Buccal product and preparation method thereof

Abstract

The invention discloses a buccal product and a preparation method thereof, and relates to the technical field of food. The buccal product provided by the invention comprises the functional layer and the solution-resistant outer layer, the functional layer comprises the active agent and the antioxidant, the antioxidant can be utilized to reduce the probability of oxidation reaction of the active agent, and the oxidation resistance of the active agent in the functional layer is improved; the dissolution-resistant outer layer has liquid permeability, so that saliva can successfully permeate into the functional layer in the mouth holding process, the active agent in the functional layer is promoted to be dissolved in the saliva and permeate into the oral cavity through the dissolution-resistant outer layer, the active agent satisfaction is provided for a user, and the disintegration speed of the dissolution-resistant outer layer is smaller than that of the functional layer; according to the preparation method, the probability that the active agent makes contact with oxygen to generate oxidation reaction in the buccal process can be reduced, the chemical stability and purity of the active agent in the buccal product are further improved, the probability that the buccal product deteriorates is reduced, and the bioavailability and buccal taste of the buccal product are improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of food, in particular to a mouth product and a preparation method thereof. BACKGROUND

[0002] The mouth product is a non-swallowing dosage form that can dissolve and release active ingredients in the oral cavity, and is widely used in the fields of oral care, health care, nicotine replacement and nutritional supplement.

[0003] In the related art, the active ingredient in the mouth product refers to a core ingredient that can directly act on the oral cavity and pharyngeal mucosa, and the purity and chemical stability of the active ingredient directly affect the mouth effect of the mouth product. However, the active ingredient in the mouth product is extremely easy to oxidize during processing and storage due to unstable structure, which leads to problems such as deterioration of the mouth product and reduction of bioavailability. SUMMARY

[0004] The present application provides a mouth product and a preparation method thereof, which are used to solve the problems of deterioration of the mouth product and reduction of bioavailability caused by easy oxidation of the active ingredient in the mouth product in the related art.

[0005] To solve the above technical problems, the present application provides a mouth product, which comprises a functional layer and a dissolution-resistant outer layer, and the dissolution-resistant outer layer is arranged outside the functional layer in the thickness direction of the mouth product. The functional layer comprises an active agent and an antioxidant, the dissolution-resistant outer layer has liquid permeability, and the disintegration rate of the dissolution-resistant outer layer is less than the disintegration rate of the functional layer.

[0006] In one embodiment, the mouth product further comprises a transition layer, which is arranged between the dissolution-resistant outer layer and the functional layer.

[0007] In one embodiment, the transition layer comprises at least one of a non-metabolic bulking agent, a pH adjusting agent, a structure stabilizer, a flavoring agent and a flavoring agent.

[0008] In one embodiment, the transition layer has a thickness of 0.2mm to 0.3mm; and / or, the transition layer has a pH detection value of 5.5 to 6.5; and / or, the non-metabolic filler includes at least one of resistant dextrin, modified chitin, chitosan, silicon dioxide, calcium hydrogen phosphate, polyvinylpyrrolidone, polyethylene glycol, inulin, microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, gellan gum, alginate, carrageenan, and agar; and / or, the structural stabilizer includes at least one of biological chitosan, oxidized chitosan, chitooligosaccharide, mannitol, sorbitol, xylitol, erythritol, citric acid, sodium citrate, sodium tartrate, sodium bicarbonate, disodium hydrogen phosphate, sodium lactate, sodium carbonate, disodium ethylenediaminetetraacetate, acacia gum, guar gum, gelatin, sodium caseinate, hydroxypropyl methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.

[0009] In one embodiment, the functional layer further includes at least one of a first film-forming agent, a drying agent, a non-metabolic filler, a binder, and a disintegrant; and / or, the solvent-resistant outer layer includes at least one of a second film-forming agent, a film-forming aid, an appearance modifier, and a binder.

[0010] In one embodiment, the active agent comprises at least one of nicotine and nicotine derivatives; and / or, the first film-forming agent comprises at least one of acrylic resin, ethyl cellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose, and polyvinyl alcohol; and / or, the second film-forming agent comprises at least one of polyvinyl butyral, cellulose acetate, acrylic resin, ethyl cellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, sodium carboxymethyl starch, and gelatin; and / or, the film-forming aid comprises at least one of hydroxypropyl methyl cellulose, gum arabic, alginate, gelatin, sodium carboxymethyl starch, sodium carboxymethyl cellulose, and polyvinyl alcohol; and / or, the drying agent comprises at least one of magnesium aluminum silicate, silica gel, aluminum oxide, and montmorillonite; and / or, the binder comprises at least one of poly N-vinyl pyrrolidone, hydroxypropyl methyl cellulose, gelatin, gum arabic, sodium carboxymethyl cellulose, alginate, pectin, xanthan gum, and malt dextrin; and / or, the disintegrant comprises at least one of microcrystalline cellulose, silicon dioxide, calcium carbonate, calcium hydrogen phosphate, sodium lauryl sulfate, starch, sodium carboxymethyl cellulose, croscarmellose sodium, gum arabic, guar gum, gelatin, sodium carboxymethyl cellulose, croscarmellose sodium, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, alginate, and polysorbate; and / or, the antioxidant comprises at least one of pine bark extract, rosemary extract, grape seed extract, resveratrol, coenzyme, anthocyanin, quercetin, protocatechuic acid, tocopherol, apple polyphenol, ascorbic acid, tea polyphenol, astaxanthin, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, tertiary butyl hydroquinone, and sodium erythorbate.

[0011] In one embodiment, the functional layer has a thickness of 0.4mm-0.5mm; and / or, the solvent-resistant outer layer has a thickness of 0.1mm-0.2mm; and / or, the oral preparation has a thickness of 0.6mm-1.5mm; and / or, the oral preparation further comprises a packaging bag, the packaging bag having a packaging cavity, the functional layer and the solvent-resistant outer layer being located in the packaging cavity.

[0012] In one embodiment, at least part of the structures in the solvent-resistant outer layer comprise through holes extending along the thickness direction of the solvent-resistant outer layer.

[0013] The application also provides a method for preparing a mouth piece, which is used for preparing the mouth piece as described above, and the method comprises: preparing functional layer particles, wherein the functional layer particles comprise active agents and antioxidants; preparing insoluble outer layer particles; preparing a first forming layer by using the functional layer particles; preparing a second forming layer by using the insoluble outer layer particles; arranging the second forming layer outside the first forming layer to obtain a preform, and performing a pressing treatment on the preform to obtain the mouth piece; wherein the mouth piece comprises a functional layer formed by the first forming layer and an insoluble outer layer formed by the second forming layer, and in the thickness direction of the mouth piece, the insoluble outer layer is arranged outside the functional layer; and the disintegration rate of the insoluble outer layer is less than the disintegration rate of the functional layer.

[0014] In one embodiment, the method further satisfies at least one of the following conditions: (1) the method further comprises: preparing transition layer particles; preparing a third forming layer on the surface of the first forming layer by using the transition layer particles; preparing a second forming layer by using the insoluble outer layer particles; arranging the second forming layer outside the third forming layer to obtain the preform, and performing a pressing treatment on the preform to obtain the mouth piece; wherein the mouth piece further comprises a transition layer formed by the third forming layer, and the transition layer is arranged between the insoluble outer layer and the functional layer; (2) the particle size of the functional layer particles is 100 μm-300 μm; (3) the preparation temperature of the functional layer particles is not more than 40℃; (4) after the pressing treatment on the preform, a through hole extending along the thickness direction of the insoluble outer layer is formed on the surface of the insoluble outer layer; (5) the relative humidity in the environment for preparing the insoluble outer layer particles is less than 30%; (6) the pressure of the pressing treatment is 1 kN-6 kN; (7) after the pressing treatment on the preform, the method further comprises: encapsulating by using an encapsulation bag to obtain the mouth piece, wherein the encapsulation bag has an encapsulation cavity, and the functional layer and the insoluble outer layer are both arranged in the encapsulation cavity.

[0015] The oral preparation provided by the present application comprises a functional layer and a solvent-resistant outer layer, and the solvent-resistant outer layer is arranged outside the functional layer in the thickness direction of the oral preparation; wherein the functional layer comprises an active agent and an antioxidant, and the antioxidant can be used to clean free radicals, reduce intermediate products in the early stage of oxidation of the active agent, chelate catalyst ions, and physically isolate, at least one aspect, to reduce the probability of oxidation of the active agent and improve the antioxidant capacity of the active agent in the functional layer; further, the solvent-resistant outer layer has liquid permeability, so that saliva can successfully penetrate into the functional layer during the oral process, promote the dissolution of the active agent in the functional layer into saliva and penetrate into the oral cavity through the solvent-resistant outer layer, and provide the user with a sense of satisfaction of the active agent; the disintegration rate of the solvent-resistant outer layer in the present application is less than the disintegration rate of the functional layer, so that the solvent-resistant outer layer can always be on the surface of the functional layer during the oral process, avoid direct exposure of the functional layer to the oral environment, reduce the probability of oxidation of the active agent in contact with oxygen during the oral process, and be beneficial to improve the chemical stability and purity of the active agent in the oral preparation, reduce the probability of deterioration of the oral preparation, and improve the bioavailability and oral taste of the oral preparation. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 A cross-sectional structure diagram of an oral preparation provided by the present application Figure 1 ;

[0017] Figure 2 A cross-sectional structure diagram of an oral preparation provided by the present application Figure 2 ;

[0018] Figure 3 A cross-sectional structure diagram of an oral preparation provided by the present application Figure 3 ;

[0019] Figure 4 A cross-sectional structure diagram of an oral preparation provided by the present application Figure 4 ;

[0020] Figure 5 A step flow chart of a preparation method of an oral preparation provided by the present application.

