Buccal product and preparation method thereof

Abstract

The invention provides a buccal product and a preparation method thereof, and relates to the technical field of buccal products. The buccal article includes a composition; the composition comprises a first mixture and a second mixture, the second mixture at least partially covers the outer layer of the first mixture; wherein the first mixture comprises a first active agent, and the first active agent comprises a first active substance; the second mixture comprises a second active agent, and the second active agent comprises a second active substance; when the buccal article is in a consumed state, the release peak of the second active substance in the second active agent is earlier than the release peak of the first active substance in the first active agent. According to the buccal product, bimodal release is achieved through the coating structure, initial satisfaction is rapidly provided, the long-acting effect is maintained, user experience is improved, and stability and safety are enhanced.

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 an emerging, non-traditional method for delivering active substances, oral products focus on their release mechanism. This mechanism directly determines the product's efficacy and user experience. An ideal oral product should precisely control the release of active substances while balancing convenience and safety.

[0003] Currently, most oral formulations utilize simple physical mixing or uniform coating techniques to achieve active substance release. While these technologies can achieve basic release functions, they have significant limitations. For example, they struggle to precisely control the release rate of active substances, preventing the implementation of multi-stage release effects. Furthermore, existing sustained-release technologies mostly rely on water-soluble or single hydrophilic substrates, which struggle to balance the requirements of rapid and sustained release in the oral environment.

[0004] In terms of user experience, oral products with a unimodal release also have drawbacks. Users may experience overly rapid ingestion of the active substance or insufficient subsequent effects, resulting in an inconsistent user experience and difficulty meeting the personalized needs of different users. These issues limit product functionality and performance, reducing user satisfaction.

[0005] In summary, existing oral preparations have significant deficiencies in active substance release technology, including uncontrollable release rates, poor adaptability of sustained-release materials, and an unstable user experience. These deficiencies not only affect product efficacy and user experience but also limit their market application and promotion. In light of this, the present application is filed. Summary of the Invention

[0006] The purpose of the present application is to provide an oral product and a preparation method thereof, wherein the oral product achieves bimodal release through a coating structure, quickly provides initial satisfaction and maintains a long-lasting effect, improves user experience, and enhances stability and safety.

[0007] In order to achieve the above-mentioned purpose of this application, the following technical solutions are specially adopted: The present application provides an oral product, comprising: a composition; The composition includes a first mixture and a second mixture; The second mixture is at least partially coated on the outer layer of the first mixture; wherein the first mixture includes a first active agent, which includes a first active substance; the second mixture includes a second active agent, which includes a second active substance; When the oral product is in a consumed state, the initial release rate of the second active substance in the second active agent is greater than the initial release rate of the first active substance in the first active agent.

[0008] In some embodiments, the first active agent further includes a coating layer, and the coating layer is coated on the outer layer of the first active substance.

[0009] In some embodiments, the coating layer is a fat-soluble coating.

[0010] In some embodiments, the first mixture further comprises at least one of a base material, a filler, and a pH adjuster; and / or, The second mixture further comprises at least one of a binder, a flavor, a salting agent, a sweetener, and a cooling agent.

[0011] In some embodiments, the first active substance includes at least one of nicotine, a nicotine derivative, caffeine, and theophylline; and / or, The second active substance includes at least one of nicotine, nicotine derivatives, caffeine and theophylline; and / or, The substrate comprises at least one of microcrystalline cellulose, sodium carboxymethyl cellulose, hypromellose, ethyl cellulose, micropowdered silica gel, and modified starch; and / or, The filler comprises at least one of xylitol, mannitol, lactitol, maltitol, erythritol, isomalt, calcium phosphate and calcium sulfate; and / or, The pH regulator comprises at least one of sodium carbonate and sodium bicarbonate; and / or, The adhesive comprises at least one of sodium alginate and gum arabic; and / or, The salting agent includes at least one of sodium chloride and potassium chloride; and / or, The sweetener comprises at least one of sucralose, neotame, aspartame, acesulfame potassium and steviol glycosides; and / or, The cooling agent includes at least one of WS-3, WS-23 and menthol substances.

[0012] In some embodiments, the oral preparation comprises the following components in parts by weight: 10~84 parts of base material; 1 to 5 parts of the first active agent; 1 to 5 parts of the second active agent; 5~20 parts of filler; 1 to 10 parts of adhesive; 0.5 to 5 parts of pH regulator; 0.2~3 parts of salting agent; Sweetener 0.2~2 parts; 2 to 15 parts of flavor; 0.1~2 parts of cooling agent.

[0013] The present application provides a method for preparing an oral product, which is used to prepare the oral product according to any one of the aforementioned embodiments, comprising: obtaining a first active agent, wherein the first active agent comprises a first active substance; preparing a first mixture including the first active agent; preparing a mixed solution comprising a second mixture; wherein the second mixture comprises a second active agent, and the second active agent comprises a second active substance; The first mixture and the mixed liquid are mixed and granulated to prepare the oral product; wherein, in the oral product, the second mixture is at least partially coated on the outer layer of the first mixture.

