate to obtain Figure 2 The sustained-release agent shown is a resin carrier of 6-methylnicotine, wherein the mass percentage of the 6-methylnicotine part in the resin carrier of 6-methylnicotine is 34.2%, that is, each gram of the resin carrier of 6-methylnicotine can release 0.342 grams of 6-methylnicotine in the oral cavity.

[0171] Sustained Release Example 4

[0172] This embodiment provides a method for preparing a sustained-release agent, comprising the following steps:

[0173] 1. Add 10 g of Amberlite IRP64 ion exchange resin into 80 mL of water and stir for 12 hours to fully swell the ion exchange resin to obtain a resin suspension;

[0174] 2. Add 6.5 g of 2-methyl nicotine dropwise to the resin suspension and stir for 12 hours to obtain a mixed solution;

[0175] 3. Filter the mixed solution, wash the filtrate with 100 mL of water twice to obtain a washed filtrate, dry the washed filtrate to obtain a sustained-release agent, wherein the sustained-release agent is a resin carrier of 2-methyl nicotine, wherein the mass percentage of the 2-methyl nicotine part in the resin carrier of 2-methyl nicotine is 35.3%, that is, each gram of the resin carrier of 2-methyl nicotine can release 0.353 grams of 2-methyl nicotine in the oral cavity.

[0176] Sustained Release Example 5

[0177] This embodiment provides a method for preparing a sustained-release agent, comprising the following steps:

[0178] 1. Add 11.3 g of β-cyclodextrin into 100 mL of water, heat to 70°C, and stir to completely dissolve the β-cyclodextrin to obtain a β-cyclodextrin solution;

[0179] 2. Add 1.85 g of 2-methyl nicotine dropwise to the β-cyclodextrin solution, stir at 70°C for 3 hours, and naturally cool to room temperature (25±5°C) to obtain a mixed solution;

[0180] 3. Transfer the mixed solution to a refrigerator at 0°C, let it stand for 24 hours, filter it, wash the filtrate twice with 30 mL of water, then wash it once with 20 mL of n-hexane, and dry the washed filtrate to obtain Figure 3 The sustained-release agent shown is a β-cyclodextrin inclusion complex of 2-methyl nicotine, wherein the mass percentage of the 2-methyl nicotine part in the β-cyclodextrin inclusion complex of 2-methyl nicotine is 12.9%, that is, each gram of the β-cyclodextrin inclusion complex of 2-methyl nicotine can release 0.129 grams of 2-methyl nicotine in the oral cavity.

[0181] Sustained Release Example 6

[0182] This embodiment provides a method for preparing a sustained-release agent, comprising the following steps:

[0183] 1. Add 11.3 g of β-cyclodextrin into 100 mL of water, heat to 70°C, and stir to completely dissolve the β-cyclodextrin to obtain a β-cyclodextrin solution;

[0184] 2. Add 2.4 g of 4-trifluoromethyl nicotine dropwise to the β-cyclodextrin solution, stir at 70°C for 3 hours, and cool naturally to room temperature (25±5°C) to obtain a mixed solution;

[0185] 3. Transfer the mixed solution to a refrigerator at 0°C, let it stand for 24 hours, filter it, wash the filtrate twice with 30 mL of water, then wash it once with 20 mL of n-hexane, and dry the washed filtrate to obtain Figure 3 The sustained-release agent shown is a β-cyclodextrin inclusion complex of 4-trifluoromethyl nicotine, wherein the mass percentage of the 4-trifluoromethyl nicotine part in the β-cyclodextrin inclusion complex of 4-trifluoromethyl nicotine is 16.2%, that is, each gram of the β-cyclodextrin inclusion complex of 4-trifluoromethyl nicotine can release 0.162 grams of 4-trifluoromethyl nicotine in the oral cavity.

[0186] Buccal tablet embodiment 1

[0187] This embodiment provides a method for preparing a buccal tablet, comprising the following steps:

[0188] 1. 0.2 g of 2-methylnicotine ditartaric acid dihydrate prepared in Example 1 of the sustained-release agent, 14.5 g of mannitol, 33.4 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum were mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0189] 2. Add 2.4 g of food flavor, 1 g of menthol and 1 g of peppermint oil to the mixture particles, mix well, and press into oval tablets with a mass of about 1.0 g to obtain Figure 5 The buccal tablet.

[0190] Buccal tablet embodiment 2

[0191] The difference between buccal tablet embodiment 2 and buccal tablet embodiment 1 is:

[0192] Step 1 is: 0.6 g of 6-chloronicotine ditartaric acid dihydrate prepared in sustained-release agent Example 2, 14.5 g of mannitol, 33 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0193] The rest is the same as in Example 1 of the buccal tablet.