[0021] BRIEF DESCRIPTION OF DRAWINGS

[0022] 10-oral preparation; 101-functional layer; 102-solvent-resistant outer layer; 103-transition layer. DETAILED DESCRIPTION

[0023] The application will be described in further detail below with specific reference being made to the drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. However, it will be apparent to one skilled in the art that parts of the present application can be practiced without some or all of these specific details. In other instances, well known process steps have not been described in detail in order not to unnecessarily obscure the present application. In addition, features of the description, operations, or characteristics described in the specification can be combined in any appropriate manner in various embodiments. Meanwhile, the steps or actions in the method description can also be sequentially adjusted or adjusted in a manner that is apparent to those skilled in the art. Therefore, the various sequences in the specification and drawings are only for the purpose of clearly describing a certain embodiment, and do not mean that the sequence is necessary, unless otherwise stated that a certain sequence must be followed.

[0024] In addition, the features, operations or characteristics described in the specification can be combined in any appropriate manner to form various embodiments. Meanwhile, the steps or actions in the method description can also be sequentially adjusted or adjusted in a manner that is apparent to those skilled in the art. Therefore, the various sequences in the specification and drawings are only for the purpose of clearly describing a certain embodiment, and do not mean that the sequence is necessary, unless otherwise stated that a certain sequence must be followed.

[0025] The serial numbers of the components in this paper, such as "first", "second", etc., are only used to distinguish the described objects, and do not have any order or technical meaning.

[0026] The molecular structure of the active agent in the oral product includes active groups, which are easily affected by oxygen, light, temperature, saliva and many other factors during the processing, storage and oral process of the oral product, and the active groups of the active agent are oxidized, which reduces the activity of the active agent, changes the flavor, and further causes the oral product to deteriorate, the bioavailability is reduced, and other problems. In the related art, although the probability of oxidation of the active agent can be reduced by microencapsulation, coating and other technologies, the microencapsulation technology is complex, and the active agent is released slowly during the oral process, which is difficult to provide enough active agent for the user to meet the feeling, and the coating technology has the problems of unstable interlayer interface, delamination and other problems, which reduces the structural stability of the oral product.

[0027] In order to solve the above problems, the present application provides an oral product 10, referring to Figure 1 and Figure 2 The oral product 10 includes a functional layer 101 and a solvent-resistant outer layer 102, and the solvent-resistant outer layer 102 is arranged outside the functional layer 101 in the thickness direction of the oral product 10; wherein the functional layer 101 includes an active agent and an antioxidant, the solvent-resistant outer layer 102 has liquid permeability, and the disintegration rate of the solvent-resistant outer layer 102 is less than the disintegration rate of the functional layer 101.

[0028] In the embodiments of the present application, the dissolution-resistant outer layer 102 is arranged on at least two opposite surfaces of the functional layer 101 having a larger area. In some embodiments, referring to Figure 1 , the dissolution-resistant outer layer 102 is arranged on two opposite surfaces of the functional layer 101 having a larger area. In some embodiments, referring to Figure 2 , the dissolution-resistant outer layer 102 is arranged on the entire outer surface of the functional layer 101.

[0029] The functional layer 101 includes active agents and antioxidants, and the active agents can include, but are not limited to, nicotine compounds, oral care agents, anti-inflammatory agents, nutritional supplements, etc., and the antioxidants are edible antioxidants; the functional layer 101 serves as a storage and release layer of the active agents, and during the oral use of the oral product 10, saliva penetrates into the functional layer 101 through the dissolution-resistant outer layer 102, and the active agents in the functional layer 101 can dissolve into the saliva and reach the oral mucosa through the dissolution-resistant outer layer 102, so as to realize the release of the active agents in the oral cavity and provide the user with a sense of satisfaction of the active agents.

[0030] In the embodiments of the present application, the antioxidants in the functional layer 101 can reduce the probability of oxidation reaction of the active agents in the functional layer 101 by at least one of the following ways: eliminating free radicals, reducing intermediate products in the initial stage of oxidation of the active agents, chelating catalyst ions, and physically isolating. In some embodiments, the functional groups in the antioxidants can combine with free radicals in the environment to reduce the free radicals to stable ingredients, thereby preventing the free radicals from attacking the active agents in the functional layer 101, so as to reduce the probability of oxidation reaction of the active agents. In some embodiments, the antioxidants can act as reducing agents to reduce the intermediate products in the initial stage of oxidation of the active agents to the original state through reversible redox reactions, thereby reversing the oxidation process of the active agents, reducing the oxidation loss of the active agents, and improving the antioxidant capacity of the active agents. In some embodiments, the antioxidants have chelating ability and can form stable coordination compounds with metal ions having catalytic activity in the oral cavity, so that the metal ions lose catalytic activity, thereby inhibiting the initiation of oxidation reaction of the active agents from the source. In some embodiments, the fat-soluble antioxidants can dissolve in the oil phase or gum base of the oral product 10 to form a protective film around the active agent molecules, thereby reducing the direct contact area between the active agents and oxygen, so as to reduce the probability of oxidation reaction of the active agents. The water-soluble antioxidants can diffuse in the water phase (for example, the contact layer of the functional layer 101 and saliva) of the functional layer 101, and preferentially react with oxygen dissolved in the water phase, thereby indirectly reducing the probability of oxidation reaction of the active agents due to contact with oxygen.

[0031] The dissolvable outer layer 102 has liquid permeability. During the oral use of the oral use article 10, saliva can permeate through the dissolvable outer layer 102 to the inside of the oral use article 10 and contact the functional layer 101, promote the active agent in the functional layer 101 to dissolve into saliva and reach the oral mucosa through the dissolvable outer layer 102, achieve the release of the active agent in the oral cavity, and provide the user with the satisfaction of the active agent.

[0032] It should be noted that the dissolvable outer layer 103 has liquid permeability. The dissolvable outer layer 103 can have a certain pore structure itself to achieve liquid permeability. Alternatively, the dissolvable outer layer 103 itself does not have a pore structure for liquid permeability, but in the case of placing the oral use article in the oral cavity, part of the material in the dissolvable outer layer 102 disintegrates or part of the material dissolves, forming channels in the dissolvable outer layer 102 for saliva to permeate, thereby achieving the liquid permeability of the dissolvable outer layer 102.

[0033] In some embodiments, the dissolvable outer layer 102 includes water-insoluble material and water-soluble material. Before the oral use of the oral use article 10, the dissolvable outer layer 102 has a dense structure, which can physically isolate the functional layer 101 from the external environment during the processing and storage of the oral use article 10, reduce the probability of the active agent in the functional layer 101 contacting oxygen, and further reduce the probability of the active agent in the oral use article 10 undergoing an oxidation reaction during processing and storage, thereby helping to prolong the shelf life of the oral use article 10. During the oral use of the oral use article 10, the water-soluble material in the dissolvable outer layer 102 dissolves to form channels for saliva to permeate, so that the dissolvable outer layer 102 has liquid permeability during the oral use. Saliva can permeate through the channels formed by the dissolution of the water-soluble material in the dissolvable outer layer 102 to the inside of the oral use article 10 and contact the functional layer 101, promote the active agent in the functional layer 101 to dissolve into saliva and reach the oral mucosa through the dissolvable outer layer 102, achieve the release of the active agent in the oral cavity, and provide the user with the satisfaction of the active agent.

[0034] In some embodiments, the dissolvable outer layer 102 includes water-insoluble material, and the dissolvable outer layer 102 includes pores. During the oral use of the oral use article 10, the pores in the dissolvable outer layer 102 serve as channels for saliva to permeate, so that the dissolvable outer layer 102 has liquid permeability. Saliva can permeate through the pores in the dissolvable outer layer 102 to the inside of the oral use article 10 and contact the functional layer 101, promote the active agent in the functional layer 101 to dissolve into saliva and reach the oral mucosa through the dissolvable outer layer 102, achieve the release of the active agent in the oral cavity, and provide the user with the satisfaction of the active agent.

[0035] Further, the disintegration rate of the dissolution-resistant outer layer 102 is less than the disintegration rate of the functional layer 101, so that the dissolution-resistant outer layer 102 is always on the surface of the functional layer 101 during the oral use of the oral use product 10, avoiding direct exposure of the functional layer 101 to the oral environment, further reducing the probability of oxidation reaction of the active agent with oxygen during the oral use, improving the chemical stability and purity of the active agent during the oral use, and further improving the bioavailability and oral taste of the oral use product 10.