[0014] In some embodiments, the first active agent includes a coating layer, and obtaining the first active agent includes: coating the first active agent.

[0015] In some embodiments, the coating process is melt coating, fluidized coating or microencapsulation.

[0016] In some embodiments, in the mixing and granulating of the first mixture and the mixed liquid, the mixing and granulating is wet granulation or dry granulation.

[0017] Compared with the prior art, the present invention has the following advantages: The present application provides an oral product and a preparation method thereof, which realizes the phased release of two active substances. Among them, the initial release rate of the second active substance in the second active agent is greater than the initial release rate of the first active substance in the first active agent. This design can not only quickly provide a higher concentration of the first active substance in the initial stage of use to meet the immediate needs of the user, but also maintain the supply of the second active substance for a longer time by slow release during subsequent use, thereby effectively improving the user experience and avoiding the problems of excessive early intake or insufficient subsequent effect in single-peak release products. In addition, the structural design is also highly flexible. By adjusting the composition ratio of the first mixture and the second mixture and the types and release rates of the first active substance and the second active substance, different release curves can be achieved to adapt to the personalized needs of different users and various usage scenarios. At the same time, the coating effect of the second mixture on the first mixture can effectively protect the active substance from the influence of the external environment, reduce loss or deterioration during storage and transportation, and thus improve the stability and safety of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0019] Figure 1 Schematic diagram of the process for preparing the oral product in the embodiment of the present application; Figure 2 This is the dissolution curve of Example 1 of the present application; Figure 3 This is the dissolution curve diagram of Example 2 of the present application; Figure 4 This is the dissolution curve diagram of Example 3 of the present application; Figure 5 This is the dissolution curve diagram of Example 4 of the present application; Figure 6 This is the dissolution curve diagram of Example 5 of the present application. DETAILED DESCRIPTION

[0020] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[0021] In one embodiment of the present application, an oral product is provided, comprising: a composition; the composition comprising a first mixture and a second mixture; the second mixture at least partially coating an outer layer of the first mixture; wherein the first mixture comprises a first active agent, which comprises a first active substance; and the second mixture comprises a second active agent, which comprises a second active substance. When the oral product is consumed, an initial release rate of the second active substance in the second active agent is greater than an initial release rate of the first active substance in the first active agent.

[0022] The oral product described above contains two mixtures: a first mixture and a second mixture. This design achieves a specific active substance release effect through the synergistic effect of the two mixtures. The second mixture is at least partially coated on the outer layer of the first mixture. This coating structure is the key design feature for achieving bimodal release, allowing the active substances in the two mixtures to be released at different rates.

[0023] The first mixture includes a first active agent, which contains a first active substance. The initial release rate of the first active substance is relatively slow, which is suitable for providing a continuous supply of the active substance during use. The second mixture includes a second active agent, which contains a second active substance. The initial release rate of the second active substance is faster, which can quickly provide the active substance during the initial use and meet the user's immediate needs.

[0024] The "consumed state" mentioned above refers to the oral product being in use, at which point the active substance within it begins to be released according to the designed mechanism. This state includes not only the user's actual use of the oral product, such as placing it in the mouth, but also the passive use of the oral product, such as when evaluating the performance of the oral product in a laboratory or other testing environment.

[0025] Specifically, the "consumed state" refers to an oral product placed in an environment or condition that can trigger the release of active substances, such as contact with liquids that simulate the oral environment, testing under specific temperature or humidity conditions, etc. This definition of "consumed state" is intended to cover all scenarios that may trigger the function of an oral product, not just actual usage scenarios.

[0026] When the oral product is consumed, the initial release rate of the second active substance in the second active agent is greater than the initial release rate of the first active substance in the first active agent. This design allows the oral product to quickly release the second active substance at the beginning of use, providing immediate satisfaction; then the slow release of the first active substance can maintain the effect for a longer period of time, thus achieving a bimodal release profile.

[0027] This bimodal release mechanism can meet the user's needs for the release rhythm of the active substance, avoiding the problems of excessive initial intake or insufficient subsequent effects that exist in single-peak release products. At the same time, the design of the coating structure also helps to improve the stability and safety of the product. In summary, this embodiment achieves a bimodal release characteristic through the unique coating structure and the difference in the release rate of the two active substances, improving the user experience while enhancing the stability and safety of the product.

[0028] In some embodiments, the first active agent further comprises a coating layer, wherein the coating layer is coated on the outer layer of the first active substance.

[0029] Furthermore, the coating layer is a fat-soluble coating.

[0030] As mentioned above, the coating layer can regulate the release rate of the first active substance, allowing it to be released at a slower rate than designed when consumed, thereby achieving a more pronounced bimodal release effect. The coating layer can also protect the first active substance from external environmental influences, such as preventing degradation or loss of efficacy during storage, transportation, or use. Furthermore, the coating layer protects the first active substance, allowing it to maintain more stable chemical and physical properties under varying environmental conditions (e.g., humidity and temperature fluctuations).