[0194] Buccal tablet embodiment 3

[0195] The difference between buccal tablet embodiment 3 and buccal tablet embodiment 1 is:

[0196] Step 1 is: 0.9 g of 2-methylnicotine ditartaric acid dihydrate prepared in sustained-release agent Example 1, 14.5 g of mannitol, 32.7 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0197] The rest is the same as in Example 1 of the buccal tablet.

[0198] Buccal tablet embodiment 4

[0199] The difference between buccal tablet embodiment 4 and buccal tablet embodiment 1 is:

[0200] Step 1 is: 1.9 g of 2-methylnicotine ditartaric acid dihydrate prepared in sustained-release agent Example 1, 14.5 g of mannitol, 30.4 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0201] The rest is the same as in Example 1 of the buccal tablet.

[0202] Buccal tablet embodiment 5

[0203] The difference between buccal tablet embodiment 4 and buccal tablet embodiment 1 is:

[0204] Step 1 is: 0.05 g of 2-methylnicotine ditartaric acid dihydrate prepared in sustained-release agent Example 1, 14.5 g of mannitol, 33.55 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0205] The rest is the same as in Example 1 of the buccal tablet.

[0206] Buccal tablet embodiment 6

[0207] This embodiment provides a method for preparing a buccal tablet, comprising the following steps:

[0208] 1. 0.5 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 14.5 g of mannitol, 33.1 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum were mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0209] 2. Add 2.4 g of food flavor, 1 g of menthol and 1 g of peppermint oil to the mixture particles, mix well, and press into oval tablets with a mass of about 1.0 g to obtain Figure 5 The buccal tablet.

[0210] Buccal tablet embodiment 7

[0211] The difference between buccal tablet embodiment 7 and buccal tablet embodiment 6 is:

[0212] Step 1 is: 1 g of the β-cyclodextrin inclusion compound of 4-trifluoromethyl nicotine prepared in Example 6 of the sustained-release agent, 14.5 g of mannitol, 32.6 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0213] The rest are the same as in Example 6 of the buccal tablet.

[0214] Buccal tablet embodiment 8

[0215] The difference between buccal tablet embodiment 8 and buccal tablet embodiment 6 is:

[0216] Step 1 is: 2.2 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 14.5 g of mannitol, 31.4 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0217] The rest are the same as in Example 6 of the buccal tablet.

[0218] Buccal tablet embodiment 9

[0219] The difference between buccal tablet embodiment 9 and buccal tablet embodiment 6 is:

[0220] Step 1 is: 3.2 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 14.5 g of mannitol, 30.4 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0221] The rest are the same as in Example 6 of the buccal tablet.

[0222] Buccal tablet embodiment 10

[0223] The difference between buccal tablet embodiment 10 and buccal tablet embodiment 6 is:

[0224] Step 1 is: 0.25 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 14.5 g of mannitol, 33.35 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0225] The rest are the same as in Example 6 of the buccal tablet.

[0226] Buccal tablet comparative example 1

[0227] The difference between buccal tablet comparative example 1 and buccal tablet embodiment 1 is:

[0228] Step 1 is: 68 mg of 2-methyl nicotine, 14.5 g of mannitol, 33.53 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed uniformly to prepare granules, and dried to obtain mixture granules;

[0229] The rest is the same as in Example 1 of the buccal tablet.

[0230] Buccal tablet comparative example 2

[0231] The difference between buccal tablet comparative example 2 and buccal tablet example 6 is:

[0232] Step 1 is: 65 mg of 2-methyl nicotine, 14.5 g of mannitol, 33.54 g of maltitol, 35 g of xylitol, 2.5 g of citric acid, 2.2 g of magnesium stearate, 1.6 g of anhydrous silica colloid, 1.2 g of sodium bicarbonate, and 5 g of xanthan gum are mixed evenly to prepare granules, and dried to obtain mixture granules;

[0233] The rest are the same as in Example 6 of the buccal tablet.

[0234] Buccal cigarette embodiment 1

[0235] This embodiment provides a method for preparing a buccal cigarette, comprising the following steps:

[0236] 1. Mix 2.9 g of 2-methylnicotine ditartaric acid dihydrate prepared in sustained-release agent Example 1, 64.5 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E to obtain a mixture;

[0237] 2. The first mixture is sterilized by ultraviolet for 3 hours, sealed and refrigerated for 24 hours, sieved, and packaged to obtain Figure 4 Snus shown.

[0238] Buccal cigarette embodiment 2

[0239] The difference between the buccal cigarette embodiment 2 and the buccal cigarette embodiment 1 is:

[0240] Step 1 is: 3.9 g of 6-chloronicotine ditartaric acid dihydrate prepared in sustained-release agent Example 2, 63.5 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0241] The rest is the same as in Example 1 of the buccal cigarette.

[0242] Buccal cigarette embodiment 3

[0243] The difference between the buccal cigarette embodiment 3 and the buccal cigarette embodiment 1 is:

[0244] Step 1 is: 5.9 g of 2-methylnicotine ditartaric acid dihydrate prepared in sustained-release agent Example 1, 61.5 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0245] The rest is the same as in Example 1 of the buccal cigarette.