[0036] In summary, the oral use product 10 provided by the present application includes the functional layer 101 and the dissolution-resistant outer layer 102, and the dissolution-resistant outer layer 102 is arranged on the outer layer of the functional layer 101 in the thickness direction of the oral use product 10. The functional layer 101 includes the active agent and the antioxidant, which can reduce the probability of oxidation reaction of the active agent by at least one of the following functions of the antioxidant: removing free radicals, reducing intermediate products in the initial stage of oxidation of the active agent, chelating catalyst ions, and physically isolating, and improve the antioxidant capacity of the active agent in the functional layer 101. Further, the dissolution-resistant outer layer 102 has liquid permeability, which can allow saliva to successfully penetrate into the functional layer 101 during the oral use, promote the dissolution of the active agent in the functional layer 101 into saliva and penetrate into the oral cavity through the dissolution-resistant outer layer 102, and provide the user with a sense of satisfaction of the active agent. The disintegration rate of the dissolution-resistant outer layer 102 is less than the disintegration rate of the functional layer 101, so that the dissolution-resistant outer layer 102 is always on the surface of the functional layer 101 during the oral use, avoiding direct exposure of the functional layer 101 to the oral environment, reducing the probability of oxidation reaction of the active agent with oxygen during the oral use, and improving the chemical stability and purity of the active agent in the oral use product 10, reducing the probability of deterioration of the oral use product 10, and improving the bioavailability and oral taste of the oral use product 10.

[0037] In some embodiments, referring to Figure 3 and Figure 4 the oral use product 10 provided by the present application further includes a transition layer 103, and the transition layer 103 is arranged between the dissolution-resistant outer layer 102 and the functional layer 101.

[0038] In some embodiments, referring to Figure 3 the dissolution-resistant outer layer 102, the transition layer 103, and the functional layer 101 are sequentially stacked in the order of: the dissolution-resistant outer layer 102, the transition layer 103, the functional layer 101, the transition layer 103, and the dissolution-resistant outer layer 102. In some embodiments, referring to Figure 4 the transition layer 103 is arranged on the entire outer surface of the functional layer 101, and the dissolution-resistant outer layer 102 is arranged on the entire outer surface of the transition layer 103.

[0039] The transition layer 103 is used to further reduce the probability of the active agent in the functional layer 101 being oxidized by contacting with oxygen in the external environment; in the case of including flavoring agents and / or flavoring agents in the transition layer 103, the transition layer 103 can also adjust the taste hierarchy of the oral preparation 10, mask the bitter taste of the active agent, reduce the irritation of the active agent, and improve the mouthfeel of the oral preparation 10.

[0040] In some embodiments, the transition layer 103 includes at least one of a non-metabolic filler, a pH adjusting agent, a structural stabilizer, a flavoring agent, and a flavoring agent.

[0041] In some embodiments, in the transition layer 103, the amount of each component is measured by mass fraction, including 5-15 parts of a non-metabolic filler, 2-6 parts of a pH adjusting agent, 5-10 parts of a structural stabilizer, 1-10 parts of a flavoring agent, and 1-10 parts of a flavoring agent.

[0042] The non-metabolic filler has a low disintegration rate, and after the non-metabolic filler is absorbed and swells in water, a colloid with high viscosity can be formed, which can wrap and adhere to the active agent released from the functional layer 101 on the oral mucosa. Not only is it beneficial to further reduce the exposure time of the active agent in the oral cavity, reduce the probability of the active agent contacting oxygen and metal ions with catalytic activity in the oral cavity, and reduce the instantaneous oxidation of the active agent, but it also improves the local effect of the active agent in the oral cavity and improves the bioavailability.

[0043] In some embodiments, the non-metabolic filler includes at least one of resistant dextrin, modified chitin, chitosan, silicon dioxide (SiO2), calcium hydrogen phosphate (CaHPO4), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), inulin, microcrystalline cellulose (MCC), sodium carboxymethyl cellulose (CMC-Na), xanthan gum, gellan gum, alginate, carrageenan, and agar.

[0044] The pH adjusting agent is used to adjust the pH value of the transition layer 103 to 5.5-6.5, and during the oral administration of the oral preparation 10, the pH value of the oral microenvironment can be adjusted to 5.5-6.5 using the transition layer 103, which is beneficial to reduce the catalytic reaction activity of metal ions in the oral cavity, improve the stability of the antioxidant in the functional layer 101, reduce the probability of the active agent being oxidized, and further improve the chemical stability and purity of the active agent during the oral administration of the oral preparation 10, thereby improving the bioavailability and oral taste of the oral preparation 10.

[0045] The pH detection value of the transition layer 103 in the present application refers to the value obtained by mixing the transition layer 103 with water or other appropriate solvents, and then using a pH electrode, pH test paper or acid-base titration liquid to detect. Exemplarily, the pH detection value of the transition layer 103 can be measured according to the test method in the national standard GB / T 12456-2008 Determination of total acid in food.

[0046] In some embodiments, the pH adjusting agent includes at least one of citric acid (CA), sodium citrate (Na3C6H5O7), sodium tartrate (Na2C4H4O6), sodium dihydrogen phosphate (NaH2PO4), disodium hydrogen phosphate (Na2HPO4), sodium lactate (C3H5NaO3), sodium bicarbonate (NaHCO3), and sodium carbonate (Na2CO3).

[0047] The structural stabilizer can form a stable three-dimensional network structure in the transition layer 103 through intermolecular forces, so as to resist the rapid dissolution of the transition layer 103 in the mouth saliva, and improve the structural stability of the transition layer 103.

[0048] In some embodiments, the structural stabilizer includes at least one of biological chitosan, oxidized chitosan, chitosan oligosaccharide (COS), mannitol, sorbitol, xylitol, erythritol, citric acid, sodium citrate, sodium tartrate, sodium bicarbonate, disodium hydrogen phosphate, sodium lactate, sodium carbonate, ethylenediaminetetraacetic acid disodium salt (EDTA-2Na), gum arabic, guar gum, gelatin, sodium caseinate, hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC), sodium carboxymethyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.

[0049] The flavoring agent and the flavoring agent can mask the bitter taste of the active agent, adjust the taste hierarchy of the oral preparation 10, and improve the mouthfeel of the oral preparation 10. In some embodiments, the flavoring agent can include, but is not limited to, a salty agent, a cooling agent, a sweetening agent, and the like. Among them, the salty agent can include at least one of sodium chloride and potassium chloride. The cooling agent can include at least one of N-ethyl-(2-isopropyl-5-methyl)cyclohexanamide (WS-3), N,2,3-trimethyl-2-(1-methylethyl)butyramide (WS-23), N-(ethoxycarbonylmethyl)-p-menthane-3-carboxamide (WS-5), N-ethyl-2,2-diisopropylbutyramide (WS-27), N-(4-methoxyphenyl)-p-menthyl-3-carboxamide (WS-12), menthol, and isomenthol. The sweetening agent can include at least one of sucralose, neotame, aspartame, acesulfame, steviol glycoside, xylitol, erythritol, mannitol, sorbitol, erythritol, maltitol, lactitol, sodium saccharin, monatin, sucralose, thaumatin, agave syrup, fructose, alitame, cyclamate, mogroside, and ammonium glycyrrhizinate.

[0050] The flavoring agent includes a flavoring agent, which is an edible flavoring agent, and can be any taste, which is not specifically limited in the present application. The flavoring agent can include natural extract flavoring agent, synthetic flavoring agent, and compounded flavoring agent; among them, the natural extract flavoring agent can include but is not limited to peppermint oil, lemon oil, linalool, licorice extract, tea polyphenol, clove oil, etc.; the synthetic flavoring agent can include but is not limited to ethyl acetate, vanillin, vanillin, menthol, geraniol, coumarin, etc.; the compounded flavoring agent can include flavoring agents obtained by secondary blending of various flavoring agents.

[0051] In some embodiments, the thickness of the transition layer 103 is 0.2mm-0.3mm, within this range, the role of the transition layer 103 in reducing the probability of oxidation reaction of the active agent with oxygen, adjusting the pH of the oral microenvironment to 5.5-6.5, adjusting the taste hierarchy of the oral preparation 10, and improving the mouthfeel of the oral preparation 10, etc. can be fully played; in some embodiments, the thickness of the transition layer 103 can be one of 0.2mm, 0.22mm, 0.24mm, 0.26mm, 0.28mm and 0.3mm or a range value of any two.

[0052] In some embodiments, the functional layer 101 further includes at least one of a first film-forming agent, a drying agent, a non-metabolic bulking agent, a binder, and a disintegrant.

[0053] In some embodiments, in the functional layer 101, the active agent, the antioxidant agent, the first film-forming agent, the drying agent, the non-metabolic filler, the binder, and the disintegrant are present in a mass ratio of 1-8:3-40:2-8:2-10:5-20:1-4:3-8, respectively.