[0031] Lipid-soluble coatings gradually dissolve or decompose under specific conditions (such as contact with saliva or in a simulated oral environment), thereby controlling the release of the first active substance. These coatings typically dissolve slowly, facilitating the slow release of the first active substance. Lipid-soluble materials generally exhibit good biocompatibility and stability, making them safe for use in the oral environment. Furthermore, the composition and thickness of the lipid-soluble coating can be adjusted to precisely control the release rate of the active substance.

[0032] The use of a fat-soluble coating allows for a more precise bimodal release effect. In the consumed state, the second active substance is released rapidly, while the first active substance, protected by the fat-soluble coating, is released more slowly, thereby prolonging the duration of action of the active substance.

[0033] In some embodiments, the first mixture further includes at least one of a base material, a filler, and a pH adjuster.

[0034] In some embodiments, the second mixture further comprises at least one of a binder, a flavor, a salting agent, a sweetener, and a cooling agent.

[0035] In some embodiments, the first active substance includes at least one of nicotine, a nicotine derivative, caffeine, and theophylline. In some embodiments, the first active substance may also include a substance with specific medical properties, such as CBD, or other substances with specific active properties, such as vitamins and capsaicin, which are not described in detail in this application.

[0036] In some embodiments, the second active substance includes at least one of nicotine, a nicotine derivative, caffeine, and theophylline. In some embodiments, the second active substance may also include a substance with specific medical properties, such as CBD, or other substances with specific active properties, such as vitamins and capsaicin, which are not described in detail in this application.

[0037] It should be noted that the first active substance and the second active substance may be the same active substance or different active substances. For example, in some embodiments, the first active substance may be selected from at least one of nicotine and a nicotine derivative, and the second active substance may also be selected from at least one of nicotine and a nicotine derivative.

[0038] 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, a nicotine-resin combination, a nicotine inclusion complex, and non-covalently bound nicotine. Non-covalently bound nicotine includes nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, and nicotine benzoate. Nicotine derivatives also include nicotine containing substituents, such as hexamethyl nicotine, hexamethyl nicotine lactate, hexamethyl nicotine malate, hexamethyl nicotine salicylate, hexamethyl nicotine cyclodextrin embedded 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. One or more mixtures thereof. In some embodiments, the substrate comprises at least one of microcrystalline cellulose, sodium carboxymethyl cellulose, hypromellose, ethyl cellulose, micropowdered silica gel, and modified starch.

[0039] In some embodiments, the filler includes at least one of xylitol, mannitol, lactitol, maltitol, erythritol, isomalt, calcium phosphate, and calcium sulfate. The addition of the filler not only enhances the structural stability of the oral product but also effectively reduces hygroscopicity, thereby extending the shelf life of the product.

[0040] In some embodiments, the pH adjuster includes at least one of sodium carbonate and sodium bicarbonate. The addition of the pH adjuster helps to optimize the oral environment, thereby improving the absorption efficiency of the active substance.

[0041] In some embodiments, the binder includes at least one of sodium alginate and gum arabic. The addition of the binder ensures the formability of the oral product and makes it easier to process during the production process.

[0042] In some embodiments, the salting agent includes at least one of sodium chloride and potassium chloride. The addition of the salting agent helps to improve the taste and mouthfeel of the oral product.

[0043] In some embodiments, the sweetener includes at least one of sucralose, neotame, aspartame, acesulfame potassium, and steviol glycosides. The addition of the sweetener helps improve the taste and mouthfeel of the oral product.

[0044] In some embodiments, the cooling agent includes at least one of WS-3, WS-23, and a menthol-based substance. The addition of a cooling agent helps improve the taste and mouthfeel of the oral product. The chemical name of WS-3 is N-ethyl-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide. The chemical name of WS-23 is N,2,3-trimethyl-2-isopropylbutanamide. Menthol substances may include, for example, but are not limited to, menthol, isomenthol, neomenthol, menthone, menthic acid, mentyl esters, menthanol derivatives, menthanol ethers, menthanal derivatives, menthanone derivatives, menthanol esters, and the like, or their pharmaceutically or orally acceptable salts, acceptable chemically modified derivatives, and the like.

[0045] In some embodiments, the oral preparation includes the following components in parts by weight: 10 to 84 parts of the substrate; for example, the substrate can be 10 parts, 20 parts, 30 parts, 40 parts, 50 parts, 60 parts, 70 parts, 80 parts, 84 parts, etc.

[0046] The first active agent is 1 to 5 parts; for example, it can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, etc.

[0047] The second active agent is 1 to 5 parts; for example, it can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, etc.

[0048] The filler is 5 to 20 parts; for example, it can be 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 12 parts, 14 parts, 15 parts, 16 parts, 18 parts, 20 parts, etc.

[0049] 1 to 10 parts of adhesive; for example, it can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, etc.

[0050] The pH adjuster is 0.5 to 5 parts; for example, it can be 0.5, 0.8, 1, 2, 3, 4, 5, etc.

[0051] The salting agent is 0.2 to 3 parts; for example, it can be 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, etc.

[0052] 0.2 to 2 parts of sweetener; for example, it can be 0.2, 0.3, 0.4, 0.5, 0.7, 0.8, 0.9, 1, 1.5, 2, etc.