[0246] Buccal cigarette embodiment 4

[0247] The difference between the buccal cigarette embodiment 4 and the buccal cigarette embodiment 1 is:

[0248] Step 1 is: 7.9 g of 2-methylnicotine ditartaric acid dihydrate prepared in sustained-release agent Example 1, 59.5 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0249] The rest is the same as in Example 1 of the buccal cigarette.

[0250] Buccal cigarette embodiment 5

[0251] The difference between the buccal cigarette embodiment 5 and the buccal cigarette embodiment 1 is:

[0252] Step 1 is: 0.9 g of 2-methylnicotine ditartaric acid dihydrate prepared in sustained-release agent Example 1, 66.5 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0253] The rest is the same as in Example 1 of the buccal cigarette.

[0254] Buccal cigarette embodiment 6

[0255] This embodiment provides a method for preparing a buccal cigarette, comprising the following steps:

[0256] 1. Mix 3.4 g of the resin carrier of 6-methylnicotine prepared in Example 3 of the sustained-release agent, 64 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E to obtain a mixture;

[0257] 2. The first mixture is sterilized by ultraviolet for 3 hours, sealed and refrigerated for 24 hours, sieved, and packaged to obtain Figure 4 Snus shown.

[0258] Buccal cigarette embodiment 7

[0259] The difference between the buccal cigarette embodiment 7 and the buccal cigarette embodiment 6 is:

[0260] Step 1 is: 3.7 g of the resin carrier of 2-methyl nicotine prepared in Example 4 of the sustained-release agent, 63.7 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0261] The rest is the same as in Example 6 of the buccal cigarette.

[0262] Buccal cigarette embodiment 8

[0263] The difference between the buccal cigarette embodiment 8 and the buccal cigarette embodiment 6 is:

[0264] Step 1 is: 5.7 g of the resin carrier of 6-methyl nicotine prepared in Example 3 of the sustained-release agent, 61.7 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0265] The rest is the same as in Example 6 of the buccal cigarette.

[0266] Buccal cigarette embodiment 9

[0267] The difference between the buccal cigarette embodiment 9 and the buccal cigarette embodiment 6 is:

[0268] Step 1 is: 7.7 g of the resin carrier of 6-methyl nicotine prepared in Example 3 of the sustained-release agent, 59.7 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0269] The rest is the same as in Example 6 of the buccal cigarette.

[0270] Buccal cigarette embodiment 10

[0271] The difference between the snus embodiment 10 and the snus embodiment 6 is:

[0272] Step 1 is: 1.4 g of the resin carrier of 6-methyl nicotine prepared in Example 3 of the sustained-release agent, 66 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0273] The rest is the same as in Example 6 of the buccal cigarette.

[0274] Buccal cigarette embodiment 11

[0275] This embodiment provides a method for preparing a buccal cigarette, comprising the following steps:

[0276] 1. Mix 7.1 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 60.3 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E to obtain a mixture;

[0277] 2. The first mixture is sterilized by ultraviolet for 3 hours, sealed and refrigerated for 24 hours, sieved, and packaged to obtain Figure 4 Snus shown.

[0278] Buccal cigarette embodiment 12

[0279] The difference between the snus embodiment 12 and the snus embodiment 11 is:

[0280] Step 1 is: 8.1 g of the β-cyclodextrin inclusion compound of 4-trifluoromethyl nicotine prepared in Example 6 of the sustained-release agent, 59.3 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0281] The rest is the same as in Example 11 of the oral cigarette.

[0282] Buccal cigarette embodiment 13

[0283] The difference between the buccal cigarette embodiment 13 and the buccal cigarette embodiment 11 is:

[0284] Step 1 is: 14.9 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 52.5 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0285] The rest is the same as in Example 11 of the oral cigarette.

[0286] Buccal cigarette embodiment 14

[0287] The difference between the snus embodiment 14 and the snus embodiment 11 is:

[0288] Step 1 is: 16.9 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 50.5 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0289] The rest is the same as in Example 11 of the oral cigarette.

[0290] Buccal cigarette embodiment 15

[0291] The difference between the snus embodiment 15 and the snus embodiment 11 is:

[0292] Step 1 is: 3.1 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 64.3 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0293] The rest is the same as in Example 11 of the oral cigarette.

[0294] Comparative Example 1 of Snus

[0295] The difference between the snus cigarette comparative example 1 and the snus cigarette embodiment 1 is:

[0296] Step 1 is: 0.98 g of 2-methyl nicotine, 66.42 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0297] The rest is the same as in Example 1 of the buccal cigarette.

[0298] Comparative Example 2 of Snus

[0299] The difference between the snus cigarette comparative example 2 and the snus cigarette example 6 is:

[0300] Step 1 is: 1.16 g of 6-methyl nicotine, 66.24 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0301] The rest is the same as in Example 6 of the buccal cigarette.