[0054] The first film-forming agent in the functional layer 101 is used to build a stable film structure through hydrogen bonds, van der Waals forces or cross-linking between its own molecules, to uniformly disperse and encapsulate the active agent and the antioxidant agent, prevent the oxidation and loss of the active agent, and improve the stability of the structure of the functional layer 101 during storage and use.

[0055] In some embodiments, the first film-forming agent includes at least one of acrylic resin, ethyl cellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, sodium carboxymethyl starch (CMS), sodium carboxymethyl cellulose, and polyvinyl alcohol (PVA).

[0056] The drying agent in the functional layer 101 is used to improve the structural rigidity of the functional layer 101 and the moisture resistance of the functional layer 101. By improving the moisture resistance of the functional layer 101, not only can the probability of hydrolysis of the active agent be reduced, and the probability of accelerated contact between the active agent and oxygen mediated by water be reduced, but also the risk of inactivation of the antioxidant agent due to dissolution and migration under high humidity conditions can be reduced, so that the antioxidant agent can fully play its role in antioxidation, the probability of oxidation of the active agent during processing and storage can be reduced, the chemical stability and purity of the active agent in the oral product 10 can be improved, the probability of deterioration of the oral product 10 can be reduced, and the bioavailability and oral taste of the oral product 10 can be improved.

[0057] In some embodiments, the drying agent includes at least one of magnesium aluminum silicate, silica gel, aluminum oxide (Al2O3), and montmorillonite.

[0058] The non-metabolic filler in the functional layer 101 is used to encapsulate the active agent by forming a high-viscosity colloid after dissolution or swelling, and adhere to the oral mucosa after being released into the oral cavity through the solvent-resistant outer layer 102. This not only helps to further reduce the exposure time of the active agent in the oral cavity, reduce the probability of contact between the active agent and oxygen and metal ions with catalytic activity in the oral cavity, and reduce the instantaneous oxidation of the active agent, but also can improve the local effect of the active agent in the oral cavity and improve the bioavailability.

[0059] The binder in the functional layer 101 can provide adhesion, film formation, thickening and gelation, and enhance the stability of the functional layer 101. In some embodiments, the binder includes at least one of N-vinyl-2-pyrrolidone (NVP), hydroxypropyl methylcellulose, gelatin, gum arabic, sodium carboxymethylcellulose and alginate.

[0060] The disintegrant in the functional layer 101 is used to improve the tabletting property of the functional layer 101 and the disintegration efficiency in the oral process, so that the functional layer 101 rapidly disintegrates under the wrapping of the dissolution-resistant outer layer 102 and is released into the oral cavity through the dissolution-resistant outer layer 102, which can not only ensure that a sufficient amount of active agent diffuses through the dissolution-resistant outer layer 102 to be absorbed by the oral mucosa, thereby improving the user's satisfaction with the active agent, but also avoid the active agent in the functional layer 101 from being exposed to the oral environment in a large amount at one time under the isolation of the dissolution-resistant outer layer 102, thereby reducing the probability of oxidation of the active agent before being absorbed by the oral mucosa.

[0061] In some embodiments, the disintegrant includes at least one of microcrystalline cellulose, silicon dioxide, calcium carbonate (CaCO3), calcium hydrogen phosphate, sodium dodecyl sulfate (SDS), starch, sodium carboxymethylcellulose, croscarmellose sodium (CCNa), gum arabic, guar gum, gelatin, sodium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose (HPC), sodium carboxymethyl starch, alginate and polysorbate.

[0062] In some embodiments, the active agent in the functional layer 101 includes at least one of nicotine and nicotine derivatives; wherein the nicotine derivatives can include at least one of nicotine salts, substituted nicotine, substituted nicotine salts. The nicotine salts can include at least one of nicotine benzoate, nicotine lactate, nicotine citrate, nicotine malate, nicotine maleate, nicotine succinate, nicotine alicyclic carboxylate, nicotine levulinic acid salt, nicotine gentisate and nicotine tartrate. The substituted nicotine can be 6-methyl nicotine. The substituted nicotine salt can be 6-methyl nicotine salt, such as 6-methyl nicotine benzoate, etc. In some embodiments, the active agent can exist in the form of crystal particles formed by crystallization of nicotine and / or nicotine derivatives.

[0063] In some embodiments, the active agent in the functional layer 101 can also be substances with medical properties or other specific active properties, such as vitamins, caffeine, tea polyphenols, theophylline, etc.

[0064] In some embodiments, the antioxidant in the functional layer 101 includes at least one of pine bark extract, rosemary extract, grape seed extract, resveratrol, coenzyme, anthocyanin, quercetin, protocatechuic acid, tocopherol, apple polyphenol, ascorbic acid, tea polyphenol, astaxanthin, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, tertiary butyl hydroquinone, and sodium erythorbate.

[0065] In some embodiments, the dissolution-resistant outer layer 102 includes at least one of a second film-forming agent, a film-forming aid, an appearance modifier, and a binder.

[0066] In some embodiments, in the dissolution-resistant outer layer 102, 15-25 parts by mass of the second film-forming agent, 2-8 parts by mass of the film-forming aid, 1-5 parts by mass of the appearance modifier, and 2-6 parts by mass of the binder are included.

[0067] The second film-forming agent in the dissolution-resistant outer layer 102 can be selected from a water-insoluble high molecular compound and / or a high molecular compound that forms a viscous colloid after being dissolved in water. The second film-forming agent serves as a film-forming skeleton of the dissolution-resistant outer layer 102, and is used to increase the molding strength of the dissolution-resistant outer layer 102 and to decrease the disintegration rate of the dissolution-resistant outer layer 102, so that the disintegration rate of the dissolution-resistant outer layer 102 is less than the disintegration rate of the functional layer 101.

[0068] In some embodiments, the second film-forming agent includes at least one of polyvinyl butyral (PVB), cellulose acetate, acrylic resin, ethyl cellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, sodium carboxymethyl starch, and gelatin.

[0069] The film-forming aid in the dissolution-resistant outer layer 102 can be selected from water-soluble materials, and the film-forming aid is used to dissolve to form channels for saliva penetration during the oral use of the oral use product 10, so that the dissolution-resistant outer layer 102 has liquid permeability during the oral use, saliva can penetrate into the interior of the oral use product 10 to contact the functional layer 101 through the channels formed by the dissolution of the water-soluble materials in the dissolution-resistant outer layer 102, promote the dissolution of the active agent in the functional layer 101 into saliva and through the dissolution-resistant outer layer 102 to the oral mucosa, achieve the release of the active agent in the oral cavity, and provide the user with the satisfaction of the active agent. In the embodiments of the present application, the content of the film-forming aid in the dissolution-resistant outer layer 102 can be adjusted to adjust the release rate of the active agent in the functional layer 101 to the oral cavity through the dissolution-resistant outer layer 102, wherein the higher the content of the film-forming aid in the dissolution-resistant outer layer 102, the more channels for saliva penetration formed by the dissolution of the film-forming aid during the oral use, the faster the release rate of the active agent in the functional layer 101 to the oral cavity through the dissolution-resistant outer layer 102, and the lower the content of the film-forming aid in the dissolution-resistant outer layer 102, the fewer channels for saliva penetration formed by the dissolution of the film-forming aid during the oral use, the slower the release rate of the active agent in the functional layer 101 to the oral cavity through the dissolution-resistant outer layer 102.

[0070] In some embodiments, the film-forming aid includes at least one of hydroxypropyl methylcellulose, gum arabic, alginate, gelatin, sodium carboxymethyl starch, sodium carboxymethyl cellulose, and polyvinyl alcohol.

[0071] The appearance modifier in the dissolution-resistant outer layer 102 is used to improve the color, luster, surface smoothness, shape stability, and recognition of the dissolution-resistant outer layer 102, and improve the appearance recognition of the oral use product.

[0072] In some embodiments, the appearance modifier includes at least one of a coloring agent, a bright film agent, and a shaping agent.

[0073] The coloring agent can include, but is not limited to, sodium copper chlorophyllin, cochineal, curcumin, carotene, anthocyanin, caramel color, iron oxide, lemon yellow, allura red, brilliant blue, and erythrosine, etc.; the bright film agent can include, but is not limited to, beeswax, palm wax, polyethylene wax, and shellac, etc.; and the shaping agent can include, but is not limited to, microcrystalline cellulose and mannitol, etc.

[0074] In some embodiments, the thickness of the functional layer 101 is 0.4 mm to 0.5 mm, within this range, the content of the active agent in the functional layer 101 can be increased to prolong the release time of the active agent in the functional layer 101 while ensuring that the overall size of the oral use product 10 meets the requirements; in some embodiments, the thickness of the functional layer 101 can be one of 0.4 mm, 0.42 mm, 0.45 mm, 0.48 mm, and 0.5 mm or a range value of any two thereof.