[0053] 2 to 15 parts of flavor; for example, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 13 parts, 15 parts, etc.

[0054] The cooling agent is 0.1 to 2 parts. For example, it can be 0.1 part, 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.7 part, 0.8 part, 0.9 part, 1 part, 1.5 parts, 2 parts, etc.

[0055] refer to Figure 1 In the examples of the present application, a method for preparing an oral product is provided, which is used to prepare the oral product in any of the above embodiments, comprising: Step S1: obtaining a first active agent, wherein the first active agent includes a first active substance.

[0056] The first active agent is a key component of the oral product prepared in this example and contains a first active substance. This first active substance can be nicotine, a nicotine derivative, caffeine, theophylline, or the like, which play a primary physiological or sensory role in the oral product. In this step, the first active agent is obtained so that it can be mixed with other components in subsequent steps to form the core component of the oral product.

[0057] Specifically, the first active agent can be purchased or prepared by chemical synthesis, etc. In some embodiments, the first active agent has a coating layer and can be purchased directly or the first active agent can be obtained and then coated.

[0058] Step S2: preparing a first mixture including a first active agent.

[0059] The first mixture is the basic component of the oral preparation and contains the first active agent and other possible components, such as a base material, a filler, and a pH adjuster. By mixing the first active agent with the other components, a homogeneous mixture is formed to prepare for subsequent process steps.

[0060] Specifically, the first active agent can be mixed with other components (including but not limited to a base material, a filler, and a pH adjuster) in a certain proportion. A mixer or other equipment can be used to ensure that the components are evenly distributed.

[0061] Furthermore, the first active agent includes a coating layer, and obtaining the first active agent includes: coating the first active substance.

[0062] As mentioned above, the coating layer controls the release rate of the first active substance, enabling it to be released slowly upon consumption. To achieve this structure, the first active substance must be coated. Coating involves encapsulating the first active substance in a layer of a specific material (such as a fat-soluble material) to form a coating layer.

[0063] Furthermore, the coating process is melt coating, fluidized coating or microencapsulation process.

[0064] As mentioned above, in order to realize the structure of the coating layer, the first active substance needs to be subjected to a coating treatment. The coating treatment is to wrap the first active substance in a layer of a specific material (such as a fat-soluble material) to form a coating layer.

[0065] Melt coating is a process in which a fat-soluble material is heated to a molten state, and then a first active substance is added thereto, so that the surface is evenly coated with a layer of the fat-soluble material. After cooling, solid coated particles are formed. This method is suitable for scenarios that require rapid coating and molding. In one embodiment, the melt coating method may include: heating the fat-soluble material to a molten state; adding the active substance particles to the molten fat-soluble material and mixing, and cooling to room temperature, thereby obtaining the sustained-release component after the melt coating treatment.

[0066] In the fluidized coating method, particles of the first active substance are placed in a fluidized bed apparatus, and a solution of a fat-soluble material is evenly sprayed onto the surface of the particles by spraying to form a coating layer. This method can achieve a more uniform coating effect and is suitable for large-scale production. In one embodiment, the fluidized coating treatment includes: placing the active substance particles in a fluidized bed apparatus so that the active substance particles are in a fluidized state; dissolving the fat-soluble material in an organic solvent to form a coating solution; spraying the coating solution onto the surface of the active substance particles in a fluidized state, and after the organic solvent evaporates, forming the sustained-release component after the fluidized coating treatment.

[0067] Microencapsulation is a method of encapsulating a first active substance in a fat-soluble material through emulsification technology. First, the first active substance is dispersed in the aqueous phase, and then the fat-soluble material is dissolved in the oil phase, and an oil-in-water emulsion is formed by emulsification. Finally, the fat-soluble material is solidified by cooling or adding a cross-linking agent to form microcapsules. This method can achieve a more refined coating effect and is suitable for scenarios where precise control of the release rate is required. In one embodiment, the microencapsulation process includes: dissolving or dispersing the active substance particles in the aqueous phase to form an inner phase; dissolving the fat-soluble material in the oil phase to form an outer phase; based on the emulsification technology, dispersing the inner phase in the outer phase to form an oil-in-water emulsion; solidifying the fat-soluble material in the emulsion by cooling or adding a cross-linking agent to form a sustained-release component after microencapsulation.

[0068] Step S3, preparing a mixed solution including a second mixture; wherein the second mixture includes a second active agent, and the second active agent includes a second active substance.

[0069] The second mixture is another important component of the oral preparation and contains a second active agent. The second active agent may include nicotine, nicotine derivatives, caffeine, theophylline, etc. These substances play a role in rapid release in the oral preparation.

[0070] The mixed liquid is a liquid mixture prepared to facilitate uniform coating of the second mixture on the outer layer of the first mixture. The mixed liquid may contain a binder, flavoring, salting agent, sweetener, cooling agent, etc.

[0071] By preparing the mixed solution, the second mixture can be evenly coated on the outer layer of the first mixture, thereby achieving a bimodal release effect. Specifically, the second active agent can be dissolved or dispersed in a suitable solvent in a certain proportion with components such as a binder, flavoring, salting agent, sweetener, and cooling agent to form a uniform mixed solution.

