Nicotine buccal product and preparation method thereof

Abstract

The invention provides a nicotine buccal product and a preparation method thereof, and relates to the field of nicotine products, and the nicotine buccal product comprises at least one effervescent granule and a base material; the effervescent granules comprise a first active agent and a coating layer; the substrate includes a second active agent and a coating material, the coating material including a plasticizer and a water-soluble binder. The effervescent granules can be rapidly disintegrated and melted after being put into the mouth, and the process promotes rapid release of the first active agent in the effervescent granules in the early stage. The coating material in the base material can adjust the release rate of the second active agent and prolong the dissolution rate of the second active agent, so that the slow-release effect is achieved. According to the buccal nicotine product, the effervescent granules and the base material are matched with each other, so that the buccal nicotine product can rapidly increase the release amount of the first active agent in the entering stage, rapid first active agent effect taking experience is provided, meanwhile, the subsequent slow release function of the second active agent is considered, and more excellent use experience is brought to consumers.

Description

Technical Field

[0001] This application relates to the field of nicotine products, and particularly to a nicotine buccal product and a preparation method thereof. Background Art

[0002] Among nicotine replacement therapy products, nicotine buccal products, as a tool designed to assist users in quitting smoking or reducing tobacco dependence, have received extensive attention in recent years.

[0003] However, existing nicotine buccal products still face significant challenges in meeting consumer needs. In particular, the nicotine release rate of nicotine buccal products is relatively slow, making it difficult to quickly achieve the rapid onset effect expected by consumers. In the initial stage of use, the "kick" of nicotine is weak, directly affecting the consumer experience and making it difficult to effectively meet the need for rapid addiction cessation. In addition, the insufficient persistence of existing nicotine buccal products is also an urgent problem to be solved.

[0004] Existing nicotine buccal products are difficult to balance the nicotine release rate and duration, resulting in a poor overall experience and thus affecting the market competitiveness of the products.

[0005] To address these deficiencies, a series of technical means have been adopted in the production process of current nicotine buccal products. For example, the release characteristics of nicotine are optimized by adjusting the formulation components or using sustained-release materials; the wettability or moisture content of nicotine buccal products is increased to promote the initial release of nicotine. However, existing technical means often have limitations in practical applications and are difficult to achieve both the rapid release and onset of nicotine and the effect of sustained slow release simultaneously. Summary of the Invention

[0006] The purpose of this application is to provide a nicotine buccal product and a preparation method thereof to solve the above problems.

[0007] A nicotine buccal product includes at least one effervescent granule and a substrate;

[0008] The effervescent granule includes a first active agent and a coating layer;

[0009] The substrate includes a second active agent and a coating material, and the coating material includes a plasticizer and a water-soluble binder.

[0010] In some embodiments, the first active agent includes at least one of nicotine, nicotine derivatives, caffeine, and theobromine;

[0011] and / or, the second active agent includes at least one of nicotine and nicotine derivatives;

[0012] And / or, the plasticizer includes at least one of diethyl phthalate, dibutyl phthalate, and polyethylene glycol;

[0013] And / or, the water-soluble binder includes at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, and polyvinyl acetal diethylamino acetate.

[0014] In some embodiments, the size of the effervescent granule in the first direction is 1 mm - 15 mm, and the size of the effervescent granule in the second direction is 1 mm - 6 mm, wherein the first direction is perpendicular to the second direction.

[0015] In some embodiments, in terms of the first mass fraction, the effervescent granule includes 10 parts - 40 parts of acid source, 10 parts - 40 parts of base source, 2 parts - 30 parts of first filler, 2 parts - 40 parts of second filler, 2 parts - 15 parts of first binder, 1 part - 8 parts of second binder, 0.5 parts - 6 parts of flavoring agent, and 0.5 parts - 10 parts of first active agent.

[0016] In some embodiments, the acid source includes at least one of citric acid, tartaric acid, fumaric acid, and malic acid;

[0017] And / or, the base source includes at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and calcium carbonate;

[0018] And / or, the first filler includes at least one of sorbitol, xylitol, erythritol, mannitol, isomalt, maltitol, and anhydrous lactitol;

[0019] And / or, the second filler includes at least one of corn starch, potato starch, pregelatinized starch, modified starch, and wheat starch;

[0020] And / or, the first binder includes at least one of polyethylene glycol, gelatin, sodium alginate, polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose;

[0021] And / or, the second binder includes at least one of sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, gelatin, sodium alginate, and polyvinylpyrrolidone;

[0022] And / or, the flavoring agent includes at least one of edible salt, sucrose, glucose, fructose, sodium saccharin, citric acid, acetic acid, and menthol.

[0023] In some embodiments, measured by the second mass parts, the base material includes 5 to 40 parts of a third filler, 10 to 50 parts of a fourth filler, 5 to 30 parts of a fifth filler, 0.5 to 3.0 parts of a plasticizer, 2.5 to 10.0 parts of a water-soluble binder, and 0.5 to 8.0 parts of a second active agent.

[0024] In some embodiments, the third filler includes microcrystalline cellulose;

[0025] The fourth filler includes at least one of erythritol, xylitol, sorbitol, mannitol, isomaltulose, maltitol, and anhydrous lactitol;

[0026] The fifth filler includes at least one of sorbitol, xylitol, erythritol, mannitol, isomaltulose, maltitol, and anhydrous lactitol.