[0075] In some embodiments, the thickness of the dissolution-resistant outer layer 102 is 0.1 mm to 0.2 mm, within which range, the structural stability of the dissolution-resistant outer layer 102 is improved, so that the dissolution-resistant outer layer 102 can fully play a role in reducing the probability of oxidation of the active agent in the processing, storage and oral use of the oral use product 10; in some embodiments, the thickness of the dissolution-resistant outer layer 102 can be one of 0.1 mm, 0.12 mm, 0.14 mm, 0.16 mm, 0.18 mm and 0.2 mm or a range value of any two thereof.

[0076] In some embodiments, the thickness of the oral use product 10 is 0.6 mm to 1.5 mm, within which range, the functions of the functional layer 101, the dissolution-resistant outer layer 102 and the transition layer 103 can be fully played, the chemical stability and purity of the active agent in the oral use product 10 are improved, the probability of deterioration of the oral use product 10 is reduced, and the bioavailability and oral taste of the oral use product 10 are improved; in some embodiments, the thickness of the oral use product 10 can be one of 0.6 mm, 0.8 mm, 1 mm, 1.3 mm and 1.5 mm or a range value of any two thereof.

[0077] In some embodiments, the oral use product 10 further comprises a packaging bag, the packaging bag has a packaging cavity, the functional layer 101 and the dissolution-resistant outer layer 102 are located in the packaging cavity, and the packaging bag is used to block air, moisture and dust from entering the inside of the oral use product 10, further improve the chemical stability and purity of the active agent in the oral use product 10, reduce the probability of moisture and deterioration of the oral use product 10, and improve the bioavailability and oral taste of the oral use product 10.

[0078] In some embodiments, the packaging bag can include, but is not limited to, an aluminum-plastic packaging bag, a full-plastic packaging bag, a paper-based packaging bag and a metallized film bag, etc.

[0079] In some embodiments, in the oral use product 10 provided in the present application, at least part of the structure in the dissolution-resistant outer layer 102 comprises a through hole extending in the thickness direction of the dissolution-resistant outer layer 102, which is beneficial to reducing the probability of oxidation reaction of the active agent in the functional layer 101, and adjusting the speed of release of the active agent into the oral cavity through the dissolution-resistant outer layer 102 in the oral use process by adjusting the size and number of the through hole, thereby further improving the satisfaction of the user with the active agent.

[0080] In some embodiments, the through hole in the dissolution-resistant outer layer 102 can be prepared by laser drilling or needle drilling.

[0081] In some embodiments, the number of through holes in the dissolution-resistant outer layer 102 is 2 to 3.

[0082] The present application provides a preparation method of an oral use product, as shown in Figure 5 The preparation method comprises the following steps:

[0083] Step S101, preparing functional layer particles, wherein the functional layer particles comprise active agents and antioxidants.

[0084] Step S102, preparing a dissolution-resistant outer layer particle.

[0085] Step S103, preparing a first molding layer using the functional layer particles.

[0086] Step S104, preparing a second molding layer using the dissolution-resistant outer layer particles.

[0087] Step S105, disposing the second molding layer on the outer layer of the first molding layer to obtain a preform, and performing a compression treatment on the preform to obtain the oral preparation.

[0088] The oral preparation obtained through step S105 comprises a functional layer molded by the first molding layer and a dissolution-resistant outer layer molded by the second molding layer, the dissolution-resistant outer layer is disposed on the outer layer of the functional layer in the thickness direction of the oral preparation, the dissolution-resistant outer layer has liquid permeability, and the disintegration rate of the dissolution-resistant outer layer is less than the disintegration rate of the functional layer.

[0089] The preparation method of the oral preparation provided in the present application can realize the preparation of the oral preparation as described in any one of the above.

[0090] In step S101, first, raw materials for preparing the functional layer particles are mixed in a high-speed mixer to obtain a first mixture; then, a solvent is added to the first mixture through a sprayer to adjust the humidity of the first mixture to a granulation state; and then, the first mixture is granulated by using a low-temperature granulation device, and the granulated particles obtained by granulation are subjected to drying treatment and sieving treatment to obtain the functional layer particles.

[0091] In some embodiments, the raw materials for preparing the functional layer particles include, in terms of mass fraction, 1-8 parts of active agents, 3-40 parts of antioxidants, 2-8 parts of a first film-forming agent, 2-10 parts of a drying agent, 5-20 parts of a non-metabolic filler, 1-4 parts of a binder, and 3-8 parts of a disintegrant.

[0092] In some embodiments, the solvent comprises water and / or ethanol.

[0093] In some embodiments, the low-temperature granulation device comprises a boiling bed granulator.

[0094] In some embodiments, the mesh size of the sieve used for sieving the granulated particles is 0.3 mm, which is beneficial to improve the uniformity of the size of the functional layer particles, and further improve the compressibility of the functional layer particles and the disintegration efficiency of the functional layer prepared based on the functional layer particles.

[0095] In step S102, the raw materials for preparing the solvent-resistant outer layer particles can be mixed and dried to obtain the solvent-resistant outer layer particles.

[0096] In some embodiments, the raw materials for preparing the solvent-resistant outer layer particles include, in terms of mass fraction, 15-25 parts of the second film-forming agent, 2-8 parts of the film-forming aid, 1-5 parts of the appearance modifier, and 2-6 parts of the binder.

[0097] After step S102 and before step S103, the solvent-resistant outer layer particles can be stored in an environment with a humidity of less than 30%.

[0098] In step S103, first, a solvent is added to the functional layer particles prepared in step S101, and the mixture is stirred to obtain a functional layer slurry; then, the functional layer slurry is poured into a mold corresponding to the functional layer to form a first molded layer.

[0099] In step S104, first, a solvent is added to the solvent-resistant outer layer particles prepared in step S102, and the mixture is stirred to obtain a solvent-resistant outer layer slurry. Then, in some embodiments, the solvent-resistant outer layer slurry is applied to two opposite surfaces with a larger area of the first molded layer to obtain a second molded layer; in some embodiments, the solvent-resistant outer layer slurry is applied to the entire surface of the first molded layer to obtain a second molded layer; in some embodiments, the solvent-resistant outer layer slurry is poured into a mold corresponding to the solvent-resistant outer layer to form a second molded layer.

[0100] In the scenario where the solvent-resistant outer layer slurry is applied to two opposite surfaces with a larger area of the first molded layer or the solvent-resistant outer layer slurry is applied to the entire surface of the first molded layer in step S104, in step S105, the first molded layer and the second molded layer applied to the surface of the first molded layer can be determined as a preform; in the scenario where the solvent-resistant outer layer slurry is poured into a mold corresponding to the solvent-resistant outer layer to form a second molded layer in step S104, in step S105, the second molded layer can be adhered to two opposite surfaces with a larger area of the first molded layer or the entire surface of the first molded layer to set the second molded layer as an outer layer of the first molded layer to obtain a preform.

[0101] In the case of obtaining a preform, in step S105, the preform including the first molded layer and the second molded layer can be subjected to a pressing treatment by using a tablet pressing device, and the preform after the pressing treatment can be subjected to a drying treatment to obtain a snus product. The embodiments of the present application can improve the interfacial bonding force between the functional layer and the solvent-resistant outer layer in the snus product by subjecting the preform to a pressing treatment, thereby improving the structural stability of the snus product.

[0102] The oral preparation prepared by the preparation method of the oral preparation provided in the application comprises a functional layer and a solvent-resistant outer layer, and in the thickness direction of the oral preparation, the solvent-resistant outer layer is arranged outside the functional layer; the antioxidant can be used to reduce the probability of oxidation reaction of the active agent in at least one aspect of removing free radicals, reducing intermediate products in the early stage of oxidation of the active agent, chelating catalyst ions, and physically isolating, thereby improving the antioxidant capacity of the active agent in the functional layer; the solvent-resistant outer layer has liquid permeability, so that saliva can successfully penetrate into the functional layer during the oral process, promote the active agent in the functional layer to dissolve into the saliva and penetrate into the oral cavity through the solvent-resistant outer layer, provide the user with a sense of satisfaction of the active agent, and the disintegration rate of the solvent-resistant outer layer is less than the disintegration rate of the functional layer, so that the solvent-resistant outer layer can always be on the surface of the functional layer during the oral process, avoid the direct exposure of the functional layer to the oral environment, reduce the probability of oxidation reaction of the active agent with oxygen during the oral process, and be beneficial to improving the chemical stability and purity of the active agent in the oral preparation, reducing the probability of deterioration of the oral preparation, and improving the bioavailability and oral taste of the oral preparation.

[0103] In some embodiments, the preparation method of the oral preparation provided in the application can further comprise:

[0104] Step A11, preparing transition layer particles.

[0105] Step A12, preparing a third forming layer on the surface of the first forming layer by using the transition layer particles.

[0106] Step A13, preparing a second forming layer by using the solvent-resistant outer layer particles.

[0107] Step A14, arranging the second forming layer outside the third forming layer to obtain the preform, and performing a pressing treatment on the preform to obtain the oral preparation.

[0108] The oral preparation obtained by step A14 further comprises a transition layer formed by the third forming layer, and the transition layer is arranged between the solvent-resistant outer layer and the functional layer, which can further reduce the probability of oxidation reaction of the active agent in the functional layer with oxygen in the external environment, and in the case that the transition layer comprises a flavoring agent and / or a flavoring agent, the taste level of the oral preparation can be adjusted, the bitterness of the active agent can be covered, the irritability of the active agent can be reduced, and the taste of the oral preparation can be improved.