[0072] Step S4, mixing the first mixture with the mixed liquid and granulating them to prepare an oral product; wherein, in the oral product, the second mixture is at least partially coated on the outer layer of the first mixture.

[0073] In the above steps, the mixing granulation is to mix the mixed solution of the first mixture and the second mixture and form granules of a certain size and shape through a granulation process. The granulation process can be wet granulation, fluidized bed granulation, etc.

[0074] During the granulation process, the second mixture evenly coats the outer layer of the first mixture, forming an at least partially encapsulated structure. This structure is key to achieving bimodal release. Through the mixing and granulation process, the first and second mixtures are combined to form an oral product with specific release characteristics.

[0075] Specifically, the first mixture and the second mixture can be mixed in a certain proportion and then granulated using a granulation device (such as a wet granulator or a fluidized bed granulator). During the granulation process, parameters such as the spray rate, temperature, and stirring speed of the mixed liquid are controlled to ensure uniformity of the particles and a good coating effect.

[0076] In some embodiments, in the mixing and granulating of the first mixture and the mixed liquid, the mixing and granulating is wet granulation or dry granulation.

[0077] Wet granulation refers to the granulation process for preparing granules with a moisture content greater than 5%, and dry granulation refers to the granulation process for preparing granules with a moisture content ≤5%.

[0078] Specific granulation processes may include, but are not limited to, fluidized bed granulation, spray drying granulation, extrusion granulation, and the like.

[0079] In some embodiments, wet granulation comprises: The first mixture is first added to the wet granulation equipment and stirred for at least 5 minutes, and then the shearing process is started, and the mixed liquid including the second mixture is added to granulate to obtain granular powder; The granular powder is subjected to a first drying treatment to obtain the granules of the bimodal sustained-release oral product.

[0080] In some embodiments, the stirring speed in the wet granulation device is 100 rpm to 500 rpm; for example, it can be 100 rpm, 200 rpm, 300 rpm, 400 rpm, 500 rpm, etc.

[0081] In some embodiments, the shear speed in the wet granulation device is 500 rpm to 2000 rpm; for example, it can be 500 rpm, 600 rpm, 800 rpm, 1000 rpm, 1200 rpm, 1500 rpm, 1800 rpm, 2000 rpm, and the like.

[0082] In some embodiments, the granulation time in the wet granulation equipment is 10 minutes to 30 minutes; for example, it can be 10 minutes, 20 minutes, 30 minutes, etc.

[0083] In some embodiments, the drying time of the first drying treatment is 10 minutes to 60 minutes, and the drying temperature can be 50°C to 60°C; for example, it can be 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, etc.

[0084] In some embodiments, dry granulation comprises: The first mixture is stirred and mixed by a fluidized bed device, and the first mixture is formed into a suspended state under the action of airflow; The mixed liquid including the second mixture is sprayed on the surface of the first mixture in a suspended state, and the granular powder is obtained after a second drying process.

[0085] In some embodiments, the stirring and mixing speed is 20 rpm to 200 rpm; for example, it can be 20 rpm, 30 rpm, 40 rpm, 50 rpm, 80 rpm, 100 rpm, 120 rpm, 150 rpm, 180 rpm, 200 rpm, etc.

[0086] In some embodiments, the air flow velocity of the fluidized bed apparatus is 0.8 m / s to 1.5 m / s; for example, it can be 0.8 m / s, 0.9 m / s, 1.0 m / s, 1.1 m / s, 1.2 m / s, 1.3 m / s, 1.4 m / s, 1.5 m / s, and the like.

[0087] In some embodiments, the bed temperature of the fluidized bed apparatus is 30° C. to 50° C.; for example, it can be 30° C., 40° C., 50° C., and so on.

[0088] In some embodiments, the mixed liquid including the second mixture is sprayed at a rate of 5 g / min to 50 g / min, and the spraying time is 10 minutes to 30 minutes. For example, the spraying rate can be 5 g / min, 7 g / min, 9 g / min, 10 g / min, 15 g / min, 20 g / min, 30 g / min, 40 g / min, 50 g / min, etc. For example, the spraying time can be 10 minutes, 20 minutes, 30 minutes, etc.

[0089] In some embodiments, the second drying process has a drying time of 10 to 30 minutes and a drying temperature of 50° C. to 80° C. For example, the drying time may be 10 minutes, 20 minutes, 30 minutes, etc. The drying temperature may be 50° C., 60° C., 70° C., 80° C., etc.

[0090] The present invention is further described below by way of specific examples. However, it should be understood that these examples are merely provided for more detailed description and are not to be construed as limiting the present invention in any form.

[0091] The method used in the embodiment: Process 1 - Melt Coating: Heat a fat-soluble material (such as glycerol monostearate, stearic acid, or beeswax) until it is molten (typically between 60°C and 90°C, depending on the melting point of the material). Add the first active substance (such as nicotine salt particles) to the molten fat-soluble material and mix thoroughly to evenly coat the surface with a fat-soluble coating. The mixture is then cooled to room temperature to allow the coating to solidify, forming coated particles (the first active agent).