[0302] Comparative Example 3 of Snus

[0303] The difference between the snus cigarette comparative example 3 and the snus cigarette example 11 is:

[0304] Step 1 is: 0.92 g of 2-methyl nicotine, 66.48 g of microcrystalline cellulose, 4 g of propylene glycol, 15 g of water, 6 g of food flavor, 2 g of sodium chloride, 1.1 g of sodium carbonate, 2.1 g of acesulfame potassium, 1.2 g of aspartame and 1.2 g of vitamin E are mixed uniformly to obtain a mixture;

[0305] The rest is the same as in Example 11 of the oral cigarette.

[0306] Chewing Gum Example 1

[0307] This embodiment provides a method for preparing chewing gum, comprising the following steps:

[0308] 1. Heat and soften 32g of chewing gum base in a 55℃ oven for 4.5h;

[0309] 2. Add 1.6 g of chewing gum base into warm water at 50°C to prepare a chewing gum base aqueous solution;

[0310] 3. Add 0.4 g of 2-methylnicotine ditartaric acid dihydrate prepared in Example 1 of the sustained-release agent, 61.2 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, and boil in a water bath at 85° C. to obtain a paste;

[0311] 4. Add the paste into the softened chewing gum base, fully squeeze, knead, stir and mix to obtain a mixed material;

[0312] 5. Calender the mixed material, cool it to room temperature, place it for 25 hours, and then cut it into 1.5g embryos by a molding machine;

[0313] 6. The embryos were aged for 16 hours at 20°C and 55% relative humidity, and then coated and polished to obtain Figure 6 Gum shown.

[0314] Chewing Gum Example 2

[0315] The difference between chewing gum embodiment 2 and chewing gum embodiment 1 is:

[0316] Step 3 is: adding 0.6 g of 6-chloronicotine ditartaric acid dihydrate prepared in Example 2 of the sustained-release agent, 61 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0317] The rest is the same as chewing gum embodiment 1.

[0318] Chewing Gum Example 3

[0319] The difference between chewing gum embodiment 3 and chewing gum embodiment 1 is:

[0320] Step 3 is: adding 0.8 g of 2-methylnicotine ditartaric acid dihydrate prepared in Example 1 of the sustained-release agent, 60.8 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0321] The rest is the same as chewing gum embodiment 1.

[0322] Chewing Gum Example 4

[0323] The difference between chewing gum embodiment 4 and chewing gum embodiment 1 is:

[0324] Step 3 is: adding 1.8 g of 2-methylnicotine ditartaric acid dihydrate prepared in Example 1 of the sustained-release agent, 59.8 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0325] The rest is the same as chewing gum embodiment 1.

[0326] Chewing Gum Example 5

[0327] The difference between chewing gum embodiment 5 and chewing gum embodiment 1 is:

[0328] Step 3 is: adding 0.1 g of 2-methylnicotine ditartaric acid dihydrate prepared in Example 1 of the sustained-release agent, 61.5 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0329] The rest is the same as chewing gum embodiment 1.

[0330] Chewing Gum Example 6

[0331] The difference between chewing gum embodiment 6 and chewing gum embodiment 1 is:

[0332] Step 3: add 0.3 g of the resin carrier of 6-methylnicotine prepared in Example 3 of the sustained-release agent, 61.3 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, and boil in a water bath at 85° C. to obtain a paste;

[0333] The rest is the same as chewing gum embodiment 1.

[0334] Chewing Gum Example 7

[0335] The difference between chewing gum embodiment 7 and chewing gum embodiment 6 is:

[0336] Step 3 is: adding 0.5 g of the resin carrier of 2-methyl nicotine prepared in Example 4 of the sustained-release agent, 61.1 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0337] The rest is the same as chewing gum embodiment 6.

[0338] Chewing Gum Example 8

[0339] The difference between chewing gum embodiment 8 and chewing gum embodiment 6 is:

[0340] Step 3 is: adding 0.8 g of the resin carrier of 6-methylnicotine prepared in Example 3 of the sustained-release agent, 60.8 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, and boiling in a water bath at 85° C. to obtain a paste;

[0341] The rest is the same as chewing gum embodiment 6.

[0342] Chewing Gum Example 9

[0343] The difference between chewing gum embodiment 9 and chewing gum embodiment 6 is:

[0344] Step 3: add 1.8 g of the resin carrier of 6-methylnicotine prepared in Example 3 of the sustained-release agent, 59.8 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, and boil in a water bath at 85° C. to obtain a paste;

[0345] The rest is the same as chewing gum embodiment 6.

[0346] Chewing Gum Example 10

[0347] The difference between chewing gum embodiment 10 and chewing gum embodiment 6 is:

[0348] Step 3 is: adding 0.1 g of the resin carrier of 6-methylnicotine prepared in Example 3 of the sustained-release agent, 61.5 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, and boiling in a water bath at 85° C. to obtain a paste;

[0349] The rest is the same as chewing gum embodiment 6.