[0109] In step A11, first, the raw materials for preparing the transition layer particles are mixed in a mixer to obtain a second mixture; then, the second mixture is granulated by a dry granulation method, and the granulated particles obtained by granulation are sieved to obtain the transition layer particles.

[0110] In some embodiments, the raw materials for preparing the transition layer particles include, in mass parts, 5-15 parts of non-metabolic filler, 2-6 parts of pH adjuster, 5-10 parts of structure stabilizer, 1-10 parts of flavoring agent, and 1-10 parts of flavoring agent.

[0111] Before step A12, the first forming layer can be prepared by step S103.

[0112] In step A12: first, a solvent is added to the transition layer particles prepared by step A11, and stirred to obtain a transition layer slurry. Then, in some embodiments, the transition layer slurry is coated on two opposite surfaces of the first forming layer with a larger area to obtain a third forming layer; in some embodiments, the transition layer slurry is coated on the entire surface of the first forming layer to obtain a third forming layer.

[0113] In step A13: first, a solvent is added to the solvent-resistant outer layer particles prepared by step S102, and stirred to obtain a solvent-resistant outer layer slurry. Then, in some embodiments, the solvent-resistant outer layer slurry is coated on the surface of the third forming layer away from the first forming layer to obtain a second forming layer; in some embodiments, the solvent-resistant outer layer slurry is coated on the entire outer surface of the third forming layer to obtain a second forming layer; in some embodiments, the solvent-resistant outer layer slurry is poured into a mold corresponding to the solvent-resistant outer layer for forming to obtain a second forming layer.

[0114] In the scenario where the solvent-resistant outer layer slurry is coated on the surface of the third forming layer away from the first forming layer or the entire outer surface of the third forming layer by step A13, in step A14, the first forming layer, the third forming layer prepared on the surface of the first forming layer, and the second forming layer coated on the surface of the third forming layer can be determined as a preform; in the scenario where the solvent-resistant outer layer slurry is poured into a mold corresponding to the solvent-resistant outer layer for forming to obtain a second forming layer by step A13, in step A14, the second forming layer can be adhered to the surface of the third forming layer away from the first forming layer or the entire outer surface of the third forming layer to set the second forming layer as an outer layer of the third forming layer to obtain a preform.

[0115] In the case of obtaining a preform, in step A14, the preform including the first forming layer, the second forming layer, and the third forming layer can be subjected to a pressing treatment by using a tablet pressing device, and the preform after the pressing treatment can be subjected to a drying treatment to obtain a smokeless tobacco product. The embodiments of the present application can improve the interfacial bonding force between the functional layer and the transition layer, and between the transition layer and the solvent-resistant outer layer in the smokeless tobacco product, and further improve the structural stability of the smokeless tobacco product by subjecting the preform to a pressing treatment.

[0116] In some embodiments, in the method for preparing the oral preparation provided in the present application, the particle size of the functional layer particles prepared in step S101 is 100-300 pm, which is beneficial to improve the flowability of the functional layer particles, improve the uniformity of the functional layer particle forming, reduce the probability of functional layer cracking, loose pieces, and uneven piece surface, and further improve the forming quality of the functional layer; in some embodiments, the particle size of the functional layer particles can be one of 100 pm, 150 pm, 190 pm, 250 pm, 280 pm, 300 pm or a range value of any two thereof.

[0117] In some embodiments, in the method for preparing the oral preparation provided in the present application, the particle size of the transition layer particles prepared in step A11 is 100-300 pm, which is beneficial to improve the flowability of the transition layer particles, improve the uniformity of the transition layer particle forming, and further improve the forming quality of the transition layer; in some embodiments, the particle size of the transition layer particles can be one of 100 pm, 150 pm, 190 pm, 250 pm, 280 pm, 300 pm or a range value of any two thereof.

[0118] In some embodiments, in the method for preparing the oral preparation provided in the present application, during the preparation of the functional layer particles in step S101, the preparation temperature of the functional layer particles does not exceed 40°C, which is beneficial to maximize the activity of the active agent.

[0119] In some embodiments, in the method for preparing the oral preparation provided in the present application, the surface of the solvent-resistant outer layer can be perforated to form through holes extending in the thickness direction of the solvent-resistant outer layer after the preform is subjected to the pressing treatment; wherein, after the preform is subjected to the pressing treatment in step S105 or step A14, the surface of the solvent-resistant outer layer can be perforated by laser perforation or needle perforation, so that at least part of the structure of the solvent-resistant outer layer includes through holes extending in the thickness direction of the solvent-resistant outer layer, which is beneficial to reduce the probability of oxidation reaction of the active agent in the functional layer, adjust the speed of the active agent released into the oral cavity through the solvent-resistant outer layer during the oral process, and further improve the user's satisfaction with the active agent.

[0120] In some embodiments, in the method for preparing the oral preparation provided in the present application, the relative humidity of the environment for preparing the solvent-resistant outer layer particles in step S102 is less than 30%, which is beneficial to reduce the water content of the solvent-resistant outer layer prepared by the solvent-resistant outer layer particles, and slow down the disintegration rate of the solvent-resistant outer layer.

[0121] In some embodiments, in the method for preparing the oral preparation provided in the present application, the pressure of the pressing treatment is 1 kN-6 kN; in the present application, the pressure of the pressing treatment of the preform in step S105 and / or step A14 is 1 kN-6 kN, which can improve the interface bonding force between the functional layer and the solvent-resistant outer layer in the oral preparation, and further improve the structural stability of the oral preparation; in some embodiments, the pressure of the pressing treatment can be one of 1 kN, 2 kN, 3 kN, 4 kN, 5 kN and 6 kN, or a range value of any two thereof.

[0122] In some embodiments, in the method for preparing the oral preparation provided in the present application, after the preform is subjected to the pressing treatment through step S105 or step A14, the method further comprises: packaging with a packaging bag to obtain the oral preparation.

[0123] In some embodiments, the packaging bag has a packaging cavity, and the functional layer and the solvent-resistant outer layer are both located in the packaging cavity. In some embodiments, the preform subjected to the pressing treatment can be subjected to nitrogen filling and packaging treatment using an aluminum-plastic composite packaging machine, so that the packaging bag is wrapped on the outside of the solvent-resistant outer layer, blocks air, moisture and dust from entering the inside of the oral preparation, further improves the chemical stability and purity of the active agent in the oral preparation, reduces the probability of moisture and deterioration of the oral preparation, and improves the bioavailability and oral taste of the oral preparation.

[0124] In some embodiments, after the packaging with the packaging bag to obtain the oral preparation, the packaged oral preparation can be stored in a cool, dry and light-proof environment (humidity less than 40%, temperature less than 25°C) to prolong the shelf life of the oral preparation.

[0125] The present application is further described in detail below through specific examples and comparative examples, so as to prepare the oral preparation through the above-mentioned method for preparing the oral preparation.

[0126] The following examples are only part of the examples of the present application, and are not a limitation on the present application. In the examples and comparative examples, unless otherwise specified, the reagents and instruments used are ordinary commercially available, and the experimental operations are performed according to the product instructions and conventional experimental specifications.

[0127] Example 1

[0128] (1) Preparation of functional layer particles:

[0129] First, 5 parts of nicotine tartrate, 10 parts of grape seed extract, 5 parts of resveratrol, 5 parts of coenzyme Q10, 2 parts of hydroxypropyl methyl cellulose, 3 parts of carboxymethyl starch sodium, 5 parts of magnesium aluminum silicate, 10 parts of resistant dextrin, 3 parts of povidone K30, and 5 parts of microcrystalline cellulose are mixed in a high-speed mixer according to the mass fraction to obtain a first mixture; then, the first mixture is humidified by adding anhydrous ethanol through a sprayer to adjust the humidity of the first mixture to a granulating state; then, the first mixture is wet granulated using a fluidized bed granulator, and the granulated particles obtained by granulation are dried at 25°C; the dried granulated particles are sieved to obtain functional layer particles; the average particle size of the functional layer particles is 200μm.

[0130] (2) Preparation of solvent-resistant outer layer particles:

[0131] 18 parts of hydroxypropyl methyl cellulose acetate, 4 parts of carboxymethyl cellulose sodium, 3 parts of polyethylene wax, and 5 parts of povidone K30 are mixed and dried to obtain solvent-resistant outer layer particles.

[0132] (3) Preparation of transition layer particles:

[0133] First, 7 parts of resistant dextrin, 3 parts of sodium citrate, 8 parts of biosuccinoglucan, 5 parts of WS-3, and 2 parts of licorice extract are mixed in a V-type mixer to obtain a second mixture; then, the second mixture is granulated by dry granulation, and the granulated particles obtained by granulation are sieved to obtain transition layer particles; the average particle size of the transition layer particles is 150μm.