[0027] This application also provides a method for preparing a nicotine buccal product for preparing the nicotine buccal product described above, the method comprising:

[0028] Coating a material containing a first active agent to form a coating layer on the surface of the material to obtain effervescent granules;

[0029] Treating a material containing a second active agent with a coating material to obtain a base material, wherein the coating material includes a plasticizer and a water-soluble binder;

[0030] Filling the base material and at least one of the effervescent granules into a packaging bag and sealing to obtain a nicotine buccal product.

[0031] In some embodiments, preparing the effervescent granules includes:

[0032] Mixing an acid source, a first filler, a first active agent, and a first solvent, adding a second binder, granulating, and performing a first drying treatment to obtain acidic granules;

[0033] Mixing a base source and a flavoring agent, adding a second binder, granulating, and performing a second drying treatment to obtain basic granules;

[0034] Mixing the acidic granules, the basic granules, a second filler, and a first binder to obtain a mixed powder;

[0035] Tabletting the mixed powder to obtain tablets;

[0036] Coating the tablets to form a coating layer on the surface of the tablets, and performing a third drying treatment to obtain the effervescent granules.

[0037] In some embodiments, preparing the base material includes:

[0038] Mix a second solvent, a plasticizer, and a water-soluble binder to prepare a coating solution;

[0039] Mix a third filler and a second active agent to obtain a first mixture;

[0040] Coat the first mixture with the coating solution to obtain a coated material;

[0041] Mix the coated material with a fourth filler to obtain a second mixture;

[0042] Mix the second mixture with a fifth filler to obtain the substrate.

[0043] Compared with the prior art, the beneficial effects of the present application include:

[0044] The present application provides a novel nicotine buccal product, which has the dual advantages of rapid release and onset of a first active agent and continuous and stable release of a second active agent, can meet the personalized needs of different consumers, and significantly improves the overall user experience and market competitiveness of the product. Specifically, the nicotine buccal product of the present application contains effervescent granules. After the effervescent granules are put into the mouth, they will quickly disintegrate and melt, and at the same time, a large amount of carbon dioxide is generated. This process promotes the rapid release of the first active agent such as nicotine-like substances in the effervescent granules in the early stage, providing consumers with the experience of rapid release and onset of the first active agent. In addition, the nicotine buccal product of the present application also includes a substrate. The coating material in the substrate can regulate the release rate of the second active agent such as nicotine-like substances. Specifically, the plasticizer can improve the gaps and defects of the film coating and prolong the dissolution rate of the second active agent to achieve a sustained release effect; the adhesion of the water-soluble binder helps to form a complete and uniform coating layer, thereby ensuring the stability and consistency of the second active agent during the release process. That is, the coating material of the present application can achieve the slow release of the second active agent in the substrate. The effervescent granules and the substrate cooperate with each other, enabling the nicotine buccal product to rapidly increase the release amount of the first active agent at the entrance stage, providing a rapid onset experience of the first active agent, while taking into account the subsequent sustained release function of the second active agent, bringing a more superior user experience to consumers.

[0045] The present application also provides a nicotine buccal product and a preparation method thereof. The nicotine buccal product prepared by using this method simultaneously has the effects of rapid release and onset of a first active agent and continuous and slow release of a second active agent. In addition, this method also has the advantages of simple operation and low production cost, which is conducive to large-scale popularization and application. Description of the Drawings

[0046] To more clearly illustrate the technical solutions of the embodiments of the present application, the accompanying drawings required for the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present application and should not be regarded as limiting the scope of the present application.

[0047] Figure 1 It is a comparison chart of the nicotine content of the nicotine buccal products in Examples 1-3 and Comparative Examples 1-3;

[0048] Figure 2 It is a comparison chart of the moisture content of the nicotine buccal products in Examples 1-3 and Comparative Examples 1-3;

[0049] Figure 3 It is a comparison curve of the nicotine dissolution ratio of the nicotine buccal products in Examples 1-3 and Comparative Examples 1-3;

[0050] Figure 4 It is a comparison chart of the effervescent effect before and after the environmental test of the nicotine buccal products in Examples 1-3 and Comparative Examples 1-3. Detailed implementation manners

[0051] As used herein, the terms:

[0052] The terms "comprising", "including", "having", "containing" or any other variation thereof as used herein are intended to cover non-exclusive inclusion. For example, a composition, step, method, article or apparatus containing the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such composition, step, method, article or apparatus.

[0053] When an equivalent, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper preferred values and lower preferred values, this should be understood to specifically disclose all ranges formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, whether or not the ranges are separately disclosed. For example, when the range "1 to 5" is disclosed, the described range should be interpreted to include the ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described herein, unless otherwise stated, the range is intended to include its end values and all integers and fractions within the range.

[0054] In these embodiments, unless otherwise specified, the parts and percentages are by mass.

[0055] "Parts by mass" refers to the basic measurement unit representing the mass ratio relationship of multiple components. 1 part can represent any unit mass, such as 1 g or 2.689 g, etc. If we say that the mass of component A is a parts by mass and the mass of component B is b parts by mass, it means the mass ratio of component A to component B is a:b. Or, it means the mass of component A is aK and the mass of component B is bK (K is any number representing a multiple factor). It should not be misunderstood that the sum of the parts by mass of all components is not limited to 100 parts. When measured by the first mass fraction, each mass fraction represents the first mass, and the first mass can be any mass. When measured by the second mass fraction, each mass fraction represents the second mass, and the second mass can be any mass. The first mass and the second mass are independent of each other and not related.