[0350] Chewing Gum Example 11

[0351] The difference between chewing gum embodiment 11 and chewing gum embodiment 1 is:

[0352] Step 3: add 0.8 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 60.8 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, and boil in a water bath at 85° C. to obtain a paste;

[0353] The rest is the same as chewing gum embodiment 1.

[0354] Chewing Gum Example 12

[0355] The difference between chewing gum embodiment 12 and chewing gum embodiment 11 is:

[0356] Step 3: add 1.5 g of the β-cyclodextrin inclusion complex of 4-trifluoromethyl nicotine prepared in Example 6 of the sustained-release agent, 60.1 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, and boil in a water bath at 85° C. to obtain a paste;

[0357] The rest is the same as chewing gum embodiment 11.

[0358] Chewing Gum Example 13

[0359] The difference between chewing gum embodiment 13 and chewing gum embodiment 11 is:

[0360] Step 3: adding 1.9 g of the β-cyclodextrin inclusion complex of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 59.7 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0361] The rest is the same as chewing gum embodiment 11.

[0362] Chewing Gum Example 14

[0363] The difference between chewing gum embodiment 14 and chewing gum embodiment 11 is:

[0364] Step 3 is: adding 3.9 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 57.7 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0365] The rest is the same as chewing gum embodiment 11.

[0366] Chewing Gum Example 15

[0367] The difference between chewing gum embodiment 15 and chewing gum embodiment 11 is:

[0368] Step 3: add 0.1 g of the β-cyclodextrin inclusion compound of 2-methyl nicotine prepared in Example 5 of the sustained-release agent, 61.5 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, and boil in a water bath at 85° C. to obtain a paste;

[0369] The rest is the same as chewing gum embodiment 11.

[0370] Chewing Gum Comparative Example 1

[0371] The difference between chewing gum comparative example 1 and chewing gum example 1 is:

[0372] Step 3 is: adding 136 mg of 2-methyl nicotine, 61.45 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0373] The rest is the same as chewing gum embodiment 1.

[0374] Chewing Gum Comparative Example 2

[0375] The difference between chewing gum comparative example 2 and chewing gum example 6 is:

[0376] Step 3 is: adding 0.10 g of 6-methyl nicotine, 61.5 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0377] The rest is the same as chewing gum embodiment 6.

[0378] Chewing Gum Comparative Example 3

[0379] The difference between the chewing gum comparative example 3 and the chewing gum example 11 is:

[0380] Step 3 is: adding 0.10 g of 2-methyl nicotine, 61.5 g of xylitol, 2.1 g of lecithin, 1.5 g of food flavor and 1.2 g of vitamin E to the chewing gum base aqueous solution, boiling in a water bath at 85° C. to obtain a paste;

[0381] The rest is the same as chewing gum embodiment 11.

[0382] Test Method

[0383] (I) Sustained release test

[0384] The oral preparations prepared in the examples and comparative examples were placed in 50 ml of phosphate buffer with a pH value of 8.1, and samples were taken for testing according to the experimental design time, so as to obtain the relationship between the sustained release degree and time of the oral preparations, and then prepare the release curve of the oral preparations. Figure 7 The release curves of the buccal tablets of buccal tablet example 1, buccal tablet example 6, buccal tablet comparative example 1, and buccal tablet comparative example 2; Figure 8 The release curves of the buccal cigarettes of buccal cigarette embodiment 1, buccal cigarette embodiment 6, buccal cigarette embodiment 11, buccal cigarette comparative example 1, buccal cigarette comparative example 2, and buccal cigarette comparative example 3; Fig. 9 These are the release curves of the chewing gums of chewing gum example 1, chewing gum example 6, chewing gum example 11, chewing gum comparative example 1, chewing gum comparative example 2, and chewing gum comparative example 3.

[0385] (II) Sensory evaluation:

[0386] Sensory test:

[0387] 20 professionally trained tasters (male: female = 1:1, average age 25-35 years old) were selected to form a scoring team. The tasters conducted sensory evaluations on Examples 1-3 and Comparative Examples 1-8 according to the items in the sensory scoring item table in Table 3, and took the average value. Team members must not smoke or drink alcohol within 2 hours before the evaluation, and must not eat foods with strong odors. Each time, take a piece of oral product and place it on the gums under the upper lip to feel the fragrance, taste, and strength of different samples and score them. The stopwatch counts the release time of nicotine derivatives and the duration of the sense of strength. Taste each sample for at least 30 minutes, then spit it out, rinse your mouth several times until there is no residual taste in the mouth, and measure the next group of samples in the same way after 10 minutes. After the test is completed, the sensory test results of Tables 2 to 4 are obtained.