[0134] (4) Preparation of the first molding layer:

[0135] First, anhydrous ethanol is added to the functional layer particles prepared by step (1) and stirred uniformly to obtain a functional layer slurry; then, the functional layer slurry is poured into the mold corresponding to the functional layer for molding to obtain the first molding layer.

[0136] (5) Preparation of the third molding layer:

[0137] First, anhydrous ethanol is added to the transition layer particles prepared by step (3) and stirred uniformly to obtain a transition layer slurry; then, the transition layer slurry is coated onto the two opposite surfaces with larger area in the first molding layer to obtain the third molding layer.

[0138] (6) Preparation of the second molding layer:

[0139] Firstly, anhydrous ethanol is added to the solvent-resistant outer layer particles prepared by step (2) and stirred to obtain a solvent-resistant outer layer slurry; then, the solvent-resistant outer layer slurry is poured into the corresponding mold of the solvent-resistant outer layer for molding to obtain a second molding layer; finally, the second molding layer is adhered to the surface of the third molding layer away from the first molding layer to realize that the second molding layer is arranged at the outer layer of the third molding layer, and a preform is obtained.

[0140] (7) Preparing a buccal preparation:

[0141] The preform is subjected to a pressing treatment by using a tablet pressing device under the condition of 5 kN and is dried at 30℃ to obtain a buccal preparation; wherein the buccal preparation comprises a functional layer molded by the first molding layer, a transition layer molded by the third molding layer, and a solvent-resistant outer layer molded by the second molding layer, and in the thickness direction of the buccal preparation, the solvent-resistant outer layer, the transition layer, and the functional layer are sequentially stacked in the order of the solvent-resistant outer layer, the transition layer, the functional layer, the transition layer, and the solvent-resistant outer layer; the thickness of the functional layer is 0.45 mm, the thickness of the solvent-resistant outer layer is 0.15 mm, the thickness of the transition layer is 0.25 mm, and the thickness of the buccal preparation is 1.25 mm.

[0142] Examples 2-3

[0143] The difference between Examples 2-3 and Example 1 is that:

[0144] In step (1), the mass fraction of nicotine tartrate, grape seed extract, resveratrol, coenzyme Q10, hydroxypropyl methyl cellulose, carboxymethyl starch sodium, magnesium aluminum silicate, resistant dextrin, povidone K30, and microcrystalline cellulose is adjusted;

[0145] In step (2), the mass fraction of hydroxypropyl methyl cellulose acetate, carboxymethyl cellulose sodium, polyethylene wax, and povidone K30 is adjusted;

[0146] In step (3), the mass fraction of resistant dextrin, sodium citrate, biological chitosan, WS-3, and licorice extract is adjusted;

[0147] In steps (4)-(6), the thicknesses of the functional layer, the transition layer, and the solvent-resistant outer layer are adjusted by adjusting the thicknesses of the first molding layer, the third molding layer, and the second molding layer, respectively.

[0148] The relevant parameters of the buccal preparations prepared by Examples 1-3 are shown in Table 1.

[0149] Table 1

[0150]

[0151]

[0152] Example 4

[0153] Example 4 differs from Example 1 in that:

[0154] Steps (3) and (5) are not included;

[0155] In step (6), the solvent-resistant outer layer slurry is coated to two opposite surfaces with larger area in the first forming layer to obtain a second forming layer, and the first forming layer and the second forming layer arranged outside the first forming layer constitute a preform.

[0156] In step (7), the oral product comprises a functional layer formed by pressing the first forming layer and a solvent-resistant outer layer formed by pressing the second forming layer, and in the thickness direction of the oral product, the solvent-resistant outer layer and the functional layer are sequentially stacked in the order of solvent-resistant outer layer, functional layer, solvent-resistant outer layer; the thickness of the oral product is 0.75 mm.

[0157] Example 5

[0158] Example 5 differs from Example 1 in that,

[0159] In step (1), the antioxidant comprises 5 parts of white resveratrol and 5 parts of apple polyphenol.

[0160] The related parameters of the oral product prepared by Example 5 are shown in Table 2.

[0161] Table 2

[0162]

[0163]

[0164] Comparative Example 1

[0165] Comparative Example 1 differs from Example 1 in that:

[0166] In step (1), 2 parts of hydroxypropyl methyl cellulose, 3 parts of carboxymethyl starch sodium, 5 parts of magnesium aluminum silicate, 10 parts of resistant dextrin, 3 parts of povidone K30, and 5 parts of microcrystalline cellulose are mixed in a high-speed mixer according to the mass fraction to obtain a first mixture.

[0167] Comparative Example 2

[0168] Comparative Example 2 differs from Example 1 in that:

[0169] In step (1), 5 parts of nicotine tartrate, 2 parts of hydroxypropyl methyl cellulose, 3 parts of carboxymethyl starch sodium, 5 parts of magnesium aluminum silicate, 10 parts of resistant dextrin, 3 parts of povidone K30, and 5 parts of microcrystalline cellulose are mixed in a high-speed mixer according to the mass fraction to obtain a first mixture.

[0170] Test method:

[0171] (1) Free radical scavenging rate test:

[0172] (i) Sample pretreatment: first, at different storage time nodes (1 day, 3 days, 5 days, 7 days, 15 days, 21 days, 30 days), take each 3 pieces of the oral preparation obtained by the above examples and comparative examples, and grind into powder; then, take 100 mg of the powder, add 10 mL of ethanol, and ultrasonically extract for 15 min; then, centrifuge for 10 min (4000 rpm), and take the supernatant sample for standby.

[0173] (ii) Preparation of DPPH (1,1-diphenyl-2-trinitrobenzene hydrazine) solution: prepare 0.1 mmol / L DPPH solution under light-proof conditions.

[0174] (iii) Reaction mixture: first, take 2 mL of the supernatant sample prepared by step (i), mix with 2 mL of the DPPH solution prepared by step (ii) to obtain a mixed solution; then, place the mixed solution in a light-proof room at room temperature for 30 min.

[0175] (iv) Absorbance determination: measure the absorbance value at 517 nm by using an ultraviolet spectrophotometer, and calculate the free radical scavenging rate by the following formula:

[0176]

[0177] Wherein, α represents the free radical scavenging rate; A c represents the absorbance value of the self-control group of the supernatant sample, which is used to deduct the interference of the color or matrix of the supernatant sample itself on the absorbance; A b represents the absorbance value of the blank control group, which is used to reflect the initial absorbance value of DPPH before the reaction of the mixed solution of the supernatant sample and the DPPH solution; A s represents the absorbance value of DPPH after the reaction of the mixed solution of the supernatant sample and the DPPH solution.

[0178] The blank control group is: DPPH + ethanol; and the self-control group of the supernatant sample is: ethanol + supernatant sample.

[0179] (2) Resveratrol retention rate test:

[0180] (i) Sample extraction: first, at different storage time nodes (1 day, 3 days, 5 days, 7 days, 15 days, 21 days, 30 days), take each 3 pieces of the oral preparation obtained by the above examples and comparative examples, and grind into powder; then, take 100 mg of the powder, add 10 mL of 70% methanol, and ultrasonically extract for 30 min; finally, centrifuge for 10 min, filter membrane filter to take the filtrate as the sample solution.

[0181] (ii) Standard solution preparation: Prepare the standard solution of resveratrol (5 μg / mL, 10 μg / mL, 20 μg / mL, 40 μg / mL, 60 μg / mL).

[0182] (iii) HPLC (high pressure liquid chromatography) detection conditions:

[0183] Chromatographic column: C18 reversed-phase column, ensuring that the separation degree of resveratrol and impurity peaks is ≥1.5;

[0184] Mobile phase: methanol-water system, flow rate 1.0 mL / min;

[0185] Detection wavelength: 280 nm;

[0186] Column temperature: 30°C;

[0187] Injection volume: 10 μL (the injection volume of the standard solution and the sample solution is consistent);

[0188] Run time: 8 min-15 min.

[0189] (iv) Standard curve establishment: inject the standard solution according to the concentration from low to high, repeat 3 times for each concentration, record the peak area (take the average value), take the concentration (μg / mL) as the abscissa (X), and the peak area (AU) as the ordinate (Y), and use Origin software for linear regression to obtain the standard curve regression equation: Y=aX+b.

[0190] (v) Resveratrol retention rate calculation:

[0191] First, inject the sample solution into HPLC, record the peak area of resveratrol (Y1), and substitute it into the standard curve regression equation to calculate the concentration of resveratrol in the sample solution (C1):

[0192]

[0193] Where C1 represents the concentration of resveratrol in the sample solution; Y1 represents the peak area of resveratrol; a and b represent the fitting coefficients of the standard curve regression equation.

[0194] Then, calculate the total content of resveratrol in the sample solution:

[0195] M1=C1×V1 (3)

[0196] Where M1 represents the total content of resveratrol in the sample solution; V1 represents the volume of the sample solution.

[0197] Finally, calculate the resveratrol retention rate:

[0198]

[0199] wherein β represents the resveratrol retention rate; M0 represents the total content of resveratrol in the sample solution corresponding to the oral preparation at the time of preparation.