[0056] "And / or" is used to indicate that either or both of the described situations may occur. For example, A and / or B includes (A and B) and (A or B).

[0057] Existing nicotine buccal products are difficult to simultaneously achieve both the rapid release and onset of nicotine in the initial stage of use and maintain the slow release of nicotine.

[0058] To improve the above problems, the present application provides a nicotine buccal product, comprising at least one effervescent granule and a substrate; the effervescent granule comprises a first active agent and a coating layer; the substrate comprises a second active agent and a coating material, and the coating material comprises a plasticizer and a water-soluble binder.

[0059] The effervescent granule can rapidly disintegrate and melt after being put into the mouth, ensuring the rapid release of the first active agent in the initial stage of use. The coating material in the substrate is conducive to the slow release of the second active agent. The nicotine buccal product of the present application contains an effervescent granule and a substrate, enabling the nicotine buccal product to have the advantages of rapid onset of the first active agent and slow release of the second active agent and a long duration of the active ingredient in the initial stage of use.

[0060] In some embodiments, the first active agent includes at least one of nicotine, nicotine derivatives, caffeine, and theobromine. Nicotine includes natural nicotine and synthetic nicotine. Nicotine derivatives include one or more of nicotine salts, nicotine in a matrix such as a sugar matrix or an organometallic complex, nicotine-resin combinations, nicotine inclusion complexes, and non-covalently bound nicotine. Among them, non-covalently bound nicotine includes nicotine citrate, nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine acetate, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, nicotine benzoate, etc. Nicotine derivatives also include nicotine with substituents, such as one or more mixtures of hexamethyl nicotine, hexamethyl nicotine lactate, hexamethyl nicotine malate, hexamethyl nicotine salicylate, hexamethyl nicotine cyclodextrin inclusion complex, hexamethyl nicotine hydrochloride, hexamethyl nicotine dihydrochloride, hexamethyl nicotine tartrate, hexamethyl nicotine tartrate dihydrate, hexamethyl nicotine sulfate, hexamethyl nicotine zinc chloride, and hexamethyl nicotine benzoate. In some embodiments, the second active agent includes at least one of nicotine and nicotine derivatives. The substances of the first active agent and the second active agent may be the same or different.

[0061] In some embodiments, nicotine derivatives include, but are not limited to, nicotine salts.

[0062] In some embodiments, the plasticizer includes at least one of diethyl phthalate (DEP), dibutyl phthalate (DBP), and polyethylene glycol; the plasticizer of the present application can effectively improve the gaps and defects of the film coating, slow down the release rate of the second active agent with the increase of the plasticizer dosage, prolong the dissolution rate of the second active agent, and further improve the sustained release effect.

[0063] In some embodiments, the water-soluble binder includes at least one of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), polyvinyl alcohol (PVA), and polyvinyl acetal diethylamino acetate (AEA).

[0064] In some embodiments, the size of the effervescent granule in the first direction is 1 mm - 15 mm, and the size of the effervescent granule in the second direction is 1 mm - 6 mm, wherein the first direction is perpendicular to the second direction.

[0065] Exemplarily, the size of the effervescent granule in the first direction can be 1 mm, 5 mm, 10 mm, 15 mm, or any value between 1 mm and 15 mm. The size of the effervescent granule in the second direction can be 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, or any value between 1 mm and 6 mm. The first direction can refer to the diameter direction of the effervescent granule, and the second direction can refer to the thickness direction of the effervescent granule.

[0066] In some embodiments, measured by the first mass fraction, the effervescent granule comprises 10 to 40 parts of an acid source, 10 to 40 parts of a base source, 2 to 30 parts of a first filler, 2 to 40 parts of a second filler, 2 to 15 parts of a first binder, 1 to 8 parts of a second binder, 0.5 to 6 parts of a flavoring agent, and 0.5 to 10 parts of a first active agent.

[0067] The content of the acid source in the effervescent granule can be 10 parts, 20 parts, 30 parts, 40 parts, or any value between 10 parts and 40 parts. The content of the base source in the effervescent granule can be 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, or any value between 10 parts and 40 parts. The content of the first filler in the effervescent granule can be 2 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, or any value between 2 parts and 30 parts. The content of the second filler in the effervescent granule can be 2 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, or any value between 2 parts and 40 parts. The content of the first binder in the effervescent granule can be 2 parts, 5 parts, 10 parts, 15 parts, or any value between 2 parts and 15 parts. The content of the second binder in the effervescent granule can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, or any value between 1 part and 8 parts. The content of the flavoring agent in the effervescent granule can be 0.5 parts, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, or any value between 0.5 parts and 6 parts. The content of the first active agent in the effervescent granule can be 0.5 parts, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, or any value between 0.5 parts and 10 parts.

[0068] In some embodiments, the acid source comprises at least one of citric acid, tartaric acid, fumaric acid, and malic acid.

[0069] In some embodiments, the base source comprises at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and calcium carbonate.

[0070] In some embodiments, the first filler comprises at least one of sorbitol, xylitol, erythritol, mannitol, isomalt, maltitol, and anhydrous lactitol.

[0071] In some embodiments, the second filler includes at least one of corn starch, potato starch, pregelatinized starch, modified starch, and wheat starch.