[0388] Table 1 Sensory scoring items

[0389]

[0390] Table 2

[0391]

[0392]

[0393] Table 3

[0394]

[0395]

[0396] Table 4

[0397]

[0398]

[0399] According to the test results in Table 2, compared with the buccal tablet comparison examples 1 and 2, the buccal tablets prepared by the buccal tablet embodiment of the present application are better than the buccal tablet comparison examples 1 and 2 in terms of flavor, sweetness, comfort, duration, irritation, etc., and the buccal tablets prepared by the buccal tablet embodiment of the present application have a better overall taste.

[0400] From the analysis of the buccal tablet examples 1, 3, 4 and 5, it can be seen that controlling the content of nicotine ditartaric acid dihydrate within an appropriate range can further ensure that the buccal tablet has a better taste.

[0401] Analysis of buccal tablet examples 6, 8, 9 and 10 shows that controlling the content of nicotine β-cyclodextrin inclusion complex within an appropriate range can further ensure that the buccal tablet has a better taste.

[0402] according to Figure 7 It can be seen that, compared with directly adding nicotine derivatives to the buccal tablets, the buccal tablets of the embodiments of the present application contain sustained-release agents, which can allow the nicotine derivatives to be released evenly, slowly and persistently in the oral cavity, prolonging the retention time of the nicotine derivatives in the oral cavity, so that the buccal products can maintain a stable effect for a long time, providing consumers with a long-lasting and peaceful physiological satisfaction; in addition, the nicotine derivatives are slowly released in the oral cavity and absorbed by the oral mucosa, thereby entering the blood and binding to the human body's nicotine receptors, which can effectively reduce the irritation to the digestive tract while playing an addiction-relieving role, and can effectively improve the taste of the buccal tablets.

[0403] According to the test results in Table 3, compared with the buccal cigarette comparison examples 1 to 3, the buccal cigarette prepared by the buccal cigarette embodiment of the present application is better than the buccal cigarette comparison examples 1 to 3 in terms of flavor, sweetness, comfort, duration, irritation, etc., and the buccal cigarette prepared by the buccal cigarette embodiment of the present application has a better overall taste.

[0404] From the analysis of the snus example 1, snus example 3, snus example 4 and snus example 5, it can be known that controlling the content of nicotine ditartaric acid dihydrate within an appropriate range can further ensure that the snus has a better taste.

[0405] From the analysis of snus example 6, snus example 8, snus example 9 and snus example 10, it can be known that controlling the content of the resin carrier of nicotine within an appropriate range can further ensure that the snus has a better taste.

[0406] Analysis of snus example 11, snus example 13, snus example 14 and snus example 15 shows that controlling the content of nicotine β-cyclodextrin inclusion complex within an appropriate range can further ensure that the snus has a better taste.

[0407] according to Figure 8It can be seen that, compared with directly adding nicotine derivatives to the snus, the snus of the embodiment of the present application contains a sustained-release agent, which can release the nicotine derivatives evenly, slowly and persistently in the oral cavity, prolong the retention time of the nicotine derivatives in the oral cavity, so that the oral product can maintain a stable effect for a long time, and provide consumers with a long-lasting and peaceful physiological satisfaction; in addition, the nicotine derivatives are slowly released in the oral cavity and absorbed by the oral mucosa, thereby entering the blood and binding to the human nicotine receptors, which can effectively reduce the irritation to the digestive tract while playing a role in relieving addiction, and can effectively improve the taste of the snus.

[0408] According to the test results in Table 4, compared with the chewing gum comparison examples 1 to 3, the chewing gum prepared by the chewing gum examples of the present application is better than the chewing gum comparison examples 1 to 3 in terms of flavor, sweetness, comfort, duration, irritation, etc., and the chewing gum prepared by the chewing gum examples of the present application has a better overall taste.

[0409] From the analysis of chewing gum example 1, chewing gum example 3, chewing gum example 4 and chewing gum example 5, it can be known that controlling the content of nicotine ditartaric acid dihydrate within an appropriate range can further ensure that the chewing gum has a better taste.

[0410] From the analysis of chewing gum example 6, chewing gum example 8, chewing gum example 9 and chewing gum example 10, it can be known that controlling the content of the nicotine resin carrier within an appropriate range can further ensure that the chewing gum has a better taste.

[0411] From the analysis of chewing gum example 11, chewing gum example 13, chewing gum example 14 and chewing gum example 15, it can be known that controlling the content of nicotine β-cyclodextrin inclusion complex within an appropriate range can further ensure that the chewing gum has a better taste.

[0412] according to Fig. 9 It can be seen that, compared with directly adding nicotine derivatives to oral tobacco, the chewing gum of the embodiment of the present application contains a sustained-release agent, which can allow the nicotine derivatives to be released evenly, slowly and persistently in the oral cavity, prolonging the retention time of the nicotine derivatives in the oral cavity, so that the oral product can maintain a stable effect for a long time, providing consumers with a long-lasting and peaceful physiological satisfaction; in addition, the nicotine derivatives are slowly released in the oral cavity and absorbed by the oral mucosa, thereby entering the blood and binding to the human body's nicotine receptors, which can effectively reduce the irritation to the digestive tract while playing an addiction-relieving role, and can effectively improve the taste of the chewing gum.