[0092] Melting temperature: should be slightly higher than the melting point of the fat-soluble material used to ensure that the material is completely melted and does not decompose.

[0093] Mixing time: usually 5 to 15 minutes to ensure that the first active substance is evenly coated.

[0094] Cooling rate: It can be cooled naturally at room temperature or accelerated by using a cooling device to control the crystal morphology and density of the coating layer.

[0095] Process 2 - Fluidized Coating: First active agent particles are placed in a fluidized bed apparatus and maintained in a fluidized state by adjusting the air flow and temperature. A lipophilic material is dissolved in an appropriate organic solvent to prepare a coating solution. The coating solution is then evenly sprayed onto the surface of the fluidized first active agent through a nozzle. The solvent rapidly evaporates, and the lipophilic material forms a uniform coating layer on the particle surface, yielding the first active agent.

[0096] Inlet air temperature: usually set between 40°C and 60°C to ensure rapid evaporation of the solvent while avoiding thermal degradation of nicotine salts.

[0097] Inlet air volume: should be adjusted according to equipment specifications and batch size to ensure that the particles are in a good fluidized state.

[0098] Spray flow rate: should match the evaporation rate of the solvent to avoid over-wetting or incomplete spray drying.

[0099] Atomization pressure: Usually 1.5 bar ~ 2.5 bar to ensure good atomization effect of coating solution.

[0100] Process 3 - Microencapsulation: The first active substance is dissolved or dispersed in the aqueous phase to form the inner phase; the lipophilic material is dissolved in the oil phase to form the outer phase. Using emulsification technology, the inner phase is dispersed in the outer phase to form an oil-in-water emulsion. The lipophilic material is then solidified (lipophilic coating) by cooling or adding a crosslinking agent, forming microcapsules encapsulating the first active substance (the first active agent).

[0101] Emulsification speed: Usually 1000rpm~3000rpm, depending on the emulsification equipment and the required microcapsule size.

[0102] Emulsification time: Usually 10 minutes to 30 minutes to ensure the formation of a stable emulsion.

[0103] Curing method: Lipid-soluble materials can be cured by cooling (e.g., from 60°C to room temperature) or by adding a cross-linking agent (e.g., calcium ions).

[0104] Microcapsule size: Usually controlled between 1 micron and 100 microns to meet the use requirements of oral products.

[0105] Process 4 - Solid Mixing: Weigh a specified weight of the sustained-release matrix, the first active agent, the filler, and the pH adjuster, and mix them in a mixer at a mixing speed of 200 rpm to 500 rpm for 15 minutes to obtain a first mixture.

[0106] Process 5-liquid mixing: Weigh a specified weight of the second active agent, binder, salting agent, sweetener, and cooling agent, add them to the solvent, and stir and mix until the solids are completely dissolved to obtain a second mixture.

[0107] Process 6 - Granulation process 1: Transfer the solid mixed product (first mixture) to the wet granulator, stir at a speed of 100rpm~500rpm, stir for more than 5 minutes, start the shear function, and the shear speed is 500rpm~2000rpm. After the speed reaches the standard, pump in the liquid mixed product (second mixture), and take out the powder after granulation for 10min~30min.

[0108] Process 7 - Granulation Process 2: The solid powder is stirred and mixed in a fluidized bed at a speed of 50-200 rpm, kept suspended in an airflow of 0.8-1.5 m / s. The bed temperature is 30-50°C. Simultaneously, a spray system atomizes the binder solution at a pressure of 0.2-0.4 MPa, controlling the spray rate between 5-50 g / min to avoid excessive wetting and agglomeration. The granulation time is controlled between 10-30 minutes. After granulation, it is directly dried online in a hot airflow at 50-80°C for 10-30 minutes. Finally, the powder is sieved to obtain a uniform powder with a mesh size of 15 or larger and a moisture content of ≤5%.

[0109] Process 8 - Drying: If Granulation Process 1 is used, the finished powder needs to be dried in a forced air drying oven at 60°C for 10-60 minutes to obtain the finished powder with the specified moisture content. If Granulation Process 2 is used, drying is not required.

[0110] Process 9 - Screening: Screen the granulated powder through a 15-mesh sieve and take the powder above 15 mesh.

[0111] Process 10 - Packaging: The powder is sent to the bag sealing production line and put into storage after filling, bag sealing, boxing, and plastic sealing.

[0112] Table 1. Specific dosage of components in Examples 1-5

[0113] In Table 1, the unit of the data under Examples 1-5 is %.

[0114] Example 1 In this example, an oral preparation was prepared.

[0115] Preparation method: (1) Melt coating (Process 1): Heat the fat-soluble material (e.g., glycerol monostearate) to 70°C to melt, add the first active substance (e.g., nicotine tartrate), and mix evenly so that the surface is evenly coated with a layer of fat-soluble material. Cool to room temperature to form coated particles (first active agent).

[0116] (2) Solid mixing (process 4): weigh the base material (such as microcrystalline cellulose), the first active agent, the filler (such as xylitol) and the pH adjuster (such as sodium carbonate), and mix them in a mixer at a speed of 200 rpm to 500 rpm for 15 minutes to obtain a first mixture.