[0072] In some embodiments, the first binder includes at least one of polyethylene glycol, gelatin, sodium alginate, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

[0073] In some embodiments, the second binder includes at least one of sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, gelatin, sodium alginate, and polyvinylpyrrolidone.

[0074] In some embodiments, the flavoring agent includes at least one of edible salt, sucrose, glucose, fructose, sodium saccharin, citric acid, acetic acid, and menthol.

[0075] In some embodiments, the effervescent granules further include a first essence, and the content of the first essence generally does not exceed 10 parts. The type and content of the first essence can be adjusted according to actual taste requirements, and no specific limitation is made in this application.

[0076] When the effervescent granules encounter saliva in the mouth, an effervescent reaction will occur rapidly, generating a large number of delicate bubbles, increasing the surface area and mass transfer in the mouth, facilitating the absorption of the first active agent including nicotine in the oral mucosa, improving the absorption efficiency of the first active agent, and enabling consumers to feel the product effect faster. Moreover, the introduction of the effervescent granules makes the taste of the buccal product more layered and dynamic. During use, the product will produce an obvious effervescent phenomenon, bringing a unique oral stimulation and freshness to the user, increasing the visual attraction and novelty of the product, and forming a sharp contrast with the relatively single taste of traditional buccal products. In addition, in this application, the components of the effervescent granules can be adjusted according to factors such as the taste preferences of different consumers and the requirements for active ingredients, so that the effervescent granules have different tastes and / or active ingredient contents, realizing the personalized customization of the product and better meeting the market segmentation needs. For example, by adjusting the types of components in the effervescent granules, the effervescent granules can have more diversified tastes such as tobacco flavor, mint flavor, fruit flavor, and cocktail flavor. During the effervescent process, the taste will gradually emit and change as the bubbles are released, forming a rich taste layer.

[0077] In some embodiments, measured by the second mass fraction, the substrate includes 5 parts to 40 parts of a third filler, 10 parts to 50 parts of a fourth filler, 5 parts to 30 parts of a fifth filler, 0.5 parts to 3.0 parts of a plasticizer, 2.5 parts to 10.0 parts of a water-soluble binder, and 0.5 parts to 8.0 parts of a second active agent.

[0078] The content of the third filler in the base material can be 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, or any value between 5 parts and 40 parts. The content of the fourth filler in the base material can be 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, or any value between 10 parts and 50 parts. The content of the fifth filler in the base material can be 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, or any value between 5 parts and 30 parts. The content of the plasticizer in the base material can be 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3.0 parts, or any value between 0.5 parts and 3.0 parts. The content of the water-soluble binder in the base material can be 2.5 parts, 3.0 parts, 4.0 parts, 5.0 parts, 6.0 parts, 7.0 parts, 8.0 parts, 9.0 parts, 10.0 parts, or any value between 2.5 parts and 10.0 parts. The content of the second active agent in the base material can be 0.5 parts, 1.0 parts, 2.0 parts, 3.0 parts, 4.0 parts, 5.0 parts, 6.0 parts, 7.0 parts, 8.0 parts, or any value between 0.5 parts and 8.0 parts.

[0079] In some embodiments, the base material further includes a second flavoring. The type and content of the second flavoring can be adjusted according to actual taste requirements, and no specific limitation is made in this application. Exemplarily, the content of the second flavoring can be 5 to 16 parts.

[0080] In some embodiments, the third filler includes microcrystalline cellulose.

[0081] In some embodiments, the fourth filler includes at least one of erythritol, xylitol, sorbitol, mannitol, isomaltulose, maltitol, and anhydrous lactitol.

[0082] In some embodiments, the fifth filler includes at least one of sorbitol, xylitol, erythritol, mannitol, isomaltulose, maltitol, and anhydrous lactitol.

[0083] This application also provides a method for preparing a nicotine buccal product for preparing the nicotine buccal product as described above. The method includes the following main steps:

[0084] Coat the material containing the first active agent to form a coating layer on the surface of the material to obtain effervescent granules;

[0085] Treat the material containing the second active agent with a coating material to obtain a base material, wherein the coating material includes a plasticizer and a water-soluble binder;

[0086] Fill at least one effervescent granule and the base material into a packaging bag and seal it to obtain a nicotine buccal product.

[0087] In some embodiments, the packaging bag is a non-woven fabric bag permeable to saliva, and the nicotine buccal product is a nicotine pouch.

[0088] In some embodiments, preparing the effervescent granules includes the following main steps:

[0089] Mix an acid source, a first filler, a first active agent, and a first solvent, add a second binder, granulate, and perform a first drying treatment to obtain acidic granules;

[0090] Mix an alkali source and a flavoring agent, add a second binder, granulate, and perform a second drying treatment to obtain alkaline granules;

[0091] Mix the acidic granules, the alkaline granules, a second filler, and a first binder to obtain a mixed powder;

[0092] Press the mixed powder into tablets to obtain tablets;

[0093] Coat the tablets to form a coating layer on the surface of the tablets, and perform a third drying treatment to obtain effervescent granules.

[0094] In this application, the tablets are coated using a coating process, which can uniformly coat the coating layer on the outer surface of the tablets, avoid the effervescent granules from being affected by moisture and becoming ineffective, and improve the storage stability and usage effect of the effervescent granules. The effervescent granules prepared in this application have good uniformity and high stability, which is conducive to the rapid release of the first active agent in the oral cavity.