[0200] Test results:

[0201] The above radical scavenging rate test and resveratrol retention rate test were performed on the oral preparations obtained by Examples 1-5 and Comparative Examples 1-2, and the test results are shown in Table 3.

[0202] Table 3

[0203]

[0204] As can be seen from the test data in Table 3, the radical scavenging rates of the oral preparations obtained by Examples 1-5 and Comparative Examples 1-2 are all reduced as the storage time of the oral preparations is prolonged, but compared with Comparative Examples 1 and 2, the radical scavenging rates of the oral preparations obtained by Examples 1-5 of the present application can still be maintained at more than 65% when the storage time reaches 30 days, indicating that the antioxidant system in the oral preparations obtained by the examples of the present application has strong stability and sustained antioxidant capacity. Further, the resveratrol retention rates of the oral preparations obtained by Examples 1-5 and Comparative Examples 1-2 are degraded as the storage time of the oral preparations is prolonged, but compared with Comparative Examples 1-2, the low-temperature granulation, layered isolation and antioxidant synergistic protection mechanism of Examples 1-5 of the present application can slow down the degradation rate of resveratrol, and the resveratrol retention rate can still be maintained at more than 85% when the storage time of the oral preparations reaches 30 days, which is conducive to improving the chemical stability of the active agent in the oral preparation and prolonging the shelf life stability of the oral preparation.

[0205] In summary, the oral preparation provided in the present application comprises a functional layer and a dissolution-resistant outer layer. In the thickness direction of the oral preparation, the dissolution-resistant outer layer is arranged outside the functional layer. The functional layer comprises an active agent and an antioxidant. The antioxidant can be used to clean free radicals, reduce intermediate products in the early stage of oxidation of the active agent, chelate catalyst ions, and physically isolate, at least one of which can reduce the probability of oxidation of the active agent and improve the antioxidant capacity of the active agent in the functional layer. Further, the dissolution-resistant outer layer has liquid permeability, so that saliva can successfully penetrate the functional layer during the oral process, promote the dissolution of the active agent in the functional layer into saliva, and penetrate the dissolution-resistant outer layer into the oral cavity, thereby providing the user with a sense of satisfaction of the active agent. The disintegration rate of the dissolution-resistant outer layer is less than that of the functional layer, so that the dissolution-resistant outer layer can always be on the surface of the functional layer during the oral process, avoiding direct exposure of the functional layer to the oral environment, reducing the probability of oxidation of the active agent in contact with oxygen during the oral process, and improving the chemical stability and purity of the active agent in the oral preparation, reducing the probability of deterioration of the oral preparation, and improving the bioavailability and oral taste of the oral preparation.

[0206] The above is a further detailed description of the present application in combination with specific embodiments, and cannot be considered as limiting the specific implementation of the present application to these descriptions. For ordinary skilled persons in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application.

Claims

1. A mouthpiece, characterized in that The oral care product comprises a functional layer and a non-soluble outer layer, wherein the non-soluble outer layer is arranged outside the functional layer in the thickness direction of the oral care product. The functional layer comprises an active agent and an antioxidant, the non-soluble outer layer has liquid permeability, and the disintegration rate of the non-soluble outer layer is less than the disintegration rate of the functional layer.

2. A smokeless tobacco product according to claim 1, wherein The oral care product further comprises a transition layer arranged between the non-soluble outer layer and the functional layer.

3. A smokeless tobacco product according to claim 2, wherein The transition layer comprises at least one of a non-metabolizable filler, a pH regulator, a structure stabilizer, a flavoring agent, and a flavoring agent.

4. A smokeless tobacco product according to claim 3, wherein The thickness of the transition layer is 0.2mm-0.3mm; and / or, The pH value of the transition layer is 5.5-6.5; and / or, The non-metabolizable filler comprises at least one of resistant dextrin, modified chitin, chitosan, silicon dioxide, calcium hydrogen phosphate, polyvinylpyrrolidone, polyethylene glycol, inulin, microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, gellan gum, alginate, carrageenan, and agar; and / or, The structure stabilizer comprises at least one of biological chitosan, oxidized chitosan, chitooligosaccharide, mannitol, sorbitol, xylitol, erythritol, citric acid, sodium citrate, sodium tartrate, sodium bicarbonate, disodium hydrogen phosphate, sodium lactate, sodium carbonate, disodium ethylenediaminetetraacetate, acacia gum, guar gum, gelatin, sodium caseinate, hydroxypropyl methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.

5. A mouthpiece according to any one of claims 1 to 4, characterised in that, The functional layer further comprises at least one of a first film-forming agent, a drying agent, a non-metabolizable filler, a binder, and a disintegrant; and / or, The non-soluble outer layer comprises at least one of a second film-forming agent, a film-forming aid, an appearance modifier, and a binder.

6. A smokeless tobacco product according to claim 5, wherein The active agent comprises at least one of nicotine and a nicotine derivative; and / or, The first film-forming agent comprises at least one of an acrylic resin, ethyl cellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose, and polyvinyl alcohol; and / or, The second film-forming agent comprises at least one of polyvinyl butyral, cellulose acetate, an acrylic resin, ethyl cellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, sodium carboxymethyl starch, and gelatin; and / or, The film-forming aid comprises at least one of hydroxypropyl methyl cellulose, acacia gum, alginate, gelatin, sodium carboxymethyl starch, sodium carboxymethyl cellulose, and polyvinyl alcohol; and / or, The drying agent comprises at least one of magnesium aluminum silicate, silica gel, aluminum oxide, and montmorillonite; and / or, The binder comprises at least one of poly-N-vinylpyrrolidone, hydroxypropyl methyl cellulose, gelatin, acacia gum, sodium carboxymethyl cellulose, alginate, pectin, xanthan gum, and malt dextrin; and / or, The disintegrant includes at least one of microcrystalline cellulose, silicon dioxide, calcium carbonate, calcium hydrogen phosphate, sodium dodecyl sulfate, starch, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, gum arabic, guar gum, gelatin, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, alginate and polysorbate; and / or, The antioxidant includes at least one of pine bark extract, rosemary extract, grape seed extract, resveratrol, coenzyme, anthocyanin, quercetin, protocatechuic acid, tocopherol, apple polyphenol, ascorbic acid, tea polyphenol, astaxanthin, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, tertiary butyl hydroquinone and sodium erythorbate.

7. A mouthpiece according to any one of claims 1 to 4, characterised in that, The thickness of the functional layer is 0.4mm-0.5mm; and / or, The thickness of the solvent-resistant outer layer is 0.1mm-0.2mm; and / or, The thickness of the oral preparation is 0.6mm-1.5mm; and / or, The oral preparation further includes an encapsulation bag having an encapsulation cavity, and the functional layer and the solvent-resistant outer layer are both located in the encapsulation cavity.

8. A mouthpiece according to any one of claims 1 to 4, characterised in that, At least part of the structure in the solvent-resistant outer layer includes a through hole extending along the thickness direction of the solvent-resistant outer layer.

9. A method of making a mouthpiece, characterized in that The preparation method for preparing the oral preparation as claimed in any one of claims 1-8, the preparation method comprising: preparing functional layer particles, wherein the functional layer particles include active agents and antioxidants; preparing solvent-resistant outer layer particles; preparing a first forming layer using the functional layer particles; preparing a second forming layer using the solvent-resistant outer layer particles; arranging the second forming layer as an outer layer of the first forming layer to obtain a preform, and performing a compression treatment on the preform to obtain the oral preparation; wherein the oral preparation includes a functional layer formed by compression of the first forming layer and a solvent-resistant outer layer formed by compression of the second forming layer, and in the thickness direction of the oral preparation, the solvent-resistant outer layer is arranged as an outer layer of the functional layer; the disintegration rate of the solvent-resistant outer layer is less than the disintegration rate of the functional layer.

10. The method of claim 9, wherein, The preparation method further satisfies at least one of the following conditions: (1) the preparation method further comprises: preparing transition layer particles; preparing a third forming layer on the surface of the first forming layer using the transition layer particles; preparing a second forming layer using the solvent-resistant outer layer particles; arranging the second forming layer as an outer layer of the third forming layer to obtain the preform, and performing a compression treatment on the preform to obtain the oral preparation; wherein the oral preparation further includes a transition layer formed by compression of the third forming layer, and the transition layer is arranged between the solvent-resistant outer layer and the functional layer; (2) the particle size of the functional layer particles is 100μm-300μm; (3) the preparation temperature of the functional layer particles is not more than 40℃; (4) after the compression treatment on the preform, a through hole extending along the thickness direction of the solvent-resistant outer layer is formed on the surface of the solvent-resistant outer layer; (5) the relative humidity in the environment for preparing the solvent-resistant outer layer particles is less than 30%; (6) the pressing force of the pressing treatment is 1 kN to 6 kN; (7) after the pressing treatment on the preform, the preparation method further comprises: packaging with a packaging bag to obtain the oral product, wherein the packaging bag has a packaging cavity, and the functional layer and the solvent-resistant outer layer are both located in the packaging cavity.

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