[0117] (3) Liquid mixing (process 5): weigh the second active agent (such as nicotine tartrate), the binder (such as povidone), the salting agent (such as sodium chloride), the sweetener (such as sucralose), the cooling agent (such as WS-23) and the solvent (such as water), and stir and mix until the solids are completely dissolved to obtain a second mixture.

[0118] (4) Granulation process (process 6): The first mixture was transferred to a wet granulator, stirred at a speed of 3000 rpm for 15 minutes, the shear function was started, the shear speed was 1200 rpm, the second mixture was pumped in, granulated for 15 minutes, and the powder was taken out.

[0119] (5) Drying (Process E): The finished powder is dried in a forced air drying oven at 60°C for 30 minutes to obtain the finished powder.

[0120] (6) Screening (Process 9): The granulated powder is passed through a 15-mesh sieve, and the powder with a mesh size of 15 or above is taken as the oral product.

[0121] (7) Packaging (Process 10): The powder (oral product) is sent to the bag sealing production line and put into storage after filling, bag sealing, boxing, and plastic sealing.

[0122] Examples 2 to 5 were used to prepare oral products, respectively. The preparation methods were basically the same as the preparation method of Example 1, except that the specific formula components were different. Please refer to Table 1 for details.

[0123] Test experiment: 1. Test method: Nicotine Release Profile Testing: This experiment used the basket method to test nicotine dissolution for Examples 1-5. Nicotine release profiles were measured using a dissolution tester in a simulated oral environment in accordance with GB / T 37172-2018, "Determination of Nicotine Release from Tobacco and Tobacco Products."

[0124] The experimental conditions are as follows: Medium: pH 6.8 phosphate buffer.

[0125] Temperature: 37 ± 0.5℃.

[0126] Stirring rate: 50 rpm.

[0127] Sampling time points: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 min.

[0128] Detection method: High performance liquid chromatography (HPLC), C18 column, mobile phase of methanol-water, or methanol-phosphate buffer (phosphate buffer pH adjusted to 7.0), volume ratio of 70:30, detection wavelength 259 nm.

[0129] 2. Test results: Table 2. Nicotine release curve test results of Examples 1-5 (%)

[0130] analyze: refer to Figures 2 to 6 The nicotine release curves of each example show different bimodal release characteristics: Example 1 shows a uniform bimodal release with a smooth and uniform release; Example 2 shows a high-intensity bimodal release with a rapid initial release that provides a strong stimulus, followed by a sustained high nicotine level in the later stages; Example 3 shows a low-intensity bimodal release with a slow overall release, suitable for users with low nicotine needs; Example 4 shows a light-in-the-first-half-heavy bimodal release with a gentle initial release and an enhanced release in the later stages; and Example 5 shows a heavy-in-the-first-half-light bimodal release with a rapid initial release and a slowed release in the later stages. These designs meet the needs of different users.

[0131] (1) The nicotine release in Example 1 is relatively smooth and uniform, with a moderate initial release rate, reaching 20.23% at 20 minutes. The rate of release then increases slightly, with a significant inflection point (28.56%) at 35 minutes, indicating that the second stage of release begins to gradually increase. The release rate further accelerates after 45 minutes, ultimately reaching 49.65% at 60 minutes. This release pattern exhibits two moderate release peaks, the first at 15 minutes to 20 minutes, providing an initial sense of satisfaction, while the second peak at 40 minutes to 45 minutes ensures subsequent sustained release, making it suitable for users who require a long-term and uniform release experience.

[0132] (2) The release rate of Example 2 was extremely fast in the early stages, with 25.61% released at 10 minutes and reaching 38.45% at 20 minutes, indicating that the first release peak occurred between 10 and 20 minutes, bringing a rapid nicotine satisfaction. Subsequently, the release rate slowed down slightly, but the release amount increased sharply at 35 minutes (56.25%), entering the second rapid release phase at this time, and reaching a peak (89.64%) between 45 and 50 minutes, then slowly tending to a plateau, and finally releasing nearly 100% at 60 minutes.

[0133] The formula has a more intense dual-peak release. The first peak is at 10-20 minutes, providing strong initial stimulation, while the second peak is at 35-45 minutes, maintaining a higher nicotine level later. It is suitable for users who need a strong sense of stimulation, especially consumers who want quick satisfaction in a short period of time.

[0134] (3) The overall release of Example 3 was relatively slow, with only 2.68% released at 5 min and only 9.88% at 20 min, showing an extremely slow release characteristic. However, a release inflection point (15.68%) appeared between 25 and 30 min, at which point the second stage of release began. The release rate was slightly accelerated, but the overall release was still relatively stable, reaching 19.68% at 40 min, gradually reaching a plateau (19.56% to 19.48%) after 50 min, and finally reaching 19.86% at 60 min.

[0135] The bimodal release of this formula is not obvious, but it can still form a slow second-stage release trend within 30 minutes. It is suitable for users with low nicotine needs, providing soft and continuous release to prevent excessive nicotine intake in a short period of time.