[0095] In some embodiments, preparing the substrate includes the following main steps:

[0096] Mix a second solvent, a plasticizer, and a water-soluble binder to prepare a coating solution;

[0097] Mix a third filler and a second active agent to obtain a first mixture;

[0098] Coat the first mixture with the coating solution to obtain the coated material;

[0099] Mix the coated material with a fourth filler to obtain a second mixture;

[0100] Mix the second mixture with a fifth filler to obtain the substrate.

[0101] The substrate prepared in this application has good uniformity and high stability, which is conducive to the sustained release of the second active agent in the oral cavity.

[0102] The implementation solutions of the present application will be described in detail below in conjunction with specific embodiments. However, those skilled in the art will understand that the following embodiments are only used to illustrate the present application and should not be regarded as limiting the scope of the present application. For those conditions not specified in the embodiments, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0103] I. Preparation of nicotine buccal products

[0104] Example 1

[0105] Example 1 provides a nicotine buccal product, including an effervescent granule and a substrate.

[0106] The effervescent granule includes 30 parts of acid source, 20 parts of base source, 10 parts of first filler, 10 parts of second filler, 6 parts of first binder, 3 parts of second binder, 1 part of flavoring agent, 3 parts of first active agent, 6 parts of first essence, and 11 parts of first solvent. Among them, the acid source is anhydrous citric acid, the base source is sodium bicarbonate, the first filler is sorbitol, the second filler is corn starch, the first binder is polyethylene glycol, the second binder is sodium carboxymethyl cellulose, the flavoring agent is edible salt, the first active agent is nicotine tartrate, the first essence is mint flavor essence, and the first solvent is deionized water.

[0107] The substrate includes 24 parts of third filler, 30 parts of fourth filler, 10 parts of fifth filler, 1.0 part of plasticizer, 5.0 parts of water-soluble binder, 3.0 parts of second active agent, 15.0 parts of second solvent, and 12.0 parts of second essence. Among them, the third filler is microcrystalline cellulose, the fourth filler is erythritol, the fifth filler is sorbitol, the water-soluble binder is polyvinyl alcohol, the plasticizer is dibutyl phthalate, the second solvent is deionized water, the second essence is mint flavor essence, and the second active agent is nicotine tartrate.

[0108] Example 1 also provides a preparation method of a nicotine buccal product, including:

[0109] (1) Preparation of effervescent granules:

[0110] Weigh the acid source, first filler, first active agent, and first solvent according to the formula ratio, mix them evenly for 30 minutes using a three-dimensional mixer, add the second binder by fluidized bed granulation method, and dry to form granules to obtain acidic granules.

[0111] Weigh the base source and flavoring agent according to the formula ratio, mix them evenly for 30 minutes using a three-dimensional mixer, and then add the second binder by fluidized bed granulation method and dry to form granules to obtain basic granules.

[0112] Mix the acidic particles, alkaline particles, second filler, first binder, and first essence in a three-dimensional mixer for 30 minutes to ensure uniform mixing of each component and obtain a mixed powder.

[0113] Place the mixed powder on a tablet press for tableting. The forming pressure is 9 - 10 tons, and the pressure is maintained for 10 seconds to press out round tablets with a diameter of 5 mm and a thickness of 3 mm.

[0114] Place the round tablets on a fluidized bed for coating to maintain the stable performance of the round tablets and prevent product failure caused by moisture absorption.

[0115] Subsequently, place the coated round tablets in an oven and keep them at a temperature of 40 °C for 1 hour to control the moisture content of the round tablets and obtain effervescent granules.

[0116] (2) Prepare the substrate:

[0117] Weigh the second solvent, plasticizer, and water-soluble binder according to the formula ratio and mix them in a homogenizer for 60 min to obtain a coating solution.

[0118] Weigh the third filler and second active agent according to the formula ratio and mix them in a three-dimensional mixer for 30 min to obtain a first mixture.

[0119] Place the first mixture on a fluidized bed and perform coating treatment on the first mixture with the prepared coating solution using the fluidized bed coating process, controlling the finished product humidity within 5%, to obtain the coated material.

[0120] Mix the coated material with the fourth filler and use a three-dimensional mixer to mix for 30 min to obtain a second mixture.

[0121] Place the second mixture on a fluidized bed and spray the second essence on the second mixture in a fluidized granulation manner to prepare essence granules 1, controlling the moisture content to be less than 5%.

[0122] Mix the essence granules 1 obtained from the previous process with the fifth filler and use a three-dimensional mixer to mix for 30 min to prepare the substrate.

[0123] (3) Fill the effervescent granules and the substrate:

[0124] Vibrating plate adjustment: Adjust the amplitude and frequency of the vibrating plate to 90 HZ and vibrate at 100 V voltage so that the effervescent granules can be stably and orderly arranged in the vibrating plate and conveyed one by one. Ensure that the conveying speed of the effervescent granules matches the overall rhythm of the bead filling machine.

[0125] Track width adjustment: Precisely adjust the width of the conveying track of the effervescent granules according to the diameter of the effervescent granules so that the effervescent granules can slide smoothly in the track without being squeezed or stuck to each other. The track width is slightly larger than 1.1 to 1.2 times the diameter of the effervescent granules.

[0126] Filling opening calibration: Align the filling opening with the filling position of the non-woven bag to ensure that the effervescent granules can accurately fall into the bag. The size of the filling opening should be appropriate, which can ensure the smooth passage of the effervescent granules and prevent multiple effervescent granules from falling simultaneously. Generally, it is 1.1 to 1.2 times the diameter of the effervescent granules, but smaller than the non-woven bag.