[0413] The embodiments of the present application are introduced in detail above. Specific examples are used in this article to illustrate the principles and implementation methods of the present application. The description of the above embodiments is only used to help understand the method and core idea of ​​the present application. At the same time, for technical personnel in this field, according to the idea of ​​the present application, there will be changes in the specific implementation method and application scope. In summary, the content of this specification should not be understood as a limitation on the present application.

Claims

1. An oral product, characterized in that: The invention comprises a sustained-release agent, wherein the sustained-release agent comprises at least one of a beta-cyclodextrin inclusion complex of a nicotine derivative and a carboxylate of a nicotine derivative.

2. The oral product according to claim 1, characterized in that The carboxylate of the nicotine derivative comprises at least one of nicotine derivative ditartaric acid dihydrate and a resin carrier of the nicotine derivative.

3. The oral product according to claim 1 or 2, characterized in that: The nicotine derivative ditartaric acid dihydrate includes at least one of 2-methylnicotine ditartaric acid dihydrate, 6-methylnicotine ditartaric acid dihydrate, 2-ethylnicotine ditartaric acid dihydrate, 6-chloronicotine ditartaric acid dihydrate, and 4-trifluoromethylated nicotine ditartaric acid dihydrate; and / or The resin carrier of the nicotine derivative includes at least one of a resin carrier of 2-methyl nicotine, a resin carrier of 6-methyl nicotine, a resin carrier of 2-ethyl nicotine, a resin carrier of 6-chloro nicotine, and a resin carrier of 4-trifluoromethylated nicotine; and / or The nicotine derivative includes a pyridine ring substituted with a substituent, and the substituent includes at least one of a halogen, a C1-C2 alkyl group, and a trifluoromethyl group.

4. The oral product according to claim 3, characterized in that The nicotine derivative includes at least one of 2-methyl nicotine, 6-methyl nicotine, 2-ethyl nicotine, 6-chloronicotine, and 4-trifluoromethylated nicotine.

5. The oral product according to claim 2, characterized in that: The oral product is a buccal cigarette; The sustained-release agent is a β-cyclodextrin inclusion complex of the nicotine derivative, the mass percentage of the β-cyclodextrin inclusion complex of the nicotine derivative in the oral product is 7.1%-14.9%, and in the β-cyclodextrin inclusion complex of the nicotine derivative, the molar ratio between the nicotine derivative and the β-cyclodextrin is (1-1.05):1; and / or The sustained-release agent is the nicotine derivative ditartaric acid dihydrate, and the mass percentage of the nicotine derivative ditartaric acid dihydrate in the oral product is 2.9%-5.9%; and / or The sustained-release agent is a resin carrier of the nicotine derivative, and the mass percentage of the resin carrier of the nicotine derivative in the oral product is 3.4%-5.7%; and / or The oral preparation further comprises microcrystalline fiber, propylene glycol, water, food flavor, sodium chloride, sodium carbonate, acesulfame potassium, aspartame and vitamin E.

6. The oral product according to claim 2, characterized in that The oral product is an oral tablet; The sustained-release agent is a β-cyclodextrin inclusion complex of the nicotine derivative, the mass percentage of the β-cyclodextrin inclusion complex of the nicotine derivative in the oral product is 0.5%-2.2%, and in the β-cyclodextrin inclusion complex of the nicotine derivative, the molar ratio between the nicotine derivative and the β-cyclodextrin is (1-1.05):1; and / or The sustained-release agent is the nicotine derivative ditartaric acid dihydrate, and the mass percentage of the nicotine derivative ditartaric acid dihydrate in the oral product is 0.2%-0.9%; and / or The oral preparation further comprises mannitol, maltitol, xylitol, citric acid, magnesium stearate, anhydrous silica colloid, sodium bicarbonate, xanthan gum, food flavor, menthol and peppermint oil.

7. The oral product according to claim 2, characterized in that The oral product is chewing gum; The sustained-release agent is a β-cyclodextrin inclusion complex of the nicotine derivative, the mass percentage of the β-cyclodextrin inclusion complex of the nicotine derivative in the oral product is 0.8%-1.9%, and in the β-cyclodextrin inclusion complex of the nicotine derivative, the molar ratio between the nicotine derivative and the β-cyclodextrin is (1-1.05):1; and / or The sustained-release agent is the nicotine derivative ditartaric acid dihydrate, and the mass percentage of the nicotine derivative ditartaric acid dihydrate in the oral product is 0.4%-0.8%; and / or The sustained-release agent is a resin carrier of the nicotine derivative, and the mass percentage of the resin carrier of the nicotine derivative in the oral product is 0.3%-0.8%; and / or The oral product further comprises chewing gum base, xylitol, food flavor, lecithin, carboxymethyl cellulose and vitamin E.