[0136] (4) The early release of Example 4 was slow, with only 5.68% released at 10 min. However, the release rate gradually accelerated after 20 min to 25 min, and a significant inflection point (18.65%) appeared at 30 min to 35 min, entering the second stage of release, releasing 26.22% at 40 min, and reaching the maximum release rate at 45 min to 50 min, and finally reaching 47.86% at 60 min.

[0137] The first release peak of this formula is relatively weak, occurring at approximately 15-20 minutes, and is mainly used for mild initial nicotine provision. The second peak occurs at 40-50 minutes, at which time the release rate is significantly increased, bringing a stronger nicotine effect in the later stage. It is suitable for users who want a mild release in the early stage and a stronger release in the later stage, and can be used in long-term use scenarios.

[0138] (5) The early release of Example 5 was faster, with 7.56% released at 5 minutes and 16.58% released at 10 minutes. The first release peak (28.67% to 36.79%) was reached at 20 minutes to 25 minutes. The release rate then slowed down, entering the second stage of sustained release at 35 minutes to 40 minutes, reaching 42.13% at 45 minutes, and finally stabilizing at 49.77% at 60 minutes.

[0139] The formula has a more obvious bimodal release. The first peak is at 20min~25min, which is suitable for users who need quick nicotine satisfaction. The second peak is relatively gentle, and the release slows down after 40min~45min, ensuring that the later release will not be too fast and cause excessive stimulation. It is suitable for users who want quick satisfaction in the early stage but do not want excessive release in the later stage.

[0140] In summary, the five formulations provided in the examples of this application, combined with a melt coating and sustained-release matrix system, successfully achieve a bimodal nicotine release profile. The immediate-release API (second active agent) rapidly releases the first wave of nicotine in the oral environment, providing immediate gratification. The sustained-release API (first active agent) combined with the sustained-release matrix gradually releases the second wave of nicotine during use, ensuring a sustained effect.

[0141] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An oral product, characterized in that: include: composition; The composition includes a first mixture and a second mixture; The second mixture is at least partially coated on the outer layer of the first mixture; wherein the first mixture includes a first active agent, which includes a first active substance; the second mixture includes a second active agent, which includes a second active substance; When the oral product is in a consumed state, the initial release rate of the second active substance in the second active agent is greater than the initial release rate of the first active substance in the first active agent.

2. The oral product according to claim 1, wherein The first active agent further includes a coating layer, which is coated on the outer layer of the first active substance.

3. The oral product according to claim 2, characterized in that The coating layer is a fat-soluble coating.

4. The oral product according to claim 1, wherein The first mixture further comprises at least one of a base material, a filler and a pH adjuster; and / or, The second mixture further comprises at least one of a binder, a flavor, a salting agent, a sweetener, and a cooling agent.

5. The oral product according to claim 4, characterized in that The first active substance includes at least one of nicotine, nicotine derivatives, caffeine and theophylline; and / or, The second active substance includes at least one of nicotine, nicotine derivatives, caffeine and theophylline; and / or, The substrate comprises at least one of microcrystalline cellulose, sodium carboxymethyl cellulose, hypromellose, ethyl cellulose, micropowdered silica gel, and modified starch; and / or, The filler comprises at least one of xylitol, mannitol, lactitol, maltitol, erythritol, isomalt, calcium phosphate and calcium sulfate; and / or, The pH regulator comprises at least one of sodium carbonate and sodium bicarbonate; and / or, The adhesive comprises at least one of sodium alginate and gum arabic; and / or, The salting agent includes at least one of sodium chloride and potassium chloride; and / or, The sweetener comprises at least one of sucralose, neotame, aspartame, acesulfame potassium and steviol glycosides; and / or, The cooling agent includes at least one of WS-3, WS-23 and menthol substances.

6. The oral product according to claim 1, wherein The oral product comprises the following components in parts by weight: 10 to 84 parts of base material; 1 to 5 parts of the first active agent; 1 to 5 parts of the second active agent; 5~20 parts of filler; 1 to 10 parts of adhesive; 0.5 to 5 parts of pH regulator; 0.2~3 parts of salting agent; Sweetener 0.2~2 parts; 2 to 15 parts of flavor; 0.1~2 parts of cooling agent.

7. A method for preparing an oral product, characterized in that: For preparing the oral product according to any one of claims 1 to 6, comprising: obtaining a first active agent, wherein the first active agent comprises a first active substance; preparing a first mixture including the first active agent; preparing a mixed solution comprising a second mixture; wherein the second mixture comprises a second active agent, and the second active agent comprises a second active substance; The first mixture and the mixed liquid are mixed and granulated to prepare the oral product; wherein, in the oral product, the second mixture is at least partially coated on the outer layer of the first mixture.

8. The preparation method according to claim 7, characterized in that The first active agent includes a coating layer, and obtaining the first active agent includes: coating the first active substance.

9. The preparation method according to claim 8, characterized in that The coating process is melt coating, fluidized coating or microencapsulation.

10. The preparation method according to claim 7, characterized in that In the mixing and granulating of the first mixture and the mixed liquid, the mixing and granulating is wet granulation or dry granulation.

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