[0127] Sensor setting: Use a photoelectric sensor or other induction devices to set a detection point near the filling opening. When an effervescent granule passes through the detection point, the sensor will send a signal to the control system. After receiving the signal, the control system will immediately stop the flaking action to ensure that only one effervescent granule falls each time.

[0128] Counting and calibration: Set a counting function in the control system of the automatic bead filling machine to count the number of flakes filled in each bag. Before formal production, conduct multiple test fillings, and calibrate and adjust the equipment parameters according to the actual filling situation to ensure that each bag can accurately contain one effervescent tablet.

[0129] Adding effervescent granules: Use an automatic bead filling machine to fill the finished base powder and effervescent granules. Place the non-woven bag at the designated position of the effervescent tablet adding device, start the device, and make the effervescent granules accurately added to the non-woven bag according to the set parameters, ensuring that each mouthpiece tobacco product contains one effervescent granule.

[0130] Packaging: Use a mouthpiece tobacco sealing machine to complete the non-woven fabric encapsulation, boxing, and plastic sealing of the finished powder.

[0131] Example 2 - 3

[0132] Prepare nicotine-containing oral products according to the preparation method of Example 1. The formulations of the nicotine-containing oral products in Examples 2 - 3 are shown in Tables 1 and 2.

[0133] Comparative Examples 1 - 3

[0134] Prepare nicotine-containing oral products according to the preparation method of Example 1. Do not add the first active agent to the effervescent granules in Comparative Example 1, and do not add the second active agent to the base material in Comparative Examples 2 and 3. The formulations of the nicotine-containing oral products in Comparative Examples 1 - 3 are shown in Tables 1 and 2.

[0135] The formulations of the effervescent granules in Examples 1 - 3 and Comparative Examples 1 - 3 are shown in Table 1 below, and the formulations of the base materials in Examples 1 - 3 and Comparative Examples 1 - 3 are shown in Table 2 below.

[0136] Table 1 Formulation Table of Effervescent Granules in Examples 1 - 3 and Comparative Examples 1 - 3

[0137]

[0138] Table 2 Formulation Table of Substrates in Examples 1-3 and Comparative Examples 1-3

[0139]

[0140] II. Performance Testing of Nicotine Orally Disintegrable Products

[0141] 2.1 Detection of Nicotine Content

[0142] The nicotine content in the nicotine orally disintegrable products of Examples 1-3 and Comparative Examples 1-3 was tested by HPLC-Aglient GC8890. Reagents: isopropanol (chromatographic grade), ethanol (chromatographic grade); Standard: nicotine standard solution in isopropanol, n-heptadecane (internal standard).

[0143] The set nicotine content in the nicotine orally disintegrable products of Examples 1-3 and Comparative Examples 1-3 was 22 mg / g. Referring to Figure 1 , the actual nicotine contents in Examples 1-3 and Comparative Examples 1-3 of this application were 20.691 mg / g, 21.003 mg / g, 20.65 mg / g, 19.998 mg / g, 20.965 mg / g, and 19.894 mg / g respectively. The loss amounts of nicotine content in Examples 1-3 and Comparative Examples 1-3 were all within the range of ±10%, indicating that the preparation method of this application has high stability.

[0144] 2.2 Detection of Moisture Content

[0145] The moisture content of the nicotine orally disintegrable products of Examples 1-3 and Comparative Examples 1-3 was tested using a Japanese KEM 710S-ADP611 device. The moisture content requirement of the nicotine orally disintegrable products was within 5%.

[0146] Referring to Figure 2 , the moisture contents of the nicotine orally disintegrable products of Examples 1-3 and Comparative Examples 1-3 were far lower than 5%, indicating that in terms of moisture content, the nicotine orally disintegrable products of Examples 1-3 and Comparative Examples 1-3 all met the requirements. The lower moisture content helped to maintain the stability and quality of the product.

[0147] 2.3 Detection of Nicotine Dissolution Ratio

[0148] The dissolution ratio of nicotine in the nicotine orally disintegrable products of Examples 1-3 and Comparative Examples 1-3 was tested using an Agilent 708-DS dissolution tester. Method: paddle method; Rotation speed: 50 rpm; Dissolution medium: 0.8 g / L potassium chloride solution, adjusted to pH 6.8 with sodium bicarbonate, Dissolution volume: 500 ml, Filter membrane: 0.2 μm, Sampling volume: 1.5 ml, without replenishing liquid.

[0149] The nicotine dissolution data of Nicotine Buccal Products in Examples 1-3 and Comparative Examples 1-3 are shown in Table 3. The comparative curves of the nicotine dissolution ratios of Nicotine Buccal Products in Examples 1-3 and Comparative Examples 1-3 are as Figure 3 shown.

[0150] Table 3 Nicotine Dissolution Data of Nicotine Buccal Products in Examples 1-3 and Comparative Examples 1-3

[0151]

[0152]

[0153] Experimental data analysis:

[0154] Initial dissolution rate (1 min - 10 min):

[0155] The nicotine dissolution amounts of Comparative Example 2 and Comparative Example 3 reached the dissolution plateau of the fitting curve within 1 - 3 min, reaching or approaching 18 - 20 mg / g of the total nicotine content, indicating that the nicotine release rate is quite fast. In the simulated human oral cavity, it is also equivalent to reaching the nicotine peak within 1 - 3 min. However, the curve became flat after 3 min - 60 min, indicating that the nicotine release amount was extremely small or almost non-existent, and the nicotine release was not persistent enough. This may be because the nicotine dose was designed in the effervescent granules, and as the effervescent granules dissolved and effervesced rapidly in water, a large amount of nicotine was released, increasing the nicotine release rate.