8. A method for preparing the oral product according to any one of claims 1 to 7, characterized in that: The method comprises the following steps: Providing raw materials, wherein the raw materials include a sustained-release agent, wherein the sustained-release agent includes at least one of a β-cyclodextrin inclusion complex of a nicotine derivative and a carboxylate of a nicotine derivative; The raw materials are mixed to obtain the oral product.

9. The preparation method according to claim 8, characterized in that: The preparation method of the sustained-release agent comprises the following steps: Adding a nicotine derivative into an aqueous solution of β-cyclodextrin so that the nicotine derivative enters the cavity of the β-cyclodextrin to obtain a first mixed solution containing a β-cyclodextrin inclusion complex of the nicotine derivative; The first mixed solution is allowed to stand at low temperature, filtered, washed, and dried to obtain the sustained-release agent, wherein the sustained-release agent comprises the β-cyclodextrin inclusion complex of the nicotine derivative.

10. The preparation method according to claim 9, characterized in that: The method for preparing the aqueous solution of β-cyclodextrin comprises the following steps: adding β-cyclodextrin to water, heating and stirring at 60° C.-80° C. until the β-cyclodextrin is completely dissolved, to obtain the aqueous solution of β-cyclodextrin; and / or In the aqueous solution of β-cyclodextrin, the mass ratio of water to β-cyclodextrin is (8-10):1; and / or In the step of adding the nicotine derivative to the aqueous solution of β-cyclodextrin, the molar ratio of the β-cyclodextrin to the nicotine derivative is 1:1.05, and / or the nicotine derivative and the aqueous solution of β-cyclodextrin are mixed by stirring, the stirring and mixing temperature is 60° C.-80° C., and the stirring and mixing time is 2 h-4 h; and / or The low temperature standing temperature is 0°C-6°C, and / or the low temperature standing time is 20h-26h; and / or The drying is vacuum drying, the temperature of the vacuum drying is 40° C.-50° C., and / or the vacuum degree of the vacuum drying is 0.05 MPa-0.2 MPa.

11. The preparation method according to claim 8, characterized in that: The preparation method of the sustained-release agent comprises the following steps: Providing a nicotine derivative and a tartaric acid solution, wherein the nicotine derivative has a pyridine ring substituted with a substituent, the substituent comprising at least one of a halogen, a C1-C2 alkyl group, and a trifluoromethyl group, and the tartaric acid solution comprises tartaric acid; adding the nicotine derivative to the tartaric acid solution so that the nicotine derivative undergoes an acid-base neutralization reaction with the tartaric acid to obtain a second mixed solution containing nicotine derivative ditartaric acid dihydrate; Refrigerating and crystallizing the second mixed solution, filtering, washing, and drying to obtain the sustained-release agent; Wherein, the sustained-release agent includes the nicotine derivative ditartaric acid dihydrate.

12. The preparation method according to claim 11, characterized in that: The preparation method of the tartaric acid solution comprises the following steps: dissolving the tartaric acid in ethanol to obtain the tartaric acid solution, wherein the weight ratio of the ethanol to the tartaric acid is (3-5):1, and / or the ethanol is 95% ethanol; and / or In the step of adding the nicotine derivative to the tartaric acid solution, the nicotine derivative and the tartaric acid solution are mixed by stirring, the stirring and mixing temperature is 20° C.-30° C., and / or, the stirring and mixing time is 3 h-4 h, and / or, the molar ratio of the tartaric acid to the nicotine derivative is (2-2.05):1; and / or The temperature of the refrigerated crystallization is 0-4°C, and / or the time of the refrigerated crystallization is 16h-20h.

13. The preparation method according to claim 8, characterized in that: The preparation method of the sustained-release agent comprises the following steps: A nicotine derivative and a resin suspension are provided, wherein the nicotine derivative has a pyridine ring substituted with a substituent, the substituent includes at least one of a halogen, a C1-C2 alkyl group, and a trifluoromethyl group, and the resin suspension includes a resin, and the resin has a carboxyl group; adding the nicotine derivative to the resin suspension so that the nicotine derivative undergoes an acid-base neutralization reaction with the resin to obtain a third mixed solution of the resin carrier containing the nicotine derivative; filtering, washing, and drying the third mixed solution to obtain the sustained-release agent; Wherein, the sustained-release agent comprises a resin carrier of the nicotine derivative.

14. The preparation method according to claim 13, characterized in that: The method for preparing the resin suspension comprises the following steps: adding the resin into water and stirring for 10 h to 14 h to obtain the resin suspension, and / or the mass ratio of the water to the resin is (7-9):1; and / or In the step of adding the nicotine derivative to the resin suspension, the mass ratio of the resin to the nicotine derivative is 1:(0.60-0.75), and / or the nicotine derivative and the resin suspension are mixed by stirring, and the stirring and mixing time is 10h-14h.

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