[0156] The initial dissolution rates of Example 1, Example 2, and Example 3 were relatively gentle, and the dissolution amounts were basically 8 - 10 mg / g. From the fitting curve, it was relatively gentle. In addition, according to the formulation design, the total nicotine content of the effervescent granules was 10 mg / g. Therefore, comparing with the dissolution curve, at the initial stage, the nicotine content of 10 mg / g was also basically completely released with the dissolution of the effervescent granules.

[0157] The dissolution rate of Comparative Example 1 was the slowest at the initial stage, and the nicotine dissolution amount was basically below 5 mg / g. This may be because no nicotine was added to the effervescent granules of Comparative Example 1, and the dissolution of the effervescent granules could not increase the nicotine release. A small amount of nicotine was basically released slowly with the dissolution of the coating layer in the substrate.

[0158] Mid - stage dissolution (20 min to 40 min):

[0159] According to the fitting curve, in Examples 1, 2, and 3, the dissolution plateau was reached within 20 min - 40 min. Example 2 reached the plateau earlier than Examples 1 and 3, with a dissolution amount of 17 - 20 mg / g, and the fitting curve was basically horizontal. At the same time, in Comparative Example 1, the release was still slow at this stage, with a dissolution amount of 15 mg / g. From the dissolution data, there was still a small amount of nicotine slowly releasing in Examples 1, 2, 3, and Comparative Example 1. In this stage, nicotine was basically released as the base coating layer slowly dissolved. Since a plasticizer was added to the coating layer, the dissolution was relatively slow.

[0160] Final-stage dissolution (40 min to 60 min):

[0161] Only Comparative Example 1 did not reach the dissolution plateau. The current dissolution amount was 18 - 19 mg / g. According to the formulation design, since the nicotine in Comparative Example 1 was basically coated in the coating layer, and at the same time, the amount of microcrystalline cellulose in Comparative Example 1 was large and insoluble in acidic solution, it could well maintain the slow release of nicotine until the end of the 60 - minute dissolution test, and nicotine release still existed.

[0162] From Table 3 and Figure 3 It can be seen that the nicotine in the nicotine buccal products of Examples 1 - 3 can be rapidly released, and at the same time, the sustained-release effect of nicotine can be maintained. This may be because the effervescent granules contain nicotine active ingredients, which can make nicotine take effect quickly and reach the feeling of being affected quickly. At the same time, the coating and plasticizer in the base material can maintain the slow release of nicotine in the base material, extend the nicotine release time, and achieve the sustained-release effect.

[0163] Compared with Examples 1 and 3, Example 2 has a more excellent nicotine release effect, can meet the rapid release of initial nicotine, and can also make nicotine slowly release in the middle and late stages of use.

[0164] 2.4 Product stability test

[0165] An environmental accelerated experiment was carried out on the nicotine buccal products of Examples 1 - 3 and Comparative Examples 1 - 3 using a programmable constant temperature and humidity test chamber to simulate air transportation, sea transportation, and the environmental conditions of the country where they are located.

[0166] Set the environmental test conditions: temperature 50 °C, humidity 90%, and placement time 5 d. The samples were sealed and stored in the box.

[0167] The comparison table of the effervescent effects of the products of Examples 1 - 3 and Comparative Examples 1 - 3 before and after the environmental test is shown in Table 4 below. The comparison diagram of the effervescent effects of the nicotine buccal products of Examples 1 - 3 and Comparative Examples 1 - 3 before and after the environmental test is as Figure 4 shown.

[0168] Table 4 Comparison Table of Effervescent Effects of Products in Examples 1-3 and Comparative Examples 1-3 Before and After Environmental Tests

[0169]

[0170]

[0171] Note: Grade 0 = no effervescent taste, Grade 1 = slight effervescent taste, Grade 2 = normal effervescent taste, Grade 3 = stronger effervescent taste, Grade 4 = intense effervescent taste.

[0172] From Table 4 and Figure 4 it can be seen that the effervescent effects of the products in Example 1, Example 2, and Comparative Example 2 remain unchanged in the initial state and after environmental tests, and can still maintain the effervescent effect under high temperature and high humidity conditions, showing good stability.

[0173] The products in Example 3, Comparative Example 1, and Comparative Example 3 have good initial effervescent effects, but after environmental tests, the effervescent effects are reduced by 1 grade. Nevertheless, their effervescent effects under environmental conditions are still relatively stable.

[0174] Generally speaking, there is little difference between the initial effervescent effects of the products in Examples 1-3 and Comparative Examples 1-3 and the effervescent effects after environmental tests, and they all show good stability, which may be related to the good sealing performance of the sealed box. In addition, the effervescent effect level is also affected by the reaction amount of the acid source and the base source, and the reaction amount of the acid source and the base source is 1:3. After comprehensively evaluating the effervescent effects of different products, it is found that the effervescent effects of Example 2 and Comparative Example 3 are relatively better.

[0175] Generally speaking, the nicotine dissolution amount and dissolution rate of the products in Examples 1-3 and Comparative Examples 1-3 are affected by the effervescent granules and the coating layer. Using a sealed system to maintain a dry environment can stabilize the effervescent effect of the effervescent granules. Therefore, in practical applications, the formula can be selected and designed according to specific needs.

[0176] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, and are not intended to limit them; although the present application has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

[0177] In addition, those skilled in the art will appreciate that although some embodiments herein include certain features included in other embodiments but not others, the combination of features of different embodiments is meant to be within the scope of this application and forms different embodiments. For example, in the claims above, any of the claimed embodiments can be used in any combination. The information disclosed in this background section is only intended to enhance the understanding of the overall background of this application and should not be regarded as an admission or any form of suggestion that this information constitutes prior art already known to those skilled in the art.

Claims

1. A nicotine buccal product, characterized in that, It includes at least one effervescent granule and a substrate; The effervescent granule includes a first active agent and a coating layer; The substrate includes a second active agent and a coating material, and the coating material includes a plasticizer and a water-soluble binder.

2. The nicotine buccal product according to claim 1, characterized in that, The first active agent includes at least one of nicotine, nicotine derivatives, caffeine, and theobromine; And / or, the second active agent includes at least one of nicotine and nicotine derivatives; And / or, the plasticizer includes at least one of diethyl phthalate, dibutyl phthalate, and polyethylene glycol; And / or, the water-soluble binder includes at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, and polyvinyl acetal diethylamine acetate; 3. The nicotine buccal product according to claim 1, characterized in that, The size of the effervescent granule in the first direction is 1 mm - 15 mm, and the size of the effervescent granule in the second direction is 1 mm - 6 mm, wherein the first direction is perpendicular to the second direction.

4. The nicotine buccal product according to any one of claims 1-3, characterized in that, Measured by the first mass fraction, the effervescent granule includes 10 parts - 40 parts of an acid source, 10 parts - 40 parts of an alkali source, 2 parts - 30 parts of a first filler, 2 parts - 40 parts of a second filler, 2 parts - 15 parts of a first binder, 1 part - 8 parts of a second binder, 0.5 parts - 6 parts of a flavoring agent, and 0.5 parts - 10 parts of a first active agent.

5. The nicotine buccal product according to claim 4, wherein, The acid source includes at least one of citric acid, tartaric acid, fumaric acid, and malic acid; And / or, the alkali source includes at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and calcium carbonate; And / or, the first filler includes at least one of sorbitol, xylitol, erythritol, mannitol, isomaltulose, maltitol, and anhydrous lactitol; And / or, the second filler includes at least one of corn starch, potato starch, pregelatinized starch, modified starch, and wheat starch; And / or, the first binder includes at least one of polyethylene glycol, gelatin, sodium alginate, polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; And / or, the second binder includes at least one of sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, gelatin, sodium alginate, and polyvinylpyrrolidone; And / or, the flavoring agent includes at least one of edible salt, sucrose, glucose, fructose, sodium saccharin, citric acid, acetic acid, and menthol; 6. The nicotine buccal product according to any one of claims 1-3, characterized in that, Measured by the second mass fraction, the substrate includes 5 parts - 40 parts of a third filler, 10 parts - 50 parts of a fourth filler, 5 parts - 30 parts of a fifth filler, 0.5 parts - 3.0 parts of a plasticizer, 2.5 parts - 10.0 parts of a water-soluble binder, and 0.5 parts - 8.0 parts of a second active agent.

7. The nicotine buccal product according to claim 6, wherein The third filler includes microcrystalline cellulose; The fourth filler includes at least one of erythritol, xylitol, sorbitol, mannitol, isomaltulose, maltitol, and anhydrous lactitol; The fifth filler includes at least one of sorbitol, xylitol, erythritol, mannitol, isomaltulose, maltitol, and anhydrous lactitol.

8. A method for preparing a nicotine buccal product, characterized in that, For preparing the nicotine buccal product as described in any one of claims 1-7, the method comprises: Coating a material containing a first active agent to form a coating layer on the surface of the material, thereby obtaining effervescent granules; Treating a material containing a second active agent with a coating material to obtain a substrate, wherein the coating material comprises a plasticizer and a water-soluble binder; Filling at least one of the effervescent granules and the substrate into a packaging bag and sealing it to obtain the nicotine buccal product.

9. The preparation method of the nicotine buccal product according to claim 8, wherein Preparing the effervescent granules comprises: Mixing an acid source, a first filler, a first active agent, and a first solvent, adding a second binder, granulating, and performing a first drying treatment to obtain acidic granules; Mixing a base source and a flavoring agent, adding a second binder, granulating, and performing a second drying treatment to obtain basic granules; Mixing the acidic granules, the basic granules, a second filler, and a first binder to obtain a mixed powder; Tableting the mixed powder to obtain tablets; Coating the tablets to form a coating layer on the surface of the tablets, and performing a third drying treatment to obtain the effervescent granules.

10. The preparation method of the nicotine buccal product according to claim 8, characterized in that, Preparing the substrate comprises: Mixing a second solvent, a plasticizer, and a water-soluble binder to prepare a coating solution; Mixing a third filler and a second active agent to obtain a first mixture; Coating the first mixture with the coating solution to obtain a coated material; Mixing the coated material with a fourth filler to obtain a second mixture; Mixing the second mixture with a fifth filler to obtain the substrate.

Images